AMORPHOUS KINASE INHIBITOR FORMULATIONS AND METHODS OF USE THEREOF
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).