Title of Invention

A PROCESS FOR THE PREPARATION OF A CONTROLLED RELEASE ANTIDIABETIC COMPOSITION

Abstract

We claim: 1. A process for the preparation of a controlled release antidiabetic composition comprising (a) mixing - (i) metformin or its pharmaceutically acceptable salt, (ii) two or more swellable poljners wherein at least one polymer is an anionic polymer selected from a group consisting of polyacrylic acid and/or its derivatives, starch derivatives, cellulose derivatives, "lms and the like or mixtures thereof, the other swellable polymer is selected from a group consisting of cellulose and cellulose derivatives, alkylene oxide homopolymers, disintegrants, gums of plant, animal or sjthetic origin and vinyl pyrrolidone polymers ^ii) one or more pharmaceutically acceptable excipient(s) that imnrove the compressibiHty of the core composition, wherein said pharmaceutically acceptable excipient is selected' from a group consisting of microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dextrins and dextrans, colloidal silicon dioxide, kaolin, titanium dioxide, fused silicon dioxide, alumina, bentonite, magnesium silicate, magnesium trisilicate, anhydrous calcium sulfate, magnesium aluminium silicate and the like,

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See section 10) A PROCESS FOR THE PREPARATION OF A CONTROLLED RELEASE ANTIDIABETIC COMPOSITION SUN PHARMACEUTICAL INDUSTRIES LTD. A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA. The foUowing speciHcation particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. A PROCESS FOR THE PREPARATION OF A CONTROLLED RELEASE ANTIDIABETIC COMPOSITION The present invention relates to a process for the preparation of a controlled release antidiabetic composition comprising a biguanide such as metformin or its pharmaceutically acceptable salt. BACKGROUND OF THE INVENTION Metformin is an antihyperglycemic agent of the biguanide class used in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Metformin hydrochloride is highly soluble in water and has intrinsically poor permeability in the lower portion of the gasfrointestinal tract and an elimination half-life of 2-6 hours. The usual starting dose of metformin is 500 mg twice a day or 850 mg once a day given with meals with maximum of 2550 mg per day. Such conventional multiple dose therapy may lead to substantial fluctuation in the plasma concentration of the drug, especially in chronic administration. A controlled drug dehvery system allows the drug to be released in a rate-controlled manner leading to a constant therapy and thereby eliminating the multiple dosing and side effects. The prior art enumerates several attempts to prepare a controlled release metformin composition. United States Patent Number 5,955,106 (hereinafter referred to as '106 patent) disclosed a pharmaceutical composition comprising metformin and a hydrocolloid forming retarding agent with the residual moisture content of about 0.5-3%. The said moisture level was maintained such that usual capping problem associated with the high-dose tablet formulations is avoided. The hydrocolloid forming retarding agents used in this invention, were selected from a group of cellulose derivatives, dextrins, starches, carbohydrate polymers, natural gums, xanthane, alginates, gelatin, polyacrylic acid, poljrvinyl alcohol and polyvinyl pyrollidones. The matrix tablets so formed could optionally be film coated with polymers such as soluble cellulose derivatives, ethyl cellulose, poly(ethacrylate-methyl methacrylate) dispersion and plasticizers such as diethyl phthalate and macrogol to mask the taste or to additionally retard the release. Metformin has a comparatively large dose and thus the dosage form tends to becoine bulky and difficult to swallow. This coupled with the problem of poor compressibility of metformin reduces the flexibility in formulating the composition to obtain the optimum release profile. We have found a composition comprising metformin or its pharmaceutically acceptable salt, two or more swellable polymers wherein at least one polymer is anionic, one or more pharmaceutically acceptable excipient(s) that improve the compressibility of thg core composition and optionally a coat comprising one or more water insoluble polymer(s) surrounding the core wherein the composition enables the poor compressibility of metformin to be brought under control and allows convenient modulation of release_jA^.ithout necessarily requiring moisture control in the; range of 0.5-3%. PCT ^plication Number WO 9947128 disclosed a pharmaceutical composition wherein particles of an inner phase comprising a highly water soluble active ingredient and an extended release material are dispersed in an outer solid continuous phase comprising an extended release material, hi the system of the present invention however, the inner phase is in the form of a core, which is surrounded by a water insoluble polymeric coat. The system of WO 9947128 consists of a matrix of an inner phase in an outer phase and would be considered as a "matrix-system" by those skilled in the art. The system of the present invention has two distinct components viz. a core and a coat such systems are regarded as reservoir type systems and provide a distinctly different kinetics and mechanisms of release, alternately, the present invention has optionally no coat, thus is a single phase matrix system without coat and is thus different. United States Patent Number 6,099,859 disclosed an osmotic controlled release tablet composition. Osmotic controlled release system differs fi:om the present invention in that the release of a drug occurs through an orifice in the semipermeable membrane coating and the osmotic pressure within the system exercises control on the release. The prior art does not disclose a process for the preparation of a controlled release antidiabetic composition comprising mixing a compressible controlled release core composition comprising metformin or its pharmaceutically acceptable salt, two or more swellable polymers wherein at least one polymer is an anionic polymer, one or more pharmaceutically acceptable excipient(s) that improve the compressibility of the core composition and converting the mixture into a core and optionally surrounding the core with a coat comprising one or more water insoluble polymer(s). OBJECT OF THE INVENTION It is an object of the present invention to provide a process for the preparation of a controlled release antidiabetic composition comprising metformin or its pharmaceutical acceptable salt in a readily compressible and controlled release form. SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of a controlled release antidiabetic composition comprising (a) mixing -(i) metformin or its pharmaceutically acceptable salt, (ii) two or more swellable polymers wherein at least one polymer is an anionic polymer selected from a group consisting of polyacrylic acid and/or its derivatives, starch derivatives, cellulose derivatives, gums and the like or mixtures thereof, the other swellable poljoner is selected from a group consisting of cellulose and cellulose derivatives, alkylene oxide homopolymers, disintegrants, gums of plant, animal or synthetic origin and vinyl pyrrolidone polymers (iii) one or more pharmaceutically acceptable excipient(s) that improve the compressibility of the core composition, wherein said pharmaceutically acceptable excipient is selected from a group consisting of microcrystalline cellulose, powdered cellulose, sihcified microcrystalline cellulose, dextrins and dextrans, colloidal sihcon dioxide, kaolin, titanium dioxide, fused silicon dioxide, alumina, bentonite, magnesium silicate, magnesium trisilicate, anhydrous calcium sulfate, magnesium aluminium silicate and the like. (b) converting the mixture into a core by conventional means and (c) optionally surrounding the core with a coat comprising one or more water insoluble polymer(s). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the plasma concentration vs time profile obtained upon administration of one embodiment of the controlled release antidiabetic composition as exemplified in Example 1 in comparison to Glucophage XR of the present invention. Figure 2 shows the plasrha concentration vs time profile obtained upon administration of one embodiment of the controlled release antidiabetic composition as exemplified in Example 2 in comparison to Glucophage XR. 4A DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for the preparation of a controlled release antidiabetic composition comprising metformin or its pharmaceutically acceptable salt. In the preferred embodiments of the process of the present invention the amount of metformin hydrochloride ranges from about 500 mg to about 1000 mg. The swellable polymeric materials used in the present invention are hydrogels that swell in, and retain a significant amoimt of water. These swellable polymers are polymeric hydrogels (crosslinked or vmcrosslinked), which swell or expand significantly in water, usually exhibiting a 2 to 50 fold or greater volume increase. The crosslinked polymers will swell and will not dissolve; uncrosslinked polymers may dissolve subsequent to swelling although dissolution is not a necessary consequence. Examples of the swellable polymers that can be used in the present invention include: • cellulose and cellulose derivatives such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), carboxymethyl cellulose (CMC), crosslinked carboxymethyl cellulose (croscarmellose) and its alkah salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl hydrophobically modified hydroxyethyl cellulose (CMHMHEC) and the like; • alkylene oxide homopolymers such as polypropylene oxide, preferably ethylene oxide homopolymers and the like; • disintegrant such as cross-linked pol)^inylpyrrolidone, cross-linked sodium carboxymethylcellulose, carboxymethyl starch, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross-linked amylose, pregelatinized starch, starch and starch derivatives. • gums of plant, animal, mineral or synthetic origin such as (i) agar, alginates, carrageenan, furcellaran derived fi^om marine plants, (ii) guar gum, gum arable, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants, (iii) microbial polysaccharides such as dextran, gellan gum, rhamsan gum, welan gum, (iv) synthetic or semi-synthetic gums such as hydroxypropyl guar and the like; It is also possible to use vinyl pyrrolidone polymers or polyvinylpyrrolidone (PVP), also referred to as Povidone as the swellable poljmiers. These are the synthetic polymers consisting essentially of linear l-vinyl-2-pyrrolidinone groups, the degree of polymerization of which results in polymers of various molecular weights, the molecular weight ranging between 2500 and 3,000,000 Daltons. PVP is commercially available as KoUidon® (BASF), Plasdone® and Peristone® (General Aniline). PVP is classified into different grades on the basis of its viscosity in aqueous solution. Different grades of PVP available are PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-60, PVP K-90 and PVP K-120. The K-value referred to in the above nomenclature is calculated from the viscosity of the PVP in aqueous solution, relative to that of water. The preferred vinyl pyrrolidone polymer used as a swellable polymer is PVP K-30, having an approximate molecular weight of 50000 Daltons. The anionic swellable polymers used in the present invention are selected from the group consisting of homo-polymers and copolymers of polyacrylic acid and polyacrylic acid derivatives, various starch derivatives, cellulose derivatives, gums and the like. Homopolymers of polyacrylic acid and its derivatives that can be used in the present invention, include, but are not limited to, various grades sold under the frade name of Carbopol® by BFGoodrich. These are high molecular weight, crosslinked, acrylic acid-based polymers. Carbopol homopolymers are polymers of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol. Carbopol copolymers are polymers of acrylic acid, modified by long chain (C10-C30) alkyl acrylates and crosslinked with allylpentaerythritol. The USP-NF, British Pharmacopoeia have adopted the generic name "Carbomer" for various Carbopol® Homopolymer polymers. The Japanese Pharmaceutical Excipients list carbopol homopolymers as "carboxyvinyl polymer" and "carboxy polymethylene". A range of different pharmaceutical grade polymers, each with special properties and applications depending upon the viscosity of the polymers and the apphcabihty are available. The Carbopol grades 934 NF, 2984, 5984 EP, for example can be used for stable emulsions and suspensions for water and solvent-based gels having viscosity ranging from 30,500 to 45,000 cps for 0.5% solution at pH 7.5. Carbopol 934P NF, 974P NF having viscosity ranging from 29,400 to 39,400 cps can be used especially for oral and mucoadhesive applications such as controlled release tablets and oral suspensions. The grades 940 NF, 980 NF having viscosity ranging from 40,000 to 65,000 cps are to be used for topical gels. The low viscosity grades of Carbopol namely, 941NF, 981 NF can be used for low viscosity sparkhng clear topical gels. The carbopol 934P is high purity grade of Carbopol 934. Depending on drug solubility, drug hydrophilicity and basic sfrength, polymer concenfration and test medium pH, Carbopol 934 P can show zero-order release profiles in tableting applications. It is also possible to use in the present invention, co-polymers of acrylate or methacrylate monomers, for example polymethacrylates marketed under the brand names of Eudragit as the anionic swellable polymers. Eudragit L and S also referred as methacrylic acid copolymers are the copolymerization products of methacrylic acid and methyl methacrylate. The ratio of free carboxy groups to the ester is approximately 1:1 in Eudragit L and approximately 1:2 in Eudragit S. Eudragit® RS and RL, also referred to as ammoniomethacrylate copolymers are copolymers synthesized from acrylic acid and methacrylic acid esters with Eudragit® RL type having 10% of functional quaternary ammonium groups and Eudragit® RS having 5% of fiinetional quaternary ammonium groups. Examples of starch derivatives that can be used as the anionic polymers include, but are not limited to, sodium starch glycolate and various other anionic starch derivatives and the like. Examples of other anionic polymers tJtiat can be used as tne swellable polymers in the present invention, include, but are not limited to gums such as sodium alginate, sold under the name of KELTONE , propylene glycol alginate and the like. Particularly, the preferred *anionic polymer used in the present invention is xanthan gum, which is a high molecular weight polysaccharide, available in various grades, viscosity ranges and of different particle sizes. The xanthan gum used in the present invention is the food fine (FF) grade, 200 mesh, supplied by Jungbunzlauer. Examples of anionic cellulose derivatives that can be used as the swellable polymers in the present invention, include, but are not limited to sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross linked sodium carboxymethyl cellulose known as crosscarmellose, sold under the name of Ac-Di-SOL®, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and the like. Particularly, the preferred swellable polymers used in the present invention are the cellulose ethers. Cellulose ethers are nonionic polymers however some cellulose ethers may be anionic for example cellulose ethers with some hydroxyl groups esterified for example hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate or cellulose ethers with the hydroxyl group further reacted to incorporate an anionic functional group for example carboxymethyl cellulose calcium and the like. The examples of the cellulose ethers include methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), carboxymethyl cellulose (CMC), crosslinked carboxymethyl cellulose (croscarmellose) and its alkaU salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), and the like. More preferably, the swellable polymers used in the present invention include various grades of the hydroxypropylmethyl cellulose available under the brand Name of Methocel. The grades available are categorized depending upon the chemical substitution and hydration rates. The Methocel Grade K, for example is used for HPMC having % methoxy content of 19-24 % and hydroxypropyl content of 7-12 % with a fastest relative rate of hydration. Similarly, the Methocel E grade is used for 28-30 % methoxy content and 7-12 % of hydroxypropyl with a more faster relative hydration rate as compared to the K grade. The F grade of Methocel indicates a 27-30 % methoxy content and 4-7.5 % of hydroxypropyl content with a slow relative hydration rate. The Methocel Grade A indicates a 27.5-31.5 % methoxy content and 0 % hydroxypropyl with slowest rate of hydration. HPMC is further categorized based on the particle size. For example, the premium grades of Methocel have particle size in the range such that 100% particles are less than 30 mesh screen and 99% of the particles are less than 40 mesh screen. The E grade has particle size in the range such that 95%) particles are less than 100 mesh screen whereas the K series has 90 % of particles less than 100 mesh screen. HPMC is further categorized according to viscosity exhibited by the 2%) HPMC solution in water. The Methocel grades based on the viscosities are KIOOLVP, K4M, K15MP, KIOOMP and E4MP. The KIOOLVP indicates a minimal viscosity of lOOcps, K4M of 4000 cps, K15MP of 15,000 and KIOOMP of 100,000 and several low viscosity grades such as E3, E5, E6, E15, E50andK3. In one embodiment of the present invention, the swellable polymer, which is a high viscosity grade cellulose derivative, preferably hydroxypropyl methyl cellulose, commercially available as Methocel KIOOM, with a viscosity of a 2 % w/w aqueous solution ranging from 80,000 to about 120,000 cps is used. In a particularly preferred embodiment the swellable polymer is a mixture of high viscosity grade of HPMC having a viscosity greater than about 10,000 cps and a low viscosity grade HPMC having a viscosity equal to or less than about 10,000 cps. In one preferred embodiment of the present invention, one of the grades of the HPMC used has viscosity of about 4000 cps and is commercially available as Methocel K4M, and the other grade of HPMC used has a viscosity of about 100,000 cps, and is commercially available as MethocelKlOOM. hi preferred embodiments of the present invention the anionic polymers is selected from a group of polyacrylic acid or a xanthan gum or mixtures thereof hi one preferred embodiments of the present invention, Carbopol 934P is used as one of the anionic swellable polymers. hi the particularly preferred embodiments of the present invention, a combination of a high molecular weight HPMC and Carbopol 934P is used. HPMC may be used in the concenfration ranging from about 10 to 15 % w/w of the total weight of the tablet. Amounts of Carbopol 934P that can be used in preferred embodiments of the present invention may vary from about 5 to about 20 % w/w of the total weight of the tablet. hi the still fiirther preferred embodiments of the present invention, a combination of high molecular weight HPMC and Xanthan gum Type FF is used. HPMC may be used in the concentration ranging from about 10 to 20 % w/w of the total weight of the tablet. More preferably, the HPMC used is a mixture of high viscosity grade of HPMC having a viscosity greater than about 10,000 cps and a low viscosity grade HPMC having a viscosity equal to or less than about 10,000 cps. In one preferred embodiment of the present invention, one of the low viscosity grades of the HPMC used has viscosity of about 4000 cps and is commercially available as Methocel K4M, and the other high viscosity grade of HPMC used has a viscosity of about 100,000 cps, and is commercially available as Methocel KIOOM. Amounts of xanthan gum that can be used in preferred embodiments of the present invention may vary from about 5 to about 20 % w/w of the total weight of the tablet. Amounts of the swellable polymers that can be used in preferred embodiments of the present invention may range from about 15 to about 40 % of the total weight of the tablet. The controlled release antidiabetic composition of the present invention contains one or more pharmaceutically acceptable excipient(s) that improve the compressibility of the core composition. These excipient(s) allow a wider range of moisture than the range of 0.5 to 3 % w/w to be retained in the core while enabling the poor compressibihty of metformin to be brought under control. The inventors do not subscribe to any theory but perhaps these excipient(s) by their wicking or dessicant action for retaining moisture or by their compressibility characteristics enable the compressibility to be brought under control. Thus excipient(s) that further modulate the release of metformin from the core can be included in the composition and provide flexibility to the formulation in obtaining the desired release profile. Examples of the excipient(s) that improve the compressibility of the core composition include microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dextrins and dextrans, colloidal silicon dioxide, kaolin, titanium dioxide, fused silicon dioxide, alumina, bentonite, magnesium silicate, magnesium trisilicate, anhydrous calcium sulfate, magnesium aluminium silicate and the like. In preferred embodiments of the present invention, the excipient used to improve the compressibility of the core composition is microcystalline cellulose. In the process for the preparation of a controlled release antidiabetic composition of the present invention, the core composition may optionally contain the excipient(s) that further modulate the rate of release of metformin from the core. These excipient(s) are selected from the group consisting of osmotic agents, inorganic or organic weak acids or weak bases and surfactants. Examples of the osmogent(s) used in the present invention include all pharmaceutically acceptable and pharmacologically inert water-soluble compounds referred to in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania (1995). Pharmaceutically acceptable water-soluble salts of inorganic or organic acids, or non-ionic organic compounds with high water solubility, e.g. carbohydrates such as sugar, or amino acids, are generally preferred. The examples of agents used for inducing osmosis include inorganic salts such as magnesium chloride or magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium hydrogen phosphate, lithium, sodium or potassium dihydrogen phosphate, salts of organic acids such as sodium or potassium acetate, magnesiimi succinate, sodium benzoate, sodium citrate or sodium ascorbate; sodium carbonate or sodium bicarbonate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, raffinose, inositol, xylitol, maltitol; water-soluble amino acids such as glycine, leucine, alanine, or methionine; urea and the like, and mixtures thereof. Examples of inorganic or organic weak acids or weak bases used in the present invention include, but are not limited to citric acid, lactic acid, ascorbic acid, tartaric acid, malic acid, fumaric acid and succinic acid and salts thereof Examples of the surfactants used in the present invention include, but are not limited to glyceride; partial glycerides, glyceride derivatives, polyhydric alcohol esters, PEG and PPG esters, polyoxyethylene and polypropylene sorbitan esters; sodium lauryl sulfate and the like. Preferred embodiments of the composition of the present invention include sodium chloride as the osmogent and sodium bicarbonate as the weak base. The additional excipient(s) used in the controlled release antidiabetic composition of the present invention include those excipient(s) which are generally used during the preparation of granules, compression e.g lubricants, glidants, disintegrants and the like. These excipients are discussed in 'Remington's Pharmaceutical Sciences, 18* edition, page 1635-38(1990). In the process for the preparation of a controlled release antidiabetic composition of the present invention, the core composition may optionally be surrounded with a coat comprising one or more water insoluble polymer(s). Examples of water insoluble polymers that may be used include cellulose ether derivatives, acrylic resins, copolymers of acryhc acid and methacryhc acid esters. Combined with the polymer material may be a hydrophobic agent, which may be a fatty acid of 10 or more carbon atoms, wax or the salts of a fatty acid or 10 or more carbon atoms such as magnesium stearate or calcium stearate. The particular hydrophobic agent may be a mixture of stearates which contain other fatty acids because the product is derived from a natural source. The purpose of the hydrophobic agent is to reduce the permeability of the water insoluble, water permeable polymer to water by adding from 25% to 50% by weight of the hydrophobic agent to said polymer based on the total combined weight of the hydrophobic agent and said polymer. Small amounts of stearates will reduce tackiness and very large amounts will reduce water permeabiUty. In the most preferred embodiments of the present invention, the water insoluble polymeric material used to coat the core is a highly water permeable, pH independent methacrylic-methacrylate polymer with quaternary ammonium groups. Plasticizers may be added to the water insoluble polymer to control any brittleness in the polymeric coat. The plasticizer used in the present invention may be selected from the group consisting of diethyl phthalate, diethyl sebacate, triethyl cifrate, diethyl phthalate, glycerol, sorbitol, crotonic acid, propylene glycol, castor oil, citric acid esters, dibutyl phthalate, dibutyl sebacate, and mixtures thereof The amount of the coating apphed on the core may vary from about 0.5 to about 20 % w/w of the total weight of the dosage form, depending on the core composition. In the preferred embodiments the amount of coating applied is from about 3% to about 5% by weight of the total weight of the dosage form. According to the process of the present invention, metformin or its pharmaceutically acceptable salt, two or more swellable polymers wherein at least one polymer is an anionic polymer, one or more pharmaceutically acceptable excipient(s) that improve the compressibility of the core composition and optionally excipient(s) that modulate the release of metformin from the core are mixed and the mixture is converted into a core by conventional means. These include wet granulation, dry granulation, direct compression, pelletization, extrusion-spheronization, layering onto inert particles such as non-pareil seeds, and the hke. The core other than the one whic|j,is already in the tablet form is further modified into a tablet by compression in a tablet press. The tablets may be single layered or compressed into multilayered tablets such as bilayered tablets. In the case of dry granulation, the dry mixture of metformin or its pharmaceutically acceptable salt, swellable polymer(s), optionally excipient(s) that modulate the release of metformin from the core and the excipients that improve the compressibility of the core composition is compressed to obtain slugs, which are then passed through suitable sieves to obtain granules. In wet granulation, the mixture is granulated with a liquid preferably, a mixture of isopropyl alcohol and water. The dried granules are compressed on a tablet compression machine. In case of direct compression, the components of the system are mixed thoroughly and directly compressed on a tablet compression machine. The compressed cores in tablet form, obtained by any one of the above methods, may optionally be subjected to coating, moulding, spraying, or immersion using a coating solution comprising one or more water insoluble polymer(s) to form the water insoluble polymeric coat. The water insoluble polymer(s) and other adjuvants such as plasticizers, opacifiers, pigments and the like are dissolved or dispersed in a suitable organic or aqueous solvent to form the coating solution. The examples that follow do not limit the scope of the invention and are presented as illustrations. EXAMPLE 1 One of the embodiments of the process for the preparation of a controlled release metformin composition of the present invention is described in the following example. The controlled release tablets of this embodiment are prepared as per the formula mentioned in Table 1 below. Stage A: Metformin hydrochloride and sodium chloride were milled and passed through 100 mesh sieve. Carbopol 934P, hydroxypropylmethyl cellulose, microcrystalline cellulose and starch were passed through 60 mesh sieve and further imiformly mixed with the blend of metformin and sodium chloride. Stage B: The powder mixture was granulated with polyvinyl pyrrolidone K-30 dissolved in isopropyl alcohol and water mixture. The granules were dried at 45° C. The dried granules were passed through a mill. Stage C: Talc, magnesium stearate and colloidal siUcon dioxide were passed throtegh 60 mesh sieve and then mixed with the granules. The lubricated granules were compressed at the required tablet weight. Stage D & E: The compressed cores were further coated with a polymeric dispersion comprising Eudragit RLIOO in isopropyl alcohol and acetone containing triethyl citrate, talcum and titanium dioxide. Table 1 Stage Number Ingredients (mg) Quantity per dosage form (mg) %w/w of the tablet Stage A 1. Metformin HCL(100#) 500.0 47.619 2. Carbopol 934P 100.0 9.523 3. Sodium chloride 40.0 3.809 4. HPMC KIOOM 180.0 17.143 5. Microcrystalline cellulose 50.0 4.7619 6. Starch 75.0 7.1428 Stage B 1. Polyvinylpyrrolidone (K-30) 20.0 1.904 2. Isopropyl alcohol Quantity sufficient q.s 3. Purified Water Quantity sufficient q.s Stage C 1. Talc 20.0 1.904 2. Magnesium stearate 10.0 0.952 3. Colloidal Silicon dioxide 10.0 0.952 Total 1000.0 95.23 Stage D 1. Eudragit RLIOO 37.04 3.527 2. Isopropyl alcohol Quantity sufficient q.s 3. Acetone Quantity sufficient q.s 4. Triethyl citrate 3.70 0.352 Stage-E 1. Talcum 5.56 0.529 2. Titanium dioxide 3.70 0.352 3. Isopropyl alcohol Quantity sufficient q.s Total weight of the coated tablet 1050 100 The tablets so obtained were subjected to dissolution testing using USP type I dissolution apparatus. The dissolution medium used was 900 ml of O.IN HCl for 0-2 hours and 900 ml of simulated intestinal fluid, pH 6.8, for 2-12 hours. The results of the dissolution test are mentioned in Table 2 below. Table 2 Time (hours) % drug released (±SD) 1 12.00± 1.53 2 29.08± 0.37 4 47.82± 0.28 8 69.20± 0.82 12 84.88± 3.42 EXAMPLE 2 This Example describes another embodiment of the process for the preparation of a controlled release metformin composition of present invention. The tablets were prepared according to the formula described in Table 3. Stage A: Metformin Hydrochloride was milled and passed through 100 mesh. Carbopol 934P and sodium bicarbonate were passed through 60 mesh and all the ingredients were mixed thoroughly. Stage B: The blend was granulated with PVP K-30 dissolved in isopropyl alcohol. The wet mass was passed through 20 mesh and the wet granules were dried in Fluidized Bed dryer at 45°C. The dried granules were passed through 30 mesh. Stage C: All the ingredients of Stage C were passed through 60 mesh and mixed with the dried, sifted granules of metformin hydrochloride. Stage D: This mixture was further granulated with PVP K-30 in isopropyl alcohol. The wet mass was passed through 20 mesh. The granules so obtained were dried in the Fluidized Bed dryer at 45°C. Stage E: All the ingredients of the step E were passed through 60 mesh. This mixture was used to lubricate the dried granules. The lubricated granules were compressed into tablets of 20.5 X 9.0 mm capsule shaped punch. Stage F & G: The compressed cores were fluther coated with a polymeric dispersion comprising Eudragit RLIOO in isopropyl alcohol and acetone containing triethyl citrate, talcum and titanium dioxide. Table 3 Stage Number Ingredients (mg) Quantity per dosage form (mg) %w/w of the tablet Stage A 1. Metformin HCL(100#) 500.0 50.0 2. Carbopol 934P 100.0 10.0 3. Sodium bicarbonate 30.0 3.0 Stage B 1. Polyvinylpyrrolidone (K-30) 12.0 1.2 2. Isopropyl alcohol Quantity sufficient q.s Stage C 1. Carbopol 934P 50.0 5.0 2. HPMC KIOOM 150.0 15.0 3. Microcrystalline Cellulose 113.0 11.3 Stage D 1. PVP K-30 10.0 1.0 2. Isopropyl Alcohol q.s q.s Stage E 1. Talc 20.0 2.0 2. Magnesium stearate 10.0 1.0 3. Colloidal silicon dioxide 5.0 0.50 Total 1000.0 100.0 Stage F 1. Eudragit RLIOO 37.04 3.527 2. Isopropyl alcohol Quantity sufficient q.s 3. Acetone Quantity sufficient q.s 4. Triethyl citrate 3.70 0.352 Stage-G 1. Talcum 5.56 0.529 2. Titanium dioxide 3.70 0.352 3. Isopropyl alcohol Quantity sufficient q.s Total weight oft he coated tablet 1050 100 The tablets so obtained were subjected to dissolution testing using USP type I dissolution apparatus. The dissolution medium used was 900 ml of O.IN HCl for 0-2 hours and 900 ml of simulated intestinal fluid, pH 6.8, for 2-12 hours. The results of the dissolution test are mentioned in Table 4 below. Table 4 Time (hours) % drug released (±SD) 1 24.63±1.15 2 42.17±3.48 4 61.98±3.5 8 84.97±3.47 12 92.03±3.64 EXAMPLE 3 This Example describes another embodiment of the process for the preparation of a controlled release metformin composition of the present invention. The tablets were prepared according to the formula described in Table 5. Stage A: Metformin Hydrochloride was milled and passed through 100 mesh. Microcrystalline cellulose, xanthan gum, hydroxypropylmethyl cellulose K4M and KIOOM, were passed through 60 mesh sieve and further uniformly mixed with the drug. Stage B: The blend was granulated with Methocel E5 dissolved in isopropyl alcohol and water mixture. The wet mass was passed through 20 mesh and the wet granules were dried in Fluidized Bed dryer at 45'C. The dried granules were passed through 30 mesh. Stage C: All the ingredients of Stage C were passed through 60 mesh and mixed with the dried, sifted granules of metformin hydrochloride. The lubricated granules were compressed at the required tablet weight. Table 5 Stage Number Ingredients (mg) Quantity per dosage form (mg) %w/w of the tablet Stage A -■• 1. Metformin HCL (100#) 1000.0 66.66 ' 2. Microcrystalline cellulose 62.5 4.166 3. Xanthan gum Type FF 75.0 5.00 4. HPMC K4M 150.0 10 ■ ■ 5. HPMCKIOOM 100.0 6.666 Stage B 1. Hydroxypropylmethyl cellulose (Methocel E5) 60.0 4.00 2. Isopropyl alcohol Quantity sufficient q.s 3. Purified Water Quantity sufficient q.s. Stage C 1. Talc 30.0 2.00 2. Magnesium stearate 15.0 1.00 3. Colloidal Silicon dioxide 7.50 0.50 Total weight oft ablet 1500.0 100 The tablets so obtained were subjected to dissolution testing using USP type I dissolution apparatus. The dissolution medium used was 900 ml of O.IN HCl for 0-2 hoiirs and 900 ml of phosphate buffer pH 6.8, for 2-12 hours. The results of the dissolution test are mentioned in Table 6 below. Table 6 Time (hours) % drug released (±SD) 1 27.55± 0.36 2 37.10±0.52 4 57.24± 0.76 8 79.50± 3.26 12 89.09± 1.76 EXAMPLE 4 This Example describes another embodiment of the process for the preparation of a controlled release metformin composition of the present invention. The tablets were prepared according to the formula described in Table 7. Stage A: Metformin Hydrochloride was milled and passed through 100 mesh.; Microcrystalline cellulose, xanthan gum, hydroxypropylmethyl cellulose K4M and KIOOM, were passed through 60 mesh sieve and fiirther uniformly mixed with the drug. Stage B: The blend was granulated with Methocel E5 dissolved in isopropyl alcohol and water mixture. The wet mass was passed through 20 mesh and the wet granules were dried in Fluidized Bed dryer at 45°C. The dried granules were passed through 30 mesh. Stage C: All the ingredients of Stage C were passed through 60 mesh and mixed with the dried, sifted granules of metformin hydrochloride. The lubricated granules were compressed at the required tablet weight. Table 7 Stage Number Ingredients (mg) Quantity per dosage form (mg) % w/w of the tablet Stage A 1. MetfonninHCL(100#) 850.0 66.66 2. Microcrystalline cellulose 53.125 4.166 3. Xanthan gum Type FF 63.750 5.00 4. HPMC K4M 127.50 10 5. HPMC KIOOM 85.0 6.666 Stage B 1. Hydroxypropyhnethyl cellulose (Methocel E5) 51.0 4.00 2. Isopropyl alcohol Quantity sufficient q.s 3. Purified Water Quantity sufficient q.s. Stage C 1. Talc 25.50 2.00 2. Magnesixun stearate 12.75 1.00 3. Colloidal Sihcon dioxide 6.375 0.50 Total weight of tablet 1275.0 100 The tablets so obtained were subjected to dissolution testing using USP type I dissolution apparatus. The dissolution medium used was 900 ml of O.IN HCl for 0-2 hours and 900 ml of phosphate buffer pH 6.8, for 2-12 hours. The results of the dissolution test are mentioned in Table 8 below. Table 8 Time (hours) % drug released (±SD) 1 29.43± 1.00 2 39.06± 0.33 4 60.09± 0.20 8 81.03±0.53 12 87.04± 0.66 EXAMPLE 5 One embodiment of the process for the preparation of a controlled release metformin composition of the present invention is described in the following example. The tablets were prepared according to the formula described below, Table 9 Stage Number Ingredients (mg) Quantity per dosage form (mg) %w/w of the tablet Stage A 1. MetfonmnHCL(100#) 500.0 47.619 2. Carbopol 934p 100.0 9.523 3. Sodium chloride 40.0 3.809 4. HPMC KIOOM 180.0 17.143 5. Microcrystalline cellulose 50.0 4.7619 6. Starch 75.0 7.1428 Stage B 1. Polyvinylpyrrolidone(K-30) 20.0 1.904 2. Isopropyl alcohol Quantity sufficient q.s 3. Purified Water Quantity sufficient q.s Stage C 1. Talc 20.0 1.904 2. Magnesium stearate 10.0 0.952 3. Colloidal Silicon dioxide 10.0 0.952 Total 1000.0 95.23 Stage D 1. EudragitRLlOO 37.04 3.527 2. Isopropyl alcohol Quantity sufficient q.s 3. Acetone Quantity sufficient q.s 4. Triethyl citrate 3.70 0.352 Stage-E 1. Talcum 5.56 0.529 2. Titanium dioxide 3.70 0.352 3. Isopropyl alcohol Quantity sufficient q.s Total weight o fthe coated tablet 1050 100 stage A: Metformin hydrochloride and sodium chloride were milled and passed through 100 mesh sieve. Carbopol 934P, hydroxypropylmethyl cellulose, microcrystaJJine cellulose and starch were passed through 60 mesh sieve and further uniformly mixed with the blend of metformin and sodium chloride. ' Stage B: The powder mixture was granulated with polyvinyl pyrrolidone K-30 dissolved in isopropyl alcohol and water mixture. The granules were dried at 45° C. The dried granules were passed through a cht mill. Stage C: Talc, magnesium stearate and colloidal siUcon dioxide were passed through 60 mesh sieve and then mixed with the granules. The lubricated granules were compressed at the required tablet weight. Stage D & E: The compressed cores were further coated with a polymeric dispersion comprising Eudragit RLIOO in isopropyl alcohol and acetone containing triethyl citrate, talcum and titanium dioxide. The coated tablets were further coated with the coating composition comprising the ingredients described in table 10. Table 10 Sr. No. Ingredieiits Mg/Tablet %w/w of the tablet Stage 1 1 HPMC E5 17.00 15.68 2 Isopropyl alcohol Quantity sufficient q.s 3 Methylene chloride Quantity sufficient q.s 4 Glimepiride 1.00 0.0922 5 PEG 6000 6.80 0.6275 6 Purified water Quantity sufficient q.s Stage 2 1 Talcum 4.40 0.406 2 Titanium dioxide 4.40 0.406 3 Isopropyl alcohol Quantity sufficient q.s Glimepiride is dissolved in methylene chloride. HPMC is dispersed in isopropyl alcohol. The dispersion is added to the glimepifide solution. PEG 6000 is melted and dissolved in water and added to the glimepiride solution with stirring. Talcum, titanium dioxide and isopropyl alcohol are milled in the colloidal mill and added to the above solution. The solution is mixed well and is used to film coat the coated tablets. The tablets so obtained were subjected to dissolution testing using USP type I dissolution apparatus. The dissolution medium used was 900ml of O.IN HCl for 0-2 hours and 900ml of simulated intestinal fluid, pH 6.8, for 2-12 hours. The results of the dissolution test are given in Table 11 below. Table 11 Time (hours) % metformin released (±SD) 1 7.14±0.53 2 28.55± 1.05 4 54.44± 1.28 8 79.31± 1.98 12 88.31± 1.32 The tablets so obtained were further subjected to dissolution testing using USP type II dissolution apparatus. The dissolution medium used was 900ml of 0.025 M Tris Buffer pH 9.0 at 50 rpm. The glimepiride release was measured using HPLC. The results of the dissolution test are given in Table 12 below. Table 12 Time (minutes) % Glimepiride released (±SD) 10 87.14± 13.34 20 96.58± 20.63 30 99.33± 21.27 45 98.64± 21.34 60 100.53± 21.09 EXAMPLE 6 The tablets containing 500 mg of metformin hydrochloride prepared according to Example 1 were tested in himian volunteers in an open label, randomized, comparative and two-way crossover study. A single oral dose containing SOO mg of metformin was administered with 240 ml of water at ambient temperatures. The volunteers fasted overnight before dosing and for 4 hours thereafter. Drinking water was prohibited 2 hours before dosing and 2 hours thereafter. Standard meals were provided at 4 and 8 hours after dosing and at appropriate times thereafter. A wash out period of 7 days was given between the doses. The blood samples were collected before dosing and at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 10, 12, 16 and 24 hours and analyzed for metformin. The mean plasma profile given in Figure 1 demonstrated usefiil modification of the drug release in vivo. Inter-patient variability in pharmacokinetic parameters was acceptable as illustrated by the % cv given in the Table 13 below. Table 13 Formulation Cmax ng/ml AUC (ng.hr/ml) Example 1 691.93(42.36) 4334.61 (40.96) Glucophage SR 500 mg 774.35 (29.56) 5482.19(31.46) EXAMPLE 7 The controlled release antidiabetic composition according to the process of Example 2 was subjected to pharmacokinetic evaluation as described in Example 6. The pharmacokinetic parameters are tabulated in Table 14. The plasma profile is represented in Figure 2. Table 14 Formulation Cmax ng/ml AUC (ng.hr/ml) Example 2 437.02 (49.00) 3324.90(51.19) Glucophage SR 500 mg 344.67 (33.96) 2977.09(88.27) We claim: 1. A process for the preparation of a controlled release antidiabetic composition comprising (a) mixing - (i) metformin or its pharmaceutically acceptable salt, (ii) two or more swellable poljners wherein at least one polymer is an anionic polymer selected from a group consisting of polyacrylic acid and/or its derivatives, starch derivatives, cellulose derivatives, "lms and the like or mixtures thereof, the other swellable polymer is selected from a group consisting of cellulose and cellulose derivatives, alkylene oxide homopolymers, disintegrants, gums of plant, animal or sjthetic origin and vinyl pyrrolidone polymers ^ii) one or more pharmaceutically acceptable excipient(s) that imnrove the compressibiHty of the core composition, wherein said pharmaceutically acceptable excipient is selected' from a group consisting of microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dextrins and dextrans, colloidal silicon dioxide, kaolin, titanium dioxide, fused silicon dioxide, alumina, bentonite, magnesium silicate, magnesium trisilicate, anhydrous calcium sulfate, magnesium aluminium silicate and the like, [b) converting the mixture into a core by conventional means and (c) optionally surrounding the core with a coat comprising one or more water insoluble polymer(s). A. process as claimed in claim 1 wherein the amount of metformin or its phamiaceutical salt is about 500 mg to about 1000 mg. 3. A process as claimed to claim 1 wherein the swellable polymer is a high viscosity grade cellulose derivative. 4. A process as claimed to claim 3 wherein the cellulose derivative is hydroxypropyl methyl cellulose (HPMC). 5. A process as claimed to claim 4 wherein a 2% w/w aqueous solution of the hydroxypropyl methyl cellulose has a viscosity in the range from 80,000 to about 120,000 cps units. 6. A process as claimed in claim 1 wherein the swellable polymer is a mixture of high viscosity grade HPMC having a viscosity greater than about 10,000 cps for a 2 % w/w aqueous solution and a low viscosity grade HPMC having a viscosity equal to or less than about 10,000 cps for a 2 % w/w aqueous solution. 7. A process as claimed in claim 6 wherein the high viscosity grade HPMC has viscosity of about 100,000 cps for a 2 % w/w aqueous solution and the low viscosity grade HPMC has viscosity of about 4,000 cps for a 2 % w/w aqueous solution. 8. A process as claimed in claim 1 wherein the anionic polymer is selected from a group of polyacrylic acid or a xanthan gum or mixtures thereof. 9. A process as claimed in claim 1 wherein the concentration of the swellable polymers ranges from about 15 to 40% of the total weight of the said dosage form. 10. A process as claimed in claim 1 wherein the pharmaceutically acceptable excipient is microcrystalline cellulose. 11. A process as claimed in claim 1 fiirther comprises excipient(s) that modulate the rate of release of metformin from the core and are selected from a group consisting of osmogents, weak acids and weak bases, surfactants and the like. 12. A process as claimed in claim 11 wherein the osmogent is sodium chloride. 13. A process as claimed in claim 11 wherein the weak base is sodium bicarbonate. 14. A process as claimed in claim 1 wherein the water insoluble polymer(s) is a highly water permeable methacrylic-methacrylate with quaternary ammonium groups. 15. A process as claimed in claim 1 wherein the amount of water insoluble polymer(s) coating ranges from about 3 to about 5 % w/w of the total weight of the dosage form. 16. A process for the preparation of a composition as claimed in claim 1 to claim 15 substantially as herein described and illustrated by the examples 1 to 7 herein. Dated this 27 day of September, 2002

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