Title of Invention

PROCESS FOR THE PREPARATION OF A STABLE ORAL ANTIDIABETIC FORMULATION OF GLIPIZIDE AND METFORMIN HYDROCHLORIDE

Abstract

Stable oral antidiabetic formulation of glipizide and metformin hydrochloride comprising inclusion complex of glipizide with cyclodextrin and non-ionic surfactant.Also process for the preparation of the formulation which comprises dry mixing metformin hydrochloride and inclusion complex of glipizide with cyclodextrin and non-ionic surfactant and pharmaceutically acceptable excipients.The formulation may be converted into solid dosage forms,if desired.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2005 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION Process for the preparation of a stable oral antidiabetic formulation of glipizide and metformin hydrochloride. APPLICANTS Name: USV Limited Nationality: Indian Address : BSD Marg, Govandi, Mumbai 400088, Maharashtra, India PREAMBLE TO THE DESCRIPTION The following specification particularly describes the nature of this invention and the manner in which it is to be performed FIELD OF INVENTION This invention relates to a process for the preparation of stable oral antidiabetic formulation of glipizide and metformin hydrochloride. PRIOR ART Glipizide is an oral antihyperglycemic drug of sulfonylurea class used in the treatment of type 2 diabetes ie non-insulin dependent diabetes mellitus (NIDDM). Glipizide has the chemical name l-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido) ethyl]phenyl] sulfonyl] urea, molecular formula C21H27N5O4S and molecular weight 445.55. Glipizide has a pKa of 5.9 and is insoluble in water and alcohol but soluble in 0. IN NaOH. Metformin hydrochloride is a biguanide class of oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride whose chemical name is (N,N-dimethylimidodicarbonimidic diamide mono-hydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It has a molecular formula of C4H12C1N5 (monohydrochloride) and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform. Metformin has a pKa of 12.4. Glipizide is known to lower blood glucose acutely by stimulating the release of insulin from the pancreas, whereas metformin hydrochloride is known to improve glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. US Patent No 6,011,049 describes the use of a combination of a glitazone antidiabetic agent and a biguanide antidiabetic agent and optionally a sulfonylurea antidiabetic agent for treating diabetes mellitus and improving glycemic control. Glipizide being a sulfonylurea class is sensitive to degradation in the presence of acidic compounds like metformin hydrochloride with generation of impurities, mainly "Glipizide Related Compound A" chemically known as [N-{2-[(4-aminosulfonyl)phenyl]ethyl}-5-methyl-pyrazinecarboxamide]. Degradation of glipizide is more pronounced at higher storage temperature because of which a high limit of 2% of impurity is allowed for Glipizide tablet in United States Pharmacopoeia 2003 (USP 26, page no. 859). Glipizide and metformin HC1 Tablets of Bristol-Myers Squibb, USA recently marketed under the brand name "Metalglip" are advised to be stored at low temperatures like 20°C - 25°C. In tropical countries like India the average temperature at most of the places most of the time is around 30°C. Therefore such drugs are likely to show pronounced degradation at such tropical climatic conditions. The "Metalglip" tablets comprise plain glipizide. OBJECTS OF INVENTION An object of the invention is to provide a stable oral antidiabetic formulation of glipizide and metformin hydrochloride having improved storage life even at high temperatures. Another object of the invention is to provide a stable oral antidiabetic formulation of glipizide and metformin hydrochloride having improved storage life even at high temperatures which is suitable for use in tropical conditions like in India. Another object of the invention is to provide a process for the preparation of a stable oral antidiabetic formulation of glipizide and metformin hydrochloride having improved storage life even at high temperatures. Another object of the invention is to provide a process for the preparation of a stable oral antidiabetic formulation of glipizide and metformin hydrochloride having improved storage life even at high temperatures which is suitable for use in tropical conditions like in India Another object of the invention is to provide a process for the preparation of a stable oral antidiabetic formulation of glipizide and metformin hydrochloride having improved storage life even at high temperatures, which is simple and easy and economical to carry out and which is suitable for carrying out on a commercial scale. DETAILED DESCRIPTION OF THE INVENTION According to the invention there is provided a stable oral antidiabetic formulation of 2.5 to 40 mg glipizide and 250 to 2000 mg metformin hydrochloride in combination with pharmaceutically acceptable excipients, wherein the glipizide is in the form of an inclusion complex with cyclodextrin and non-ionic surfactant. According to the invention there is also provided process for the preparation of a stable oral antidiabetic formulation of glipizide and metformin hydrochloride comprising dry mixing 250 - 2000 mg metformin hydrochloride and inclusion complex of 2.5 - 40 mg glipizide with cyclodextrin and non-ionic surfactant and excipients and optionally converting the formulation into solid dosage forms in known manner. The inclusion complex of glipizide may be prepared in accordance with the procedure described in our US Patent No. 6,464,988B1. The term cyclodextrin includes its derivatives and may be alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, or alkyl or hydroxy alkyl derivatives thereof. Preferably cyclodextrin may be beta cyclodextrin, gamma cyclodextrin, hydroxypropyl beta cyclodextrin and/or randomly methylated beta cyclodextrin. The non-ionic surfactant may be any pharmaceutically acceptable non-ionic surfactant such as polyoxyl nonionic surfactant, preferably polyoxyl-40-castor oil, polyoxyethylene-20-stearyl ether, polyoxyl-35-castor oil, polyoxyethylene-20-sorbitan monooleate or polyoxyethylene-20-sorbitan monolaurate. Immediate release form of metformin hydrochloride may be prepared by techniques commonly known in the art. Sustained release form of metformin hydrochloride may be prepared in accordance with the process described in our PCT publication No. WO 02/28181 Al or any other process known in the art. The pharmaceutically acceptable excipients include excipients commonly used in pharmaceutical formulations and may be, for example, diluents, such as lactose, maltodextrin, dicalcium phosphate, tricalcium phosphate, calcium carbonate, microcrystalline cellulose, starch or sucrose, binders such as polyvinyl pyrrolidone, starch, gelatin or acacia, glidants or lubricants such as colloidal silicone dioxide, talc, glyceryl behenate, magnesium stearate or hydrogenated vegetable oil or disintegrants such as sodium starch glycolate, crosspovidone, cross carmellose sodium or starch alginic acid. The solid dosage forms may be tablets optionally film coated, capsules or dry powder formulated in known manner. The tablets may be single layer tablets or bilayer tablets comprising a first layer of sustained release metformin granules optionally mixed with excepients and a second layer of mixture of glipizide-cyclodextrin inclusion complex with excepients. The inclusion complex of glipizide and metformin hydrochloride may be dry mixed in granular forms prepared in known manner. The following examples illustrate the invention but do not limit the scope thereof. Example 1: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 μm) was wetted with the solution (rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 μm was added and further mixed in the high shear mixer for 1 hour,(Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil :: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin, and polyoxyl-40-castor oil. 400 gm of polyvinylpyrrolidone was mixed with 400 gm purified water and heated to 80 - 90°C . 100 gm of rnaize starch was dispersed in 150 gm of purified water and the slurry was added to the hot polyvinylpyrrolidone solution and mixed to get uniform paste. 5000 gm of metformin hydrochloride and 200 gm of sodium starch glycolate were mixed and granulated. The polyvinylpyrrolidone-starch paste was added to the granules and the wet mass was further granulated. The granules of immediate release metformin hydrochloride were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 70 gm of colloidal silicone dioxide and 30 gm of magnesium stearate. The granule mix was pressed into tablets containing metfonnin.hydrochloride 500 mg and glipizide 5 mg and coated with 0.85% hydroxypropyl cellulose Example 2: Polyoxyl-40-castor oil (5 gm) was dissolved in rectified spirit (57.5 ml). Beta cyclodextrin (130 gm, particle size 10-70μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (25 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil:: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl- 40-castor oil. 400 gm of polyvinylpyrrolidone was mixed with 400 gm purified water and heated to 80 - 90°C. 100 gm of maize starch was dispersed in 150 gm of purified water and the slurry was added to the hot polyvinylpyrrolidone solution and mixed to get uniform paste. 5000 gm of metformin hydrochloride and 200 gm of sodium starch glycolate were mixed and granulated. The polyvinylpyrrolidone-starch paste was added to the granules and the wet mass was further granulated. The granules of immediate release metformin hydrochloride were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 70 gm of colloidal silicone dioxide and 30 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 500 mg and glipizide 2.5mg and coated with 0.85% hydroxypropyl cellulose. Example 3: Polyoxyl-40-castor oil (2.5 gm) was dissolved in rectified spirit (28.75 ml). Beta cyclodextrin (65 gm, particle size 10-70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (12.5 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil:: .1 : 0.2), The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl- 40-castor oil. 400 gm of polyvinylpyrrolidone was mixed with 400 gm purified water and heated to 80 - 90°C. 100 gm of maize starch was dispersed in 150 gm of purified water and the slurry was added to the hot polyvinylpyrrolidone solution and mixed to get uniform paste. 5000 gm of metformin hydrochloride and 200 gm of sodium starch glycolate were mixed and granulated. The polyvinylpyrrolidone-starch paste was added to the granules and the wet mass was further granulated. The granules of immediate release metformin hydrochloride were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 70 gm of colloidal silicone dioxide and 30 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 500 mg and glipizide 1.25 mg and coated with 0.85% hydroxypropyl cellulose. Example 4: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 urn) was wetted with the solution (rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 urn was added and mixed in the high shear mixer for 1 hour (Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil :: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil. 680 gm of polyvinylpyrrolidone was mixed with 680 gm purified water and heated to 80 - 90°C. 170 gm of maize starch was dispersed in 255 gm of purified water and the slurry was added to the hot polyvinylpyrrolidone solution and mixed to get uniform paste. 8500 gm of metformin hydrochloride and 340 gm of sodium starch glycolate were mixed and granulated. The polyvinylpyrrolidone-starch paste was added to the granules and the wet mass was further granulated. The granules of immediate release metformin hydrochloride were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 119 gm of colloidal silicone dioxide and 51 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 850 mg and glipizide 5 mg and coated with 0.85% hydroxypropyl cellulose. Example 5: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 μm) was wetted with the solution (rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour (Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil :: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl- 40-castor oil. 800 gm of polyvinylpyrrolidone was mixed with 800 gm purified water and heated to 80 - 90°C. 200 gm of maize starch was dispersed in 300 gm of purified water and the slurry was added to the hot polyvinylpyrrolidone solution and mixed to get uniform paste. 10000 gm of metformin hydrochloride and 400 gm of sodium starch glycolate were mixed and granulated. The polyvinylpyrrolidone-starch paste was added to the granules and the wet mass was further granulated. The granules of immediate release metformin hydrochloride were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 140 gm of colloidal silicone dioxide and 60 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 1000 mg and glipizide 5 mg and coated with 0.85% hydroxypropyl cellulose. Example 6: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 urn was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil:: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil. 150 gm of starch was mixed with 175 gm purified water and the slurry was added to 690 ml of hot water (heated to 80 - 90°C) to form starch paste. 5000 gm of metformin hydrochloride, 50 gm of sodium starch glycolate and 470 gm of microcrystalline cellulose were mixed and granulated. The starch paste was added to the granules and the wet mass was further granulated. The granules of immediate release metformin were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 40 gm of colloidal silicone dioxide, 50 gm of sodium starch glycolate, 160 gm of starch, 50 gm of talc and 40 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 500 mg and glipizide 5 mg. Example 7: Polyoxyl-40-castor oil (5 gm) was dissolved in rectified spirit (57.5 ml). Beta cyclodextrin (130 gm, particle size 10 - 70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (25 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil :: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil. 150 gm of starch was mixed with 175 gm purified water and the slurry was added to 690 ml of hot water (heated to 80 - 90°C) to form starch paste. 5000 gm of metformin hydrochloride, 50 gm of sodium starch glycolate and 470 gm of microcrystalline cellulose were mixed and granulated. The starch paste was added to the granules and the wet mass was further granulated, The granules of metformin hydrochloride in immediate release form were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 40 gm of colloidal silicone dioxide, 50 gm of sodium starch glycolate, 160 gm of starch, 50 gm of talc and 40 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 500 mg and glipizide 2.5 mg. Example 8: Polyoxyl-40-castor oil (2.5 gm) was dissolved in rectified spirit (28.75 ml). Beta cyclodextrin (65 gm, particle size 10-70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (12.5 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil :: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil. 150 gm of starch was mixed with 175 gm purified water and the slurry was added to 690 ml of hot water (heated to 80 - 90°C ) to form starch paste. 5000 gm of metformin hydrochloride, 50 gm of sodium starch glycolate and 470 gm of microcrystalline cellulose were mixed and granulated. The starch paste was added to the granules and the wet mass was further granulated. The granules of metformin hydrochloride in immediate release form were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 40 gm of colloidal silicone dioxide, 50 gm of sodium starch glycolate, 160 gm of starch, 50 gm of talc and 40 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 500 mg and glipizide 1.25 mg. Example 9: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil:: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil. 255 gm of starch was mixed with 298 gm purified water and the slurry was added to 1170 ml of hot water (heated to 80 - 90°C) to form starch paste. 8500 gm of metformin hydrochloride, 85 gm of sodium starch glycolate and 799 gm of microcrystalline cellulose were mixed and granulated. The starch paste was added to the granulates and the wet mass was further granulated. The granules of metformin hydrochloride in immediate release form were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 68 gm of colloidal silicone dioxide, 85 gm of sodium starch glycolate, 272 gm of starch, 85 gm of talc and 68 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 850 mg and glipizide 5 mg. Example 10: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil :: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil. 300 gm of starch was mixed with 350 gm purified water and the slurry was added to 1380 ml of hot water (heated to 80 - 90°C) to form starch paste. 10000 gm of metformin hydrochloride, 100 gm of sodium starch glycolate and 940 gm of microcrystalline cellulose were mixed and granulated. The starch paste was added to the granules and the wet mass was further granulated. The granules of metformin hydrochloride in immediate release form were dried and sized by using 16-mesh sieve. Metformin granules and glipizide granules were mixed with 80 gm of colloidal silicone dioxide, 100 gm of sodium starch glycolate, 320 gm of starch, 100 gm of talc and 80 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 1000 mg and glipizide 5 mg. Example 11: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil:: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get a solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil which was passed through 60 mesh sieve and mixed with 1091 mg of lactose granules, 150 gm of microcrystalline cellulose, 100 gm of sodium starch glycolate, 50 gm of sodium lauryl sulphate, 100 gm of crosspovidone, 10 gm of colloidal silicone dioxide and 10 gm of magnesium stearate to form a granule mixture. 1460 gm of stearic acid was melted at 70°C . 5000 gm metformin hydrochloride was heated to 70°C and granulated with the stearic acid melt at 70°C. After granulation, the granulate mass was mixed continuously with gradual cooling to room temperature. 400 gm of shellac and 60 gm of polyvinyl pyrollidone were dissolved in 660 gm of isopropyl alcohol. The solution was gradually added to the metformin stearic acid granulate and mixed till dough mass formed, which was dried at 45°C for 2 hours and sized through 2.4 mm screen to break the agglomerates. The granules of metformin hydrochloride in sustained release form (1310 gm) were blended with 20 gm of colloidal silicone dioxide and 40 gm of magnesium stearate.. Metformin granules and Glipizide granules were compressed into bilayer tablets of metformin hydrochloride 500 mg(top layer) and glipizide 5 mg (bottom layer). Example 12: Polyoxyl-40-castor oil (5 gm) was dissolved in rectified spirit (57.5 ml). Beta cyclodextrin (130 gm, particle size 10 - 70 urn) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (25 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil:: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil which was passed through 60 mesh sieve and mixed with 1251 mg of lactose granules, 150 gm of microcrystalline cellulose, 100 gm of sodium starch glycolate, 50 gm of sodium lauryl sulphate, 100 gm of crosspovidone, 10 gm of colloidal silicone dioxide and 10 gm of magnesium stearate to form a granule mixture. 1460 gm of stearic acid was melted at 70°C. 5000 gm metformin hydrochloride was heated to 70°C and granulated with the stearic acid melt at 70°C. After granulation, the granulate mass was mixed continuously with gradual cooling to room temperature. 400 gm of shellac and 60 gm of polyvinyl pyrollidone were dissolved in 660 gm of isopropyl alcohol. The solution was gradually added to the metformin stearic acid granulate and mixed till dough mass formed, which was dried at 45 °C for 2 hours and sized through 2.4 mm screen to break the agglomerates. The granules of metformin hydrochloride in sustained release form (1310 gm) were blended with 20 gm of colloidal silicone dioxide and 40 gm of magnesium stearate.. Metformin granules and Glipizide granules were compressed into bilayer tablets containing metformin hydrochloride 500 mg (top layer) and glipizide 2.5 mg (bottom layer). Example 13: Polyoxyl-40-castor oil (10 gm) was dissolved in rectified spirit (115 ml). Beta cyclodextrin (260 gm, particle size 10-70 μm) was wetted with the solution ( rectified spirit : beta cyclodextrin :: 1 : 2.26) and further mixed in a high shear mixer. To the semisolid mixture, glipizide (50 gm) milled to a particle size of 2 to 40 μm was added and mixed in the high shear mixer for 1 hour ( Glipizide : beta cyclodextrin :: 1 : 2, glipizide : polyoxyl-40-castor oil:: 1 : 0.2). The resulting semisolid mass was dried at 40 - 60°C to get solid inclusion complex of glipizide with beta cyclodextrin and polyoxyl-40-castor oil which was passed through 60 mesh sieve and mixed with 1091 mg of lactose granules, 150 gm of microcrystalline cellulose, 100 gm of sodium starch glycolate, 50 gm of sodium lauryl sulphate, 100 gm of crosspovidone, 10 gm of colloidal silicone dioxide and 10 gm of magnesium stearate to form a granule mixture. 2250 gm of stearic acid was melted at 70°C. 10000 gm metformin hydrochloride was heated to 70°C and granulated with the stearic acid melt at 70°C. After granulation the granulate mass was mixed continuously with gradual cooling to room temperature. 600 gm of shellac and 250 gm of polyvinyl pyrollidone were dissolved in 1500 gm of isopropyl alcohol. The solution was gradually added to the metformin stearic acid granulate and mixed till a dough mass formed, which was dried at 45 °C for 2 hours and sized through 2.4 mm screen to break the agglomerates. The granules of metformin hydrochloride in sustained release form were blended with 40 gm of colloidal silicone dioxide and 80 gm of magnesium stearate.. Metformin granules and Glipizide granules were compressed into bilayer tablets containing metformin hydrochloride 1000 mg (top layer) and glipizide 5 mg (bottom layer). Example 14: 400 gm of polyvinylpyrrolidone was mixed with 400 gm purified water and heated to 80 - 90°C. 100 gm of maize starch was dispersed in 150 gm of purified water and the slurry was added to the hot polyvinylpyrrolidone solution and mixed to get uniform paste. 5000 gm of metformin hydrochloride and 200 gm of sodium starch glycolate were mixed and granulated. The polyvinylpyrrolidone-starch paste was added to the granules and the wet mass was further granulated. The granules of metformin hydrochloride in immediate release form were dried and sized by using 16-mesh sieve. Metformin granules were mixed with 50 gm of glipizide,70 gm of colloidal silicone dioxide and 30 gm of magnesium stearate. The granule mix was pressed into tablets containing metformin hydrochloride 500 mg and glipizide 5 mg and coated with 0.85% hydroxypropyl cellulose. Stability study: Stability studies of tablets of Examples 1,6, 11 and 14 were carried out to evaluate degradation of glipizide and generation of impurities, mainly "glipizide impurity A" chemically known as [N-{2-[(4-aminosulfonyl)phenyl]ethyl}-5-methyl-pyrazinecarboxamide] over prolonged storage at room temperature and at higher temperatures. The impurity analysis was done using the gradient HPLC (High Pressure Liquid Chromatography) system equipped with 250 X 4.6 mm, C18, 5 μm column and mobile phase of NaH2P04 buffer pH 6.0 : THF (500 :10) with Methanol and UV detector to estimate the percentage of impurity generation. The results were as shown in the following Tables: Table 1: Tablets stored at room temperature % impurity generated with respect to glipizide Initial After 3 months After 6 months After 18 months Example 1 impurity A 0.098 0.102 0.110 0.176 Total RS* 0.122 0.130 0.144 0.201 Example 6 impurity A 0.095 0.103 0.112 0.177 Total RS* 0.126 0.138 0.152 0.217 Example 11 impurity A 0.099 0.104 0.115 0.180 Total RS* 0.125 0.146 0.154 0.222 Example 14 impurity A 0.094 0.236 0.514 1.987 Total RS* 0.121 0.136 0.148 0.215 *RS = Related substances Table 2: Tablets stored at 45 C % impurity generated with respect to glipizide Initial After 3 months After 6 months Example 1 impurity A 0.098 0.185 0.268 Total RS* 0.122 0.212 0.311 Example 6 impurity A 0.095 0.188 0.271 Total RS* 0.126 0.216 0.324 Example 11 impurity A 0.099 0.185 0.259 Total RS* 0.125 0.218 0.325 Example 14 impurity A 0.094 0.896 1.756 Total RS* 0.121 1.021 1.974 * RS = Related Substances Table 3: Tablets stored at 40°C with 75% humidity % impurity generated with respect to glipizide Initial After 3 months After 6 months Example 1 impurity A 0.098 0.177 0.242 Total RS* 0.122 0.208 0.298 Example 6 impurity A 0.095 0.180 0.268 Total RS* 0.126 0.211 0.317 Example 11 impurity A 0.099 0.178 0.240 Total RS* 0.125 0.213 0.315 Example 14 impurity A 0.094 0.984 2.001 Total RS* 0.121 1.261 2.156 *RS = Related Substances The Tables 1 to 3 clearly establish that the percentagesof impurities generated over prolonged storage at room temperature and accelerated temperature are significantly reduced in case of the tablets of Examples 1,6 and 11 containing inclusion complex of glipizide with cyclodextrin and non-ionic surfactant as compared to the tablets of Example 14 containing plain glipizide. Table 3 also shows in the case of tablets of Example 14 maximum rise in impurity to about 2.156 % at 40°C with 75% humidity. According to the invention degradation of glipizide and generation of impurities is thus significantly reduced thereby imparting stability to the tablets over a long storage period even at high temperature. Therefore, the tablets of the invention are also suitable for use in tropical conditions like in India. The process of the invention involves simple mixing, which is easy and economical to carry out and is also suitable for carrying out on a commercial scale. WE CLAIM: 1. A process for the preparation of a stable oral antidiabetic formulation of glipizide and metformin hydrochloride comprising dry mixing 250 - 2000 mg metformin hydrochloride and inclusion complex of 2.5 - 40 mg glipizide with cyclodextrin and non-ionic surfactant and excipients and optionally converting the formulation into solid dosage forms in known manner. 2. A process as claimed in claim 1, wherein the inclusion complex of glipizide and metformin hydrochloride are mixed together in granular form. 3. A process as claimed in claim lor 2, wherein the metformin hydrochloride in immediate release form is mixed with glipizide. 4. A process as claimed in claim 1 or 2, wherein the metformin hydrochloride in sustained release form is mixed with glipizide. 5. A process for the preparation of stable oral antidiabetic formulation of glipizide and metformin hydrochloride substantially as herein described. Dated this16th day of January 2004 (Jose MA) of Khaitan & Co Agent for the Applicants

Documents:

52-mum-2004-abstract(14-3-2005).doc

52-mum-2004-abstract(14-3-2005).pdf

52-mum-2004-cancelled pages(14-3-2005).pdf

52-mum-2004-claims(granted)-(14-3-2005).doc

52-mum-2004-claims(granted)-(14-3-2005).pdf

52-mum-2004-correspondence(4-5-2007).pdf

52-mum-2004-correspondence(ipo)-(24-10-2007).pdf

52-mum-2004-form 1(16-1-2004).pdf

52-mum-2004-form 19(20-1-2004).pdf

52-mum-2004-form 2(granted)-(14-3-2005).doc

52-mum-2004-form 2(granted)-(14-3-2005).pdf

52-mum-2004-form 26(16-1-2004).pdf

52-mum-2004-form 3(16-1-2004).pdf

52-mum-2004-form 8(20-1-2004).pdf