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 pharmaceutically acceptable tablet; 
 (iii) about 25-35% by weight of lactose or a hydrate thereof based on the total amount of the pharmaceutically acceptable tablet; 
 (iv) about 5% by weight of crospovidone based on the total amount of the pharmaceutically acceptable tablet; 
 (v) about 0.5% by weight of silicon dioxide based on the total amount of the pharmaceutically acceptable tablet; and 
 (vi) about 0.5% by weight of magnesium stearate based on the total amount of the pharmaceutically acceptable 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 pharmaceutically acceptable tablet; and 
 (ii) about 0.5% by weight of magnesium stearate based on the total amount of the of the pharmaceutically acceptable 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);
 wherein the pharmaceutically acceptable tablet releases at least 70% of the compound after about 20 minutes when the composition is tested in 900 mL sodium acetate buffer at pH 4.5 using a USP Apparatus II (Paddle Method) at 37° C., with a paddle speed of 75 rpm; and 
 wherein the total mass of the pharmaceutically acceptable tablet is 600 mg. 
 
     
     
         2 . The pharmaceutically acceptable tablet of  claim 1 , comprising less than about 3% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         3 . The pharmaceutically acceptable tablet of  claim 1 , comprising less than about 1% 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 1 , 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). 
     
     
         5 . 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 pharmaceutically acceptable tablet; 
 (iii) about 25-35% by weight of lactose or a hydrate thereof based on the total amount of the pharmaceutically acceptable tablet; 
 (iv) about 5% by weight of crospovidone based on the total amount of the pharmaceutically acceptable tablet; 
 (v) about 0.5% by weight of silicon dioxide based on the total amount of the pharmaceutically acceptable tablet; and 
 (vi) about 0.5% by weight of magnesium stearate based on the total amount of the pharmaceutically acceptable 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 pharmaceutically acceptable tablet; and 
 (ii) about 0.5% by weight of magnesium stearate based on the total amount of the of the pharmaceutically acceptable 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);
 wherein the tablet disintegrates in less than 2 minutes as tested using USP <701> for uncoated tablets; and 
 wherein the total mass of the pharmaceutically acceptable tablet is 600 mg. 
 
     
     
         6 . The pharmaceutically acceptable tablet of  claim 5 , comprising less than about 3% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         7 . The pharmaceutically acceptable tablet of  claim 5 , comprising less than about 1% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         8 . The pharmaceutically acceptable tablet of  claim 5 , 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). 
     
     
         9 . 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 179 mg microcrystalline cellulose; 
 (iii) about 179 mg lactose or a hydrate thereof; 
 (iv) about 30 mg crospovidone; 
 (v) about 3 mg of silicon dioxide; and 
 (vi) about 3 mg of magnesium stearate; 
 an extragranular blend, wherein the extragranular blend comprises: 
 (i) about 3 mg of silicon dioxide; and 
 (ii) about 3 mg magnesium stearate; 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); and
 wherein the total mass of the pharmaceutically acceptable tablet is 600 mg. 
 
     
     
         10 . The pharmaceutically acceptable tablet of  claim 9 , comprising less than about 3% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         11 . The pharmaceutically acceptable tablet of  claim 9 , comprising less than about 1% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         12 . The pharmaceutically acceptable tablet of  claim 9 , 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). 
     
     
         13 . 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 179 mg microcrystalline cellulose; 
 (iii) about 179 mg lactose or a hydrate thereof; 
 (iv) about 30 mg crospovidone; 
 (v) about 3 mg of silicon dioxide; and 
 (vi) about 3 mg of magnesium stearate; 
 an extragranular blend, wherein the extragranular blend comprises: 
 (i) about 3 mg of silicon dioxide; and 
 (ii) about 3 mg magnesium stearate; 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);
 wherein the pharmaceutically acceptable tablet releases at least 70% of the compound after about 20 minutes when the composition is tested in 900 mL sodium acetate buffer at pH 4.5 using a USP Apparatus II (Paddle Method) at 37° C., with a paddle speed of 75 rpm; and 
 wherein the total mass of the pharmaceutically acceptable tablet is 600 mg. 
 
     
     
         14 . The pharmaceutically acceptable tablet of  claim 13 , comprising less than about 3% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         15 . The pharmaceutically acceptable tablet of  claim 13 , comprising less than about 1% by weight of the compound represented by Formula (II) based on the weight of the compound of Formula (I). 
     
     
         16 . The pharmaceutically acceptable tablet of  claim 13 , 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).