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Details for Patent: 8,288,440

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Details for Patent: 8,288,440

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)
Assignee: Merck Sharp & Dohme Corp. (Rahway, NJ)
Filing Date:Jan 13, 2010
Application Number:12/686,812
Claims:1. A process of producing a pharmaceutical composition comprising suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, comprising the steps of: (a) blending about 60-5% of a first batch of crystalline suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof active ingredient 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 or a pharmaceutically acceptable salt or hydrate thereof 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.

2. The process of claim 1, wherein the first batch of crystalline active ingredient has a mean particle size of less than about 50 .mu.m and the second batch of crystalline active ingredient has a mean particle size of about 120-160 .mu.m.

3. The process of claim 1, wherein 95% of the first batch of crystalline active ingredient is less than about 100 .mu.m and 95% of the second batch of crystalline active ingredient is less than about 300 .mu.m.

4. The process of claim 1, wherein step a) is blending about 40-20% of a first batch of crystalline active ingredient having a mean particle size of about 25 to 45 .mu.m and about 60-80% of a second batch of crystalline active ingredient having a mean particle size of about 130-180 .mu.m.

5. The process of claim 1, wherein step a) is blending about 30% of a first batch of crystalline active ingredient having a mean particle size of about 25 to 45 .mu.m and about 70% of a second batch of crystalline active ingredient having a mean particle size of about 130-180 .mu.m.

6. The process of claim 1, wherein the active ingredient is suberoylanilide hydroxamic acid.

7. The process of claim 2, wherein the active ingredient is suberoylanilide hydroxamic acid.

8. The process of claim 3, wherein the active ingredient is suberoylanilide hydroxamic acid.

9. The process of claim 4, wherein the active ingredient is suberoylanilide hydroxamic acid.

10. The process of claim 5, wherein the active ingredient is suberoylanilide hydroxamic acid.

11. The process of claim 1, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition has an in vitro dissolution profile with a similarity factor (f2) of at least 50 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.

12. The process of claim 2, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition has an in vitro dissolution profile with a similarity factor (f2) of at least 50 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.

13. The process of claim 3, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition has an in vitro dissolution profile with a similarity factor (f2) of at least 50 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.

14. The process of claim 4, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition has an in vitro dissolution profile with a similarity factor (f2) of at least 50 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.

15. The process of claim 5, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition has an in vitro dissolution profile with a similarity factor (f2) of at least 50 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.

16. The process of claim 6, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition 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.

17. The process of claim 7, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition 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.

18. The process of claim 8, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition 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.

19. The process of claim 9, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition 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.

20. The process of claim 10, wherein about 100 mg of the blended crystalline active ingredient in the pharmaceutical composition 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.

21. A process of producing a pharmaceutical composition comprising suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, wherein about 100 mg of the active ingredient has an in vitro dissolution profile with a similarity factor (f2) of at least 50 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, comprising the steps of: (a) milling crystalline suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof to produce at least a first batch of milled crystalline active ingredient having a mean particle size in the range of about 25 to 45 .mu.m; (b) crystallizing suberoylanilide hydroxamic acid or a pharmaceutically acceptable salt or hydrate thereof to produce at least a second batch of crystalline active ingredient having a mean particle size in the range of about 130 to 180 .mu.m; (c) blending said at least first batch with said at least second batch of crystalline active ingredient; and (d) producing said pharmaceutical composition from said blended first and second batch.

22. The process of claim 21, wherein in step (c), about 60-80% of the second batch crystalline active ingredient is blended with about 40-20% of the first batch milled crystalline active ingredient.

23. The process of claim 21, wherein step (d) is performed by encapsulating a portion of the blended crystalline active ingredient.

24. The process of claim 22, wherein the active ingredient is suberoylanilide hydroxamic acid.
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