Title of Invention

EXTENDED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING DILTIAZEM HCI

Abstract

The present invention relates to process for the preparation of novel stable extended release pharmaceutical compositions comprising upto about 80%w/w of Diltiazem HCI suitable for once a day dosing, the pharmaceutical composition being exempt of wetting agent in mixture with Diltiazem HCI. The extended release pharmaceutical composition exhibits pH independent in-vitro release profile in 900ml of distilled water / pH 6.8 phosphate buffer / 0.1N HCI / pH 4.5 acetate buffer at 100 rpm using USP type II apparatus. The preparation of the present invention is capable of being filled in capsule and comprise of pellets of single release profile.

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See Section 10) TITLE OF INVENTION "EXTENDED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING DILTIAZEM HCI" Themis Laboratories Private Limited, a company incorporated under the Companies Act, 1956 and having its corporate office Unit No. S-4, Khira Industrial Estate, B. M. Bhargava Road, Santacruz (West), Mumbai - 400 054, Maharashtra State, India an Indian Company The following specification particularly describes the nature of the invention and the manner in which it is to be performed. ORIGINAL 830/MUM/2003 GRANTED 19-6-2007 Field of the invention: This invention relates to process for preparation of novel stable extended release pharmaceutical compositions comprising Diltiazem salt such as Diltiazem HCI. Background of the invention: Diltiazem HCI, an anti-anginal agent blocks the influx of calcium ions in smooth and cardiac muscle, thus exhibiting potential cardiovascular activity. It also has negative chronotropic effect and negative ionotropic effect on heart muscles. Diltiazem HCI, being an acidic salt of basic drug is more soluble in acidic media and is freely soluble in water. The half-life of Diltiazem HCI is of the order of about 4 hours and is therefore recommended to be taken 3-4 times a day for effective therapy. Various attempts have been made to provide Diltiazem HCI in extended release composition to reduce the frequency of administration making it suitable for once daily administration. Extended release compositions comprising Diltiazem HCI that are intended to be administered for once a day dosing should ideally exhibit an in-vitro drug release profile of N.M.T 20% of Diltiazem HCI after 2 hours; N.M.T 50% of Diltiazem HCI after 4 hours; N.M.T 85% of Diltiazem HCI after 8 hours; and N.L.T. 70% of Diltiazem HCI after 16 hours Where "NMT" and "NLT" stands for "Not More Than" and "Not Less Than" respectively. U.S. Patents 5529791, 5288505, Canadian Patent application CA 2307547 and CA 2292247 discloses an extended release galenical bead compositions wherein Diltiazem HCI is mixed with wetting agents that are essential to maintain the solubility of Diltiazem HCI and being unaffected by the pH and other adverse conditions in Gl tract. The beads are coated with a microporous membrane comprising atleast a water-soluble or water dispersible polymer or copolymer and a water, acid and base insoluble polymer and pharmaceutically acceptable adjuvant. U.S. Patent 4960596 and Canadian Patent CA 1331740 describe a slow release acid free galenical microgranules preparation comprising an inert central core. These inert cores were wetted with polyvinylpyrrolidone solution and active substance was deposited until the granules were dried. The operation was repeated several times till the quantity of active substance has been used up. Thereafter the microgranules were coated with an outer membrane comprising a mixture of shellac, ethylcellulose and talc or aqueous suspension of ethylcellulose and dibutylsebacate. However, it is essential Further and other objects will be clear from the summary of the invention and detailed description of the invention thereof. Summary of the invention: The present invention relates to process for the preparation of novel stable extended release pharmaceutical compositions comprising Diltiazem salt such as Diltiazem HCI suitable for once a day dosing. Extended release pharmaceutical composition of the present invention is prepared in the form of extended release pellets comprising Diltiazem HCI. Extended release pellet comprises of drug core that contains drug layer deposited on inert core that are further coated with a polymer membrane. In contrast to the preparation disclosed in the prior art that comprises mixture of pellets to achieve the desired release profile for once a day dosing, the present invention discloses preparation of Diltiazem HCI containing pellets of single release profile and yet achieves the desired drug release profile that are suitable for once a day dosing. The extended release pharmaceutical compositions containing Diltiazem HCI comprises drug layer that is exempt of wetting agent and yet achieves the desired pH independent in - vitro drug release profile. This is in contrast to the compositions disclosed in U.S. Patents 5529791, US 5288505, Canadian Patent application CA 2307547 and CA 2292247 where use of wetting agent is essential for maintaining the solubility of Diltiazem HCI that is unaffected by the pH and other adverse conditions in Gl tract. Further, the extended release pharmaceutical composition of the present invention is also exempt of shellac thereby avoiding unnecessary precaution and needless additional drying and processing time thus making the product economical. Extended release pharmaceutical composition comprising Diltiazem HCI exhibits pH independent in-vitro drug release profile when analyzed in USP type II apparatus using 900ml of distilled water / 0.1N HCI / pH 4.5 acetate buffer / pH 6.8 phosphate buffer at 100 rpm. An extended release pellet prepared by the process of the present invention is capable of being encapsulated in sized capsules and is stable atleast for a period of 2 years. Brief Description of Drawing: Figure 1 is the graphical representation of drug release profile of extended release pellets comprising Diltiazem HCI in different media. Description: contrast to compositions disclosed in the prior art that are unsuitable for once a day dosing, the present invention relates to process for the preparation of novel stable extended release pharmaceutical compositions comprising Diltiazem salt such as Diltiazem HCI suitable for once a day dosing. Extended release pharmaceutical composition is prepared in the form of pellets and is capable of being filled into sized capsule. The preparation of the present invention contains pellets of single release profile. The preparation of the present invention achieves the desired pH independent in - vitro drug release profile suitable for once a day dosing. This is in particular contrast to the preparation disclosed in US Patent 5529790, US 5376384, Canadian Patent application CA 2110853 and CA 1327006 that requires mixture of pellets to achieve the desired in-vitro drug release profile. Extended release pharmaceutical pellet compositions of the present invention essentially comprises of drug core that are coated with a polymer membrane. Each drug core comprises of drug layer deposited on inert core. Each drug layer comprises of Diltiazem HCI, binder and optionally other pharmaceutical ingredients. Deposition of drug layer on inert cores is accomplished by layering or coating. Drug layer of the present invention is exempt of wetting agent and yet achieves the desired solubility thereby exhibiting pH independent in-vitro drug release profile which is in contrast to the prior art U.S. Patents 5529791, 5288505, Canadian Patent CA 2111085, Canadian Patent application CA 2307547 and CA 2292247 that essentially requires wetting agent in admixture with Diltiazem HCI to achieve the desired solubility unaffected by pH. In an embodiment of the invention, drug core is prepared by layering Diltiazem HCI optionally with other pharmaceutical ingredient alternating with binder as multiple layers on inert core. In another embodiment of the invention drug core is prepared by coating Diltiazem HCI, binder, antitack agent optionally with other pharmaceutical ingredient as single layer on inert core. The drug core is optionally further coated with binder and antitack agent to obtain hardened drug core. The drug core or the hardened drug core is further coated with a polymer membrane. The polymer membrane comprises of water insoluble polymer upto about 100% w/w of the polymer membrane, plasticizer from about 0% to about 30%w/w of the polymer membrane and pharmaceutically acceptable additive from about 0% to about 30%w/w of the polymer membrane. The thickness of the polymer membrane coated on drug core or hardened drug core is less than 50 microns, preferably less than 20 microns, more preferably less than 15 microns. Any equipment, suitable to the process described, for the preparation of extended release pellets comprising Diltiazem HCI can be utilized. Preferably the equipments are selected from coating pan, fluid bed processor preferably bottom spray, CF coater and the likes. The process can be carried out in single equipment or utilizes two or more equipments. Extended release pellets of the present invention are capable of being filled into sized capsule that delivers therapeutic effective dose of Diltiazem HCI and are suitable for once a day dosing. These extended release pellets filled in capsule exhibits pH independent in-vitro drug release profile in USP type II apparatus using 900ml of distilled water / pH 6.8 phosphate buffer/0.1N HCI/pH 4.5 acetate buffer at 100 rpm. Diltiazem HCI extended release pellets of the present invention is distinct from the prior art as it ■ is suitable for once a day dosing; ■ do not make use of wetting agent in admixture with Diltiazem HCI; ■ do not use shellac in the composition; ■ uses pellets of single release profile in the formulation; ■ contains polymer membrane having a thickness of preferably less than 20 microns; ■ is stable atleast for a period of two years; ■ uses from about 0% to about 30%w/w of filling material (talc) in polymeric membrane. Detailed Description of the Invention: The present invention relates to process for the preparation of stable novel extended release pharmaceutical pellet compositions comprising Diltiazem HCI suitable for once a day dosing wherein, a) the drug layer comprising Diltiazem HCI, binder and other pharmaceutical ingredient is deposited on inert core to obtain drug core, the drug layer being exempt of wetting agent; b) coating drug core with a polymer membrane comprising water insoluble polymer to obtain extended release pellets exhibiting pH independent in-vitro release profile at 100 rpm using USP type II apparatus. Extended release pellets of the present invention are capable of being filled into sized capsule and comprises pellets of single release profile. The pharmaceutical composition of the present invention is exempt of wetting agent in admixture with Diltiazem HCI and shellac. The process for preparing such compositions is described in the following two stages. Stage I: Preparation of Drug Core: The first stage in the preparation of extended release pellets comprising Diltiazem HCI is the preparation of drug core. Drug core according to the present invention is prepared by depositing drug layer comprising Diltiazem HCI on inert core. Deposition of drug layer is accomplished by layering or coating drug layer on inert core to obtain layered drug core or coated drug core respectively. Layered drug core comprise of alternate multiple layers of binder and drug blend comprising Diltiazem HCI and other pharmaceutical ingredients on inert core. This is achieved by spraying binder on inert core followed by layering drug blend of Diltiazem HCI and other pharmaceutical ingredients. This alternate process of spraying binder and layering drug blend is repeated several times till the drug blend is exhausted. The layered drug core is optionally further coated with binder and antitack agent to obtain hardened drug core. This is achieved by spraying suspension of binder and antitack agent in aqueous, alcoholic or hydroalcoholic media on drug core. Coated drug core comprise of coating Diltiazem HCI, binder, antitack agent and optionally other pharmaceutical ingredient as single layer on inert core. This is achieved by spraying dispersion containing Diltiazem HCI, binder, antitack agent and other pharmaceutical ingredient from aqueous, alcoholic or hydroalcoholic media. Drug core prepared by the present invention is in contrast to the prior art as it is exempt of wetting agent and shellac. Preparation of layered drug core comprise steps of: a) preparation of drug blend achieved by mixing Diltiazem HCI of particle size upto about 150 microns with other pharmaceutical ingredients other than wetting agent and shellac in a suitable mixer; b) preparation of binder dispersion or solution which is accomplished by dispersing and / or dissolving binder in a suitable solvent; c) spraying binder dispersion or solution on inert core followed by deposition of drug blend comprising Diltiazem HCI; d) repeating step c) till the drug blend is exhausted to obtain drug core; e) drying and sizing. The drug core after sizing is optionally coated with binder dispersion to obtain hardened drug core. The processing steps for the preparation of hardened drug core comprise of: a) preparation of binder dispersion or solution which is accomplished by dispersing and / or dissolving binder in a suitable solvent; b) addition of antitack agent to step a); c) spraying dispersion obtained in step b) on drug core to obtain hardened drug core: d) drying and sizing. Preparation of coated drug core comprise steps of: a) preparation of binder dispersion or solution which is accomplished by dispersing and / or dissolving binder in a suitable solvent; b) preparation of drug solution which is accomplished by dissolving Diltiazem HCI in a suitable solvent; c) mixing of binder dispersion or solution with drug solution; d) addition of other pharmaceutical ingredient preferably an antitack agent to the above mixture to obtain drug binder dispersion; e) spraying drug binder dispersion on inert core to achieve drug core; f) drying and sizing. The inert core used in the preparation of drug core can be made up of any pharmaceutically acceptable inert excipient and has an average particle size of 1680 microns to 250 microns preferably between 1000 microns to 500 microns. Preferably inert core is made up of sugar and starch. Other pharmaceutical ingredient used in the preparation of drug core is selected from diluents, antitack agents and their mixtures. Diluent used for the preparation of drug core is selected from the group of starch, starch derivatives, cellulose derivatives such as microcrystalline cellulose, glycols such as polyethylene glycol, cross linked povidone, crosslinked carboxymethyl cellulose and its sodium salt, natural gums and its derivatives such as sodium alginate, clays, alkali metal salts such as dibasic calcium phosphates, monobasic sodium phosphates, carbonates such as calcium carbonate and oxides of metal such as magnesium oxide and their mixtures, preferably starch. Antitack agent used in the preparation of drug core is selected from talc, colloidal silicon dioxide, stearates such as calcium stearate and magnesium stearate and their mixtures, preferably talc with or without colloidal silicon dioxide. Binder used in the preparation of drug core is selected from the group of cellulose derivatives such as cellulose ethers selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polymethacrylates natural gums, alginates and polyvinylpyrollidone, preferably hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose used as binder in the present invention has a nominal viscosity from about 3cps to about 18cps when measured at 2%w/w solution at 20 degree centigrade. Solvent used for dispersing and / or dissolving binder and drug is selected from water, alcohol and their mixtures, preferably water. The drug core or the hardened drug core so obtained are dried to achieve the moisture content of less than 5%w/w and preferably less than 3%w/w. Drying of drug core is accomplished in any suitable drier such as tray drier, fluid bed drier and the likes. Drug core or hardened drug core after drying are sifted through desired mesh to obtain drug core or hardened drug core of desired particle size. The drug core or the hardened drug core prepared by the process of the invention comprise of following ingredients, the percentage being expressed on weight basis of the final composition. Ingredients % w/w Inert core Upto about 60% Diltiazem HCI Upto about 80% Binder Upto about 15% Other Pharmaceutical Ingredient Upto about 15 % Preferably, the drug core or the hardened drug core comprise of following ingredients, the percentage being expressed on weight basis of the final composition. Ingredients % w/w Inert core About 10% to about 60% Diltiazem HCI About 30% to about 70% Binder About 2% to 12% Other Pharmaceutical Ingredient About 1.5% to 10% Stage II Preparation of Extended Release Pellets: The drug core or the hardened drug core prepared by the process of the invention is further processed to obtain extended release pellets comprising Diltiazem HCI. These extended release pellets are achieved by coating drug core or hardened drug core with a polymer membrane. The polymer membrane that extends the release of Diltiazem HCI from the drug layer comprises of water insoluble polymer, from about 0% to about 30% w/w of pharmaceutically acceptable additive and from about 0% to about 30%w/w of plasticizer, relative to the total weight of the polymer membrane. The thickness of the polymer membrane coated on drug core or hardened drug core is less than 50 microns, preferably less than 20 microns, more preferably less than 15 microns. Extended release pellets comprising Diltiazem HCI are achieved by spraying a solution or dispersion of water insoluble polymer, plasticizer and pharmaceutically acceptable additive from a suitable solvent on drug core or hardened drug core. Preparation of extended release pellets comprise steps of: a) dispersing or dissolving water insoluble polymer in a suitable solvent to obtain coating dispersion or solution; b) addition of plasticizer and / or pharmaceutically acceptable additive to step a); c) spraying the dispersion obtained in step b) on drug core or hardened drug core to obtain extended release pellets; d) drying and / or curing and sizing. Water insoluble polymer present in the polymer membrane is selected from polymethacrylates, cellulose derivatives such as cellulose ethers as listed in Handbook of Pharmaceutical Excipients, 2nd Edition, The Pharmaceutical Press, London, 1994. In particular, water insoluble polymer is selected from Poly(ethyl acrylate, methylmethacrylate) 2:1 marketed under the trade name of Eudragit RTM NE30D of Rohm Pharma, Germany, Poly(ethyl acrylate methylmethacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 marketed under the trade name of Eudragit RTM RL of Rohm Pharma, Germany, Poly(ethyl acrylate methylmethacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 marketed under the trade name of Eudragit RTM RS of Rohm Pharma, Germany, Poly(methacrylic acid, methyl methacrylate) 1:1 marketed under the trade name of Eudragit RTM L of Rohm Pharma, Germany, Poly(methacrylic acid, ethyl acrylate) 1:1 marketed under the trade name of Eudragit RTM L 30D - 55 and Eudragit RTM L100 -55 of Rohm Pharma, Germany, Poly(methacrylic acid, methyl methacrylate) 1:2 marketed under the trade name of Eudragit RTM S of Rohm Pharma, Germany, and ethylcellulose marketed under the trade name of Ethocel RTM of Dow, U.S.A., Aquacoat RTM of FMC, USA and Surelease RTM of Colorcon, USA, polyvinyl alcohol, polyvinyl acetate and cellulose acetate. This water insoluble polymer is coated on drug core or hardened drug core as a single layer and is used alone or in a suitable mixture. Alternatively, drug core or hardened drug core is coated with a water insoluble polymer/s in more than one layer wherein the polymer in different layers may be same or different. Plasticizer used in the polymer membrane is commonly used pharmaceutically acceptable plasticizer such as triacetin, triethylcitrate, dibutylsebacate, polyethylene glycol, miglyol, cetyl alcohol and their mixtures thereof. Pharmaceutical acceptable additive is preferably from one or more antitack agents and water soluble cellulose ether polymers. Antitack agents are selected from talc, colloidal silicon dioxide, stearates such as calcium stearate, magnesium stearate, glyceryl monostearate and glyceryl behenate and their mixtures preferably talc with or without colloidal silicon dioxide. Water soluble cellulose ethers polymers are selected from the hydroxyethylcellulose, carboxymethylcellulose and its pharmaceutically acceptable salts, hydroxypropylcellulose and hydroxypropylmethylcellulose preferably hydroxypropylmethylcellulose. Water insoluble polymer is dispersed and / or dissolved in a suitable solvent selected from water, alcohol, organic solvent/s and their suitable mixtures. In an embodiment of the invention the process for the preparation of extended release pellets comprising Diltiazem HCI is completely carried out using aqueous media. Alternatively, a part or whole process is carried out using water and / or alcohol and / or organic solvent/s. These extended release pellets comprising Diltiazem HCI are dried to achieve the moisture content of less than 5%w/w and preferably less than 3%w/w. Drying of these extended release pellets is accomplished in any suitable drier such as tray drier, fluid bed drier and the likes. Extended released pellets obtained by the process of the invention are sifted through desired mesh to obtain pellets of desired particle size. The polymer membrane of the extended release pellets comprising Diltiazem HCI prepared by the process of the invention comprise of following ingredients, the percentage being expressed on weight basis of the polymer membrane. Ingredients % w/w Water Insoluble Polymer Upto about 100% Plasticizer 0% to about 30% Pharmaceutical acceptable additive 0% to about 30% Preferably, the polymer membrane comprise of following ingredients, the percentage being expressed on weight basis of the polymer membrane. Ingredients % w/w Water Insoluble Polymer About 40% to about 95% Plasticizer 2.5% to about 30% Pharmaceutical acceptable additive 2.5% to about 30% The invention is now illustrated with a non-limiting example. Example 1 1.1 Preparation of drug binder dispersion: Water is poured into a stainless steel container and Diltiazem HCI (70%w/w) is added in small portion with stirring. Stirring is continued till a clear drug solution is obtained. Water is poured into second stainless container and Hydroxypropylmethylcellulose (HPMC) (5.25%w/w) is added in small portion with stirring. Stirring is continued till HPMC is completely dispersed and dissolved in water. The above two solution are mixed to obtain drug - binder solution and colloidal silicon dioxide (0.70%w/w) and talc (1.75%w/w) is added with stirring. The resulting dispersion is filtered through desired mesh. 1.2 Preparation of Drug core: Inert core are introduced in fluid bed bottom spray processor. The drug core is obtained by continuous spraying of the drug - binder dispersion on inert core. The drug core obtained is dried in the same equipment till the moisture content of drug core is less than 3% w/w. Drug core so obtained are sifted through desired mesh to remove any undersize and oversize drug core. 1.3 Preparation of Coating Solution or Dispersion: Methanol and Methylene chloride is poured in a stainless steel container and ethylcellulose (3.76%w/w) is added in small portions with stirring. Stirring is continued till a clear. coating solution is obtained. Triacetin (0.37%w/w) is slowly added with stirring in the coating solution and the resulting solution is filtered to through desired mesh. Alternatively, aqueous dispersion of ethylcellulose (3.76% w/w) can also be used for the preparation of extended release pellets comprising Diltiazem HCI. In that case aqueous dispersion of ethylcellulose is poured in stainless steel container and water is added in small portions with stirring. Talc is added with stirring and the resulting dispersion is filtered through desired mesh. 1.4 Preparation of Extended Release Pellets: Drug core obtained are introduced in fluid bed bottom spray processor and they are coated with the coating dispersion obtained above to obtain extended release pellets. These extended release pellets are dried in the same equipment till the moisture content of these pellets is less than 3% w/w. These pellets alternatively may be cured at about 40°C for about 12-24 hours. Extended release pellets so obtained are sifted through desired mesh to remove any undersize and oversize drug core. Final composition of pellets comprising Diltiazem HCI expressed in percentage weight by weight of the final composition is listed below. Ingredients Ex. 1 (%w/w) Inert core (25 - 30# ASTM) 18.17 Diltiazem HCI 70.00 HPMC 5.25 Talc 1.75 Colloidal Silicon Dioxide 0.70 Ethylcellulose 3.76 Triacetin 0.37 Water * QS Methanol * QS Dichloromethane * QS * Evaporated during the process QS - Quantity Sufficient Example 2 2.1 Preparation Of Drug Blend: Diltiazem HCI (70%w/w) (200 mesh A.S.T.M.) and Talc (6.54%w/w) was passed through desired mesh and are placed in a planetary mixer. Mixing is carried but for 10 minutes with intermittent racking to obtain drug blend. 2.2 Preparation of Binder Solution: Water is poured into a stainless steel container and Hydroxypropylmethylcellulose (HPMC) (4.10%w/w) is added in small portion with stirring. Stirring is continued till HPMC is completely dispersed and dissolved in water. 2.3 Preparation of Drug Core: Inert core are introduced in coating pan. The drug core is obtained by alternate spraying of the binder solution on inert core followed by deposition of drug blend. This process of alternate spraying of binder solution and deposition of drug blend is repeated several times to completely deposit the drug blend. The drug core obtained is dried in tray drier to achieve moisture content of less than 3% w/w. Drug core so obtained are sifted through desired mesh to remove any undersize and oversize drug core. 2.4 Preparation of Hardened Drug Core: Binder solution is prepared as described in 2.2. Talc is added to this solution. Resulting dispersion is filtered through desired mesh and is sprayed on drug core in coating pan to obtain hardened drug core. Hardened drug core so obtained are dried and sifted as described above. 2.5 Preparation of Coating Solution or Dispersion: Coating solution or dispersion is prepared as described in 1.3 2.6 Preparation of Extended Release Pellets: Extended release pellets comprising Diltiazem HCI is prepared as described in 1.4. Final composition of pellets comprising Diltiazem HCI expressed in percentage weight by weight of the final composition is listed below. Ingredients Ex. 2 (%w/w) Inert core (25 - 30# ASTM) 13.53 Diltiazem HCI 70.00 HPMC 4.10 Talc 6.54 Ethylcellulose 5.30 Triacetin 0.53 Water * QS Methanol * QS Dichloromethane * QS * Evaporated during the process QS - Quantity Sufficient Example 3-4 Extended release pellets comprising Diltiazem HCI is prepared as described in example 1. Ingredients Ex.3 (% w/w) Ex.4 (% w/w) Inert core (25 - 30# ASTM) 18.17 51.77 Diltiazem HCI 70.00 36.30 HPMCE15 5.25 3.63 Talc 2.12 0.91 Starch - 1.82 Colloidal Silicon Dioxide 0.70 0.36 Ethylcellulose - 4.74 Aqueous dispersion of Ethyl . 3.76 cellulose (solid content) Triacetin - 0.47 Water * QS QS Methanol * - QS Dichloromethane * . QS *Evaporated during the process Dissolution Studies: The extended release pellets comprising Diltiazem HCI is analyzed in-vitro at 100rpm in USP apparatus, Type I or Type II in 900 ml distilled water / pH 6.8 phosphate buffer / 0.1N HCI / pH 4.5 acetate buffer at 100 rpm. The specification of acceptable drug release profile of Diltiazem HCI extended release pellets is given below in table I. Table I: Drug release profile of Diltiazem HCI extended release pellets Time (hours) Mean % Drug Release 2 N.M.T. 20 4 N.M.T. 50 8 N.M.T. 85 16 N.L.T. 70 Preferably the acceptable drug release profile of Diltiazem HCI extended release pellets is given in table II. Table II: Preferable drug release profile of Diltiazem HCI extended release pellets Time (hours) Mean % Drug Release 2 N.M.T. 15% 4 about 15%-about 45% 8 about 50% - about 85% 16 N.L.T. 75% The pellets prepared as per example 1 of the present invention is analyzed in-vitro in USP Type II apparatus using 900ml of distilled water / pH 6.8 phosphate buffer / 0.1N HCI / pH 4.5 acetate buffer at 100 rpm. The drug release profile of these pellets is different media is depicted in the figure I. It is evident from the figure I that cumulative mean % drug release from the extended release pellets comprising Diltiazem HCI is substantially same irrespective of the pH of the media in which it is analyzed. In other words Diltiazem HCI extended release pellets exhibits pH independent in - vitro drug release profile with a maximum variation of less than 20% and preferably less than 15%. If the extended release pellets comprising Diltiazem HCI releases drug too fast to comply the desired in-vitro dissolution profile, it may receive an additional coat to achieve the desired in-vitro dissolution profile. Extended release pellets comprising Diltiazem HCI complying with the desired dissolution profile is filled in capsule to deliver the therapeutic dose of Diltiazem HCI. Extended release pellets comprising Diltiazem HCI are filled into sized capsule to deliver the therapeutic dose of about 90mg, 120mg, 180mg, 240mg, 300mg, 360mg and 420mg. The extended release pellets filled in capsule are stable atleast for a period of 6months at 40 degree centigrade and 75% relative humidity indicating that the formulation can be assigned a shelf life of 24 months at room temperature. A bioequivalent studies was carried out using Diltiazem HCI extended release capsule 120mg prepared by the process of the invention against Tizac extended release capsule RTM 120 mg of Biovail as reference product. Extended release capsule containing Diltiazem HCl120 mg was found to be bioequivalent to reference product. Claims: We claim 1. A stable extended release pharmaceutical composition comprising Diltiazem HCI for once a day dosing wherein, the composition comprises of: a) an inert core, preferably made up of sugar and starch; b) a drug layer comprising of Diltiazem HCI, binder and anti-tack agent layered or coated on the inert core to obtain drug core; c) optionally coating drug core with binder and anti-tack agent to obtain hardened drug core; d) coating drug core or hardened drug core with a polymer membrane comprising of a water insoluble polymer to obtain extended release composition; said drug layer is exempt of wetting agent and the said composition is exempt of shellac. 2. A composition as claimed in claim 1 wherein, Diltiazem HCI is up to 80%w/w of the composition; binder is selected from the group of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polymethacrylates, natural gums, alginates and polyvinylpyrollidone, preferably hydroxypropylmethylcellulose up to 15%w/w, more preferably from 2%w/w to 12%w/w of the composition; anti-tack agent is selected from talc, colloidal silicon dioxide, stearate such as calcium stearate, magnesium stearate and mixtures thereof, preferably up to 15%w/w, more preferably from 1.5%w/w to 10%w/w of the composition; 3. A composition as claimed in claim 1 wherein, water insoluble polymer is selected from group of cellulose derivatives, polymethacrylates and mixtures thereof, preferably ethylcellulose up to 100%w/w, more preferably from 40%w/w to 95%w/w of the polymer membrane. 4. A composition as claimed in claim 1 wherein, the polymer membrane further comprises plasticizer selected from triacetin, triethylcitrate, dibutylsebacate, polyethylene glycol, miglyol, cetyl alcohol and mixtures thereof, preferably triacetin from 2.5%w/w to 30%w/w of the polymer membrane. 5. A composition as claimed in claim 1 wherein, the polymer membrane further comprises anti-tack agent selected from talc, colloidal silicon dioxide, stearates such as calcium stearate, magnesium stearate and mixtures thereof, preferably talc from 2.5%w/w to 30%w/w of the polymer membrane. 6. A process for the preparation of stable extended release pharmaceutical composition comprising Diltiazem HCI for once a day dosing, comprises steps of: a) preparation of drug core by layering a mixture of Diltiazem HCI, anti-tack agent and / or diluent alternating with binder dispersion or solution on an inert core; or preparation of drug core by spraying the dispersion or solution comprising Diltiazem HCI, binder, anti-tack agent and / or diluent on an inert core; b) optionally coating the drug core with binder to obtained hardened drug core; c) coating drug core or hardened drug core with water insoluble polymer using solvent selected from the group of alcohol, organic solvent/s, water and mixtures thereof to obtain extended release pellets; the drug layer is exempt of wetting agent and the composition is exempt of shellac. 7. A process as claimed in claim 6, wherein the preparation of layered drug core comprise steps of: a) preparation of drug blend by mixing Diltiazem HCI with anti-tack agent and / or diluent in a mixer; b) preparation of binder dispersion or solution by dispersing and / or dissolving binder in a solvent selected from the group of alcohol, water and mixtures thereof; c) spraying binder dispersion or solution on inert core followed by deposition of drug blend comprising Diltiazem HCI; d) repeating step c) till the drug blend is exhausted to obtain drug core; e) drying and sizing. 8. A process as claimed in claim 6, wherein the preparation of coated drug core comprise steps of: a) preparation of binder dispersion or solution by dispersing and / or dissolving binder in a solvent selected from the group of alcohol, water and mixtures thereof; b) preparation of drug solution by dissolving Diltiazem HCI in a solvent selected from the group of alcohol, water and mixtures thereof; c) mixing of binder dispersion or solution with drug solution; d) addition of anti-tack agent(s) and / or diluent to the above mixture to obtain drug binder dispersion; e) spraying drug binder dispersion on inert core to achieve drug core; f) drying and sizing. 9. A process as claimed in claim 6, wherein the preparation of hardened drug core comprise steps of: a) preparation of binder dispersion or solution which is accomplished by dispersing and / or dissolving binder in a solvent selected from the group of alcohol, water and mixtures thereof; b) addition of anti-tack agent to the dispersion; c) spraying dispersion on drug core to obtain hardened drug core; d) drying and sizing. 10. A process as claimed in claim 6, wherein the preparation of extended release pellets comprising Diltiazem HCI comprises step of deposition of polymer membrane which comprise steps of: a) dispersing or dissolving water insoluble polymer in a solvent selected from the group of alcohol, organic solvent/s, water and mixtures thereof to obtain coating dispersion or solution; b) optionally adding plasticizer up to 30%w/w of the polymer membrane; c) optionally adding anti-tack agent up to 30%w/w of the polymer membrane; d) spraying the resulting dispersion on drug core or hardened drug core to obtain extended release pellets; e) drying, optionally curing and sizing. Dated this 27th day of July 2004 Dr. Prabuddha Ganguli (Patent Agent on,record);

Documents:

830-mum-2003-abstract(28-7-2004).doc

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830-mum-2003-cancelled pages(19-6-2007).pdf

830-mum-2003-claims(granted)-(19-6-2007).doc

830-mum-2003-claims(granted)-(19-6-2007).pdf

830-mum-2003-correspondence(19-6-2007).pdf

830-mum-2003-correspondence(ipo)-(13-7-2007).pdf

830-mum-2003-drawing(28-7-2004).pdf

830-mum-2003-form 1(19-6-2007).pdf

830-mum-2003-form 1(28-7-2004).pdf

830-mum-2003-form 13(4-5-2007).pdf

830-mum-2003-form 19(28-7-2004).pdf

830-mum-2003-form 2(granted)-(19-6-2007).doc

830-mum-2003-form 2(granted)-(19-6-2007).pdf

830-mum-2003-form 3(14-2-2005).pdf

830-mum-2003-form 3(18-8-2003).pdf

830-mum-2003-form 3(23-9-2004).pdf

830-mum-2003-form 3(28-7-2004).pdf

830-mum-2003-form 3(4-8-2005).pdf

830-mum-2003-form 5(18-8-2003).pdf

830-mum-2003-form 5(28-7-2004).pdf

830-mum-2003-form-pct-isa-210(19-8-2003).pdf

830-mum-2003-power of attorney(18-8-2003).pdf

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