Amorphous kinase inhibitor formulations and methods of use thereof

Abstract

Provided herein is an amorphous compound represented by Formula (I): and compositions thereof, which are useful in the treatment of disorders related to the activity of the c-KIT and PDGFRα kinases, and oncogenic forms thereof.

1 . A pharmaceutically acceptable tablet for orally delivering 50 mg of a compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       comprising:
 an intragranular blend, wherein the intragranular blend comprises: 
 (i) a solid dispersion having 50 mg of the compound wherein the compound is present in amorphous form and hydroxypropyl methyl cellulose acetate succinate; 
 (ii) about 25-35% by weight microcrystalline cellulose based on the total amount of the tablet; 
 (iii) about 25-35%% by weight of lactose or a hydrate thereof based on the total amount of the tablet; 
 (iv) about 5% by weight of crospovidone based on the total amount of the tablet; 
 (v) about 0.5% by weight of silicon dioxide based on the total amount of the tablet; and 
 (vi) about 0.5% by weight of magnesium stearate based on the total amount of the pharmaceutical tablet; and 
 an extragranular blend, wherein the extragranular blend comprises: 
 (i) about 0.5% by weight of silicon dioxide based on the total amount of the tablet; and 
 (ii) about 0.5% by weight of magnesium stearate based on the total amount of the of the tablet; and 
 wherein the tablet disintegrates in less than 2 minutes as tested using USP <701> for uncoated tablets. 
 
     
     
         2 . A pharmaceutically acceptable tablet for orally delivering 50 mg of a compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       comprising:
 an intragranular blend, wherein the intragranular blend comprises: 
 (i) a solid dispersion having 50 mg of the compound wherein the compound is present in amorphous form and hydroxypropyl methyl cellulose acetate succinate; 
 (ii) about 25-35% by weight microcrystalline cellulose based on the total amount of the tablet; 
 (iii) about 25-35%% by weight of lactose or a hydrate thereof based on the total amount of the tablet; 
 (iv) about 5% by weight of crospovidone based on the total amount of the tablet; 
 (v) about 0.5% by weight of silicon dioxide based on the total amount of the tablet; and 
 (vi) about 0.5% by weight of magnesium stearate based on the total amount of the pharmaceutical tablet; 
 an extragranular blend, wherein the extragranular blend comprises: 
 (i) about 0.5% by weight of silicon dioxide based on the total amount of the tablet; and 
 (ii) about 0.5% by weight of magnesium stearate based on the total amount of the of the tablet; and 
 less than about 10% by weight of an impurity compound represented by Formula (II): 
 
       
         
           
           
               
               
           
         
       
       based on the weight of the compound of Formula (I). 
     
     
         3 . The pharmaceutically acceptable tablet of  claim 2 , comprising less than about 3% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         4 . The pharmaceutically acceptable tablet of  claim 2 , comprising less than about 1% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         5 . The pharmaceutically acceptable tablet of  claim 2 , comprising about 0.1% by weight to about 0.5% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         6 . A pharmaceutically acceptable tablet for orally delivering 50 mg of a compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       comprising:
 an intragranular blend, wherein the intragranular blend comprises: 
 (i) a solid dispersion having 50 mg of the compound wherein the compound is present in amorphous form and hydroxypropyl methyl cellulose acetate succinate; 
 (ii) about 25-35% by weight microcrystalline cellulose based on the total amount of the tablet; 
 (iii) about 25-35%% by weight of lactose or a hydrate thereof based on the total amount of the tablet; 
 (iv) about 5% by weight of crospovidone based on the total amount of the tablet; 
 (v) about 0.5% by weight of silicon dioxide based on the total amount of the tablet; and 
 (vi) about 0.5% by weight of magnesium stearate based on the total amount of the pharmaceutical tablet; 
 an extragranular blend, wherein the extragranular blend comprises: 
 (i) about 0.5% by weight of silicon dioxide based on the total amount of the tablet; and 
 (ii) about 0.5% by weight of magnesium stearate based on the total amount of the of the tablet; and 
 less than about 10% by weight of an impurity compound represented by Formula (III): 
 
       
         
           
           
               
               
           
         
       
       based on the weight of the compound of Formula (I). 
     
     
         7 . The pharmaceutically acceptable tablet of  claim 6 , comprising less than about 3% by weight of the compound represented by Formula (III) based on the weight of the compound of Formula (I). 
     
     
         8 . The pharmaceutically acceptable tablet of  claim 6 , comprising less than about 1% by weight of the compound represented by Formula (III) based on the weight of the compound of Formula (I). 
     
     
         9 . The pharmaceutically acceptable tablet of  claim 6 , comprising about 0.1% by weight to about 0.5% by weight of the compound represented by Formula (III) based on the weight of the compound of Formula (I).