WO2011161521A1

WO2011161521A1 - Compositions comprising metformin and rosiglitazone

Info

Publication number: WO2011161521A1
Application number: PCT/IB2011/001403
Authority: WO
Inventors: Shirishkumar Kulkarni; Satish Kumar Dalal; Harshal Anil Jahagirdar; Kishore Kumar Konda
Original assignee: Lupin Limited
Priority date: 2010-06-21
Filing date: 2011-06-21
Publication date: 2011-12-29

Abstract

A composition comprising: a core which comprises of metformin, rosiglitazone, and pharmaceutically acceptable excipients and permeable coating. The invention further involves a composition comprising a core which comprises of metformin, rosiglitazone,and pharmaceutically acceptable excipients and permeable coating comprising ammonio methacrylate copolymer. A process of manufacturing a tablet comprising metformin and rosiglitazone wherein the process comprises of preparing granules of rosiglitazone by mixing rosiglitazone with molten carrier, preparing granules of metformin, mixing and compression of granules followed by coating with permeable coating.

Description

COMPOSITIONS COMPRISING METFORMIN AND ROSIGLITAZONE

Field of the Invention:

The invention relates to composition comprising rosiglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof and metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof.

Background of the Invention:

Type 2 diabetes is a chronic disease in which the pancreas produces some insulin which is relatively inadequate for the body's needs and sometimes produce more than normal quantities of insulin. A major feature of type 2 diabetes is insulin resistance, in this condition the pancreas produce insulin but the body cells lack insulin sensitivity and cannot utilize it effectively to let glucose inside and produce energy and thus the sugar (glucose) stays in the blood. This causes hyperglycemia (high blood glucose). To compensate, the pancreas produces more insulin, the cells sense this flood of insulin and become more resistant, resulting in high glucose levels and often times high insulin levels.

When the person with type 2 diabetes cannot achieve normal or near-normal blood glucose levels with diet and exercise, medication may be used to lower blood glucose levels. Type 2 diabetes medications include, for example, sulfonylureas which stimulate the beta cells of the pancreas to release more insulin (Chlorpropamide, glipizide, glyburide, and glimepiride); biguanides which signal the liver to decrease its production of glucose, which increases glucose levels in the blood stream (metformin); meglitinides which signal the pancreas to make more insulin in response to the glucose levels in the blood (repaglinide, nateglinide); alpha-glucosi las^inhibitors which help the body to lower blood glucose levels by blocking the breakdown of starches in the intestine. They also slow the breakdown of some sugars, such as table sugar. Their action slows the rise in blood glucose levels after a meal (Acarbose, meglitol), DPP-4 Inhibitors which lower blood sugar levels by blocking an enzyme known as dipeptidyl peptidase IV or DPP-4 that normally deactivates a protein (GLP- 1) that keeps insulin circulating in the blood. Slowing the deactivation process helps reduce sugar production, lowering blood glucose levels and thiazolidinediones which increase insulin sensitivity in cells (troglitazone, rosiglitazone, pioglitazone) or the combination of the mentioned classes of antihyperglycemic agents.

Rosiglitazone, (5-[4-[2-(N-methyl-N-(2-pyridyl) amino) ethoxy] benzyl] - thiazolidine-2, 4- Dione], is a member of the thiazolidinedione class of agents used to treat type 2 diabetes mellitus. Rosiglitazone is an oral antidiabetic agent, which acts primarily by increasing insulin sensitivity. Rosiglitazone improves glycemic control while reducing the circulating insulin levels. Rosiglitazone is a selective agonist for nuclear peroxisome proliferator- activated receptor-γ (PPARy). It binds to PPARy, which activates insulin-responsive genes that regulate carbohydrate and lipid metabolism. Rosiglitazone requires insulin to be present for its action. Rosiglitazone exerts its principal effects by increasing insulin sensitivity in peripheral tissue but also may lower glucose production by the liver. It increases glucose transport into muscle and adipose tissue by enhancing the synthesis and translocation of specific forms of the glucose transporters. The dose range for rosiglitazone is 0.1 mg to l OOmg.

The chemical structure of Rosiglitazone is shown below:

JL_Metformin^.( ^^ a biguanide antidiabetic agent that improves glucose tolerance in patients with type 2 diabetes. Metformin decreases hepatic glucose production and intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia and does not cause hyperinsulinemia. The dose range for metformin is 1 OOmg to 3000mg. Metformin is marketed as IR tablets with a dose of 500mg, 625mg, 750mg, 850mg and lgm, and as ER tablets with a dose of 500mg, 750mg and lgm.

The chemical structure of Metformin is shown below:

The above listed classes of drugs act in different ways to lower blood glucose levels, there is no "best pill" or treatment for type 2 diabetes as each individual responds differently to different drugs. A combination of 2, or even 3, types of anti-diabetic drugs is generally prescribed. Some combinations are available together in one pill. Some of the approved combinations include the following: thiazolidinedione and biguanide, a sulfonylurea and biguanide, a DPP-4 inhibitor and biguanide, a sulfonylurea and a thiazolidinedione, a meglitinide and biguanide.

The marketed formulation of rosiglitazone and metformin is an immediate-release dosage form containing rosiglitazone maleate and metformin hydrochloride known as AVANDAMET®. AVANDAMET® is recommended in cases where metformin alone does not adequately control type 2 diabetes. The available dosages are as rosiglitazone: metformin: 1 mg: 500 mg, 2 mg: 500 mg, 4 mg: 500 mg, 2 mg: 1000 mg, and 4 mg: 1000 mg and is dosed in divided doses with meals.

There are number of prior arts which disclose compositions comprising metformin and rosi-glitazon©:—^■ : ^{" " — ~} US 2008/0206336 discloses an oral dosage form comprising an erodable core, comprising Compound A (thiazolidinedione) and another antidiabetic agent, the core having erodable coating under predetermined pH conditions.

US 2005/0175700 discloses an oral dosage form comprising, (i) an erodable core, which core comprises rosiglitazone and (ii) an erodable coating surrounding said core, which coating comprises one or more openings extending substantially completely through said coating but not penetrating said core and communicating from the environment of use to said core; characterized in that release of rosiglitazone or a pharmaceutically acceptable salt or solvate thereof from the dosage form occurs through the said opening(s) by the erosion of said erodable core and through erosion of said erodable coating under pre-determined pH conditions.

US 2006/0193913 discloses a controlled release pharmaceutical composition comprising a particulate form of rosiglitazone, or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable carrier US 2008/0139624 discloses an oral dosage form comprising pellets of a first composition and pellets of a second composition, each composition comprising rosiglitazone, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier therefor, wherein the first and second compositions are arranged to release drug at differing release rates on administration. US 2008/0166408 discloses an oral dosage form, such as a bilayer tablet, comprising a first layer of a first composition and a second layer of a second composition, each composition comprising rosiglitazone or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier therefor, wherein the first and_se.c.ond-composit-ions-are- arranged to release drug at differing release rates on administration US 2007/0281023 discloses a sustained release pharmaceutical composition which composition comprises an insulin sensitizer (rosiglitazone) and a pharmaceutically acceptable carrier therefor, wherein the composition arranged to provide a combination of non-modified and sustained release of the insulin sensitizer.

US 2007/0141146 discloses a controlled release oral dosage form comprising rosiglitazone or a pharmaceutically acceptable salt or [solvate] hydrate thereof, dispersed in a carrier comprising a pharmaceutically acceptable waxy mixture of glyceride-based materials, wherein the oral dosage form comprises a stable polymorphic form of a macrogol glyceride.

US 2007/0275054 discloses a pharmaceutical composition, comprising a thiazolidinedione, metformin hydrochloride and a pharmaceutically acceptable carrier, wherein the thiazolidinedione and metformin hydrochloride are each dispersed within its own pharmaceutically acceptable carrier in the pharmaceutical composition.

WO01/35940 discloses a pharmaceutical composition comprising a thiazolidinedione metformin hydrochloride, and a pharmaceutically acceptable carrier, wherein the thiazolidinedione is formulated upon the surface of the metformin hydrochloride.

US 2005/0249809 discloses a pharmaceutical dosage form comprising a controlled release component comprising an antihyperglycemic drug in combination with a second component comprising a thiazolidinedione derivative and a disintegrating agent. The dosage formulation exhibits a significant increase in bioavailability of the thiazolidinedione derivative component compared to conventional immediate release dosage forms containing only a thiazolidinedione derivative. US 2005/0163842 discloses formulations comprising amorphous rosiglitazone and metformin dispersed in a solid polymeric matrix; wherein the solid polymeric matrix swells upon imbition of water. Formulations include formulations for retention in the stomach and upper gastrointestinal tract. Controlled-release dosage forms in which the release of the rosiglitazone, the metformin, or both are controlled are described. US 2004/0161462 discloses a pharmaceutical dosage form having a first and second active drug, said dosage form comprising: (a) a controlled release core comprising an antihyperglycemic drug and at least one pharmaceutically acceptable excipient; and (b) an immediate release thiazolidinedione derivative containing component. WOO 1/82867 discloses an invention which relates to a combination drug product comprising rosiglitazone and a biguanide. In particular, the product comprises a core of metformin; at least a portion thereof has a layer or coat thereon of rosiglitazone.

WO2007/043853 discloses an invention which relates to a composition comprising a combination of different types of antidiabetic substances that are selected from the group containing: sulfonylureas, meglitinides, biguanides or inhibitors of alpha-glucoside with thiazolidinediones for the treatment of type 2 diabetes mellitus.

US 2006/0141023 discloses an orally administered pharmaceutical composition that is a combination of two or more antidiabetic agents in which one of the antidiabetic agents is present in an extended release form and the other antidiabetic agent is present in an immediate release form.

WO2007/073136 Synergistic pharmaceutical composition comprising a synergistic combination of a thiazolidinedione (glitazone) and a biguanide for treating type-2 Diabetes Mellitus is disclosed.

WO2004/069229 discloses a process for dual release combination of pharmaceutical ingredients, more particularly, antidiabetic drugs, comprising extended release of biguanide and immediate release of thiazolinedione in a multilayer formulation. IN3 04/MW508$2-relates-to^h^^ containing anfi¾iaBeTic substance such as metformin or its pharmaceutically effective salts or pro-drug as modified release either singly or in combination with drugs and the process of the preparation for the same. US 2003/0187074 discloses an oral delivery system for the treatment of non-insulin dependent diabetes mellitus in humans includes a pharmaceutically effective amount of a biguanide and a water-insoluble polymeric carrier, providing for a controlled release of the biguanide independent of environmental pH. US 2009/01 10728 relates to a solid dosage form comprising: a matrix core which comprises a hydrophobic material and a water soluble pharmaceutical agent; and a modified release coating surrounding the matrix core, wherein the modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent; wherein the solid dosage form is capable of releasing the pharmaceutical agent at a zero order release rate for a period of at least four hours after administration to a subject. The application discloses rosiglitazone and metformin as water soluble pharmaceutical agent.

US 2006/0204578 discloses a dual controlled release osmotic device comprising: a) a core comprising a first active agent-containing controlled release layer and a second active agent- containing controlled release layer in direct contact therewith, wherein the second active agent containing layer surrounds the first active agent containing layer and b) a membrane surrounding the core, wherein the membrane comprises at least one preformed passageway in communication with at least one of the first and second active agent-containing controlled release layers; whereby the osmotic device provides a controlled release of the first active agent through the at least one preformed passageway according to a first release profile and the second layer provides a controlled release of the second active through the at least one preformed passageway according to a second release profile. Specification discloses metformin and/or rosiglitazone as a first and/or second active agent.

US 2004/0096499 discloses a dosage form of combination of high dose high solubility active i-ngredient7¾5-mOdified ingredient as immediate release suitable^" for swallowing; which comprises an inner portion having a low dose active ingredient as immediate release and an outer portion having a high dose, high solubility active ingredient as modified release, wherein said inner portion is covered by the outer portion from all the sides except a top surface that remains uncovered; wherein outer portion comprises: a) micro matrix particles containing high dose, high solubility active ingredient and one or more hydrophobic release controlling agent wherein the ratio of high dose, high solubility active ingredient and hydrophobic release controlling agent is in the range of 100:2.5 to 100:30 and b) a coating of one or more hydrophobic release controlling agents on said micro matrix particles, wherein the ratio of micro matrix particles and hydrophobic release controlling agent is in the range of 100:2.5 to 100:30. Specification [claim 68] discloses rosiglitazone maleate as low dose antidiabetic active ingredient and [claim25] discloses metformin as high solubility active ingredient. Metformin has high aqueous solubility and due to its high solubility the formulation comprising metformin may show problems of dose dumping. Rosiglitazone has a very low dose and thus composition comprising metformin and rosiglitazone may have problems associated with uniformity of content and dose dumping of metformin. Although number of approaches have been disclosed in the prior art for preparing a composition comprising metformin and rosiglitazone there is always a need to develop a better and cost effective composition. The invention describes composition comprising metformin and rosiglitazone and pharmaceutical acceptable excipients and a permeable coating. The invention also provides a composition of rosiglitazone and/ or metformin in which rosiglitazone is in immediate release or controlled release form and metformin is in controlled release form. Summary of the Invention:

One embodiment discloses a composition comprising:

(i) a core which comprises of metformin, rosiglitazone,and pharmaceutically acceptable excipients

(ii) permeable.coating —

Another embodiment discloses a process of manufacturing composition comprising metformin and rosiglitazone wherein the process comprises: (a) preparing granules of rosiglitazone by mixing rosiglitazone with molten carrier,

(b) preparing granules of metformin,

(c) mixing and compression of granules of step (a) and (b),

(d) followed by coating with permeable coating.

Another embodiment discloses a process of manufacturing composition comprising metformin and rosiglitazone wherein the process comprises:

(a) preparing granules of metformin using a granulating solution comprising rosiglitazone,

(b) mixing and compression of the granules of step (a) with pharmaceutically acceptable excipients,

(c) followed by coating with permeable coating.

Another embodiment discloses a composition comprising:

(a) metformin,

(b) rosiglitazone,

wherein metformin is in extended release form and rosiglitazone is in immediate release form and

(c) a permeable coating.

Another embodiment discloses a composition comprising:

(a) metformin

(B) rosiglitazone,

wherein metformin and rosiglitazone is in controlled release form and

(c) a permeable coating. Detailed Description of the Invention:

The invention relates to composition comprising core comprising rosiglitazone or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; and metformin or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof and pharmaceutically acceptable excipients and a permeable coating.

As used herein, the term "immediate release" assumes the definition as widely recognized in the art of pharmaceutical sciences. An immediate release form releases drug immediately after administration

As used herein, the term "controlled release" assumes the definition as widely recognized in the art of pharmaceutical sciences. A controlled release form controls or modifies the release of drug over an extended period of time.

The term controlled release composition may also be denoted by prolonged release composition, programmed release composition, timed release composition, modified release composition, site specific release composition, sustained release composition, extended release composition, slow release composition,, delayed release composition, osmotic dosage form, bioadhesive composition, gastroretentive composition and other such dosage forms.

As used herein the term rosiglitazone would include all forms of rosiglitazone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. The most preferred form is rosiglitazone maleate.

As used herein the term metformin would include all forms of metformin or pharmaceutically-acceptable -saksres-tersT^olvatesTiiydrate^'STTrielHbul^'ites, prodrugs or isomers thereof. The most preferred form is metformin hydrochloride. The composition may be in the form of tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, and timed release tablets), pellets, beads, granules, spheroids, particles, powders, capsules microcapsules, tablets in capsules, microspheres, matrix formulations, microencapsulation.

The term "pharmaceutically-acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of metformin and rosiglitazone the active ingredient selected for use.

As the term indicates the "permeable coating" means a coating which allows for the passage of an external fluid such as water and biological fluids and the antihyperglycemic drug present in the core. The permeable coating may comprise of controlled release polymer.

One embodiment discloses a composition comprising: (i) a core comprising (a) metformin (b) rosiglitazone and pharmaceutically acceptable excipients and (ii) a permeable coating. The preferred form of rosiglitazone is rosiglitazone maleate and metformin is metformin hydrochloride. The term "core" means the mixture of the active ingredient(s) and the pharmaceutically- acceptable excipients which can be in the form of powder, beads, pellets, granules, microcapsules, microgranules, tablet, compact, spheroid, particles and the like. The core may further comprise of controlled release polymer.

The composition may contain pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrating agents; glidants; stabilizers; osmotic agents and surface active agents.

Another embodiment discloses a composition comprising: (a) metformin,

(b) rosiglitazone, wherein metformin is in controlled release form and rosiglitazone is in immediate release form and

(c) a permeable coating.

Another embodiment discloses a composition comprising:

(a) metformin,

(b) rosiglitazone, wherein metformin and rosiglitazone is in controlled release form and

(c) a permeable coating Examples of binders include, potato starch; modified starch; gelatin; wheat starch; corn starch; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (hypromellose), ethyl cellulose and sodium carboxy methyl cellulose; natural gums such as acacia, alginic acid and guar gum; liquid glucose; dextrin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; gelatin; poly propylene glycol; tragacanth; hydrogenated vegetable oil; castor oil; paraffin; higher aliphatic alcohols; higher alphatic acids; long chain fatty acids; fatty acid esters; and wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, stearic acid and stearyl alcohol.

Examples of diluents include, pharmaceutically acceptable inert fillers such as microcrystalline cellulose; lactose; dibasic or tribasic calcium phosphate; saccharides confectioner's sugar; compressible sugar; dextrates; dextrin; dextrose; fructose; lactitol; mannitol; sucrose; starch; xylitol; sorbitol; talc; calcium carbonate; and calcium sulphate.

The disintegrating agents include water swellable substances, for example, low-substituted hydroxypropyl cellulose, e.g. L-HPC; cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethylcellulose (sodium croscarmellose); sodium starch glycolate; sodium carboxymethylcellulose; sodium carboxymethyl starch; ion-exchange resins such as polacrillin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; celluloses or cellulose derivatives and combinations comprising one or more of the foregoing water swellable substances.

The lubricants may include, but are not limited to, Mg, Al or Ca or Zn stearate; polyethylene glycol; glyceryl behenate; glyceryl monosterate; mineral oil; sodium stearyl fumarate; stearic acid; hydrogenated vegetable oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; polyethylene glycol; ethylene oxide polymers; and colloidal silica.

The glidants may include, but are not limited to, magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide; and silicon hydrogel.

The composition may optionally contain a surface active agent. The surface active agents may include, but are not limited to, fatty acid; olefin; alkylcarbonyl; silicon elastomer; sulfate ester; petty alcohol sulfate; sulfate pete and oil; sulfonic acid-base; fat sulfonate; alkylaryl sulfonate; lignin sulfonate; phosphoric acid ester; polyoxyethylene; polyoxyethylene caster oil; polyglycerol; polyol; imidazol; altanolamine; hetamine; sulfobecamine; phosphotide; polyoxyethylene-sorbitan fat acid ester (Tween); and sorbitan ester (Span).

The osmotic agents may include, but are not limited to sodium chloride; potassium chloride; magnesium sulfate; magnesium chloride; sodium sulfate; lithium sulfate; urea; inositol; sucrose; lactose; glucose; sorbitol; fructose; mannitol; dextrose; magnesium succinate; and potassium acid phosphate.

The controlled release polymer may be selected from water soluble polymer, water insoluble polymer, waxy material or combination thereof.

The^"preferre^'d-c^"o^"nlrolled^"relcase polymer is water soluble polymer which may be selected^" from alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose (hypromellose); sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; glycerol fatty acid esters, sorbitan esters, lecithins, other natural, semi-synthetic, or synthetic di-, oligo-, and polysaccharides such as galactomannans, tragacanth, agar, guar gum, gum arabic, pectin, acacia, karaya, locust bean gum, xanthan gum, pullulan, collagen, casein, aligns, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, scleroglucan and polyfructans, maltodextrin; methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, gelatin, starch, crosslinked starch, microcrystalline cellulose, chitin, poly(hydroxyalkyl methacrylate), polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate; and mixtures and blends thereof..

Water insoluble polymer may be selected from cellulose acylate; cellulose ethyl ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose diacetate; cellulose triacetate; mono-, di- and tricellulose alkan, mono-, di- and tricellulose aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvinylacetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); poly (vinyl acetate); poly vinyl alcohols; polyacrylamide derivatives ammonio methacrylate copolymers such as Eudragit RS and RL , poly acrylic acid and poly acrylate and methacrylate copolymers such as Eudragit S and L, aminoacryl-methacrylate copolymer Eudragit RS-PM, polyvinyl acetaldiethylamino acetate, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, polyacrylamides, Polyox( polyethylene oxides), diesters of polyglucan, cellulose butyrate, cellulose propionate, shellac and the like. Waxy material may be selected from carnauba wax; beeswax; Chinese wax; spermaceti; lanolin; bayberry wax; candelilla wax; castor wax; esparto wax; Japan wax; jojoba oil; ouricury wax; rice bran wax; ceresin waxes; montan wax; ozokerite; peat waxes; paraffin wax; polyethylene waxes; and polyglycerol fatty acid esters.

Combination of controlled release polymers is also included within the scope of the invention.

The permeable coating may also comprise of controlled release polymer. The coating may also be made permeable by the addition of pore forming agents. Other excipients such as plasticizers, lubricants, colorants may also be added in the coating. Suitable plasticizers include for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i- octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2- ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

The pore forming agents may be polymeric or non polymeric in nature. Any water soluble material present in the coating which dissolves and forms pores in the coating layer may act as pore forming agents. Pore forming agents may be selected form of potassium salts such as potassium chloride, sodium salts as sodium chloride, calcium salts, magnesium salts, amino acids, week acids, carbohydrates such as sucrose; mannitol; sorbitol, lactose, polymers with amino and/or acid functions or polyvinyl pyrrolidine.. Examples are aspargine, glutamine, leucin, neroleucine, isoleucine, magnesium citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide. The permeable coating may be applied using aqueous, non aqueous or combination solvents. The coating operation may be conducted in standard equipment such as a fluid bed coater, a wurster coater or a rotary bed coater.

The composition may be manufactured by various methods known in the art such as by dry granulation, slugging, roller compaction, wet granulation (using aqueous / nonaqueous solvents), melt granulation, solid dispersion, direct compression, double compression, extrusion spheronization, layering, High shear mixture granulation, Fluid bed granulation, spray drying, steam granulation, moisture activated dry granulation, moist granulation, thermal adhesion granulation, foam granulation and the like. Compaction of the blend into coprimate may be carried out using a slugging technique or roller compaction. The milling of the granules may be carried out according to conventional milling methods.

The solvent which may be used for manufacturing the composition may be aqueous, non aqueous or combination thereof.

Melt granulation technique involves melting of the carrier at a higher temperature. The carrier for melt granulation may be selected from different grades of polyethylene glycols, cellulose ethers and acrylates, · various molecular weight of polyethylene oxides, poly methacrylate derivatives, poloxamers, thermoplastic aliphatic poly (esters) such as poly (lactide) (PL A), poly (glycolide) (PGA) and copolymer of lactide and glycolide, poly (lactide-co-glycolide) (PLGA). Starch and starch derivatives, sugars and sugar alcohols and waxes.

Another embodiment discloses a process of manufacturing composition comprising: metformin and rosiglitazone wherein the process comprises:

^' ( a ) ^"preparing granules of ro igTftazone by mixing rosiglitazone wiflTmolten carrier

(b) preparing granules of metformin,

(c) mixing and compression of granules of (a) and (b), (d) followed by coating with permeable coating.

(c) followed by coating with permeable coating. The invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Example 01:

Procedure:

Granulation I

Metformin Hydrochloride was sifted. Povidone was dissolved in required quantity of water to form clear solution and was used to granulate Metformin hydrochloride. The granules of Metformin hydrochloride were dried in a tray dryer and sifted.

Granulation II Microcrystalline Cellulose, Lactose Monohydrate, Sodium Starch Glycolate were sifted and mixed uniformly. Rosightazone Maleate was sifted and all ingredients were mixed geometrically. Polyethylene glycol was melted and the sifted mixture was added with stirring at room temperature. The granules thus obtained were sifted.

Mixing and compression

Granules of Metformin Hydrochloride, granules of Rosightazone Maleate and Hypromellose were mixed uniformly. The granules were lubricated and compressed using suitable punch. The tablet so obtained was then coated. Example 02:

Procedure:

Metformin was granulated using a solution or dispersion of rosiglitazone and povidone in water/hydroalcoholic solvent. The granules were dried and then were uniformly mixed with microcrystalline cellulose, hypromellose and magnesium stearate and compressed using suitable punch to obtain tablets. The tablets were coated using above coating solution.

Example 03:

Procedure:

Claims

1. A composition comprising:

(ii) permeable coating.

2. The composition of claim 1 where in the permeable coating comprise of controlled release polymer.

3. The composition of claim 2 wherein the controlled release polymer is water soluble polymer, Water insoluble polymer, waxy material or combination thereof.

4. A composition comprising:

(i) a core which comprises of metformin, rosig^'litazone,and pharmaceutically acceptable excipients

(ii) permeable coating comprising ammonio methacrylate copolymer.

5. The composition according to claim 4 wherein the ammonio methacrylate copolymers is ammonio methacrylate copolymer, Type A or ammonio methacrylate copolymer, Type B or combination thereof.

6. The composition according to claim 4 wherein the core may contain controlled release

7. The composition according to claim6 wherein the controlled release polymer is water soluble polymer, water insoluble polymer, waxy material or combination thereof.

8. The composition according to claim 7 wherein the water soluble polymer is selected from alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and

5 hydroxypropyl methyl cellulose (hypromellose); sodium or calcium carboxymethyl cellulose, methyl ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; glycerol fatty acid esters, sorbitan esters, lecithins, other natural, semi-synthetic, or synthetic di-, oligo-, and polysaccharides such as galactomannans, tragacanth, agar, guar gum, gum arabic, pectin, acacia, karaya, locust bean gum, xanthan gum, pullulan, collagen, casein, aligns,

10 ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, scleroglucan and polyfructans, maltodextrin; methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide,

15 carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, gelatin, starch, crosslinked starch, microcrystalline cellulose, chitin, poly(hydroxyalkyl methacrylate), polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate; and mixtures and blends thereof.

20

9. The composition according to claim 8 wherein the water soluble polymer is alkyl celluloses.

10. A process of manufacturing a tablet comprising metformin and rosiglitazone wherein the —2-5-— rocess comprises. of:

(a) preparing granules of rosiglitazone by mixing rosiglitazone with molten carrier,

(b) preparing granules of metformin,

(c) mixing and compression of granules of step (a) and (b), (d) followed by coating with permeable coating.

1 1. The composition of claim 10 where in the permeable coating comprise of controlled release polymer.

12. The composition of claim 1 1 wherein the controlled release polymer is water soluble polymer, Water insoluble polymer, waxy material or combination thereof.

13. A process of manufacturing tablet composition comprising metformin and rosiglitazone wherein the process comprises:

(c) followed by coating with permeable coating.

14. The composition of claim 13 where in the permeable coating comprise of controlled release polymer.

15. The composition of claim 14 wherein the controlled release polymer is water soluble polymer, Water insoluble polymer, waxy material or combination thereof.