Indian Patents. 204612:DOSAGE FORM FOR TREATMENT OF DIABETES MELLITUS

Title of Invention	DOSAGE FORM FOR TREATMENT OF DIABETES MELLITUS
Abstract	A dosage from for treatment of diabetes mellitus and condition associated with it comprising a combiniation of biguanide and long-acting sulfonyl urea such that the long-acting sulfonyl urea is released immediately and the biguanide is released in a controllwed manner.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See section 10) DOSAGE FORM FOR TREATMENT OF DIABETES MELLITUS 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 following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. DOSAGE FORM FOR TREATMENT OF DIABETES MELLITUS The present invention relates to a dosage form for treatment of diabetes mellitus and preconditions assjociated-with it comprising^a^ornbination^of biguanide and long-acting sulfonyl urea such that the long-acting sulfonyl urea is released immediately and the biguanide is released in a controlled manner. BACKGROUND OF THE INVENTION Non-insulin dependent diabetes mellitus (NTDDM), also known as maturity-onset diabetes or diabetes mellitus type 2, is a frequent metabolic disease and the main cause of hyperglycemia. It is a heterogeneous disease with complex, unclarified metabolic aspects. Insulin secretion may appear normal or even excessive, but it is insufficient to compensate for insulin resistance. The disease is characterized by three main abnormalities of metabolism contributing to hyperglycemia. These include the partial or complete decrease in insulin secretion, resistance of the peripheral tissues to insulin and increased hepatic production of glucose in fasting conditions. Diet and physical exercise cause a reduction in insulin-resistance and lead to an improvement in the pancreas deficit over a period of time. H When these provisions are not sufficient, a pharmacological agent(s) needs to be taken V for control of hyperglycemia. Sulfonyl ureas and biguanide derivatives have been used in 1 diabetes therapy. The use of these classes of compounds in the monotherapy has been effective in obtaining a glycometabolic control in diabetic patients. Biguanide derivatives like metformin, phenformin and buformin, generally in the form of their hydrochloride salt, have been used.as anti-hyperglycemic agents in the treatment of non-insulin dependent diabetes mellitus. The mechanism of action of the drugs belonging to this class includes reduction in hepatic glucose production, decrease in intestinal absorption of glucose, and increase in glucose uptake and utilization. Biguanides improve 2 glucose tolerance in patients with diabetes mellitus type 2, lowering both basal and post- _ prandial plasma glucose. With biguanide therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Although phenformin is still used widely as an anti-hyperglycernic agent, metformin is * the preferred biguanide, as it exerts a better normoglycemic action with a lower risk of lactic acidosis - a common side-effect with phenformin therapy. Metformin is also known to lower blood triglyceride levels and assist in weight reduction. The sulfonyl ureas used in the treatment of diabetes mellitus type 2 include acetohexamide, carbutamide, chlorpropamide, glipizide, glyburide (glibenclamide), glimepiride, gliclazide, glibornuride, gliquidone, glisoxepid, glyhexamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, etc. These sulfonyl ureas are used as their bases and not as salts. The mechanism of action of these drugs involves lowering of blood glucose concentration mainly by stimulating release of endogenous insulin from beta cells of the pancreas, and thus they act as hypoglycemic agents. The sulfonyl ureas are used as an adjunct to diet for the management of non-insij]in dependent diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet alone. To achieve maximum reduction in post-prandial blood-glucose concentration, the sulfonyl urea is administered 30 minutes prior to each meal. Out of these long-acting sulfonyl ureas can be enumerated as carbutamide, chlorpropamide, glibenclamide, gliclazide, glimepiride. In particular, glimepiride has a more pronounced in vitro insulin secretory activity as compared to the other sulfonyl ureas. The drug achieves therapeutically equivalent blood glucose control with lower fasting plasma insulin levels. Since hyperinsulinaemia leads to acceleration of atherosclerosis, glimepiride has a major advantage over currently available sulfonyl ureas. In addition, extrapancreatic effects may also play a role in the activity of glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. It is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of KlDDM patients. Glimepiride is also safe for use in the elderly and those with renal impairment. It has a quick onset of 3 action and, at the same time, its duration of action is prolonged so that it needs to be administered only once a day. Hence, glimepiride is the preferred sulfonylurea. As referred to herein, "conditions associated with diabetes mellitus" includes those* conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus. When used herein the term "conditions associated with pre-diabetic state^includes conditions such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, obesity ,SA"S^^Si^»^^b^^^^^^^^m^w^^^ and hyperinsulinaemia. "Conditions„t,asso.ciated, with diabetes mellitus" itself include hyperglycemia, insulin resistance, including acquired insulin resistance and obesity. Further conditions associated with diabetes mellitus itself inculed hypretension and ardiovascular disease, especially atherosclerosis and conditipjis^sjpjsiated-withjrisulm resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance and gestationaLdiabetes. "Complications associated with diabetes mellitus" includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy. Renal diseases associated with Type II diabetes include nephropathy, glomerulohephritis, glomerular sclerosis, nephritic syndrome, hypertensive nephrosclerosis and end stage renal disease. The 54th edition of the Physicians" Desk Reference, copyright 2000, suggests that the monotherapy with metformin hydrochloride, commercially available under the trade name Glucophage® from Bristol-Myers Squibb Co., may be effective in patients who have not responded to sulfonyl ureas or who have only a partial response to sulfonyl ureas or who have ceased to respond to sulfonyl ureas. In such patients, if adequate glycemic control is not attained with Glucophage® monotherapy, the combination of Glucophage® and a sulfonyl urea may have a synergistic effect. Also, monotherapy with the sulfonyl ureas has been found to give a positive response, which lasts for 4-5 years, but it becomes ineffective in a large number of patients over a period of time. This is referred to as the "secondary failure" associated with the oral therapy with hypoglycemic agents. In both these cases, a combination of biguanides and sulfonyl ureas is used. The biguanides are able to act on insulin resistance but cannot stimulate insulin secretion, 4 while the sulfonyl ureas can stimulate insulin release but are unable to act on insulin resistance. A combination therapy of a biguanide and a sulfonyl urea has a synergistic "•* effect on glucose control, since both agents act by different but complementary mechanisms. Although the 54th Edition of Physician Desk Reference is suggesting of a combination therapy of a biguanide and a sulfonyl ureas it does not disclose the. manners of delivering them from a single unit dosage form. Particularly it does not disclose immediate release of a long-acting sulfonyl urea for maximum reduction of post-prandial-glucose and sustained release of a biguanide as a once-a-day dosage regimen. United States Patent No. 5,922,769 (769) claims a method of treating non-insulin dependent diabetes mellitus in cases of secondary failure comprising administering to the subject in need of the same a combination of glibenclamide and metformin, expressed as the hydrochloride, in a weight ratio higher than 1:100. The patent also discloses the results of a clinical study, which indicates that the maximum dose of glibenclamide, which does not cause any side-effects, is 15mg/day, while that for metformin is 1500 mg/day, and that the use of such a combination in a ratio lower than that claimed would result in formulations that do not attain the optimum therapeutic effect. The patent claims the combination of glibenclamide and metformin in a tablet form. The patent does not disclose a formulation wherein the sulfonyl urea will be released immediately and the biguanide will be released in a controlled manner. United States Patent No. 6,031,004 ("004) discloses the use of a combination of novel salts of metformin and glyburide, in the treatment of diabetes mellitus type 2. In this invention, both metformin salt and glyburide are released immediately. United States Patent No. 6,099,862 ("862) claims a controlled release pharmaceutical tablet which consists essentially of (a) a core consisting essentially of: (i) metformin or a pharmaceutically acceptable salt thereof, (ii) glipizide, (iii) polyvinylpyrrolidone, and (iv) sodium lauryl sulfate, (b) optionally a seal coat around the core, (c) a semipermeable membrane coating covering said core comprising - (i) cellulose acetate, (ii) polyethylene glycol with an average molecular weight between 380 and 420, and (iii) a plasticizer, and 5 (d) at least one passageway in the semipermeable membrane to allow the release of the metformin and glipizide from the core to the environment of use to provide therapeutic levels of metformin and glipizide from twelve to twenty-four hour periods. A dosage form comprising a biguanide and a long-acting sulfonyl urea that immediately releases a sulfonyl urea, such as glimepiride, after administration of the dosage form, and releases, a biguanide, such as metformin, such that the biguanide in a controlled manner is not disclosed by the "862 patent. The prior art thus does not mention any such formulations or systems containing combinations of a biguanide and long-acting sulfonyl urea wherein the long-acting sulfonyl urea is released immediately and the biguanide is released hi a controlled manner. Prior art compositions of long-acting sulfonyl urea such as glimepiride is given once-daily and those of biguanide such as metformin are given twice daily. Thus there is a need for a unit dosage form that would provide the combination of the long-acting sulfonyl urea and the biguanide and be suitable for once-daily administration. Such a unit dosage form minimizes the need for the patient to take multiple dosage form at different times. The resulting patient convenience improves patient compliance to the prescribed dosage regimen and thus improves therapy. OBJECT OF THE INVENTION The object of the present invention is to provide a dosage form for treatment of diabetes mellitus and conditions associated with it, comprising a long-acting sulfonyl urea and a biguanide wherein the long-acting sulfonyl urea is released immediately and the biguanide is released in a controlled manner. SUMMARY OF THE INVENTION The present invention provides a pharmaceutical dosage form for the treatment of diabetes mellitus and conditions associated with it; comprising an immediate release composition comprising a long-acting sulfonyl urea and a controlled release composition comprising a biguanide. 6 DETAILED DESCRIPTION OF THE INVENTION The dosage form of the present invention is designed to allow immediate release of the ,s ^ long-acting sulfonyl urea and a controlled release of the biguanide. Those skilled in the art would realize that by immediate release of the long-acting sulfonyl urea typically one means that release of the long-acting sulfonyl urea occurs substantially immediately after administration of the dosage form, for instance or for illustrative purpose, about 80% or more of the total amount of sulfonyl urea may be released in 30 minutes. Examples of biguanide antidiabetic agents that may be used in the present invention include metformin, phenformin and buformin and their pharmaceutically acceptable salts. Examples of long-acting sulfonyl ureas that may be used in the present invention include carbutamide, chlorpropamide, glyburide (glibenclamide), glimepiride, gliclazide, glibornuride, glyhexamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide and the like. In the preferred embodiments of the present invention the dosage form comprises of metformin or its pharmaceutically acceptable salt as the preferred biguanide antidiabetic agent used in an amount of 500 mg and glimepiride as the long-acting sulfonyl urea used in an amount of 1.0 mg. The invention covers any dosage form in which the immediate release composition comprising a long-acting sulfonyl urea and the biguanide composition released in a controlled manner are physically separated, or compartmentalized, so as to achieve different release rates of the two drugs. Such separation, or compartmentalization, may be on a macro-scale, for instance, with the different drugs being incorporated into separate units (such as tablets, powder, granules, pellets etc) for simultaneous or sequential administration, or separation of the two drugs may be on a micro-scale, for instance, with the two drugs being present within the same unit. Two separate units when present are formed into a single unit dosage form by filling them into capsules. 7 In the dosage form of the present invention, the immediate release and»the controlled II release composition may be in the form of either multiparticulates such as particles, pellets or granules, or present as concentric or lammar tablet layers or as\single units such s; =■. as a compressed tablet. The multiparticulates may be made by any of the conventional methods, including mixing, granulation, extrusion, spheronisation, layering of non-pareil seeds, etc, and various other methods known to a person skilled in the art. A compressed " tablet core may be obtained by compressing the multiparticulates in a tablet die. The biguanide composition may be surrounded by a controlled release coating comprising controlled release material selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic non-polymeric compounds, hydrophilic polymers and the like, using conventional coating methods. The coated multiparticulates or tablets of the biguanide composition and the uncoated multiparticulates or tablets of the second long-acting sulfonyl urea composition, may be filled into capsules. Alternatively, tablets of the biguanide composition may be surrounded by the immediate release long-acting sulfonyl urea composition and compressed in a compression coating tablet machine or a second layer of the long-acting sulfonyl urea composition may be compressed onto the compressed biguanide composition to form bilayer tablets. In the preferred embodiments of the present invention, the biguanide controlled release composition comprises a biguanide and one or more rate controlling excipient(s). The rate controlling excipient(s) used in the present invention may be any material that slows the rate of release* of the drug from the dosage form. Usually, the rate controlling excipient(s) is/are a polymer or a fatty compound or a mixture thereof. It may also comprise an ion-exchange resin. Examples of rate controlling polymers that may be used in the present invention include, but are not limited to: • cellulose ethers 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 alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose 8 (HEMC), hydrophobically modified hydroxyethyl cellulose .(HMHEC), * hydrophobically modified ethylhydroxyethylcellulose ;" (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl hydrophobically modified hydroxyethyl cellulose (CMHMHEC), and thelike; • vinyl pyrrolidone polymers such as crosslinked polyvinylpyrrolidone or crospovidone, copolymers of vinyl pyrrolidone and vinyl acetate; • alkylene oxide homopolymers such as polypropylene oxide, preferably ethylene oxide homopolymers • a superdisintegrant polymer such as cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, carboxymethyl starch, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross-linked amylose, starch derivatives, cross-linked carboxymethylcellulose • gums of plant, animal, mineral or synthetic origin such as (i) agar, alginates, carrageenan, furcellaran derived from marine plants, (ii) guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants, (iii) microbial polysaccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum, and (iv) synthetic or semi-synthetic gums such as propylene glycol alginate, hydroxypropyl guar and modified starches like sodium starch glycolate, and the like; and • an acrylic acid polymer such as cross-linked polymer available under the trade name Carbopol® or homopolymers and co-polymers of acrylate or methacrylate monomers for example polymethacrylates marketed under the brand names of Eudragit®, particularly Eudragit® RS and Eudragit® RL. Examples of fatty compounds that may be used as the rate controlling excipients in the present invention include various waxes such as digestible, long chain (C8 -C50, especially C12 -C4o), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocarbons having a melting point of between 25° and 90° C are preferred. 9 In one embodiment of the present invention, the rate controlling excipient(s) is/are a, mixture of one or more hydrophilic swellable polymer(s). In a preferred embodiment of the present invention the hydrophilic swellable polymer(s) that may be used is vinyl pyrrolidone polymers or polyvinylpyrrolidone (PVP), also referred to as Povidone as the swellable polymers. These are the synthetic polymers consisting essentially of linear 1-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 Kollidon® (BASF), Plasdone® and Peristone® (General Aniline). PVP is classified into different grades on the Isasis 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. In yet another embodiment of the present invention the rate controlling excipient(s) may be 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 trade 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 10 applications depending upon the viscosity of the polymers and the applicability 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 haying 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 sparkling clear topical gels. The carbopol 934P is high purity grade of Carbopol 934. Depending on drug solubility, drug hydrophilicity and basic strength, polymer concentration 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 rate controlling excipient(s). 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 functional quaternary ammonium groups. Examples of starch derivatives that can be used in the biguanide composition as the rate controlling excipient(s) include, but are not limited to, sodium starch glycolate and various other anionic starch derivatives and the like. Examples of other anionic polymers that can be used as the rate controlling excipient(s) include, but are not limited to, gums such as Xanthan gums, sodium alginate, sold under the name of KELTONE®, propylene glycol alginate and the like. The preferred gum used as the rate controlling excipient in 11 the present invention is xanthan gum, which is a high molecular weight polysaccharide available in various grades, viscosity ranges and of different particle sizes. % ■ t t. "• Particularly, the preferred rate controlling excipient(s) used in the present invention is the cellulose ethers. 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 alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), and the like. More preferably, the rate controlling excipient(s) used in the biguanide composition of 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. 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. 12 HPMC is further categorized according to viscosity exhibited by the 2% HPMQ, solution in water. The grades based on the viscosities are K100LVP, K4M, KIJMP^KIQOMP and E4MP. The K100LVP indicates a minimal viscosity of lOOcps, K4M%>f 4000 cps," K15MP of 15,000 and K100MP of 100,000 and several low viscosity grides" such as E3, E5,E6,E15,E50andK3. \"\ •"■ In one embodiment of the present invention, the rate controlling excipient(s), is U high, viscosity grade cellulose derivative, preferably hydroxypropyl methyl cellulose, commercially available as Methocel® K100M, with a viscosity of a 2 % w/w aqueous solution ranging from 80,000 to about 120,000 cps. In preferred embodiments the rate controlling excipient(s) used in the present invention may be a mixture of high viscosity grade of HPMC having a viscosity greater than about 10,000 cps and low viscosity grade HPMC having a viscosity equal to or less than about 10,000 cps. hi the preferred embodiments of the present invention the rate controlling excipient(s) is selected from a group of polyacrylic acid or a xanthan gum or mixtures thereof. Carbopol 934P is used as one of the rate controlling excipient(s). In the further 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 concentration ranging from about 10 to 15 % w/w by weight 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. In the preferred embodiments of the present invention, a combination of high molecular weight HPMC and Xanthan gum is used. HPMC may be used in the concentration ranging from about 10 to 20 % w/w of the total weight of the tablet and amounts of xanthan gum used may vary from about 5 to about 20 % w/w of the total weight of the tablet. More preferably, the HPMC used is a mixture of high viscosity grade of HPMC 13 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 the preferred embodiments of the present invention, the biguanide controlled release composition contains one or more pharmaceutically acceptable excipient(s) thatimprove , the compressibility of the biguanide 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 compressibility 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. By doing so, they enable one to include in the formulation excipient(s) that would otherwise create difficulty in keeping moisture within a range of 0.5-3 %. 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 the further preferred embodiments the biguanide controlled release composition of the present invention may be comprised of excipient(s) that further modulate the rate of release of biguanide from the composition. These may be 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 14 Science and Practice of Pharmacy; edition 19; Mack Publishing Cpmpany, Easto^n,? Pennsylvania (1995). Pharmaceutically acceptable water-soluble salts "of inorganic or • organic acids, or non-ionic organic compounds with high watei 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, magnesium 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, raffinose, 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. The additional excipient(s) used in the biguanide 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, 18th edition, page 1635-38(1990). In a preferred embodiment of the process of making the composition, the biguanide and the rate controlling excipient(s) are sifted and mixed with the binder in a rapid mixer granulator and granulated. In another preferred embodiments of the present invention, 15 only a part of the total polymeric swelling agent is included in the composition ,and the •■> remaining is mixed at the lubrication stage with the dried granules. Admixture of"water -and organic solvent is the preferred granulating agent. The granules thus bbfaiiied are wet milled through a screen and then dried in a fluidisedbed drier at 40-50°C to amoisture" content of 2-3%. The dried granules are then milled through a 2mm screen and are mixed with one or more lubricants. In more preferred embodiments, as described above, the remaining part of the rate controlling excipient(s) is/are mixed at this stage. The lubricated granules are then compressed to obtain the compressed tablets or cores. In addition to the above ingredients, the biguanide composition of the present invention may be covered 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 acrylic acid and methacrylic 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 permeability. In one of the preferred embodiments of the present invention, the water insoluble polymeric material used to coat the biguanide composition in the form of a core is a highly water permeable, pH independent methacryhc-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 citrate, diethyl phthalate, 16 glycerol, sorbitol, crotonic acid, propylene glycol, castor oil, citric acid esters^ dibutyl phthalate, dibutyl sebacate, and mixtures thereof. ,; Depending on the biguanide composition, the amount of the water insoluble \polymeric coating applied on the core may vary from about 0.5 to about 20 % w/w of .the total weight of the dosage form. The coating agents are dispersed in a solvent: of solvent""" system, and the solution or dispersion so obtained is used to coat the biguanide- * containing cores. Various solvents and mixtures of solvents can be used to provide the" coating agent solution or dispersion. Some of the preferred solvents include water, halogen hydrocarbons like trichloroethylene, methylene chloride (dichloromethane), carbon tetrachloride, and chloroform; alcohols such as absolute alcohol, isopropanol and methanol; low molecular weight esters like ethyl acetate and amyl acetate; and ketones such as acetone, 2-butanone and the like. A preferred embodiment of the present invention uses a mixture of acetone and isopropyl alcohol. 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. In one embodiment of the present invention, the immediate release long-acting sulfonyl urea layer is introduced by mixing the sulfonyl urea with pharmaceutical adjuvants such as film-forming agents, plasticisers and the like, in a suitable solvent or solvent system, and coating the biguanide-containing cores, using conventional coating methods known to a person skilled in the art. Examples of film-forming agents that may be used in the present invention along with the long-acting sulfonyl urea include cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethyl cellulose, methyl cellulose, methacrylic acid/methacrylate esters, polyvinyl acetate phthalate, shellac and the like, or mixtures thereof. Hydroxypropyl methylcellulose (HPMC) is used as the preferred film-forming agent along with the long-acting sulfonyl urea in the present invention, in an amount ranging from about 2% to about 20% by weight of the coated biguanide-containing core, more preferably from about 15% to about 20% by weight of the core. Examples of plasticisers that may be used in the present invention include, but are not limited to 17 glycerol, propylene glycol, polyethylene glycol, sorbitol, triacetin, diethyl phthalate, mineral oil, petrolatum, lanolin and the like, hi a preferred embodiment of the present invention, polyethylene glycol (PEG) 6000 is used as the plasticiser in an amount ranging s from 0% to about 5% by weight of the core, more preferably from about 0.1o/oto about 1% by weight of the core. The long-acting sulfonyl urea is dissolved inf/nlethylene chloride. HPMC dispersed in isopropyl alcohol and the long-acting sulfonyl urea are mixed in a solvent system and further mixed with the PEG 6000 previously *rneited_and\X dissolved in water. The solution thus obtained is used to coat the biguanide-containing core to a desired weight gain, in a conventional tablet-coating pan. The tablets afe,theh dried in a tray drier at a temperature of 40-50°C for 24 hours. The examples that follow do not limit the scope of the invention and are presented as illustrations. EXAMPLE 1 One embodiment of the present invention is described in the following example. The tablets were prepared according to the formula described as follows, 18 Table 1 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 umformly 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 clit mill. Stage C: Talc, magnesium stearate and colloidal silicon 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 RL100 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 2. 19 Table 2 Glimepiride is dissolved in methylene chloride. HPMC is dispersed in isopropyl alcohol The dispersion is added to the glimepiride 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 aboveisolution. 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 0.1N HC1 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 3 below. TABLE 3 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 4 below. 20 TABLE 4 We claim: metformin or its pharmaceutically acceptable salt. Dated this 27th day of September 2002. 1. A dosage form for the treatment of diabetes mellitus and conditions associated with it, comprising an immediate release composition comprising a long-acting^sulfonyl urea ■ and a controlled release composition comprising a biguanide. 2. A dosage form according to claim 1 wherein the biguanide is selected from a group consisting of metformin, phenformin, buformin and their pharmaceuticals "accepJtableL salts,, 3. A dosage form according to claim 2 wherein the biguanide is metformin or its pharmaceutically acceptable salts. 4. A dosage form according to claim 1 wherein the long-acting sulfonyl urea is selected form a group consisting of carbutamide, chlorpropamide, glyburide (glibenclamide), glimepirjdA,—gliclazide, glibornuride, glyhexamide," phenbutamide, tolazamide, tolbutamide and tolcyclamide. 5. A dosage form according to claim 4 wherein the long-acting sulfonyl urea is glimepiride. 6. A dosage form according to claim 5 wherein the composition contams 1.0 mg of glimepiride. 7. A dosage form according to claim 3 wherein the composition contains 500.0 mg of i 21

Full Text

FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
DOSAGE FORM FOR TREATMENT OF DIABETES MELLITUS
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 following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

DOSAGE FORM FOR TREATMENT OF DIABETES MELLITUS
The present invention relates to a dosage form for treatment of diabetes mellitus and

preconditions assjociated-with it comprising^a^ornbination^of biguanide and long-acting sulfonyl urea such that the long-acting sulfonyl urea is released immediately and the biguanide is released in a controlled manner.
BACKGROUND OF THE INVENTION
Non-insulin dependent diabetes mellitus (NTDDM), also known as maturity-onset diabetes or diabetes mellitus type 2, is a frequent metabolic disease and the main cause of hyperglycemia. It is a heterogeneous disease with complex, unclarified metabolic aspects. Insulin secretion may appear normal or even excessive, but it is insufficient to compensate for insulin resistance. The disease is characterized by three main abnormalities of metabolism contributing to hyperglycemia. These include the partial or complete decrease in insulin secretion, resistance of the peripheral tissues to insulin and increased hepatic production of glucose in fasting conditions. Diet and physical exercise cause a reduction in insulin-resistance and lead to an improvement in the pancreas deficit over a period of time.
H When these provisions are not sufficient, a pharmacological agent(s) needs to be taken V for control of hyperglycemia. Sulfonyl ureas and biguanide derivatives have been used in 1 diabetes therapy. The use of these classes of compounds in the monotherapy has been effective in obtaining a glycometabolic control in diabetic patients.
Biguanide derivatives like metformin, phenformin and buformin, generally in the form of their hydrochloride salt, have been used.as anti-hyperglycemic agents in the treatment of non-insulin dependent diabetes mellitus. The mechanism of action of the drugs belonging to this class includes reduction in hepatic glucose production, decrease in intestinal absorption of glucose, and increase in glucose uptake and utilization. Biguanides improve
2

glucose tolerance in patients with diabetes mellitus type 2, lowering both basal and post- _ prandial plasma glucose. With biguanide therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Although phenformin is still used widely as an anti-hyperglycernic agent, metformin is * the preferred biguanide, as it exerts a better normoglycemic action with a lower risk of lactic acidosis - a common side-effect with phenformin therapy. Metformin is also known to lower blood triglyceride levels and assist in weight reduction.
The sulfonyl ureas used in the treatment of diabetes mellitus type 2 include acetohexamide, carbutamide, chlorpropamide, glipizide, glyburide (glibenclamide), glimepiride, gliclazide, glibornuride, gliquidone, glisoxepid, glyhexamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, etc. These sulfonyl ureas are used as their bases and not as salts. The mechanism of action of these drugs involves lowering of blood glucose concentration mainly by stimulating release of endogenous insulin from beta cells of the pancreas, and thus they act as hypoglycemic agents. The sulfonyl ureas are used as an adjunct to diet for the management of non-insij]in dependent diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet alone. To achieve maximum reduction in post-prandial blood-glucose concentration, the sulfonyl urea is administered 30 minutes prior to each meal. Out of these long-acting sulfonyl ureas can be enumerated as carbutamide, chlorpropamide, glibenclamide, gliclazide, glimepiride.
In particular, glimepiride has a more pronounced in vitro insulin secretory activity as compared to the other sulfonyl ureas. The drug achieves therapeutically equivalent blood glucose control with lower fasting plasma insulin levels. Since hyperinsulinaemia leads to acceleration of atherosclerosis, glimepiride has a major advantage over currently available sulfonyl ureas. In addition, extrapancreatic effects may also play a role in the activity of glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. It is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of KlDDM patients. Glimepiride is also safe for use in the elderly and those with renal impairment. It has a quick onset of
3

action and, at the same time, its duration of action is prolonged so that it needs to be administered only once a day. Hence, glimepiride is the preferred sulfonylurea.
As referred to herein, "conditions associated with diabetes mellitus" includes those* conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus. When used herein the term "conditions associated with pre-diabetic state^includes conditions such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, obesity
,SA"S^^Si^»^^b^^^^^^^^m^w^^^
and hyperinsulinaemia. "Conditions„t,asso.ciated, with diabetes mellitus" itself include
hyperglycemia, insulin resistance, including acquired insulin resistance and obesity.

Further conditions associated with diabetes mellitus itself inculed hypretension and

ardiovascular disease, especially atherosclerosis and conditipjis^sjpjsiated-withjrisulm resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance and gestationaLdiabetes. "Complications
associated with diabetes mellitus" includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy. Renal diseases associated with Type II diabetes include nephropathy, glomerulohephritis, glomerular sclerosis, nephritic syndrome, hypertensive nephrosclerosis and end stage renal disease.
The 54th edition of the Physicians" Desk Reference, copyright 2000, suggests that the monotherapy with metformin hydrochloride, commercially available under the trade name Glucophage® from Bristol-Myers Squibb Co., may be effective in patients who have not responded to sulfonyl ureas or who have only a partial response to sulfonyl ureas or who have ceased to respond to sulfonyl ureas. In such patients, if adequate glycemic control is not attained with Glucophage® monotherapy, the combination of Glucophage® and a sulfonyl urea may have a synergistic effect. Also, monotherapy with the sulfonyl ureas has been found to give a positive response, which lasts for 4-5 years, but it becomes ineffective in a large number of patients over a period of time. This is referred to as the "secondary failure" associated with the oral therapy with hypoglycemic agents. In both these cases, a combination of biguanides and sulfonyl ureas is used. The biguanides are able to act on insulin resistance but cannot stimulate insulin secretion,
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while the sulfonyl ureas can stimulate insulin release but are unable to act on insulin resistance. A combination therapy of a biguanide and a sulfonyl urea has a synergistic "•* effect on glucose control, since both agents act by different but complementary mechanisms. Although the 54th Edition of Physician Desk Reference is suggesting of a combination therapy of a biguanide and a sulfonyl ureas it does not disclose the. manners of delivering them from a single unit dosage form. Particularly it does not disclose immediate release of a long-acting sulfonyl urea for maximum reduction of post-prandial-glucose and sustained release of a biguanide as a once-a-day dosage regimen.
United States Patent No. 5,922,769 (769) claims a method of treating non-insulin dependent diabetes mellitus in cases of secondary failure comprising administering to the subject in need of the same a combination of glibenclamide and metformin, expressed as the hydrochloride, in a weight ratio higher than 1:100. The patent also discloses the results of a clinical study, which indicates that the maximum dose of glibenclamide, which does not cause any side-effects, is 15mg/day, while that for metformin is 1500 mg/day, and that the use of such a combination in a ratio lower than that claimed would result in formulations that do not attain the optimum therapeutic effect. The patent claims the combination of glibenclamide and metformin in a tablet form. The patent does not disclose a formulation wherein the sulfonyl urea will be released immediately and the biguanide will be released in a controlled manner.
United States Patent No. 6,031,004 ("004) discloses the use of a combination of novel salts of metformin and glyburide, in the treatment of diabetes mellitus type 2. In this invention, both metformin salt and glyburide are released immediately.
United States Patent No. 6,099,862 ("862) claims a controlled release pharmaceutical tablet which consists essentially of (a) a core consisting essentially of: (i) metformin or a pharmaceutically acceptable salt thereof, (ii) glipizide, (iii) polyvinylpyrrolidone, and (iv) sodium lauryl sulfate, (b) optionally a seal coat around the core, (c) a semipermeable membrane coating covering said core comprising - (i) cellulose acetate, (ii) polyethylene glycol with an average molecular weight between 380 and 420, and (iii) a plasticizer, and
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(d) at least one passageway in the semipermeable membrane to allow the release of the metformin and glipizide from the core to the environment of use to provide therapeutic levels of metformin and glipizide from twelve to twenty-four hour periods. A dosage form comprising a biguanide and a long-acting sulfonyl urea that immediately releases a sulfonyl urea, such as glimepiride, after administration of the dosage form, and releases, a biguanide, such as metformin, such that the biguanide in a controlled manner is not disclosed by the "862 patent.
The prior art thus does not mention any such formulations or systems containing combinations of a biguanide and long-acting sulfonyl urea wherein the long-acting sulfonyl urea is released immediately and the biguanide is released hi a controlled manner. Prior art compositions of long-acting sulfonyl urea such as glimepiride is given once-daily and those of biguanide such as metformin are given twice daily. Thus there is a need for a unit dosage form that would provide the combination of the long-acting sulfonyl urea and the biguanide and be suitable for once-daily administration. Such a unit dosage form minimizes the need for the patient to take multiple dosage form at different times. The resulting patient convenience improves patient compliance to the prescribed dosage regimen and thus improves therapy.
OBJECT OF THE INVENTION
The object of the present invention is to provide a dosage form for treatment of diabetes mellitus and conditions associated with it, comprising a long-acting sulfonyl urea and a biguanide wherein the long-acting sulfonyl urea is released immediately and the biguanide is released in a controlled manner.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical dosage form for the treatment of diabetes mellitus and conditions associated with it; comprising an immediate release composition comprising a long-acting sulfonyl urea and a controlled release composition comprising a biguanide.
6

DETAILED DESCRIPTION OF THE INVENTION
The dosage form of the present invention is designed to allow immediate release of the ,s ^ long-acting sulfonyl urea and a controlled release of the biguanide. Those skilled in the art would realize that by immediate release of the long-acting sulfonyl urea typically one means that release of the long-acting sulfonyl urea occurs substantially immediately after administration of the dosage form, for instance or for illustrative purpose, about 80% or more of the total amount of sulfonyl urea may be released in 30 minutes.
Examples of biguanide antidiabetic agents that may be used in the present invention include metformin, phenformin and buformin and their pharmaceutically acceptable salts.
Examples of long-acting sulfonyl ureas that may be used in the present invention include carbutamide, chlorpropamide, glyburide (glibenclamide), glimepiride, gliclazide, glibornuride, glyhexamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide and the like.
In the preferred embodiments of the present invention the dosage form comprises of metformin or its pharmaceutically acceptable salt as the preferred biguanide antidiabetic agent used in an amount of 500 mg and glimepiride as the long-acting sulfonyl urea used in an amount of 1.0 mg.
The invention covers any dosage form in which the immediate release composition comprising a long-acting sulfonyl urea and the biguanide composition released in a controlled manner are physically separated, or compartmentalized, so as to achieve different release rates of the two drugs. Such separation, or compartmentalization, may be on a macro-scale, for instance, with the different drugs being incorporated into separate units (such as tablets, powder, granules, pellets etc) for simultaneous or sequential administration, or separation of the two drugs may be on a micro-scale, for instance, with the two drugs being present within the same unit. Two separate units when present are formed into a single unit dosage form by filling them into capsules.
7

In the dosage form of the present invention, the immediate release and»the controlled
II release composition may be in the form of either multiparticulates such as particles,
pellets or granules, or present as concentric or lammar tablet layers or as\single units such s; =■.
as a compressed tablet. The multiparticulates may be made by any of the conventional
methods, including mixing, granulation, extrusion, spheronisation, layering of non-pareil
seeds, etc, and various other methods known to a person skilled in the art. A compressed "
tablet core may be obtained by compressing the multiparticulates in a tablet die. The
biguanide composition may be surrounded by a controlled release coating comprising
controlled release material selected from the group consisting of enteric polymers, water
insoluble polymers, hydrophobic compounds, hydrophilic non-polymeric compounds,
hydrophilic polymers and the like, using conventional coating methods. The coated
multiparticulates or tablets of the biguanide composition and the uncoated
multiparticulates or tablets of the second long-acting sulfonyl urea composition, may be
filled into capsules. Alternatively, tablets of the biguanide composition may be
surrounded by the immediate release long-acting sulfonyl urea composition and
compressed in a compression coating tablet machine or a second layer of the long-acting
sulfonyl urea composition may be compressed onto the compressed biguanide
composition to form bilayer tablets.
In the preferred embodiments of the present invention, the biguanide controlled release composition comprises a biguanide and one or more rate controlling excipient(s). The rate controlling excipient(s) used in the present invention may be any material that slows the rate of release* of the drug from the dosage form. Usually, the rate controlling excipient(s) is/are a polymer or a fatty compound or a mixture thereof. It may also comprise an ion-exchange resin. Examples of rate controlling polymers that may be used in the present invention include, but are not limited to:
• cellulose ethers 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 alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose
8

(HEMC), hydrophobically modified hydroxyethyl cellulose .(HMHEC), *
hydrophobically modified ethylhydroxyethylcellulose ;" (HMEHEC),
carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl
hydrophobically modified hydroxyethyl cellulose (CMHMHEC), and thelike;
• vinyl pyrrolidone polymers such as crosslinked polyvinylpyrrolidone or crospovidone, copolymers of vinyl pyrrolidone and vinyl acetate;
• alkylene oxide homopolymers such as polypropylene oxide, preferably ethylene oxide homopolymers
• a superdisintegrant polymer such as cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, carboxymethyl starch, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross-linked amylose, starch derivatives, cross-linked carboxymethylcellulose
• gums of plant, animal, mineral or synthetic origin such as (i) agar, alginates, carrageenan, furcellaran derived from marine plants, (ii) guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants, (iii) microbial polysaccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum, and (iv) synthetic or semi-synthetic gums such as propylene glycol alginate, hydroxypropyl guar and modified starches like sodium starch glycolate, and the like; and
• an acrylic acid polymer such as cross-linked polymer available under the trade name Carbopol® or homopolymers and co-polymers of acrylate or methacrylate monomers for example polymethacrylates marketed under the brand names of Eudragit®, particularly Eudragit® RS and Eudragit® RL.
Examples of fatty compounds that may be used as the rate controlling excipients in the present invention include various waxes such as digestible, long chain (C8 -C50, especially C12 -C4o), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocarbons having a melting point of between 25° and 90° C are preferred.
9

In one embodiment of the present invention, the rate controlling excipient(s) is/are a, mixture of one or more hydrophilic swellable polymer(s). In a preferred embodiment of the present invention the hydrophilic swellable polymer(s) that may be used is vinyl pyrrolidone polymers or polyvinylpyrrolidone (PVP), also referred to as Povidone as the swellable polymers. These are the synthetic polymers consisting essentially of linear 1-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 Kollidon® (BASF), Plasdone® and Peristone® (General Aniline). PVP is classified into different grades on the Isasis 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.
In yet another embodiment of the present invention the rate controlling excipient(s) may be 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 trade 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
10

applications depending upon the viscosity of the polymers and the applicability 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 haying 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 sparkling clear topical gels. The carbopol 934P is high purity grade of Carbopol 934. Depending on drug solubility, drug hydrophilicity and basic strength, polymer concentration 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 rate controlling excipient(s). 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 functional quaternary ammonium groups.
Examples of starch derivatives that can be used in the biguanide composition as the rate controlling excipient(s) include, but are not limited to, sodium starch glycolate and various other anionic starch derivatives and the like. Examples of other anionic polymers that can be used as the rate controlling excipient(s) include, but are not limited to, gums such as Xanthan gums, sodium alginate, sold under the name of KELTONE®, propylene glycol alginate and the like. The preferred gum used as the rate controlling excipient in
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the present invention is xanthan gum, which is a high molecular weight polysaccharide available in various grades, viscosity ranges and of different particle sizes. % ■
t t. "•
Particularly, the preferred rate controlling excipient(s) used in the present invention is the cellulose ethers. 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 alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), and the like.
More preferably, the rate controlling excipient(s) used in the biguanide composition of 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. 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.
12

HPMC is further categorized according to viscosity exhibited by the 2% HPMQ, solution
in water. The grades based on the viscosities are K100LVP, K4M, KIJMP^KIQOMP
and E4MP. The K100LVP indicates a minimal viscosity of lOOcps, K4M%>f 4000 cps,"
K15MP of 15,000 and K100MP of 100,000 and several low viscosity grides" such as E3,
E5,E6,E15,E50andK3. \"\ *•"■
In one embodiment of the present invention, the rate controlling excipient(s), is U high, viscosity grade cellulose derivative, preferably hydroxypropyl methyl cellulose, commercially available as Methocel® K100M, with a viscosity of a 2 % w/w aqueous solution ranging from 80,000 to about 120,000 cps. In preferred embodiments the rate controlling excipient(s) used in the present invention may be a mixture of high viscosity grade of HPMC having a viscosity greater than about 10,000 cps and low viscosity grade HPMC having a viscosity equal to or less than about 10,000 cps.
hi the preferred embodiments of the present invention the rate controlling excipient(s) is selected from a group of polyacrylic acid or a xanthan gum or mixtures thereof. Carbopol 934P is used as one of the rate controlling excipient(s).
In the further 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 concentration ranging from about 10 to 15 % w/w by weight 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.
In the preferred embodiments of the present invention, a combination of high molecular weight HPMC and Xanthan gum is used. HPMC may be used in the concentration ranging from about 10 to 20 % w/w of the total weight of the tablet and amounts of xanthan gum used may vary from about 5 to about 20 % w/w of the total weight of the tablet. More preferably, the HPMC used is a mixture of high viscosity grade of HPMC
13

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 the preferred embodiments of the present invention, the biguanide controlled release

composition contains one or more pharmaceutically acceptable excipient(s) thatimprove , the compressibility of the biguanide 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 compressibility 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. By doing so, they enable one to include in the formulation excipient(s) that would otherwise create difficulty in keeping moisture within a range of 0.5-3 %. 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 the further preferred embodiments the biguanide controlled release composition of the present invention may be comprised of excipient(s) that further modulate the rate of release of biguanide from the composition. These may be 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
14

Science and Practice of Pharmacy; edition 19; Mack Publishing Cpmpany, Easto^n,? Pennsylvania (1995). Pharmaceutically acceptable water-soluble salts "of inorganic or • organic acids, or non-ionic organic compounds with high watei 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, magnesium 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, raffinose, 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.
The additional excipient(s) used in the biguanide 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, 18th edition, page 1635-38(1990).
In a preferred embodiment of the process of making the composition, the biguanide and the rate controlling excipient(s) are sifted and mixed with the binder in a rapid mixer granulator and granulated. In another preferred embodiments of the present invention,
15

only a part of the total polymeric swelling agent is included in the composition ,and the •■> remaining is mixed at the lubrication stage with the dried granules. Admixture of"water -and organic solvent is the preferred granulating agent. The granules thus bbfaiiied are wet milled through a screen and then dried in a fluidisedbed drier at 40-50°C to amoisture" content of 2-3%. The dried granules are then milled through a 2mm screen and are mixed with one or more lubricants. In more preferred embodiments, as described above, the remaining part of the rate controlling excipient(s) is/are mixed at this stage. The lubricated granules are then compressed to obtain the compressed tablets or cores.
In addition to the above ingredients, the biguanide composition of the present invention may be covered 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 acrylic acid and methacrylic 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 permeability.
In one of the preferred embodiments of the present invention, the water insoluble polymeric material used to coat the biguanide composition in the form of a core is a highly water permeable, pH independent methacryhc-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 citrate, diethyl phthalate,
16

glycerol, sorbitol, crotonic acid, propylene glycol, castor oil, citric acid esters^ dibutyl
phthalate, dibutyl sebacate, and mixtures thereof.
,;

Depending on the biguanide composition, the amount of the water insoluble \polymeric
coating applied on the core may vary from about 0.5 to about 20 % w/w of .the total weight of the dosage form. The coating agents are dispersed in a solvent: of* solvent""" system, and the solution or dispersion so obtained is used to coat the biguanide- * containing cores. Various solvents and mixtures of solvents can be used to provide the" coating agent solution or dispersion. Some of the preferred solvents include water, halogen hydrocarbons like trichloroethylene, methylene chloride (dichloromethane), carbon tetrachloride, and chloroform; alcohols such as absolute alcohol, isopropanol and methanol; low molecular weight esters like ethyl acetate and amyl acetate; and ketones such as acetone, 2-butanone and the like. A preferred embodiment of the present invention uses a mixture of acetone and isopropyl alcohol. 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.
In one embodiment of the present invention, the immediate release long-acting sulfonyl urea layer is introduced by mixing the sulfonyl urea with pharmaceutical adjuvants such as film-forming agents, plasticisers and the like, in a suitable solvent or solvent system, and coating the biguanide-containing cores, using conventional coating methods known to a person skilled in the art. Examples of film-forming agents that may be used in the present invention along with the long-acting sulfonyl urea include cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethyl cellulose, methyl cellulose, methacrylic acid/methacrylate esters, polyvinyl acetate phthalate, shellac and the like, or mixtures thereof. Hydroxypropyl methylcellulose (HPMC) is used as the preferred film-forming agent along with the long-acting sulfonyl urea in the present invention, in an amount ranging from about 2% to about 20% by weight of the coated biguanide-containing core, more preferably from about 15% to about 20% by weight of the core. Examples of plasticisers that may be used in the present invention include, but are not limited to
17

glycerol, propylene glycol, polyethylene glycol, sorbitol, triacetin, diethyl phthalate, mineral oil, petrolatum, lanolin and the like, hi a preferred embodiment of the present invention, polyethylene glycol (PEG) 6000 is used as the plasticiser in an amount ranging s from 0% to about 5% by weight of the core, more preferably from about 0.1o/oto about 1% by weight of the core. The long-acting sulfonyl urea is dissolved inf/nlethylene chloride. HPMC dispersed in isopropyl alcohol and the long-acting sulfonyl urea are mixed in a solvent system and further mixed with the PEG 6000 previously *rneited_and\X dissolved in water. The solution thus obtained is used to coat the biguanide-containing core to a desired weight gain, in a conventional tablet-coating pan. The tablets afe,theh dried in a tray drier at a temperature of 40-50°C for 24 hours.
The examples that follow do not limit the scope of the invention and are presented as illustrations.
EXAMPLE 1
One embodiment of the present invention is described in the following example. The tablets were prepared according to the formula described as follows,
18
Table 1

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 umformly 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 clit mill.
Stage C: Talc, magnesium stearate and colloidal silicon 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 RL100 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 2.
19
Table 2

Glimepiride is dissolved in methylene chloride. HPMC is dispersed in isopropyl alcohol
The dispersion is added to the glimepiride 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 aboveisolution. 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 0.1N HC1 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 3 below.
TABLE 3

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 4 below.
20
TABLE 4

We claim:
metformin or its pharmaceutically acceptable salt. Dated this 27th day of September 2002.
1. A dosage form for the treatment of diabetes mellitus and conditions associated with it, comprising an immediate release composition comprising a long-acting^sulfonyl urea ■ and a controlled release composition comprising a biguanide.
2. A dosage form according to claim 1 wherein the biguanide is selected from a group consisting of metformin, phenformin, buformin and their pharmaceuticals "accepJtableL salts,,
3. A dosage form according to claim 2 wherein the biguanide is metformin or its pharmaceutically acceptable salts.
4. A dosage form according to claim 1 wherein the long-acting sulfonyl urea is selected form a group consisting of carbutamide, chlorpropamide, glyburide (glibenclamide), glimepirjdA,—gliclazide, glibornuride, glyhexamide," phenbutamide, tolazamide, tolbutamide and tolcyclamide.
5. A dosage form according to claim 4 wherein the long-acting sulfonyl urea is glimepiride.
6. A dosage form according to claim 5 wherein the composition contams 1.0 mg of glimepiride.
7. A dosage form according to claim 3 wherein the composition contains 500.0 mg of
i

21

Documents:

940-mum-2001-claims(granted)-(30-9-2002).pdf

940-mum-2001-claims(granted)-(30-9-2003).doc

940-mum-2001-correspondence(17-4-2006).pdf

940-mum-2001-correspondence(ipo)-(8-5-2006).pdf

940-mum-2001-correspondence1(25-02-2009).pdf

940-mum-2001-form 1(28-9-2001).pdf

940-mum-2001-form 18(23-9-2005).pdf

940-mum-2001-form 2(granted)-(30-9-2002).pdf

940-mum-2001-form 2(granted)-(30-9-2003).doc

940-mum-2001-form 3(30-9-2002).pdf

940-mum-2001-form 5(17-4-2006).pdf

940-mum-2001-other document(05-03-2009).pdf

940-mum-2001-pct-ipea-409(28-9-2001).pdf

940-mum-2001-pct-isa-210(28-9-2001).pdf

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Patent Number

204612

Indian Patent Application Number

940/MUM/2001

PG Journal Number

24/2007

Publication Date

15-Jun-2007

Grant Date

28-Feb-2007

Date of Filing

28-Sep-2001

Name of Patentee

SUN PHARMACEUTICAL INDUSTRIES LTD.

Applicant Address

ACME PLAZA,ANDHERI-KURLA ROAD, ANDHERI(E), MUMBAI-400059, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	Tyebji,Ziauddin Z.	of Sun Pharmaceutical Advanced Research Centre, Akota Road,Akota, Baroda 390020 Gujarat,India

PCT International Classification Number

A 61 K 031

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA