This application claims the benefit of Indian Provisional Application No. IN 201621013502, filed on 18 ^ta Apr 2016, this is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients and process for preparation of such compositions. The present invention also relates to the use of compositions comprising apixaban for treating or preventing the risk of thromboembolic disorders such as deep vein thrombosis, pulmonary embolism, non-valvular atrial fibrillation.

BACKGROUND OF THE INVENTION

"Apixaban" which is chemically known as 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-7-oxo-6-[4- (2-oxo-l-piperidinyl)phenyl]-lH-pyrazolo[3,4-c]pyridine-3-ca rboxamide was first disclosed by Pinto et al in US 6,967,208. The document further discloses that the compounds of the invention may be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable vehicle, diluent, or carrier and use of same for the treatment or prevention of a thromboembolic disorders.

Jiacheng et al in WO 2003/049681A2 discloses process for the preparation of apixaban and other pyrazole -pyridine derivatives.

Rafael et al in WO 2007/001385 A2 discloses alternative process for the preparation of apixaban and other pyrazole -pyridine derivatives. It further discloses crystalline form N-l and form H2-2 of apixaban.

Patel et al in WO 2011/106478A1 discloses that apixaban is a poorly soluble compound. The poor solubility results in slow and incomplete drug release and poor bioavailability. Therefore, it discloses a composition comprising crystalline apixaban particles having a maximally limited mean particle size and a pharmaceutically acceptable diluent or carrier. The disclosed compositions have the particle size d (0.9) less than 89 μπι of active ingredient to meet appropriate dissolution rate. Though the document provides granulation process for making tablets, it emphasize that the dry granulation provides better dissolution profile when compared with a tablet made by wet granulation.

Richard in WO 2010/147978A1 discloses solubility-improved form of apixaban wherein the dosage form provides controlled release of apixaban.

Therefore, there is an unmet need for new pharmaceutical composition comprising apixaban that exhibits desired dissolution rate. The present invention is directed towards the same.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

In one embodiment, the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein Apixaban is in crystalline or amorphous form. If crystalline apixaban is used for making the pharmaceutical compositions, the according to present invention, it can be micronized or un-micronized form.

In another embodiment, the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein Apixaban is in crystalline, preferably in N- 1 form.

In another embodiment, the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban composition is prepared by judiciously selecting the excipients. The various excipients used in the compositions are selected from the group comprising of binders, diluents, disintegrants, lubricants, wetting agents or surfactants. In still another embodiment, the present invention relates to a process for preparation of pharmaceutical compositions comprising Apixaban or pharmaceutically acceptable salts thereof. Typically, the processes such as wet granulation, dry granulation, direct compression, solid dispersion or hydrophilization are used to manufacture the pharmaceutical compositions according to present invention.

In further embodiment, the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is in solid dispersion, optionally containing a polymer.

In yet another embodiment, the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is in hydrophilized form.

Various objects, features, embodiments and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof and method of preparation of such compositions.

As used herein the term "Apixaban" means the chemical compound 1 -(4methoxyphenyl)-7-oxo- 6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyra zolo[3,4c]pyridine-3-carboxamide. However, various salts, polymorphs, solvates, enantiomers, stereoisomers could also be used. Further the compound could be used as amorphous, crystalline or mixtures thereof. Preferably, as crystalline N-l form. The active agent can be used in range of 0.5-20% w/w of the total composition. Typically, the amount of active agent present in the composition according to present invention is in the range of 1% to 10 % w/w and more preferably from 2% to 5% w/w. In one aspect, the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein Apixaban is used in micronized or un- micronized form. As used herein, the term "micronized Apixaban" means particles of Apixaban having d (0.9) equal to or less than about of 50 μιτι, particularly between 1 μιτι to 50 μιτι, more particularly between 2 μιτι to 20 μιτι. It is observed that compositions prepared by using Apixaban of particles d (0.9) about 20 μιτι exhibited required dissolution properties.

The term "d(0.9)", as used herein, with reference to the size of micronized apixaban particles, indicate that about 90% of particles measured have a size less than the defined d (0.9) value, and that about 10% of particles measured have a size greater than the defined d(0.9) value. The particle size distribution of apixaban particles of the present invention may be determined using an optical microscopic method, sedimentation techniques, for example, pipette analysis using an Andreas sen pipette, sedimentation scales, photo sedimentometers or sedimentation in a centrifugal force field, pulse methods, for example, using a Coulter counter, or sorting by means of gravitational or centrifugal force, sieve analysis, laser diffraction or ultrasound attenuation spectroscopy. The particle size distribution of apixaban particles of the present invention is particularly determined through laser diffraction using a Malvern® Mastersizer laser diffraction instrument.

The term "particles" refers to individual drug substance particles whether the particles exist singly or are agglomerated.

The effect of particle size on tablet dissolution was also studied on the tablet compositions prepared according to the present invention. As it is well established principle that tablet dissolution plays an important role and it correlates drug release in the body for poorly soluble drugs such as Apixaban. So, to study this effect, different tablet formulation batches were prepared with Apixaban different particle size i.e., d (0.9) up to about 100 μΜ and tested in dissolution media, phosphate buffer pH 6.8. The results revealed that particle size of Apixaban definitely has impact on tablet dissolution and hence on the drug release. The higher the particle size, the lower the dissolution. Hence a particle size below 20 μιτι is preferred. The pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable excipients judiciously selected from a group comprising diluents, binders, disintegrants, lubricants, wetting agents or surfactants, coloring agents, flavoring agents or any other excipients known in the art.

Suitable examples of diluents include but are not limited to corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch, pregelatinized starch or mixtures thereof. Preferably diluent is selected from dicalcium phosphate, microcrystalline cellulose, lactose, mannitol, starch. Diluents can be present alone or as mixture of more than one in the range up to 95% by weight of the composition.

Suitable examples of binders include but are not limited to polyvinylpyrrolidone, starch mucilage, pregelatinized starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, microcrystalline cellulose, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxy propyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, dextrin, gelatin, guar gum and combinations thereof. Preferably binder is selected from starch, hydroxy propyl cellulose, hydroxypropylmethyl cellulose. Binders can be present alone or as mixture of more than one in the range up to 35% by weight of the composition.

Suitable examples of disintegrants include but are not limited to cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose (crosscarmellose sodium), calcium carboxymethyl cellulose, microcrystalline cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof. Preferably disintegrant is selected from cross-linked polyvinylpyrrolidone, sodium starch glycolate, crosscarmellose sodium. Disintegrants can be present alone or as mixture of more than one in the range up to 30% by weight of the composition.

Surfactants or wetting agents can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic and zwittetionic surfactants. Suitable examples of wetting agents or surfactants include but are not limited to sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylene sorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide -propylene oxide block copolymers (Pluronic®) or ethoxylated triglycerides. The amount of wetting agent employed varies in the range of about 0% to about 20% w/w of the total composition. Preferably, sodium lauryl sulphate is employed as a wetting agent.

Suitable examples of lubricants include but are not limited to calcium stearate, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate or a mixture of one or more. The lubricants can be used in the range of up to 3% by weight of the composition.

In still further aspect, the pharmaceutical composition of Apixaban or pharmaceutically acceptable salts thereof according to present invention can be prepared by conventional processes such as dry granulation, wet granulation and direct compression. The present inventors have found that the apixaban formulations having desired dissolution profile are preferably prepared by using direct compression process. The process involves co-sifting and mixing of apixaban and other excipients. The blend thus obtained is compressed to form tablets of desired size and hardness between 3-15kp. The tablets are further coated with functional or nonfunctional film coatings. The film coating materials include cellulosic polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and the like, polyvinylpyrrolidone, natural gums etc.

In another preferred aspect, the present invention provides pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof that are prepared by solid dispersion technique, utilizing conventional process for forming solid dispersions. Such processes include mechanical, thermal and solvent processes. Exemplary mechanical processes include milling and extrusion; thermal processes including high temperature fusion, solvent-modified fusion and melt-congeal processes; and solvent processes including non-solvent precipitation, spray-coating and spray-drying. Preferably, the solid dispersion of apixaban obtained according to present invention results in predominantly or at least a major portion (at least 70%) of apixaban being in the amorphous state.

Preferably, the solid amorphous dispersions of apixaban is formed by "solvent processing," which comprises the steps of dissolving apixaban and one or more polymers in a common solvent. "Common" here means that the solvent, which can be a mixture of compounds, will dissolve both apixaban and the polymer(s). After both apixaban and the polymer have been dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent. Exemplary processes to remove solvents are spray-drying, spray-coating (pan-coating, fluidized bed coating, etc.), and precipitation by rapid mixing of the polymer and apixaban solution with water, or some other non-solvent.

The polymers used for preparation of solid dispersion referred here are either cellulosic or non- cellulosic in nature. Typical examples of few polymers are vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, or cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and polyethylene polyvinyl alcohol copolymers, carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGITS® manufactured by Rohm Tech Inc., of Maiden, Mass.; amine -functionalized polyacrylates and polymethacrylates; proteins; and carboxylic acid functionalized starches such as starch glycolate, acrylate and methacrylate copolymers, and polyoxyethylene-polyoxypropylene copolymers. Exemplary commercial grades of such copolymers include the EUDRAGITS, which are copolymers of methacrylates and acrylates, and the PLURONICS supplied by BASF, which are polyoxyethylene-polyoxypropylene copolymers, cellulosic polymers such as cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl cellulose acetate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate etc. Preferably polymer is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrolidone as sinle or as mixtures thereof. The polymers employed are used in the range of about 0.5-50% by weight of the composition. The solvents used for above processes include those that are acceptable for preparation of pharmaceutical compositions. Typical examples are alcohols such as methanol, ethanol, n- propanol, iso-propanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propylacetate; and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1, 1-trichloroethane. Lower volatility solvents such as dimethyl acetamide or dimethylsulfoxide can also be used. Mixtures of solvents, such as methanol and acetone, can also be used, as can mixtures with water, so long as the polymer and apixaban are sufficiently soluble.

The solid dispersion preparation process involves:

a) dissolving drug, polymer in common solvent

b) pre-mix of diluent, surfactant, disintegrant is prepared

c) solution of a) sprayed on to step b) to form granules in high/low shear mixer granulator d) the granules are mixed with disintegrant and lubricated

e) the final mixture is then compressed in to tablets and coated with non-functional or functional coating.

In still another aspect, the present invention provides pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is present in hydrophilized form. The hydrophilized form referred to in the present invention involves process in which: a. first granules comprising the apixaban, in hydrophilized form, are prepared by moist granulation; and

b. the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.

The moist granulation of process step (a) can be carried out in a mixer (mixer granulation) or in a fluidized bed (fluidized bed granulation) by introducing apixaban either to the pre-mixed bed of excipients as a solid or it is suspended in the granulating liquid. Preferably, apixaban suspended in the granulating liquid, is introduced on to the pre-mixed bed of excipients. The granulating liquid used according to the invention contains a solvent, optionally a hydrophilic binding agent and, if appropriate, a wetting agent. The hydrophilic binding agent can be dispersed in the granulating liquid or preferably dissolved therein.

The solvents used for the granulating liquid can be organic solvents, such as, for example, ethanol, methylene chloride or acetone, or water or mixtures thereof.

The hydrophilic binding agents employed for the granulating liquid are pharmaceutically suitable hydrophilic additives, preferably those which dissolve in the solvent of the granulating liquid. Preferably, hydrophilic polymers such as, for example, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low- substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), gelatine, guar gum, partially hydrolysed starch, alginates or xanthan are employed. Particularly preferably, HPMC is employed as a hydrophilic binding agent. The hydrophilic binding agent can be present here in a concentration of 1 to 15% w/w based on the total mass of the pharmaceutical composition, preferably of 1 to 8%.

In still another aspect, the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is provided as immediate release dosage forms such as tablets, capsules, granules, multiparticulate systems or modified release dosage forms. The modified release may be achieved by using methods known in the art, preferably by using functional coating. The functional coating polymers include hydroxypropyl methyl cellulose, ethyl cellulose, cellulose actate phthalate, acrylate polymers available under brand name Eudragit L, Eudragit S, Kollicoat etc.

The compositions of the present invention can be packed into suitable containers such as blisters, bottles or pouch. Further, the packages may optionally contain a desiccant or an antioxidant or oxygen absorbent or combinations thereof. The following experiments are provided to exemplarily illustrate various aspects of the inventive subject matter presented herein. However, it should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.

EXAMPLES:

Example-1

Table 1: Composition of Apixaban tablet formulation

The above test composition of Example 1 is prepared by following method:

Apixaban (micronized and/or unmicronized), Lactose, Microcrystalline Cellulose, Croscarmellose sodium, Sodium lauryl sulphate and Magnesium stearate were blended. The blended raw materials were granulated using a dry granulation process. Then the dry granulated materials were blended with the extragranular materials. The blended materials were compressed into tablets and film coated with a conventional coating dispersion.

Example-2

Table 2: Composition of Apixaban tablet formulation

The above test composition of Example 2 is prepared by following method:

Apixaban (micronized and/or unmicronized), mannitol, pregelatinized starch, croscarmellose sodium, sodium lauryl sulphate and magnesium stearate were blended. The blended raw materials were granulated using a dry granulation process. Then the dry granulated materials were blended with the extragranular materials. The blended materials were compressed into tablets and film coated with a conventional coating dispersion.

Example-3

Table 3: Composition of Apixaban tablet formulation

The above test composition of Example 3 is prepared by following method: Apixaban (micronized and/or unmicronized) and hydroxypropylmethylcellulose (optional) are dissolved in ethanol and methylene chloride. The solution thus prepared is sprayed onto the original mixture of microcrystalhne cellulose, lactose, sodium lauryl sulphate and croscarmellose as a granulating liquid in the course of a fluidized bed granulation or in rapid mixer granulator. After drying and sieving the resulting granules, magnesium stearate is added and mixed. The press-ready mixture thus obtained is compressed to give tablets of suitable size. The subsequent coating of the tablets is carried out using Opadry.

Example-4

Table 4: Composition of Apixaban tablet formulation

The above test composition of Example 4 is prepared by following method:

Co-sift and mix Apixaban (micronized and/or unmicronized), Lactose, Microcrystalline Cellulose, Croscarmellose sodium and Sodium lauryl sulphate in blender. Lubricate the blend and compress to tablets of suitable size. The compressed tablets are coated with Opadry dispersion until the desired weight is achieved.

Example-5

Table 5: Composition of Apixaban tablet formulation

7 Magnesium Stearate 0.5-3

8 Opadry film coating 1-10

The above test composition of Example 5 is prepared by following method:

Co-sift and mix Apixaban (micronized and/or unmicronized), dicalclum phosphate, Microcrystalline Cellulose, Sodium starch glycolate and Sodium lauryl sulphate in blender. Lubricate the blend and compress to tablets of suitable size. The compressed tablets are coated with Opadry dispersion until the desired weight is achieved.

Example-6

Table 6: Composition of Apixaban tablet formulation

The above test composition of Example 6 is prepared by following method:

Solution of apixaban (micronized and/or unmicronized), hydroxypropylmethylcellulose and sodium lauryl sulphate is prepared in solvent mixture of ethanol and methylene chloride. The solution thus prepared is sprayed onto the physical mixture of microcrystalline cellulose, lactose and croscarmellose as a granulating liquid in the course of a fluidized bed granulation. After drying and sieving the resulting granules, lubricate with magnesium stearate. The press-ready mixture thus obtained is compressed to give tablets having suitable size. The subsequent coating of the tablets is carried out using Opadry dispersion. Example-7

Table 7: Composition of Apixaban tablet formulation

The above test composition of Example 7 is prepared by following method:

Hydroxypropylmethylcellulose and sodium lauryl sulphate are dissolved in water. The micronized apixaban is suspended in this solution. The suspension thus prepared is sprayed onto the physical mixture of microcrystalline cellulose, lactose and croscarmellose as a granulating liquid in the course of a fluidized bed granulation or in rapid mixer granulator. After drying and sieving the resulting granules, lubricate with magnesium stearate. The press-ready mixture thus obtained is compressed to give tablets having suitable size. The subsequent coating of the tablets is carried out using Opadry.

Study of effect of API particle size on tablet dissolution:

To study the effect of Apixaban particle size on tablet dissolution, tablet compositions as described in any of the above examples were prepared with different particle size (A- d (0.9): 5.8 μιη, B- d (0.9): 9 μιτι; C- d (0.9): 101 μιτι) and compressed to attain hardness between 3- 15kp. Then were tested in USP apparatus II in 900ml 0.05 M Sodium Phosphate Buffer with 0.05% SLS, pH 6.8 at 75 rpm. The results revealed that particle size of Apixaban d (0.9) below 20 μιτι qualified dissolution criteria of not less than 75% of the labeled amount in 30minutes for immediate release tablets. The results are summarized in the table below: Table 8: Effect of particle size on tablet dissolution

Thus Apixaban of particle size (d (0.9)) below 20 μηι is preferred.