FORM 2
THE PATENTS ACT 1970 (39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
(Section 10 and rule 13)
"PHARMACEUTICAL COMPOSITIONS OF SAXAGLIPTIN"
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
having office at
Glenmark House,
HDO - Corporate Bldg,
Wing -A, B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099, INDIA
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF INVENTION
[0001] The present invention relates to the pharmaceutical compositions comprising Saxagliptin or its pharmaceutically acceptable salts thereof, and a process for preparing the same.
BACKGROUND OF THE INVENTION
[0002] Saxagliptin is an orally-active inhibitor of the DPP4 enzyme. Saxagliptin,(lS,3S,5S)-2-[(2S)-2-Amino-2-(3hydroxytricyclo[3.3.1.13,7]dec-l -yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitriIe, its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Pat. No. 6,395,767. U.S. Pat. No. 7,420,079 discloses Saxagliptin and its hydrochloride, trifluoroacetic acid and benzoate salts, as well as Saxagliptin monohydrate. Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb for the treatment of type 2 diabetes.
[0003] Though the literature suggests that Saxagliptin is susceptible to degradation in pharmaceutical composition, very few attempts have been made in the past to develop the stable pharmaceutical composition of Saxagliptin. One of possible solutions of the aforementioned problem is described by Desai et.al in US7951400. Patent 7951400 describes an ability of Saxagliptin to undergo intramolecular cyclization leading to the formation of a degradant called as cyclic amidine (mainly cis-cyclic amidine (CA)), which is not therapeutically active and therefore, its formation is not desirable. The stress generated in regular pharmaceutical operations and/or the exposure of saxagliptin to the commonly used pharmaceutical excipients triggers the cyclization, resulting into the formation of cyclic amidine. The preferred composition of patent 7951400, comprises a saxagliptin embedded within a film coat sprayed over an inert core tablet and thereby avoids the direct contact of saxagliptin with excipients and provides minimal stress to saxagliptin during the manufacturing of a pharmaceutical composition. However the composition described in patent 400, are difficult to optimize and manufacture, and are equally time consuming. Therefore the composition of Saxagliptin or its pharmaceutically acceptable

salts thereof, prepared by conventional pharmaceutical processes, having an acceptable stability profile are highly desired.
SUMMARY OF INVENTION
[0004] The present invention provides a core composition comprising Saxagliptin or pharmaceutically acceptable salts thereof, wherein the saxagliptin is in an intimate contact with the pharmaceutically acceptable excipients.
[0005] In another embodiment, the core composition comprising saxagliptin or pharmaceutically acceptable salts thereof, in an intimate contact with pharmaceutically acceptable excipients, -has the cyclic amidine impurity within the acceptable range.
[0006] In one of the preferred embodiments, the core composition comprising saxagliptin or pharmaceutically acceptable salts thereof, in an intimate contact with pharmaceutically acceptable excipients, has cis- cyclic amidine, trans-cyclic amidine and amide impurities within the acceptable range.
[0007] In one of the preferred embodiments, the core composition comprising saxagliptin or pharmaceutically acceptable salts thereof in an intiniate contact with pharmaceutically acceptable excipients, has cis- cyclic amidine, trans-cyclic amidine and amide impurities within the acceptable range when exposed to the temperature 40°C and Relative humidity of 75% for the three months.
[0008] The present invention also describes a method of manufacturing compositions having Saxagliptin or its pharmaceutically acceptable salts thereof wherein the drug is in an intimate contact with excipients and having cis- cyclic; amidine, trans-cyclic amidine and amide impurities within the acceptable range.

DETAILED DESCRIPTION OF INVENTION
[0009] It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements found in typical pharmaceutical compositions and methods of stabilization. Those of ordinary skill in the art will recognize that other elements and/or steps are desirable and/or required in implementing the present invention. Furthermore, the embodiments identified and illustrated herein are for exemplary purposes only, and are not meant to be exclusive or limited in their description of the present invention.
[0010] The phrase "intimate contact" as used herein, meant that the Saxagliptin is in direct contact with the excipients used in the tablet.
[0011] "Acceptable stability profile" or "impurities within the acceptable range" or "impurities controlled" as used herein means that the pharmaceutical compositions meets the stability requirements led down by US FDA for the approvals of generic pharmaceutical compositions.
[0012] As used herein, the term "drug" or "active ingredient" or "active" shall refer to Saxagliptin base, hydrates of Saxagliptin base, anhydrous Saxagliptin base or its pharmaceutically acceptable salts or its hydrates thereof.
[0013] As used herein, the term "pharmaceutically acceptable salts" shall refer to salts prepared from pharmaceutical ly acceptable non toxic bases or acids including inorganic or organic bases and inorganic or organic acids, however HC1 salt of saxagliptin or its hydrates are preferred.

[0014] Saxagliptin is susceptible to an intramolecular cyclization and forms cyclic amidine as degradant which is not therapeutically active and hence not desirable. Cyclic amidine impurity arises due the routine pharmaceutical operations and the excipients used in preparation of pharmaceutical composition of Saxagliptin. A pharmaceutical composition, of present invention, maintains said impurities within the acceptable range, regardless of their source or the mechanism of degradation. For the purpose of this invention, the tablet core can be prepared by wet granulation, direct compression and dry granulation (slugging or roller compaction).
[0015] In an important aspect of the present invention, the core tablet comprises a Saxagliptin base in an intimate contact with the pharmaceutically acceptable excipients, wherein the cis-cyclic amidine, trans-cyclic amidine and amide impurities are within the acceptable range. Saxagliptin base of the pharmaceutical composition may be amorphous or crystalline or hydrate or solvate, however for the purpose of present invention saxagliptin base anhydrous or hemihydrates or monohydrate are preferred.
[0016] In another important aspect of the present invention, the core tablet comprises a Saxagliptin salt in an intimate contact with the pharmaceutically acceptable excipients, wherein the cis-cyclic amidine, trans-cyclic amidine and amide impurities are within the acceptable range.
[0017] In the preferred aspect, the core tablet comprises a Saxagliptin Hydrochloride in an intimate contact with the pharmaceutically acceptable excipients, wherein the cis- cyclic amidine, trans-cyclic amidine and amide impurities are within the acceptable range. The said pharmaceutical composition comprising Saxagliptin Hydrochloride can be produced by one or more ways.
[0018] In a preferred aspect, the pharmaceutical composition comprising Saxagliptin Hydrochloride in an intimate contact with the pharmaceutically acceptable excipients can be

prepared by directly admixing the Saxagliptin Hydrochloride with the pharmaceutically acceptable excipients, with or without the aid of any solvent.
[0019] In a more preferred aspect the pharmaceutical composition comprising Saxagliptin Hydrochloride in an intimate contact with the pharmaceutically acceptable excipients, is prepared by spraying or adding, the solution or suspension containing Saxagliptin base in the 0.1 N HC1 over the pharmaceutically acceptable excipients. Though it is not required, but it is preferred to use the pharmaceutically acceptable binder in the solution or suspension containing Saxagliptin base in the 0.1 N HC1, for the better adhesive properties in the granulate. The solution or suspension containing Saxagliptin base in the 0.1 N HCI, optionally containing the binder is maintained at pH less than 3, more preferably at pH less than or equal to 2. In accordance with the current aspect of the present invention, Saxagliptin base is added to the 0.1 N HCI containing a suitable binder, the mixture is stirred to produce uniform suspension. The granulating suspension thus produced was either added to the powder blend comprising filler, disintegrant and/ or binder in the high speed mixer granulator or sprayed onto the fluidized bed comprising filler, disintegrant and/ or binder, which is followed by drying, milling, mixing and tabletting.
[0020] In one of the preferred embodiments the core tablet comprising Saxagliptin base or its Hydrochloride salt contains an acidifying agent in addition to the other pharmaceutical acceptable agents.
[0021] More particularly the core tablets of present invention can be further coated with the film coat.
[0022] The present invention provides the pharmaceutical core composition comprises
a) 2.5 or 5 mg of Saxagliptin base or equivalent amount of hydrates or salts thereof
b) 170-220 mg of diluent or diluents
c) 10-15 mg of disintegrants

d) 5 -10 mg of binders
e) 1 -5 mg of glidant and/or lubricants Optionally an acidifying agent
f) Optionally coated with the film coat
wherein the Saxagliptin is in an intimate contact with the excipients.
[0023] In one of the preferred embodiment, the core composition comprising Saxagliptin or its pharmaceutically acceptable salts thereof wherein the drug is in an intimate contact with excipients and % of cyclic amidine impurity is controlled. Particularly cis-cyclic amidine trans-cyclic amidine and amide impurity in initial as well as stability stage. More particularly, the present invention describes a pharmaceutical composition having Saxagliptin or its pharmaceutically acceptable salts thereof wherein the cis-cyclic amidine impurity is not more than 0.5%, preferably not more than 0.3%, more preferably not more than 0.2% at 3M 40°C/75% RH. In accordance with the present invention, a preferred embodiment also describes a pharmaceutical composition having Saxagliptin or its pharmaceutically acceptable salts thereof wherein the trans-cyclic amidine impurity is not more than 0.2%, preferably not more than 0.1%, more preferably not more than 0.05% at 3M 40°C/75% RH. In accordance with the present invention, another preferred embodiment also describes a pharmaceutical composition having Saxagliptin or its pharmaceutically acceptable salts thereof wherein the amide impurity is not more than 0.1 %, preferably not more than 0.05%, more preferably not more than 0.02% at 3M 40°C/75% RH.
[0024] In addition to the active ingredient, the tabletting powder also contains number of inert materials known as excipients. They may be classified according to the role they play in the tablet. The primary composition includes fillers, binders or diluents, lubricants, disintegrants and glidants. Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted to these excipients through pretreatment steps, such as wet granulation, slugging, spray drying etc.

[0025] One or more fillers or diluents can be selected. Examples of pharmaceutically acceptable fillers or diluents include, but are not limited to, sucrose, and lactose, in particular lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, powdered cellulose. Different grades of lactose or microcrystalline cellulose can be used. In case of a water soluble active ingredient, like the one described in this invention, more preferably water insoluble fillers, such as starch, microcrystalline cellulose, dibasic calcium phosphate dihydrate, and anhydrous dibasic calcium phosphate, preferably microcrystalline cellulose, can be used in addition or instead of the water soluble fillers. In preferred embodiment combination of water soluble and water insoluble fillers are used. Combination of lactose and microcrystalline cellulose is the preferred diluents for this invention. The total weight percentage of filler ranges between about 65 % and about 90% by weight, preferably from about 75 to about 80 %.
[0026] Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. One or more disintegrants can be selected. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., crospovidone, cross-linked Ca-CMC and Na-CMC, Sodium starch glycoalte. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. Croscarmellose sodium is the preferred disintegrant for this formulation. Preferably the disintegrant is present in the tablet formulation in an amount of from about 1% to about 10 % by weight, and can be from about 3 % to about 8% by weight, and most preferred, can be from about 4.5% to about 5.5% by weight.
[0027] Another commonly used class of excipients in tablets is binders. Binders are agents, which impart cohesive qualities to the powdered material. The compositions described herein also can comprise binders, examples of pharmaceutically acceptable binders include, but are not limited to, povidones (e.g., PVP K-30, PVP K-60, and PVP K-90), cellulose derivatives (e.g., methylcellulose and sodium carboxymethylcellulose), gelatin, polyethylene glycol,

polymethacrylates, ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, pregelatinized starch and sodium alginate, wherein povidones are preferred, and wherein PVP K -30 is particularly preferred. . The total weight percentage of binder ranges between about 1 % and about 5% by weight, Most preferred range is about 3 %.
[0028] A glidant can be used to improve powder flow properties prior to and during tabletting and to reduce caking. Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, tribasic calcium phosphate and the like. Talc is preferably included as a glidant in an amount up to about 4%, preferably about 3% to about 2.0%, by weight of the tablet, more preferably from about 1 to about 0.5%,
[0029] Lubricants are typically added to prevent the tabletting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and the like. In one embodiment, magnesium stearate is included as a lubricant in an amount of about 0.2% to about 2.0%, preferably about 1 %, by weight of the tablet.
[0030] Core composition of the present invention can further be coated. The invention may comprise a nonfunctional coating. A nonfunctional coating can comprise a polymer component, for example HPMC, PVA etc. optionally with other ingredients, for example, one or more plasticizers, colorants, etc. The term "nonfunctional" in the present context means having no substantial effect on release properties of the tablet, and the coating serves another useful purpose. For example, such a coating can impart a distinctive appearance to the tablet, provide protection against attrition during packaging and transportation, improve

ease of swallowing, and/or have other benefits. A nonfunctional coating should be applied in an amount sufficient to provide complete coverage of the tablet. Typically an amount of about 1% to about 10%, more typically an amount of about 2% to about 5%, by weight of the tablet as a whole, is suitable
EXAMPLES
[0031] The following examples describe compositions of the present invention containing Saxagliptin or its pharmaceutically acceptable salts thereof, but they are not to be interpreted as limiting the scope of the claims
EXAMPLE 1:

Ingredient Qty/Tab (in mg)
Saxagliptin HCL dihyhydrate 5.58
Lactose Monohydrate 73.12
Microcrystalline Cellulose 110.00
Croscarmellose Sodium 6.75
Povidone 6.75
Purifeid Water qs
Croscarmellose Sodium 4.50
Microcrystalline cellulose 20.00
Talc 1.00
Magnesium stearate 2.30
Core tablet weight 230.00
Opadry ® II-Complete Film Coating System 7.00
Coated tablet weight 237.00
The manufacturing process consists of following steps:
Saxagliptin hydrochloride dihydrate, microcrystalline cellulose, croscarmellose sodium and lactose monohydrate were co sifted and added to high speed mixer granulator and mixed for desired time. Dry mix was granulated with povidone solution in water. Granules were dried till desired LOD was achieved. Drying was followed by sifting of granules and blending it with extragranular excipients such as pre-sifted microcrystalline cellulose, croscarmellose

Sodium for required time. This blending was followed by lubrication with Mg-stearate for sufficient time. Lubricated granules were compressed on suitable punches.
Core tablets obtained by above process were coated with PVA based Opdry till desired weight gain was achieved.
EXAMPLE 2:

Ingredient Qty/Tab (in mg)
Saxagliptin 5.00
Lactose Monohydrate 73.70
Microcrystalline Cellulose 110.00
Croscarmellose Sodium 6.75
Povidone 6.75
0.1NHC1 qs
Croscarmellose Sodium 4.50
Microcrystalline cellulose 20.00
Talc 1.00
Magnesium stearate 2.30
Core tablet weight 230.00
Opadry ® H-Complete Film Coating System 7.00
Coated tablet weight 237.00
The manufacturing process consists of following steps:
Co sifted microcrystalline cellulose, croscarmellose sodium and lactose monohydrate were added in fluidized bed processor and mixed for desired time. Dry mix was granulated with binder suspension containing Saxagliptin and povidone in 0.1N HC1. Granules were dried till desired LOD was achieved. Drying was followed by sifting of granules and blending it with extragranular excipients such as pre-sifted microcrystalline cellulose, croscarmellose Sodium for required time. This blending was followed by lubrication with Mg-stearate for sufficient time. Lubricated granules were compressed on suitable punches.
Core tablets obtained by above process were coated with PVA based Opdry till desired weight gain was achieved.
EXAMPLE 3:

Ingredient Qty/Tab (in mg)
Lactose Monohydrate 141.45
Microcrystalline Cellulose 110.00
Croscarmellose Sodium 6.75
Saxagliptin 5.00
Hydroxypropyl methyl cellulose 9.00
0.1NHC1 qs
Croscarmellose Sodium 4.50
Microcrystalline cellulose 20.00
Talc 1.00
Magnesium stearate 2.30
Core tablet weight 300.00
Opadry ® II-Complete Film Coating System 9.00
Coated tablet weight 309.00
The manufacturing process consists of following steps:
Co sifted microcrystalline cellulose, croscarmellose sodium and lactose monohydrate were added in fluidized bed processor and mixed for desired time. Dry mix was granulated with binder suspension containing Saxagliptin and HPMC in 0.1N HC1. Granules were dried till desired LOD was achieved. Drying was followed by sifting of granules and blending it with extragranular excipients such as pre-sifted microcrystalline cellulose, croscarmellose Sodium for required time. This blending was followed by lubrication with Mg-stearate for sufficient time. Lubricated granules were compressed on suitable punches.
Core tablets obtained by above process were coated with PVA based Opdry till desired weight gain was achieved.
EXAMPLE 4:

Ingredient Qty/Tab (in mg)
Saxagliptin Hcl dihyhydrate 5.58
Lactose Monohydrate 60.00
Microcrystalline Cellulose 129.87
Croscarmellose Sodium 6.75
Croscarmellose Sodium 4.50
Microcrystalline cellulose 20.00

Talc 1.00
Magnesium stearate 2.30
Core tablet weight 230.00
Opadry ® II-Complete Film Coating System 7.00
Coated tablet weight 237.00
The manufacturing process consists of following steps:
Saxagliptin hydrochloride dihydrate, microcrystalline cellulose, croscarmellose sodium and lactose monohydrate were co sifted and mixed in blender for desired time. The dry mix was passed through roller compactor to get flakes/ribbons. The flakes/ribbons were sifted through multimill with desired mesh. Sifting was followed by mixing and blending of granules with extragranular excipients such as pre-sifted microcrystalline cellulose, croscarmellose Sodium for required time. This blending was followed by lubrication with Mg-stearate for sufficient time. Lubricated granules were compressed on suitable punches.
Core tablets obtained by above process were coated with PVA based Opdry till desired weight gain was achieved.
EXAMPLE 5:

Ingredient Qty/Tab (in mg)
Saxagliptin 5.00
Lactose Monohydrate 110.58
Microcrystalline Cellulose 99.62
Croscarmellose Sodium 11.50
Talc 1.00
Magnesium stearate 2.30
Core tablet weight 230.00
Opadry ® II-Complete Film Coating System 7.00
Coated tablet weight 237.00
The manufacturing process consists of following steps:

Saxagliptin hydrochloride dihydrate, microcrystalline cellulose, croscarmellose sodium and lactose monohydrate were co sifted and blended in blender for desired time. The premix was prelubricated with talc in a blender for specified. This blending was followed by lubrication with Mg-stearate for sufficient time. Lubricated granules were compressed on suitable punches.
Core tablets obtained by above process were coated with PVA based Opadry till desired weight gain was achieved.
Claims:
1. A pharmaceutical composition comprising a core wherein saxagliptin, pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients are in intimate contact.
2. The core of 1, wherein saxagliptin hydrochloride and pharmaceutically acceptable excipients are in intimate contact.
3. The core of claim 2, wherein saxagliptin hydrochloride is produced in situ.
4. The pharmaceutical composition comprising a core, wherein saxagliptin hydrochloride and pharmaceutically acceptable excipients are in intimate contact, forms less than the 0.1% of cyclic amidine impurity, after 3 months exposure at 40°C/75% RH.
5. The pharmaceutical composition of claim 4, wherein cyclic amidine impurity is less than 0.05%, after 3 months exposure at 40°C/75% RH.
6. The pharmaceutical composition of claim 5, wherein cyclic amidine impurity is less than 0.02%, after 3 months exposure at 40°C/75% RH.
7. The pharmaceutical composition comprising a core wherein saxagliptin hydrochloride and pharmaceutically acceptable excipients are in intimate contact, forms cis cyclic amidine and trans cyclic amidine impurities less than 0.5% and 0.2% respectively after 3 months exposure 40°C/75% RH.
8. Pharmaceutical composition of claim 7, wherein cis cyclic amidine and trans cyclic amidine impurity is less than 0.3% and 0.1% respectively after 3 months exposure 40°C/75% RH.

9. Pharmaceutical composition of claim 7, wherein cis cyclic amidine and trans cyclic
amidine impurity are less than 0.2% and 0.0.05% respectively after 3 months exposure to
40°C/75% RH.
10. A method of preparation of pharmaceutical composition comprising saxagliptin or its
pharmaceutically acceptable salts thereof, wherein the saxagliptin is in an intimate contact
with the pharmaceutically acceptable excipients in the core.