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 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).