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 composition 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, wherein the compound and the hydroxypropyl methyl cellulose acetate succinate are present in a ratio of about 25:75, and wherein the compound is present in the solid dispersion in an amount of 25 weight percent based on the total weight of the solid dispersion;
(ii) about 25-35% by weight microcrystalline cellulose based on the total amount of the pharmaceutically acceptable composition;
(iii) about 25-35% by weight of lactose or a hydrate thereof based on the total amount of the pharmaceutically acceptable composition;
(iv) about 5% by weight of crospovidone based on the total amount of the pharmaceutically acceptable composition;
(v) about 0.5% by weight of silicon dioxide based on the total amount of the pharmaceutically acceptable composition; and
(vi) about 0.5% by weight of magnesium stearate based on the total amount of the pharmaceutically acceptable composition; 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 pharmaceutically acceptable composition; and
(ii) about 0.5% by weight of magnesium stearate based on the total amount of the of the pharmaceutically acceptable composition;
wherein the pharmaceutically acceptable composition releases at least 80% of the compound in 40 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, wherein the buffer contains 0.25% sodium lauryl sulfate (wt/v);
wherein the composition comprises 33 weight percent of the solid dispersion based on the total weight of the composition; and
wherein the total mass of the composition is 600 mg.
2. The pharmaceutically acceptable composition of claim 1 , comprising less than about 3% by weight of an impurity compound represented by Formula (II):
based on the weight of the compound of Formula (I).
3. A pharmaceutically acceptable composition for orally delivering 50 mg of a compound represented by Formula (I):
comprising:
an intragranular blend, wherein the intragranular blend comprises:
a) a solid dispersion comprising:
i) 50 mg of the compound, wherein the compound is present in amorphous form, and
ii) hydroxypropyl methyl cellulose acetate succinate,
wherein the compound and the hydroxypropyl methyl cellulose acetate succinate are present in a ratio of about 25:75, and wherein the compound is present in the solid dispersion in an amount of 25 weight percent based on the total weight of the solid dispersion;
b) microcrystalline cellulose; and
c) lactose or a hydrate thereof; and
an extragranular blend, wherein the extragranular blend comprises a glidant; wherein the pharmaceutically acceptable composition releases at least 80% of the compound in 40 minutes when the composition is tested in 900 mL sodium acetate buffer at pH about 4.5 using a USP Apparatus II (Paddle Method) at about 37° C., with a paddle speed of about 75 rpm, wherein the buffer contains 0.25% sodium lauryl sulfate (wt/v);
wherein the composition comprises 33 weight percent of the solid dispersion based on the total weight of the composition; and
wherein the total mass of the composition is 600 mg.
4. The pharmaceutically acceptable composition of claim 3 , wherein the glidant is silicon dioxide.
5. The pharmaceutically acceptable composition of claim 3 , wherein the extragranular blend comprises:
about 0.5% by weight of silicon dioxide based on the total amount of the pharmaceutically acceptable composition; and
about 0.5% by weight of magnesium stearate based on the total amount of the of the pharmaceutically acceptable composition.
6. The pharmaceutically acceptable composition of claim 3 , comprising less than about 3% by weight of an impurity compound represented by Formula (II):
based on the weight of the compound of Formula (I).
7. A pharmaceutically acceptable composition for orally delivering 50 mg of a compound represented by Formula (I):
comprising:
an intragranular blend, wherein the intragranular blend comprises:
a) a solid dispersion comprising:
i) 50 mg of the corn pound, wherein the corn pound is present in amorphous form; and
ii) hydroxypropyl methyl cellulose acetate succinate,
wherein the compound is present in the solid dispersion in an amount of 25 weight percent based on the total weight of the solid dispersion; and
wherein the compound and the hydroxypropyl methyl cellulose acetate succinate are present in a ratio of corn pound: hydroxypropyl methyl cellulose acetate succinate of about 25:75; and
an extragranular blend, wherein the extragranular blend comprises a glidant;
wherein the pharmaceutically acceptable composition releases at least 80% of the compound in 40 minutes when the corn position 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, wherein the buffer contains 0.25% sodium lauryl sulfate (wt/v);
wherein the composition comprises 33 weight percent of the solid dispersion based on the total weight of the composition; and
wherein the total mass of the composition is 600 mg.
8. The pharmaceutically acceptable composition of claim 7 , comprising:
b) about 25-35% by weight microcrystalline cellulose based on the total amount of the pharmaceutically acceptable composition.
9. The pharmaceutically acceptable composition of claim 7 , comprising:
c) about 25-35% by weight of lactose or a hydrate thereof based on the total amount of the pharmaceutically acceptable composition.
10. The pharmaceutically acceptable composition of claim 7 , wherein the glidant is silicon dioxide.
11. The pharmaceutically acceptable composition of claim 7 , wherein the extragranular blend comprises:
about 0.5% by weight of silicon dioxide based on the total amount of the pharmaceutically acceptable composition; and
about 0.5% by weight of magnesium stearate based on the total amount of the of the pharmaceutically acceptable composition.
12. The pharmaceutically acceptable composition of claim 7 , comprising less than about 3% by weight of an impurity compound represented by Formula (II):
based on the weight of the compound of Formula (I).