The present invention relates to a pharmaceutical composition comprising apixaban prepared by a non-aqueous wet granulation process wherein the composition releases at least 80% of apixaban in 30 minutes, when measured in United States

Pharmacopeia (USP) type 2 dissolution apparatus, at a stirring speed of 75 rpm and temperature of 37°C ± 0.5°C in 900 mL of pH 6.8 phosphate buffer containing sodium lauryl sulphate.

Background of the Invention

Apixaban is a factor Xa inhibitor used for the treatment or prevention of a thromboembolic disorder, and is disclosed in U.S. Patent No. 6,967,208. Commercially, apixaban tablets are marketed by Bristol Myer Squibb under the trade name Eliquis ^® .

PCT application No. WO 2011/106478 discloses that the formulations of apixaban that were made using a wet granulation process as well as those using larger particle size of the drug substance resulted in less than optimal exposures, which can present quality control challenges. It further discloses a dry granulation process for preparing a composition comprising crystalline apixaban particles having a D90 equal to or less than about 89 μιη as measured by laser light scattering.

Apixaban has an Occupational Exposure Limit (OEL) of around 8.3 μg/m ³ . Drugs having an OEL value of less than 10 μg/m ³ are considered potent and require special containment area. Although there are several granulation processes that can be used in formulating dosage forms, the choice of which granulation process to use is limited for potent drugs. Since the drug content in the compositions comprising potent drugs is low, such compositions are generally not well suited for dry methods such as roller compaction, which may lead to problems in achieving an even drug distribution in the composition of the drug. Further, the machines as well as operations used in dry granulation are difficult to build in a contained way and pose a risk of airborne contamination. Hence, wet granulation is considered a preferable process over dry granulation for potent drugs such as apixaban.

Therefore, the present inventors have now developed an apixaban composition which is prepared by non-aqueous wet granulation method, but still provides the desired dissolution characteristics. Summary of the Invention

There is provided a pharmaceutical composition comprising wet granulated apixaban and at least one pharmaceutical excipient, wherein the wet granulated apixaban is granulated using an organic solvent and the composition releases at least 80% of apixaban in 30 minutes, when measured in United States Pharmacopeia (USP) type 2 dissolution apparatus, at a stirring speed of 75 rpm, at a temperature of 37°C ± 0.5°C in 900 mL of pH 6.8 phosphate buffer containing sodium lauryl sulphate (SLS).

Detailed Description of the Invention

A first aspect of the present invention provides a pharmaceutical composition comprising wet granulated apixaban and at least one pharmaceutical excipient, wherein the wet granulated apixaban is granulated using an organic solvent and the composition releases at least 80% of apixaban in 30 minutes, when measured in United States

Pharmacopeia (USP) type 2 dissolution apparatus, at a stirring speed of 75 rpm, at a temperature of 37°C ± 0.5°C in 900 mL of pH 6.8 phosphate buffer containing sodium lauryl sulphate.

A second aspect of the present invention provides a wet granulated apixaban composition prepared by non-aqueous granulation process wherein the ratio of organic solvent to intra-granular mass during the granulation process is from about 1 :0.2 to about 1 :0.6.

A third aspect of the present invention provides a wet granulated apixaban composition prepared by non-aqueous granulation process wherein the ratio of organic solvent to intra-granular mass during the granulation process is from about 1 :0.2 to about 1 :0.6 and the composition releases at least 80% of apixaban in 30 minutes, when measured in United States Pharmacopeia (USP) type 2 dissolution apparatus, at a stirring speed of 75 rpm, at a temperature of 37°C ± 0.5°C in 900 mL of pH 6.8 phosphate buffer containing sodium lauryl sulphate.

According to one embodiment of the present invention, at least 85% of apixaban is released in 30 minutes.

According to one embodiment of the present invention, apixaban is in crystalline form. According to another embodiment, apixaban has a particle size D90 of not less than 100 μιη, in particular from about 100 μιη to about 200 μιη, e.g., 120 μιη - 150 μιη.

According to another embodiment, the apixaban composition is stable at a temperature of 40°C and 75% relative humidity (RH) for a period of 3 months.

The term "intra-granular mass" as used herein means an intra-granular component of the composition comprising apixaban and one or more pharmaceutically acceptable excipients along with the organic solvents used during the granulation phase.

The term "non-aqueous wet granulation" as used herein means that apixaban is granulated using organic solvents selected from the group consisting of ethanol, isopropyl alcohol, dichloromethane, dimethylsulphoxide, dimethylformamide, N-methyl-2- pyrrolidone, dimethylacetamide, acetic acid or mixtures thereof.

According to another embodiment, the organic solvent is dichloromethane.

According to another embodiment, the non-aqueous granulation is high shear wet granulation.

According to another embodiment, the non-aqueous granulation may be carried out in a rapid mixer granulator.

The term "D90 value" means at least 90% of the apixaban particles have a volume diameter in the specified range when measured by a light scattering method such as by a Malvern Mastersizer.

A fourth aspect of the present invention provides a non-aqueous wet granulation process for the preparation of a pharmaceutical composition wherein the process comprises:

a) dissolving/dispersing apixaban in an organic solvent;

b) blending and granulating the pharmaceutically acceptable excipients with the solution/dispersion of step a); and

c) compressing/filling the granules of step b) into suitable size tablets/capsules.

According to another embodiment, the solution or dispersion of step a) further comprises one or more pharmaceutically acceptable excipients.

According to another embodiment, a portion of apixaban is added to the pharmaceutically acceptable excipients of step b). A fifth aspect of the present invention provides a non-aqueous wet granulation process for the preparation of a pharmaceutical composition wherein the process comprises:

a) granulating apixaban with a granulating liquid prepared using an organic solvent;

b) blending the granules of step a) with one or more pharmaceutically acceptable excipients; and

c) compressing/filling the granules of step b) into suitable size tablets/capsules.

According to another embodiment, apixaban may be partly added to the granulating liquid of step a).

According to another embodiment, the granulating liquid of step a) further comprises one or more pharmaceutically acceptable excipients.

Examples of pharmaceutically acceptable excipients include binders, diluents, lubricants/glidants, surfactants, disintegrants or mixtures thereof.

Examples of binders include carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch or mixtures thereof.

Examples of diluents include microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, potassium chloride, powdered cellulose, sodium chloride, sorbitol or mixtures thereof.

Examples of disintegrants include low substituted hydroxypropyl-cellulose, croscarmellose sodium (e.g. Ac Di Sole, Primellose®), crospovidone (e.g. Kollidon®, Polyplasdone®), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab®, Primoljel®) and starch, or mixtures thereof.

Examples of lubricants or glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, or mixtures thereof.

Examples of surfactants include sodium lauryl sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, benzalkonium chloride, alkyl poly(ethylene oxide), copolymers of poly(ethylene oxide) and poly(propylene oxide) commercially known as poloxamers or poloxamines, polyvinyl alcohol (PVA), fatty alcohols, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyethylene glycol fatty acid ester, alkylene glycol fatty acid mono ester, sucrose fatty acid ester, sorbitol monolaurate (Span ^® 20 or Span ^® 80), polyoxyethylene sorbitan fatty acid ester (polysorbates), or mixtures thereof.

The composition may be further coated with a functional or non-functional coating. The coating of the present invention may further comprise excipients selected from the group comprising plasticizers, binders, opacifiers, anti-tacking agents, anti- foaming agents, colors, film-forming polymers, or mixtures thereof. Organic or aqueous solvents may be used during the coating process. Solvents may be selected from the group comprising water, acetone, isopropyl alcohol, ethanol, isopropyl acetate, dichloromethane, or mixtures thereof.

Examples of plasticizers include propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglyceride, cetyl alcohol, or mixtures thereof.

Examples of opacifiers include titanium dioxide, silicon dioxide, talc, calcium carbonate, behenic acid, or mixtures thereof.

Examples of anti-tacking agents include talc, colloidal silicon dioxide, or mixtures thereof.

Examples of anti -foaming agents include silicon based surfactants, e.g., simethicone; vegetable oils; waxes; hydrophobic silica; polyethylene glycol; or mixtures thereof.

Coloring agents may be selected from FDA approved colorants such as iron oxide, lake of tartrazine, allura red, titanium dioxide, or mixtures thereof.

Examples of film-forming polymers include hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, or mixtures thereof. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry ^® , may also be used for coating.

Coating may be carried out by using any conventional coating techniques known in the art, such as spray coating in a conventional coating pan, fluidized bed processor, or dry powder coating.

EXAMPLES

Example 1

Manufacturing process:

1. Apixaban, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulphate and croscarmellose sodium were sifted together.

2. Povidone was dissolved in dichloromethane to obtain a solution.

3. Blend of step 1) was granulated with solution of step 2) to obtain granules.

4. Granules of step 3) were lubricated with magnesium stearate.

5. Lubricated granules of step 4) were compressed into a suitable size tablet.

6. Tablets obtained in step 5) were coated with Opadry™ Pink dispersion. Dissolution studies

The dissolution tests were carried out using tablets prepared in Example 1 and Eliquis ^® tablet.

The dissolution was carried out in United States Pharmacopeia (USP) type 2 dissolution apparatus, at a stirring speed of 75 rpm, at a temperature of 37±0.5°C, in 900 mL of pH 6.8 phosphate buffer containing 0.05% SLS.

Table 1: Dissolution profile of Example 1 and Eliquis ^® tablet.

The results of the dissolution tests are shown in Table 1. It is evident that tablets prepared according to Example 1 provide a release profile which is comparable to Eliquis ^® tablet.