WO2022070209A1

WO2022070209A1 - Biphasic release fixed dose combination formulations

Info

Publication number: WO2022070209A1
Application number: PCT/IN2021/050945
Authority: WO
Inventors: Ganesh Arun Katkar; HariHaran VENUGOPAL; Rajeev Raghuvanshi; Vijayaraghavan T PANCHANATHAN; M. Pavan KUMAR; Rama Krishna THOTA; Gajanan B KASAWAR; Ravi Prasada Rao MUGADA
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2020-09-29
Filing date: 2021-09-28
Publication date: 2022-04-07

Abstract

The present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising immediate release formulations of vildagliptin and extended or sustained release formulations of metformin or pharmaceutically acceptable salt thereof. Methods of preparing such formulations are also provided. The specification also relates to use of such formulations for the improvement and/or management of glycaemic control as an adjunct to diet and exercise in patients with Type 2 diabetes mellitus.

Description

BIPHASIC RELEASE FIXED DOSE COMBINATION FORMULATIONS

TECHNICAL FIELD OF THE INVENTION

The present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin or pharmaceutically acceptable salt thereof. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION

Type-2 (or Type II) diabetes is the most common form of diabetes and it is one of the most prevalent chronic diseases. Over 100 million people worldwide have type-2 diabetes and the prevalence is increasing dramatically in both the developed and developing countries. Type-2 diabetes is a lifelong illness, which generally starts in middle age or later part of life, but can start at any age. Patients with type-2 diabetes do not respond properly to insulin, the hormone that normally allows the body to convert blood glucose into energy or store it in cells to be used later. The problem in type-2 diabetes is a condition called insulin resistance where the body produces insulin, in normal or even high amounts, but certain mechanisms prevent insulin from moving glucose into cells. Because the body does not use insulin properly, glucose rises to unsafe levels in the blood, the condition known as hyperglycemia. Treatment of type 2 diabetes initially starts with diet and exercise, followed by oral antidiabetic monotherapy. During long-term treatment these regimens do not sufficiently control hyperglycemia in many patients, leading to a requirement for combination therapy within several years following diagnosis. However, co-prescription of two or more oral antidiabetic drugs may result in treatment regimens that are complex and difficult for many patients to follow. Combining two or more oral antidiabetic agents into a single formulations provides a potential means of delivering combination therapy without adding to the complexity of patients' daily regimens. Vildagliptin is a DPP -IV inhibitor, works by enhancing the levels of active incretin hormones, which enhance insulin and reduce glucagon secretions, thereby reduce blood glucose levels. It is used for the treatment or improvement in glycemic control in patients with Type 2 diabetes. Vildagliptin is available as 50 mg tablets and marketed as Galvus®. Chemically, vildagliptin is (S)-l-[(3-hydroxy-l- adamantyl)amino]acetyl-2-cyano-pyrrolidine with the following structure:

Metformin is a member of the biguanide class of an oral antihyperglycemics and available in various salt forms, e.g. hydrochloride. Metformin is used in the management of type 2 diabetes mellitus. It is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Chemically, metformin hydrochloride is 1 - carbamimidamido-N, N-dimethylmethanimidamide hydrochloride with the following structure:

Pharmacologic mechanism of action of metformin is different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects, except in special circumstances) and does not cause hyperinsulinemia. Metformin is marketed in the United States in the form of extended release tablets under brand names Fortamet®, Glucophage® and Glumetza®. Extended-release formulations of metformin have advantages over immediate-release in terms of affording a more uniform maintenance of blood plasma active drug concentrations and providing better patient compliance by reducing the frequency of administration required. Numerous studies have been conducted to address the formulation and drug release systems of combination of antidiabetic drugs and attempts have been made to improve the formulation stability.

A combination therapy of vildagliptin (50 mg) with metformin HCI (500 mg - 1000 mg) is indicated for the treatment of type 2 diabetes mellitus, and it is marketed under brand name Galvus Met®. However in this combination therapy both vildagliptin and metformin are present in immediate release form. Currently there is no approved/marketed composition comprising vildagliptin is in immediate release profile and metformin as extended release profile.

Common side effects of fixed dose combination of conventional immediate release tablets containing vildagliptin and metformin hydrochloride are severe nausea, vomiting, pain in and around the stomach (abdominal pain), and loss of appetite because of simultaneous release of both the active in stomach. Dose dumping of both active simultaneously may cause hypoglycemia due to synergetic effect or a very rare, but serious side effect of Metformin HCI called lactic acidosis. Also from the formulation perspective, it is difficult to formulate fixed dose combination of vildagliptin and metformin where the release profile is different. Vildagliptin is sensitive to moisture and therefore subject to product stability issues i.e. degradation of the active ingredient. Metformin is typically produced by a wet granulation process and is known to be very difficult to process and moisture is known to be detrimental for vildagliptin stability. Roller compaction is also known to be unacceptable due to poor compaction properties and a direct compression process is not recommended for such high drug load formulations. Poor compressibility and tablet friability are known issues and hence were another main emphasis during the development. Therefore, there remains a need for stable and industrially acceptable pharmaceutical composition comprising vildagliptin and metformin whose manufacturing process is simple, reliable, and economical which may be conducted using standard manufacturing methods and raw materials.

Accordingly, the present invention provides biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin or pharmaceutically acceptable salt thereof, where one active ingredient (vildagliptin) releases instantaneously (formulated as immediate release) and another active ingredient (metformin) can release drug over a period of time (formulated as sustained release). The biphasic release pharmaceutical formulations of the present invention are stable, increased shelf life and this design itself improve patient compliance by minimizing gastrointestinal side effect and also helps to reduce dosing frequency of individual component. The said fixed dose combination formulations according to the present invention can be used for the improvement of glycemic control as an adjunct to diet and exercise in patients with Type-2 diabetes mellitus.

OBJECT OF THE INVENTION

The present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin or pharmaceutically acceptable salt thereof.

In one aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof.

In another aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein vildagliptin and metformin or pharmaceutically acceptable salts thereof are present in the said pharmaceutical formulations in an amount of about 25-100 mg and 500- 1000 mg respectively.

In yet another aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof and one or more rate controlling polymer.

In yet another aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof and one or more rate controlling polymer, wherein the metformin or pharmaceutically acceptable salt thereof is present in an amount of more than 70% based on the total weight of said metformin formulation.

In yet another aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein the said fixed dose combination formulation is administered once daily.

In yet another aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein the said formulation upon storage at a temperature of about 40°C and relative humidity of about 75% for up to six months produces not more than 1% of total vildagliptin impurities. In another aspect, the present specification relates to biphasic release bilayer tablet formulations comprising fixed dose combination of vildagliptin and metformin, said tablet formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and iii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein vildagliptin and metformin or pharmaceutically acceptable salts thereof are present in the said pharmaceutical formulations in an amount of about 25-100 mg and 500- 1000 mg respectively.

The present specification also relates to use of biphasic release fixed dose combination formulations comprising vildagliptin and metformin for the improvement and/or management of glycaemic control as an adjunct to diet and exercise in patients with Type 2 diabetes mellitus whose diabetes is not adequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of Vildagliptin and metformin hydrochloride, as separate tablets.

BRIEF DESCRIPTION OF FIGURES

Figure 1: Dissolution profile of vildagliptin from the pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin.

Figure 2: Dissolution profile of metformin hydrochloride from the pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin. DESCRIPTION OF INVENTION

In yet another aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein the said fixed dose combination formulation is administered once daily. In yet another aspect, the present specification relates to biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein the said formulation upon storage at a temperature of about 40°C and relative humidity of about 75% for up to six months produces not more than 1% of total vildagliptin impurities.

In another aspect, the present specification relates to biphasic release bilayer tablet formulations comprising fixed dose combination of vildagliptin and metformin, said tablet formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and iv) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein vildagliptin and metformin or pharmaceutically acceptable salts thereof are present in the said pharmaceutical formulations in an amount of about 25-100 mg and 500- 1000 mg respectively.

The term “pharmaceutical formulations” as used herein refers to oral dosage forms preferably in the form of tablets, bilayer tablets, capsules, sachets and the like. These solid dosage forms are generally prepared by using one or more suitable pharmaceutically acceptable excipients. The term composition or formulation are used herein interchangeably. The term “fixed dose combination” as used herein refers to a single dosage formulation comprising two or more different drugs, in this case vildagliptin and metformin or pharmaceutically acceptable salt thereof, at a precise ratio, namely, in certain fixed doses.

The term “immediate release” as used herein refers to immediate or instant release of drug from the compositions or formulations after administration. The term “extended release or sustained release” relates to release of drug from the compositions wherein said release only occurs some times after the administration and releases for a prolonged period of time. The extended release or sustained release formulations prolongs the release at a controlled rate to reduce dosing frequency. These terms are also used by the pharmacopoeias and the FDA. Whilst immediate-release dosage forms are designed to give a fast onset of drug action, modifications in drug release are often desirable to increase the stability, safety and efficacy of the drug, to improve the therapeutic outcome of the drug treatment and/or to increase patient compliance and convenience of administration.

The term “biphasic release” as used herein refers to composition or formulation which is having both immediate release and extended release or sustained release profile. Preferably the biphasic release fixed dose combination formulations according to the present invention, is having some immediate release formulations/portions which will release one drug from the formulations immediately after administration and extended or sustained release formulation/portion which will continue to release the other drug from formulations for a prolong time after administration. The biphasic release profile of a composition aims to achieve an initial plasma peak of a drug which is essential for quick onset of action and followed by extended release of drug to maintain the required therapeutically effective plasma concentration throughout the day.

The term “vildagliptin” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. The amount of vildagliptin or pharmaceutically acceptable salts thereof are employed in the present composition is in the range of 25-100 mg, e.g. 50 mg, 75 mg.

The term “metformin” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Preferably metformin is present in the salt form, e.g. metformin hydrochloride. The therapeutic effective dose of metformin or pharmaceutically acceptable salts thereof is 500-1000 mg. The amount of metformin or pharmaceutically acceptable salts (metformin hydrochloride) thereof are employed in the present composition is in the range of 500-1000 mg, e.g. 500 mg, 850 mg, 1000 mg.

The term “rate controlling polymers” as used in the context of the present specification relates to one or more pharmaceutically acceptable polymers which controls the drug release from the formulation. The rate controlling polymers helps to achieve extended release or delayed or sustained release profile.

Suitable "rate controlling polymers" may include but not limited to one or more hydrophilic polymers, hydrophobic polymers, natural polymers, bioadhesive polymer, pH-dependent or pH-independent, enteric, degradable, non-degradable, enteric polymers, melt extrusion polymers and the like.

Suitable hydrophilic polymers may include one or more of cellulosic polymers/copolymers or its derivatives including, but not limited to methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or acrylamide derivatives, and the like. Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates and the like.

Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate and the like.

Suitable bioadhesive polymers selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly( valeric acid), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof and the like.

Other rate controlling polymers suitable for use in the invention include, but are not limited to, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobiityl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly( ethylene oxide), poly (ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrol idone, polyvinylphenol, Polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co- capro lactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)), polyorthoesters, blends and copolymers thereof and the like. Methacrylates can be but not limited to Eudragit® L; Eudragit® S; Eudragit® FS 30 D; Eudragit® L30D-55; and Eudragit® L100-55, Eudragit RL PO, Eudragit RL 100, Eudragit RL 30 D, Eudragit ® E, Eudragit ® NE and the like.

Pharmaceutically acceptable excipients

The pharmaceutical formulations of the present inventions further comprises one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipients” include, but not limited to, diluents, disintegrants, binders, lubricants, glidants, acidifying agent, alkalizing agent, stabilizers, surfactants, sweetener, film coating materials, plasticizers, pigments, opacifiers, coloring agents and the like.

Suitable diluents, may be selected from, but not limited to the group consisting of different grades of starches, such as maize starch, potato starch, rice starch, wheat starch, pregelatinised starch, fully pregelatinised starch; cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such as mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose; oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium hydrogenphosphate; particularly preferably the fillers are selected from the group consisting of, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, spray dried lactose, and anhydrous lactose and the like.

Suitable disintegrants may be selected from, but not limited to the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, crosslinked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose, and disintegrating aids such as magnesium alumino-metasilicate and ion exchange resins like polacrilin potassium; particularly preferably the disintegrants are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone and the like.

Suitable binders may be selected from, but not limited to the group consisting of polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch and the like.

Suitable lubricants may be selected from, but not limited to the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium stearate; particularly preferably the lubricant is magnesium stearate and sodium stearyl fumarate and the like.

Suitable glidants, may be selected from, but not limited to the group consisting of colloidal silica, hydrophobic colloidal silica and magnesium trisilicate, such as talc and the like.

Composition may contain acidifying and alkalinizing agent. Acidifying agents can be selected from, but not limited to citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and mixtures thereof and the like. Alkalizing agent can be selected from, but not limited to magnesium oxide, aluminium oxide, ammonium hydroxide, magaldrate, an alkali metal salt or alkaline earth metal salt, such as sodium bicarbonate, calcium carbonate or sodium citrate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide or calcium carbonate and meglumine and the like. Composition may contain surfactants. Suitable surfactants as component can be selected from, but not limited to the group consisting of anionic surfactants, preferably sodium lauryl sulphate; polyethylene glycols (PEGs), preferably those PEGs having molecular weight in the range of about 2000 to 10000, more preferably PEG 3350, PEG 4000, PEG 6000, PEG 8000; Polysorbates, preferably Tween 20, Tween 80 or Span 80; fatty acid esters, preferably propylene glycol caprylates such as Capmul PG- 8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleates and caprylates (Capmul MCM); esters of polyethylene glycol and fatty acids, such as Labrasol and Solutol; castor oil ethoxylate (glycerol polyethylene glycol ricinoleate) such as Cremophor EL and Cremophor RH 40. More preferably the surfactant is selected from the group consisting of sodium lauryl sulphate; PEG 3350, PEG 4000, PEG 600 or, PEG 8000 and preferably PEG 6000; Tween 20 or Tween 80; and esters of polyethylene glycol and fatty acids, most preferably sodium lauryl sulphate and PEG 6000 and in particular sodium lauryl sulphate and the like.

Suitable sweeteners may be selected from, but not limited to the group consisting of aspartame, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.

Suitable film-forming agents and coating materials, if used, may include, but are not limited to hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, polyvinylalcohol, , methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, shellac, liquid glucose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester and the like. Suitable plasticizers, if used, may include, but are not limited to polyethylene glycol, diethyl phthalate and glycerol, acetyl tributyl citrate. Preference is given to polyethylene glycol and the like.

Vildagliptin Formulations

The vildagliptin or pharmaceutically acceptable salt thereof formulations of the present specification are preferably in solid oral dosage forms, and having immediate release profile. Examples of such dosage form includes, are but not limited to spheroids, pellets, granules, powders, multiple unit particles, and the like. The said formulations/portions are prepared by using one or more pharmaceutically acceptable excipients and the methods employed for such formulations is preferably dry granulation. Such methods are well known in the art. The immediate release vildagliptin formulations are ready to be used for further processing for the preparation of fixed dose combination formulations according to present inventions.

Metformin formulations

The metformin or pharmaceutically acceptable salt thereof formulations of the present specification are preferably in solid oral dosage forms, and having extended or sustained release profile. Examples of such dosage form includes, are but not limited to spheroids, pellets, granules, powders, multiple unit particles, and the like.

The extended release metformin formulations/portion comprise one or more rate controlling polymers and one or more pharmaceutically acceptable excipients. The use of rate controlling polymer aids to achieve extended release profile. The hydrophilic rate controlling polymers are being preferred. The extended release metformin formulation contains drug loading of more than 60% (w/w), preferably more than 70% (w/w). The drug loading refers to amount of metformin or pharmaceutically acceptable salts thereof is present in the formulation based on the total weight of the metformin formulation. The high drug load of metformin according to the present invention are suitably designed to accommodate high dose of metformin in the formulation while maintaining the extended release profile and makes the formulation of suitable size which could easily be swallowed by the patients. The extended release metformin formulations/portions can be prepared by one or more of various methods, but not limited wet granulation, hot melt granulation, fluid bed granulation, spray granulation, extrusion-spheronization and the like. The spray granulation process is being preferred. The metformin formulations accordingly are ready to be used for further processing for the preparation of fixed dose combination formulations according to present inventions. The selection of excipients and the granulation process are critical to maintain the high drug load and the extended release profile and also stability of the overall fixed dose combination formulations.

The sustained or extended release metformin formulation of the present specification when subjected to an in vitro dissolution study in 1000 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, exhibits a characteristic release profile of metformin or pharmaceutically acceptable salt thereof in the manner of: i) releases no more than 50% in 1 hour, ii) releases at least about 45% and no more than 80% in 3 hours, and iii) releases at least about 80% in 10 hours.

Fixed dose combination formulations

The biphasic pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin according to the present specification can be prepared by making the individual formulations or components of vildagliptin or metformin as described above in the present specification, which can then be formulated in to a suitable dosage forms like tablets, bilayer tablets, capsules, sachets and the like. The bilayer tablets are being preferred. Alternatively, the individual components can be filled in a capsule or a sachet. The size/dimensions of the individual compositions can be modified in such a way that it can be filled in the capsule of a suitable size. Alternatively, the individual components can be further processed to form a bilayer tablet or inlay tablet.

The pharmaceutical formulations comprising fixed dose combination of the present specification comprising vildagliptin and metformin is having biphasic release profile. Typically, vildagliptin formulations are prepared in immediate release profile and metformin formulations are prepared in extended or sustained release profile. The release profile are selected based on the need, and therapeutic effective dose of the vildagliptin and metformin, so that the unit composition can be administered once daily. The biphasic pharmaceutical formulations of the present specification can be further coated with suitable film-forming agents and/or coating materials to form a subcoating or enteric coating. Such coating methods are well known in the art.

The biphasic pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin the present specification may be suitably packed in to any conventional pack like stick pack, blister pack, HDPE bottle or any other packaging well known in the art.

The biphasic release pharmaceutical formulations of the present specification is expected to be stable throughout the shelf life which can be established by subjecting the compositions to accelerated and long term stability studies.

The biphasic release pharmaceutical formulations comprising fixed dose combination of vildagliptin and metformin of the present specification can be used for the improvement and/or management of glycaemic control as an adjunct to diet and exercise in patients with Type 2 diabetes mellitus whose diabetes is not adequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of Vildagliptin and metformin hydrochloride, as separate tablets.

The following examples will further describe certain specific aspects and embodiments of the invention in greater details and are not intended to limit the scope of invention.

EXAMPLES

Example 1: Immediate release (IR) formulations of vildagliptin.

Process:

1. All the excipients- microcrystalline Cellulose, hydroxyl propyl cellulose, copovidone, lactose, sodium starch glycolate, croscarmallose sodium were milled using suitable screen size.

2. The milled materials obtained in step 1 and vildagliptin were then blended in to a blender.

3. The blended materials obtained in step 2 were milled using suitable screen size, and lubricated with talc and/or magnesium Stearate in a blender.

4. The blended materials obtained in step 3 were ready for further processing. Example 2: Extended release (ER) formulations of metformin.

Process:

1. The intra-granular materials were taken in a rapid mixed granulator (RMG) and mixed for appropriate time.

2. Required quantity of purified water was taken into SS vessel and copovidone was added slowly and stirred until lump free solution was observed.

3. Granulated the material of step 1 with binder solution of step 2 using atomised spray gun assembly at appropriate parameters to get desired wet mass size.

4. The wet mass obtained in step 3 was dried in fluidised bed drier at desired temperature. 5. The dried granules obtained in step 4 were milled.

6. The milled granules of step 5 were mixed with extra-granular materials in a blender and subsequently lubricated with talc and magnesium Stearate in a blender.

7. The blended materials obtained in step 6 were ready for further processing.

Example 3: Some fixed dose combination formulations comprising vildagliptin and metformin formulations as per the present specification are described below:

Process:

1. The immediate release formulations of vildagliptin were prepared according to example 1.

2. The extended release formulations of metformin were prepared according to example 2. 3. The fixed dose combination formulations were prepared by taking the formulation obtained in step 1 & step 2 and compressed into bilayer tablet or matrix tablet or filled in a capsule of suitable size.

Stability Study:

The stability of the pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin as per the present specification were evaluated through accelerated stability studies. The composition was prepared according to the formula and process of example 3b, and the compositions was subjected to stability study at 40 °C/75% RH and at 30 °C/75% RH. The composition was found to be stable at accelerated conditions. Table 1 represents the study result data.

Table 1: Stability study of pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin.

Further, the comparative degradation of vildagliptin of the pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin as per the present specification (example 3 a) was evaluated through accelerated stability study and was compared against the reference product Galvus Met® (50 mg vildagliptin and 500 mg metformin HC1). The results were given in Table 2. This study demonstrates that the pharmaceutical formulation as per the present specification are found to be more stable when compare to the reference product and expected to increase the shelf life.

Table 2: Comparative degradation study of vildagliptin of pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin and the reference product.

In-vitro dissolution study:

The release profile of the pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin as per the present specification was evaluated through in-vitro dissolution studies. The fixed dose combination formulation was prepared according to the formula and process of example 3b, and was subjected to an in vitro dissolution study in in 1000 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus (paddle). Figure 1 & 2 represent the dissolution profile of vildagliptin and metformin hydrochloride respectively. The release profile demonstrates that formulations according to the present specification exhibits biphasic release profile, wherein vildagliptin is having immediate release profile and the metformin is having sustained or extended release profile.

Pharmacokinetic study:

The pharmacokinetic parameters of pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin as per the present specification was evaluated in-vivo through comparative bioavailability studies. The adverse events to ensure the safety of the study subjects were also evaluated.

The fixed dose combination formulation was prepared according to the formula and process of present specification and referred herein as test product (T). The reference product used for vildagliptin and metformin in the study was Galvus (Vildagliptin) 50 mg tablets of Novartis Europharm UK (Rl) and Metsmall Sustained Release (Metformin Hydrochloride) Tablets 1000 mg of Dr. Reddy's Laboratories Ltd., India (R2) respectively. The pharmacokinetic parameters of the test and the reference products were assessed in an open label, balanced, randomized, two-treatment, two- period, two-sequence, single-dose, crossover, oral bioequivalence study in normal healthy, adult, human subjects under fed conditions. The measured pharmacokinetic parameters of vildagliptin and metformin were summarized below table 3. The study results demonstrate that test product when compared to the respective reference products met the bioequivalence criteria. Further, the test and reference products were well tolerated by the subjects. No adverse event were reported after administration of test products. Table 3: Comparative bioavailability studies of pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin

Claims

We Claim:

1. A biphasic release pharmaceutical formulation comprising fixed dose combination of vildagliptin and metformin, said formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof.

2. The composition of claim 1, wherein vildagliptin and metformin or pharmaceutically acceptable salts thereof are present in the said pharmaceutical formulation in an amount of about 25-100 mg and 500-1000 mg respectively.

3. The composition of claim 1 , wherein the said metformin formulations comprising one or more rate controlling polymer.

4. The composition of claim 3, wherein the metformin or pharmaceutically acceptable salts thereof is present in an amount of more than 70% based on the total weight of said metformin formulations.

5. The composition of claim 3, wherein the said rate controlling polymer is selected from one or more of hydroxymethyl celluloses, ethyl cellulose, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, methylcelluloses, carboxymethyl celluloses, sodium carboxymethyl celluloses, carboxyethyl celluloses, carboxy polymethylenes, hydroxypropyl methyl phthalates, polyvinylpyrrolidones, cellulose acetates, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates, sodium alginate,

28 gums such as acacia gum, guar gum, tragacanth gum, and xanthan gum, methacrylic acid copolymers or mixtures thereof.

6. The composition of claim 1, wherein the said metformin formulations are prepared by spray granulation process.

7. The composition of claim 1, wherein the said formulation upon storage at a temperature of about 40°C and relative humidity of about 75% for up to six months produces not more than 1% of total vildagliptin impurities.

8. The composition of claim 1, wherein the said pharmaceutical formulation is selected from matrix tablet, bilayer tablet and capsules.

9. The composition of claim 1, wherein the said fixed dose combination formulation is administered once daily.

10. A biphasic release bilayer tablet formulation comprising fixed dose combination of vildagliptin and metformin, said tablet formulation comprising: i) immediate release formulations of vildagliptin or pharmaceutically acceptable salts thereof, and ii) extended or sustained release formulations of metformin or pharmaceutically acceptable salts thereof, wherein vildagliptin and metformin or pharmaceutically acceptable salts thereof are present in the said tablet formulation in an amount of about 25-100 mg and 500-1000 mg respectively, and wherein the metformin or pharmaceutically acceptable salts thereof is present in an amount of more than 70% based on the total weight of said metformin formulations.