DESC:TECHNICAL FIELD OF INVENTION
The invention relates to a pharmaceutical compositions comprising fixed dose combination of metformin and vildagliptin or pharmaceutically acceptable salt thereof. The composition comprises a core and layers coated on the core, wherein the core comprises first active and coat on core comprises second active. By applying coating layer of vildagliptin or pharmaceutically acceptable salt thereof over core, compositions comprising fixed dose combination of metformin and vildagliptin with excellent storage stability can be prepared. Such compositions exhibits improved storage stability and particularly, levels of degradants in the formulation can be effectively controlled during storage. The invention also includes a process of preparing such compositions and method of treating type-2 diabetes mellitus by administering the composition to a patient in need thereof.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a common disorder more prevalent in developed countries. It is a metabolic disease in which there is a high blood sugar level over a prolonged period. Drugs of choice for therapy include biguanides, DPP-IV inhibitors, sulfonylurea, thiazolidinedione, alphaglucosidase inhibitor, amylin analog, glucagon-like peptide-1 (GLP-1) or incretin mimetic, meglitinide and insulin.

Dipeptidyl-peptidase-IV (DPP-4) inhibitors are an oral drug class that was introduced in 2006 and that seems easy to use and do not require regular glucose monitoring or dose adjustments.

Vildagliptin is an orally active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Chemically vildagliptin is (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl] pyrrolidine-2-carbonitrile with the chemical structure illustrated below in Formula 1.

Formula 1

Vildagliptin is marketed in the europe in the form of tablets under the brand name Galvus® and in combination with metformin under the brand name Eucreas® marketed by Novartis.

Metformin is an antihyperglycemic agent from the biguanide class and available in various salt forms, e.g. hydrochloride. Chemically, metformin hydrochloride is 1-carbamimidamido-N,N-dimethylmethanimidamide hydrochloride with the following structure:

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.

U.S. Patent No. US 6,340,475 discloses a controlled-release pharmaceutical composition designed for gastric retention and controlled delivery of metformin.

Extended-release formulations of metformin are disclosed in several U.S. patents
(US Patent No. 6,635,280; 6,866,866; 6,475,521 and 6,660,300).

It is well known in the art that vildagliptin is an unstable compound and it is highly unstable when exposed to air and humidity, it degrades and form impurities. In addition, vildagliptin is reactive against the excipients employed in developing formulations (EP 2468361).

U.S. Patent No. 6,166,063 discloses a DPP4 inhibiting compound, vildagliptin, its use in treating type-2 diabetes mellitus and pharmaceutical compositions thereof.

EP 2468361 A1 discloses a pharmaceutical composition, comprising vildagliptin granules which are coated with at least one coating layer and one or more than one excipients.

U.S. Patent Application Publication No. 2012/0202820 discloses invention related to a pharmaceutical composition that comprises the active substance metformin in combination with one of the active substances sitagliptin or vildagliptin.

U.S. Patent Application Publication No. 2014/0287040 discloses composition comprising a vildagliptin and metformin and the processes for the preparation thereof.

PCT Publication No. WO 2007/041053 discloses a composition of DPP-4 inhibitors preferably vildagliptin and metformin.

PCT Publication No. WO 2007/078726 discloses pharmaceutical compositions comprising fixed-dose combinations of a dipeptidyl peptidase-4 inhibitor and metformin.
Indian Patent app. No. 2669/CHENP/2006 discloses pharmaceutical compositions comprising vildagliptin.
Although various attempts have been made earlier for preparing pharmaceutical compositions comprising fixed dose combination of metformin and vildagliptin or pharmaceutically acceptable salt thereof, there is still need to develop alternative or novel pharmaceutical compositions which are stable and are having desired release profile.

SUMMARY OF THE INVENTION
In one general aspect, there is provided a pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a) wherein coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and at least suitable polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof; and
(c) optionally, a second coating layer disposed over the first coating layer comprising one or more excipients.

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof; and optionally a seal coat over the core;
(b) first coating layer coated over the core obtained in step (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and at least one polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof; and
(c) optionally, a second coating layer disposed over the first coating layer comprising one or more excipients.

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and at least one polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof; and
(c) optionally, second coating layer disposed over the first coating layer comprising one or more excipients, wherein release of metformin is immediate or modified release.

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) a comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and hydroxypropyl methylcellulose; and
(c) optionally, second coating layer disposed over the first coating layer comprising one or more excipients.

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and hydroxypropyl cellulose; and
(c) optionally, second coating layer disposed over the first coating layer comprising one or more excipients.

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and polyvinyl pyrrolidone; and
(c) optionally, second coating layer disposed over the first coating layer comprising one or more excipients.

In another general aspect the suitable polymers used in coating may be present in an amount within the range from about 1% to about 20% w/w, preferably from about 5 to about 15% w/w of the composition. Examples of suitable polymers used in coating include, but are not limited to, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP) hydroxypropyl methylcellulose (HPMC), gum acacia, as well as other conventional binding agent and/or mixtures thereof, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP).

In another general aspect, the pharmaceutical composition comprising vildagliptin and metformin or pharmaceutically acceptable salt thereof comprises:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating comprising about 50mg of vildagliptin; about 16 to 24mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof;
(c) optionally second coating applied over first coating layer.

In another general aspect, the outer coating layer further comprises colorants and one or more polymers to differentiate compositions of various strengths. The components of the outermost layer may be similar as in the outer layer.

In another general aspect, the pharmaceutical composition comprises:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a), wherein said coating layer comprises about 10% to about 50% w/w of vildagliptin or pharmaceutically acceptable salt thereof and about 5% to about 15% w/w of suitable polymer, wherein suitable polymer is selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof.
(c) optionally, second coating layer disposed over the first coating layer of (b) comprising one or more pharmaceutically acceptable excipients.

In another general aspect, the pharmaceutical composition comprising vildagliptin and metformin or pharmaceutically acceptable salt thereof comprising:
(a) about 20% w/w to about 75% w/w of metformin or pharmaceutically acceptable salt or hydrates thereof;
(b) about 1.5% w/w to about 20% w/w of vildagliptin or pharmaceutically acceptable salt or hydrates thereof;
(c) about 1% w/w to about 7% w/w of suitable polymer of combination thereof;
(d) optionally one or more pharmaceutically acceptable excipients.

In another general aspect, the pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer comprising about 50mg of vildagliptin or pharmaceutically acceptable salt thereof; about 16 to 24mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof;
(c) optionally, second coating applied over first coating layer.

In another general aspect, there is provided a process for preparation of pharmaceutical composition, which process comprises steps of:
(a) mixing metformin or pharmaceutically acceptable salt thereof; with one or more pharmaceutical excipients, granulating the mixture using suitable binder solution followed by drying to get granules which on lubrication compressed to form core or tablet;
(b) dissolving vildagliptin or pharmaceutically acceptable salt thereof and at least one polymer selected form hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof in suitable solvent to form coating solution;
(c) coating the core obtained in step (a) by coating solution obtained in step (b) to form first coating layer; and
(d) optionally, second coating layer disposed over the first coating layer obtained in step (c).

In another general aspect, there is provided a process for preparing pharmaceutical composition of vildagliptin and metformin or pharmaceutically acceptable salt thereof wherein the process comprises steps of:
(a) preparing a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) coating a layer over the core obtained in step (a) to obtain a coated core wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof;
(c) optionally, coating a second coating layer over the coated core obtained in step (b).

In another general aspect, the coating layers on the core are applied by spray coating. Perforated pan coaters and fluid bed coaters can be used for the coating.
In another general aspect, the process for preparation of stable pharmaceutical composition comprises combination of metformin and vildagliptin or pharmaceutically acceptable salt thereof, wherein the first coating layer, the second coating layer, are applied as a suspension of the polymer in a coating solvent.

In another general aspect, the stable pharmaceutical composition comprises combination of metformin and vildagliptin or pharmaceutically acceptable salt thereof, retains at least 90% w/w of total potency of vildagliptin and metformin and pharmaceutically acceptable salt thereof after storage at 40°C and 75% relative humidity for at least 3 months.
In another general aspect, there is provided a method of treating type-2 diabetes mellitus comprising administering the pharmaceutical composition in a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION
The inventors of the invention have surprisingly found that it is possible to formulate a pharmaceutical composition of vildagliptin and metformin or pharmaceutically acceptable salt thereof; which can exhibit superior chemical and physical stability by specialized coating of vildagliptin or pharmaceutically acceptable salt thereof; over core comprising metformin or pharmaceutically acceptable salt thereof.

The term "vildagliptin" used throughout the specification refers to not only vildagliptin per se, but also various pharmaceutically acceptable salts and pharmaceutically acceptable hydrates thereof.

The term "metformin" used throughout the specification refers to not only metformin per se, but also various pharmaceutically acceptable salts and pharmaceutically acceptable hydrates thereof.

The term "core" used throughout the specification refers to a "core", "tablet core", “tablet core composition" or "core composition" which comprises metformin or pharmaceutically acceptable salt or hydrates thereof.

The core employed in the composition of the invention may include conventional pharmaceutical excipients to enable formation of a pharmaceutically acceptable solid core comprising metformin and pharmaceutically acceptable salt thereof.

The core may be formed of one or more pharmaceutical excipients selected from, but not limited to one or more of bulking agents or fillers, binders, disintegrants, release retarding agents and lubricants.

In an embodiment, the core preferably contain a) at least one release retarding agents, bulking agent or filler; b) optionally at least one binder; c) optionally at least one disintegrant; and d) preferably but optionally at least one lubricant, wherein a) the release retarding agents, bulking agent or filler is present in an amount within the range from about 1% to about 95% w/w, preferably from about 10% to about 85% w/w; b) the binder is present in an amount within the range from about 0% to about 20% w/w, preferably from about 1% to about 10% w/w; c) the disintegrant is present in an amount within the range from about 0% to about 20% w/w, and preferably from about 0.25% to about 10% w/w; and d) the lubricant is present in an amount within the range from about 0% to about 5% w/w, preferably from about 0.2% to about 2% w/w of the composition.

In another embodiment, the bulking agents are microcrystalline cellulose and lactose monohydrate; the disintegrant is croscarmellose sodium; and the lubricant is magnesium stearate.

The core or core tablet present in the composition of the invention can be prepared by a variety of processes and order of addition of excipients. The utility of these formulations is not limited to a specific dosage form or manufacturing process. The core may be manufactured by wet granulation, dry granulation, direct blending or any other pharmaceutically acceptable process.

In another embodiment, there is provided a pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof; and
(c) optionally, second coating layer disposed over the first coating layer comprising one or more excipients.

In another embodiment, there is provided a pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof; and optionally a seal coating over the core;
(b) first coating layer coated over the core (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and at least one polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof; and
(c) optionally, second coating layer disposed over the first coating layer comprising one or more excipients.

In another embodiment, the process of preparing the core or core tablet includes the steps of blending the one or more excipients such as release retarding agents, bulking agent, optionally binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate tablet formation.
The release controlling substances which can be used may be selected from the group consisting of hydrophilic agents (e.g. water-soluble polymers), lipophilic agents (water-insoluble polymers) and inert matrix agents, wherein the hydrophilic agents are selected from the group of pharmaceutical excipients which generate a gel in contact with water, including cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like; noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers, polyethylene oxide and mixtures thereof; the lipophilic agents are selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable, castor, cottonseed oils, glyceril behenate and the like; ethyl cellulose; acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof; and the inert agents are selected from the group consisting of thermoplastic polymers, which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.

The bulking agents or fillers may be present in the core in an amount within the range from about 1% to about 95% w/w and preferably from about 10% to about 85% w/w of the composition. Examples of bulking agents or fillers suitable for use herein include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, compressible sugars, and other known bulking agents or fillers, and/or mixtures thereof, preferably microcrystalline cellulose.

The binder may be present in the core in an amount within the range from about 0% to about 20% w/w, preferably from about 0.1% to about 10% w/w of the composition. Examples of binders suitable for use herein include, but are not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinylpyrrolidone (PVP) (molecular weight ranging from about 5,000 to about 1,000,000, preferably about 40,000), hydroxypropyl methylcellulose (HPMC), lactose, gum acacia, ethyl cellulose, cellulose acetate, as well as a wax binder such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax, as well as other conventional binding agent and/or mixtures thereof, preferably hydroxypropyl cellulose.

The disintegrant may be optionally present in the core in an amount within the range from about 0% to about 20% w/w, preferably from about 0.25% to about 10% w/w of the composition. Examples of disintegrants suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose or other known disintegrant, preferably croscarmellose sodium.

The lubricant may be present in the core in an amount within the range from about 0.1% to about 5% w/w, preferably from about 0.2% to about 2% w/w of the composition. Examples of tableting lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate or hydrogenated vegetable oils and fats, or mixtures thereof, preferably magnesium stearate.

The first coating layer of the composition comprises one or more pharmaceutical excipients and optionally one or more polymers. In a preferred embodiment, the first coating layer of the composition comprises vildagliptin or pharmaceutically acceptable salt thereof and polymer.
The coating composition for first coating contains vildagliptin or pharmaceutically acceptable salt thereof and at least one polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof and a coating solvent, which may be aqueous or non aqueous but preferably is water, which is used for processing and removed by drying. Suitable polymer for first coating layer may be selected from, but not limited water-soluble polymer, water-insoluble polymer, or mixtures thereof. Particularly, water-soluble polymers are preferred.

Examples of polymers suitable for first coating layer include, but not limited to hydroxypropyl methylcellulose, ethyl cellulose, methacrylic polymers or hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinylpyrrolidone. The coating layer may also optionally include a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; polyvinyl alcohol and an anti-adherent or glidant such as talc, fumed silica or magnesium stearate, opacifying agent such as titanium dioxide. The coating layer may also include iron oxide based colorants.
The suitable polymers used in coating may be present in an amount within the range from about 1% to about 20% w/w, preferably from about 5% to about 15% w/w of the composition. Examples of suitable polymers used in coating include, but are not limited to, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP) hydroxypropyl methylcellulose (HPMC), gum acacia, as well as other conventional binding agent and/or mixtures thereof, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP).
Examples of suitable coating solvents includes, but not limited to water, ethanol, methanol, and isopropyl alcohol, with water being preferred.

The first coating layer comprising vildagliptin or pharmaceutically acceptable salt thereof may be present in an amount within the range from about 4% to about 50%, preferably from about 5 to about 40% w/w of the composition.
The second coating layer of the composition of the invention comprises suitable polymer which may be functional or non functional with suitable solvent employed to facilitate the coating, which preferably is water, which is used for processing and removed by drying.

The amount of vildagliptin or pharmaceutically acceptable salt thereof in the first coating layer is in the range from about 5% to about 80%, preferably from about 20 to about 70% w/w, based on the weight of the coating layer.

The first coating layer containing vildagliptin or pharmaceutically acceptable salt thereof may be present in an amount within the range from about 2% to about 50%, preferably from about 3% to about 30% w/w of the composition. The composition of the present invention further may comprise an outermost protective layer comprising one or more polymers and one or more pharmaceutical excipients.

In another embodiment, the pharmaceutical composition comprising vildagliptin and metformin or pharmaceutically acceptable salt thereof comprises:
(a) about 20% to about 75% of metformin or pharmaceutically acceptable salt or hydrates thereof;
(b) about 1.5% to about 20% of vildagliptin or pharmaceutically acceptable salt or hydrates thereof;
(c) about 1% to about 7% of suitable one or more polymer or combination thereof;
(d) optionally one or more pharmaceutically acceptable excipients.

In another embodiment, the pharmaceutical composition comprising vildagliptin and metformin or pharmaceutically acceptable salt thereof comprises:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating comprising about 50mg of vildagliptin; about 16 to 24mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof;
(c) optionally second coating applied over first coating layer.

In another embodiment, the pharmaceutical composition comprises:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a), wherein said coating layer comprises about 10% to about 50% w/w of vildagliptin or pharmaceutically acceptable salt thereof and about 5% to about 15% w/w of suitable polymer, wherein suitable polymer is selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof.
(c) optionally, second coating layer disposed over the first coating layer of (b) comprising one or more pharmaceutically acceptable excipients.

Pharmaceutical excipients suitable for employing in the coating layers of the composition may include, but not limited to, bulking agents or diluents, binders, plasticizers, lubricants, colorants, pH adjusting agents, or mixtures thereof.

In another embodiment, there is provided a process for preparing pharmaceutical composition of vildagliptin and metformin or pharmaceutically acceptable salt thereof wherein the process comprises steps of:
(a) preparing a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) coating a layer over the core obtained in step (a) to obtain a coated core wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof;
(c) optionally, coating a second coating layer over the coated core obtained in step (b).

In another embodiment, there is provided a process for preparation of pharmaceutical composition comprising combination of metformin and vildagliptin or pharmaceutically acceptable salt thereof, which process comprises steps of:
(a) mixing metformin or salt thereof with one or more pharmaceutical excipients, granulating the mixture using suitable binder solution followed by drying to get granules which on lubrication compressed to form core or tablet;
(b) dissolving vildagliptin or pharmaceutically acceptable salt thereof and at least one polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof in suitable solvent to form coating solution;
(c) coating the core obtained in step (a) by coating solution obtained in step (b) to form first coating layer;
(d) optionally, second coating layer disposed over the first coating layer obtained in step (c).

In accordance with the present invention, a preferred method is provided for preparing the core or core tablet comprising metformin or pharmaceutically acceptable salt thereof employed in the composition of the invention which includes the steps of blending the one or more excipients such as release retarding agent, bulking agent, optionally binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate tablet formation.
The core or core tablet present in the composition of this invention can be prepared by a variety of processes and order of addition of excipients. The utility of these formulations is not limited to a specific dosage form or manufacturing process. The cores may be manufactured by wet granulation, dry granulation, direct blending or any other pharmaceutically acceptable process.

It has been surprisingly found that the coated composition of the invention exhibits superior chemical and physical stability having desired solubility and dissolution profile as compared to composition tablets which is prepared by traditional methods using conventional dry granulation or wet granulation.
The composition of the invention may be formulated in a suitable dosage form including, but not limited to, a tablet, caplet, mini-tablet, pellets, granules, capsule, capsule filled with mini-tablets or pellets or combinations thereof.
The invention further provides a method of treating type-2 diabetes mellitus comprising administering the pharmaceutical composition in a patient in need thereof.

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
In accordance with the Present Invention coated tablet formulations are set out below.

Example-1:

Vildagliptin and Metformin HCl SR Tablets
Sr. No. Ingredients Strengths
Metformin HCl SR Tablet (50+500) mg (50+850) mg (50+1000) mg
Core Tablet Formulation mg/Tablets
1. Metformin Hydrochloride 500.000 850.000 1000.000
2. Microcrystalline Cellulose 7.0-9.0
3. Polyvinylpyrrolidone 6.0-16.0
4. Purified water q.s.
5. Methocel K100MCR 220.0-270.0
6. Magnesium Stearate 5.0-9.0
Total Tablet Weight 765.000 1125.000 1280.000
Seal coating
7. Instacoat Sol IC-S-1643 12.0-28.0
8. Isopropyl alcohol q.s.
9. Dichloromethane q.s.
Weight of Tablet after seal coating 750-800 1150-1200 1250-1350
Vildagliptin Coating
10. Vildagliptin 50.00
11. Polyethylene Glycol 9-15
12. Polymer* 16-24
13. Purified Talc 4-6
14. Purified water q.s.
Weight of Tablet after Drug coating 850-900 1225-1280 1370-1450
Top Coating
15. Instacoat White 18.00 26.00 28.00
16. Purified water q.s. q.s. q.s.
Weight of Tablet after Top coating 870-920 1250-1380 1400-1470

* Polymer: Hydroxypropyl methyl cellulose (Hypromellose 5CPS); Hydroxypropyl cellulose; Polyvinylpyrrolidone or combinations thereof

Manufacturing Process:
1. Mill Metformin Hydrochloride through 0.5 mm S.S. perforated screen at Impact forward high speed.
2. Mix microcrystalline cellulose and Metformin Hydrochloride thoroughly.
3. Dissolve Povidone in purified water and granulate the step-2 material till suitable dough mass is formed.
4. Dry the wet mass in fluidized bed dryer.
5. Pass the dried granules through #20 mesh (ASTM 425µ).
6. Prelubrication material and Metformin Hydrochloride dried granules mix in Octagonal blender for 20 minutes at slow speed.
7. Add Magnesium Stearate in above prelubricated blend and Lubricate for 5 minutes in Octagonal blender at slow speed.
8. Compress the Lubricated blend on double rotary tablet compression machine at 150-250 Newton hardness. During compression weight variation of the Tablets should not more than 1 %w/w of the target weight of the tablet.
9. Transfer compressed Metformin Hydrochloride Tablets to Autocoater Pan and dry for 10 minutes at 50ºC.
10. Dissolve Instacoat Sol IC-S-1643 in Isopropyl alcohol and Dichloromethane mixture under stirring.
11. Seal coat the compressed tablet with Instacoat Sol IC-S-1643 solution of Step-9. After desired weight gain dry the tablets in coating pan for 30 minutes at 45ºC.
12. Dissolve Vildagliptin, suitable polymer (Hypromellose 5CPS; Hydroxypropyl cellulose Hydroxypropyl cellulose; Polyvinyl pyrrolidone or combinations thereof) and Polyethylene Glycol in Purified water under stirring. Add Purified Talc under stirring and stir the solution for 30 minutes.
13. Coat the seal coated tablet with drug coat solution of Step-11. After desired weight gain dry the tablets in coating pan for 30 minutes at 50ºC.
14. Prepare top coating solution of Instacoat white in Purified water under stirring.
15. Coat the Vildagliptin coated tablets with top coating solution of Step-13. After desired weight gain dry the tablets in coating pan for 30 minutes at 50ºC.

Example-2:

Vildagliptin and Metformin HCl SR Tablets
Sr. No. Ingredients Strengths
Metformin HCl SR Tablet (50+500) mg (50+850) mg (50+1000) mg
Core Tablet Formulation mg/Tablets
17. Metformin Hydrochloride 500.000 850.000 1000.000
18. Microcrystalline Cellulose 7.0-9.0
19. Polyvinylpyrrolidone 6.0-16.0
20. Purified water q.s.
21. Methocel K100MCR 220.0-270.0
22. Magnesium Stearate 5.0-9.0
Total Tablet Weight 765.000 1125.000 1280.000
Vildagliptin Coating
23. Vildagliptin 50.00
24. Polyethylene Glycol 9-15
25. Polymer* 16-24
26. Purified Talc 4-6
27. Purified water q.s.
Weight of Tablet after Drug coating 850-900 1225-1280 1370-1450
Top Coating
28. Instacoat White 18.00 26.00 28.00
29. Purified water q.s. q.s. q.s.
Weight of Tablet after Top coating 870-920 1250-1380 1400-1470

* Polymer: Hydroxypropyl methyl cellulose (Hypromellose 5CPS); Hydroxypropyl cellulose; Polyvinylpyrrolidone or combinations thereof

Manufacturing Process:
As described in Example 1.
,CLAIMS:1. A pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a), wherein coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone or combination thereof; and
(c) optionally, second coating layer disposed over the first coating layer of (b) comprising one or more polymer.

2. The pharmaceutical composition of claim 1, wherein the first coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and 5-15% w/w of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof.

3. The pharmaceutical composition of claim 1, wherein the first coating layer comprises from about 5% to about 50% w/w of vildagliptin or pharmaceutically acceptable salt thereof of the total tablet weight.

4. The pharmaceutical composition of claim 1, wherein the said pharmaceutical dosage form is tablet, capsule and capsule filled with minitablet or pellet.

5. A pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer coated over the core (a), wherein said coating layer comprises about 10% to about 50% w/w of vildagliptin or pharmaceutically acceptable salt thereof and about 5% to about 15% w/w of suitable polymer, wherein suitable polymer is selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof.
(c) optionally, second coating layer disposed over the first coating layer of (b) comprising one or more pharmaceutically acceptable excipients.

6. A pharmaceutical composition comprising vildagliptin and metformin or pharmaceutically acceptable salt thereof comprising:
(a) about 20% w/w to about 75% w/w of metformin or pharmaceutically acceptable salt or hydrates thereof;
(b) about 1.5% w/w to about 20% w/w of vildagliptin or pharmaceutically acceptable salt or hydrates thereof;
(c) about 1% w/w to about 7% w/w of suitable polymer of combination thereof;
(d) optionally one or more pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, wherein the release of metformin or pharmaceutically acceptable salt thereof is in the form of immediate or modified release.

8. A pharmaceutical composition comprising:
(a) a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) first coating layer comprising about 50mg of vildagliptin or pharmaceutically acceptable salt thereof; about 16 to 24mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof;
(c) optionally, second coating applied over first coating layer.

9. A process for preparing pharmaceutical composition of vildagliptin and metformin or pharmaceutically acceptable salt thereof wherein the process comprises steps of:
(a) preparing a core comprising metformin or pharmaceutically acceptable salt thereof;
(b) coating a layer over the core obtained in step (a) to obtain a coated core wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinylpyrrolidone or combination thereof;
(c) optionally, coating a second coating layer over the coated core obtained in step (b).

10. A method of treating type 2 diabetes mellitus comprising administration of the composition of any of the preceding claim to a patient in need thereof.