DESC:TECHNICAL FIELD OF THE INVENTION
The field of the invention relates to a solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in an amorphous form, an intercalating agent and a pharmaceutically acceptable excipient.

BACKGROUND OF THE INVENTION
Activated Factor Xa, whose major useful role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (Factor Xa, Factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of Factor Xa can generate 138 molecules of thrombin inhibition, Factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system. Accordingly, Factor Xa inhibitors are a class of compounds that are efficacious for the treatment of thromboembolic disorders.

Apixaban is an anticoagulant for the treatment of venous thromboembolic events. It was approved in the United States for reduction of risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; prophylaxis of deep vein thrombosis (“DVT”), which may lead to pulmonary embolism (“PE”), in patients who have undergone hip or knee replacement surgery; and treatment of DVT and PE, and for the reduction in the risk of recurrence of DVT and PE following initial therapy. Apixaban is chemically described as 1-(4­methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4­c]pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a molecular weight of 459.5 g/mol.

U.S. Patent No. 6,967,208 B2 discloses apixaban as a Factor Xa inhibitor.

U.S. Patent Nos. 7,005,435 B2, 6,989,391 B2, 6,995,172 B2, 7,338,963 B2, 7,371,761 B2, 7,531,535 B2, 7,691,846 B2 and 7,960,411 B2 disclose different analogues of apixaban.

U.S. Patent No. 9,326,945 B2 discloses apixaban formulations.

U.S. Patent No. 9,045,473 B2 discloses amorphous forms of apixaban.

U.S. Publication No. 20150018386 A1 discloses amorphous form of apixaban, process of preparation and compositions thereof.

U.S. Publication No. 20130064888 A1 discloses a pharmaceutical tablet dosage form of apixaban.

International (PCT) Publication No. WO2015121472 discloses pharmaceutical composition comprising apixaban and a low viscosity polymer.

International (PCT) Publication No. WO2010147978 discloses solubility-improved form of apixaban.

The prior art teaches various dosage forms and process for preparation of apixaban composition, but still there exists a need in the art for alternate ways to formulate composition of apixaban especially immediate release pharmaceutical composition having improved characteristics such as good chemical stability, excellent dissolution properties and bioavailability.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in an amorphous form, an intercalating agent and pharmaceutically acceptable excipients.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban, an intercalating agent and pharmaceutically acceptable excipients, wherein the amorphous apixaban is formed in situ during the preparation of the pharmaceutical composition.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban, wherein the composition is devoid of crystalline apixaban.

In another general aspect, there is provided a pharmaceutical composition comprising apixaban in an amorphous form, an intercalating agent and pharmaceutically acceptable excipients, wherein the weight ratio of apixaban to intercalating agent ranges from about 1: 0.05 to about 1: 1.5.

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising apixaban in an amorphous form, an intercalating agent and pharmaceutically acceptable excipients, wherein the weight ratio of apixaban to intercalating agent ranges from about 1: 0.2 to about 1: 0.8.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban, wherein apixaban is present in an amount ranges from about 0.8 % w/w to about 8 % w/w of the composition.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban and an intercalating agent, wherein the weight ratio of apixaban to intercalating agent ranges from about 1: 0.8 to about 1: 1.2.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban and an intercalating agent, wherein the intercalating agent is present in an amount ranges from about 0.8 % w/w to about 4 % w/w of the composition.

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in an amorphous form, an intercalating agent and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in an amorphous form, an intercalating agent and a pharmaceutically acceptable excipient, wherein the weight ratio of apixaban to intercalating agent ranges from about 1: 0.05 to about 1: 1.5 and wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another general aspect, there is provided a solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in an amorphous form, an intercalating agent and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients selected from the group of fillers, diluents, disintegrants, superdisintegrants, sorbents, antiadherents, lubricants, glidants, preservatives, flavoring agents, colouring agent, solvents, vehicles or combination thereof.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban and an intercalating agent, wherein the composition is devoid of crystalline apixaban.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban, wherein the composition provides immediate release of amorphous apixaban.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban, wherein the composition is present in the form of powder, tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablets or premixed powder filled in capsule.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban, wherein the composition is in tablet dosage form.

In another general aspect, there is provided a pharmaceutical composition comprising amorphous apixaban, wherein the composition provides storage stability when stored at temperature 40°C and 75% relative humidity for at least 6 months.

In another general aspect, there is provided a process for preparing a solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in amorphous form, an intercalating agent and a pharmaceutically acceptable excipients, said process comprising steps of:
(a). dissolving crystalline apixaban in organic solvent to prepare a solution,
(b). adding an intercalating agent to the solution of step (a) to prepare a granulating fluid,
(c). adding pharmaceutically acceptable excipients in a granulating fluid obtained in step (b) to obtain a granulated mass,
(d). drying the granulated mass of step (c) to obtain granules containing amorphous apixaban,
(e). compressing the granules obtained in step (d) to prepare a tablet, and
(f). optionally, coating the tablet obtained in step (e) with a film forming polymer, wherein the pharmaceutical composition is devoid of crystalline apixaban.

DETAILED DESCRIPTION OF THE INVENTION

Without binding to any particular theory, inventors of the invention state that the term “intercalating agent” is used herein referes to specify the agent whose molecules get inserted between the molecules of other compound(s) with layered structures.

The term “immediate release” is used herein referes to the pharmacologically active ingredient or agent that is released from the dosage form immediately such that not less than 80% of the pharmaceutically active agent in the formulation is released within 45 minutes when dissolution is measured according to the USP 31 NF 26 section 711.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable materials or vehicles that are suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

In an embodiment, the solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in amorphous form, an intercalating agent and a pharmaceutically acceptable excipient.

In another embodiment, the solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in amorphous form, an intercalating agent and a pharmaceutically acceptable excipient, wherein the weight ratio of apixaban to intercalating agent ranges from about 1: 0.2 to about 1: 0.8.

In another embodiment, the solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in amorphous form, an intercalating agent and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutically acceptable excipients selected from the group of fillers, diluents, disintegrants, superdisintegrants, sorbents, antiadherents, lubricants, glidants, preservatives, flavoring agents, colouring agent, solvents, vehicles or combination thereof.

In another embodiment, the pharmaceutical composition comprising amorphous apixaban and an intercalating agent, wherein the composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition comprising amorphous apixaban, wherein the composition provides immediate release of amorphous apixaban.

In another embodiment, the pharmaceutical composition comprising amorphous apixaban, wherein the composition provides storage stability when stored at temperature 40°C and 75% relative humidity for at least 6 months.

In another embodiment, the process for preparing a solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of apixaban in amorphous form, an intercalating agent and pharmaceutically acceptable excipients, said process comprising steps of:
(a). dissolving crystalline apixaban in organic solvent to prepare a solution,
(b). adding intercalating agent to the solution of step (a) to obtain a granulating fluid,
(c). granulating pharmaceutically acceptable excipients with the a granulating fluid obtained in step (b) to obtain a granulated mass,
(d). drying the granulated mass of step (c) to obtain granules containing amorphous apixaban,
(e). compressing the granules obtained in step (d) to prepare a tablet, and
(f). optionally, coating the tablet obtained in step (e) with a film forming polymer, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition comprising: (a) about 2.5% by weight of amorphous apixaban; (b) about 1% to 2% by weight of a lubricant; (c) about 1% to 2% by weight of a intercalating agent; (d) about 60 % to 90% by weight of a diluent; (e) about 4 % to 6% by weight of a disintegrant, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition comprising: (a) amorphous apixaban present in a unit dosage strength of 1 to 5 milligrams; (b) about 0.5 % to 1.5 % by weight of a lubricant; (c) about 1.2 % by weight of a intercalating agent; (d) about 85 % by weight of a diluent; and (e) about 4.5 % by weight of a disintegrant, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, diluent is either microcrystalline cellulose or lactose monohydrate, lactose anhydrous or in combination thereof. In another embodiment, disintegrant is croscarmellose sodium.

In another embodiment, amorphous apixaban is present in unit dosage strength of 2.5 and 5 milligrams.

In another embodiment, the compressed dosage form may be tablets, tablet in capsule, pellets or granules, pellets filled in capsules, bilayer tablets and minitablet.

In another embodiment, the composition is present in the form of powder, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet and premixed powder filled in capsule.

In another embodiment, the pharmaceutical composition is in the tablet dosage form.

In another embodiment, the tablet further coated with suitable coating material to get desired moisture protection.

In another embodiment, the pharmaceutical composition further comprising one or more agents selected from the group comprising of flavoring agents, colorants, and sweeteners.

In another embodiment, the intercalating agent is selected from the group of povidone, hydroxypropylmethylcellulose, hydroxy propyl cellulose and vinylpyrrolidone-vinyl acetate copolymers.

In another embodiment, the ratio of apixaban to intercalating agent is preferably is in the ranges from about 1: 0.05 to about 1: 1.5, about 1: 0.2 to about 1: 0.8, most preferably about 1: 0.5.

In another embodiment, the intercalating agent is povidone. In another embodiment, the intercalating agent is hydroxypropylmethylcellulose. In another embodiment, the intercalating agent is hydroxy propyl cellulose. In another embodiment, the intercalating agent is vinylpyrrolidone-vinyl acetate copolymers.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 2.5 mg of amorphous apixaban; b) 2.5 mg of hydroxypropylmethylcellulose; c) 49.93 mg of lactose anhydrous; d) 39.07 mg of microcrystalline cellulose; e) 5 mg of croscarmellose sodium; f) 1 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 5 mg of amorphous apixaban; b) 5 mg of hydroxypropylmethylcellulose; c) 99.86 mg of lactose anhydrous; d) 78.14 mg of microcrystalline cellulose; e) 10 mg of croscarmellose sodium; f) 2 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 2.5 mg of amorphous apixaban; b) 1.25 mg of polyvinylpyrrolidone; c) 51.18 mg of lactose monohydrate; d) 39.07 mg of microcrystalline cellulose; e) 5 mg of croscarmellose sodium; f) 1 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 2.5 mg of amorphous apixaban; b) 1.25 mg of hydroxy propyl methyl cellulose; c) 51.18 mg of lactose monohydrate; d) 39.07 mg of microcrystalline cellulose; e) 5 mg of croscarmellose sodium; f) 1 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 2.5 mg of amorphous apixaban; b) 1.25 mg of hydroxypropylcellulose; c) 51.18 mg of lactose monohydrate; d) 39.07 mg of microcrystalline cellulose; e) 5 mg of croscarmellose sodium; f) 1 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 5 mg of amorphous apixaban; b) 2.50 mg of polyvinylpyrrolidone; c) 102.36 mg of lactose monohydrate; d) 78.14 mg of microcrystalline cellulose; e) 10 mg of croscarmellose sodium; f) 2 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 5 mg of amorphous apixaban; b) 2.50 mg of hydroxypropylcellulose; c) 102.36 mg of lactose monohydrate; d) 78.14 mg of microcrystalline cellulose; e) 10 mg of croscarmellose sodium; f) 2 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 5 mg of amorphous apixaban; b) 2.50 mg of hydroxy propyl methyl cellulose; c) 102.36 mg of lactose monohydrate; d) 78.14 mg of microcrystalline cellulose; e) 10 mg of croscarmellose sodium; f) 2 mg of magnesium stearate; and g) a film coating, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the film coating is about 3 mg of total weight of the composition.

In another embodiment, the film coating is about 6 mg of total weight of the composition

In another embodiment, the pharmaceutical composition is prepared by direct compression, dry granulation method or wet granulation methods.

In another embodiment, the pharmaceutical composition comprising amorphous apixaban, wherein amount of apixaban is about 0.5 % w/w to about 10% w/w of the composition.

In another embodiment, the filler or diluent is present in amount ranges from about 5.0 % w/w to about 95 % w/w of the composition.

In another embodiment, the intercalating agent is present in amount ranges from about 1.0 % w/w to about 4 % w/w of the composition.

In another embodiment, the glidant is present in amount ranges from about 0.25 % w/w to about 2 % w/w of the composition.

In another embodiment, lubricant is present in amount ranges from about 0.5 % w/w to about 1.5 % w/w of the composition.

In another embodiment, the coating material is present in amount ranges from about 2.0 % w/w to about 5.0 % w/w of the composition.

In another embodiment, the composition provides immediate release of amorphous apixaban.

In another embodiment, the coating material comprises one or more coating agents selected from lactose monohydrate, triacetin, hydroxylpropyl methylcellulose, titanium dioxide or mixture thereof (Opadry).

In another embodiment, the pharmaceutical composition exhibits dissolution properties such that more than 80%, preferably more than 85%, more preferably more than 90% of apixaban is dissolved in 30 minutes in 900 ml of 0.1 M HCI solution.

In another embodiment, the stable pharmaceutical composition comprising apixaban, wherein the composition retains at least 90% of the potency of apixaban when stored at temperature 40°C and 75% relative humidity for a period of at least 6 months.

In another embodiment, the stable pharmaceutical composition comprising apixaban in amorphous form, an intercalating agent and pharmaceutical acceptable excipients, wherein the composition comprises less than 1% w/w of total impurity.

In another embodiment, the stable pharmaceutical composition comprising apixaban in amorphous form, an intercalating agent and pharmaceutical acceptable excipients, wherein the composition comprises less than 0.5% of total impurity.

In another embodiment, the stable pharmaceutical composition comprising apixaban in amorphous form, an intercalating agent and pharmaceutical acceptable excipients, wherein the composition comprises less than 0.1% w/w of total unknown impurity.

In another embodiment, the stable pharmaceutical composition comprising apixaban in amorphous form, an intercalating agent and pharmaceutical acceptable excipients, wherein the composition comprises less than 0.05% of total unknown impurity.

In another embodiment, the pharmaceutical composition is in the form of a tablet comprising: a) 2.5 mg of amorphous apixaban; b) 1.25 mg to 5 mg of intercalating agent; c) one or more pharmaceutically acceptable excipients and d) a film coating wherein said pharmaceutical composition is prepared by the process comprising the steps of:
(a). dissolving crystalline apixaban in organic solvent to prepare a solution,
(b). adding intercalating agent to the solution of step (a) to prepare a granulating fluid,
(c). granulating the pharmaceutically acceptable excipients with a granulating fluid obtained in step (b) to prepare a granulated mass,
(d). drying the granulated mass of step (c) to obtain granules containing amorphous apixaban,
(e). compressing the granules obtained in step (d) to prepare a tablet, and
(f). optionally, coating the tablet obtained in step (e) with a film forming polymer, wherein the pharmaceutical composition is devoid of crystalline apixaban.

In another embodiment, the conversion of crystalline apixaban form in to amorphous form in the composition is effected in presence of different intercalating agents in the granulation process. The different intercalating agent comprises different polymers.

In another embodiment, the crystalline apixaban along with an intercalating agent is dissolved in polar solvents like methanol, isopropyl alcohol, dichloromethane. This solution then granulated/adsorbed on the dry mix resulting in the conversion of crystalline form in to amorphous form in the pharmaceutical composition.

In another embodiment, the conversion of crystalline form to amorphous form is performed by using different manufacturing methods like Top spray adsorption, Rapid mixer granulation and solvent evaporation by using spray drying technique.

In another embodiment, the apixaban used as starting material for the preparation of the pharmaceutical composition is in crystalline form and having particle size with D90 more than 90 µm.

In another embodiment, the apixaban used as starting material for the preparation of the pharmaceutical composition is in crystalline form and having particle size with D90 more than 200 µm.

In another embodiment, the apixaban used as starting material for the preparation of the pharmaceutical composition is in crystalline form and having particle size with D90 is in the range of about 110 µm to about 400 µm.

Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to fillers, diluents, disintegrants, lubricants, glidants, solubility or wetting enhancers, complex forming agents, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, surfactant, antioxidants, and the like. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Examples of the intercalating agent suitable for use in the composition can be selected but are not limited to polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, Vinylpyrrolidone-vinyl acetate copolymers or mixtures thereof. A preferred intercalating agent selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose.

Examples of the fillers or diluents suitable for use in the composition of the invention can be selected but are not limited to starches, such as potato starch, rice starch, maize starch, wheat starch, pregelatinized starch, fully pregelatinized starch, cellulose, such as powdered celluloses, microcrystalline cellulose, or silicified microcrystalline cellulose, mannitol, erythritol, calcium salts, such as calcium hydrogen phosphate dihydrate, anhydrous dibasic calcium phosphate, xylitol, sorbitol, lactose monohydrate, or mixtures thereof. A preferred diluent is microcrystalline cellulose. Microcrystalline cellulose is available from several suppliers and includes Avicel PH 101, Avicel PH 102, Avicel, PH 103, Avicel PH 105, and Avicel PH 200, manufactured by the FMC Corporation

Examples of the disintegrants suitable for use in the composition of the invention can be selected but are not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, maize starch, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch or mixtures thereof. A prefered disintegrant is croscarmellose sodium. Croscarmellose sodium NF Type A is commercially available under the trade name "Ac-di-sol."

Examples of the surfactant selected from the group consisting of sodium stearate, polyoxyethylene stearates, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, poloxamers, polyoxyethylene castor oil derivatives, phospholipids, polysorbate and a mixture thereof. Preferably, surfactant is selected from sodium dodecanesulfonate, sodium oleyl sulfate, polysorbate and sodium laurate mixed with stearates and talc.

Examples of the lubricant/glidant suitable for use in the composition of the invention can be selected but are not limited to stearic acid, talc, siliconised talc, colloidal silicone dioxide, micronised talc, sodium stearyl fumarate, magnesium stearate, zinc stearate or mixtures thereof. Preferable lubricant/glidant is magnesium stearate.

Examples of the plastisizers suitable for use in the composition of the invention can be selected but are not limited to triacetin, diethyl phthalate, dibutyl sebacate, tributyl sebacate and polyethylene glycol, and mixtures thereof.

An anti-oxidant may optionally be added to the formulation to impart chemical stability. The anti-oxidant is selected from the group consisting of a-tocopherol, y-tocopherol, 1\-tocopherol, extracts of natural origin rich in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA). In one embodiment, the antioxidant is BHT or BHA.

Solvent is a substance that can chemically different liquid, solid or gas. Examples of solvent suitable for use in oral pharmaceutical composition may be comprises, but not limited to purified water, methanol, isopropyl alcohol, dichloromethane, glycerol, propylene glycol, ethanol, chlordiazepoxide hydrochloride or mixture thereof.

Preferred dosage forms for the pharmaceutical compositions of the invention are tablets which are prepared by compression methods. Such tablets may be film-coated such as with a mixture of hydroxypropylcellulose and hydroxypropylmethylcellulose containing titanium dioxide and/or other coloring agents, such as iron oxides, dyes, and lakes; a mixture of polyvinyl alcohol (PVA) and polyethylene glycol (PEG) containing titanium dioxide and/or other coloring agents, such as iron oxides, dyes, and lakes; or any other suitable immediate-release film-coating agent(s). The coat provides taste masking and additional stability to the final tablet.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The invention will now be described with reference to the following examples, which serve to illustrate the various embodiments of the invention and which are not intended to be limiting. The skilled person will appreciate that modifications are within the spirit and scope of the invention.

EXAMPLES
Example 1: Apixaban Composition
Table 1
Sr No Ingredients mg/
Tablet mg/
Tablet
1A 1B
1. Apixaban 5.00 2.50
2. Povidone 2.50 1.25
3. Methanol q.s. q.s.
4. Dichloromethane or
Isopropyl Alcohol q.s. q.s.
5. Lactose monohydrate 102.36 51.18
6. Microcrystalline cellulose 78.14 39.07
7. Croscarmellose sodium 10.00 5.00
8. Magnesium Stearate 2.00 1.00
Weight of core tablet 200.00 100.00
Film Coating
9. Opadry 6.00 3.00
10. Isopropyl Alcohol q.s. q.s.
11. Dichloromethane q.s. q.s.
Film Coated Tablet Weight 206.00 103.00

Manufacturing Process:
Crystalline apixaban was dissolved in organic solvent to prepare a solution and an intercalating agent was added to this solution to get a granulating fluid. Further, granulating fluid was added over excipients to get a granulated mass and further dried to obtain granules containing amorphous apixaban. The obtained granules were compressed to a tablet, and optionally, coating was done with a film forming polymer.

Example 2: Apixaban Composition
Table 2
Sr No Ingredients mg/
Tablet mg/
Tablet
2A 2B
1. Apixaban 5.00 2.50
2. Hypromellose 2.50 1.25
3. Methanol q.s. q.s.
4. Dichloromethane or
Isopropyl Alcohol q.s. q.s.
5. Lactose monohydrate 102.36 51.18
6. Microcrystalline cellulose 78.14 39.07
7. Croscarmellose sodium 10.00 5.00
8. Magnesium Stearate 2.00 1.00
Weight of core tablet 200.00 100.00
Film Coating
9. Opadry 6.00 3.00
10. Isopropyl Alcohol q.s. q.s.
11. Dichloromethane q.s. q.s.
Film Coated Tablet Weight 206.00 103.00

Manufacturing Process: Manufacturing process was similar as described for Example 1.

Example 3: Apixaban Composition
Table 3
Sr No Ingredients mg/
Tablet mg/
Tablet
3A 3B
1. Apixaban 5.00 2.50
2. Hydroxypropylcellulose 2.50 1.25
3. Methanol q.s. q.s.
4. Dichloromethane or
Isopropyl Alcohol q.s. q.s.
5. Lactose monohydrate 102.36 51.18
6. Microcrystalline cellulose 78.14 39.07
7. Croscarmellose sodium 10.00 5.00
8. Magnesium Stearate 2.00 1.00
Weight of core tablet 200.00 100.00
Film Coating
9. Opadry 6.00 3.00
10. Isopropyl Alcohol q.s. q.s.
11. Dichloromethane q.s. q.s.
Film Coated Tablet Weight 206.00 103.00

Manufacturing Process: Manufacturing process was similar as described for Example 1.

Example 4: Apixaban Composition
Table 4
Sr No Ingredients mg/
Tablet mg/
Tablet
4A 4B
1. Apixaban 5.00 2.50
2. Hydroxypropylcellulose 5.00 2.50
3. Methanol q.s. q.s.
4. Dichloromethane or
Isopropyl Alcohol q.s. q.s.
5. Anhydrous Lactose 99.86 49.93
6. Microcrystalline cellulose 78.14 39.07
7. Croscarmellose sodium 10.00 5.00
8. Magnesium Stearate 2.00 1.00
Weight of core tablet 200.00 100.00
Film Coating
9. Opadry 9.00 4.5
10. Isopropyl Alcohol q.s. q.s.
11. Dichloromethane q.s. q.s.
Film Coated Tablet Weight 209.00 104.50

Manufacturing Process: Manufacturing process was similar as described for Example 1.

Stability Data:
Tablet 5: Results of stability studies for Example 1B
Parameters Apixaban Tablet
Top Spray By RMG
Condition Initial 6M, 40 °C/75% Initial 6M, 40°C/75%
Assay 97.0 98.8 100.2 99.8
Impurity
Acid impurity ND 0.006 ND 0.006
Amino acid Impurity ND 0.010 ND 0.009
Unknown Impurity 0.039 0.036 0.043 0.037
Total Impurities 0.052 0.162 0.043 0.172
ND: Not Detected
,CLAIMS:1. A solid pharmaceutical composition for oral administration comprising therapeutically effective amount of apixaban in an amorphous form, an intercalating agent and a pharmaceutically acceptable excipient, wherein the weight ratio of the apixaban to intercalating agent ranges from about 1: 0.2 to about 1:08.

2. The solid pharmaceutical composition of claim 1, wherein the pharmaceutical composition is devoid of crystalline apixaban.

3. The solid pharmaceutical composition of claim 1, wherein the weight ratio of the apixaban to the intercalating agent is about 1: 0.5.

4. The solid pharmaceutical composition of claim 1, wherein the intercalating agent is selected from povidone, hydroxypropyl cellulose or hydroxypropylmethyl cellulose.

5. The solid pharmaceutical composition of claim 1, wherein the apixaban used as starting material for the preparation of the pharmaceutical composition is in crystalline form and having particle size with D90 more than 90 µm.

6. The solid pharmaceutical composition of claim 5, wherein the crystalline apixaban used as starting material has particle size with D90 is in the range of about 110 µm to about 400 µm.

7. A solid pharmaceutical composition for oral administration comprising: (a) amorphous apixaban present in an unit dosage strength of about 1 to 5 % by weight; (b) about 0.5 to 1.5% by weight of a lubricant; (c) about 1.2% by weight of a intercalating agent; (d) about 85% by weight of a diluent; and (e) about 4.5% by weight of a disintegrant, wherein the pharmaceutical composition is devoid of crystalline apixaban.

8. The solid pharmaceutical composition of claim 7, wherein an intercalating agent is selected from povidone, hydroxypropylcellulose or hydroxypropylmethyl cellulose.

9. The solid pharmaceutical composition of claim 7, wherein an intercalating agent is povidone.

10. The solid pharmaceutical composition of claim 7, wherein an intercalating agent is hydroxypropylmethyl cellulose.