Apixaban formulations

Abstract

Compositions comprising crystalline apixaban particles having a D90 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 tablet comprising up to about 5 mg of apixaban, a pharmaceutically acceptable diluent or carrier, and an optional coating,
 wherein apixaban comprises crystalline apixaban,   wherein the pharmaceutically acceptable diluent or carrier comprises at least one filler, at least one disintegrating agent, at least one lubricant, and at least one surfactant as a wetting aid for apixaban,   wherein the at least one filler constitutes a main portion of the tablet by weight, 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 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.   
     
     
         11 . The tablet as defined in  claim 10 , wherein the crystalline apixaban comprises Form N-1 of apixaban. 
     
     
         12 . The tablet as defined in  claim 10 , wherein a content of the at least one filler in the tablet is at least about 85 wt % based on a weight of the tablet calculated without the optional coating. 
     
     
         13 . The tablet as defined in  claim 10 , wherein the at least one surfactant is sodium lauryl sulfate, sodium stearate, polysorbate 80, or a poloxamer. 
     
     
         14 . The tablet as defined in  claim 10 , wherein the at least one surfactant is sodium lauryl sulfate. 
     
     
         15 . The tablet as defined in  claim 10 , which has a surfactant content of 0.25 wt % to 2 wt %. 
     
     
         16 . The tablet as defined in  claim 14 , which has a sodium lauryl sulfate content of 0.25 wt % to 2 wt %. 
     
     
         17 . The tablet as defined  claim 10 , wherein the tablet comprises about 2.5 mg to about 5 mg of apixaban. 
     
     
         18 . The tablet as defined  claim 10 , wherein the tablet comprises 2.5 mg of apixaban. 
     
     
         19 . The tablet as defined  claim 10 , wherein the tablet comprises 5 mg of apixaban. 
     
     
         20 . A tablet comprising up to about 5 mg of apixaban, a pharmaceutically acceptable diluent or carrier, and an optional coating,
 wherein the pharmaceutically acceptable diluent or carrier comprises at least one filler, at least one lubricant, and at least one disintegrating agent,   wherein the at least one filler constitutes a main portion of the tablet by weight, 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 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.   
     
     
         21 . The tablet as defined in  claim 20 , wherein the pharmaceutically acceptable diluent or carrier comprises at least one of a starch, gelatin, a natural sugar, a wax, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, croscarmellose sodium, bentonite, carboxymethylcellulose, polyethylene glycol, microcrystalline cellulose, and povidone. 
     
     
         22 . The tablet as defined in  claim 20 , wherein the at least one filler comprises microcrystalline cellulose and/or lactose. 
     
     
         23 . The tablet as defined in  claim 20 , wherein the pharmaceutically acceptable diluent or carrier comprises lactose, magnesium stearate, croscarmellose sodium, and microcrystalline cellulose. 
     
     
         24 . The tablet as defined in  claim 23 , wherein the pharmaceutically acceptable diluent or carrier further comprises at least one surfactant as a wetting aid for apixaban. 
     
     
         25 . The tablet as defined in  claim 24 , wherein the at least one surfactant is sodium lauryl sulfate. 
     
     
         26 . The tablet as defined in  claim 20 , wherein a content of the at least one filler in the tablet is at least about 85 wt % based on a weight of the tablet calculated without the optional coating. 
     
     
         27 . The tablet as defined  claim 20 , wherein the tablet comprises about 2.5 mg to about 5 mg of apixaban. 
     
     
         28 . The tablet as defined  claim 20 , wherein the tablet comprises 2.5 mg of apixaban. 
     
     
         29 . The tablet as defined  claim 20 , wherein the tablet comprises 5 mg of apixaban. 
     
     
         30 . An immediate release tablet comprising up to about 5 mg of apixaban and a pharmaceutically acceptable diluent or carrier, which is prepared by a process comprising:
 blending raw materials comprising crystalline apixaban particles; and   granulating using dry granulation,   wherein the crystalline apixaban particles have a D 90  equal to or less than 89 μm.   
     
     
         31 . The tablet as defined in  claim 30 , wherein the crystalline apixaban particles comprise Form N-1 of apixaban. 
     
     
         32 . The tablet as defined in  claim 30 , wherein the D 90  is equal to or less than 85 μm. 
     
     
         33 . The tablet as defined in  claim 30 , wherein the D 90  is equal to or less than 50 μm. 
     
     
         34 . The tablet as defined in  claim 30 , wherein the D 90  is equal to or less than 30 μm. 
     
     
         35 . The tablet as defined in  claim 30 , wherein the D 90  is equal to or less than 25 μm. 
     
     
         36 . The tablet as defined  claim 30 , wherein the tablet comprises about 2.5 mg to about 5 mg of apixaban. 
     
     
         37 . The tablet as defined  claim 30 , wherein the tablet comprises 2.5 mg of apixaban. 
     
     
         38 . The tablet as defined  claim 30 , wherein the tablet comprises 5 mg of apixaban. 
     
     
         39 . A process for preparing an immediate release tablet comprising up to about 5 mg of apixaban, a pharmaceutically acceptable diluent or carrier, and an optional coating, the process comprising:
 blending raw materials comprising crystalline apixaban particles; and   granulating using dry granulation,   wherein the crystalline apixaban particles have a D 90  equal to or less than 89 μm.   
     
     
         40 . The process as defined in  claim 39 , wherein the tablet comprises about 2.5 mg to about 5 mg of apixaban. 
     
     
         41 . The process as defined in  claim 39 , wherein the tablet comprises 2.5 mg of apixaban. 
     
     
         42 . The process as defined in  claim 39 , wherein the tablet comprises 5 mg of apixaban. 
     
     
         43 . A method of treating a thromboembolic disorder in a person in need thereof, comprising administering to the person the tablet of  claim 17 . 
     
     
         44 . A method of treating a thromboembolic disorder in a person in need thereof, comprising administering to the person the tablet of  claim 27 . 
     
     
         45 . A method of treating a thromboembolic disorder in a person in need thereof, comprising administering to the person the tablet of  claim 20 .