Oral Formulations of a Hedgehog Pathway Inhibitor

• US 20110135739A1
• Filed: 11/08/2010
• Published: 06/09/2011
• Est. Priority Date: 11/06/2009
• Status: Abandoned Application

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Sheikh, Hana, Lee, John J., Carter, Bennett
• Application Number:
  US12/941,987
• Publication Number:
  US 20110135739A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Oral formulations of the drug product IPI-926 are described. Pharmaceutical formulations (e.g., solid dosage forms) that are useful for the oral administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., IPI-926), to a human or animal subject are disclosed.

The formulations can further include, for example and without limitation, one or more other pharmaceutically-acceptable filler(s), binder(s), surfactant(s), and disintegrant(s); as well as one or more other therapeutic agent(s). Methods of preparing and using said formulations are also disclosed.

Claims

1. A pharmaceutical formulation comprising a compound of formula (I):

2. The formulation of claim 1, wherein from 10 percent to 60 percent of the formulation have a particle size of less than 250 micrometers.

3. The formulation of claim 1, wherein from 10 percent to 30 percent of the formulation have a particle size of less than 250 micrometers.

4. The formulation of claim 1, wherein from 20 percent to 90 percent of the formulation have a particle size that is greater than or equal to 250 micrometers.

5. The formulation of claim 4, wherein from 30 percent to 80 percent of the formulation have a particle size that is greater than or equal to 500 micrometers.

6. The formulation of claim 1, wherein from 40 percent to 90 percent of the formulation have a particle size that is greater than or equal to 250 micrometers.

7. The formulation of claim 6, wherein from 40 percent to 80 percent of the formulation have a particle size that is greater than or equal to 500 micrometers.

8. The formulation of claim 1, wherein from 10 percent to 60 percent of the formulation have a particle size of less than 250 micrometers;

and from 40 percent to 90 percent of the formulation have a particle size that is greater than or equal to 250 micrometers.

9. The formulation of claim 8, wherein from 40 percent to 80 percent of the formulation have a particle size that is greater than or equal to 500 micrometers.

10. The formulation of claim 1, wherein the formulation has a particle size of at most about 1000 micrometers.

11. The formulation of claim 10, wherein from 20 percent to 90 percent of the formulation have a particle size of from 250 micrometers to 1000 micrometers.

12. The formulation of claim 11, wherein from 30 percent to 70 percent of the formulation have a particle size of from 500 micrometers to 1000 micrometers.

13. The formulation of claim 10, wherein from 40 percent to 90 percent of the formulation have a particle size of from 250 micrometers to 1000 micrometers.

14. The formulation of claim 13, wherein from 40 percent to 80 percent of the formulation have a particle size of from 500 micrometers to 1000 micrometers.

15. The formulation of claim 14, wherein from 40 percent to 80 percent of the formulation have a particle size of from 500 micrometers to 850 micrometers.

16. The formulation of claim 10, wherein from 10 percent to 60 percent of the formulation have a particle size of less than 250 micrometers;

and from 40 percent to 90 percent of the formulation have a particle size of from 250 micrometers to 1000 micrometers.

17. The formulation of claim 16, wherein from 40 percent to 80 percent of the formulation have a particle size of from 500 micrometers to 1000 micrometers.

18. The formulation of claim 17, wherein from 40 percent to 80 percent of the formulation have a particle size of from 500 micrometers to 850 micrometers.

27. The formulation of claim 1, wherein when the formulation is stirred at 37°

C. in a dissolution media selected from 0.1 N aqueous HCl and 0.1 N aqueous HCl/0.5% Tween and at an maximum concentration selected from 0.011 mg of the compound of formula (I)/mL of dissolution media, 0.033 mg of the compound of formula (I)/mL of dissolution media, and 0.133 mg of the compound of formula (1)/mL of dissolution media, dissolution of the compound of formula (I) is at least 75% complete after 90 minutes as determined by HPLC.

28. The formulation of claim 1, wherein when the formulation is stable upon actual or simulated storage at 5°

C. for at least 6 months.

29. The formulation of claim 1, wherein when the formulation is stable upon actual or simulated storage at 25°

C./60% relative humidity for at least 3 months.

30. The formulation of claim 1, wherein when the formulation is stable upon actual or simulated storage at 40°

C./75% relative humidity for 1 month.

31. The formulation of claim 1, wherein administration of a single dose of the formulation to a beagle dog produces a mean peak plasma concentration (Cmax) of the compound of formula (I) of between about 190 and 220 ng/mL for a formulation containing 30 mg of the compound of formula (I) and between about 60 and 80 ng/mL for a formulation containing 10 mg of the compound of formula (I).

32. The formulation of claim 1, wherein daily administration of the formulation to a human produces a mean steady state area under the concentration time curve (AUC_{(0-24 hrs)}) of the compound of formula (I) of between 5000 and 15,000 nghr/mL.

33. The formulation of claim 1, wherein the formulation comprises between 5% and 50% (w/w) of the active compound of formula (I).

34. The formulation of claim 33, wherein the formulation comprises between 5% and 15% (w/w) of the active compound of formula (I).

35. The formulation of claim 1, wherein the formulation comprises from 5 milligrams to 500 milligrams of the active compound of formula (I).

36. The formulation of claim 35, wherein the formulation comprises 10 milligrams or 30 milligrams of the active compound of formula (I).

37. The formulation of claim 33, wherein the formulation comprises between 20% and 30% (w/w) of the active compound of formula (I).

38. The formulation of claim 1, wherein the formulation comprises from 110 milligrams to 130 milligrams of the active compound of formula (I).

39. The formulation of claim 38, wherein the formulation comprises 120 milligrams of the active compound of formula (I).

40. The formulation of claim 1, wherein the compound of formula (I) is the hydrochloride salt.

41. The formulation of claim 1, wherein the formulation is a solid dosage form.

42. The formulation of claim 41, wherein the solid dosage form is a capsule or tablet.

43. The formulation of claim 42, wherein the solid dosage form is a capsule.

44. The formulation of claim 43, wherein the capsule is a gelatin capsule or a hydroxypropyl methylcellulose capsule.

45. The formulation of claim 1, wherein the formulation further comprises a filler.

46. The formulation of claim 45, wherein the filler is selected from microcrystalline cellulose, lactose, compressible sugar, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, and calcium sulfate.

47. The formulation of claim 45, wherein the filler is microcrystalline cellulose.

48. The formulation of claim 1, wherein the formulation further comprises a binder.

49. The formulation of claim 48, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, pregelatizined starch, sucrose, and acacia gum.

50. The formulation of claim 49, wherein the binder is polyvinylpyrrolidone.

51. The formulation of claim 1, wherein the formulation further comprises a surfactant.

52. The formulation of claim 51, wherein the surfactant is selected from Tween 80, Tween 20, sodium laurel sulfate and sodium dodecyl sulfate.

53. The formulation of claim 52, wherein the surfactant is Tween 80.

54. The formulation of claim 1, wherein the formulation further comprises a disintegrant.

55. The formulation of claim 54, wherein the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, and starch.

56. The formulation of claim 1, wherein the formulation further comprises microcrystalline cellulose, polyvinylpyrrolidine and Tween 80.

57. The formulation of claim 56, wherein the formulation further comprises croscarmellose sodium.

58. The formulation of claim 1, wherein the formulation comprises:

59. The formulation of claim 1, wherein the formulation comprises:

60. The formulation of claim 1, wherein the formulation comprises:

61. The formulation according to claim 1, wherein the formulation is prepared by granulation.

69. A method of treating cancer comprising orally administering a pharmaceutical formulation as claimed in claim 1 to a patient in need thereof.

70. The method of claim 69, wherein the method further comprises the step of administering one or more other cancer therapeutic agents.

19. An oral pharmaceutical dosage formulation, comprising a compound of formula (I):

20. The formulation of claim 19, wherein at least 60% of particles of said formulation have a particle size of greater than 500 micrometers.

21. The formulation of claim 19, wherein at least 80% of particles of said formulation have a particle size of greater than 500 micrometers.

22. An oral pharmaceutical dosage formulation, comprising a compound of formula (I):

23. The formulation of claim 22, wherein at least 40% of particles of said formulation have a particle size of greater than 250 micrometers.

24. The formulation of claim 22, wherein at least 50% of particles of said formulation have a particle size of greater than 250 micrometers.

25. The formulation of claim 22, wherein at least 20% of particles of said formulation have a particle size of greater than 500 micrometers.

26. The formulation of claim 22, wherein at least 50% of particles of said formulation have a particle size of greater than 500 micrometers.

62. A method of making a pharmaceutical formulation comprising granulating a mixture of a compound of formula (I):

63. The method of claim 62, wherein the liquid comprises water.

64. The method of claim 63, wherein the liquid is an aqueous solution of a surfactant.

65. The method according to claim 62, wherein the ratio of the weight of the liquid to the weight of the granulation is greater than 0.25.

66. The method according to claim 62, wherein the method further comprises granulating a filler in the mixture.

67. The method according to claim 62, wherein the method further comprises granulating a binder in the mixture.

68. The method according to claim 62, further comprising the step of drying the granulation.