Formulation of Syk inhibitors
Disclosed are pharmaceutical compositions comprising a compound having the formula: or a pharmaceutically acceptable salt thereof, or a hydrate of thereof, and at least one pharmaceutically acceptable polymer. The pharmaceutically acceptable salt of the compound of Formula I, or a hydrate thereof, can be a mesylate salt, including, for example, a mono-mesylate or a bis-mesylate salt, or a hydrate thereof. Also disclosed are methods of use for the pharmaceutical composition.
1. A composition comprising:
(i) a bis-mesylate salt of a compound of Formula I:
or a hydrate thereof, and
(ii) hydroxypropylmethylcellulose.
2. The composition of claim 1 , wherein the bis-mesylate salt is a monohydrate, bis-mesylate salt of the compound of Formula I.
3. The composition of claim 1 , wherein the bis-mesylate salt is a polymorph having an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.7, 12.9, 17.7, and 18.1.
4. The composition of claim 3 , wherein the bis-mesylate salt is a polymorph having an X-ray diffraction pattern further comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 13.8, 16.9, 22.9 and 26.1.
5. The composition of claim 1 , further comprising methanesulfonic acid.
6. The composition of claim 1 , wherein the bis-mesylate salt of the compound of Formula I is dispersed within a polymer matrix of the hydroxypropylmethylcellulose.
7. The composition of claim 1 , further comprising water.
8. The composition of claim 1 , wherein the composition is a feed solution for spray drying.
9. The composition of claim 1 , wherein the composition is a spray-dried powder.
10. The composition of claim 9 , wherein the powder is non-crystalline.
11. The composition of claim 9 , wherein the powder is characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.3 and between 26.1 to 26.6.
12. The composition of claim 1 , wherein the composition is a tablet.
13. The composition of claim 12 , further comprising at least one diluent, binder, disintegrant, surfactant, glidant, or lubricant, or any combinations thereof.
14. The composition of claim 13 , wherein one of the at least one diluent is mannitol.
15. The composition of claim 12 , further comprising any one or more of crospovidone, poloxamer, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose.
16. A composition comprising:
(i) a compound of Formula I:
or a cation thereof;
(ii) methanesulfonic acid, or an anion thereof; and
(iii) hydroxypropylmethylcellulose.
17. The composition of claim 16 , wherein the methanesulfonic acid, or an anion thereof, and the compound of Formula I, or a cation thereof, are present in the composition in a molar ratio of the methanesulfonic acid, or an anion thereof, to the compound of Formula I, or a cation thereof, of between 2:1 and 3:1.
18. The composition of claim 16 , wherein the composition comprises a polymer matrix obtainable from the hydroxypropylmethylcellulose.
19. The composition of claim 18 , wherein the compound of Formula I, or a cation thereof, and the methanesulfonic acid, or an anion thereof, are dispersed within the polymer matrix.
20. The composition of claim 16 , further comprising water.
21. The composition of claim 16 , wherein the composition is a feed solution for spray drying.
22. The composition of claim 16 , wherein the composition is a spray-dried powder.
23. The composition of claim 22 , wherein the powder is non-crystalline.
24. The composition of claim 23 , wherein the powder is characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.3 and between 26.1 to 26.6.
25. The composition of claim 16 , wherein the composition is a tablet.
26. The composition of claim 25 , further comprising at least one diluent, binder, disintegrant, surfactant, glidant, or lubricant, or any combinations thereof.
27. The composition of claim 26 , wherein one of the at least one diluent is mannitol.
28. The composition of claim 16 , further comprising any one or more of crospovidone, poloxamer, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose.
29. A unit dosage form comprising the composition of claim 1 .
30. A unit dosage form comprising the composition of claim 16 .
31. A composition comprising:
(i) a bis-mesylate salt of a compound of Formula I:
or a hydrate thereof, wherein the bis-mesylate salt is a polymorph having an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.7, 12.9, 17.7, and 18.1, and
(ii) hydroxypropylmethylcellulose, wherein the a bis-mesylate salt of a compound of Formula I, or a hydrate thereof, is dispersed within a polymer matrix of the hydroxypropylmethylcellulose.
32. The composition of claim 31 , further comprising water.
33. The composition of claim 32 , wherein the composition is a feed solution for spray drying.
34. The composition of claim 31 , wherein the composition is a spray-dried powder.
35. The composition of claim 34 , wherein the powder is non-crystalline.
36. The composition of claim 35 , wherein the composition is a tablet.
37. The tablet of claim 36 , further comprising at least one diluent, binder, disintegrant, surfactant, glidant, or lubricant, or any combination thereof.
38. The composition of claim 37 , wherein one of the at least one diluent is mannitol.
39. The composition of claim 38 , further comprising at least one component selected from the group of crospovidone, poloxamer, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose.
40. The composition of claim 3 , wherein the bis-mesylate salt is a polymorph having an X-ray diffraction pattern further comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 13.8, 16.9, 22.9 and 26.1.
41. The composition of claim 1 , wherein the hydroxypropylmethylcellulose comprises from about 1% w/w to about 50% w/w of the composition.
42. The composition of claim 1 , wherein the hydroxypropylmethylcellulose comprises from about 5% w/w to about 25% w/w of the composition.
43. The composition of claim 1 , wherein the hydroxypropylmethylcellulose comprises from about 10% w/w to about 20% w/w of the composition.
44. The composition of claim 16 , wherein the hydroxypropylmethylcellulose comprises from about 1% w/w to about 50% w/w of the composition.
45. The composition of claim 16 , wherein the hydroxypropylmethylcellulose comprises from about 5% w/w to about 25% w/w of the composition.
46. The composition of claim 16 , wherein the hydroxypropylmethylcellulose comprises from about 10% w/w to about 20% w/w of the composition.
47. The composition of claim 31 , wherein the hydroxypropylmethylcellulose comprises from about 1% w/w to about 50% w/w of the composition.
48. The composition of claim 31 , wherein the hydroxypropylmethylcellulose comprises from about 5% w/w to about 25% w/w of the composition.
49. The composition of claim 31 , wherein the hydroxypropylmethylcellulose comprises from about 10% w/w to about 20% w/w of the composition.
50. The composition of claim 31 wherein the bis-mesylate salt of the compound of Formula I, or a hydrate thereof, comprises from about 30% w/w to about 45% w/w of the composition, and hydroxypropylmethylcellulose comprises from about 10% w/w to about 30% w/w of the composition.
51. The composition of claim 50 further comprising mannitol from about 20% w/w to about 30% w/w of the composition.
52. The composition of claim 50 further comprising poloxamer from about 1% w/w to about 5% w/w of the composition.
53. The composition of claim 50 further comprising colloidal silicon dioxide from about 1% w/w to about 2% w/w of the composition.
54. The composition of claim 50 further comprising microcrystalline cellulose from about 1% w/w to about 5% w/w of the composition.
55. The composition of claim 50 further comprising magnesium stearate from about 0.5% w/w to about 2% w/w of the composition.
56. The composition of claim 50 further comprising crospovidone from about 5% w/w to about 15% w/w of the composition.
57. The composition of claim 31 , wherein:
a) the bis-mesylate salt of a compound of Formula I, or a hydrate thereof, comprises from about 30% w/w to about 45% w/w of the composition;
b) hydroxypropylmethylcellulose comprises from about 10% w/w to about 30% w/w of the composition;
c) mannitol comprises from about 20% w/w to about 30% w/w of the composition;
d) crospovidone comprises from about 5% w/w to about 15% w/w of the composition;
e) colloidal silicon dioxide comprises from about 1% w/w to about 2% w/w of the composition; and
f) microcrystalline cellulose comprises from about 1% w/w to about 5% w/w of the composition.