FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"STABILIZED PHARMACEUTICAL FORMULATION COMPRISING
VILDAGLIPTIN"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West) Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to stabilized pharmaceutical composition comprising Vildagliptin or its pharmaceutically acceptable salts, its process for preparation and use of such a composition for the treatment of diabetes and other metabolic diseases.
BACKGROUND OF INVENTION
Type 2 diabetes is an increasingly prevalent disease with high frequency of complications that in long term leads to a significant reduction of life expectancy. Further, the disease causes a number of microvascular complications, such as adult-onset loss of vision, renal failure, and amputations. In addition, the presence of type 2 diabetes is associated with a two to five fold increase in cardiovascular disease risk. There are various classes of drugs working through different mechanisms that have been developed over the decade in order to manage the diabetes as well as other metabolic diseases.
Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are one such class of agents that have been found useful for treatment of diabetes and metabolic diseases. DPP-4 inhibitors are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), which metabolises incretins like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These incretins play an important role in insulin secretion and blood glucose control regulation. DPP-IV inhibitors inhibits the inactivation of DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas (Makrilakis K., The Role of DPP-4 Inhibitors in the Treatment Algorithm of Type 2 Diabetes Mellitus: When to Select, What to Expect Int. J. Environ. Res. Public Health 2019, 16, 2720). Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins that are thus found to be useful in managing type 2 diabetes mellitus, which is a significant risk factor for coronary disease, heart failure, stroke, and many other cardiovascular conditions.

Vildagliptin is a DPP-IV inhibitor also known as LAF-237, was developed by Novartis for the treatment of type 2 diabetes. The drug is disclosed in patent application no. WO 0034241. Chemically, Vildagliptin is (S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl }pyrrolidine-2- carbonitril, with the chemical structure illustrated below in Formula 1.

The drug was approved in Europe in Sep 2007 for treatment of diabetes and is marketed under the brand name Galvus® in strengths of 50 mg as tablet dosage form.
The formulation of Vildagliptin poses difficulties as the drug shows instability in presence of air and humidity (WO 2006135723 page no 2, line 24-26). In presence of air and/or moisture was found to degrade structurally and develop behavioural changes, thereby reducing the shelf life of the drug product in addition to the instabilities in presence of atmospheric conditions, Vildagliptin was found to react with the excipients employed in developing formulations containing the same, leading to production of impurities (EP 2468361 page no 2, para 009). There have been efforts in the prior art to overcome the stability issues and prepare a tablet formulation of Vildagliptin. For eg. WO0034241 discloses Vildagliptin tablets manufactured by alcoholic granulation. This method is however not useful as the alcoholic granulation is an expensive procedure, further it also has the problem of ensuring the elimination of the organic solvent employed in the final product.
WO2006078593 discloses formulation of DPPIV inhibitors including Vildagliptin prepared by a direct-compression method. The application identifies that Vildalgiptin is not a compressible solid and has high dosages and accordingly

provides excipients that can be used for the direct compression process. It also discloses a novel crystal form of Vildagliptin having lower water solubility. There is no data however in the application to show that the formulation obtained is stable.
WO2006021455 relates to Vildagliptin tablets manufactured by melt granulation. Melt granulation is an expensive procedure since it requires high input of energy and is not suitable for heat sensitive material because of the elevated temperature involved.
EP2468361 relates to Vildagliptin granules, which are coated in a fluidized bed with pullulan or polyvinyl alcohol. The process however requires granulation with organic solvents, melt granulation and preparation of coated granules.
Thus, there exists a need to prepare a stable formulation of Vildagliptin prepared by a simple process that can be used in the industrial scale. The applicant has developed such a formulation of Vildagliptin that has improved stability, is simple to prepare and has good tabletting properties e.g. hardness, friability etc.
SUMMARY OF INVENTION:
The present invention relates to a stable pharmaceutical composition of Vildagliptin or a pharmaceutically acceptable salt thereof with desired physical and chemical properties. The present invention also relates to process of preparation of the said composition and use of such composition for treatment of diabetes and metabolic disease.
Specifically, the present invention further provides a stabilized pharmaceutical composition comprising Vildagliptin or its pharmaceutically acceptable salts thereof, wherein said composition comprises a polysaccharide polymer and pharmaceutically acceptable excipients, wherein Vildagliptin or its pharmaceutically acceptable salts is in admixture with the polysaccharides polymers and the pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF INVENTION
The present invention provides stabilized pharmaceutical composition comprising Vildagliptin, its process for preparation and use of such composition for the treatment of diabetes and other metabolic diseases.
More particularly, the present invention provides a stabilized pharmaceutical composition comprising Vildagliptin or its pharmaceutically acceptable salts thereof, wherein said composition comprises a polysaccharide polymer and pharmaceutically acceptable excipients, wherein Vildagliptin or its pharmaceutically acceptable salts is in admixture with the polysaccharides polymers and the pharmaceutically acceptable excipients.
In one of the preferred embodiment, the present invention provides a stabilized pharmaceutical composition comprising Vildagliptin or its pharmaceutically acceptable salts thereof, wherein said composition comprises a polysaccharide polymer and pharmaceutically acceptable excipients, wherein Vildagliptin or its pharmaceutically acceptable salts is in admixture with the polysaccharides polymers and the pharmaceutically acceptable excipients, wherein the composition does not contain calcium phosphate.
The amount of Vildagliptin or its pharmaceutically acceptable salts thereof, present in the composition may be from about 15% to about 60%. In a preferred embodiment, the amount of Vildagliptin or a pharmaceutically salt thereof may be about 20%) to about 40% by weight of the composition. The pharmaceutically acceptable salt of Vildagliptin may be selected from salt of acid for e.g. Hydrochloric acid, methanesulfonic acid, sulphuric acid, phosphoric acid, citric acid, lactic acid and acetic acid. In a preferred embodiment, Vildagliptin is used in the form of a base. In another preferred embodiment, Vildagliptin is used as its hydrochloride salt.

The polysaccharide polymer according to the present invention may be selected from one or more of, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, and chitin. In a preferred embodiment, the polysaccharide polymer is Pullulan. Pullulan is a water soluble polysaccharide polymer, produced from starch by fermentation. It is available commercially as white non crystalline powder, for e.g. from Hayashibara - A Nagase group company.
The amount of polysaccharide polymer in the composition of the present invention may be in the range of about 0.5% to about 10%, preferably about 1% to about 8% and more preferably about 1.5% to about 5% by weight of the composition.
Without being bound by theory, the present inventors have found that a composition comprising Vildagliptin, a polysaccharide polymer like pullulan and other pharmaceutically acceptable excipients was stable for atleast 36 months at accelerated stability conditions of 30°C and 65% relative humidity. In fact, the present inventors studied the stability of formulation for Vildagliptin, with and without Pullulan and found that under accelerated conditions of 40°C and 75% relative humidity, the composition of Vildagliptin without pullulan showed higher level of impurity in mere 3 months of storage. Such a result was unexpected, especially because, in the composition Vildagliptin was not physically separated from the excipients used in the composition but was in admixture with other pharmaceutically acceptable excipients used in the composition.
The pharmaceutically acceptable excipients that may be used according to the present invention may be selected from one or more of diluent, disintegrant, glidant and lubricant. Suitable diluents that may be used according to the present invention are microcrystalline cellulose, maltose, sucrose, starch dextrin, mannitol, sorbitol, anhydrous lactose, lactose monohydrate, or mixture thereof. In a preferred embodiment, the diluent is lactose. The amount of diluents may be in the range of

about 5% to about 90% preferably about 20% to about 80% and most preferably about 40% to about 70%) by weight of the composition.
Suitable disintegrants that may be used according to the present invention are from crospovidone, croscarmellose sodium, sodium starch glycolate low-substituted hydroxypropyl cellulose or pregelatinized starch, magnesium aluminum silicate or polacrilin potassium or mixture thereof. The amount of disintegrant used may be in the range of about 1% to about 25%, preferably about 2% to about 15% and most preferably about 3% to about 10%. In preferred embodiment, the disintegrant may be sodium starch glycolate or low substituted hydroxypropyl cellulose or a combination of both is used.
Suitable glidants that may be used according to the present invention are colloidal silicon dioxide, talc, aluminum silicate, magnesium silicate or mixture thereof. The amount of glidants used may be in the range of about 0.05% to about 5%, preferably about 0.1% to about 3% and most preferably about 0.2% to about 4%. by weight of the composition. In preferred embodiment, the glidant may be colloidal silicon dioxide.
Suitable lubricants that may be used according to the present invention are sodium stearyl fumarate, magnesium stearate, stearic acid, metal stearates, boric acid, glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, glycerol palmitostearate or mixture thereof. The amount of lubricants used may be in the range of about 0.005% to about 20% preferably about 0.1% to about 10% and most preferably about 0.5% to about 5% by weight of the composition.In a preferred embodiment the lubricants may be magnesium stearate.
The composition of the present invention may be formulated in a suitable solid 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. In a preferred embodiment, the dosage form is in the form of a tablet.

The present invention also relates to process of preparing the composition of the present invention. The composition of the present invention may be prepared by processes well known in the art. Commercially, pharmaceutical formulations are prepared by one of three methods, wet granulation, direct compression or dry granulation, also known as slugging or roller compaction. Wet granulation is the most commonly used method for reproducing compressed tablets. However, a major limitation of this technique is the stability issues faced by moisture or heat sensitive ingredients. The dry granulation process involves compacting powder mixtures into large pieces or compacts that are subsequently broken down or sized into granules, avoids moisture in the process, however the tablets manufactured by dry granulation tend to be softer than those manufactured by wet granulation, rendering them more difficult to process using post-tableting techniques, e.g. film coating and is not widely used in the manufacture of tablets.
The present inventors have found that the composition of the present invention can be directly compressed to form tablets, avoiding any contact with the moisture during the tabletting process. The present invention thus provides a stable Vildagliptin pharmaceutical tablet formulation, capable of being compressed, preferably directly compressed, into a tablet having adequate hardness/friability, low sensitivity to moisture, improved stability, an acceptable dissolution pattern in treated patients.
More specifically, the composition of the present invention may be prepared by a method as follows: (a) Mixing Vildagliptin or a pharmaceutically acceptable salt thereof, the at least one polysaccharide polymer, and pharmaceutically acceptable excipients together to obtain an admixture (b) compressing the admixture obtained in step (a) to form a compressed tablet dosage form
In another embodiment, the present invention relates to method of use of the pharmaceutical composition of the invention in the treatment of conditions such as non-insulin-dependent diabetes mellitus and other metabolic diseases. The

composition of the present invention may be used for treatment of conditions like arthritis, obesity, allograft transplantation and calcitonin-osteoporosis.
The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and resulls. These examples arc not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.
Example 1

Sr no Inactive ingredients % w/w
1 Vildagliptin 25.00
2 Lactose 67.00
3 Sodium Starch Glycolate 5.00
4 Pullulan 2.00
5 Magnesium Stearate 1.00
Total Weight 100
Manufacturing Process:The required quantities of Vildagliptin, Lactose, Sodium Starch Glycolate, Pullulan, and Magnesium Stearate are sifted, mixed together and compressed into tablet. Example 2

Sr.no
Inactive ingredients % w/w
1 Vildagliptin 25.00
2 Microcrystalline Cellulose 40.00
3 Lactose 27.00
4 Sodium Starch Glycolate 5.00
5 Pullulan 2.00
6 Magnesium Stearate 1.00
Total Weight 100
Manufacturing Process: The required quantities of Vildagliptin, microcrystalline cellulose, lactose, sodium starch glycolate, pullulan, and magnesium stearate are sifted mixed together and compressed into tablet.

Example 3

Sr.no
Inactive ingredients % w/w
1 Vildagliptin 25.00
2 Microcrystalline Cellulose 40.00
3 Lactose 25.00
4 Pullulan 4.00
5 Sodium Starch Glycolate 5.00
6 Magnesium Stearate 1.00
Total Weight 100
Manufacturing Process: The required quantities of Vildagliptin, microcrystalline cellulose, lactose, sodium starch glycolate, pullulan, and magnesium stearate are sifted, mixed together and compressed into tablet.
Comparative Example 1:

Sr.no
Inactive ingredients % w/w
1 Vildagliptin 26.32
2 Microcrystalline Cellulose 67.11
3 Sodium Starch Glycolate 5.26
4 Hydrophobic Colloidal Silica 0.26
5 | Magnesium Stearate 1.05
Total Weight 100
Manufacturing Process: The required quantities of Vildagliptin, microcrystalline cellulose, sodium starch glycolate, Hydrophobic colloidal silica, Magnesium Stearate are sifted, mixed together and compressed into tablet.
The pharmaceutical composition of the Example 1 and Comparative Example 1 were subjected to different accelerated conditions of stability at 40°C and 75% relative humidity 30°C and 75% relative humidity and 25°C and 75% relative humidity. The table below provides data of analysis of the composition for impurities it was observed that 3 months, the composition of the comparative example (without a polysaccharide polymer like pullulan) had higher impurity levels as compared to the Example 1 of the invention. The data is as presented below:

Table 1: 3 Month stability study of Example 1

BLQ Below limit of quantification ND : Not detected Table 2: 3 Month stability study of comparative Example 1

Sr no Related substance Limit Temperature

40°C
/75%RH 30°C /75%RH 25°C /75%RH
1 Vildagliptin impurity A NMT 0.3 % 0.208 % 0.200 % ■0.091 %
2 Vildagliptin impurity B NMT 0.3 % 0.400% 0.082 % BLQ*
3 Vildagliptin impurity C NMT 0.3 % 0.222 % BLQ* ND#
4 Individual unknown impurity NMT 0.3 % ND# ND# ND#
5 Total impurity NMT 0.3 % 0.830% 0.830% 0.091%

Sr no Related substance Limit Temperature

40°C
/75%RH 30°C
/75%RH 25°C
/75%RH
1 Vildagliptin impurity A NMT 0.3 % 0.065 % 0.097 % 0.084 %
2 Vildagliptin impurity B NMT 0.3 % 0.258 % 0.099 % BLQ*
3 Vildagliptin impurity C NMT 0.3 % 0.116% BLQ* ND#
4 Individual unknown impurity NMT 0.3 % ND# ND# ND#
5 Total impurity NMT 0.3 % 0.439 % 0.196% 0.084 %
BLQ Below limit of quantification ND#: Not detected

CLAIMS:
1. A stabilized pharmaceutical composition comprising Vildagliptin or its pharmaceutically acceptable salts thereof, wherein said composition comprises a polysaccharide polymer and one or more pharmaceutically acceptable excipients wherein, Vildagliptin or its pharmaceutically acceptable salts is in admixture with the polysaccharides polymers and the pharmaceutically acceptable excipients.
2. The stabilised pharmaceutical composition according to claim 1, comprising Vildagliptin or its pharmaceutically acceptable salts thereof with polysaccharide polymer other pharmaceutically acceptable excipients further, wherein the composition does not comprises dibasic calcium phosphate.
3. The pharmaceutical composition according to claim 1, wherein the Vildagliptin or its pharmaceutically acceptable salts is present in an amount of about 15% to about 60 % by weight of the composition, polysaccharide polymers in an amount of about 0.5% to about 10 % by weight of the composition and one or more pharmaceutical excipients in an amount of about 30 % to about 85%. Wherein, the pharmaceutically acceptable excipient is, wherein the composition does not comprises dibasic calcium phosphate.
4. The pharmaceutical composition according to claim 1, wherein polysaccharide polymers is selected from amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin or mixture thereof.

5. The pharmaceutical composition according to claim 1, wherein the other pharmaceutically acceptable excipient comprises a diluents selected from microcrystalline cellulose, maltose, sucrose, starch dextrin, mannitol, sorbitol, anhydrous lactose, lactose monohydrate, or mixture thereof.
6. The pharmaceutical composition according to claim 1, wherein the other pharmaceutically acceptable excipient comprises a disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate low-substituted hydroxypropyl cellulose or pregelatinized starch, magnesium aluminum silicate or polacrilin potassium or mixture thereof.
7. The pharmaceutical composition according to claim 1, wherein the other pharmaceutically acceptable excipient comprises a lubricant selected sodium stearyl fumarate, magnesium stearate, stearic acid, metal stearates, boric acid, glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, glycerol palmitostearate or mixture thereof.
8. The pharmaceutical composition according to claim 1, wherein diluent is present in an amount of about 5 % to about 90 % by weight of the composition, disintegrant is present in an amount of about 1 % to about 25 % by weight of the composition and wherein lubricant is present in an amount of about 0.005% to about 20 % by weight of the composition.
9. The pharmaceutical composition according to Claim 1, comprising about 20% to about 40% Vildagliptin by weight of the composition, about 1.5% to about 5% pullulan by weight of the composition, about 40% to about 70% Lactose by weight of the composition about 3% to about 10% sodium starch glycolate by weight of the composition and about 0.5%) to about 5% of magnesium stearate by weight of the composition.
10. The process for preparing the pharmaceutical composition according to Claim 1, wherein the process comprises:

(a) Mixing Vildagliptin or a pharmaceutically acceptable salt thereof, with at least one or more polysaccharide polymer, and pharmaceutically acceptable excipients together to obtain mixture
(b) Compressing the mixture obtained in step (a) to form a compressed tablet dosage form.