DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of Dipeptidyl peptidase-IV (DPP-IV) inhibitors for use in treatment of Diabetes Mellitus (DM). More particularly, the invention relates to a modified release dosage form comprising a composition of Vildagliptin or a pharmaceutically acceptable salt thereof with desired physical and chemical parameters. The invention also provides various formulations and methods of preparing the same.

BACKGROUND OF THE INVENTION
Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors. While some of these factors are under personal control, such as diet and obesity, other factors are not, such as increasing age, female gender, and genetics. It is estimated that 366 million people had type 2 diabetes mellitus in 2011; by 2030 this would have risen to 552 million. Thus, research for anti-diabetic drugs becomes important as type 2 diabetes is an incredibly prevalent disease in the modern world and new treatment choices are much needed.
Dipeptidyl peptidase-IV (DPP-IV), a serine protease belonging to the group of post-proline/alanine cleaving amino-dipeptidases, specifically removes the two N-terminal amino acids from proteins having proline or alanine in position 2. Although the physiological role of DPP-IV has not been completely established, it is believed to play an important role in neuropeptide metabolism, T-cell activation, gastric ulceration, functional dyspepsia, obesity, appetite regulation, IFG and diabetes. A compound having a DPP-IV inhibitory activity is expected to show effect on impaired glucose tolerance, postprandial hyperglycemia and fasting hyperglycemia observed in type I and type II diabetes and the like, obesity or diabetic complications associated therewith and the like.
Vildagliptin is an oral anti-hyperglycemic agent (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Dipeptidyl peptidase-4 (DPP-4) is the enzyme responsible for the rapid degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). This activity increases levels of active incretins and enhances pancreatic islet a- and ß-cell responsiveness to glucose, thus improving insulin secretion and reducing inappropriate glucagon production, improving insulin sensitivity, improving postprandial lipid and lipoprotein metabolism, and reducing fasting and prandial glucose and HbA1c. Thus, Vildagliptin has been shown to reduce hyperglycemia (high blood sugar).
Worldwide public health efforts to address a variety of chronic conditions are being undermined by an alarmingly low adherence to therapies. Non-adherence is a serious problem in patients on long-term treatment, accounting for up to 50% of cases where drugs fall short of their therapeutic goals. For non-adherent patients, the benefits of extended duration of treatment may not be sufficiently apparent. Adherence problems are prevalent where self-administration of treatment is required, including acute and chronic illnesses, a prominent disease being diabetes. And once daily dosing might be of great importance in resource-limited settings.
Current marketed products are with Vildagliptin 50 mg tablets or a combination of Vildagliptin and Metformin Hydrochloride. However, with said marketed therapies the Vildagliptin has to be administered twice a day either alone or in combination. Considering patient compliance the present therapies fall short in addressing the problem pertaining to adherence to oral therapies. Further, from a health economic perspective, higher adherence rates with once-daily dosing relative to multiple dosing in a number of conditions were consistently associated with corresponding lower costs of health care resources utilization The twice-daily regimen has difficulty with medication adherence, increased cost of therapy, and possibility of more side effects.
An extended release dosage form allows a drug to be slowly released in the body over an extended period of time especially to reduce dosing frequency. Typically taken once a day, these formulations keep the therapeutic dose at a steady level in the body for longer periods of time. Though they typically have a slightly slower onset compared to their immediate-release counterparts, however, they maintain a more consistent level of the drug in the body, Hence, better treatment outcomes for longer periods of time while also lowering the occurrence of side effects with improved patient compliance can be achieved with an extended release dosage form of Vildagliptin.
There are three important commercially available processes for making compressed tablets: wet granulation, direct compression and dry granulation which is also known as slugging or roller compaction. The method of preparation and selection of different type of excipients results in the desired physical characteristics for tablet formulation that allow the rapid compression of the tablets. After compression, the tablets have a number of additional attributes to comply with, such as appearance, hardness, disintegrating ability and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing and the properties of the final tablets. Pre-formulation studies are usually done to determine the chemical and physical compatibility of the active component with proposed excipients. The properties of the drug, its dosage forms and the economics of the operation will determine selection of the best process for tableting. Generally, both wet granulation and direct compression are used in developing a tablet.
In wet granulation all of the required functionality of a compression mix – good flow, good compactability, uniform distribution of drug and controllable drug release, good stability – can be built in using wet granulation without relying on the intrinsic properties of the drug or the excipients. Nevertheless, a major limitation of this technique is the stability issues faced by moisture or heat sensitive ingredients. Dry-granulation process, on the other hand, does not entail heat or moisture, and hence is especially suitable for active ingredients that are sensitive to solvents, or labile to moisture and at elevated temperatures the powder mixture is roller compacted into ribbons that are milled into granules. However, 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.
Since, compressed tablets are the most widely used solid dosage form so they must satisfy a number of physical requirements in terms of hardness, disintegration ability, friability and uniformity. To address the above mentioned issues, direct compression can be utilized. Direct compression is a popular choice because it provides the shortest, most effective, least complex way to produce tablets. Further, moisture or heat sensitive ingredients can also be used in this type of process.
However, direct compression does require a very critical selection of excipients in comparison to granulation processes because the raw materials must demonstrate good flowability and compressibility for successful operation. Most APIs tend to have poor compressibility, which affects the quality of tablets if the formulation calls for a large proportion of API. At the same time, there can also be problems when low amounts of actives need to be incorporated into tablets because it is difficult to accurately blend a small amount of active in a large amount of excipient to achieve the desired uniformity and homogeneity. For instance, segregation of the different components can occur. This means there is not a uniform distribution of tablet ingredients being fed to the press, and thus batch to batch consistency of the manufactured tablet cannot be assured. One of the principal risk factors for segregation is the wide particle size distribution in direct compression formulations, in which active ingredients tend to be at the fine end of the range. Where there is a wide range of particle sizes, there is an increased likelihood of sifting, where the smaller particles 'slip through' the bigger ones. Other bulk powder properties are also important for successful tableting, such as good flowability, and all of these factors combine to place a high requirement on the excipients used for direct compression.
In view of the above mentioned drawbacks of granulation processes and furthermore due to Vildagliptin’s sensitivity towards moisture the manufacturing of Vildagliptin becomes an onerous task.
Further, there is also a need to look into moisture driven degradation of Vidagliptin formulation leading to significant increase in the impurity content at different stability conditions.

Related Prior arts:
US20100021539A1 relates to a modified release formulation of 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile.
CN103040759A relates to a sustained-release oral solid preparation by using Vildagliptin as an active component. The oral solid preparation is made by a formulation technique using Vildagliptin as the main component and pharmaceutically acceptable adjuvant, including but not limited to sustained-release matrix tablets, sustained-release diaphragm-controlled tablets, diaphragm-controlled and matrix sustained-release tablets, and sustained-release capsules prepared from sustained-release particles (pills).
Indian Patent application no. 8973/DELNP/2007 relates to a pharmaceutical tablet formulation comprising (a) a compound as an active ingredient; (b) a hydroxypropyl methylcellulose with an apparent viscosity of 80,000cP to 120,000cP (nominal value 100,000cP) when present in a 1% solution; (c) a microcrystalline cellulose; and (d) a magnesium stearate.
Indian Patent application no. 4409/DELNP/2014 describes a pharmaceutical tablet formulation comprising (a) Vildagliptin or the corresponding amount of a pharmaceutically acceptable salt thereof; (b) a hydroxypropyl methylcellulose other than hydroxypropyl methylcellulose K100M with an apparent viscosity of 80,000 cP to 120,000 cP (nominal value 100,000 cP) when present in a 2% solution and optionally a filler and/or a lubricant.
Hence, there is a need in the art for an extended release pharmaceutical composition of Vildagliptin with satisfactory physical, chemical, desired dissolution profile and stability parameters. The developed extended release formulation would have to be administered once a day which would result in better adherence, patient compliance, persistence, and associated economic impact.
From the above disclosure and identified prior arts, it is clear that though options exist for disorders associated with type-2 DM however, many such treatment options are associated with some or more side effects. Therefore, there is still a need for an extended release pharmaceutical composition of Vildagliptin with satisfactory physical, chemical, desired dissolution profile and stability parameters. The developed extended release formulation would have to be administered once a day which would result in better adherence, patient compliance, persistence, and associated economic impact.
Accordingly, there is a further need to formulate a composition comprising Vildagliptinor a pharmaceutically acceptable salt thereof for rapid degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide and improves insulin secretion. It also acts by reducing inappropriate glucagon production, improving insulin sensitivity, improving postprandial lipid and lipoprotein metabolism, and reducing fasting and prandial glucose and HbA1c and reduce hyperglycemia (high blood sugar).
It has been found that this may be achieved through the administration of a stable composition comprising Vildagliptinor a pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable carriers as disclosed in the present invention.

OBJECTIVE OF THE INVENTION
The objective of the present invention is to develop an extended release pharmaceutical composition with desired physical and chemical parameters.
Another objective of the present invention is to develop a dipeptidyl peptidase IV inhibiting (DPP-IV) pharmaceutical composition with once a day therapeutically effective dosing.
Another objective of the present invention is to develop a dipeptidyl peptidase IV inhibiting pharmaceutical composition with increased patient compliance.
Another objective of the present invention is to develop extended release dipeptidyl peptidase IV inhibiting (DPP-IV) pharmaceutical composition with desired stability.
Yet another objective of the present invention is to develop extended release dipeptidyl peptidase IV inhibiting pharmaceutical composition’s solid dosage forms with desired physical and chemical parameters.

SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition of Dipeptidyl peptidase-IV (DPP-IV) inhibitors for use in treatment of Diabetes Mellitus (DM). More particularly, the invention relates to a modified release dosage form comprising a composition of Vildagliptin or a pharmaceutically acceptable salt thereof with desired physical and chemical parameters. The invention also provides various formulations and methods of preparing the same.
The present invention provides a solid extended release pharmaceutical composition comprising:
(a) a dipeptidyl peptidase IV inhibitor;
(b) at least one high molecular weight hydrophilic polymer, and
(c) optionally one or more pharmaceutically acceptable carriers.
The present invention further provides a process comprising preparing a tablet dosage form of the pharmaceutical composition, the process comprising:
(a) blending Vildagliptin or a pharmaceutically acceptable salt thereof, the at least one high molecular weight hydrophilic polymer, and pharmaceutically acceptable excipients together to obtain a pharmaceutical tablet formulation; and
(b) compressing the tablet formulation obtained in step (a) to form a compressed tablet dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure1: Illustrates comparative dissolution profile of formulation (F5, F6, F7 and F8) in 0.1N HCl.
Figure2: Illustrates comparative dissolution profile of formulation (F5, F6, F7 and F8) in pH 6.8 Phosphate buffer.
Figure 3: Illustrates comparative dissolution profile of clinical batches(F9 and F10) in 0.01 N HCl.
Figure 4: Illustrates comparative dissolution profile of clinical batches (F9 and F10) in 0.1 N HCl.
Figure 5: Illustrates comparative dissolution profile of clinical batches (F9 and F10) in acetate buffer of pH 4.5.
Figure 6: Illustrates comparative dissolution profile of clinical batches (F9 and F10) in phosphate buffer of pH 6.8.

DETAILED DESCRIPTION OF THE INVENTION
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. The specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the res tills arc contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
In addition to the active or therapeutic ingredients, tablets may contain a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet. The primary composition includes filler, binder, lubricant and glidant. Without excipients most drugs and pharmaceutical ingredients cannot be directly-compressed into tablets. This is primarily due to the poor flow and cohesive properties of most drugs. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted through pretreatment steps, such as wet granulation, slugging, spray drying spheronization or crystallization.
The present invention relates to once a day extended release solid dosage form of a pharmaceutical composition comprising a dipeptidyl peptidase IV inhibitor.
In one embodiment of the present invention, the dipeptidyl peptidase IV inhibitor (DPP-IV) is useful for preventing or treating diabetes mellitus, non-insulin dependent diabetes mellitus, obesity, arthritis, osteoporosis, and similar diseases.
In another embodiment the present invention provides a solid extended release pharmaceutical composition comprising:
(a) a dipeptidyl peptidase IV inhibitor;
(b) at least one high molecular weight hydrophilic polymer; and
(c) optionally one or more pharmaceutically acceptable carriers.
In an embodiment, the present invention provides that the dipeptidyl peptidase IV inhibitor is selected from the group consisting of Vildagliptin, Sitagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Gasogliptin, Dutogliptin or a pharmaceutically acceptable salt thereof. Preferably, the dipeptidyl peptidase IV inhibitor isVildagliptin.
In another embodiment, the dipeptidyl peptidase IV inhibitor is Vildagliptin. Vildagliptin is readily soluble in water and hence, is rapidly absorbed with more than 90% oral bioavailability. Due to high solubility in water, and rapid absorption, it poses problem is formulating stable extended release formulations of Vildagliptin. The present invention provides stable extended release formulations of Vildagliptin.
Further in one embodiment, the present invention relates to an extended release pharmaceutical composition comprising Vildagliptin in combination with other ingredients which provides a synergistic effect.
In another embodiment, the present invention relates to a solid dosage form of Vildagliptin pharmaceutical composition which achieves a prolonged therapeutic effect by continuously releasing medication over an extended period after administration of single dose.
In one embodiment, the present invention relates to development of Vildagliptin matrix based extended release solid dosage form, for the treatment of type 2 diabetes.
In yet another embodiment, Vildagliptin in combination with hydrophilic polymers with specific viscosity ranges results in a synergetic pharmaceutical composition with desired stability, therapeutic effects and compact form. Compact dosage form is an oral solid dosage form such as tablets which are easy to swallow and more preferably being small in size with length less than 17 mm and width less than 7 mm having shape easier to swallow such as modified oblong.
In another embodiment, the present invention relates to a pharmaceutical composition comprising of Vildagliptin in combination with hydrophilic polymers to result in a solid dosage form with desired level of stability, dissolution rates, and compact tablet.
In one embodiment, the present invention describes an extended release stable pharmaceutical solid dosage form containing once a day therapeutically effective dose of Vildagliptin with a combination of hydrophilic polymers with desired physical and chemical parameters.
In one embodiment, the present invention relates to a stable pharmaceutical solid dosage form comprising of Vildagliptin, hydrophilic release retarding polymers and other excipients.
In one embodiment of the present invention, the release retarding polymers are high molecular weight polymers.
In one embodiment of the present invention, the present invention relates to a matrix based extended release solid dosage form of Vildagliptin comprising release retarding polymers. The release retarding polymers are high molecular weight (molecular weight of not less than 40,000) hydrophilic release retarding polymers. Preferably, the hydrophilic release retarding polymer is selected from, but not limited to, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, polymers of acrylic acid such as Carbomer or a combination thereof. Further, the pharmaceutical composition comprises the high molecular weight hydrophilic polymer in an amount of 10-60% by weight of the composition.
In one embodiment of the present invention, the extended release solid dosage forms are prepared by direct compression method using high molecular weight polymers either alone or in combination so as to have compact tablets with good physical properties like flow, wider range of hardness and less friability and a satisfactory impurity data over a stability study.
In one embodiment the extended release solid dosage forms are prepared by direct compression method using high molecular weight polymers either alone or in combination so as to have compact tablets which does not show tendency of dose dumping.
In one embodiment the extended release solid dosage forms are prepared by direct compression method using hydroxypropyl methyl cellulose polymer with high viscosity of 150,000-280,000 cps based on 2% of solution either alone or in combination so as to have compact tablets which does not show tendency of dose dumping.
In one embodiment of the present invention, the pharmaceutical composition of the 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 one embodiment, the Vildagliptin pharmaceutical solid dosage form is a compact pharmaceutical tablet formulation with desired physical and chemical parameters.
In one embodiment, the present invention provides a 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 and improved pharmacokinetic profile in treated patients.
In one embodiment, the present invention relates to a compact extended release pharmaceutical tablet formulation with desired physical parameters like more compressibility and less friability with expected release profile and acceptable impurity levels at accelerated condition.
In one embodiment the extended release tablets are prepared by direct compression method using high molecular weight polymers either alone or in combination to have compact tablets with good physical properties like flow, wider range of hardness and less friability and with acceptable impurity levels.
In yet another embodiment, the present invention describes pharmaceutical composition manufactured with direct blending process to form compact pharmaceutical tablets which are easier for administration.
The present invention further provides that use of sodium carboxy methyl cellulose as a release retarding polymer not only helps in achieving extended release profile but also helps in improving stability of the product. Further sodium carboxymethyl cellulose alone with combination of two or more different viscosity grades (low viscosity & high viscosity) can help in achieving desired dissolution profile, desired physical andrequired chemical properties.
In one embodiment, the pharmaceutical composition comprises of the sodium carboxymethyl cellulose with combination of two or more different grades (low viscosity & high viscosity) upto 70% by weight of composition and one or more pharmaceutically acceptable excipients such as fillers, glidants, lubricants, colorants.
In yet another embodiment, an extended release pharmaceutical composition comprising:
a) Vildagliptin;
b) the sodium carboxymethyl cellulose with combination of two or more different viscosity grades upto 70% by weight of composition;
c) microcrystalline cellulose between 8-10% by weight of composition;
d) colloidal silicon dioxide, between 0.5-1.0% by weight of composition;
e) magnesium stearate, between 0.5 -1.0% by weight of composition;
f) colorant between 0.5-1.5% by weight of composition;
and one or more pharmaceutically acceptable excipients.
In yet another embodiment, the pharmaceutical composition comprises of the sodium carboxymethyl cellulose with combination of two or more different grades (low viscosity & high viscosity) upto 70% by weight of composition;
microcrystalline cellulose between 8-10% by weight of composition;
colloidal silicon dioxide, between 0.5-1.0% by weight of composition;
magnesium stearate, between 0.5 -1.0% by weight of composition;
and one or more pharmaceutically acceptable excipients; wherein the ratio of high viscosity and low viscosity sodium carboxymethyl cellulose in range of 5:2 or 5:1.
In yet another embodiment, the pharmaceutical composition comprises of the sodium carboxymethyl cellulose with combination of two or more different grades (low viscosity & high viscosity) upto 70% by weight of composition;
with optionally microcrystalline cellulose upto 10% by weight of composition;
glidant upto 0.5% by weight of composition;
lubricant upto 1% by weight of composition;
colorant upto 2% by weight of composition.
In one embodiment, the pharmaceutical composition comprises of hydroxypropyl methyl cellulose polymer with viscosity of 150,000-280,000 cps (Methocel K 200 M, Methocel K200 M CR, Hydrocel CW-200000, Benecel K200M pharm) or Hydroxyethyl Cellulose (Natrosol 250 HHX), alone or in combination.
In one embodiment, the pharmaceutical composition comprises of sodiumcaroboxymethyl cellulose polymer of high viscosity 7500 to 10000 cps for 1% solution (CEKOL 100000), or low viscosity 2500 to 3500 cps for 1% solution (CEKOL 30000 P) or combination thereof.
In another embodiment, the pharmaceutical composition comprises of hydroxypropyl methyl cellulose polymer with viscosity of 150,000-280,000 cps and hydroxypropyl methyl cellulose polymer with viscosity of 80,000-120,000 cps in combination with a ratio of 5:1 to 1:1, more preferably with a ratio of 3:1 to 2:1 to form a solid dosage form with direct blending which are easy for swallowability.
In yet another embodiment, the present invention provides an extended release pharmaceutical composition comprising:
vildagliptin or a pharmaceutically acceptable salt thereof,
hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000 cps, and
hydroxypropyl methylcellulose having viscosity ranging from 80,000 to 120,000 cps,
optionally microcrystalline cellulose,
optionally hydroxypropyl cellulose ,
optionally sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution,
optionally sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution,
optionally colloidal silicon dioxide as a glidant,
a lubricant, and
optionally a pharmaceutically acceptable colour;
wherein the hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000cps and that having viscosity ranging from 80,000 to 120,000cps are present in a ratio ranging from 5:1 to 1:1, more preferably ranging from 3:1 to 2:1.
In yet another embodiment the present invention provides an extended release pharmaceutical composition comprising
about 26.66% w/w vildagliptin,
about 30.00% w/w hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000,
about 10 % w/w hydroxypropyl methylcellulose having viscosity ranging from 80,000 to 120,000 cps,
about 28.08% w/w microcrystalline cellulose,
about 3.00% w/w hydroxypropyl cellulose
about 0.50% w/w colloidal silicon dioxide,
about 0.50% w/w magnesium stearate, and
about 1.25% w/w pigment blend;
wherein the hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000 and that having viscosity ranging from 80,000 to 120,000 ranges are present in a ratio ranging from 5:1 to 1:1, more preferably in a ratio of 3:1.
In yet another embodiment of present invention provides an extended release pharmaceutical composition comprising
about 33.33% w/w vildagliptin,
about 20.00% w/w hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000,
about 10 % w/w hydroxypropyl methylcellulose having viscosity ranging from 80,000 to 120,000 cps,
about 31.11% w/w microcrystalline cellulose,
about 3.00% w/w hydroxypropyl cellulose
about 0.50% w/w colloidal silicon dioxide,
about 0.50% w/w magnesium stearate, and
about 1.56% w/w pigment blend;
wherein the hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000cps and that having viscosity ranging from 80,000 to 120,000cps are present in a ratio ranging from 5:1 to 1:1, more preferably in a ratio of 2:1.
In yet another embodiment the present invention provides an extended release pharmaceutical composition comprising:
vildagliptin in an amount ranging from 26.67% w/w to 33.33% w/w;
hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000, in an amount ranging from 24.00% w/w to 30.00% w/w;
sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution, in an amount ranging from 0% w/w to 35.73% w/w;
sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution), in an amount of 0-10.00% w/w;
microcrystalline cellulosein an amount ranging from 8.35% w/w to 25.42% w/w;
hydroxypropyl cellulose in an amount ranging from3.00% w/w to 3.75% w/w;
colloidal silicon dioxide in an amount ranging from 0.50% w/w to 0.62% w/w;
magnesium stearate in an amount ranging from 0.50% w/w to 0.62% w/w; and
pigment blue in an amount ranging from 1.25% w/w to 1.56% w/w;
wherein the sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution and Sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution are present in a ratio ranging from 5:1 to 1:0.5, and more preferably from 3:1 to 1:0.8.
In yet another embodiment, the pharmaceutical composition comprises of hydroxypropyl methyl cellulose polymer with viscosity of 150,000-280,000 cps and high molecular weight (molecular weight of not less than 40,000), sodium carboxy methyl cellulose in combination leading to a solid dosage form which are easier for administration.
In another embodiment of the present invention, the invention describes a pharmaceutical solid dosage form manufactured to form a compact tablet with direct blending process having satisfactory physical parameters, comparative dissolution profile (USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C) as per target. Moreover, the tablet formulationprovides an effective blood concentration for a time period ranging between 15 minutes to16 hours for Vildagliptin or a pharmaceutically acceptable salt thereof (not more than 30% of Vildagliptin at the end of 15 to 30 minutes; between 35% to 65% of Vildagliptin after 2 hrs or 3 hrs. and not less than 80% of Vildagliptin at the end of 16 hrs.) and satisfactory stability data in terms of acceptable impurity level upon storage at accelerated condition.
In a further embodiment, the present invention also describes pharmaceutical tablet formulation, where in the unit dosage form vildagliptin is present in an amount of 25% weight to 35% weight of the final pharmaceutical composition.
In one embodiment, the present invention describes a pharmaceutical tablet formulation having tablet hardness and friability in the desired range to obtain the dosage form with acceptable physical and chemical parameters.
In one embodiment, the present invention describes the pharmaceutical tablet formulation as having tablet hardness in the range of 5-30kg/cm2.Preferably, the hardness is in the range of 7-10 kg/cm2, 11-16 kg/cm2, 25-29 kg/cm2, 15-18 kg/cm2, 18-20 kg/cm2, or 10-14 kg/cm2.
One embodiment of the present invention describes the pharmaceutical tablet formulation having friability in the range of 0.01% to 0.5% at 300 rotations. Preferably, the friability at 300 rotations is 0.334%, 0.088%, or 0.01%.
In one embodiment, no damage is observed for the pharmaceutical tablet formulation in a friability test conducted at 100 rotations.
In one embodiment of the present invention, the pharmaceutical composition is stable and comprises of impurities less than 1.28%. Preferably, the pharmaceutical composition comprises of impurities less than 0.61%. Preferably, the pharmaceutical composition comprises of impurities less than 0.58%.
In one embodiment, the release rate of vildagliptin or a pharmaceutically acceptable salt thereoffrom the tablet formulationis:
a. not more than 36% in 1 hour;
b. from about 42% to about 75% in4 hours;
c. from about 71% to about 96% in 8 hrs; and
d. not less than (NLT) 95% in 16 hours;
wherein the dissolution is measured using a USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C.
In one embodiment, the present invention describes pharmaceutical tablet formulation comprising 100 mg of Vildagliptin or a salt, wherein;
- not more than30% of Vildagliptin at the end of 15 to 30 minutes;
- between 35 to 65% of Vildagliptin after 2 hours or 3 hours;
- not less than 80% of Vildagliptin at the end of 16 hours;
wherein the dissolution is measured using a USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C.
In another embodiment, the pharmaceutical tablet formulations comprise hydroxypropyl methylcellulose, in an amount ranging from 10% to 60% by weight of the pharmaceutical composition, preferably ranging from 20% to 40% by weight of the pharmaceutical composition. More preferably, the hydroxypropyl methylcellulose is present between 20% by weight and 30% by weight of the pharmaceutical composition.
In another embodiment, the pharmaceutical tablet formulations comprise hydroxyethyl cellulose, preferably between 20% by weight and 50% by weight of the pharmaceutical composition. More preferably, the hydroxyethyl cellulose is present between 35.73% by weight and 40% by weight of the pharmaceutical composition.
In another embodiment, the pharmaceutical tablet formulations comprising combination of sodium carboxy methyl cellulose, preferably between 10% by weight and 40% by weight of the pharmaceutical composition and high molecular weight hydroxypropyl methyl cellulose polymer with viscosity of 150,000-280,000 cpspreferably between 20% by weight and 30% by weight of the pharmaceutical composition. More preferably, the sodium carboxy methyl cellulose is present between 10% by weight and 35.73% by weight and high molecular weight hydroxypropyl methyl cellulose polymer with viscosity of 150,000-280,000 cps is present between 24% by weight and 30% by weightof the pharmaceutical composition.
Further, the pharmaceutical tablet formulation comprises a high viscosity sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution or a low viscosity sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution or a combination thereof; wherein Sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution and Sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution are present in the combination in a ratio ranging from 5:1 to 1:0.5, and more preferably from 3:1 to 1:0.8.
In a further aspect, the present invention concerns a process for preparing a tablet, in unit dosage form, which comprises:
(a) blending Vildagliptin or a pharmaceutically acceptable salt thereof, hydrophilic polymer, and pharmaceutically acceptable excipients together to obtain a pharmaceutical tablet formulation; and
(b) compressing the tablet formulation obtained in step (a) to form a compressed tablet as unit dosage form.
The term “Vildagliptin” used throughout the specification refers to not only Vildagliptin per se, but also various pharmaceutically acceptable salts and pharmaceutically acceptable hydrates, solvates, polymorphs thereof.

EXAMPLES
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 results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.

Example 1
Table 1
Formula F1 (With combination of polymers like Hydroxyethyl cellulose and Hydroxypropyl cellulose)
Batch No. F1
Sl. No. Ingredients % w/w
1 Vildagliptin 28.57
2 Hydroxyethyl Cellulose 40.00
3 Microcrystalline Cellulose 20.43
4 Hydroxypropyl Cellulose 10.00
5 Colloidal Silicon Dioxide 0.50
6 Magnesium Stearate 0.50
Tablet Weight 100.00

Manufacturing Process:
1. To prepare the pharmaceutical composition, Vildagliptin, Hydroxyethyl Cellulose, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Colloidal Silicon Dioxide and Magnesium Stearate were sifted, blended together and compressed into tablet.

Table 2
Physical parameters
Parameters Batch No. F1
Ranges observed
Hardness (kg/cm2) 7.9 – 9.1
Friability at 300 rotations 0.334%

Observation: Maximum hardness achieved was only up to 9 kg/cm2 with friability of 0.334%.

Example 2
Table 3
Formula F2 (With combination of polymers like Hydroxypropyl Methylcellulose, Hydroxyethyl cellulose and Hydroxypropyl cellulose)

Batch No. F2
Sl. No. Ingredients % w/w
1 Vildagliptin 26.67
2 Hydroxypropyl Methylcellulose 24.00
3 Hydroxyethyl Cellulose 35.73
4 Microcrystalline Cellulose 8.35
5 Hydroxypropyl Cellulose 3.00
6 Colloidal Silicon Dioxide 0.50
7 Magnesium Stearate 0.50
8 Pigment Blue 1.25
Tablet Weight 100.00

Manufacturing Process:
1. Vildagliptin, Hydroxypropyl Methylcellulose, Hydroxyethyl Cellulose, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Colloidal Silicon Dioxide, Magnesium Stearate and Pigment Blue were sifted, blended together and compressed into tablet.
Table 4
Physical parameters
Parameters Batch No. F2
Ranges observed
Hardness (kg/cm2) 11.9 – 15.5
Friability at 300 rotations 0.088%

Table 5
Related substances on stability for B. No. F2
Batch No Condition Amide Impurity (%) Unknown Impurity Total Impurities (%)
Unknown 1 Unknown 2
F2
Initial 0.06 0.05% ND 0.21
1M 40/75 0.23 0.09% 0.16% 0.50
2M 40/75 0.53 0.12% 0.45% 1.10
3M 40/75 0.65 0.09% 0.54% 1.28
3M 30/75 0.25 0.08% 0.14% 0.47
3M 25/60 0.23 0.10% 0.13% 0.46
ND: not detected
Observation: There was a significant improvement in physical parameters with maximum hardness upto 15.5 kg/cm2 with friability of just 0.088%.

Example 3
Table 6
Formula F3& F4 (With combination of polymers like Hydroxypropyl Methylcellulose, and Hydroxypropyl cellulose)
S. No.
Ingredients Batch No. F3 Batch No. F4
% w/w % w/w
1 Vildagliptin 33.33 26.66
2 Hydroxypropyl methylcellulose (viscosity ranging from 150,000 to 280,000cps) 20.00 30.00
3 Hydroxypropyl methylcellulose (viscosity ranging from 80,000 to 120,000cps) 10.00 10.00
4 Microcrystalline Cellulose 31.11 28.08
5 Colloidal Silicon Dioxide 0.50 0.50
6 Magnesium Stearate 0.50 0.50
7 Hydroxypropyl cellulose 3.00 3.00
8 Pigment Blend 1.56 1.25
Tablet Weight 100.00 100.00

Manufacturing Process (common for both the batches):
1. Sift all the materials, blend it together and compress into tablets.

Table 7
Physical parameters
Batch No. F3 F4
Parameters Ranges observed
Hardness (kg/cm2) 13.5 – 15.1 25.8-27.5
Friability at 300 rotations 0.01% 0.01%

Table 8
Stability Data for Related substances for 6 months

B. No Stability Time point Stability Condition Related Substance
Amide Impurity Unknown Impurity Total Impurity
F3 Initial Initial BLQ# ND* BLQ#
1 Month 40°C /75%RH 0.14 0.10 0.33
2 Month 40°C /75%RH 0.24 0.19 0.53
3 Month 40°C /75%RH 0.31 0.26 0.65
3 Month 30°C /75%RH 0.14 0.10 0.33
3 Month 30°C/65%RH 0.12 0.10 0.30
3 Month 25°C/60%RH BLQ 0.10 0.15
6 Month 40°C /75%RH 0.43 0.41 1.05
6 Month 30°C /75%RH 0.20 0.16 0.51
6 Month 30°C/65%RH 0.19 0.15 0.59
6 Month 25°C/60%RH 0.15 0.11 0.41
F4 Initial Initial BLQ ND BLQ
1 Month 40°C /75%RH 0.15 0.11 0.36
2 Month 40°C /75%RH 0.25 0.20 0.56
3 Month 40°C /75%RH 0.28 0.23 0.61
3 Month 30°C /75%RH 0.12 0.11 0.31
3 Month 30°C/65%RH 0.12 0.11 0.30
3 Month 25°C/60%RH 0.11 0.10 0.26
6 Month 40°C /75%RH 0.41 0.38 1.00
6 Month 30°C /75%RH 0.20 0.15 0.52
6 Month 30°C/65%RH 0.19 0.15 0.50
6 Month 25°C/60%RH 0.15 0.11 0.41
*ND: not detected
#BLQ: Below limit of quantification
Observation: Degradation product profile up to 6 Months accelerated condition and real time condition was studied and found satisfactory.

Example 4
Table 9
Formula F5, F6, F7 and F8 (With combination of polymers like Hydroxypropyl Methylcellulose and Sodium Carboxymethyl cellulose)

S. No. Ingredients Batch No. F5 Batch No. F6 Batch No. F7 Batch No. F8
% w/w % w/w % w/w % w/w
1 Vildagliptin 26.67 26.67 26.67 33.33
2 Hydroxypropyl Methylcellulose 24.00 24.00 24.00 30.00
3 Sodium carboxymethyl cellulose (High viscosity grade: CEKOL 100000) 35.73 26.67 18.67 x
4 Sodium carboxymethyl cellulose (low viscosity grade: CEKOL 30000 P) x x x 10.00
5 Microcrystalline Cellulose 8.35 17.42 25.42 20.10
6 Hydroxypropyl Cellulose 3.00 3.00 3.00 3.75
7 Colloidal Silicon Dioxide 0.50 0.50 0.50 0.62
8 Magnesium Stearate 0.50 0.50 0.50 0.62
9 Pigment Blue 1.25 1.25 1.25 1.56
Tablet Weight 100.00 100.00 100.00 100.00

Manufacturing Process:
1. Sift all the materials, blend it together and compress into tablets.
Table 10
Physical parameters
Parameters F5 F6 F7 F8
Ranges observed Ranges observed Ranges observed Ranges observed
Hardness (kg/cm2) 15.9 – 17.6 15.5 – 16.8 18.1 – 19.5 10.7 – 13.5
Friability at 100 rotations Nil Nil Nil Nil

Table 11
Dissolution data
Dissolution data of Vildagliptin Extended Release tablets 100 mg in pH 6.8 phosphate buffer
(USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C)
Time in Hours % Release for B. No. F5 % Release for B. No. F6 % Release for B. No. F7 % Release for B. No. F8
1 13 16 17 25
2 23 27 29 39
3 33 37 39 50
4 42 46 48 60
6 58 60 63 75
8 71 72 76 85
12 88 89 91 97
Dissolution data of Vildagliptin Extended Release tablets 100 mg in 0.1N HCl
(USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C)
Time in Hours % Release for B. No. F5 % Release for B. No. F6 % Release for B. No. F7 % Release for B. No. F8
1 26 28 28 35
2 39 42 43 53
3 49 52 53 65
4 58 61 62 75
6 73 76 76 88
8 85 88 86 96
12 97 102 97 102

The Figures 1-2 illustrate the comparative dissolution profile of Formulation F5, F6, F7 and F8 in different mediums.

Table 12
Stability Data for Related substances
Batch No
Condition
Amide Impurity (%) Unknown Max (%) Total Impurities (%)
Limit (1.0%) Limit (0.5%) Limit (2.0%)
F5 Initial 0.05 BLQ# 0.01% 0.13
3Wk 40/75 0.15 0.07% 0.06% 0.29
2M-40/75 0.24 0.07% 0.15% 0.46
F6 Initial 0.05 BLQ# 0.01% 0.15
3Wk 40/75 0.15 0.07% 0.06% 0.29
2M-40/75 0.26 0.07% 0.16% 0.49
F7 Initial 0.05 0.01% % BLQ# 0.10
3Wk 40/75 0.16 0.08% 0.07% 0.32
2M-40/75 0.27 0.08% 0.16% 0.51
#BLQ: Below limit of quantification
Observation: It was observed that despite using combination of release retarding polymer like HPMC & Na-CMC, similar or better stability data was achieved.

Example 5
Example 5 refers to clinical study batches of Example 3 (Formula F3&F4) that were taken as per below details:
Table 13
Formula F9 and F10 (With combination of polymers like Hydroxypropyl Methylcellulose, and Hydroxypropyl cellulose)

S. No.
Ingredients Batch No. F9
(Clinical batch of F3) Batch No. F10
(Clinical batch of F4)
% w/w % w/w
1 Vildagliptin 33.33 26.66
2 Hydroxypropyl methylcellulose
(viscosity ranging from 150,000 to 280,000cps) 20.00 30.00
3 Hydroxypropyl methylcellulose
(viscosity ranging from 80,000 to 120,000cps) 10.00 10.00
4 Microcrystalline Cellulose 31.11 28.08
5 Colloidal Silicon Dioxide 0.50 0.50
6 Magnesium Stearate 0.50 0.50
7 Hydroxypropyl Cellulose 3.00 3.00
8 Pigment Blend 1.56 1.25
Tablet Weight 100.00 100.00

Manufacturing Process (common for both the batches):
1. Sift all the materials, blend it together and compress into tablets.
Table 14
Dissolution data
Dissolution data of Vildagliptin Extended Release tablets 100 mg in 0.01 N HCL (USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C)
Time in Hours % Released for F9 % Released for F10
1 29 24
2 43 36
3 55 46
4 64 54
6 79 68
8 89 78
12 101 93
16 104 97
Dissolution data of Vildagliptin Extended Release tablets 100 mg in 0.1 N HCL
(USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C)
Time in Hours % Released for F9 % Released for F10
1 36 29
2 54 43
3 66 54
4 75 65
6 89 79
8 96 89
12 100 100
16 100 104
Dissolution data of Vildagliptin Extended Release tablets 100 mg in pH 4.5 acetate buffer (USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C)
Time in Hours % Released for F9 % Released for F10
1 28 23
2 43 35
3 54 45
4 64 53
6 78 67
8 87 78
12 98 93
16 101 101
Dissolution data of Vildagliptin Extended Release tablets 100 mg in pH 6.8 phosphate buffer (USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C)
Time in Hours % Released for F9 % Released for F10
1 27 21
2 40 32
3 50 41
4 59 49
6 72 62
8 81 72
12 93 86
16 97 95

The Figures 3-6 illustrate the comparative dissolution profile of Formulation F9 and F10 in different mediums
Table 15
Stability Data for Related substances
B.No Condition Related Substance
Amide Impurity Unknown Impurity Total Impurity
F9 Initial BLQ# BLQ# BLQ#
F10 Initial BLQ# ND* BLQ#
#BLQ: Below limit of quantification
*ND: Not detected
Observation: This strategy of HPMC polymer combination even at scale up level gave desirable physical parameters with good range of hardness and low friability and target release profile.
,CLAIMS:1. A solid extended release pharmaceutical composition comprising:
(a) a dipeptidyl peptidase IV inhibitor;
(b) at least one high molecular weight hydrophilic polymer; and
(c) optionally one or more pharmaceutically acceptable carriers.

2. The composition as claimed in claim 1, wherein the high molecular weight hydrophilic polymer is present in an amount of 10-60% by weight of the composition.

3. The composition as claimed in claim 1, wherein the dipeptidyl peptidase IV inhibitor is selected from the group consisting of Vildagliptin, Sitagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Gasogliptin, Dutogliptin or a pharmaceutically acceptable salt thereof.

4. The composition as claimed in claim 1, wherein the dipeptidyl peptidase IV inhibitor is Vildagliptin or a pharmaceutically acceptable salt thereof.

5. The composition as claimed in claim 1, wherein the hydrophilic polymer is a release retarding polymer selected from either a high molecular weight hydroxypropyl methylcellulose or its combination with a hydrophilic polymer selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polymers of acrylic acid, or a combination thereof.

6. The composition as claimed in claim 5, wherein the hydrophilic polymer is hydroxypropyl methyl cellulose with a viscosity ranging from 150,000-280,000 cps based on 2% of solution.

7. The composition as claimed in claim 5, wherein the hydrophilic polymer is a combination of hydroxypropyl methyl cellulose with viscosity ranging from 150,000 to 280,000 cps and hydroxypropyl methyl cellulose with viscosity ranging from 80,000 to 120,000 cps with a ratio of 5:1 to 1:1, more preferably with a ratio of 3:1 to 2:1.

8. The composition as claimed in claim 6 or 7, wherein the composition comprises hydroxypropyl methyl cellulose in an amount ranging from 10% to 60% by weight of the pharmaceutical composition, and preferably in an amount ranging from 20% to 40% by weight of the pharmaceutical composition.

9. The composition as claimed in claim 5, wherein the composition comprises hydroxyethyl cellulose polymer in an amount ranging from 20% to 50% by weight of the pharmaceutical composition.

10. The composition as claimed in claim 5, wherein the hydrophilic polymer is a combination of hydroxypropyl methyl cellulose and sodium carboxy methyl cellulose;
wherein the viscosity of the hydroxypropyl methyl cellulose ranges from 150,000 to 280,000 cps.

11. The composition as claimed in claim 10, wherein the composition comprises sodium carboxy methyl cellulose in an amount ranging from 10% to 40% by weight ofthe pharmaceutical composition.

12. The composition as claimed in claim 5, wherein the hydrophilic polymer comprises a high viscosity sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution, or a low viscosity sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution, or a combination thereof; wherein sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution and sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution are present in the combination in a ratio ranging from 5:1 to 1:0.5, and more preferably from 3:1 to 1:0.8.

13. The composition as claimed in claim 1, wherein the composition further comprises pharmaceutically acceptable excipients.

14. The composition as claimed in claim 1, wherein the solid dosage form includes but is not limited to tablets, caplets, mini-tablets, pellets, granules, capsule, capsule filled with mini-tablets or pellets or combinations thereof.

15. The composition as claimed in claim 14, wherein the solid dosage form is a tablet formulation comprising Vildagliptin in an amount ranging from 25% to 35% by weight of the pharmaceutical composition;
wherein hardness of the tablet ranges from 5-30kg/cm2 and friability of the tablet ranges from 0.01% to 0.5% at 300 rotations.

16. The composition as claimed in claim 15, wherein the tablet formulationprovides an effective blood concentration for a time period ranging between 15 minutes to16 hours for Vildagliptin or a pharmaceutically acceptable salt thereof.

17. The composition as claimed in claim 16, wherein the release rate of Vildagliptin or a pharmaceutically acceptable salt thereof from the tablet formulation is:
a. not more than 36% in 1 hour;
b. from about 42% to about 75% in4 hours;
c. from about 71% to about 96% in 8 hrs; and
d. not less than 95% in 16 hours;
wherein the dissolution is measured using a USP type II apparatus with sinkers at 75 rpm in 900 ml at 37°C.

18. An extended release pharmaceutical composition comprising:
Vildagliptin or a pharmaceutically acceptable salt thereof,
Hydroxypropyl Methylcellulose having viscosity ranging from 150,000 to 280,000 cps, and
Hydroxypropyl methylcellulose having viscosity ranging from 80,000 to 120,000 cps,
optionally Microcrystalline Cellulose,
optionally Hydroxypropyl Cellulose ,
optionally Sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution,
optionally Sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution,
optionally Colloidal Silicon Dioxide as a glidant,
a lubricant, and
optionally a pharmaceutically acceptable colour;
wherein the Hydroxypropyl Methylcellulose having viscosity ranging from 150,000 to 280,000cps and that having viscosity ranging from 80,000 to 120,000cps are present in a ratio ranging from 5:1 to 1:1, more preferably ranging from 3:1 to 2:1.

19. An extended release pharmaceutical composition comprising
about 26.66% w/w Vildagliptin,
about 30.00% w/w Hydroxypropyl Methylcellulose having viscosity ranging from 150,000 to 280,000,
about 10 % w/w Hydroxypropyl Methylcellulose having viscosity ranging from 80,000 to 120,000 cps,
about 28.08% w/w Microcrystalline Cellulose,
about 3.00% w/w Hydroxypropyl Cellulose,
about 0.50% w/w Colloidal Silicon Dioxide,
about 0.50% w/w Magnesium Stearate, and
about 1.25% w/w Pigment Blend;
wherein the Hydroxypropyl Methylcellulose having viscosity ranging from 150,000 to 280,000 and that having viscosity ranging from 80,000 to 120,000 are present in a ratio ranging from 5:1 to 1:1, more preferably in a ratio of 3:1.

20. An extended release pharmaceutical composition comprising
about 33.33% w/w Vildagliptin,
about 20.00% w/w Hydroxypropyl Methylcellulose having viscosity ranging from 150,000 to 280,000,
about 10 % w/w Hydroxypropyl Methylcellulose having viscosity ranging from 80,000 to 120,000 cps,
about 31.11% w/w Microcrystalline Cellulose,
about 3.00% w/w Hydroxypropyl Cellulose,
about 0.50% w/w Colloidal Silicon Dioxide,
about 0.50% w/w Magnesium Stearate, and
about 1.56% w/w Pigment Blend;
wherein the Hydroxypropyl Methylcellulose having viscosity ranging from 150,000 to 280,000cps and that having viscosity ranging from 80,000 to 120,000cps are present in a ratio ranging from 5:1 to 1:1, more preferably in a ratio of 2:1.

21. An extended release pharmaceutical composition comprising:
vildagliptin in an amount ranging from 26.67% w/w to 33.33% w/w;
hydroxypropyl methylcellulose having viscosity ranging from 150,000 to 280,000, in an amount ranging from 24.00% w/w to 30.00% w/w;
sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution, in an amount ranging from 0% w/w to 35.73% w/w;
sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution), in an amount of 0-10.00% w/w;
microcrystalline cellulosein an amount ranging from 8.35% w/w to 25.42% w/w;
hydroxypropyl cellulose in an amount ranging from3.00% w/w to 3.75% w/w;
colloidal silicon dioxide in an amount ranging from 0.50% w/w to 0.62% w/w;
magnesium stearate in an amount ranging from 0.50% w/w to 0.62% w/w; and
pigment blue in an amount ranging from 1.25% w/w to 1.56% w/w;
wherein the sodium carboxymethyl cellulose having viscosity ranging from 7500 to 10000 cps for 1% solution and sodium carboxymethyl cellulose having viscosity ranging from 2500 to 3500 cps for 1% solution are present in a ratio ranging from 5:1 to 1:0.5, and more preferably from 3:1 to 1:0.8.

22. An extended release pharmaceutical composition comprising:
a)Vildagliptin;
b) the sodium carboxymethyl cellulose with combination of two or more different viscosity grades upto 70% by weight of composition;
c) microcrystalline cellulose between 8-10% by weight of composition;
d) colloidal silicon dioxide, between 0.5-1.0% by weight of composition;
e) magnesium stearate, between 0.5 -1.0% by weight of composition;
f) colorant between 0.5-1.5% by weight of composition;
and one or more pharmaceutically acceptable excipients.

23. The composition as claimed in claim 22, wherein the sodium caroboxymethyl cellulose polymer comprises of different viscosity grade polymers selected from high viscosity 7500 to 10000 cps for 1% solution (CEKOL 100000), or low viscosity 2500 to 3500 cps for 1% solution (CEKOL 30000 P) or combination thereof.

24. The composition as claimed in any of the preceding claims, wherein the composition is matrix based composition and the release of Vildagliptin is pH independent.

25. The composition as claimed in any of the preceding claims, as and when used in diabetes mellitus, non-insulin dependent diabetes mellitus, obesity, arthritis, osteoporosis, and similar diseases.

26. A process for preparing the pharmaceutical composition as claimed in claim 1, wherein the process comprises a direct compression method.

27. The process as claimed in claim 26, wherein the process comprises preparing a tablet dosage form, comprising:
(a) blending Vildagliptin or a pharmaceutically acceptable salt thereof, the at least one high molecular weight hydrophilic polymer, and pharmaceutically acceptable excipients together to obtain a pharmaceutical tablet formulation; and
(b) compressing the tablet formulation obtained in step (a) to form a compressed tablet dosage form.