Apixaban formulations

Abstract

Compositions comprising crystalline apixaban particles having a D 90 equal to or less than 89 μm, and a pharmaceutically acceptable carrier, are substantially bioequivalent and can be used to for the treatment and/or prophylaxis of thromboembolic disorders.

1 - 9 . (canceled) 
     
     
         10 . A solid pharmaceutical composition comprising about 2.5 mg to about 5 mg of apixaban and a pharmaceutically acceptable diluent or carrier,
 wherein apixaban comprises crystalline apixaban, and   wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL of a dissolution medium at 37° C., at least 77 wt % of apixaban in the solid pharmaceutical composition dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.   
     
     
         11 . The composition as defined in  claim 10 , wherein the crystalline apixaban comprises Form N-1 of apixaban. 
     
     
         12 . The composition as defined in  claim 10 , wherein apixaban is granulated during preparation of the solid pharmaceutical composition. 
     
     
         13 . The composition as defined in  claim 12 , wherein apixaban is granulated by dry granulation. 
     
     
         14 . The composition as defined in  claim 10 , wherein the pharmaceutical composition comprises 2.5 mg of apixaban. 
     
     
         15 . The composition as defined in  claim 10 , wherein the pharmaceutical composition comprises 5 mg of apixaban. 
     
     
         16 . The composition as defined in  claim 10 , which is a tablet. 
     
     
         17 . The composition as defined in  claim 10 , which is a capsule. 
     
     
         18 . The composition as defined in  claim 14 , which is a tablet. 
     
     
         19 . The composition as defined in  claim 14 , which is a capsule. 
     
     
         20 . The composition as defined in  claim 15 , which is a tablet. 
     
     
         21 . The composition as defined in  claim 15 , which is a capsule. 
     
     
         22 . A solid pharmaceutical composition comprising about 2.5 mg to about 5 mg of apixaban and a pharmaceutically acceptable diluent or carrier,
 wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL of a dissolution medium at 37° C., at least 77 wt % of apixaban in the solid pharmaceutical composition dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.   
     
     
         23 . The composition as defined in  claim 22 , wherein apixaban is granulated during preparation of the solid pharmaceutical composition. 
     
     
         24 . The composition as defined in  claim 23 , wherein apixaban is granulated by dry granulation. 
     
     
         25 . The composition as defined in  claim 22 , wherein the pharmaceutical composition comprises 2.5 mg of apixaban. 
     
     
         26 . The composition as defined in  claim 22 , wherein the pharmaceutical composition comprises 5 mg of apixaban. 
     
     
         27 . The composition as defined in  claim 22 , which is a tablet. 
     
     
         28 . The composition as defined in  claim 22 , which is a capsule. 
     
     
         29 . The composition as defined in  claim 25 , which is a tablet. 
     
     
         30 . The composition as defined in  claim 25 , which is a capsule. 
     
     
         31 . The composition as defined in  claim 26 , which is a tablet. 
     
     
         32 . The composition as defined in  claim 26 , which is a capsule. 
     
     
         33 . A tablet comprising about 2.5 mg to about 5 of apixaban and a pharmaceutically acceptable diluent or carrier,
 wherein the tablet exhibits a mean C max  and/or AUC for apixaban upon administration that is from 80% to 125% of a mean C max  and/or AUC, respectively, of a reference tablet comprising an equivalent amount of apixaban and the pharmaceutically acceptable diluent or carrier, and   wherein the reference tablet is prepared using crystalline apixaban particles having a D 90  equal to about 30 μm as a raw material.   
     
     
         34 . The tablet as defined in  claim 33 , wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL of a dissolution medium at 37° C., at least 77 wt % of apixaban in the tablet dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate. 
     
     
         35 . The tablet as defined in  claim 33 , wherein the reference tablet is prepared using dry granulation. 
     
     
         36 . The tablet as defined in  claim 33 , wherein the crystalline apixaban particles used in preparing the reference tablet comprise Form N-1 of apixaban. 
     
     
         37 . The tablet as defined in  claim 33 , wherein the tablet comprises 2.5 mg of apixaban. 
     
     
         38 . The tablet as defined in  claim 33 , wherein the tablet comprises 5 mg of apixaban. 
     
     
         39 . A capsule comprising about 2.5 mg to about 5 of apixaban and a pharmaceutically acceptable diluent or carrier,
 wherein the capsule exhibits a mean C max  and/or AUC for apixaban upon administration that is from 80% to 125% of a mean C max  and/or AUC, respectively, of a reference capsule comprising an equivalent amount of apixaban and the pharmaceutically acceptable diluent or carrier, and   wherein the reference capsule is prepared using crystalline apixaban particles having a D 90  equal to about 30 μm as a raw material.   
     
     
         40 . The capsule as defined in  claim 39 , wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL of a dissolution medium at 37° C., at least 77 wt % of apixaban in the capsule dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate. 
     
     
         41 . The capsule as defined in  claim 39 , wherein the crystalline apixaban particles used in preparing the reference capsule comprise Form N-1 of apixaban. 
     
     
         42 . The capsule as defined in  claim 39 , wherein the capsule comprises 2.5 mg of apixaban. 
     
     
         43 . The capsule as defined in  claim 39 , wherein the capsule comprises 5 mg of apixaban.