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Claims for Patent: 6,676,967

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Claims for Patent: 6,676,967

Title: Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia
Abstract:Methods for reducing flushing in individuals being treated for hyperlipidemia with nicotinic acid are disclosed. According to the methods of the present invention, flushing can be reduced in individuals under going nicotinic acid therapy without causing drug-induced hepatotoxicity to a level that would require the nicotinic acid therapy to be discontinued by orally administering to the individuals intermediate nicotinic acid formualtions having unique biopharmaceutical characteristics as a single dose once per day. While the methods of the present invention contemplate administering the intermediate release nicotinic acid formulations at any time during a 24 hour period, it is preferable to administer them once-a-day as a single dose during the evening or at night between about 6:00 pm. and 12:00 a.m., preferably between about 8:00 p.m. and 12:00 a.m., and most preferably between about 8:00 p.m. and 10:00 p.m.
Inventor(s): Cefali; Eugenio A. (Fort Lauderdale, FL), Bova; David J. (Boca Raton, FL)
Assignee: KOS Pharmaceuticals, Inc. (Miami, FL)
Application Number:08/962,422
Patent Claims: 1. A method of reducing flushing in an individual being treated for a lipidemic disorder and effectively treating the lipidemic disorder with an intermediate release nicotinic acid formulation suitable for oral administration once-a-day as a single dose without causing treatment-limiting hepatotoxicity and treatment-limiting elevations in uric acid or glucose levels or both in the individual to a level which would require use of the nicotinic acid formulation to be discontinued by the individual, comprising: orally administering to the individual once per day as a single dose an effective amount of an intermediate release nicotinic acid formulation without causing treatment-limiting hepatotoxicity and treatment-limiting elevations in uric acid or glucose levels or both in the individual to a level which would require use of the intermediate nicotinic acid formulation by the individual to be discontinued, the intermediate release nicotinic acid formulation having a dissolution curve similarity fit factor F2 of at least about 79, and an in vitro dissolution profile, when measured in a type I dissolution apparatus (basket) according to U.S. Pharmacopeia XXII, at about 37.degree. C. in deionized water at about 100 rpm, as follows (a) less than about 15% of the nicotinic acid is released after about 1 hour in the apparatus, (b) between about 15% and about 30% of the nicotinic acid is released after about 3 hours in the apparatus, (c) between about 30% and about 45% of the nicotinic acid is released after about 6 hours in the apparatus, (d) between about 40% and about 60% of the nicotinic acid is released after about 9 hours in the apparatus, (e) between about 50% and about 75% of the nicotinic acid is released after about 12 hours in the apparatus, and (f) at least about 75% of the nicotinic acid is released after about 20 hours in the apparatus.

2. The method of claim 1, wherein approximately 100% of the nicotinic acid is released after about 20 hours in the apparatus.

3. The method of claim 1, wherein the nicotinic acid formulation is a tablet.

4. The method of claim 3, wherein said tablet contains nicotinic acid in an amount selected from the group consisting of about 375 mg, about 500 mg and about 750 mg.

5. The method of claim 1, wherein the in vitro dissolution profile is as follows: (a) between about 9.6% and about 13.8% of the nicotinic acid is released after about 1 hour in the apparatus, (b) between about 21.2% and about 27.8% of the nicotinic acid is released after about 3 hours in the apparatus, (c) between about 35.1% and about 44.2% of the nicotinic acid is released after about 6 hours in the apparatus, (d) between about 45.6% and about 58.5% of the nicotinic acid is released after about 9 hours in the apparatus, (e) between about 56.2% and about 72% of the nicotinic acid is released after about 12 hours in the apparatus, and (f) at least about 75% of the nicotinic acid is released after about 20 hours in the apparatus.

6. The method of claim 5, wherein approximately 100% of the nicotinic acid is released after about 20 hours in the apparatus.

7. The method of claim 5, wherein the nicotinic acid formulation is a tablet.

8. The method of claim 7, wherein said tablet contains nicotinic acid in an amount selected from the group consisting of about 375 mg, about 500 mg and about 750 mg.

9. The method of claim 3, wherein the in vitro dissolution profile is as follows: (a) between about 9.6% and about 13.8% of the nicotinic acid is released after about 1 hour in the apparatus, (b) between about 21.2% and about 27.8% of the nicotinic acid is released after about 3 hours in the apparatus, (c) between about 35.1% and about 44.2% of the nicotinic acid is released after about 6 hours in the apparatus, (d) between about 45.6% and about 58.5% of the nicotinic acid is released after about 9 hours in the apparatus, (e) between about 56.2% and about 72% of the nicotinic acid is released after about 12 hours in the apparatus, and (f) at least about 75% of the nicotinic acid is released after about 20 hours in the apparatus.

10. The method of claim 9, wherein approximately 100% of the nicotinic acid is released after about 20 hours in the apparatus.

11. The method of claim 9, wherein the nicotinic acid formulation is a tablet.

12. The method of claim 11, wherein said tablet contains nicotinic acid in an amount selected from the group consisting of about 375 mg, about 500 mg and about 750 mg.

13. The method of claim 1, wherein the single dose is administered to the individual during the evening or at night.

14. The method of claim 1, wherein the single dose is administered to the individual between about 6 pm and 12 am.

15. The method of claim 1, wherein the single dose is administered to the individual between about 8 pm and 10 pm.

16. A method of reducing flushing in an individual being treated for a lipidemic disorder and effectively treating the lipidemic disorder with an intermediate release nicotinic acid formulation suitable for oral administration once-a-day as a single dose without causing treatment-limiting hepatotoxicity and treatment-limiting elevations in uric acid or glucose levels or both in the individual to a level which would require use of the nicotinic acid formulation to be discontinued by the individual, comprising: orally administering to the individual once per day as a single dose an effective amount of an intermediate release nicotinic acid formulation without causing treatment-limiting hepatotoxicity and treatment-limiting elevations in uric acid or glucose levels or both in the individual to a level which would require use of the intermediate nicotinic acid formulation by the individual to be discontinued, the intermediate release nicotinic acid formulation containing at least about 1000 mg of nicotinic acid and having a dissolution curve similarity fit factor F2 of at least about 44, and an in vitro dissolution profile, when measured in a type I dissolution apparatus (basket) according to U.S. Pharmacopeia XXII, at about 37.degree. C. in deionized water at about 100 rpm, as follows (a) less than about 15% of the nicotinic acid is released after about 1 hour in the apparatus, (b) between about 15% and about 30% of the nicotinic acid is released after about 3 hours in the apparatus, (c) between about 30% and about 45% of the nicotinic acid is released after about 6 hours in the apparatus, (d) between about 40% and about 60% of the nicotinic acid is released after about 9 hours in the apparatus, (e) between about 50% and about 75% of the nicotinic acid is released after about 12 hours in the apparatus, and (f) at least about 75% of the nicotinic acid is released after about 20 hours in the apparatus.

17. The method of claim 16, wherein approximately 100% of the nicotinic acid is released after about 20 hours in the apparatus.

18. The method of claim 16, wherein the nicotinic acid formulation is a tablet.

19. The method of claim 16, wherein the in vitro dissolution profile is as follows: (a) between about 9.6% and about 13.8% of the nicotinic acid is released after about 1 hour in the apparatus, (b) between about 21.2% and about 27.8% of the nicotinic acid is released after about 3 hours in the apparatus, (c) between about 35.1% and about 44.2% of the nicotinic acid is released after about 6 hours in the apparatus, (d) between about 45.6% and about 58.5% of the nicotinic acid is released after about 9 hours in the apparatus, (e) between about 56.2% and about 72% of the nicotinic acid is released after about 12 hours in the apparatus, and (f) at least about 75% of the nicotinic acid is released after about 20 hours in the apparatus.

20. The method of claim 19, wherein approximately 100% of the nicotinic acid is released after about 20 hours in the apparatus.

21. The method of claim 19, wherein the nicotinic acid formulation is a tablet.

22. The method of claim 16, wherein the in vitro dissolution profile is as follows: (a) between about 9.6% and about 13.8% of the nicotinic acid is released after about 1 hour in the apparatus, (b) between about 21.2% and about 27.8% of the nicotinic acid is released after about 3 hours in the apparatus, (c) between about 35.1% and about 44.2% of the nicotinic acid is released after about 6 hours in the apparatus, (d) between about 45.6% and about 58.5% of the nicotinic acid is released after about 9 hours in the apparatus, (e) between about 56.2% and about 72% of the nicotinic acid is released after about 12 hours in the apparatus, and (f) at least about 75% of the nicotinic acid is released after about 20 hours in the apparatus.

23. The method of claim 22, wherein approximately 100% of the nicotinic acid is released after about 20 hours in the apparatus.

24. The method of claim 22, wherein the nicotinic acid formulation is a tablet.

25. The method of claim 16, wherein the single dose is administered to the individual during the evening or at night.

26. The method of claim 25, wherein the single dose is administered to the individual between about 6 pm and 12 am.

27. The method of claim 25, wherein the single dose is administered to the individual between about 8 pm and 10 pm.
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