Details for Patent: 8,093,295

Title:	Formulations of suberoylanilide hydroxamic acid and methods for producing the 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 (Jersey City, NJ), Cohen; Benjamin Max (Cranford, NJ), 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), Sell; Brian (Royersford, PA), Starbuck; Cindy (Doylestown, PA), Tung; Hsien-Hsin (Grayslake, IL), Wang; Qingxi (Ambler, PA), Capodanno; Vincent R. (Hillsborough, NJ)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Filing Date:	May 16, 2006
Application Number:	11/663,165
Claims:	1. A pharmaceutical composition for oral administration comprising about 100 mg suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient in solid form, wherein the entire 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, and optionally a pharmaceutically acceptable excipient, 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. 2. The pharmaceutical composition of claim 1 that 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 that 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. 3. The pharmaceutical composition of claim 1, wherein f2 is 60 to 100. 4. The pharmaceutical composition of claim 3 that 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 that is formulated as a powder in two capsules or two tablets, wherein the amount of active ingredient in each capsule or tablet is about 50 mg of suberoylanilide hydroxamic acid. 5. The pharmaceutical composition of claim 3, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 6. The pharmaceutical composition of claim 5, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 7. The pharmaceutical composition of claim 5, 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. 8. The pharmaceutical composition of claim 5, 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. 9. The pharmaceutical composition of claim 1, wherein f2 is 65 to 100. 10. The pharmaceutical composition of claim 9 that 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; or that 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. 11. The pharmaceutical composition of claim 9, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 12. The pharmaceutical composition of claim 11, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 13. The pharmaceutical composition 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. 14. The pharmaceutical composition 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. 15. The pharmaceutical composition of claim 1, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid of Form I. 16. The pharmaceutical composition of claim 1, wherein f2 is 70 to 100. 17. The pharmaceutical composition of claim 16 that 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; or that 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. 18. The pharmaceutical composition of claim 16, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid of Form I. 19. The pharmaceutical composition of claim 16, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 20. The pharmaceutical composition of claim 19, 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., and lacking peaks at 13.4-14.0 and 22.7-23.0 degrees 2.theta. using a Copper X-ray source. 21. The pharmaceutical composition of claim 19, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 22. The pharmaceutical composition of claim 19, 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. 23. The pharmaceutical composition of claim 19, 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. 24. The pharmaceutical composition of claim 1, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 25. The pharmaceutical composition of claim 24, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 26. The pharmaceutical composition of claim 24, 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 pharmaceutical composition of claim 26 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. 28. The pharmaceutical composition of claim 27, 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. 29. The pharmaceutical composition of claim 24, 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., and lacking peaks at 13.4-14.0 and 22.7-23.0 degrees 2.theta. using a Copper X-ray source. 30. The pharmaceutical composition of claim 24, 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. 31. The pharmaceutical composition of claim 24 obtained by the process of: (a) blending about 60-5% of a first batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of less than about 60 .mu.m and about 40-95% of a second batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of about 100-250 .mu.m; and (b) encapsulating a portion of the blended crystalline suberoylanilide hydroxamic acid to produce the pharmaceutical composition. 32. The pharmaceutical composition of claim 24 or 11, wherein the % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 33. The pharmaceutical composition of claim 24 or 11, 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%. 34. A single pharmaceutical oral dosage unit form comprising about 120 mg to about 600 mg of suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient in solid form, wherein a portion of said dosage unit form comprising 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, and optionally a pharmaceutically acceptable excipient, 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. 35. The single pharmaceutical oral dosage unit form of claim 34, wherein a portion of said dosage unit form comprising about 100 mg of the active ingredient has an in vitro dissolution profile with a similarity factor (f2) of at least 70 to 100 compared to the reference dissolution profile. 36. The single pharmaceutical oral dosage unit form of claim 35, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid of Form I. 37. The single pharmaceutical oral dosage unit form of claim 35, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 38. The single pharmaceutical oral dosage unit form of claim 37, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 39. The single pharmaceutical oral dosage unit form of claim 37, 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. 40. The single pharmaceutical oral dosage unit form of claim 37, 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. 41. The single pharmaceutical oral dosage unit form of claim 35 that is formulated as a powder in a single capsule or tablet, wherein the amount of active ingredient in the capsule or tablet is about 200 mg of suberoylanilide hydroxamic acid. 42. The single pharmaceutical oral dosage unit form of claim 34, wherein a portion of said dosage unit form comprising about 100 mg of the active ingredient has an in vitro dissolution profile with a similarity factor (f2) of at least 60 to 100 compared to the reference dissolution profile. 43. The single pharmaceutical oral dosage unit form of claim 42, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 44. The single pharmaceutical oral dosage unit form of claim 43, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 45. The single pharmaceutical oral dosage unit form of claim 43, 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. 46. The single pharmaceutical oral dosage unit form of claim 43, 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. 47. The single pharmaceutical oral dosage unit form of claim 42 that is formulated as a powder in a single capsule or tablet, wherein the amount of active ingredient in the capsule or tablet is about 200 mg of suberoylanilide hydroxamic acid. 48. The single pharmaceutical oral dosage unit form of claim 34, wherein a portion of said dosage unit form comprising about 100 mg of the active ingredient has an in vitro dissolution profile with a similarity factor (f2) of at least 65 to 100 compared to the reference dissolution profile. 49. The single pharmaceutical oral dosage unit form of claim 48, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 50. The single pharmaceutical oral dosage unit form of claim 49, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 51. The single pharmaceutical oral dosage unit form of claim 49, 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. 52. The single pharmaceutical oral dosage unit form of claim 49, 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. 53. The single pharmaceutical oral dosage unit form of claim 48 that is formulated as a powder in a single capsule or tablet, wherein the amount of active ingredient in the capsule or tablet is about 200 mg of suberoylanilide hydroxamic acid. 54. The single pharmaceutical oral dosage unit form of claim 34, that is formulated as a powder blend of the active ingredient with or without the excipient in capsule form. 55. The single pharmaceutical oral dosage unit form of claim 54, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid. 56. The single pharmaceutical oral dosage unit form of claim 54, 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. 57. The single pharmaceutical oral dosage unit form of claim 54, 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., and lacking peaks at 13.4-14.0 and 22.7-23.0 degrees 2.theta. using a Copper X-ray source. 58. The single pharmaceutical oral dosage unit form of claim 37, 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., and lacking peaks at 13.4-14.0 and 22.7-23.0 degrees 2.theta. using a Copper X-ray source. 59. The single pharmaceutical oral dosage unit form of claim 54, 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. 60. The single pharmaceutical oral dosage unit of claim 56 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 single pharmaceutical oral dosage unit. 61. The single pharmaceutical oral dosage unit of claim 60, 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. 62. The single pharmaceutical oral dosage unit of claim 54 obtained by the process of: (a) blending about 60-5% of a first batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of less than about 60 .mu.m and about 40-95% of a second batch of crystalline suberoylanilide hydroxamic acid having a mean particle size of about 100-250 .mu.m; and (b) encapsulating a portion of the blended crystalline suberoylanilide hydroxamic acid to produce the single pharmaceutical oral dosage unit. 63. The single pharmaceutical oral dosage unit form of claim 54 or 37, 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%. 64. The single pharmaceutical oral dosage unit form of claim 54 or 37, wherein the % volume of active ingredient with particle size less than about 105 microns is about 45-85% and the % volume of active ingredient with particle size more than about 105 microns is about 55-15%. 65. The single pharmaceutical oral dosage unit form of claim 34, wherein the active ingredient is crystalline suberoylanilide hydroxamic acid of Form I. 66. The single pharmaceutical oral dosage unit form of claim 34 that is formulated as a powder in a single capsule or tablet, wherein the amount of active ingredient in the capsule or tablet is about 200 mg of suberoylanilide hydroxamic acid. 67. A pharmaceutical composition for oral administration comprising about 100 mg of suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient in solid form, wherein the entire 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, and optionally a pharmaceutically acceptable excipient, 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. 68. A single pharmaceutical oral dosage unit form comprising about 120 mg to about 600 mg of suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient in solid form, wherein a portion of said dosage unit form comprising 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, and optionally a pharmaceutically acceptable excipient, 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.