Formulations of suberoylanilide hydroxamic acid and methods for producing same
View Patent ↗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.
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 μm 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 μm; 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 μm and the second batch of crystalline active ingredient has a mean particle size of about 120-160 μm.
3. The process of claim 1 , wherein 95% of the first batch of crystalline active ingredient is less than about 100 μm and 95% of the second batch of crystalline active ingredient is less than about 300 μm.
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 μm and about 60-80% of a second batch of crystalline active ingredient having a mean particle size of about 130-180 μm.
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 μm and about 70% of a second batch of crystalline active ingredient having a mean particle size of about 130-180 μm.
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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 (f 2 ) 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° 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 μm;
(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 μm;
(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.