Title of Invention

PROCESS FOR PREPARING A UNIT DOSAGES FORM FOR THE TREATMENT OF DIABETES MELLITUS

Abstract

The present invention provides A process for preparing a unit dosage form for the treatment of diabetes mellitus and conditions associated with diabetes mellitus, comprising a. providing a delayed release composition comprising mixing biguanide antidiabetic agent with pharmaceutically acceptable excipients, and coating the composition with a delayed release coat comprising delayed release material selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic non- polymeric compounds and mixtures thereof, b. providing a second immediate release composition comprising mixing a sulfonyl urea and pharmaceutical3y acceptable excipients, and c. converting the compositions obtained in steps 'a' and 'b' above into a unit dosage form, whereby the composition releases the biguanide antidiabetic agent after a predetermined time spacing or interval after administration of the dosage form, and releases the sulfonyl urea immediately upon oral administration of the said unit dosage form.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See section 10) DOSAGE FORM FOR TREATMENT OF DIABETES MELL1TUS. 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 MELL1THS. The present invention relates to a process for preparing a unit dosage form for the treatment of diabetes mellitns and conditions associated with diabetes mellitus. The dosage form comprising a biguanidc in a delayed release form and a sulfonyl urea in an immediate release form. More particularly.'the present invention relates to a process for preparing a unit dosage form that immediately releases a sulfonyl urea after administration of the dosage form about 30 minutes prior to meals, and releases a biguanidc at the time the meal is taken or at a predetermined time after the meal is taken. BACKGROUND OF THE INVENTION Non-insulin dependent diabetes mcflitus (NIDDM). also known as maturity-onset diabetes or diabetes mellitus type 2. is a frequent metabolic disease and the main cause of hypcrglyccmia. It is a heterogeneous disease with complex, unclarificd 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 hypcrglyccmia. 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. When these provisions arc not sufficient, a pharmacological agent needs to be taken for control of hypcrglyccmia. Sulfonyl ureas and biguanidc derivatives have been used in diabetes therapy. The use of these classes of compounds in monotherapy has been effective in obtaining a glycometabolic control in diabetic patients. Biguanidc derivatives like metformin, phcnformin 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. Biguanidcs improve glucose tolerance in patients with diabetes mellitus type 2, lowering both basal and post-prandial plasma glucose. With biguanidc 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- 2 hyperglycemic agent, metformin is (he preferred biguanide, as it exerts a better normoglycenuc 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, glibomuride, 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-insulin 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. The 55th edition of the Physicians* Desk Reference, copyright 2001, 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, 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. 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 3 indicates that the maximum dose of glibenclamide, which does not cause any side-effects, is 15 nig/day, while that for met form in 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 after a delay period, particularly after a predetermined delay period. United States Patent No. 6,031,004 C004) 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, (Hi) 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 plasticiser, and (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. With the administration of controlled release tablets, steady state plasma levels are achieved and thus effective levels are already present when a dose is administered. On the other hand, when immediate release tablets such as those of the above mentioned patents, i.e. '004 and 769 patents or the present invention, are given, the effective plasma levels should be obtained at a time such that a maximum reduction in post-prandial blood glucose is obtained. In this case, maximum reduction in post-prandial blood-glucose can be obtained by administering glipizide about 30 minutes before meals, and hence, an immediate release of glipizide is essential. On the other hand, metformin is given with food. The systems of the '004 patent and the 769 patent do not allow release of glipizide 30 minutes before meals and at the same time delay release of metformin particularly for a predetermined time until or after the meal is ingested. A dosage form comprising a biguanide and a sulfonyl urea that immediately releases a sulfonyl urea, such as glipizide, after administration of the dosage form 30 minutes prior to meals, and releases after a delay, a biguanide, such as metformin, such that the biguanide is released at the time the meal is taken or at a predetermined time after the meal is taken, would provide optimum clinical benefits. 4 A plethora of" prior arts relate to pharmaceutical compositions that release a drug after a delay. Some prior arts that relate to release of drug after a predetermined time include United States Patent No 3,247,066; European patent application no 408496A2; United States Patent No. 4,871,549; United States Patent no. 5,229,131; PCT Publication no WO 9918938 and PCT Publication no WO 074655. All of these relate to systems comprising a core that swells upon imbibing fluid from the surrounding and a coat that ruptures due to the pressure exerted upon it by the swelling core. However, none of these prior arts suggest that it would benefit the treatment of diabetes mellitus by administration of a dosage form comprising a biguanide in a delayed release form and a sulfonyl urea in an immediate release form. Further they do not disclose or include an enabling description of a dosage form that immediately releases a sulfonyl urea after administration of the dosage form about 30 minutes prior to meals and releases a biguanide at the time the meal is taken or at a predetermined time after the meal is taken. We have found that a usual difficulty in working with the systems is the variability in the time at which the coat ruptures. For instance, if in five to ten out of a hundred times the coatings do not open or rupture at about the predetermined time but open at a significantly prolonged time, then the desired release at the predetermined time is not achieved reliably. We have found the compositions wherein the coating reliably opens or'ruptures with low variability in the time of opening or rupturing to release the biguanide antidiabetic agent. The prior art thus does not mention any formulations or systems containing combinations of a biguanide and a sulfonyl urea, wherein the sulfonyl urea is released immediately and the biguanide is released after a lag period. OBJECT OF THE INVENTION It is an object of the present invention to provide a process for the preparation of a dosage form for the treatment of diabetes mellitus and conditions associated with diabetes mellitus, comprising a biguanide in a delayed release form and a sulfonyl urea in an immediate release form. It is a further object of the present invention to provide a process for the preparation of a dosage form that immediately releases a sulfonyl urea after administration of the dosage form about 30 minutes prior to meals and releases a biguanide at the time the meal is taken or at a predetermined time after the meal is taken. 5 It is a still further object of the present invention to provide a process for the preparation of a dosage form that immediately releases a sulfonyl urea after administration of the dosage form about 30 minutes prior to meals and releases a biguanidc at the time the meal is taken or at a predetermined time after the meal is taken in a reliable maiihcr wherein the variability in time at which the biguanidc is released is low. SUMMARY OF THE INVENTION Accordingly the invention relates to a process for preparing a Linjt dosage form for the treatment of diabetes mcllitus and conditions associated with diabetes iVtcllitus. comprising a. mixing a biguanidc antidiabctic agent and phamiaccutically acceptable cxcipicnts. b. mixing a sulfonyl urea and pharmaccutically acceptable excipicnts. and c. converting the mixtures obtained in steps ;a" and ;b" into a unit dosage form, whereby the biguanidc nntidiabclic agent is rcli-nsccj after a delay and the sulfonyl urea is released immediately upon oral administration of the said unit dosage form. As referred to herein, -conditions associated with diabetes mcllitus' includes those conditions associated with the pre-diabctic stale, conditions associated with diabetes mcllitus itself and complications associated with diabetes mellitus. When uscd herein the term 'conditions associated with pre-diabctic state" includes conditions sucn as insulin resistance, including hereditary insulin resistance, impaired glucose tolerancc? obesity and hypcrinsulinacmia. "Conditions associated with diabetes mcllitus" itself include hvperglycemia, insulin resistance, including acquired insulin resistance and obesity. Further conditions associated with diabetes nicllitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance and gcstationai diabetes. 'Complications associated with diabetes mcllitus' includes renal disease, especially renal disease associated with Type II diabetes. neuropatlty and retinopathy. Renal diseases associated with Type II diabetes include nephropathy, glom.erulonephritis, glomcrular sclerosis, nephritic syndrome, hypertensive ncphrosclcrosis and end stage rcna| disease 6 DETAILED DESCRIPTION OF THE INVENTION The dosage form is designed to allow immediate release of the sulfonyl urea and a delayed release of the biguanide antidiabetic agent. Those skilled in the art would realize thai by immediate release of the sulfonyl urea typically one means that the dosage form is adapted to release the sulfonyl urea substantially immediately after administration of the dosage form, for instance or for illustrative purpose, about 80% or more of the total amount of sulfony! urea may be released in 30 minutes. By delayed release one typically means that release of the biguanide is delayed after administration of the dosage form, such that not more than about 10% of the total amount of the biguanide is released in about 30 to about 45 minutes. Thereafter, the dosage form is adapted to release the biguanide antidiabetic agent substantially immediately, for instance or for illustrative purposes, preferably about 70% of the total amount of the biguanide may be released in about 150 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 sulfonyl ureas that may be used in the present invention include acelohexamide, carbutamide, chlorpropamide, glipizide, glyburide (glibenelamide), glimepiride, gliclazide, glibomuride, gliqmdone, glisoxepid, glyhexamide, phenbutamide, tolazamide, tolbutamidc, tolcyclamide, and the like. The invention covers any dosage form in which the first biguanide composition and the second sulfonyl urea composition 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. In the dosage form of the present invention, the first and second composition may be in the form of either multiparticulates such as particles, pellets or granules, or present as concentric or laminar tablet layers or as single units such as a compressed tablet. The multiparticulaies may be 7 obiaincd by any of the conventional methods, including mixing, granulation, extrusion, sphcronisation. layering of non-parcil seeds, etc, and various other methods known to a person skilled in the art, A compressed tablet core may be obtained by compressing the mutiparticulates in a tablet die. The first composition is surrounded by a delayed release coating comprising delayed 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 flic first biguanide composition and the uncoatcd multiparticulates or tablets of the second sulfonyl urea composition, may be filled into capsules. Alternatively, tablets of the first biguanide composition may be surrounded by the second sulfonyl urea composition and compressed in a compression coating tablet machine, or a second layer of the sulfonyl urea composition may be compressed onto the compressed biguanide composition to form bilayer tablets. In a preferred embodiment of the present invention the dosage form prepared comprises a spaced drug delivery system wherein the first composition is a timed release composition that releases the biguanide antidinbelic agent after a predetermined time spacing or interval after administration of the dosage form. Thus, the biguanide is released at a predetermined time spacing or interval after the immediate release of the sulfonyl urea from the second composition. In another preferred embodiment of the spaced drug delivery system, the first timed release composition comprises a core comprising a biguanide antidiabetic agent, a swelling agent, and optionally water soluble compound(s) for inducing osmosis, and a timed release coat comprising one or more film forming polymers. The method of obtaining the spaced drug delivery system of the present invention comprises mixing the biguanide with the polymeric swelling agent and optionally the water soluble compound(s) for inducing osmosis and other pharmaceutically ! acceptable adjuvants, and compressing the mixture to obtain a core of the biguanide. This core is then covered with a layer of the timed release coat using conventional coating methods to obtain the first timed release biguanide composition. In the spaced drug delivery system, the timed release composition imbibes fluids from the environment of use causing the polymeric swelling agent in the core to swell. The biguanide is released after the timed release coat ruptures under the influence of mechanical pressure exerted by the swelling of the polymeric swelling agents present in the tablet 8 ;orc. The time of rupture of the coat can be controlled by varying (a) the degree and rate of .welling of the core; (b) the timed release coat composition by using different components and atios of these components; and (c) the thickness of the coal. The polymeric swelling agent used in the timed release composition includes one or more wellable hydrophilic polymers. The quantity or relative proportion of the polymers is subject to onstderable variation. However, a sufficient quantity of ths material is present in the tablet or ore to provide, upon uptake of water, a swelling pressure in excess of the cohesive strength of lie coating surrounding the tablet or core. Preferably, the polymers are employed in the dry state r in a form that has substantial capacity for water uptake. Examples of swellable hydrophilic olymers that may be used in the timed release composition as the polymeric swelling agent iclude vinylpyrrolidone polymers such as povidone, or crosslinked polyvinylpyrrolidone such as rospovidone; cellulose and cellulose derivatives such as microcrystalline cellulose, lethylcellulose, othylcellulose, hydroxypropylcellulose, hydroxypropyl methylceliulose, arboxyalkyl celluloses or crosslinked carboxyalkylcclluloses and their alkali salts; sodium starch lycolate, starch and starch derivatives, ion-exchange resins and mixtures thereof Preferably, one f the swelling agents used is selected from the group consisting of crosslinked sodium irboxymethyl cellulose, crosslinked polyvinylpyrrolidone and sodium starch glycolate. he alkali salt of crosslinked carboxyalkyl cellulose, i.e. crosslinked sodium carboxymethyl ;llulose, also known as croscarmellose sodium or Ac-Di-Sol, is available commercially as ymcel® ZSX, Pharmacel® XL, Primellose® or Solutab®. Th$ amount of swelling agent that may ; used is dependent on the desired time of rupture of the timed release coat, nature and amounts "other components in the core, as well as the composition and thickness of the coat. Generally, oscarmellose sodium may be used as the polymeric swelling agent, in an amount ranging from wut 0.5% to about 50% by weight of the core, preferably from about 2% to about 40% by sight of the core, more preferably from about 5% to about 20% by weight of the core. In ecific preferred embodiments the croscarmellose sodium is used in a range from about 6% to out 10% by weight of the core, more preferably from about 7% to about 9% by weight of the ire. nyl pyrrolidone polymers or polyvinyl pyrrolidone (PVP), a|so referred to as Povidone, are nthetic polymers consisting essentially of linear l-vinyl-2-pyrr0|jdinone groups, the degree of lymerization of which results in polymers of various molecular weights, the molecular weight 9 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 basis of its viscosity in aqueous solution. Different grades of PVP available are PVP K-12, PVP K-I5, PVP K-17, PVP K-25. PVP K-30, PVP K-60, PVP K-90 and PVP K-120. The K- vnlue referred to in the above nomenclature is calculated from the viscosity of the PVP in aqueous solution, relative to that of water. Crospovidone or cross-PVP, the synthetic crosslinked homopolymer of N-vinyl-2-pyrroIidinone, may also be used as a swellable hydrophilic polymer. It is commercially available as Kollidon CL and Polyplasdone XL, and has a molecular weight higher than 1,000,000 Daltons. Crospovidone is used in an amount ranging from about 2% to about 5% by weight of the core. The preferred vinyl pyrrolidone polymer for use as a swellable hydrophilic polymer is PVP K-30, having an approximate molecular weight of 50,000 Daltons. It may be used in an amount ranging from about 0.5% to about 5% by weight of the core, more preferably from about 1% to about 2% by weight of the core. Sodium starch glycolate, the sodium salt of carboxymethyl ether of starch, may also be used as the polymeric swelling agent. It has a molecular weight ranging between 500,000 and 1,000,000 Daltons, and is commercially available as Explotab and Primojel. Sodium starch glycolate may be used in the present invention in an amount ranging from about 0.5% to about 40% by weight of the core, preferably from about 2% to about 40% by weight of the core, more preferably from about 2% to about 10% by weight of the core. Water-soluble compounds suitable for inducing osmosis, i.e. osmotic agents or osmogents are generally used in the core of the timed release composition when the drug itself does not exert sufficient osmotic pressure in order to imbibe fluid from the surroundings. Osmogents that may be present in the core of the timed release composition include all pharmaceutically acceptable and pharmacologically inert water-soluble compounds referred to in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy, edition 20, Lippincott Williams and Wilkins, Philadelphia (2000). Pharmaceutically acceptable water-soluble salts of inorganic or organic acids, or non-ionic organic compounds with high water solubility, e.g. carbohydrates such as sugar, or amino acids, are generally preferred. The examples of agents used for inducing osmosis include inorganic salts such as magnesium chloride or magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium hydrogen phosphate, lithium, sodium or potassium dihydrogen phosphate, salts of organic acids such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate or 10 sodium ascorbate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, laclose. raffmose; water-soluble amino acids such as glycine, leucine, alanine, or methionine; urea and the like, and mixtures thereof. The amount ol" osmogents that may be used depends on the particular osmogent that is used and may range from about 1% to about 60% by weight of the core. In preferred embodiments, the core of the timed release composition further comprises a wicking agent. Materials suitable for use as wicking agents in the timed release composition and include, but are not limited to, colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, sodium lauryl sulfate, microcrystalline cellulose, low molecular weight polyvinyl pyrrolidone, bentonite, magnesium aluminum silicate, and the like. Microcrystalline cellulose (MCC) is used in the preferred embodiment as the wicking agent. It is made up of a chain of about 250 glucose molecules in the form of a microcrystal, consisting primarily of crystallite aggregates obtained by removing amorphous regions of a pure cellulose source material by hydrolytic degradation using mineral acid. MCC has an average molecular weight of about 36,000 Daltons and is available in various grades, which differ in bulk density, particle size and moisture content. It is commercially available as Vivapur®, Avicel®, Vivacel®, Emcocel®, Fibrocel® and Tabulose®. Avicel® PH 102, having a mean particle size of lOO/i m, i.e. 8% or less of the particles are retained on a # 60 sieve (as defined by ASTM, American Society for Testing and Materials), and 45% or more of the particles are retained on a #200 sieve (as defined by ASTM), and having a moisture content of the timed release composition, in an amount ranging from about 2% to about 5% by weight of the core, more preferably from about 2% to about 3% by weight of the core. In addition to the above ingredients, the biguanide-containing core of the timed release composition may optionally contain pharmaceutically acceptable excipients such as binders, disintegrants, lubricants and the like. Examples of binders used commonly include starch, gelatin, sugars like sucrose, glucose, dextrose, molasses and lactose; acacia, sodium alginate, cellulose derivatives like methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like; polymers such as polyvinyl pyrrolidone, Veegum, polyethylene glycol, waxes and the like. Examples of lubricants that may be used in the timed release composition include talc, magnesium stearate, calcium stearate, aluminium stearate, stearic acid, hydrogenated vegetable 11 oils, colloidal silicon dioxide, polyethylene glycol, cellulose derivatives such as carboxyalkyl cellulose and ils alkali salts, or mixtures thereof. Hydrophobic or water insoluble lubricants may reduce the water imbibing properties of the core whereas hydrophilic or water soluble lubricants do not, and are preferred. A more preferred lubricant is colloidal silicon dioxide. A mixture of colloidal silicon dioxide and magnesium stearaic may be used as the preferred lubricant. More preferred embodiments use a combination of microcrystalline cellulose and colloidal silicon dioxide as the wicking agents with colloidal silicon dioxide also functioning as a lubricant. Colloidal silicon dioxide is available commercially as Aerosil® from Degussa-Huls, Nippon and Fischer GmbH. The preferred colloidal silicon dioxide lubricant is Aerosil® 200, with an approximate external surface area of 200m2/g. The colloidal silica may be used in amounts in the range of about 0.5 % to about 5% by weight of the core. In a preferred embodiment of the process of making the timed release composition, the biguanide and the polymeric swelling agent are sifted and mixed with the binder in a rapid mixer gramriator ajid granulated. In more preferred embodiments of the present invention 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. Water is the preferred granulating agent. The granules thus obtained are wei milled through a screen and then dried in a fluidised bed drier at 40-50°C to a moisture content of 2-3%. The dried granules are then milled through a 2mm screen and arc mixed with one or more lubricants and the wicking agent. In more preferred embodiments, as described above, the remaining part of the polymeric swelling agent is mixed at this stage. The lubricated granules may be filled into hard gelatin capsules, or may be compressed to obtain the compressed tablets or cores. The biguanide-containing compressed cores are covered with a timed release coat comprising one or more film forming polymers. The film forming polymers that may be used to form this timed release coat are selected from the group consisting of water insoluble polymers, pH dependent polymers, and mixture of water soluble and water insoluble polymers. Examples of film forming polymers that may be used include cellulose ester derivatives like methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate, cellulose acetate phthalate, pH-independent copoiymers of methacrylic acid and methacrylic acid esters commercially available as Eudragit®, or mixtures thereof. The time of release of the biguanide may be varied by varying the components used to form the timed release coat, and/or by varying the ratio in which these components are used. By selecting the suitable components and by using 12 them in suitable ratios, the biguanide release can be obtained at a predetermined time after oral administration of the dosage form. A preferred embodiment of the invention uses a mixture of ethyl cellulose and hydroxypropyl methylcellulose (HPMC) to form the delayed release coat. The mixture is used in n preferred weight ratio of 0:20 to 20:0 of ethyl cellulose : HPMC, more preferably 6:3 to 9:?. The coating agents are dispersed in a solvent or 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 dichloromethane and methanol in a preferred ratio of 1:10 to 10:1 of dichloromethane : methanol, more preferably in a ratio of about 3:1 to about 6:1. The compressed cores/capsules containing the biguanide are coated with the coating solution to a defined weight gain, the thickness of the coat depending on the predetermined time of biguanide release. The coating material may be applied by any procedure which provides a continuous film of essentially uniform thickness. One method of coating involves rotating a bed of uncoated cores in a conventional tablet coating pan and applying a solution or dispersion of the coating agent in a suitable solvent by pouring or spraying the solution onto the moving cores. Other coating procedures such as fluid bed coating, vertical spray coating, and the like can also be employed. The coated cores are dried by exposing them to warm, dry air and may be cured, if necessary, by air drying, baking or force drying. In one embodiment of the present invention, the compressed core is coated with a ethyl cellulose : HPMC solution to a weight gain in the range of about 2% to about 20% by weight of the compressed core, preferably from about 5% to about 10% by weight of the core; more preferably from about 9% to about 10% by weight of the compressed core. The cores are coated in an automated perforated coating pan followed by drying and curing of the coated cores in a tray drier for 24 hours at 40-50°C. The first timed release biguanide composition in the form of tablets/capsules and the second sulfonyl urea composition in the form of multiparticulates or tablets may be filled into capsules. Alternatively, tablets of (he first timed release biguanide composition may be surrounded by the 13 second sulfonyl urea composition and compressed in a compression coating tablet machine to obtain a single unit dose form with timed release biguanide core composition and an immediate release sulfony! urea coat composition. The second sulfonyl i'rea composition may be included in the spaced drug delivery system of the present invention in different ways. Multipaniculates of sulfonyl urea may be obtained by mixing the sulfonyl ure excipients, such as binders, fillers, disintegrants and the like, pr by further granulating the mixture using water as the preferred granulating agent. The granules po obtained are dried and lubricated with one or more lubricants. In one embodiment of the spaced drug delivery system of (He present invention, the immediate release sulfonyl urea layer is introduced by mixing the ?ulfonyl 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 timed release composition, using conventional coating methods known to a person skilled in the art. Examples ol THm-Ibrrrimg agents that may be used in the present invention along with the sulfonyl urea include cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethyl cellulose, methyl cellulose, microcrystatline cellulose, methacrylic acid/methacrylate esiers, polyvinyl acetate phthal^e, shellac and the like, or mixtures thereof. Hydroxypropyl methyTcellulose (HPMC) is used z$ the preferred film-forming agent along with the sulfonyl urea in the present invention, in an amount ranging from about 2% to about 20% by weight of the biguanide-containing timed release composition, more preferably from about 2% to about 5% by weight of the core. Examples of plasticisers that may be used in the present invention include, but are not limited to glyceroL propylene glycol, polyethylene glycol, sorbitol, triacetin, diethyl phthalate, mineral oil, petrolatum, lanolin and the like. In a preferred embodiment of the present invention, polyethylene glycol (PEG) 4000 is used as the plasticiser in an amount ranging from 0% .to about 5% by weight of the core, more preferably from about 0.1 % to about 1 % by weight of the core. The sulfoPyl urea, HPMC arid PEG 4000 are mixed in a solvent system comprising a mixture of isopropariol and dichloromethane in a ratio ranging from 0:10 to 10:0, more preferably from 1:5 to 5:1. Tl^ solution thus obtained is used to coat the biguanide-containing core to a desired weight gain, in a conventional tablet coating pan. The tablets are then dried in a tray drier at a temperature of 40'50°C for 24 hours. The following examples do not limit the scope of the invention and are presented as illustrations. 14 Example 1 The dosage form of the present invention is oblained as mentioned in Table 1 below. Table I Ingredients | Quantity (mg) Percent (%) w/w. A. Immediate release sullonyl urea granules - Glipizide 5.0 6.67 Microcrystalline cellulose (MCC) 13.0 17.33 Lactose monohydrate 51.175 68.23 Polyvinyl pyrrolidone (PVP K-30) 1.5 2.0 Sodium starch glycolate 3.5 4.67 Sodium JauryJ sulfate 0.075 O.I Magnesium stearate 0.75 1.0 Total 75 100.0 B. Delayed release biguanide core - Core- Metformin hydrochloride 500.0 83.33 Croscarmellose sodium (Ac-Di-So!) 50.0 8.33 Com starch, plain ( as 10% starch paste) 17.0 2.83 Microcrystalline cellulose (MCC) 13.5 2.25 Colloidal silicon dioxide 13.5 2.25 Magnesium stearate 6.0 1.0 Total 600.0 100.0 Coat - Ethyl cellulose 40.7 coated to a weight gain of 9.5% by weight of the ' core. Hydroxypropyl melhylcelluiose 16.3 The immediate release sulfonyl urea granules were obtained by sifting glipizide, lactose monohydrate and microcrystalline cellulose (MCC) and sodium starch glycolate through a # 40 sieve (as defined by American Society for Testing and Materials, ASTM) and blending the powders suitably. A solution of PVP K-30 in water was used to granulate the dry powder blend. The granules thus obtained were dried to a moisture content of not more than 3%. These granules were then passed through a # 25 sieve (as defined by ASTM). The granules were finally mixed with talc and magnesium stearate to obtain the final granules. The method of preparation of the delayed release biguanide core included sifting the metformin hydrochloride and croscarmellose sodium through a suitable sieve and mixing them in a rapid mixer granulator. The dry powder blend was then granulated using 3 0% starch paste, followed by wet milling the wet mass through a Fitz mill. The granules so obtained were dried to a moisture content of 3-4%. The dry granules are then milled in a Fitz mill through a 1.5mm screen, followed by sifting of the granules through a # 16 sieve (as defined by ASTM). These granules of metformin hydrochloride were then mixed 15 with MCC, colloidal silicon dioxide and magnesium stearate, and the lubricated mixture thus obtained was compressed on a rotary compression machine using oblong shaped punches. The tablets were then coated in a conventional coating pan using a solution of ethyl cellulose and HPMC in a mixture-of melhanol and didiloromethane.- The delayed release biguanide core was then mixed with 75mg of the immediate release sulfonyl urea granules and encapsulated in a size '0' hard gelatin capsule. The delayed release biguanide composition and 75mg of sulfonyl urea granules were subjected to dissolution studies using pH 6.8 buffer at 37±0.5°C, in a USP Type II apparatus (rpm = 75). The release profile for metfonnin is recorded in Table 2 below, while that for glipizide is recorded in Table 3 below.-The opening time of the timed release coating on the biguanide core was observed for 30 tablets, which were subjected to dissolution testing. It was found that all the tablets opened reliably at about 1 hour to about 1.3 hour after start of the dissolution test. Time (roins) % metformin released (±S.D.) 45 I ±0.5 105 91 ±6.89 120 98 ±4.26 Table 3. Time (rain) % glipizide released (± S.D.) 45 88 ±2.19 Example 2 The dosage form of the present invention is obtained as mentioned in Table 4 below. 16 Table 4 Ingredients Quantity (mg) Percent (%) w/w. A. Immediate release sulfonyl urea granules - Glipizide 5.0 6.67 Lactose monohydrate 64.175 85.56 Sodium starch glycolate 3.5 4.67 Polyvinyl pyrrolidone (PVp K-30) 1.5 2.0 Sodium lauryJ sulfate (SLS) 0.075 0.1 f jVfagnesi'um stearaie / 0.75 I 1.0 \ Total l~ 75 100.0 B. Delayed release biguanide core - Core- Metformin . hydroch loride 500.0 83.33 Croscarmellose sodium (Ac-Di-SoU 50.0 8.33 Cora starch, plain ( as 10% starch paste) 17.0 2.83 Microcrystailine cellulose (MCC) 13.5 2.25 Colloidal silicon dioxide 13.5 2.25 Magnesium stearate 6.0 1.0 Total 600.0 100.0 Coat- Ethyl cellulose 42.0 coated to a weight gain of 9.8% by weight of the core. Hydroxypropyl methylcellulose 16.8 The immediate release sulfonyl urea granules were obtained by sifting glipizide, lactose monohydrate and MCC through a # 40 sieve (as defined by American Society for Testing and Materials, ASTM) and blending the powders suitably. A solution of PVP K-30 and SLS in water was used to granulate the dry powder blend. The rest of the procedure remains the same as for Example 1 above. The delayed release biguanide cores were also prepared as per the method given in Example 1 above. The immediate release sulfonyl urea granules (75mg) were mixed with the delayed release biguanide core and the mixture was encapsulated. The delayed release biguanide composition and the sulfonyl urea granules were subjected to dissolution studies using pH 6.8 buffer at 37±0.5°C, in a USP Type II apparatus (rpm = 75). The release profile for metformin is recorded in Table 5 below, while that for glipizide is recorded in Table 6 below. The opening time for timed release costing on the biguantie core was observed for 30 tablets which were subjected to dissolution testing, it was found that all tablets opened reliably at about 1 hour to about 1.3 hour after start of the dissolution test. 17 Table 5 Time (min) % mctformin released 45 1 120 91 ±5.33 Table 6. Time (min) % gUpizide released 45 98 ±1.55 Example 3. The tablets are prepared as per the formula mentioned in Table 7 below. Table 7 Ingredients | Quantity (me) Percent (%) w/w. Core Metformin hydrochloride 500.0 90.9 Polyvinylpyrrolidone (PVP K-90) 10.0 1.S2 Ac-Di-Sol 34.5 6.27 Magnesium stearate 5.5 1.0 Coat Ethyl cellulose, Ethocel N-10 32.0 Coated to 8-9%w/w of the core. HPMC E5 LV 12.0 Sulfonyl urea coat Glipizide 5.0 Loaded to 5%w/\v of the coated tablet. HPMC E5 LV 22.5 PEG 4000 2.25 Top color coat Color Coated to 2.9%w/w of the sulfonyl urea loaded tablet. HPMC E5 LV 16.6 PEG 4000 1.66 The method of preparation of the dosage form involves the following steps. Metformin hydrochloride, PVP K-90 and a part of the Ac-Di-Sol were sifted and mixed in a rapid mixer granulator for 10 minutes. This mixture was then granulated with sufficient quantity of purified water and the granules thus obtained were wet miffed through a #10 sieve (as defined by American Society for Testing and Materials, ASTM). These granules were then dried in a fiuidized bed drier at a temperature of 40-50°C, to moisture content of 2-3%. The dried granules were again passed-through a #20 sieve (as defined by American Society for Testing and Materials, ASTM). The sifted granules were mixed with magnesium stearate and the remaining pan of the Ac-Di-Sol, in a double cone blender, followed by compression on a rotary compression machine using suitable punches to obtain the cores. A solution of ethyl" cellulose (Ethocel STD-10) and HPMC (E5 LV grade) in a solvent system containing a 4:1 mixture of 18 dichloromethane and methanol, was (hen used to coat the compressed cores to a weight gain of 8% by weight of the compressed cores, in a perforated coating pan. The tablets were then dried in a tray drier at 40-50°C for 24 hours. Glipizide. HPMC (E5 LV grade) and PEG 4000 were then dissolved in a J:3 mixture of isopropano) and dichloromethane to obtain a solution, which was loaded on the dried polymer-coated tablets to a weight gain of 5% w/w. The tablets were again dried in a tray drier at 40-50°C for 24 hours after glipizide-loading, and a (op color coat was applied to the tablets using a solution of a pharmaceutical ly acceptable color with HPMC (E5 LV grade) and PEG 4000 in a 1:3 mixture of isopropanol and dichloromethane. The tablets were finally dried in tray driers at 40-50°C for 24 hours. The color-coated tablets so obtained were subjected to dissolution studies using pH 6.8 buffer at 37±0.5°C, in a USP Type II apparatus (rpm = 50). The release profile for metformin is recorded in Table 5 below, while that for glipizide is recorded in Table 6 below. Table 8 Time (min) % metformin released (± S.D.) 30 - 120 43 ± 36.6 150 80 ±22.19 Table 9 Time (min) % glipizide released (± S.D.) 15 7S±5.19 30 89 ± 8.45 Example 4 The dosage form of the present invention is obtained as mentioned in Table 10 below. 19 Table 10 Ingredients Quantity (mg) Percent (%) wAv. A. Immediate release sulfonvl urea granules - Glibendamide 5.0 6.67 Lactose monohydrate 64.175 85.48 Sodium starch glycolate 3.5 4.67 Polyviny) pyn-olidone (PVP K-30) 1.5 2.0 Sodium lauryl sulfate (SLS) 0.075 0.1 Magnesium stearate 0.75 1.0 Total 75 100.0 B. Delayed release biguanide core - Core- Metformin hydrochloride 500.0 83.33 Croscarmellose sodium (Ac-Di-Sol) 50.0 8.33 Com starch, plain ( as 10% -starch paste) 17.0 2.83 Microcrystalline cellulose (MCC) 13.5 2.25 Colloidal silicon dioxide 13.5 2.25 Magnesium stearate 6.0 1.0 Total 600.0 100.0 Coat- Ethy! cellulose 42.0 coated to a weight gain of 9. 8% by weight of the core. Hydroxypropyl methylcellulose 16.8 The dosage form was prepared by a procedure similar to Example 2. The immediate release sulfonyl urea granules (75mg) were mixed with the delayed release biguanide core and the mixture was encapsulated. The delayed release biguanide composition and the sulfonyl urea granules were subjected to dissolution studies using 0.025M trisbuffer pH 9.01 at 37±0.5°C, in a USP Type n apparatus (rpm = 50). The release profile for glibenclamide is recorded in Table 11 below. Table 11 Time (min) % glipizide released (± S.D.) 15 93 ±2.09 30 95 ±1.72 45 96 ±1.53 While the invention has been described with reference to specific embodiments, this was done for purposes of illustration only and should not be considered to limit the spirit or the scope of the invention. 20 We claim - 1. A process for preparing a unit dosage form for the treatment of diabetes mellitus and conditions associated with diabetes mellitus, comprising a. providing a delayed release composition comprising mixing biguanide antidiabetic agent with pharmaceutically acceptable excipients, and coating the composition with a delayed release coat comprising delayed release material selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic non- polymeric compounds and mixtures thereof, b. providing a second immediate release composition comprising mixing a sulfonyl urea and pharmaceutically acceptable excipients, and c. converting the compositions obtained in steps 'a' and 'b' above into a unit dosage form, whereby the composition releases the biguanide antidiabetic agent after a predetermined time spacing or interval after administration of the dosage form, and releases the sulfonyl urea immediately upon oral administration of the said unit dosage form. 2. A process as claimed in claim 1, wherein the biguanide is selected from a group consisting of metformin, phenformin and buformin, and their pharmaceutically acceptable salts. 3. A process as claimed in claim 1, wherein the sulfonyl urea is selected from a group consisting of acetohexamide, carbutamide, chlorpropamide, glipizide, glyburide (glibenclamide), glimepiride, gliclazide, glibornuride, gliquidone, glisoxepid, glyhexamide, phenbutamide, tolazamide, tolbutamide and tolcyclamide. 4. A process as claimed in claim 1, wherein the delayed release composition is a timed release composition, and wherein the pharmaceutically acceptable excipients used to obtain the timed release composition are swelling agent(s) and water soluble compound(s) for inducing osmosis. 5. A process as claimed in claim 1 wherein the second composition is provided by mixing a sulfonyl urea and pharmaceutically acceptable excipients, whereby the sulfonyl urea is released immediately upon oral administration. 6. A process as claimed in claim 4, wherein the swelling agent is selected from the group consisting of croscarmellose sodium, crosslinked polyvinylpyrrolidone and sodium starch glycolate. 7. A process as claimed in claim 4, wherein the core optionally comprises a wicking agent. 8. A process as claimed in claim 7, wherein the wicking agent is microcrystalline cellulose. 9. A process as claimed in claim 7, wherein the wicking agent is colloidal silicon dioxide. 21 10. A process as claimed in claim 4, wherein the core optionally comprises starch. 11. A process as claimed in claim 4, wherein the coat surrounding the timed release composition comprises a mixture of ethyl cellulose and hydroxypropyl methyl cellulose (HPMC). 12. A process as claimed in claim 11, wherein the ethyl cellulose and hydroxypropyl methylcellulose are used in a weight ratio of 6:3 to 9:3. 13. A process as claimed in claim 11, wherein the timed release composition is coated to a weight gain of about 5% to about 10%. 14. A process as claimed in claim 13, wherein the timed release composition is coated to a weight gain of about 9% to about 10%. 15. A process as claimed in claim 1, wherein the delayed release composition is prepared by mixing a biguanide antidiabetic agent, croscarmellose sodium in an amount ranging from about 6% to about 10% by weight of the composition, and microcrystalline cellulose in an amount ranging from about 2% to about 5% by weight of the composition, and converting the mixture so obtained into said delayed release composition by conventional methods. 16. A process as claimed in claim 15, wherein the biguanide antidiabetic agent is metformin, the croscarmellose sodium is used in an amount ranging from about 7% to about 9% by weight of the composition, and the microcrystalline cellulose is used in an amount ranging from about 2% to about 3% by weight of the composition. 22 ted this 17th day of September, 2001.

Documents:

37-mum-2001-abstract(20-9-2001).doc

37-mum-2001-abstract(20-9-2001).pdf

37-mum-2001-abstract(amended)-(16-4-2003).pdf

37-mum-2001-abstract(granted)-(18-6-2004).doc

37-mum-2001-abstract(granted)-(18-6-2004).pdf

37-mum-2001-cancelled pages(13-1-2003).pdf

37-mum-2001-cancelled pages(26-4-2002).pdf

37-mum-2001-cancelled pages(30-5-2002).pdf

37-mum-2001-cancelled pages(7-3-2002).pdf

37-mum-2001-claims(20-9-2001).doc

37-mum-2001-claims(20-9-2001).pdf

37-mum-2001-claims(amended)-(13-1-2003).pdf

37-mum-2001-claims(amended)-(16-4-2003).pdf

37-mum-2001-claims(amended)-(26-4-2002).pdf

37-mum-2001-claims(amended)-(30-5-2002).pdf

37-mum-2001-claims(amended)-(7-3-2002).pdf

37-mum-2001-claims(granted)-(18-6-2004).doc

37-mum-2001-claims(granted)-(18-6-2004).pdf

37-mum-2001-correspondence 1(12-1-2001).pdf

37-mum-2001-correspondence 2(11-4-2003).pdf

37-mum-2001-correspondence 3(3-6-2004).pdf

37-mum-2001-correspondence(ipo)-(18-6-2004).pdf

37-mum-2001-description(complete)-(20-9-2001).pdf

37-mum-2001-description(granted)-(18-6-2004).pdf

37-mum-2001-description(provisional)-(12-1-2001).pdf

37-mum-2001-diagram(12-3-2003).pdf

37-mum-2001-diagram(granted)-(18-6-2004).pdf

37-mum-2001-form 1(1-3-2001).pdf

37-mum-2001-form 1(12-1-2001).pdf

37-mum-2001-form 2(20-9-2001).doc

37-mum-2001-form 2(20-9-2001).pdf

37-mum-2001-form 2(granted)-(18-6-2004).doc

37-mum-2001-form 2(granted)-(18-6-2004).pdf

37-mum-2001-form 2(provisional)-(12-1-2001).doc

37-mum-2001-form 2(provisional)-(12-1-2001).pdf

37-mum-2001-form 2(title page)-(20-9-2001).pdf

37-mum-2001-form 2(title page)-(granted)-(18-6-2004).pdf

37-mum-2001-form 2(title page)-(provisional)-(12-1-2001).pdf

37-mum-2001-form 3(18-2-2002).pdf

37-mum-2001-form 3(26-4-2002).pdf

37-mum-2001-form 4(16-1-2003).pdf

37-mum-2001-form 5(20-9-2001).pdf

37-mum-2001-form 9(2-6-2004).pdf

37-mum-2001-power of authority(20-9-2001).pdf

37-mum-2001-specification(amended)-(26-4-2002).pdf

37-mum-2001-specification(amended)-(7-3-2002).pdf