WO2019234581A1

WO2019234581A1 - Pharmaceutical compositions of axitinib

Info

Publication number: WO2019234581A1
Application number: PCT/IB2019/054572
Authority: WO
Inventors: Arra Ganga Srinivas; Rajaram Patil; Arun DANGE; Onkar DESHMUKH; Rahul Dabre; Ulhas Dhuppad; Sushrut Kulkarni
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2018-06-04
Filing date: 2019-06-03
Publication date: 2019-12-12

Abstract

The present invention provides a stable pharmaceutical composition of axitinib or salt thereof. There is also provided process of preparation of such composition. In particular there is provided stable pharmaceutical composition comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients. Further, there is provided a stable pharmaceutical composition comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients and wherein the composition is free of crystalline form XLI.

Description

PHARMACEUTICAL COMPOSITIONS OF AXITINIB

RELATED APPLICATIONS

This application claims priority from the Indian provisional application No. 201821020792 filed on Jun 4, 2018, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to novel and stable pharmaceutical composition of axitinib or salt thereof. The invention further provides process of preparing such compositions.

BACKGROUND OF THE INVENTION

The compound, N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzami- de or 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]i- ndazole, of the following structure:

is known as Axitinib.

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3. These receptors are implicated in pathologic angiogenesis, tumor growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Clinical trials have shown the use of axitinib for the treatment of various cancers, including liver cancer, melanoma, mesothelioma, non-small cell lung cancer, prostate cancer, renal cell carcinoma, soft tissue sarcomas and solid tumors. Inlyta™ (axitinib) has been approved in the United States, Europe, Japan and other jurisdictions for the treatment of renal cell carcinoma.

Axitinib, as well as pharmaceutically acceptable salts thereof, is described in U.S. Pat. No. 6,534,524. Methods of making axitinib are described in U.S. Pat. Nos. 6,884,890 and 7,232,910, in U.S. Publication Nos. 2006/0091067 and 2007/0203196 and in International Publication No. WO 2006/048745. Dosage forms of axitinib are described in U.S. Publication No. 2004/0224988.

Axitinib is weak base, non-hygrospic, classified as Biopharmaceutics Classification System (BCS) class II (low solubility, high permeability), and exhibits polymorphism. Axitinib was approved by USFDA in 2012 and is marketed under the brand name Inlyta®, and is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior systemic treatment. Axitinib is a white to light yellow powder and a molecular weight of 386.47 Daltons. As per the EMEA scientific discussion of Axitinib and Campeta et al (U.S. Patent. Nos. 8,791,140) there are disclosed several polymorphic forms of Axitinib like crystalline Form XXV, Form IX, Form XII, Form XV and amorphous form of Axitinib. A number of crystalline solvates and hydrate forms have been observed and an amorphous form has been prepared.

Ye et al in U.S. Pub. No. 2006/0094763 disclosed different crystalline forms like crystalline Form I, Form II, Form III, Form IV, Form VI, Form VII and Form VIII of Axitinib. Polymorphic Form IV is physically and chemically stable and is believed to be the thermodynamically most stable form of axitinib.

Polymorphism has been given importance owing to its relevance due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles. A stable polymorphic form of a drug remains a clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability. Considering several complexities in the drug substance, there is a need to prepare a stable pharmaceutical composition of axitinib or salt thereof. The present invention provides such compositions and process of preparation of such compositions.

SUMMARY OF THE INVENTION

In one embodiment of the invention, there is provided a stable pharmaceutical composition of axitinib or salt thereof. The embodiment also provides process of preparation of such composition.

In another embodiment of the invention, there is provided stable pharmaceutical composition comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients.

In another embodiment of the invention, the calcium phosphate is monobasic or dibasic. In another embodiment of the invention, axitinib is present as axitinib hydrochloride. In another embodiment of the invention, axitinib or salt thereof is present in crystalline form. In another embodiment of the invention, the crystalline form of axitinib or salt thereof is form IV. In another embodiment of the invention, the composition is free of any other crystalline forms. In yet another embodiment of the invention, the composition is free of crystalline form XLI of axitinib or salt thereof. In another embodiment of the invention, the composition of axitinib or salt thereof is free amorphous form of axitinib or salt thereof.

In another embodiment of the invention, axitinib or salt thereof is present from about 0.5mg to about 50mg, or about 1 mg or about 5mg. In another embodiment of the invention, the calcium phosphate is present in about 1 mg to 50 mg, or about 5 mg to 30 mg, or about 11 mg or 23 mg.

In still another embodiment of the invention, there is provided stable pharmaceutical composition comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients, and wherein the weight ratio of axitinib or salt thereof and calcium phosphate is from about 1: 1 to about 1:30 or about 1:5 or about 1: 11. In further embodiments of the invention, the pharmaceutical acceptable excipients comprises suitable pharmaceutical carriers and one or more coating agents. In one embodiment, the coating agents are devoid of metal oxide such iron oxide and the like.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising: (a) a core comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients and (b) coating substantially covering the core comprising pharmaceutical acceptable excipients, and wherein the coating is devoid of metal oxide such iron oxide and the like.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients, wherein the weight ratio of axitinib or salt thereof to calcium phosphate is from about 1 : 1 to about 1:30.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising a core and coating, wherein the core comprises: (a) lmg of axitinib or salt thereof; (b) about 85mg of lactose; (c) about 1 lmg of calcium phosphate; (d) about 0.5mg of colloidal silicon dioxide; (e) about lmg of magnesium stearate, and the coating comprises hydroxypropylmethylcellulose, lactose and calcium carbonate; and wherein the coating is devoid of metal oxide.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising a core and coating, wherein the core comprises: (a) 5mg of axitinib or salt thereof; (b) about 168 mg of lactose; (c) about 23mg of calcium phosphate; (d) about lmg of colloidal silicon dioxide; (e) about 2mg of magnesium stearate, and the coating comprises hydroxypropylmethylcellulose, lactose and calcium carbonate; and wherein the coating is devoid of metal oxide.

In general embodiment of the invention, there is provided process of preparing such compositions. DETAILED DESCRIPTION OF THE INVENTION

The term“free” in the present invention means that complete absence of any crystalline form other than form IV.

The term "therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

The term“salt” in the present invention relates to a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, para-toluene sulfonates (tosylates), formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, .gamma. -hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates.

In another embodiment of the invention, axitinib is present as axitinib hydrochloride. Moreover, a person skilled in art can include any other salt of axitinib in the present invention to obtain such stable composition.

In another embodiment of the invention, axitinib or salt thereof is present in crystalline form, wherein the crystalline form of axitinib or salt thereof is form IV. In another embodiment of the invention, the composition is free of any other crystalline form of axitinib or salt thereof. In yet another embodiment of the invention, the composition is free of crystalline form XLI of axitinib or salt thereof. In preferred embodiment, the composition contains form IV of axitinib hydrochloride which completely free of any other crystalline or amorphous form.

In another embodiment of the invention, axitinib or salt thereof is present from about 0.5mg to about 50mg, or about 5mg to about 25mg, or about lOmg to about 20mg. Alternatively, the composition contains axitinib or salt thereof in about 1 mg or about 5mg. In one embodiment, the axitinib or salt thereof is present in micronized form and the particle size (d90) ranges from about ImM to about IOOmM or about 5mM to about 90 pMm or about 10 mM to about 80 mM, or about 20 mM to about 60 mM, or about 30 mM to about 50 mM.

In another embodiment of the invention, the calcium phosphate is monobasic or dibasic. In another preferred embodiment, the calcium phosphate is dibasic calcium phosphate. In another embodiment of the invention, the calcium phosphate is present in about 1 mg to 50 mg, or about 5 mg to 30 mg. In another embodiment, the calcium phosphate is present in about 5 to 40mg, or about lOmg to 35mg, or about l5mg to 25mg. In another embodiment, alternatively the calcium phosphate is present in about 11 mg or 23 mg.

The composition of the present invention can be formulated as pharmaceutical compositions suitable for mammalian medical use. Any suitable route of administration may be employed for providing a patient with an effective dosage axitinib or salt thereof. For example, peroral or parenteral formulations and the like may be employed. Dosage forms include capsules, tablets, dispersions, suspensions and the like, e.g. enteric-coated capsules and/or tablets, capsules and/or tablets containing enteric-coated pellets of axitinib or salt thereof. The invention may be formulated in compositions including those suitable for oral, rectal, topical, nasal, ophthalmic, or parenteral (including intraperitoneal, intravenous, subcutaneous, or intramuscular injection) administration. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the pharmaceutical arts.

The pharmaceutical composition of the present invention includes a core and a coating. The core includes axitinib or salt thereof and excipients. The pharmaceutically acceptable core excipients may include fillers, diluents, disintegrants and lubricants.

Suitable fillers or diluents are known in the art. Suitable fillers include ductile fillers and brittle fillers. For example, suitable fillers include, but are not limited to, lactose (monohydrate, spray- dried monohydrate, anhydrous and the like), lactilol, starch, dextrin, glucose, silicic acid, sucrose, sorbitol, sodium saccharin, acesulfame potassium, xylitol, aspartame, mannitol, polyvinyl pyrrolidone, low molecular weight hydroxypropyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight carboxymethyl cellulose, ethylcellulose, a suitable inorganic calcium salt such as dicalcium phosphate, alginates, gelatin, polyethylene oxide, acacia, magnesium aluminum silicate, and polymethacrylates, or a combination thereof. In one embodiment, fillers include agents selected from the group consisting of microcrystalline cellulose and lactose monohydrate, or a combination thereof. In one embodiment, the filler concentration ranges from 50% to about 90%, or about 60% to about 85%, or preferably about 70% to about 80% of the weight of the composition.

Suitable disintegrants are also known in the art. Suitable disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate, or a combination thereof. In one disntegrants concentration ranges from about 0.5% to about 30%, or about 1% to about 20%, or about 5% to about 15% of the weight of the composition.

Suitable lubricants are also known in the art. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate, or combinations thereof. In one embodiment, the lubricant includes magnesium stearate. In one embodiments, the concentration of lubricants ranges from about 05% to about 20%, or 1% to about 15%, or about 5% to about 10% of the weight of the composition.

A suitable coating or coating excipient of the present invention does not include metal oxide such iron oxide. The coating comprises of polymers, plasticizers, diluents or fillers, and colorants. Suitable polymers are known in the art. Suitable polymers include, but are not limited to, cellulosics such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methylcellulose, and sodium carboxymethylcellulose. Further examples of polymers include vinyls such as polyvinyl pyrrolidone. In an embodiment, the polymer is hydroxypropyl methylcellulose. Suitable plasticizers are known in the art. Suitable plasticizers include, but are not limited to, polyhydric alcohols such as glycerol and polyethylene glycols and acetate esters such as glycerol triacetate or glyceryl triacetate, which are known as triacetin, and triethyl citrate. In an embodiment, the coating of the present invention is an aqueous coating. The coating or aqueous coating of the present invention comprises a polymer, a plasticizer, a pharmaceutically acceptable diluent or filler and optionally a colorant and wherein the aqueous coating is devoid of metal oxide. In one embodiment, the coating concentration ranges from about 1% to about 20%, or about 2% or about 15%, or about 3% to about 10% of the weight of the composition.

The compositions of the present invention may include a colorant or a glidant. Such colorants are available from a number of commercial vendors and are well known to those skilled in the art. Suitable glidants are known in the art. Suitable glidants include, but are not limited to, silicon dioxide, talc and cornstarch. In still another embodiment of the invention, there is provided stable pharmaceutical composition comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients, and wherein the weight ratio of axitinib or salt thereof and calcium phosphate is from about 1 : 1 to about 1 :30 or about 1:5 or about 1: 11 , and wherein the axitinib or salt thereof is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib or salt thereof.

In still another embodiment of the invention, there is provided stable pharmaceutical composition comprising a therapeutically effective amount of axitinib hydrochloride, calcium phosphate and pharmaceutical acceptable excipients, and wherein the weight ratio of axitinib or salt thereof and calcium phosphate is from about 1 : 1 to about 1:30 or about 1:5 or about 1: 11, and wherein the axitinib hydrochloride is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib hydrochloride.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising: (a) a core comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients, and (b) coating substantially covering the core comprising pharmaceutical acceptable excipients, and wherein the coating is devoid of metal oxide such iron oxide and the like, and wherein the axitinib or salt thereof is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib or salt thereof.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising: (a) a core comprising about lmg or about 5mg of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients and (b) coating substantially covering the core comprising pharmaceutical acceptable excipients, and wherein the coating is devoid of metal oxide such iron oxide and the like, and wherein the axitinib or salt thereof is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib or salt thereof. In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising: (a) a core comprising about lmg or about 5mg of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients, and (b) coating substantially covering the core comprising pharmaceutical acceptable excipients, and wherein the coating is devoid of metal oxide such iron oxide and the like, and wherein the weight ratio of axitinib or salt thereof to calcium phosphate is from about 1: 1 to about 1:30, and wherein the axitinib or salt thereof is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib or salt thereof.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising a therapeutically effective amount of axitinib or salt thereof, calcium phosphate and pharmaceutical acceptable excipients, wherein the weight ratio of axitinib or salt thereof to calcium phosphate is from about 1 : 1 to about 1:30, and wherein the axitinib or salt thereof is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib or salt thereof.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising a core and coating, wherein the core comprises: (a) lmg of axitinib or salt thereof; (b) about 85mg of lactose; (c) about 1 lmg of calcium phosphate; (d) about 0.5mg of colloidal silicon dioxide; (e) about lmg of magnesium stearate, and the coating comprises hydroxypropylmethylcellulose, lactose and calcium carbonate; and wherein the coating is devoid of metal oxide, and wherein the axitinib or salt thereof is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib or salt thereof.

In further embodiment of the invention, there is provided a stable pharmaceutical composition comprising a core and coating wherein the core comprises: (a) 5mg of axitinib or pharmaceutically acceptable salt thereof; (b) about 168 mg of lactose; (c) about 23mg of calcium phosphate; (d) about lmg of colloidal silicon dioxide; (e) about 2mg of magnesium stearate, and the coating comprises hydroxypropylmethylcellulose, lactose and calcium carbonate; and wherein the coating is devoid of metal oxide, and wherein the axitinib or salt thereof is present in crystalline form IV, and wherein the composition is free of any other crystalline form or amorphous form axitinib or salt thereof.

The pharmaceutical composition of the present invention provides protection of axitinib or salt thereof from degradation, including photodegradation and oxidative degradation. In an embodiment, the pharmaceutical composition of the present invention provides protection of axitinib from photodegradation, and wherein the composition comprises coating devoid of metal oxide.

The pharmaceutical composition of the present invention provides protection of axitinib or salt thereof from degradation throughout prolonged storage. Prolonged storage may be at least 9 months, at least 12 months, at least 24 months or at least 36 months. In an embodiment, prolonged storage may be at least 36 months.

One embodiment of the invention relates to methods of treating abnormal cell growth in a subject comprising administering to the subject an amount of a pharmaceutical composition according to the present invention. In an embodiment, the abnormal cell growth is cancer. In another embodiment, the cancer is liver cancer, melanoma, mesothelioma, non-small cell lung cancer, prostate cancer, renal cell carcinoma, soft tissue sarcomas and solid tumors.

In general embodiment of the invention, there is provided process of preparing such compositions. The compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.

While this invention has been described in terms its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. EXAMPLES

EXAMPLE 1: Tablet compositions

Below is the formula for preparing the tablet composition as per the invention.

The specific examples with detailed procedure is given in example 2 and 3.

EXAMPLE 2: Tablet composition of Axitinib lmg and 5mg using base granulation approach.

The Axitinib tablet of lmg and 5mg has been prepared according to below formula and process.

Manufacturing process:

• All required ingredients were weighed as per formula.

• Weighed quantity of anhydrous lactose (SupeTab 21AN) and anhydrous dibasic calcium phosphate (Fujicalin SG) were sifted through ASTM # 40.

• Dry Mixing: Sifted mass of above step was transferred into rapid mixer granulator and dry mixed for 10 minutes with slow impeller speed.

• Purified Water Addition: Weighed quantity of purified water was added into above step in not more than 1 min at slow speed of impeller and at chopper off position.

• Kneading: After binder addition kneading was done for 30 seconds with impeller at slow speed and chopper off. Continue kneading was done for additional 30 seconds with impeller and chopper at slow speed.

• Drying: Drying was carried out in a fluid bed dryer cum processor at an inlet temperature of 40°C- 60°C, with 20 to 90 % Airflow until the LOD - NMT 2.0 % w/w was achieved.

• Sizing: Dried granules were milled using co-mill with 0.45 mm screen. Milled granules were passed through 60# and then passed and retained portions were collected separately.

• Blending: A) Weighed quantity of axitinib and dried granules of 60# passed portion (1: 1) were mixed and co-sift through 40#. B) Mixed and co-sift drug-granules mixture of step A and 60# passed portion (1: 1) through 40# sieve. C) Mixed and co-sift drug-granules mixture of step B and 60# passed portion (1 : 1) through 40# sieve. D) Mixed and co-sift drug-granules mixture of step C and remaining 60# passed portion and 60# retained portion through 40#. E) Transferred blend of above step D in blender and mixed it for 10 minutes at 10+1 RPM and then mixed blend was passed through 40#. F) Mixed above step E in blender and mixed it for 10 minutes at 10±1 RPM.

• Lubrication: Weighed quantity of colloidal silicon dioxide and magnesium stearate were passed through 40# and 60# respectively, then mixed it with step F for 5 minutes at 10±1 RPM.

• Compression: Compression was done using lubricated blend of above step with suitable tooling’s. Film Coating: Coating was done with above compressed tablets using Opadry II Red and purified water.

EXAMPLE 3: Stability studies of tablet composition of example 2.

Following are the results of stability studies obtained from tablet made as per example 2.

• For 1 mg: HDPE 40 CC HW container contains 180 tablets with 1 gm silica desiccant

• For 5 mg: HDPE 40 CC HW container contains 60 tablets with 1 gm silica desiccant EXAMPLE 4: Tablet composition of Axitinib lmg and 5 mg using wet granulation approach. The Axitinib tablet of lmg and 5mg has been prepared according to below formula and process.

Manufacturing process:

• All required ingredients were weighed as per formula.

• Weighed quantity of axitinib, anhydrous lactose (SupeTab 21AN), anhydrous dibasic calcium phosphate (Fujicalin SG) and colloidal sillicon dioxide were sifted through ASTM # 40.

• Water Addition: Weighed quantity of purified water was added into above step in not more than 1 min at slow speed of impeller and at chopper off position. • Kneading: After binder addition kneading was done for 30 seconds with impeller at slow speed and chopper off.

Continue kneading was done for additional 30 seconds with impeller and chopper at slow speed.

• Sizing: Dried granules were passed through 30# and retained amount of granules were milled using co-mill with 0.8 mm screen and added to 30# passed portion.

• Blending: Weighed quantity of colloidal silicon dioxide and microcrystalline cellulose were passed through 40# and mixed with above step in blender for 10 minutes at 10±1 RPM

• Lubrication: Weighed quantity of Magnesium Stearate was passed through 60# and mixed with above step for 5 minutes at 10±1 RPM.

• Compression: Compression was done using lubricated blend of above step with suitable tooling’s.

• Film Coating: Coating was done with above compressed tablets using Opadry II Red and purified water.

EXAMPLE 5: Stability studies of tablet composition of example 4.

Following are the results of stability studies obtained from tablet made as per example 4.

• For 5 mg: HDPE 40 CC HW container contains 60 tablets with 1 gm silica desiccant

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS WE CLAIM:

1. A stable pharmaceutical composition comprising a therapeutically effective amount of Axitinib or pharmaceutically acceptable salt thereof, calcium phosphate and pharmaceutical acceptable excipients.

2. The pharmaceutical composition of claim 1 , wherein the calcium phosphate is monobasic or dibasic.

3. The pharmaceutical composition of claim 1, wherein the Axitinib is present in crystalline form.

4. The pharmaceutical composition of claim 1 , wherein the Axitinib is present in amorphous form.

5. The pharmaceutical composition of claim 1, wherein the composition is free of crystalline form XLI.

6. The pharmaceutical composition of claim 1, wherein the Axitinib is present from about 0.5mg to about 50mg.

7. The pharmaceutical composition of claim 1, wherein the Axitinib is present from about 0.5mg to about lOmg.

8. The pharmaceutical composition of claim 1, wherein the Axitinib is present in about 1 mg or about 5mg.

9. The pharmaceutical composition of claim 1 , wherein the calcium phosphate is present from about 1 mg to 50 mg.

10. The pharmaceutical composition of claim 1, wherein the calcium phosphate is present from about 5 mg to 30 mg.

11. The pharmaceutical composition of claim 1 , wherein the calcium phosphate is present from about 11 mg or 23 mg.

12. The pharmaceutical composition of claim 1, wherein a weight ratio of Axitinib to calcium phosphate is from about 1 : 1 to about 1:30.

13. The pharmaceutical composition of claim 1, wherein a weight ratio of Axitinib to calcium phosphate is from about 1 :5 or about 1: 11.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical acceptable excipients comprises diluents, lubricants, glidants and one or more coating agents.

15. The pharmaceutical composition of claim 14, wherein the coating agents are devoid of metal oxide such iron oxide and the like.

16. A stable pharmaceutical composition comprising: (a) a core comprising a therapeutically effective amount of Axitinib or pharmaceutically acceptable salt thereof, calcium phosphate and pharmaceutical acceptable excipients and (b) coating substantially covering the core comprises pharmaceutical acceptable excipients, and wherein the coating is devoid of metal oxide such iron oxide and the like.

17. A stable pharmaceutical composition comprising a therapeutically effective amount of Axitinib or pharmaceutically acceptable salt thereof, calcium phosphate and pharmaceutical acceptable excipients, wherein the weight ratio of Axitinib to calcium phosphate is from about 1 : 1 to about 1:30.

18. A stable pharmaceutical composition comprising a core and coating, wherein the core comprises: (a) lmg of Axitinib or pharmaceutically acceptable salt thereof; (b) about 85mg of lactose; (c) about l lmg of calcium phosphate; (d) about 0.5mg of colloidal silicon dioxide; (e) about lmg of magnesium stearate, and the coating comprises hydroxypropylmethylcellulose, lactose and calcium carbonate; and wherein the coating is devoid of metal oxide.

19. A stable pharmaceutical composition comprising a core and coating wherein the core comprises: (a) 5mg of Axitinib or pharmaceutically acceptable salt thereof; (b) about 168 mg of lactose; (c) about 23mg of calcium phosphate; (d) about lmg of colloidal silicon dioxide; (e) about 2mg of magnesium stearate, and the coating comprises hydroxypropylmethylcellulose, lactose and calcium carbonate; and wherein the coating is devoid of metal oxide.