Title of Invention

"A PROCESS FOR THE PREPARATION OF CONTROLLED RELEASE TABLETS OF METFORMIN"

Abstract

The present invention relates to controlled-release tablets of metformin and processes for their preparation, wherein the tablets comprise 16% by weight of the composition of hydrophilic polymers consisting of anionic and nonionic polymers in a ratio 1:1 to 1:5. The anionic polymer is sodium carboxymethylcellulose and the nonionic polymer is hydroxypropyl methylcellulose, having a average molecular weight in the range of 1,80,000 to 2,50,000.

Full Text

The present invention relates to a process for preparing controlled release tablets of metformin. Controlled drug delivery applications include both sustained / extended delivery and targeted delivery on a one time or sustained basis. Controlled release formulations can be used to reduce the amount of drug necessary to cause the same therapeutic effect in-patients. The convenience of fewer and more effective doses also increases patient compliance. Metformin, a biguanide derivative is an oral anti-hyperglycemic drug used in the management of non-insulin dependent diabetes mellitus (type 2-diabetes). It is estimated that 60 percent of patients with type 2 diabetes who receive oral therapy are currently required to take doses of multiple pills several times a day in order to manage this condition. Controlled release formulation help these patients in controlling their blood sugar better by making it easier to comply with their daily treatment regimen. Metformin is a high dose drug and has poor compressibility. Therefore, the tendency of capping is particularly high during the production of tablets. It is the problem of tabletting such poorly compressible active matter, and especially those which are clinically prescribed at high dose levels that has led many workers to employ different processes to prepare controlled release formulations. For example, Lipha1 discloses use of framework forming auxiliary substances such as polyvinyl acetate as retarding agent in the preparation of metformin delayed release tablets for improving the compressibility. The disadvantage of using such framework forming auxiliary substance is that they have to be processed with organic solvents. These organic solvents are not just expensive in comparison to water but are also difficult to remove completely and therefore may lead to the problem of residual solvent, in such preparations. US Pat. No. 6,117,451 provides a direct tabletting, free flowing particulate metformin hydrochloride formulation in the form of tabletting powder, capable of being directly compressed into a tablet having adequate hardness. It employs specific particle size and 1 'Lipha, technical information Glucophage® August 1991, "Bundesverband der Pharmazeutischen Industrie e. v.", Publ. Note Liste 1993, Edition Cantor, Aulendorf 1993). density range excipients to improve the flow and compressibility characteristics. Use of these excipients not only adds to the cost but also makes the process cumbersome. PCT patent application WO 99/47128 describes a method for preparing a biphasic controlled release metformin tablets. The method comprises forming an inner solid particulate phase comprising individual particles comprising metformin and an extended release material and mixing the individual particles forming the inner solid particulate phase with an outer solid continuous phase comprising an extended release material to thereby disperse and embed the individual particles forming the inner solid particulate phase in the outer solid continuous phase. The inner particulate phase is prepared by wet granulating metformin and an extended release material by water or organic solvents. The inner particulate.phase is then dried and mixed with the outer continuous phase and compressed to form tablets. Two step granulation provides the desired extended release and tackles the problem of capping but may result in segregation of granules / particles due to different particle sizes and densities during compression. Therefore, content uniformity becomes difficult to achieve. Moreover, the large number of processing steps and more processing time lead to high manufacturing cost. US Pat. No. 5,955,106 discloses a pharmaceutical composition comprising metformin and method of producing the composition wherein the composition has a residual moisture content of about 0.5 to 3% by weight. A key disclosure in US 5,955,106 is that the residual moisture content of 0.5-3% by weight is critical to avoid capping of tablets. The process has the limitation of maintaining residual moisture content of the composition below 3% by weight, which according to the disclosure of the patent is critical to avoid capping of the tablets. The present invention addresses the drawbacks and problems associated with the currently available technologies and provide a simple, cost effective and efficient delivery system for controlled release metformin on a commercial scale. In the present invention these objectives have been achieved by using a combination of non-ionic and anionic hydrophilic polymers, wherein the total hydrophilic polymer concentration is at least 16% by weight of the composition. Accordingly, the process of the present invention comprises of: a. dry blending metformin with at least 16% by weight of hydrophilic polymers consisting of anionic and nonionic polymers in a ratio 1:1 to 1:5, and other excipients as described herein; i.the anionic polymer is sodium carboxymethylcellulose and ii. the nonionic polymer is hydroxypropyl methylcelulose, having a average molecular weight in the range of 1,80,000 to 2,50,000 and b. granulating the blend to prepare granules, c. drying and sizing the granules; and d. compressing the granules to make tablets. Anionic polymers are the one which carry negatively charged ions, whereas non-ionic polymers do not carry any charge with them. The preferred nonionic hydrophilic polymer for the present invention is hydroxypropyl methylcellulose with an average molecular weight in the range of 1,80,000 to 2,50,000, preferably about 2,15,000 with a methoxy degree of substitution ranging from 19 to 24% and hydroxypropyl molar substitution ranging from 7 to 12%. The preferred anionic hydrophilic polymer for the present invention is sodium carboxymethylcellulose with a viscosity in the range of 400 to 800 cps. Metformin is highly soluble in water and therefore the release of the drug from a matrix system is mainly through diffusion. Therefore, it is necessary for controlled release of metformin to have high viscosity polymers in the matrix system. Combination of hydroxypropyl methylcellulose and sodium carboxymethylcellulose results in rheological synergism whereby the resultant viscosity is considerably higher than the arithmetic mean. This is attributed to the fact that a strong hydrogen bond induced cross-linking takes place between the carboxylic group of sodium carboxymethylcellulose and the hydroxyl group of the hydroxypropyl methylcellulose. Surprisingly, when a combination of hydroxypropyl methylcellulose with an average molecular weight in the range of 1,80,000 to 2,50,000 with a methoxy degree of substitution ranging from 19 to 24% and hydroxypropyl molar substitution ranging from 7 to 12% and sodium carboxymethylcellulose with a viscosity in the range of 400 to 800 cps as hydrophilic polymer is mixed with metformin, the mixture has excellent compressibility and the tablets prepared are hard with lower friability values. Moreover tablets produced have extended release up to 12 hrs. In addition to the active and hydrophilic polymers, the formulations of the present invention may contain other excipients, which act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents. Careful selection of the diluent not only improves the flow and compressibility characteristics of the blend but also aids in solving the problem of capping. However, as metformin is a high dosage drug, addition of diluent is not necessary. If required, lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose and mannitol may be used as diluent. Use of microcrystalline cellulose is however preferred. Binders impart cohesiveness to the blend and also improve the flow and hardness. In the present invention the polymers used impart such properties. However, excipients like starch, sugars, gums, low molecular weight hydroxypropyl methylcellulose and hydroxypropylcellulose may also be used as binders. Lubricants of the present invention may be selected from talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. Glidants may be selected from Colloidal silicon dioxide (aerosil) or talc. The process of the present invention comprises the steps of a. dry blending metformin with at least 16% by weight of hydrophilic polymers consisting of anionic and nonionic polymers in a ratio 1:1 to 1:5, and other excipients selected from amongst diluents, binders, lubricants and glidants; i. the anionic polymer is sodium carboxymethylcellulose, constituting 3 to 10% by weight of the composition, and ii. the nonionic polymer is hydroxypropyl methylcellulose, having a average molecular weight in the range of 1,80,000 to 2,50,000, constituting 10 to 20% by weight of the composition; b. granulating the blend to prepare granules, c. drying and sizing the granules; and d. compressing the granules to make tablets. The tablets can be optionally coated using the standard coating processes. For the purpose of the present invention the dry blend of metformin could be prepared with hydrophilic polymer (s): hydroxypropyl methylcellulose and sodium carboxymethylcellulose, and optionally other excipients. The powder blend may be sifted through a screen of suitable fineness to remove or break up lumps. This screening also affords additional mixing. For large quantities of powder twin shell blender, double cone blender, planetary mixers may be used. The blend could be wet granulated with water or with aqueous dispersion of the binder. For granulation, water or aqueous dispersion of the binder is added to the blend while mixing. The powder mass is wetted with water or the binding solution until the mass has the proper consistency. The wet mass is forced through 8 or 10-mesh screen, however for large quantities comminuting mills suitable for wet screening may be used. Wet granules are dried in trays or in fluidized bed dryer. In drying, it is desirable to maintain a residual amount of moisture in the granulation. This is necessary to maintain the various granulation ingredients such as polymers in a hydrated state. Also, the residual moisture content contributes to the reduction of the static electric charges on the particles. The stability of the product containing moisture sensitive active ingredients may be related to the moisture content of the product. In the present invention the preferred residual moisture content of the granules is between 3.5-6.0% by weight. After drying, the granules are reduced in particle size by passing through a small mesh screen. After sizing, the granules are lubricated and compressed to form tablets. The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention anyway. In the following examples 1-6, metformin tablets were prepared by the process of the present invention using hydrophilic polymers in a concentration of at least 16% by weight of the composition which consists of 10-20% of hydroxypropyl methylcellulose with an average molecular weight in the range of 1,80,000 to 2,50,000, with a methoxy degree of substitution ranging from 19 to 24% and hydroxypropyl molar substitution ranging from 7 to 12% and 3-10% sodium carboxymethylcellulose with a viscosity in the range of 400 to 800 cps . Table 1 provides the in-vitro release profile of the controlled release tablets of metformin prepared by the composition and process of examples (1-6) in phosphate buffer pH 6.8 (900ml), USP2at50rpm. Examples 1 -6 (Table Removed) *Sodium carboxymethylcellulose having 400-800 cps viscosity. ** Hydroxypropyl methylcellulose with an average molecular weight in the range of 1,80,000 to 2,50,000, with a methoxy degree of substitution ranging from 19 to 24% and hydroxypropyl molar substitution ranging from 7 to 12%. Process: 1. Mix metformin with sodium carboxymethylcellulose, hydroxypropyl methylcellulose and diluent. 2. Granulate with a sufficient quantity of a solution of binder in water. 3. Pass the wet mass through a # 10 BSS and dry in a fluidized bed dryer at about 60°C. 4. Pass the dry-mass through a # 22 BSS, lubricate and compress into capsule shaped tablets. Table 1. Release profile of the controlled release tablets of metformin prepared as per Examples 1-6 in Phosphate buffer pH 6.8 (900 ml), DSP 2 at 50 rpm. (Table Removed) WE CLAIM: 1. A process for the preparation of controlled release tablets of metformin, comprising the following steps of; a. dry blending metformin with at least 16% by weight of hydrophilic polymers consisting of anionic and nonionic polymers in a ratio 1:1 to 1:5, and other excipients selected from amongst diluents, binders, lubricants and glidants; wherein i. the anionic polymer is sodium carboxymethylcellulose, constituting 3 to 10% by weight of the composition, and ii. the nonionic polymer is hydroxypropyl methylcellulose, having a average molecular weight in the range of 1,80,000 to 2,50,000, constituting 10 to 20% by weight of the composition; b. granulating the blend to prepare granules, c. drying and sizing the granules; and d. compressing the granules to make tablets. 2. The process according to claim 1, wherein the diluents are selected from one or more of lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose and mannitol. 3. The process according to claim 1, wherein the binders are selected from starch, sugars, gums, low molecular weight hydroxypropyl methylcellulose and hydroxypropylcellulose. 4. The process according to claim 1, wherein the lubricants are selected from one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. 5. The process according to claim 1, wherein the glidants are selected from one or more of colloidal silicon dioxide and talc. 6. The process according to claim 1, wherein the granules are dried to a residual moisture content of between 3.5 to 6.0% by weight. 7. The process according to claim 1, wherein the tablet produced has an extended release up to 12 hours. 8. A process for preparing controlled release tablets of metformin substantially as described and illustrated by the examples herein.

Documents:

1134-del-2001-abstract.pdf

1134-del-2001-claims.pdf

1134-del-2001-correspondence-others.pdf

1134-del-2001-correspondence-po.pdf

1134-del-2001-description (complete).pdf

1134-del-2001-form-1.pdf

1134-del-2001-form-19.pdf

1134-del-2001-form-2.pdf

1134-del-2001-form-3.pdf