FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION
STABLE PHARMACEUTICAL COMPOSITIONS OF SAXAGLIPTIN OR SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C INDUSTRIAL AREA, CHIKALTHANA, AURANGABAD-431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
There is provided a stable pharmaceutical composition of saxagliptin or salts thereof. The composition comprises a core made from plurality of saxagliptin components. By using special components of saxagliptin in the formulation, composition with excellent storage stability can be prepared; particularly levels of degradants in the formulation can be effectively controlled. Such composition of saxagliptin gives flexibility of preparing it by conventional methods involving simple manufacturing steps. The following specification particularly describes the invention and the manner in which it is to be performed.

Description
The present invention relates to a stable pharmaceutical composition of saxagliptin or salts thereof. In particular, the invention relates to composition comprising plurality of saxagliptin components. Such composition of saxagliptin exhibit relatively improved storage stability and particularly, levels of degradants in the formulation during storage can be effectively controlled. The invention also includes a process of preparing such compositions and method of treating type-II diabetes mellitus by administering the composition to a patient in need thereof.
Saxagliptin is an orally active inhibitor of the dipeptidyl peptidase-4 (DPP4) enzyme. After a meal intake, insulinotropic hormone glucagon-like peptide-1 (GLP-1) is released which in turn induces insulin release from the pancreas. Some of the GLP-1 is inactivated by the DPP4 present in plasma and intestinal capillary endothelium. Therefore, if the DPP4 is inhibited, more GLP-1 will be available to activate insulin release from the pancreas. The advantage of this mechanism of insulin release is that insulin is secreted only in response to a meal. Therefore, problems of hypoglycemia associated with other diabetes drugs are less likely with a DPP4 inhibitor.
Chemically saxagliptin is (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo [3.3.1.1]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,monohydrate or (1S,3S,5S)-2- [(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo [3.1.0]hexane-3-carbonitrile with the structure


Saxagliptin alone or in combination with other anti-diabetic agents are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-II diabetes mellitus in multiple clinical conditions. It is marketed in the United States in the form of tablets under the brand name Onglyza®.
It is well known in the art that saxagliptin is an unstable compound and it is prone to an intra-molecular cyclization. The resultant degradant, cyclic amidine (mainly cis-cyclic amidine) is not therapeutically active and therefore, its formation is not desirable. This cyclization reaction can occur both in solid state and solution state. The rate of intra-molecular cyclization of saxagliptin is accelerated when formulations are subject to commonly used processing activities such as wet granulation, roller compaction, or tabletting. In addition, most commonly used excipients, when mixed with saxagliptin, can accelerate the rate of cyclization. Moreover, the level of cis-cyclic amidine increases when the drug to excipient ratio increases posing more challenges for low strength dosage forms. Thus, these properties of saxagliptin posses major challenge in devising conventional and stable dosage form with ease of manufacture.
Numerous studies have been conducted to address the formulation and drug release systems of DPP4 inhibitor’s and several attempts have also been made to improve the formulation stability.
U.S. Patent No. 6,395,767 discloses a DPP4 inhibiting compound, saxagliptin and its use in treating type-II diabetes mellitus.
PCT Publication No. WO 2011/052825 discloses a composition of DPP4 inhibitors and anti-diabetic compounds for use in the treatment of diabetes.
U.S. Patent Application Publication No. 2005/0208133 discloses a multiple drug release systems, its composition and methods of its preparation.

PCT Publication No. WO 2002/085335 discloses a composition providing control release of medicament. The composition contains several coatings, which controls the release of the medicament.
U.S. Patent No. 7,951,400 discloses a saxagliptin tablet containing several coating layers of polyvinyl alcohol.
The compositions disclosed in the prior art suggests that stable formulations of saxagliptin can be prepared by applying drug in the form of a coating along with several polymer coatings. However, apart from its complex structure, the process of preparing such formulations requires critical optimization and control of several processing steps such as layer coating, drying temperature, which are detrimental for drug release pattern and the stability of the end formulation.
The prior art also suggests that when saxagliptin is placed in the core of the formulation, the resulting formulations would have compromised stability.
Thus, there still exists an enduring need for alternative, improved and stable pharmaceutical composition of saxagliptin, involving simple manufacturing process, which is suitable for commercial production.
The inventors of the present invention have surprisingly found that it is possible to formulate pharmaceutical compositions of saxagliptin, which can exhibit superior chemical and physical stability and involve simple manufacturing process.
In one general aspect, there is provided a stable pharmaceutical composition comprising plurality of saxagliptin components, which comprises of particles of one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate thereof and optionally, one or more pharmaceutical excipients.

In another general aspect, there is provided a stable pharmaceutical composition comprising plurality of saxagliptin components, which comprises of particles of one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate thereof, optionally with one or more pharmaceutical excipients, wherein said components are further coated with one or more polymers.
In another general aspect, the saxagliptin components are in the form of solid particles, granules, beads, or pellets.
In another general aspect, the saxagliptin components are completely or partially coated saxagliptin or salts, hydrates, anhydrate thereof.
In another general aspect, there is provided a stable pharmaceutical composition comprising plurality of saxagliptin components, which comprises of particles of one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate thereof.
In another general aspect, there is provided a stable pharmaceutical composition comprising plurality of saxagliptin components, which comprises of particles of one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate thereof and a polymer selected from hydroxypropyl methylcellulose, polyvinyl alcohol, or mixtures thereof.
In another general aspect, there is provided a process for the preparation of plurality of saxagliptin components, which process comprises of: coating particles of one or more pharmaceutical excipients completely or partially with saxagliptin or salts, hydrates, anhydrate thereof.
In another general aspect, there is provided a process for preparation of a stable pharmaceutical composition comprising saxagliptin or salts, hydrates, anhydrate thereof, which process comprises of:

(a) providing plurality of saxagliptin components comprising one or more
pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate
thereof and optionally, with one or more polymers and one or more
pharmaceutical excipients;
(b) optionally, mixing the saxagliptin components with one or more
pharmaceutical excipients to form a blend;
(c) formulating the saxagliptin components prepared in step (a) or the blend
prepared in step (b) in a suitable dosage form.
In another general aspect, the coating of saxagliptin or salts, hydrates, anhydrate thereof on the particles of the pharmaceutical excipients is applied by spray coating. Perforated pan coaters and fluid bed coaters can be used for the coating.
In another general aspect, in the process for preparation of saxagliptin components, the saxagliptin coating is applied as a suspension of saxagliptin or salts, hydrates, anhydrate thereof and optionally with one or more polymers in a coating solvent.
In another general aspect, the stable pharmaceutical composition of saxagliptin or salts, hydrates thereof retains at least 90% w/w of total potency of saxagliptin 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-II diabetes mellitus in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.
The stable pharmaceutical composition of the present invention comprises plurality of saxagliptin components comprising particles of one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate

thereof optionally with one or more pharmaceutical excipients and one or more polymers.
The pharmaceutical composition of the present invention exhibits excellent storage stability over the storage period.
In an embodiment, the stable pharmaceutical composition of the present invention may be characterized by lower level of degradant cis-cyclic amidine.
In another embodiment, the stable pharmaceutical composition of saxagliptin or salts, hydrates thereof retains at least 90% w/w of the total potency of saxagliptin after storage at 30°C and 60% relative humidity, at 40°C and 75% relative humidity, or at 25°C and 60% relative humidity for at least 3 months.
The term "saxagliptin" used throughout the specification refers to not only saxagliptin per se, but also various pharmaceutically acceptable salts and pharmaceutically acceptable hydrates thereof.
The term "saxagliptin component" used throughout the specification refers to particles, agglomerates, granules, pellets, microspheres, liposomes, sphericles, or any solid physical form known to the person skilled in the art of one or more pharmaceutical excipients partially or completely coated or complexed with saxagliptin or salts, hydrates, anhydrate thereof and optionally one or more pharmaceutical excipients and polymers. The present invention also embraces the dosage forms prepared by processing the components as defined herein (for instance, tablets prepared by compressing the saxagliptin components). It should be understood that the components in the final dosage form of the present invention may or may not be physically separated.

The term "particles of pharmaceutical excipients" as used throughout the specification refers to as a single or an aggregate of all physical forms of pharmaceutical excipients.
The saxagliptin components of the present invention comprises particles of one or more pharmaceutical excipients completely or partially coated with saxagliptin or salts, hydrates, anhydrate thereof optionally with one or more pharmaceutical excipients and one or more polymers.
Particles of the pharmaceutical excipients in the saxagliptin components of the present invention are selected from the group consisting of fillers/diluents, binders, glidants, lubricants, disintegrants, and plasticizers.
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.
In an embodiment, the saxagliptin component of the present invention comprises plurality of particles of lactose, microcrystalline cellulose and croscarmellose sodium coated with saxagliptin or salts, hydrates, anhydrate thereof and one or more polymers.
The amount of saxagliptin in the components may range from about 1% to about 99% w/w of the component.
In an embodiment, the stable pharmaceutical composition of the present invention comprises plurality of saxagliptin components comprising particles of

one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate thereof and one or more polymers.
The saxagliptin and polymer coating may comprise at least one polymer and a coating solvent, which preferably is water, which is used for processing and removed by drying. Suitable polymer may be selected from, but not limited water-soluble polymer, water-insoluble polymer, or mixtures thereof. Particularly, water-soluble polymers are preferred.
Examples of polymers suitable for first coating layer include, but not limited to hydroxypropyl methylcellulose, ethyl cellulose, methacrylic polymers or hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose. The coating layer may also optionally include a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; and an anti-adherent or glidant such as talc, fumed silica or magnesium stearate. The amount of polymer in the components may range from about 0.5% to about 50% w/w of the component.
Examples of suitable coating solvents includes, but not limited to water, ethanol, methanol, and isopropyl alcohol, with water being preferred.
The saxagliptin and polymer coating composition may comprise one or more plasticizers in an amount sufficient to minimize effect of the formulation processing (e.g. upon compression into tablet dosage form) on the coating integrity. The composition of the coating also provides advantageous mechanical properties to the coating.
The amount of plasticizer in the coating composition may range from about 5 to about 50%, preferably from about 5 to about 30% w/w of the coating layer.

The coating layer will preferably be formed by coating polymer layer in an amount within the range from about 10 to about 99%, preferably from about 20 to about 99% w/w of the component, plasticizer in an amount within the range from about 1 to about 30%, preferably from about 5 to about 20% w/w of the component, and anti-adherent or glidant in an amount within the range for about 15 to about 30%, preferably from about 10 to about 15% w/w of the component.
In an embodiment, the pharmaceutical composition of the present invention comprises a core comprising plurality of saxagliptin components and optionally one or more pharmaceutical excipients.
The core employed in the composition of the invention may include conventional pharmaceutical excipients to enable formation of a pharmaceutically acceptable solid core. The core may be in the form of a tablet, bead, beadlet, or pill.
In an embodiment, the core may contain one or more additional anti-diabetic agents, other than saxagliptin, in an amount within the range from about 0.1 to about 70% wt/wt and preferably from about 1 to about 50% w/w of the composition.
The core may be formed of one or more pharmaceutical excipients selected from, but not limited to one or more of bulking agents or fillers, binders, disintegrants, and lubricants.
In an 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 using saxagliptin components.
In an embodiment, the process of preparing the cores includes the steps of blending the saxagliptin components with one or more excipients such as bulking agent, optionally binder and optionally disintegrant followed by formulating the blend in the form of cores. A lubricant will be preferably added to the blend to facilitate tablet formation.
The composition of the present invention further may comprise an outer protective layer comprising one or more polymers and one or more pharmaceutical excipients.
The outer coating layer may include colorant as desired, such as within the range from about 0.5 to about 5.0% w/w, based on the total weight of the outermost coating layer.

The outer protective coating layer 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, nut 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 stable pharmaceutical composition of saxagliptin or salts, hydrates thereof, the process comprises of:
(a) providing plurality of saxagliptin components which comprises of particles of
one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates,
anhydrate thereof along with one or more polymers and optionally one or more
pharmaceutical excipients;
(b) optionally, mixing the saxagliptin components with one or more
pharmaceutical excipients to form a blend;
(c) formulating the saxagliptin components prepared in step (a) or the blend
prepared in step (b) in a suitable dosage form.
The process for the preparation of plurality of saxagliptin components of the present invention comprises a step of coating particles of pharmaceutical excipients completely or partially with saxagliptin or salts, hydrates thereof and one or more polymers. The coated saxagliptin particles may be dried in order to get components suitable for formulating in a solid dosage form.
In a further embodiment, in preparing the saxagliptin components of the invention, coating suspensions including saxagliptin or salts, hydrates thereof and coating polymer are prepared in water. Other coating solvents, which may be employed include ethanol, methanol, and isopropyl alcohol, with water being preferred.

It has been surprisingly found that the composition of the present invention exhibits superior chemical and physical stability when manufactured using conventional dry granulation, wet granulation, direct compression or slugging.
The composition of the present invention may be formulated in suitable a dosage form including, but not limited to, a tablet, caplet, mini-tablet, pellets, granules, capsule filled with mini-tablets or pellets or combinations thereof.
The present invention further provides a method of treating type-II diabetes mellitus in a patient which method comprising 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.
In accordance with the Present Invention coated tablet formulations are set out below.

Example 1: Saxagliptin Tablet

Sr. No. Ingredients Qty/Tab
Core Tablets
Dry Mix
1 Lactose Monohydrate 98.00
2 Microcrystalline Cellulose 90.00
3 Croscarmellose sodium 10.00
Binder
4 Saxagliptin HCl 5.60
5 Hypromellose or HPC or PVP or vinylpyrrolidone-vinyl acetate and Glyceryl Caprylocaprate 5.60
6 PEG 6000 1.00
7 Dichloromethane qs
8 Methanol qs
Lubricant
9 Magnesium stearate 2.00
Film Coating
10 Opadry 5.00
Total 220.2
Process: Mixture of lactose monohydrate, microcrystalline cellulose and croscarmellose sodium was loaded and blended in the in the fluidized bed processor.
A binder dispersion of drug was prepared by mixing saxagliptin HCl, hypromellose/ HPC/ PVP/ vinylpyrrolidone-vinyl acetate and glyceryl caprylocaprate in PEG 6000, dichloromethane and methanol.

The binder dispersion was then coated on the excipients in the fluidized bed processor to form granules, which were then sifted, milled and lubricated by blending with magnesium stearate.
The lubricated granules were then compressed into tablets and the tablets are coated with opadry coating dispersion.

We Claim
1. A stable pharmaceutical composition comprising plurality of saxagliptin components, which comprises of particles of one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates thereof and optionally, with one or more polymers.
2. The stable pharmaceutical composition of claim 1, wherein the plurality of saxagliptin components forms the core of the composition.
3. The stable pharmaceutical composition of claim 1, wherein the particles of pharmaceutical excipients comprises lactose, microcrystalline cellulose, croscarmellose sodium, and mixture thereof.
4. The stable pharmaceutical composition of claim 1, wherein the polymer comprises one or more water-soluble polymers, water-insoluble polymers, or mixtures thereof.
5. The stable pharmaceutical composition of claim 4, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose, polyvinyl alcohol, or mixture thereof.
6. The stable pharmaceutical composition of claim 1, wherein the saxagliptin components comprises from about 1% to about 99% w/w of saxagliptin or salts, hydrates thereof.
7. The stable pharmaceutical composition of claim 1, wherein the saxagliptin components are in the form of solid particles, granules, beads, or pellets.

8. The stable pharmaceutical composition of claim 1, wherein the composition retains at least 90% w/w of the total potency of saxagliptin after storage at 30°C and 60% relative humidity for at least 3 months.
9. A process for preparation of stable pharmaceutical composition of claim 1, which process comprises of:
(a) providing plurality of saxagliptin components which comprises of particles of
one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates,
anhydrate thereof and optionally with one or more pharmaceutical excipients and
one or more polymers;
(b) optionally, mixing the saxagliptin components with one or more
pharmaceutical excipients to form a blend;
(c) formulating the saxagliptin components prepared in step (a) or the blend
prepared in step (b) in a suitable dosage form.
10. A tablet comprising:
(a) a core comprising of plurality of saxagliptin components, which components comprises of particles of one or more pharmaceutical excipients coated with saxagliptin or salts, hydrates, anhydrate thereof and optionally, with one or more pharmaceutical excipients and one or more polymers.
(b) optionally, an outer protective coating layer coated on the tablet core comprising one or more polymers, and optionally with one or more pharmaceutical excipients.