Claims for Patent: 8,450,372

Summary for Patent: 8,450,372

Title:	Formulations of suberoylanilide hydroxamic acid and methods for producing same
Abstract:	The present invention provides a pharmaceutical composition or crystalline composition with a specific dissolution profile, which comprises suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. The present invention provides a process of producing said crystalline composition or pharmaceutical composition. The present invention also provides compositions with a specific particle size distribution.
Inventor(s):	Wong; Jeannie Chow (Chicago, IL), Cote; Aaron S. (West Windsor, NJ), Dienemann; Erik A. (Metuchen, NJ), Gallagher; Kimberly (Green Lane, PA), Ikeda; Craig (Harleysville, PA), Moser; Justin (Collegeville, PA), Rajniak; Pavol (Lansdale, PA), Reed; Robert A. (Line Lexington, PA), Starbuck; Cindy (Branchburg, NJ), Tung; Hsien-Hsin (Edison, NJ), Wang; Qingxi (Ambler, PA), Cohen; Benjamin Max (Cranford, NJ), Capodanno; Vincent R. (Hillsborough, NJ), Sell; Brian (Royersford, PA), Miller; Thomas A. (Wakefield, MA)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:	12/686,843
Patent Claims:	1. A method of treating cancer in a patient comprising the step of orally administering to the patient a pharmaceutical composition comprising suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient in solid form, wherein about 100 mg of the active ingredient has an in vitro dissolution profile with a similarity factor (f2) of at least 56 to 100 compared to the reference dissolution profile of 52.7% dissolved at 10 minutes, 61.7% dissolved at 15 minutes, 67.7% dissolved at 20 minutes, 75.5% dissolved at 30 minutes, 82.6% dissolved at 45 minutes, and 87.0% dissolved at 60 minutes in vitro, wherein the dissolution profile is measured using a USP Dissolution Apparatus II with a helical sinker in 900 mL of 2.0% Tween at a temperature of 37.+-.0.5.degree. C., and paddles rotated at 100 rpm, and optionally a pharmaceutically acceptable excipient. 2. A method of treating cancer in a patient comprising the step of orally administering a pharmaceutical composition comprising suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient in solid form, wherein about 100 mg of the active ingredient has an in vitro dissolution profile of 46-60% dissolved at 10 minutes, 55-69% dissolved at 15 minutes, 61-75% dissolved at 20 minutes, 69-83% dissolved at 30 minutes, 76-90% dissolved at 45 minutes, and 80-94% dissolved at 60 minutes in vitro, wherein the dissolution profile is measured using a USP Dissolution Apparatus II with a helical sinker in 900 mL of 2.0% Tween at a temperature of 37.+-.0.5.degree. C., and paddles rotated at 100 rpm, and optionally a pharmaceutically acceptable excipient. 3. The method of claim 1, wherein the % volume of active ingredient with particle sizes from about 120 to about 250 microns is in the range of about 4.0% to about 12%, and the % volume of active ingredient with particle sizes from about 35 to about 40 microns is in the range of about 3.0% to about 7%. 4. The method of claim 2, wherein the % volume of active ingredient with particle sizes from about 120 to about 250 microns is in the range of about 4.0% to about 12%, and the % volume of active ingredient with particle sizes from about 35 to about 40 microns is in the range of about 3.0% to about 7%. 5. The method of claim 1, wherein the pharmaceutical composition is formulated as a powder in a single capsule or tablet, wherein the amount of the active ingredient is about 100 mg of suberoylanilide hydroxamic acid; or is formulated as a powder in two capsules or tablets, wherein the amount of active ingredient in each capsule or tablet is about 50 mg of suberoylanilide hydroxamic acid. 6. The method of claim 1, wherein the pharmaceutical composition is formulated as a powder in a single capsule or tablet, wherein the amount of the active ingredient is about 200 mg of suberoylanilide hydroxamic acid. 7. The method of claim 1, wherein f2 is 60 to 100. 8. The method of claim 1, wherein f2 is 65 to 100. 9. The method of claim 1, wherein f2 is 70 to 100. 10. The method of claim 1, wherein the pharmaceutical composition is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 11. The method of claim 2, wherein the pharmaceutical composition is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 12. The method of claim 3, wherein the pharmaceutical composition is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 13. The method of claim 4, wherein the pharmaceutical composition is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 14. The method of claim 7, wherein the pharmaceutical composition is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 15. The method of claim 8, wherein the pharmaceutical composition is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 16. The method of claim 9, wherein the pharmaceutical composition is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 17. The method of claim 10, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 18. The method of claim 11, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 19. The method of claim 12, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 20. The method of claim 13, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 21. The method of claim 14, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 22. The method of claim 15, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 23. The method of claim 16, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 24. The method of claim 10, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid and characterized by an X-ray diffraction pattern comprising characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2.theta. using a Copper X-ray source. 25. The method of claim 11, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid and characterized by an X-ray diffraction pattern comprising characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2.theta. using a Copper X-ray source. 26. The method of claim 12, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid and characterized by an X-ray diffraction pattern comprising characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2.theta. using a Copper X-ray source. 27. The method of claim 13, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid and characterized by an X-ray diffraction pattern comprising characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2.theta. using a Copper X-ray source. 28. The method of claim 14, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid and characterized by an X-ray diffraction pattern comprising characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2.theta. using a Copper X-ray source. 29. The method of claim 15, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid and characterized by an X-ray diffraction pattern comprising characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2.theta. using a Copper X-ray source. 30. The method of claim 16, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid and characterized by an X-ray diffraction pattern comprising characteristic peaks at 9.4, 17.5, 19.4, 20.0, 24.0 and 28.0 degrees 2.theta. using a Copper X-ray source. 31. The method of claim 1, wherein the active ingredient is obtained by the process of: (a) blending about 60-5% of a first batch of crystalline active ingredient having a mean particle size of less than about 60 .mu.m and about 40-95% of a second batch of crystalline active ingredient having a mean particle size of about 100-250 .mu.m; and (b) encapsulating a portion of the blended crystalline active ingredient to produce the pharmaceutical composition. 32. The method of claim 1, wherein the active ingredient is obtained by the process of: (a) blending 40-20% of a first batch of crystalline active ingredient having a mean particle size of 25 to 45 .mu.m and 60-80% of a second batch of crystalline active ingredient having a mean particle size of 130-180 .mu.m; and (b) encapsulating a portion of the blended crystalline active ingredient to produce the pharmaceutical composition. 33. The method of claim 32, wherein step (a) comprises the step of: blending 30% of a first batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of 25 to 45 .mu.m and 70% of a second batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of 130-180 .mu.m. 34. The method of claim 24, wherein the active ingredient is obtained by the process of: (a) blending 40-20% of a first batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of 25 to 45 .mu.m and 60-80% of a second batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of 130-180 .mu.m; and (b) encapsulating a portion of the blended crystalline suberoylanilide hydroxamic acid to produce the pharmaceutical composition. 35. The method of claim 34, wherein step (a) comprises the step of: blending 30% of a first batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of 25 to 45 .mu.m and 70% of a second batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of 130-180 .mu.m. 36. The method of claim 10, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid with unit cell parameters of a=10.9 .ANG., b=7.9 .ANG., c=16.4 .ANG., .alpha.=90.degree., .beta.=97.8.degree., .gamma.=90.degree., space group P2.sub.1/n. 37. The method of claim 11, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid with unit cell parameters of a=10.9 .ANG., b=7.9 .ANG., c=16.4 .ANG., .alpha.=90.degree., .beta.=97.8.degree., .gamma.=90.degree., space group P2.sub.1/n. 38. The method of claim 1, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 39. The method of claim 2, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 40. The method of claim 10, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 41. The method of claim 11, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 42. The method of claim 24, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 43. The method of claim 25, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 44. The method of claim 36, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 45. The method of claim 37, wherein the total % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the total % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 46. The method of claim 1, wherein the cancer is non-Hodgkins Lymphoma. 47. The method of claim 2, wherein the cancer is non-Hodgkins Lymphoma. 48. The method of claim 10, wherein the cancer is non-Hodgkins Lymphoma. 49. The method of claim 11, wherein the cancer is non-Hodgkins Lymphoma. 50. The method of claim 24, wherein the cancer is non-Hodgkins Lymphoma. 51. The method of claim 25, wherein the cancer is non-Hodgkins Lymphoma. 52. The method of claim 36, wherein the cancer is non-Hodgkins Lymphoma. 53. The method of claim 37, wherein the cancer is non-Hodgkins Lymphoma. 54. The method of claim 38, wherein the cancer is non-Hodgkins Lymphoma. 55. The method of claim 39, wherein the cancer is non-Hodgkins Lymphoma. 56. The method of claim 40, wherein the cancer is non-Hodgkins Lymphoma. 57. The method of claim 41, wherein the cancer is non-Hodgkins Lymphoma. 58. The method of claim 42, wherein the cancer is non-Hodgkins Lymphoma. 59. The method of claim 43, wherein the cancer is non-Hodgkins Lymphoma. 60. The method of claim 44, wherein the cancer is non-Hodgkins Lymphoma. 61. The method of claim 45, wherein the cancer is non-Hodgkins Lymphoma.