Title of Invention	A PHARMACEUTICAL COMPOSITION CONTAINING NIMESULIDE
Abstract	The invention disclosed in this application relates to a nimesulide controlled release pharmaceutical composition.The composition is used for tretment of inflammatory conditions and for removal of pains,the dosage is effective for a period of 18.0 to 24.0 hours thereby reducing the dose of the drug,which improves the patient compliance and is in thye form of tablets or coated pellets filled in capsule releasing the active ingredients as initial dose and maintenance dose in vitro at a specifi9c rate. This invention also discloses a process for the preparation of the above composition.

Title of Invention

A PHARMACEUTICAL COMPOSITION CONTAINING NIMESULIDE

Abstract

The invention disclosed in this application relates to a nimesulide controlled release pharmaceutical composition.The composition is used for tretment of inflammatory conditions and for removal of pains,the dosage is effective for a period of 18.0 to 24.0 hours thereby reducing the dose of the drug,which improves the patient compliance and is in thye form of tablets or coated pellets filled in capsule releasing the active ingredients as initial dose and maintenance dose in vitro at a specifi9c rate. This invention also discloses a process for the preparation of the above composition.

Full Text	The invention relates to a controlled release pharmaceutical composition containing nimesulide. The composition is useful for the treatment of inflammatory conditions and to remove all kinds of pains. The composition is particularly useful for removing pains associated with osteoarthritis and traumatic injury. The composition is therapeutically effective for a period of 18.0 to 24.0 hours there by reducing the dose of the drug, which consequently improves the patient compliance. The composition of the present invention is either in the form of a tablet or coated pellets filled in capsule releasing the active ingredient as initial dose and maintenance dose in vitro at a specified rate. Nimesulide has the chemical formula given below. C13H12N2O5S Formula 1 Nimesulide is non-steroidal anti-inflammatory drug (NSAID) that also has antipyretic and analgesic properties. It is administered orally or rectally at a dose of 100 and 200mg twice daily, respectively, for a variety of inflammatory disorders as well as for removing pains. In children, nimesulide dose is commonly 5mg/kg/day divided into 2 or 3 daily doses administered in the form of suspension, granules or suppositories. This compound is effective in reducing pains associated with osteroarthritis, cancer, thrombophlebitis, oral and general surgery, dysmenorrhoea in adults and pain, fever and inflammation accompanying respiratory tract infections, otorhinolaryngological diseases and traumatic injury in adults and children. Nimesulide appeared to be at least as effective as other non-steroidal antiinflammatory drugs (NSAIDs) in all of the above said indications. Nimesulide has been well tolerated by adults, elderly and pediatric patients. It has a pharmacodynamic profile suggestive of a reduced propensity to cause adverse gastrointestinal effects associated with NSAIDs. Though the compound is weakly acidic (pKa 6.5) and differs from other NSAIDs in that chemical structure contains a sulfonanilide moeity as the acidic group (Davis,R. and Brogden, R. N., Drugs, 48(3): 431, 1994). The mechanism of action of nimesulide appears to differ from that of most conventional NSAIDs. Nimesulide selectively inhibits the formation of proinflammatory prostagladins with less effect on those prostagladins that have gastroprotective action. As a consequence, nimesulide is better tolerated by the gastrointestinal tract than most other NSAIDs, while exerting equivalent efficacy. It exhibits a neuroprotective effect against β- amyloid induced cell death. Nimesulide inhibits non-inflammatory mechanisms of neurodegeneration. The COX-2 inhibition may have potential as an additional therapeutic agent in human inflammatory neuropathis. The other mechanism of action of nimesulide including free radical scavenging, inhibition of histamine release and activity, inhibition of proteases (Ex.: elastage, collagenase). potent inhibition of induced platelet aggregation (Tognella, S., Drugs, 46(suppl 1): 275,1993). Recently, Nakatsugi et.al, ( through Chem. Absts, 130(12):148406k,1999) reported that repeated administration of nimesulide to Min. mice in their diet significantly decreased the size of the polyps in intestine. These authors claims that nimesulide is a good candidate as a colon cancer chemo-preventive agent with low toxicity. Nimesulide is practically insoluble in water and freely soluble in O.IN NaOH and phosphate buffer pH 8.0 with surfactant. The solubility of nimesulide can be improved by making complexes with P-cyclodextrins (Piel et al, J. Pharm. Sci,, 86,475,1997). However making complexation employing p-cyclodextrins is costlier and use of methylene chloride may cause toxic effects. Dischiena and Ginseppe (Eur Pat. Appl 880, 965, 1998) disclosed a topical pharmaceutical formulation containing nimesulide and an excipient consisting of an acrylic polymer or copolymer dispersed in oil and water with an emilsifier do not strain yellow skin. Bertacchi et al., (Acta Toxicol. Ther.,18(l), 33, 1997) reported that a 3% nimesulide cream would possesses a good analgesic and anti-inflammatory activity and well local tolerability without side effects. Girola et al, (Acta Toxicol Ther.,18(l), 17, 1997) suggested that 3% nimesulide cream showed statistically significant activity, in acute goute injury, than 1% diclofenac gel. Wober et al.,(Int. J. Clin. Pract. 52(3), 169,1998) observed that nimesulide exhibited high therapeutic equivalence and tolerance when compared to diclofenac in acute subdeltoid bursitis and bicipital tendinitis. After oral administration of pure nimesulide 50.0 to 200.0mg to healthy adult volunteers, peak serum concentration of 1.98 to 9.85mg/L are achieved within 1.2 to 3.17 hours. Oral drug absorption is nearly complete and concomitant administration of food may decrease the rate but not the extent of absorption of nimesulide. The elimination half-life of nimesulide ranges from 1.56 to 4.9 hors. The short biological half-life of nimesulide necessitates frequent administration. Till today there is no composition containing nimesulide which releases the drug in a controlled manner thereby not only reducing the amount of the drug to be administered but also enhancing the effectiveness of the drug. Considering the good tolerance of the drug by all the categories of patients namely adults, elderly persons and infants it was observed that development of controlled release pharmaceutical composition containing nimesulide may be very useful for the treatment of inflammatory conditions as well as for removing various kinds of pains. The sustained release of the drug from its dosage form can be obtained by different ways. One method utilises the embedding of the drug into a matrix of other excipients that are relatively water insoluble and hence dissolve and release the embedded drug slowly at a controlled rate into the digestive tract. The other approach is to shape the drug and excipients into granules or pellets as an active core and then these are coated with substances possessing film forming characteristics and low solubility profile. The major draw back associated with many of these technologies for controlled release of water insoluble drugs is the variations in their drug release profile from batch to batch and also from manufacturer to manufacturer. These variations in release profile may also due to changes in particle size and crystalline nature of the drug. Further, formulating a water insoluble drug into sustained release pharmaceutical dosage form is that not all the drug made available to the biological system during its transport though the digestive tract. However the above drawbacks can be over come by solid dispersion technique. Accordingly the main objective of the present invention is to provide a novel controlled release pharmaceutical composition containing nimesulide which is useful for the treatment of inflammatory conditions as well as for removing all kinds of pains. Another objective of the present invention is to provide a novel controlled release pharmaceutical composition containing nimesulide, which is effective for a longer period of time as well, requires only small doses. Yet another objective of the present invention is to provide a novel controlled release pharmaceutical composition containing nimesulide where the release profile of the drug is uniform. It is still another objective of the present invention to provide a novel pharmaceutical composition which is therapeutically effective over an extended period of at least 18.0 to 24.0 hours by providing sufficient amount of the drug immediately, i.e. within 0,5 to 1.0 hour to provide an initial therapeutically effective serum concentration, and to releasing the remaining amount of the drug at a rate sufficient to maintain the drug concentration in therapeutically effective range over a desired period of time. It is another objective of the present invention to provide an oral controlled release pharmaceutical composition containing nimesulide useful for the treatment of inflammatory conditions and reducing pains which releases 50 to lOOmg of drug within 0.5 to 1.0 hour after oral administration of the composition as initial dose, the remaining drug being release at the rate of 6.0 to 14,0 mg/hour over a period of 15.0 to 18.0 hour as maintenance dose. Still another objective of the present invention is to provide a method for preparing the novel controlled release pharmaceutical composition containing nimesulide, which is useful for the treatment of inflammatory conditions as well as for removing all kinds of pains. The present invention is based on our finding that in vitro dissolution profile of nimesulide from a composition containing fine particulate form of nimesulide or its solid dispersion when granulated or coated with release controlling polymeric composition which substantially maintain the integrity of the granules or pellets in varying pH conditions of gastrointestinal tract but is permeable to nimesulide, follows zero order release kinetics until a substantial amount, namely 80 to 90%, of the drug is released. This composition, when administered orally to humans in conjunction with an initial dose of nimesulide for immediate release, provides relief of pain over an extended period of 18.0 to 24.0 hours, with better patient compliance. Accordingly, the present invention provides a novel oral controlled release pharmaceutical composition, useful for the treatment of inflammation and for reducing pains, which comprises an inner core composed of sucrose and starch, the inner core having a coating of an active layer comprising fine particulate form of nimesulide and a hydrophilic polymer as binder, the active layer having a coating of a release modulating polymeric composition comprising of a hydrophobic polymer or a mixture thereof The resulting composition may be filled into a capsule or compressed into a tablet by known method. In a preferred embodiment of the invention the particulate form of nimesulide may be in the form of solid dispersion. The active layer may optionally contain a surface-active agent and/or a hydrophobic material. The release modulating polymeric composition may optionally contain a hydrophilic material, a plasticizer, a colouring agent, an anti sticking agent, or a mixture thereof Statement of invention: According to the present invention there is also provided a process for the preparation of the above said formulation, which comprises i. Preparing inner core comprising sucrose and starch, ii. Coating the inner core with an active layer comprising fine particulate form of nimesulide suspended in a solution of hydrophilic polymer in an organic solvent or a mixture thereof iii. Coating the active layer with a release controlling polymeric composition comprising of hydrophobic polymer or a mixture thereof iv. encapsulating the coated pellets by conventional methods Or Compressing the coated pellets into tablets using inert pharmaceutical excipients like fillers and lubricants. The following materials may optionally be used in the process for the preparation of said formulation. a) Solid dispersion of nimesulide, a surface-active agent and/or a hydrophobic material in coating the inner cores with an active layer. b) a plasticizer, a hydrophilic material or a mixture thereof in release modulating polymeric composition for controlling drug release. In a preferred embodiment of the present invention the amount of sucrose employed in the inner core may range from 400.0 to 700,0 mg more preferably from 450.0 to 650.0 mg and starch from 300.0 to 600.0 mg more preferably from 400.0 to 500.0 mg per gram of nonpareil seeds (N.P. Seeds). The amount of nimesulide employed in the active layer may range from 200.0 to 900.0 mg more preferably from 400.0 to 700.0 mg per gram of drug-loaded pellets. A hydrophilic polymer such as polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose ( HPMC) and the like may be employed as binding agent in the active core; the amount of which may range from 10.0 to 100.0mg more preferably from 20.0 to 60.0 mg per gram of pellets. In a preferred embodiment of the invention the particulate form of nimesulide may be its solid dispersion into a matrix of hydrophilic substance. The hydrophilic substance may be selected from among the water soluble polymers such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidine (PVP), polyethylene glycol (PEG) or water swellable / dispersible substances such as pre-gelatinised starch (PGS), hydroxyethyl starch (HES), dextrins (D) and the like. The amount of nimesulide in the solid dispersion may range from 500.0 - 950.0mg, preferably 700.0 - 900.0mg per gram of dispersion. The amount of hydrophilic substance may range from 50.0 to 500.0mg preferably from 100.0 - 300.0 mg per gram of solid dispersion. Known pharmaceutical methods such as common solvent and solvent deposition methods may be used to prepare the solid dispersions. The solvent may be selected from among acetone, ethyl alcohol, isopropyl alcohol, chloroform and the like or a mixture there of in which nimesulide is soluble. The dispersion may be applied on to nonpareil seeds using conventional coating equipment or any suitable coating equipment. A surface-active agent such as sodium lauryl sulphate, dioctyl sodium sulfosuccinate, polysorbate 80 and the like may optionally be employed in coating the inner core with active layer. The amount of such surface-active agent may range from 4.0 to 40.0mg more preferably from 8.0 to 20.0mg per gram of pellets. A hydrophobic material such as hydrogenated castor oil, cetyl alcohol, hydroxypropyl methylcellulose phthalate, ethyl cellulose and the like may optionally be employed in the active layer. The amount of such hydrophobic material may range from 10.0 to 100.0mg more preferably from 20.0 to 60.0 mg per gram of pellets. The active layer can be applied in a suitable manner using conventional coating equipment or other suitable coating equipment, for example, in the form of suspension/solution in organic solvent mixture or a hydro alcoholic mixture as medium. In yet another embodiment of the invention for coating the pellets with release modulating polymeric composition a hydrophobic polymer such as methacrylic acid copolymer (esters) or its aqueous latex dispersion (Eudragit RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) or a mixture thereof may be used. The amount of such polymer may range from 25.0 to 250.0mg preferably from 50.0 to 200.0mg per gram of pellets. The release modulating polymeric composition may optionally contain a hydrophilic material selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and the like ; a plasticizer selected from propylene glycol, diethyl phthalate, polyethylene glycol, triethyl citrate, hydrogenated castor oil and the like; a colouring agent selected from titanium dioxide, quinoline yellow and and the like; antisticking agents selected from talc, magnesium stearate, colloidal silicon dioxide and the like. The amounts of such optional agents may range from 10.0 to 100.0mg, 5.0 to 50.0mg, 0,4 to 8.0mg and 10,0 to 50.0mg per gram of pellets hi that order. The release modulating polymeric composition is applied on to active layered pellets in a mechanised perforating pan or using suitable coating equipment. Polymer coated pellets are filled in to hard gelatin capsules or compressed into tablets after mixing with known inert pharmaceutical excipients such as filler and lubricants. If compressed into tablet, the fillers such as starch, anhydrous lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like may be employed. The amount of such filler may range from 120,0 to 360,0 mg preferably from 160.0 to 280.0mg per tablet. The excipients such as talc, magnesium stearate, colloidal silicon dioxide, hydrogenated castor oil may be employed as lubricants in tabletting and the amount may range from 1.0 to lO.Omg more preferably from 2.0 - S.Omg per tablet. According to another feature of the invention there is provided novel oral controlled release pharmaceutical composition useful for the treatment of inflammation and for reducing pains comprising granules of nimesulide, a surface active agent and a release modulating polymeric composition compressed into tablets using inert pharmaceutical excipients such as fillers and lubricants. The composition may optionally contain nimesulide in the form of solid dispersion and/or a hydrophilic material and a plasticizer. According to another feature of the present invention there is provided a process for the preparation of oral controlled release pharmaceutical formulation containing nimesulide useful for the treatment of inflammation and for reducing pains which comprises. i, preparing granules comprising of fine particles of nimesuUde, a surface-active gent, and a release modulating polymer. ii. compressing the granules into tablets using inert pharmaceutical excipients such as fillers and lubricants. The following materials may optionally be used in the process for the preparation of granules for controlled release pharmaceutical composition. These are solid dispersion of nimesulide and / or hydrophilic release modulating material and a plasticizer. In a prefered embodiment of the present invention to prepare tablets the amount of nimesulide employed in preparing the tablets may rage from 100.0 to 400.0mg, preferably from 150.0 to 250.0mg more preferably from 175.0 to 225.0mg per tablet In a preferred embodiment of the present invention to prepare granules comprising of nimesulide, a surface active agent such as sodium lauryl sulphate, polysorbate 80 and the like may be employed; the amount of which may range from 0.3 - 3.0mg, preferably from 0.9 to 1.5mg per tablet. In yet another embodiment of the invention to prepare granules by wet granulation method hydrophobic polymers such as methacrylic acid copolymer (esters) or its aqueous latex dispersion (Eudragit RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) or a mixture thereof may be used. The amoimt of such polymer may range from 4.0 to 120.0mg, preferably from 8.0 to 60.0mg per tablet. In a preferred embodiment of the present invention to prepare tablets by dry granulation method a hydrophilic polymer such as hydroxy propyl methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxy ethyl cellulose and the like may be used. The amount of such polymer may range from 4.0 to 120.0 mg. preferably from 8,0 to 60.0mg per tablet. A solid dispersion of nimesulide prepared as described earlier may optionally be employed in preparing the tablets. A hydrophilic polymer such as polyvinylpyrrolidone(PVP), hydroxypropyl cellulose(HPC), hydroxypropyl methyl cellulose(HPMC), and the like may optionally be employed as release modulating agent in granules prepared by wet granulation method; the amount of such polymer may range from 1.0 to 30.0mg per tablet. In a preferred embodiment of the invention the fillers and lubricants employed in tablet are selected from known inert pharmaceutical excipients. The inert fillers such as lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like may be employed in tabletting the granules. The amount of filler employed may range from 20.0 to 60.0 mg, preferably from 30.0 to 50.0mg per tablet. The excipients such as talc, magnesium stearate, colloidal silicon dioxide, hydrogenated castor oil and the like may be employed as lubricants in tabletting and the amount may range from 1.0 to 10.0mg more preferably from 2.0 - 5.0mg per tablet. The granules are prepared by known methods and compressed in to tablets on a rotary tablet press. The invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. EXAMPLE -1 a) Composition of the inner core mg/gram Sucrose 600.0 Starch 400.0 Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%. b) Composition of active layer mg/gram Nimesulide 700.0 Polyvinylpyrrolidone 70.0 Sodium lauryl sulphate 17.5 Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment. c) Composition of coating layer mg/gram Ethyl cellulose 50.0 Hydroxypropyl methylcellulose 12.5 Polyethylene Glycol 10.0 Talc 10.0 The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in a solvent blend consisting of isopropyl alcohol and methylene chloride. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200.0mg of nimesulide. EXAMPLE - 2 a) Composition of the inner core mg/gram Sucrose 550.0 Starch 450.0 Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%. b) Composition of active layer mg/gram Nimesulide 350.0 Polyvinylpyrrolidone 35.0 Sodium lauryl sulphate 8.0 Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment. c) Composition of coating layer mg/gram Ethyl cellulose 40.0 Hydroxypropyl methylcellulose 20,0 Propylene glycol 9.0 Talc 9.0 The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in a solvent blend consisting of isopropyl alcohol and methylene chloride. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide. EXAMPLE - 3 a) Composition of the inner core mg/gram Sucrose 650.0 Starch 350.0 Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%. b) Composition of active layer mg/gram Nimesulide 800.0 Polyvinylpyrrolidone 80.0 Polysorbate 80 8.0 Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment. c) Composition of coating layer mg/gram Ethyl cellulose 50.0 Polyvinylpyrrolidone 15.0 Polyethylene Glycol 5.0 Talc 10.0 The film forming polymer composition made of ethyl cellulose and polyvinylpyrrolidone along with the plasticizer is dissolved in isopropyl alcohol. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide. EXAMPLE - 4 a) Composition of the inner core mg/gram Sucrose 550.0 Starch 450.0 Synq) is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%. b) Composition of active layer mg/gram Nimesulide 450.0 Polyvinylpyrrolidone 45.0 Dioctyl sodium sulphosuccinate 10.0 Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Dioctyl sodium sulphosuccinate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained step (a) in a coating equipment. c) Composition of coating layer mg/gram Ethyl cellulose 40.0 Hydroxypropyl methylcellulose 20.0 Polyethylene Glycol 9.0 Talc 9.0 The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in a solvent blend consisting of isopropyl alcohol and methylene chloride. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide. EXAMPLE - 5 a) Composition of the inner core mg/gram Sucrose 600.0 Starch 400.0 Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%. b) Composition of active layer mg/gram Nimesulide 700.0 Polyvinylpyrrolidone 70.0 Sodium lauryl sulphate 17.5 Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and acetone. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment. c) Composition of coating layer mg/gram Ethyl cellulose 40.0 Polyvinylpyrrolidone 20,0 Polyethylene Glycol 5.0 Talc 10.0 The film forming polymer composition made of ethyl cellulose and polyvinylpyrrolidone along with the plasticizer is dissolved in isopropyl alcohol. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide. EXAMPLE - 6 a) Composition of the inner core mg/gram Sucrose 500.0 Starch 500.0 Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%. b) Composition of active layer mg/gram Nimesulide 350.0 Polyvinylpyrrolidone 35.0 Polysorbate 80 8.0 Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Polysorbate 80 is added and dissolved in the above solution. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment. c) Composition of coating layer mg/gram Ethyl cellulose 50.0 Hydroxypropyl methylcellulose 25.0 Propylene Glycol 12.5 Talc 7.5 The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in isopropyl alcohol Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide. EXAMPLE -7 a) Composition of the granules mg/tablet Nimesulide 200.0 Polyvinylpyrrolidone 20.0 Solid dispersion of nimesulide is prepared by dissolving nimesulide in acetone and polyvinylpyrrolidone in isopropyl alcohol, the two solutions are mixed using a mechanical stirrer. The solvent is evaporated under reduced pressure in a rotary evaporator. The solid dispersion is milled to a fine powder. b) Composition of the inner core mg/gram Sucrose 500.0 Starch 500.0 Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%. c) Composition of active layer mg/gram Nimesulide solid dispersion 350.0 Hydroxypropyl methylcellulose 35.0 Polymer solution is made by dissolving hydroxypropyl methylcellulose in solvent blend consisting of isopropyl alcohol and acetone. Nimesulide solid dispersion obtained in step (a) is dispersed into the polymer solution with the aid of mechanical stirrer. This suspension is coated on to the core pellets obtained in step (b) suitable coating equipment. d) Composition of coating layer mg/gram Ethyl cellulose 50.0 Hydroxypropyl methylcellulose 25.0 Propylene Glycol 12.5 Talc 7.5 The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in isopropyl alcohol. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (c) in a mechanised perforated coating pan. The pellets are dried and compressed into tablet to contain 200mg of nimesulide. EXAMPLE -8 a) Composition of the granules mg/tablet Nimesulide 200.0 Polyvinylpyrrolidone 15.0 Polysorbate 80 0.8 Nimesulide is granulated with solution of polyvinylpyrrolidone and polysorbate 80 in a hydroalcoholic mixture. The granules are dried. b) Composition of the tablet mg/tablet Nimesulide granules obtained in step (a) 215.8 Hydroxypropylmethyl cellulose 50.0 Colloidal silicon dioxide 2.0 Hydrogenated castor oil 5.0 The dried granules obtained in step (a) are mixed with hydroxypropylmethyl cellulose, lubricated with colloidal silicon dioxide and hydrogenated castor oil, and compressed into tablets on a rotary tablet press. EXAMPLE-9 a) Composition of the granules mg/tablet Nimesulide 200.0 Polyvinylpyrrolidone 15.0 Polysorbate 80 0.8 Ethyl cellulose 60.0 Nimesulide is granulated with solution of ethyl cellulose, polyvinylpyrrolidone and polysorbate 80 in Isopropyl alcohol. The granules are dried. b) Composition of the tablet mg/tablet Nimesulide granules obtained in step (a) 275.8 Colloidal silicon.dioxide 2.0 Hydrogenated castor oil 5.0 The dried granules obtained in step (a) are lubricated with colloidal silicon dioxide and hydrogenated castor oil and compressed into tablets on a rotary tablet press. EXAMPLE -10 a) Composition of the granules mg/tablet Nimesulide 200.0 Polyvinylpyrrolidone 20.0 Solid dispersion of nimesulide is prepared by dissolving nimesulide irt acetone and polyvmylpynrolidone m isopropyl alcohol, the two solutions are mixed using a mechanical stirrer. The solvent is evaporated under reduced pressure in a rotary evaporator. The solid dispersion is milled to a fine powder. b) Composition of the tablet mg/tablet Nimesulide solid dispersion of step(a) 220.0 Hydroxypropylmethyl cellulose 50.0 Lactose 20,0 Colloidal silicon dioxide 2.0 Magnesium stearate 5.0 The solid dispersion obtained in step (a) is mixed with hydroxypropylmethyl cellulose, lactose and lubricated with colloidal silicon dioxide and magrnesium stearate and compressed into slugs on a roll compactor. These slugs are milled to granules, the granules are lubricated with magnesium stearate and compressed into tablets on a rotary tablet press. EXAMPLE-11 a) Composition of the granules mg/tablet Nimesulide 200.0 Polyvinylpyrrolidone 20.0 Solid dispersion of nimesulide is prepared by dissolving nimesulide in acetone and polyvinylpyrrolidone in isopropyl alcohol, the two solutions are mixed using a mechanical stirrer. The solvent is evaporated under reduced pressure in a rotary evaporator. The solid dispersion is milled to a fine powder. b) Composition of the tablet mg/tablet Nimesulide solid dispersion obtained in step (a) 220.0 Hydroxypropylmethyl cellulose 50.0 Lactose 10,0 Colloidal silicon dioxide 2.0 Hydrogenated castor oil 5.0 The solid dispersion obtained in step (a) is mixed with hydroxypropylmethyl cellulose, lactose, lubricated with colloidal silicon dioxide and hydrogenated castor oil, and compressed into slugs on a roll compactor. These slugs are milled to granules, the granules are lubricated with hydrogenated castor oil and compressed into tablets on a rotary tablet press. Advantages of the invention: The formulation of the invention 1. Relieves pain over an extended period of time when compared to conventional oral formulation of nimesulide. 2. Reduces dosing frequency. 3. Reduces the total dose administered. 4. Improves patient compliance. WE Claim: - 1. A novel nimesulide pharmaceutical composition which releases the active ingredient over an extended period having polymer as active core contains Polyvinylpyrrolidone (PVP), organic solvents; Isopropyl alcohol, surface active agents Sodium lauryl sulphate, Polysorbate 80, dioctyl sodium sulfosuccinate, hydrophobic polymeric material namely ethyl cellulose, hydrophilic material like hydroxy propyl methyl cellulose (HPMC), Polyvinyl phthalate (PVP), plasticizers (Propylene glycol), colouring agents like titanium dioxide , and anti-adhering agents talc, magnesium stearate, colloidal silicon-di-oxide, and fillers like microcrystalline cellulose, dicalcium phosphate anhydrous to form tablets or capsules, which comprises of a. An inner core composed of sucrose and starch, b. The inner core having a coating of an active layer comprising fine particulate form of nimesulide, c. The active layer having a coating of a release modulating polymeric composition comprising of hydrophobic polymer or a mixture thereof 2. A pharmaceutical composition as claimed in claim 1 wherein the amount of nimesulide employed is selected in the active core ranges from 200.0 to 900.0 mg/g, more preferably 400.0 to 700.0 mg per gram of drug loaded pellets 3. A Pharmaceutical composition as claimed in claims 1 to 2 wherein the polymer employed as binder in the active core is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) or hydroxypropylmethylcellulose (HPMC), 4. A Pharmaceutical composition as claimed in claims 1 to 3 wherein the amount of polymer employed in the active core ranges from 10.0 to 100.0 mg, more preferably from 20.0 to 60.0 mg/g of composition. 5. A Pharmaceutical composition as claimed in claims 1 to 4 wherein the nimesulide employed in the active core is in the form of a solid dispersion in a hydrophilic substance selected from water soluble polymer such as hydroxyethyl cellulose (HEC), hydroxylpropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidine (PVP), polyethylene glycol (PEG), or water swellable / dispersible substances such as pre-gelatinised starch (PGS), hydroxyethyl starch (HES), dextrins (D). 6. A pharmaceutical composition as claimed in claim 5 where in the amount of nimesulide employed in the solid dispersion ranges from 500.0 to 950.0 mg preferably from 700 to 900 mg/g of dispersion and the amount of polymer used in the solid dispersion ranges from 50.0 to 500.0 mg preferably from 100.0 to 300.0 mg/g of dispersion. 7. A pharmaceutical composition as claimed in claims 5 & 6 wherein the organic solvent used in preparation of solid dispersion of nimesulide is selected from ethyl alcohol, isopropyl alcohol, acetone, chloroform and the like. 8. A Pharmaceutical composition as claimed in claims 1 to 7 wherein the surface-active agent employed in the active core is selected from sodium lauryl sulphate, dioctyl sodium sulfosuccinate, polysorbate-80 and the like. 9. A formulation as claimed in claims 1 to 8 wherein the amount of surface-active agent employed in the active core ranges from 4.0 to 40.0mg/g, more preferably from 8.0 to 20.0 mg/g of pellets. 10.A pharmaceutical composition as claimed in claims 1 to 9 wherein the hydrophobic material employed in the active core is selected from hydrogenated castor oil, cetyl alcohol, hydroxypropyl methylcellulose phthalate, ethyl cellulose and the like. ILA formulation as claimed in claims 1 to 10 wherein the amount of hydrophobic material employed in the active core ranges from 10.0 to 100.0mg, more preferably from 20.0 to 60.0 mg per gram of pellets. 12. A Pharmaceutical composition as claimed in claims 1 to 11 wherein the organic solvent used in coating of active layer on to nonpareil seeds is selected from ethyl alcohol, isopropyl alcohol, acetone and the like. 13. A Pharmaceutical composition as claimed in claims 1 to 12 wherein the hydrophobic polymer employed in coating the pellets with release modulating polymeric composition is selected from methacrylic acid copolymer (esters) or its aqueous latex dispersion (Eudragit RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) and the like. 14. A Pharmaceutical composition as claimed in claims 1 to 13 wherein the amount of polymer used in the release modulating polymer composition ranges from 25.0 to 250.0mg preferably from 50.0 to 200.0mg per gram of the composition. 15.A Pharmaceutical composition as claimed in claims 13 & 14 where in the hydrophilic material employed in release modulating polymeric composition is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), Hydroxypropylmethyl cellulose(HPMC) and the like. 16.A Pharmaceutical composition as claimed in claims 13 to 15 wherein the amount of hydrophilic material employed in the release modulating polymer composition ranges from 10.0 to 100.0 mg per gram of the composition. 17. A Pharmaceutical composition as claimed in claims 1 to 16 wherein the coating adjuvants such as plasticizer, colouring agents and antiadhering agents are employed. Adjuvants such as propylene glycol, diethyl phthalate, polyethylene glycol, triethyl citrate, hydrogenated castor oil and the like as plasticizers; titanium dioxide, quinoline yellow as colouring agents; and talc magnesium stearate, colloidal silicon dioxide and the like as anti-adhering agents are employed in the composition. 18. A pharmaceutical composition as claimed in claims 1 to 17 wherein the organic solvent employed in coating of release modulating polymer composition is selected from ethyl alcohol, isopropyl alcohol, acetone and the like. 19. A Pharmaceutical composition as claimed in claims 1 to 18 wherein the composition formed into pellets are compressed into tablet or encapsulated by conventional methods. 20.A pharmaceutical composition as claimed in claim 19 where in the filler employed in compressing the pellets into tablet is selected from anhydrous lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like. 21. A Pharmaceutical composition as claimed in claims 19 & 20 where in the amount of filler employed in tablet ranges from 120.0 to 360.0 mg preferably from 160.0 to 280.0 mg per tablet. 22.A process for the preparation of a pharmaceutical composition, which releases the active ingredient over an extended period and useful for treating inflammatory conditions and reducing pains there by providing relief over an extended period which comprises i. forming of inner core of sucrose and starch, ii. coating the inner core with an active layer comprising fine particulate form of nimesulide dispersed and / or dissolved in a solution of hydrophilic polymer in an orgamc solvent or a mixture there of iii. coating the active layer with a release controlling polymeric composition comprising of hydrophobic polymer or a mixture there of 23.A process as claimed in claim 22 wherein the amount of nimesulide employed in the active core ranges from 200.0 to 900.0 mg/g, more preferably 400.0 to 700.0mg per gram of drug loaded pellets. 24. A process as claimed in claims 22 to 23 wherein the polymer employed as binder in the active core is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC) and the like 25.A process as claimed in claims 22 to 24 wherein the amount of polymer employed in the active core ranges from 10.0 to 100.0mg more preferably from 20.0 to 60.0mg/g of composition. 26. A process as claimed in claims 22 to 25 wherein the nimesulide employed in the active core is in the form of a solid dispersion in a hydrophilic substance selected from water soluble polymer such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidine (PVP), polyethylene glycol (PEG) or water swellable / dispersible substances such as pre-gelatinised starch (PGS), hydroxyethyl starch (HES), dextrins (D) and the like. 27.A process as claimed in claims 22 to 26 wherein the amount of nimesulide employed in the solid dispersion ranges from 500.0 to 950.0mg preferably from 700 to 900mg/g of dispersion and the amount of polymer used in the solid dispersion ranges from 50.0 to 500.0mg preferably from 100.0 to 300.0mg/g of dispersion. 28. A process as claimed in claims 22 to 27 wherein the organic solvent used in preparation of solid dispersion of nimesulide is selected from ethyl alcohol, isopropyl alcohol, acetone, chloroform and the like. 29.A process as claimed in claims 22 to 28 wherein the surface-active agent employed in the active core is selected from sodium lauryl sulphate, dioctyl sodium sulfosuccinate, polysorbate-80 and the like. 30.A process as claimed in claims 22 to 29 wherein the amount of surface-active agent employed in the active core ranges from 4.0 to 40.0mg/g, more preferably from 8.0 to 20.0 hydrophilic mg/g of pellets. 31 .A process as claimed in claims 22 to 30 wherein the hydrophobic material employed in the active core is selected from hydrogenated castor oil, cetyl alcohol, hydroxypropyl methylcellulose phthalate, ethyl cellulose and the like. 32.A process as claimed in claims 22 to 31 wherein the amoimt of hydrophobic material employed in the active core ranges from 10.0 to lOO.Omg more preferably from 20.0 to 60.0 mg per gram of pellets. 33.A process as claimed in claims 22 to 32 wherein the organic solvent used in coating of active layer on to nonpareil seeds is selected from ethyl alcohol, isopropyl alcohol, acetone and the like. 34. A process as claimed in claims 22 to 33 wherein the hydrophobic polymer employed in coating the pellets with release modulating polymeric composition is selected from methacrylic acid copolymers (esters) or its aqueous latex dispersions (Eudragit RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) and the like. 35. A process as claimed in claims 22 to 34 wherein the amount of polymer used in the release modulating polymer composition ranges from 25.0 to 250.0mg preferably from 50.0 to 200.0mg per gram of the composition. 36.A process as claimed in claims 22 & 35 where in the hydrophilic material employed in release modulating polymeric composition is selected from polyvinyl pyrrolidone (PVP), hydroxy propyl cellulose (HPC), Hydroxy propylmethyl cellulose and the like. 37. A process as claimed in claims 22 to 36 wherein the amount of hydrophilic material employed in the release modulating polymer composition ranges from 10.0 to 100.0 mg per gram of the composition. 38. A process as claimed in claims 22 to 37 wherein the coating adjuvants such as plasticizer, colouring agents and antiadhering agents. Adjuvants such as propylene glycol, diethyl phthalate, polyethylene glycol, triethyl citrate, hydrogenated castor oil and the like as plasticizers; titanium dioxide, quinoline yellow as colouring agents; and talc, magnesium stearate, colloidal silicon dioxide and the like as anti-adhering agents are employed. 39. A process as claimed in claims 22 to 38 wherein the organic solvent employed in coating of release modulating polymer composition is selected from ethyl alcohol, isopropyl alcohol, acetone and the like. 40. A process as claimed in claims 22 to 39 wherein the composition formed in to pellets is compressed into tablet or encapsulated by conventional methods. 41. A process as claimed in claims 22 to 40 where in the filler employed in compressing the pellets into tablets are selected from anhydrous lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like. 42. A process as claimed in claims 22 to 41 where in the amount of filler employed in tablet ranges from 120.0 to 360.0 mg preferably from 160.0 to 280.0 mg per tablet. 43. A novel pharmaceutical formulation & process for the preparation which releases active ingredient over an extended period for treating inflammatory conditions and reducing pains substantially as here in described with reference to the examples 1 to 11.

Full Text

The invention relates to a controlled release pharmaceutical composition containing nimesulide. The composition is useful for the treatment of inflammatory conditions and to remove all kinds of pains. The composition is particularly useful for removing pains associated with osteoarthritis and traumatic injury. The composition is therapeutically effective for a period of 18.0 to 24.0 hours there by reducing the dose of the drug, which consequently improves the patient compliance. The composition of the present invention is either in the form of a tablet or coated pellets filled in capsule releasing the active ingredient as initial dose and maintenance dose in vitro at a specified rate.
Nimesulide has the chemical formula given below.
C13H12N2O5S
Formula 1
Nimesulide is non-steroidal anti-inflammatory drug (NSAID) that also has
antipyretic and analgesic properties. It is administered orally or rectally at a
dose of 100 and 200mg twice daily, respectively, for a variety of
inflammatory disorders as well as for removing pains. In children, nimesulide
dose is commonly 5mg/kg/day divided into 2 or 3 daily doses administered in
the form of suspension, granules or suppositories. This compound is effective
in reducing pains associated with osteroarthritis, cancer, thrombophlebitis,
oral and general surgery, dysmenorrhoea in adults and pain, fever and
inflammation accompanying respiratory tract infections,
otorhinolaryngological diseases and traumatic injury in adults and children. Nimesulide appeared to be at least as effective as other non-steroidal antiinflammatory drugs (NSAIDs) in all of the above said indications. Nimesulide has been well tolerated by adults, elderly and pediatric patients. It has a pharmacodynamic profile suggestive of a reduced propensity to cause adverse gastrointestinal effects associated with NSAIDs.
Though the compound is weakly acidic (pKa 6.5) and differs from other NSAIDs in that chemical structure contains a sulfonanilide moeity as the acidic group (Davis,R. and Brogden, R. N., Drugs, 48(3): 431, 1994). The mechanism of action of nimesulide appears to differ from that of most conventional NSAIDs. Nimesulide selectively inhibits the formation of proinflammatory prostagladins with less effect on those prostagladins that have gastroprotective action. As a consequence, nimesulide is better tolerated by the gastrointestinal tract than most other NSAIDs, while exerting equivalent efficacy. It exhibits a neuroprotective effect against β- amyloid induced cell

death. Nimesulide inhibits non-inflammatory mechanisms of
neurodegeneration. The COX-2 inhibition may have potential as an additional therapeutic agent in human inflammatory neuropathis. The other mechanism of action of nimesulide including free radical scavenging, inhibition of histamine release and activity, inhibition of proteases (Ex.: elastage, collagenase). potent inhibition of induced platelet aggregation (Tognella, S., Drugs, 46(suppl 1): 275,1993).
Recently, Nakatsugi et.al, ( through Chem. Absts, 130(12):148406k,1999) reported that repeated administration of nimesulide to Min. mice in their diet significantly decreased the size of the polyps in intestine. These authors claims that nimesulide is a good candidate as a colon cancer chemo-preventive agent with low toxicity.
Nimesulide is practically insoluble in water and freely soluble in O.IN NaOH and phosphate buffer pH 8.0 with surfactant. The solubility of nimesulide can be improved by making complexes with P-cyclodextrins (Piel et al, J. Pharm. Sci,, 86,475,1997). However making complexation employing p-cyclodextrins is costlier and use of methylene chloride may cause toxic effects.
Dischiena and Ginseppe (Eur Pat. Appl 880, 965, 1998) disclosed a topical pharmaceutical formulation containing nimesulide and an excipient consisting of an acrylic polymer or copolymer dispersed in oil and water with an emilsifier do not strain yellow skin.
Bertacchi et al., (Acta Toxicol. Ther.,18(l), 33, 1997) reported that a 3% nimesulide cream would possesses a good analgesic and anti-inflammatory activity and well local tolerability without side effects.
Girola et al, (Acta Toxicol Ther.,18(l), 17, 1997) suggested that 3% nimesulide cream showed statistically significant activity, in acute goute injury, than 1% diclofenac gel.
Wober et al.,(Int. J. Clin. Pract. 52(3), 169,1998) observed that nimesulide exhibited high therapeutic equivalence and tolerance when compared to diclofenac in acute subdeltoid bursitis and bicipital tendinitis.
After oral administration of pure nimesulide 50.0 to 200.0mg to healthy adult volunteers, peak serum concentration of 1.98 to 9.85mg/L are achieved within 1.2 to 3.17 hours. Oral drug absorption is nearly complete and concomitant administration of food may decrease the rate but not the extent of absorption of nimesulide. The elimination half-life of nimesulide ranges from 1.56 to

4.9 hors. The short biological half-life of nimesulide necessitates frequent administration.
Till today there is no composition containing nimesulide which releases the drug in a controlled manner thereby not only reducing the amount of the drug to be administered but also enhancing the effectiveness of the drug. Considering the good tolerance of the drug by all the categories of patients namely adults, elderly persons and infants it was observed that development of controlled release pharmaceutical composition containing nimesulide may be very useful for the treatment of inflammatory conditions as well as for removing various kinds of pains.
The sustained release of the drug from its dosage form can be obtained by different ways. One method utilises the embedding of the drug into a matrix of other excipients that are relatively water insoluble and hence dissolve and release the embedded drug slowly at a controlled rate into the digestive tract. The other approach is to shape the drug and excipients into granules or pellets as an active core and then these are coated with substances possessing film forming characteristics and low solubility profile.
The major draw back associated with many of these technologies for controlled release of water insoluble drugs is the variations in their drug release profile from batch to batch and also from manufacturer to manufacturer. These variations in release profile may also due to changes in particle size and crystalline nature of the drug. Further, formulating a water insoluble drug into sustained release pharmaceutical dosage form is that not all the drug made available to the biological system during its transport though the digestive tract. However the above drawbacks can be over come by solid dispersion technique.
Accordingly the main objective of the present invention is to provide a novel controlled release pharmaceutical composition containing nimesulide which is useful for the treatment of inflammatory conditions as well as for removing all kinds of pains.
Another objective of the present invention is to provide a novel controlled release pharmaceutical composition containing nimesulide, which is effective for a longer period of time as well, requires only small doses.
Yet another objective of the present invention is to provide a novel controlled release pharmaceutical composition containing nimesulide where the release profile of the drug is uniform.

It is still another objective of the present invention to provide a novel pharmaceutical composition which is therapeutically effective over an extended period of at least 18.0 to 24.0 hours by providing sufficient amount of the drug immediately, i.e. within 0,5 to 1.0 hour to provide an initial therapeutically effective serum concentration, and to releasing the remaining amount of the drug at a rate sufficient to maintain the drug concentration in therapeutically effective range over a desired period of time.
It is another objective of the present invention to provide an oral controlled release pharmaceutical composition containing nimesulide useful for the treatment of inflammatory conditions and reducing pains which releases 50 to lOOmg of drug within 0.5 to 1.0 hour after oral administration of the composition as initial dose, the remaining drug being release at the rate of 6.0 to 14,0 mg/hour over a period of 15.0 to 18.0 hour as maintenance dose.
Still another objective of the present invention is to provide a method for preparing the novel controlled release pharmaceutical composition containing nimesulide, which is useful for the treatment of inflammatory conditions as well as for removing all kinds of pains.
The present invention is based on our finding that in vitro dissolution profile of nimesulide from a composition containing fine particulate form of nimesulide or its solid dispersion when granulated or coated with release controlling polymeric composition which substantially maintain the integrity of the granules or pellets in varying pH conditions of gastrointestinal tract but is permeable to nimesulide, follows zero order release kinetics until a substantial amount, namely 80 to 90%, of the drug is released. This composition, when administered orally to humans in conjunction with an initial dose of nimesulide for immediate release, provides relief of pain over an extended period of 18.0 to 24.0 hours, with better patient compliance.
Accordingly, the present invention provides a novel oral controlled release pharmaceutical composition, useful for the treatment of inflammation and for reducing pains, which comprises an inner core composed of sucrose and starch, the inner core having a coating of an active layer comprising fine particulate form of nimesulide and a hydrophilic polymer as binder, the active layer having a coating of a release modulating polymeric composition comprising of a hydrophobic polymer or a mixture thereof The resulting composition may be filled into a capsule or compressed into a tablet by known method.

In a preferred embodiment of the invention the particulate form of nimesulide may be in the form of solid dispersion. The active layer may optionally contain a surface-active agent and/or a hydrophobic material. The release modulating polymeric composition may optionally contain a hydrophilic material, a plasticizer, a colouring agent, an anti sticking agent, or a mixture thereof
Statement of invention:
According to the present invention there is also provided a process for the preparation of the above said formulation, which comprises
i. Preparing inner core comprising sucrose and starch,
ii. Coating the inner core with an active layer comprising fine particulate
form of nimesulide suspended in a solution of hydrophilic polymer in an
organic solvent or a mixture thereof iii. Coating the active layer with a release controlling polymeric
composition comprising of hydrophobic polymer or a mixture thereof iv. encapsulating the coated pellets by conventional methods
Or
Compressing the coated pellets into tablets using inert pharmaceutical
excipients like fillers and lubricants.
The following materials may optionally be used in the process for the preparation of said formulation.
a) Solid dispersion of nimesulide, a surface-active agent and/or a hydrophobic material in coating the inner cores with an active layer.
b) a plasticizer, a hydrophilic material or a mixture thereof in release modulating polymeric composition for controlling drug release.
In a preferred embodiment of the present invention the amount of sucrose employed in the inner core may range from 400.0 to 700,0 mg more preferably from 450.0 to 650.0 mg and starch from 300.0 to 600.0 mg more preferably from 400.0 to 500.0 mg per gram of nonpareil seeds (N.P. Seeds).
The amount of nimesulide employed in the active layer may range from 200.0 to 900.0 mg more preferably from 400.0 to 700.0 mg per gram of drug-loaded pellets. A hydrophilic polymer such as polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose ( HPMC) and the like may be employed as binding agent in the active core; the amount

of which may range from 10.0 to 100.0mg more preferably from 20.0 to 60.0 mg per gram of pellets.
In a preferred embodiment of the invention the particulate form of nimesulide may be its solid dispersion into a matrix of hydrophilic substance. The hydrophilic substance may be selected from among the water soluble polymers such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidine (PVP), polyethylene glycol (PEG) or water swellable / dispersible substances such as pre-gelatinised starch (PGS), hydroxyethyl starch (HES), dextrins (D) and the like. The amount of nimesulide in the solid dispersion may range from 500.0 - 950.0mg, preferably 700.0 - 900.0mg per gram of dispersion. The amount of hydrophilic substance may range from 50.0 to 500.0mg preferably from 100.0 - 300.0 mg per gram of solid dispersion.
Known pharmaceutical methods such as common solvent and solvent deposition methods may be used to prepare the solid dispersions. The solvent may be selected from among acetone, ethyl alcohol, isopropyl alcohol, chloroform and the like or a mixture there of in which nimesulide is soluble. The dispersion may be applied on to nonpareil seeds using conventional coating equipment or any suitable coating equipment.
A surface-active agent such as sodium lauryl sulphate, dioctyl sodium sulfosuccinate, polysorbate 80 and the like may optionally be employed in coating the inner core with active layer. The amount of such surface-active agent may range from 4.0 to 40.0mg more preferably from 8.0 to 20.0mg per gram of pellets.
A hydrophobic material such as hydrogenated castor oil, cetyl alcohol, hydroxypropyl methylcellulose phthalate, ethyl cellulose and the like may optionally be employed in the active layer. The amount of such hydrophobic material may range from 10.0 to 100.0mg more preferably from 20.0 to 60.0 mg per gram of pellets.
The active layer can be applied in a suitable manner using conventional coating equipment or other suitable coating equipment, for example, in the form of suspension/solution in organic solvent mixture or a hydro alcoholic mixture as medium.
In yet another embodiment of the invention for coating the pellets with release modulating polymeric composition a hydrophobic polymer such as methacrylic acid copolymer (esters) or its aqueous latex dispersion (Eudragit

RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) or a mixture thereof may be used. The amount of such polymer may range from 25.0 to 250.0mg preferably from 50.0 to 200.0mg per gram of pellets.
The release modulating polymeric composition may optionally contain a hydrophilic material selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and the like ; a plasticizer selected from propylene glycol, diethyl phthalate, polyethylene glycol, triethyl citrate, hydrogenated castor oil and the like; a colouring agent selected from titanium dioxide, quinoline yellow and and the like; antisticking agents selected from talc, magnesium stearate, colloidal silicon dioxide and the like. The amounts of such optional agents may range from 10.0 to 100.0mg, 5.0 to 50.0mg, 0,4 to 8.0mg and 10,0 to 50.0mg per gram of pellets hi that order.
The release modulating polymeric composition is applied on to active layered pellets in a mechanised perforating pan or using suitable coating equipment. Polymer coated pellets are filled in to hard gelatin capsules or compressed into tablets after mixing with known inert pharmaceutical excipients such as filler and lubricants.
If compressed into tablet, the fillers such as starch, anhydrous lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like may be employed. The amount of such filler may range from 120,0 to 360,0 mg preferably from 160.0 to 280.0mg per tablet. The excipients such as talc, magnesium stearate, colloidal silicon dioxide, hydrogenated castor oil may be employed as lubricants in tabletting and the amount may range from 1.0 to lO.Omg more preferably from 2.0 - S.Omg per tablet.
According to another feature of the invention there is provided novel oral controlled release pharmaceutical composition useful for the treatment of inflammation and for reducing pains comprising granules of nimesulide, a surface active agent and a release modulating polymeric composition compressed into tablets using inert pharmaceutical excipients such as fillers and lubricants.
The composition may optionally contain nimesulide in the form of solid dispersion and/or a hydrophilic material and a plasticizer.

According to another feature of the present invention there is provided a process for the preparation of oral controlled release pharmaceutical formulation containing nimesulide useful for the treatment of inflammation and for reducing pains which comprises.
i, preparing granules comprising of fine particles of nimesuUde, a surface-active gent, and a release modulating polymer.
ii. compressing the granules into tablets using inert pharmaceutical excipients such as fillers and lubricants.
The following materials may optionally be used in the process for the preparation of granules for controlled release pharmaceutical composition. These are solid dispersion of nimesulide and / or hydrophilic release modulating material and a plasticizer.
In a prefered embodiment of the present invention to prepare tablets the amount of nimesulide employed in preparing the tablets may rage from 100.0 to 400.0mg, preferably from 150.0 to 250.0mg more preferably from 175.0 to 225.0mg per tablet
In a preferred embodiment of the present invention to prepare granules comprising of nimesulide, a surface active agent such as sodium lauryl sulphate, polysorbate 80 and the like may be employed; the amount of which may range from 0.3 - 3.0mg, preferably from 0.9 to 1.5mg per tablet.
In yet another embodiment of the invention to prepare granules by wet granulation method hydrophobic polymers such as methacrylic acid copolymer (esters) or its aqueous latex dispersion (Eudragit RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) or a mixture thereof may be used. The amoimt of such polymer may range from 4.0 to 120.0mg, preferably from 8.0 to 60.0mg per tablet.
In a preferred embodiment of the present invention to prepare tablets by dry granulation method a hydrophilic polymer such as hydroxy propyl methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxy ethyl cellulose and the like may be used. The amount of such polymer may range from 4.0 to 120.0 mg. preferably from 8,0 to 60.0mg per tablet. A solid dispersion of nimesulide prepared as described earlier may optionally be employed in preparing the tablets.

A hydrophilic polymer such as polyvinylpyrrolidone(PVP), hydroxypropyl cellulose(HPC), hydroxypropyl methyl cellulose(HPMC), and the like may optionally be employed as release modulating agent in granules prepared by wet granulation method; the amount of such polymer may range from 1.0 to 30.0mg per tablet.
In a preferred embodiment of the invention the fillers and lubricants employed in tablet are selected from known inert pharmaceutical excipients. The inert fillers such as lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like may be employed in tabletting the granules. The amount of filler employed may range from 20.0 to 60.0 mg, preferably from 30.0 to 50.0mg per tablet. The excipients such as talc, magnesium stearate, colloidal silicon dioxide, hydrogenated castor oil and the like may be employed as lubricants in tabletting and the amount may range from 1.0 to 10.0mg more preferably from 2.0 - 5.0mg per tablet.
The granules are prepared by known methods and compressed in to tablets on a rotary tablet press.
The invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXAMPLE -1
a) Composition of the inner core mg/gram
Sucrose 600.0
Starch 400.0
Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%.
b) Composition of active layer mg/gram
Nimesulide 700.0
Polyvinylpyrrolidone 70.0
Sodium lauryl sulphate 17.5
Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment.
c) Composition of coating layer mg/gram
Ethyl cellulose 50.0
Hydroxypropyl methylcellulose 12.5
Polyethylene Glycol 10.0
Talc 10.0
The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in a solvent blend consisting of isopropyl alcohol and methylene chloride. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200.0mg of nimesulide.

EXAMPLE - 2
a) Composition of the inner core mg/gram
Sucrose 550.0
Starch 450.0
Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%.
b) Composition of active layer mg/gram
Nimesulide 350.0
Polyvinylpyrrolidone 35.0
Sodium lauryl sulphate 8.0
Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment.
c) Composition of coating layer mg/gram
Ethyl cellulose 40.0
Hydroxypropyl methylcellulose 20,0
Propylene glycol 9.0
Talc 9.0
The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in a solvent blend consisting of isopropyl alcohol and methylene chloride. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide.

EXAMPLE - 3
a) Composition of the inner core mg/gram
Sucrose 650.0
Starch 350.0
Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%.
b) Composition of active layer mg/gram
Nimesulide 800.0
Polyvinylpyrrolidone 80.0
Polysorbate 80 8.0
Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment.
c) Composition of coating layer mg/gram
Ethyl cellulose 50.0
Polyvinylpyrrolidone 15.0
Polyethylene Glycol 5.0
Talc 10.0
The film forming polymer composition made of ethyl cellulose and polyvinylpyrrolidone along with the plasticizer is dissolved in isopropyl alcohol. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide.

EXAMPLE - 4
a) Composition of the inner core mg/gram
Sucrose 550.0
Starch 450.0
Synq) is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%.
b) Composition of active layer mg/gram
Nimesulide 450.0
Polyvinylpyrrolidone 45.0
Dioctyl sodium sulphosuccinate 10.0
Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Dioctyl sodium sulphosuccinate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained step (a) in a coating equipment.
c) Composition of coating layer mg/gram
Ethyl cellulose 40.0
Hydroxypropyl methylcellulose 20.0
Polyethylene Glycol 9.0
Talc 9.0
The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in a solvent blend consisting of isopropyl alcohol and methylene chloride. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide.

EXAMPLE - 5
a) Composition of the inner core mg/gram
Sucrose 600.0
Starch 400.0
Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%.
b) Composition of active layer mg/gram
Nimesulide 700.0
Polyvinylpyrrolidone 70.0
Sodium lauryl sulphate 17.5
Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and acetone. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Sodium lauryl sulphate is added and dissolved in the above solution with stirring. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment.
c) Composition of coating layer mg/gram
Ethyl cellulose 40.0
Polyvinylpyrrolidone 20,0
Polyethylene Glycol 5.0
Talc 10.0
The film forming polymer composition made of ethyl cellulose and polyvinylpyrrolidone along with the plasticizer is dissolved in isopropyl alcohol. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide.

EXAMPLE - 6
a) Composition of the inner core mg/gram
Sucrose 500.0
Starch 500.0
Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%.
b) Composition of active layer mg/gram
Nimesulide 350.0
Polyvinylpyrrolidone 35.0
Polysorbate 80 8.0
Polymer solution is made by dissolving polyvinylpyrrolidone in solvent blend consisting of isopropyl alcohol and water. Nimesulide is dispersed into the polymer solution with the aid of mechanical stirrer. Polysorbate 80 is added and dissolved in the above solution. This suspension is coated onto the core pellets obtained in step (a) in a coating equipment.
c) Composition of coating layer mg/gram
Ethyl cellulose 50.0
Hydroxypropyl methylcellulose 25.0
Propylene Glycol 12.5
Talc 7.5
The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in isopropyl alcohol Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (b) in a mechanised perforated coating pan. The pellets are dried and filled into capsules to contain 200mg of nimesulide.

EXAMPLE -7
a) Composition of the granules mg/tablet
Nimesulide 200.0
Polyvinylpyrrolidone 20.0
Solid dispersion of nimesulide is prepared by dissolving nimesulide in acetone and polyvinylpyrrolidone in isopropyl alcohol, the two solutions are mixed using a mechanical stirrer. The solvent is evaporated under reduced pressure in a rotary evaporator. The solid dispersion is milled to a fine powder.
b) Composition of the inner core mg/gram
Sucrose 500.0
Starch 500.0
Syrup is made by dissolving sucrose in sufficient quantity of purified water by the aid of heat. Sucrose is coated with starch by dry powder layering method using sucrose syrup as binding agent. The pellets thus obtained are dried to reduce the moisture content to less than 2%.
c) Composition of active layer mg/gram
Nimesulide solid dispersion 350.0
Hydroxypropyl methylcellulose 35.0
Polymer solution is made by dissolving hydroxypropyl methylcellulose in solvent blend consisting of isopropyl alcohol and acetone. Nimesulide solid dispersion obtained in step (a) is dispersed into the polymer solution with the aid of mechanical stirrer. This suspension is coated on to the core pellets obtained in step (b) suitable coating equipment.
d) Composition of coating layer mg/gram
Ethyl cellulose 50.0
Hydroxypropyl methylcellulose 25.0
Propylene Glycol 12.5
Talc 7.5
The film forming polymer composition made of ethyl cellulose and hydroxypropyl methylcellulose along with the plasticizer is dissolved in isopropyl alcohol. Talc is dispersed into the polymer solution with the aid of a mechanical stirrer. This polymeric dispersion is coated onto the pellets obtained in step (c) in a mechanised perforated coating pan. The pellets are dried and compressed into tablet to contain 200mg of nimesulide.

EXAMPLE -8
a) Composition of the granules mg/tablet
Nimesulide 200.0
Polyvinylpyrrolidone 15.0
Polysorbate 80 0.8
Nimesulide is granulated with solution of polyvinylpyrrolidone and polysorbate 80 in a hydroalcoholic mixture. The granules are dried.
b) Composition of the tablet mg/tablet
Nimesulide granules obtained in step (a) 215.8
Hydroxypropylmethyl cellulose 50.0
Colloidal silicon dioxide 2.0
Hydrogenated castor oil 5.0
The dried granules obtained in step (a) are mixed with hydroxypropylmethyl cellulose, lubricated with colloidal silicon dioxide and hydrogenated castor oil, and compressed into tablets on a rotary tablet press.

EXAMPLE-9
a) Composition of the granules mg/tablet
Nimesulide 200.0
Polyvinylpyrrolidone 15.0
Polysorbate 80 0.8
Ethyl cellulose 60.0
Nimesulide is granulated with solution of ethyl cellulose, polyvinylpyrrolidone and polysorbate 80 in Isopropyl alcohol. The granules are dried.
b) Composition of the tablet mg/tablet
Nimesulide granules obtained in step (a) 275.8
Colloidal silicon.dioxide 2.0
Hydrogenated castor oil 5.0
The dried granules obtained in step (a) are lubricated with colloidal silicon dioxide and hydrogenated castor oil and compressed into tablets on a rotary tablet press.

EXAMPLE -10
a) Composition of the granules mg/tablet
Nimesulide 200.0
Polyvinylpyrrolidone 20.0
Solid dispersion of nimesulide is prepared by dissolving nimesulide irt acetone and polyvmylpynrolidone m isopropyl alcohol, the two solutions are mixed using a mechanical stirrer. The solvent is evaporated under reduced pressure in a rotary evaporator. The solid dispersion is milled to a fine powder.
b) Composition of the tablet mg/tablet
Nimesulide solid dispersion of step(a) 220.0
Hydroxypropylmethyl cellulose 50.0
Lactose 20,0
Colloidal silicon dioxide 2.0
Magnesium stearate 5.0
The solid dispersion obtained in step (a) is mixed with hydroxypropylmethyl cellulose, lactose and lubricated with colloidal silicon dioxide and magrnesium stearate and compressed into slugs on a roll compactor. These slugs are milled to granules, the granules are lubricated with magnesium stearate and compressed into tablets on a rotary tablet press.

EXAMPLE-11
a) Composition of the granules mg/tablet
Nimesulide 200.0
Polyvinylpyrrolidone 20.0
Solid dispersion of nimesulide is prepared by dissolving nimesulide in acetone and polyvinylpyrrolidone in isopropyl alcohol, the two solutions are mixed using a mechanical stirrer. The solvent is evaporated under reduced pressure in a rotary evaporator. The solid dispersion is milled to a fine powder.
b) Composition of the tablet mg/tablet
Nimesulide solid dispersion
obtained in step (a) 220.0
Hydroxypropylmethyl cellulose 50.0
Lactose 10,0
Colloidal silicon dioxide 2.0
Hydrogenated castor oil 5.0
The solid dispersion obtained in step (a) is mixed with hydroxypropylmethyl cellulose, lactose, lubricated with colloidal silicon dioxide and hydrogenated castor oil, and compressed into slugs on a roll compactor. These slugs are milled to granules, the granules are lubricated with hydrogenated castor oil and compressed into tablets on a rotary tablet press.
Advantages of the invention:
The formulation of the invention
1. Relieves pain over an extended period of time when compared to conventional oral formulation of nimesulide.
2. Reduces dosing frequency.
3. Reduces the total dose administered.
4. Improves patient compliance.

WE Claim: -
1. A novel nimesulide pharmaceutical composition which releases the active
ingredient over an extended period having polymer as active core contains Polyvinylpyrrolidone (PVP), organic solvents; Isopropyl alcohol, surface active agents Sodium lauryl sulphate, Polysorbate 80, dioctyl sodium sulfosuccinate, hydrophobic polymeric material namely ethyl cellulose, hydrophilic material like hydroxy propyl methyl cellulose (HPMC), Polyvinyl phthalate (PVP), plasticizers (Propylene glycol), colouring agents like titanium dioxide , and anti-adhering agents talc, magnesium stearate, colloidal silicon-di-oxide, and fillers like microcrystalline cellulose, dicalcium phosphate anhydrous to form tablets or capsules, which comprises of
a. An inner core composed of sucrose and starch,
b. The inner core having a coating of an active layer comprising fine
particulate form of nimesulide,
c. The active layer having a coating of a release modulating polymeric
composition comprising of hydrophobic polymer or a mixture thereof
2. A pharmaceutical composition as claimed in claim 1 wherein the amount of nimesulide employed is selected in the active core ranges from 200.0 to 900.0 mg/g, more preferably 400.0 to 700.0 mg per gram of drug loaded pellets
3. A Pharmaceutical composition as claimed in claims 1 to 2 wherein the polymer employed as binder in the active core is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) or hydroxypropylmethylcellulose (HPMC),
4. A Pharmaceutical composition as claimed in claims 1 to 3 wherein the amount of polymer employed in the active core ranges from 10.0 to 100.0 mg, more preferably from 20.0 to 60.0 mg/g of composition.
5. A Pharmaceutical composition as claimed in claims 1 to 4 wherein the nimesulide employed in the active core is in the form of a solid dispersion in a hydrophilic substance selected from water soluble polymer such as hydroxyethyl cellulose (HEC), hydroxylpropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidine (PVP), polyethylene glycol (PEG), or water swellable / dispersible substances such as pre-gelatinised starch (PGS), hydroxyethyl starch (HES), dextrins (D).
6. A pharmaceutical composition as claimed in claim 5 where in the amount of nimesulide employed in the solid dispersion ranges from 500.0 to 950.0 mg preferably from 700 to 900 mg/g of dispersion and the amount of polymer used in the solid dispersion ranges from 50.0 to 500.0 mg preferably from 100.0 to 300.0 mg/g of dispersion.

7. A pharmaceutical composition as claimed in claims 5 & 6 wherein the organic solvent used in preparation of solid dispersion of nimesulide is selected from ethyl alcohol, isopropyl alcohol, acetone, chloroform and the like.
8. A Pharmaceutical composition as claimed in claims 1 to 7 wherein the surface-active agent employed in the active core is selected from sodium lauryl sulphate, dioctyl sodium sulfosuccinate, polysorbate-80 and the like.
9. A formulation as claimed in claims 1 to 8 wherein the amount of surface-active agent employed in the active core ranges from 4.0 to 40.0mg/g, more preferably from 8.0 to 20.0 mg/g of pellets.
10.A pharmaceutical composition as claimed in claims 1 to 9 wherein the hydrophobic material employed in the active core is selected from hydrogenated castor oil, cetyl alcohol, hydroxypropyl methylcellulose phthalate, ethyl cellulose and the like.
ILA formulation as claimed in claims 1 to 10 wherein the amount of hydrophobic material employed in the active core ranges from 10.0 to 100.0mg, more preferably from 20.0 to 60.0 mg per gram of pellets.
12. A Pharmaceutical composition as claimed in claims 1 to 11 wherein the
organic solvent used in coating of active layer on to nonpareil seeds is
selected from ethyl alcohol, isopropyl alcohol, acetone and the like.
13. A Pharmaceutical composition as claimed in claims 1 to 12 wherein the hydrophobic polymer employed in coating the pellets with release modulating polymeric composition is selected from methacrylic acid copolymer (esters) or its aqueous latex dispersion (Eudragit RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) and the like.
14. A Pharmaceutical composition as claimed in claims 1 to 13 wherein the amount of polymer used in the release modulating polymer composition ranges from 25.0 to 250.0mg preferably from 50.0 to 200.0mg per gram of the composition.

15.A Pharmaceutical composition as claimed in claims 13 & 14 where in the hydrophilic material employed in release modulating polymeric composition is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), Hydroxypropylmethyl cellulose(HPMC) and the like.
16.A Pharmaceutical composition as claimed in claims 13 to 15 wherein the amount of hydrophilic material employed in the release modulating polymer composition ranges from 10.0 to 100.0 mg per gram of the composition.
17. A Pharmaceutical composition as claimed in claims 1 to 16 wherein the
coating adjuvants such as plasticizer, colouring agents and antiadhering
agents are employed. Adjuvants such as propylene glycol, diethyl
phthalate, polyethylene glycol, triethyl citrate, hydrogenated castor oil and
the like as plasticizers; titanium dioxide, quinoline yellow as colouring
agents; and talc magnesium stearate, colloidal silicon dioxide and the like
as anti-adhering agents are employed in the composition.
18. A pharmaceutical composition as claimed in claims 1 to 17 wherein the
organic solvent employed in coating of release modulating polymer
composition is selected from ethyl alcohol, isopropyl alcohol, acetone and
the like.
19. A Pharmaceutical composition as claimed in claims 1 to 18 wherein the
composition formed into pellets are compressed into tablet or encapsulated
by conventional methods.
20.A pharmaceutical composition as claimed in claim 19 where in the filler employed in compressing the pellets into tablet is selected from anhydrous lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like.
21. A Pharmaceutical composition as claimed in claims 19 & 20 where in the amount of filler employed in tablet ranges from 120.0 to 360.0 mg preferably from 160.0 to 280.0 mg per tablet.
22.A process for the preparation of a pharmaceutical composition, which releases the active ingredient over an extended period and useful for treating inflammatory conditions and reducing pains there by providing relief over an extended period which comprises

i. forming of inner core of sucrose and starch,
ii. coating the inner core with an active layer comprising fine particulate
form of nimesulide dispersed and / or dissolved in a solution of
hydrophilic polymer in an orgamc solvent or a mixture there of iii. coating the active layer with a release controlling polymeric
composition comprising of hydrophobic polymer or a mixture there
of
23.A process as claimed in claim 22 wherein the amount of nimesulide employed in the active core ranges from 200.0 to 900.0 mg/g, more preferably 400.0 to 700.0mg per gram of drug loaded pellets.
24. A process as claimed in claims 22 to 23 wherein the polymer employed as binder in the active core is selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC) and the like
25.A process as claimed in claims 22 to 24 wherein the amount of polymer employed in the active core ranges from 10.0 to 100.0mg more preferably from 20.0 to 60.0mg/g of composition.
26. A process as claimed in claims 22 to 25 wherein the nimesulide employed in the active core is in the form of a solid dispersion in a hydrophilic substance selected from water soluble polymer such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidine (PVP), polyethylene glycol (PEG) or water swellable / dispersible substances such as pre-gelatinised starch (PGS), hydroxyethyl starch (HES), dextrins (D) and the like.
27.A process as claimed in claims 22 to 26 wherein the amount of nimesulide employed in the solid dispersion ranges from 500.0 to 950.0mg preferably from 700 to 900mg/g of dispersion and the amount of polymer used in the solid dispersion ranges from 50.0 to 500.0mg preferably from 100.0 to 300.0mg/g of dispersion.
28. A process as claimed in claims 22 to 27 wherein the organic solvent used in preparation of solid dispersion of nimesulide is selected from ethyl alcohol, isopropyl alcohol, acetone, chloroform and the like.
29.A process as claimed in claims 22 to 28 wherein the surface-active agent employed in the active core is selected from sodium lauryl sulphate, dioctyl sodium sulfosuccinate, polysorbate-80 and the like.

30.A process as claimed in claims 22 to 29 wherein the amount of surface-active agent employed in the active core ranges from 4.0 to 40.0mg/g, more preferably from 8.0 to 20.0 hydrophilic mg/g of pellets.
31 .A process as claimed in claims 22 to 30 wherein the hydrophobic material employed in the active core is selected from hydrogenated castor oil, cetyl alcohol, hydroxypropyl methylcellulose phthalate, ethyl cellulose and the like.
32.A process as claimed in claims 22 to 31 wherein the amoimt of hydrophobic material employed in the active core ranges from 10.0 to lOO.Omg more preferably from 20.0 to 60.0 mg per gram of pellets.
33.A process as claimed in claims 22 to 32 wherein the organic solvent used in coating of active layer on to nonpareil seeds is selected from ethyl alcohol, isopropyl alcohol, acetone and the like.
34. A process as claimed in claims 22 to 33 wherein the hydrophobic polymer employed in coating the pellets with release modulating polymeric composition is selected from methacrylic acid copolymers (esters) or its aqueous latex dispersions (Eudragit RS, Eudragit RL, Eudragit NE or Eudragit RS30D, Eudragit RL30D, Eudragit NE30D); ethylcellulose or its aqueous latex dispersion, (Surelease, Aquacoat ECD) and the like.
35. A process as claimed in claims 22 to 34 wherein the amount of polymer used in the release modulating polymer composition ranges from 25.0 to 250.0mg preferably from 50.0 to 200.0mg per gram of the composition.
36.A process as claimed in claims 22 & 35 where in the hydrophilic material employed in release modulating polymeric composition is selected from polyvinyl pyrrolidone (PVP), hydroxy propyl cellulose (HPC), Hydroxy propylmethyl cellulose and the like.
37. A process as claimed in claims 22 to 36 wherein the amount of hydrophilic material employed in the release modulating polymer composition ranges from 10.0 to 100.0 mg per gram of the composition.

38. A process as claimed in claims 22 to 37 wherein the coating adjuvants such
as plasticizer, colouring agents and antiadhering agents. Adjuvants such as
propylene glycol, diethyl phthalate, polyethylene glycol, triethyl citrate,
hydrogenated castor oil and the like as plasticizers; titanium dioxide, quinoline
yellow as colouring agents; and talc, magnesium stearate, colloidal silicon
dioxide and the like as anti-adhering agents are employed.
39. A process as claimed in claims 22 to 38 wherein the organic solvent
employed in coating of release modulating polymer composition is selected
from ethyl alcohol, isopropyl alcohol, acetone and the like.
40. A process as claimed in claims 22 to 39 wherein the composition formed in
to pellets is compressed into tablet or encapsulated by conventional methods.
41. A process as claimed in claims 22 to 40 where in the filler employed in compressing the pellets into tablets are selected from anhydrous lactose, starch, microcrystalline cellulose, dicalcium phosphate anhydrous and the like.
42. A process as claimed in claims 22 to 41 where in the amount of filler employed in tablet ranges from 120.0 to 360.0 mg preferably from 160.0 to 280.0 mg per tablet.
43. A novel pharmaceutical formulation & process for the preparation which
releases active ingredient over an extended period for treating inflammatory
conditions and reducing pains substantially as here in described with reference
to the examples 1 to 11.

Documents:

155-mas-1999- abstract.pdf

155-mas-1999- claims duplicate.pdf

155-mas-1999- claims original.pdf

155-mas-1999- correspondence others.pdf

155-mas-1999- correspondence po.pdf

155-mas-1999- descripition complete duplicate.pdf

155-mas-1999- descripition complete original.pdf

155-mas-1999- descripition provisional.pdf

155-mas-1999- form 1.pdf

155-mas-1999- form 19.pdf

155-mas-1999- form 5.pdf

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Patent Number

204987

Indian Patent Application Number

155/MAS/1999

PG Journal Number

26/2007

Publication Date

29-Jun-2007

Grant Date

13-Mar-2007

Date of Filing

08-Feb-1999

Name of Patentee

NATCO PHARMA LIMITED

Applicant Address

NATCO Houce,Road No. 2, Banjara Hills, Hyderabad - 33,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	VENKATA RAO PAVULURI	NATCO PHARMA LIMITED,NATCO Houce,Road No. 2, Banjara Hills, Hyderabad - 33,INDIA.
2	KHADGAPATHI PODILI.	NATCO PHARMA LIMITED,NATCO Houce,,Road No. 2, Banjara Hills, Hyderabad - 33,,INDIA
3	RAMA RAO PENDYALA

PCT International Classification Number

A61K31/18

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA