DESC:TECHNICAL FIELD OF INVENTION

The invention relates to a pharmaceutical composition comprising vildagliptin or pharmaceutically acceptable salt thereof. The composition comprises an inert core and layers coated on the inert core, wherein the coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer. By applying coating layer of vildagliptin or pharmaceutically acceptable salt thereof over inert core, composition with excellent storage stability having excellent release profile can be prepared. Such composition of vildagliptin or pharmaceutically acceptable salt thereof exhibit improved storage stability and levels of degradants in the formulation can be effectively controlled during storage. The invention also includes a process of preparing such composition and method of treating type-2 diabetes mellitus by administering the composition to the 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-IV) 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-IV) 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 by Novartis in the Europe in the form of tablets under the brand name Galvus® and in combination with metformin under the brand name Eucreas®.

It is well known in the art that vildagliptin is an unstable compound having high susceptibility to air and humidity. Vildagliptin is unstable when exposed to air and humidity. This fact causes impurities to occur in the composition and leads to incorporation of undesired components into the composition (EP 2468361).

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

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 formulation comprising a dipeptidylpeptidase IV (DPP-IV) inhibitor.

PCT Publication No. WO 2007/041053 discloses a composition of DPP-IV inhibitors preferably vildagliptin and metformin as a tablet and process for the preparation thereof.

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 invention which relates to a direct compressed pharmaceutical composition.

PCT Publication No. WO 2014/013505 discloses a novel amorphous form of vildagliptin, process for its preparation and pharmaceutical compositions comprising it.

PCT Publication No. WO 2006/078593 disclosed crystalline Form A of vildagliptin.

Although various attempts have been made earlier for preparing pharmaceutical compositions of vildagliptin or pharmaceutically acceptable salt thereof there is still need to develop alternative pharmaceutical composition which is stable, having desired dissolution rate.

SUMMARY OF THE INVENTION

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

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) at least one inert core;
(b) at least first coating layer comprising vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer coated over the core; wherein suitable polymer comprises 5-15% of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof; and
(c) optionally, an outer coating layer disposed over the first coating layer comprising one or more pharmaceutically acceptable excipients.

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

In another general aspect, the second coating layer further comprises colorants and one or more excipients to differentiate compositions of various strengths.

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

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

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) at least one inert core;
(b) at least first coating layer coated over the core said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof; and;
(c) optionally, an outer coating layer disposed over the first coating layer comprising one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) at least one inert core;
(b) first coating layer comprising about 50mg of vildagliptin; about 12-28mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) optionally second coating applied over first coating layer.

In another general aspect, there is provided a pharmaceutical composition comprising:
(a) about 10% to about 50% of vildagliptin;
(b) about 12mg to about 28mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) optionally one or more coating or pharmaceutically acceptable excipients.

In another general aspect, there is provided a process for preparation of a pharmaceutical composition which process comprises steps of:
(a) providing at least one inert core;
(b) at least one coating layer applied over inert core and said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof; and
(d) optionally, second coating comprising one or more excipients over the first coating layer.

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, there is provided a pharmaceutical composition comprising:
(a) one or more core;
(b) at least first coating layer comprising vildagliptin or pharmaceutically acceptable salt thereof coated over the core;
(c) Optionally, an outer coating layer disposed over the first coating layer; and
(d) Optinally coated core obtained in step b or c further filled in to suitable size capsule.

In another general aspect, there is provided a process for preparation of pharmaceutical composition comprising:
(a) one or more core;
(b) at least first coating layer coated over the core wherein said layer comprises vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) Optionally, an outer coating layer comprising one or more excipients disposed over the first coating layer; and
(d) Optinally coated core obtained in step b or c further filled in to suitable size capsule or mixed with extragrnular material and filled in to capsule or compressed in to tablet dosage form.

In another general aspect, there is provided a process for preparing pharmaceutical composition of vildagliptin or pharmaceutically acceptable salt thereof wherein the process comprises steps of:
(a) preparation of inert core;
(b) at least first coating layer applied over the core obtained in step (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) optionally second coating layer applied over coated core obtained in step (b).

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

In another general aspect, the stable pharmaceutical composition of vildagliptin or pharmaceutically acceptable salt thereof, retains at least 90% w/w of total potency of vildagliptin or 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 in a patient which method comprises administering the pharmaceutical composition as substantially described herein to the patient.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the invention have surprisingly found that it is possible to formulate a stable pharmaceutical composition of vildagliptin or pharmaceutically acceptable salt thereof, which can exhibit superior chemical and physical stability by specialized coating comprising vildagliptin or pharmaceutically acceptable salt thereof applied over the core.

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 "core" or "inert core" used throughout the specification refers to a "core", "tablet core", "placebo", "placebo core tablet", "tablet core composition" or "core composition" “Pellet” etc.

The core employed in the composition of the invention may include conventional pharmaceutical excipients to enable formation of a pharmaceutically acceptable solid core or specialized pharmaceutical excipients to enable coating over them. The core may be in the form of a tablet, bead, beadlet, sphere or pill.

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, glidants, disintegrants, and lubricants.

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

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

In another embodiment a pharmaceutical composition comprises:
(a) about 10% to about 50% of vildagliptin;
(b) about 12mg to about 28mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) optionally one or more coating or pharmaceutically acceptable excipients.

In another embodiment, a process for preparation of pharmaceutical composition of vildagliptin or pharmaceutically acceptable salt thereof wherein the process comprises steps of:
(a) preparation of inert core;
(b) at least first coating layer applied over the core obtained in step (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or Polyvinyl pyrrolidone or combination thereof;
(c) optionally second coating layer applied over coated core obtained in step (b).

In another embodiment, a pharmaceutical composition comprises:
(a) at least one inert core
(b) first coating layer comprising about 50mg of vildagliptin; about 12-28mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) optionally second coating applied over first coating layer.

In another embodiment, the core preferably contain a) at least one 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 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 cores 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 cores may be manufactured by wet granulation, dry granulation, direct blending or any other pharmaceutically acceptable process.

In an embodiment, the process of preparing the cores includes the steps of blending the one or more excipients such as bulking agent, optionally binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate tablet formation.

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 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, polyvinyl pyrrolidone (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 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 suitable polymer.

The coating formulation for first coating contains vildagliptin or pharmaceutically acceptable salt thereof and at least one polymer 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, hydroxypropyl cellulose, polyvinylpyrrolidone , ethyl cellulose, methacrylic polymers or hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP K-30) and combination thereof. 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, polyvinyl pyrrolidone (PVP) hydroxypropyl methylcellulose (HPMC), gum acacia, as well as other conventional binding agent and/or mixtures thereof, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone (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 and polymer will preferably be formed by coating polymer layer with active in an amount within the range from about 10% to about 70%, preferably from about 15% to about 60% w/w of the first coating layer, optionally plasticizer in an amount within the range from about 1% to about 30%, preferably from about 5% to about 20% w/w of the first coating layer, and anti-adherent or glidant in an amount within the range for about 5% to about 30%, preferably from about 10% to about 20% w/w of the first coating layer.

The first coating layer comprising vildagliptin or pharmaceutically acceptable salt thereof may be present in an amount within the range from about 5% to about 60%, preferably from about 5% to about 50% 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 10% to about 70% w/w, based on the weight of the coating layer.

The first coating layer (containing vildagliptin) may be present in an amount within the range from about 3% to about 50%, preferably from about 5% to about 40% w/w of the composition. The composition of the invention further may comprise an outermost protective layer comprising one or more polymers and one or more pharmaceutical excipients.

In an embodiment, the composition of the invention includes an outer layer where the coating suspension is coated onto the first coated composition and second coat form a protective coating layer thereon.

The outermost protective coating layer if present may be present in an amount within the range from about 1% to about 10%, preferably from about 1% to about 5% w/w of the composition.

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.

The invention further provides a process for preparation of pharmaceutical composition of vildagliptin or pharmaceutically acceptable salt thereof, the process comprises of:
(a) providing at least one inert core;
(b) coating the inert core with at least first coating layer comprising vildagliptin or pharmaceutically acceptable salt thereof and one or more polymer selected from hydroxypropyl cellulose or hydroxypropyl methyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) drying the coated core to form first coating thereon; and
(d) optionally second coating comprising one or more excipients over the first coating layer.

In accordance with the invention, a preferred method is provided for preparing the cores employed in the composition of the invention which includes the steps of blending the one or more excipients such as bulking agent, binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate tablet formation.

It has been 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 in a patient in which a method comprises administering the pharmaceutical composition as substantially described herein to the patient.

The present 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.

Example 1: Vildagliptin composition
Sr. No. Ingredients % W/W % W/W % W/W % W/W
Core material (Pellet)
1 Celphere CP-102 (Microcrystalline Cellulose Pellets) 38-42 38-42 38-42 38-42
Drug coating solution
1 Vildagliptin 17-25 17-25 17-25 17-25
2 Polyethylene glycol 400 4.5-5.5 4.5-5.5 4.5-5.5 4.5-5.5
3 Hypromellose 3CPS 6-10 6-10 6-10 6-10
4 Purified Talc 1.5-2.5 1.5-2.5 1.5-2.5 1.5-2.5
5 Purified water q.s. q.s. q.s. q.s.
Weight of Drug Coated Pellets 72-77 72-77 72-77 72-77
Top Coating
1 Hypromellose 3CPS 2.2-4.5 3.2-4.5 - -
2 Hydroxypropyl cellulose (HPC) 2.2-4.5 - 3.2-4.5 -
3 Polyvinylpyrrolidone (PVP K-30) 2.2-4.5 - - 3.2-4.5
4 Polyethylene glycol 6000 0.8-1.5 0.8-1.5 0.8-1.5 0.8-1.5
5 Purified Talc 0.2-0.6 0.2-0.6 0.2-0.6 0.2-0.6
6 Purified water q.s. q.s. q.s. q.s.
Weight of coated pellets 75-85 75-85 75-85 75-85
Extra granular material
1 Mannitol SD 200 6-10 6-10 6-10 6-10
2 Lactose anhydrous 4-8 4-8 4-8 4-8
3 Povidone K 30 0.5-1.5 0.5-1.5 0.5-1.5 0.5-1.5
4 Sodium starch glycolate 3-5 3-5 3-5 3-5
5 Magnesium stearate 0.5-1.5 0.5-1.5 0.5-1.5 0.5-1.5
Total Tablet weight 100% 100% 100% 100%

Process:
1. Coating solution with active (Vildagliptin) is prepared by dissolving Vildagliptin, Polyethylene glycol 400 and hypromellose 3CPS or Hydroxypropyl cellulose (HPC) or Polyvinylpyrrolidone (PVP K-30) in purified water under stirring to make solution. Then talc was added and resulting solution stirred for 30 minutes under mechanical stirrer.
2. Then coat the Microcrystalline Cellulose Pellets (Celphere) in Fluidized bed processor (FBP) with drug coating solution (Step-1) till desired weight gain achieved.
3. Top coating solution is prepared by adding Hypromellose 3 CPS, Polyethylene Glycol 6000 and Purified Talc in purified water under mechanical stirrer for 45 minutes.
4. Drug coated pellets (Step-2) are coated with top coating solution (Step-3) in FBP till desired weight gain is achieved and dried.
5. Lactose anhydrous, Mannitol SD 200, Povidone K 30 and Sodium starch glycolate were passed through suitable sieve and then vildagliptin coated pellets were blended with these material for 20 minutes at slow speed in double cone blender and then lubricated with pre sifted magnesium stearate for 3 minutes in blender.
6. The lubricated blend is compressed on suitable compression machine to obtain tablets of suitable size.

Example 2: Vildagliptin composition

Sr. No. Ingredients Mg/Tablet Mg/Tablet Mg/Tablet
Core material (Pellet)
1 Celphere CP-102 (Microcrystalline Cellulose Pellets) 90-110 90-110 90-110
Drug coating solution
1 Vildagliptin 50 50 50
2 Polyethylene glycol 400 10-14 10-14 10-14
3 Hypromellose 3CPS 15-25 15-25 15-25
4 Purified Talc 3-7 3-7 3-7
5 Purified water q.s. q.s. q.s.
Weight of Drug Coated Pellets 180-205 180-205 180-205
Top Coating
1 Hypromellose 3CPS 7-11 - -
2 Hydroxypropyl cellulose (HPC) - 7-11 -
3 Polyvinylpyrrolidone (PVP K-30) - - 7-11
4 Polyethylene glycol 6000 2-5 2-5 2-5
5 Purified Talc 0.75-1.5 0.75-1.5 0.75-1.5
6 Purified water q.s. q.s. q.s.
Weight of coated pellets 195-220 195-220 195-220
Extra granular material
1 Mannitol SD 200 15-25 15-25 15-25
2 Lactose anhydrous 10-20 10-20 10-20
3 Povidone K 30 1.5-3.5 1.5-3.5 1.5-3.5
4 Sodium starch glycolate 8-12 8-12 8-12
5 Magnesium stearate 2-3 2-3 2-3
Total Tablet weight 230-280 230-280 230-280

Process:
1. Coating solution with active (Vildagliptin) is prepared by dissolving Vildagliptin, Polyethylene glycol 400 and hypromellose 3CPS/ Hydroxypropyl cellulose (HPC)/ Polyvinylpyrrolidone (PVP K-30) in purified water under stirring to make solution. Then talc was added and resulting solution stirred for 30 minutes under mechanical stirrer.
2. Then coat the Microcrystalline Cellulose Pellets (Celphere) in Fluidized bed processor (FBP) with drug coating solution (Step-1) till desired weight gain achieved.
3. Top coating solution is prepared by adding Hypromellose 3 CPS, Polyethylene Glycol 6000 and Purified Talc in purified water under mechanical stirrer for 45 minutes.
4. Drug coated pellets (Step-2) are coated with top coating solution (Step-3) in FBP till desired weight gain is achieved and dried.
5. Lactose anhydrous, Mannitol SD 200, Povidone K 30 and Sodium starch glycolate were passed through suitable sieve and then vildagliptin coated pellets were blended with these materials for 20 minutes at slow speed in double cone blender. Then blend was lubricated with pre sifted magnesium stearate for 3 minutes in blender.
6. The lubricated blend is compressed on suitable compression machine to obtain tablets of suitable size

Example 3: Vildagliptin composition (Tablet with core)

Sr. No. Ingredients mg/Tablets mg/Tablets mg/Tablets
CORE
1 Lactose anhydrous 60-80 60-80 60-80
2 Microcrystalline cellulose 112 24-36 24-36 24-36
3 Povidone K 30 4-10 4-10 4-10
4 Sodium starch glycolate 8-12 8-12 8-12
5 Magnesium stearate 1-2 1-2 1-2
Core weight 110-150 110-150 110-150
Drug coating solution
1 Vildagliptin 50 50 50
2 Polyethylene glycol 400 8-16 8-16 8-16
3 Hypromellose 3CPS 12-28 - -
4 Hydroxypropyl cellulose (HPC) - 12-28 -
5 Polyvinylpyrrolidone (PVP K-30) - - 12-28
6 Purified Talc 3-8 3-8 3-8
7 Purified water q.s. q.s. q.s.
Weight of Coated Tablet 180-220 180-220 180-220
Top Coating
1 Hypromellose 3CPS 8-12 8-12 8-12
2 Polyethylene glycol 6000 2-4 2-4 2-4
3 Purified Talc 0.8-1.6 0.8-1.6 0.8-1.6
4 Purified water q.s. q.s. q.s.
Total Tablet weight 200-240 200-240 200-240

Manufacturing Process:
Core preparation
1. Sift Lactose anhydrous, Microcrystalline cellulose PH 112, Povidone K 30 and sodium starch glycolate through #40 mesh. Mix sifted material in double cone blender for 15 minutes.
2. Sift Magnesium stearate through #60 mesh and lubricate the step 1 blend for 3 minutes in DCB at slow speed.
3. Compress the tablet with desired weight and thickness on double rotary compression machine.

Coating:
4. Coating solution with active (Vildagliptin) is prepared by dissolving Vildagliptin, Polyethylene glycol 400 and hypromellose 3CPS/ Hydroxypropyl cellulose (HPC)/ Polyvinylpyrrolidone (PVP K-30) in purified water under stirring to make solution. Then talc was added and resulting solution stirred for 30 minutes under mechanical stirrer.
5. Then coat the core with drug coating solution (Step-1) till desired weight gain achieved.
6. Top coating solution is prepared by adding Hypromellose 3 CPS, Polyethylene Glycol 6000 and Purified Talc in purified water under mechanical stirrer for 45 minutes.
7. Drug coated pellets (Step-2) are coated with top coating solution (Step-3) in coating machine to get desired weight and then dried.

Example 4: Vildagliptin composition (Capsule with pellets)

Sr. No. Ingredients Mg/Tablet Mg/Tablet Mg/Tablet
Core material (Pellet)
1 Celphere CP-102 (Microcrystalline Cellulose Pellets) 90-110 90-110 90-110
Drug coating solution
1 Vildagliptin 50 50 50
2 Polyethylene glycol 400 10-14 10-14 10-14
3 Hypromellose 3CPS 15-25 - -
4 Hydroxypropyl cellulose (HPC) - 15-25 -
5 Polyvinylpyrrolidone (PVP K-30) - - 15-25
6 Purified Talc 3-7 3-7 3-7
7 Purified water q.s. q.s. q.s.
Weight of Drug Coated Pellets 180-205 180-205 180-205
Top Coating
1 Hypromellose 3CPS 7-11 7-11 7-11
2 Polyethylene glycol 6000 2-5 2-5 2-5
3 Purified Talc 0.75-1.5 0.75-1.5 0.75-1.5
4 Purified water q.s. q.s. q.s.
Weight of coated pellets 195-220 195-220 195-220
Capsule Filling
1 EHG Capsule size ‘1’ 71-81 71-81 71-81
Total capsule weight 260-300 260-300 260-300

Process:
1. Coating solution with active (Vildagliptin) is prepared by dissolving Vildagliptin, Polyethylene glycol 400 and hypromellose 3CPS/ Hydroxypropyl cellulose (HPC)/ Polyvinylpyrrolidone (PVP K-30) in purified water under stirring to make solution. Then talc was added and resulting solution stirred for 30 minutes under mechanical stirrer.
2. Then coat the Microcrystalline Cellulose Pellets (Celphere) in Fluidized bed processor (FBP) with drug coating solution (Step-1) till desired weight gain achieved.
3. Top coating solution is prepared by adding Hypromellose 3 CPS/ Hydroxypropyl cellulose (HPC)/ Polyvinylpyrrolidone (PVP K-30), Polyethylene Glycol 6000 and Purified Talc in purified water under mechanical stirrer for 45 minutes.
4. Drug coated pellets (Step-2) are coated with top coating solution (Step-3) in FBP till desired weight gain is achieved and dried.
5. These coated pellets filled in size ‘1’ EHG Capsules.

Example 5: Vildagliptin composition (Capsule with minitab)

Sr. No. Ingredients mg/Tablets mg/Tablets mg/Tablets
Minitab formula
1 Lactose anhydrous 16-20 16-20 16-20
2 Microcrystalline cellulose 112 6-9 6-9 6-9
3 Povidone K 30 1-2.5 1-2.5 1-2.5
4 Sodium starch glycolate 2-3 2-3 2-3
5 Magnesium stearate 0.25-0.50 0.25-0.50 0.25-0.50
Minitab weight 30.00 30.00 30.00
Drug coating solution
1 Vildagliptin 12.50 12.50 12.50
2 Polyethylene glycol 400 2-4 2-4 2-4
3 Hypromellose 3CPS 3-7 - -
4 Hydroxypropyl cellulose (HPC) - 3-7 -
5 Polyvinylpyrrolidone (PVP K-30) - - 3-7
6 Purified Talc 0.75-2 0.75-2 0.75-2
7 Purified water q.s. q.s. q.s.
Weight of Drug Coated Pellets 45-55 45-55 45-55
Top Coating
1 Hypromellose 3CPS 2-3 2-3 2-3
2 Polyethylene glycol 6000 0.5-1.0 0.5-1.0 0.5-1.0
3 Purified Talc 0.20-0.40 0.20-0.40 0.20-0.40
4 Purified water q.s. q.s. q.s.
Top coated minitab weight 50-60 50-60
Capsule filling
1 EHG Capsule size '1' 71-81 71-81 71-81
2 Minitab per capsule 4 4 4
Total Capsule weight 290-310 290-310 290-310

Manufacturing Process:
Dummy Mini tablet fomulation:
1. Sift Lactose anhydrous, microcrystalline cellulose PH 112, Povidone K 30 and sodium starch glycolate through #40 mesh. Mix sifted material in double cone blender for 15 minutes.
2. Sift Magnesium stearate through #60 mesh and lubricate the step 1 blend for 3 minutes in DCB at slow speed.
3. Compress the tablet with desired weight and thickness on double rotary compression machine.

Vildagliptin minitab preparation:
4. Vildagliptin drug coating solution is prepared by dissolving Vildagliptin, Polyethylene glycol 400 and hypromellose 3CPS/ Hydroxypropyl cellulose (HPC)/ Polyvinylpyrrolidone (PVP K-30) in purified water under stirring.
5. Add talc to step 1 solution and stir for 30 minutes under mechanical stirrer.
6. Coat the dummy minitab in Auto coater with drug coating solution of step 2 till desired weight gain achieved.
7. Top coating solution is prepared adding Hypromellose 3 CPS, Polyethylene Glycol 6000 and Purified Talc in purified water under mechanical stirrer for 45minutes.
8. Drug coated minitab of step 3 is coated with top coating solution of step 4 in Auto coater till desired weight gain is achieved.

Capsule filling:
1. Four Vildaglitpin minitablets filled in each size ‘1’ EHG capsules to get final 50mg strength of Vildagliptin Immediate release formulation.
,CLAIMS:1. A pharmaceutical composition comprising:
(a) at least one inert core;
(b) at least first coating layer coated over the core, wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and suitable polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or Polyvinyl pyrrolidone or combination thereof;
(c) optionally second coating layer disposed over the first coating layer comprising one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the first coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and 5-15% of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone 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) at least one inert core;
(b) at least first coating layer coated over the core, said coating layer comprises about 10% to about 50% vildagliptin or pharmaceutically acceptable salt thereof and about 5% to about 15% suitable polymer, wherein suitable polymer is selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or Polyvinyl pyrrolidone or combination thereof.
(c) optionally second coating layer disposed over the first coating layer comprising one or more pharmaceutically acceptable excipients.

7. A pharmaceutical composition comprising:
(a) about 10% to about 50% of vildagliptin;
(b) about 12mg to about 28mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) optionally one or more coating or pharmaceutically acceptable excipients.

8. A process for preparing pharmaceutical composition of vildagliptin or pharmaceutically acceptable salt thereof wherein the process comprises steps of:
(a) preparation of inert core;
(b) at least first coating layer applied over the core obtained in step (a) wherein said coating layer comprises vildagliptin or pharmaceutically acceptable salt thereof and polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or Polyvinyl pyrrolidone or combination thereof;
(c) optionally second coating layer applied over coated core obtained in step (b).

9. A pharmaceutical composition comprising:
(a) at least one inert core
(b) first coating layer comprising about 50mg of vildagliptin; about 12-28mg of polymer selected from hydroxypropyl methylcellulose or hydroxypropyl cellulose or polyvinyl pyrrolidone or combination thereof;
(c) optionally second coating applied over first coating layer.

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