Formulations of a compound modulating kinases
Provided are compositions comprising Compound I having the following structure: or a pharmaceutically acceptable salt thereof, and a solubilizing agent; methods of making the same; and methods of using the same.
1. A method for preparing a composition comprising 40% to 60% W/W of Compound I:
wherein Compound I is a crystalline HCl salt characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.3, 23.3 and 28.2°2θ as determined on a diffractometer using Cu-Kα radiation; 20% to 35% W/W of a poloxamer; 10% to 22% W/W of an excipient; 1% to 5% W/W of a disintegrant; and 0.5% to 3% W/W of a lubricant; wherein the method comprises (1) mixing Compound I and the poloxamer to provide a first mixture; (2) roller-compacting the first mixture to provide roller-compacted ribbons; (3) milling the roller-compacted ribbons to provide granules; (4) blending the granules, the excipient and the disintegrant to form a second mixture; and (5) blending the second mixture and the lubricant to provide a final blend.
2. The method of claim 1 , wherein the mixing in (1) employs a convection mixer; the roller-compacting in (2) employs a dry granulator to provide roller-compacted ribbons; the milling in (3) employs screening mills or cutting mills; the blending in (4) employs a diffusion mixer; and the blending in (5) employs a diffusion mixer.
3. The method of claim 1 , wherein the poloxamer is poloxamer 407 .
4. The method of claim 1 , wherein the excipient is mannitol; the disintegrant is crospovidone; and the lubricant is magnesium stearate.
5. The method of claim 1 , wherein the poloxamer is poloxamer 407 ; the excipient is mannitol; the disintegrant is crospovidone; and the lubricant is magnesium stearate.
6. A composition prepared by the method of claim 1 .
7. The composition of claim 6 , wherein the poloxamer is poloxamer 407 .
8. The composition of claim 6 , wherein the diffractogram further comprises peaks at 16.6 and 20.9°2θ±0.2°.
9. The composition of claim 6 , comprising 45% to 55% W/W of Compound I; 24% to 32% W/W of poloxamer; 14% to 20% W/W of excipient; 2% to 4% W/W of disintegrant; and 1.0% to 2.5% W/W of lubricant.
10. The composition of claim 6 , comprising 48% to 53% W/W of Compound I; 26% to 29% W/W of poloxamer; 15% to 18% W/W of excipient; 2.5% to 3.5% W/W of disintegrant; and 1.2% to 1.8% W/W of lubricant.
11. The composition of claim 6 , comprising about 51.2% W/W of Compound I; about 27.6% W/W of poloxamer; about 16.8% W/W of excipient; about 3% W/W of disintegrant; and about 1.5% W/W of lubricant.
12. The composition of claim 6 , wherein the excipient is mannitol; the disintegrant is crospovidone; and the lubricant is magnesium stearate.
13. The composition of claim 6 , wherein the poloxamer is poloxamer 407 ; the excipient is mannitol; the disintegrant is crospovidone; and the lubricant is magnesium stearate.
14. The composition of claim 13 , comprising 45% to 55% W/W of Compound I; 24% to 32% W/W of poloxamer 407 ; 14% to 20% W/W of mannitol; 2% to 4% W/W of crospovidone; and 1.0% to 2.5% W/W of magnesium stearate.
15. The composition of claim 13 , comprising 48% to 53% W/W of Compound I; 26% to 29% W/W of poloxamer 407 ; 15% to 18% W/W of mannitol; 2.5% to 3.5% W/W of crospovidone; and 1.2% to 1.8% W/W of magnesium stearate.
16. The composition of claim 13 , comprising about 51.2% W/W of Compound I; about 27.6% W/W of poloxamer 407 ; about 16.8% W/W of mannitol; about 3% W/W of crospovidone; and about 1.5% W/W of magnesium stearate.