Sustained release ranolazine formulations

• US 20030100566A1
• Filed: 09/27/2002
• Published: 05/29/2003
• Est. Priority Date: 09/10/1998
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Palo Alto Incorporated (Gilead Sciences Inc.)
• Inventors: Langridge, John Richard, Wolff, Andrew A., Baker, Fiona
• Granted Patent: US 6,620,814 B2
• Time in Patent Office: Days
• US Class Current: 514/252.12
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

A sustained release ranolazine formulation contains an intimate mixture of ranolazine and a partially neutralized pH-dependent binder to form a film that is mostly insoluble in aqueous media below pH 4.5 and soluble in aqueous media above pH 4.5. The formulation is suitable for twice daily administration of ranolazine and is useful for controlling the rate of dissolution of ranolazine, and to maintain human plasma ranolazine levels at between 550 and 7500 ng base/mL.

Claims

1. A method for treating a human patient suffering from a cardiovascular disease selected from arrhythmias, variant and exercise-induced angina, and myocardial infarction by administering a sustained release pharmaceutical dosage form including at least 50% by weight ranolazine in no more than two tablets per dose to the human patient to maintain ranolazine plasma levels in the human patient of from about 550 to about 7500 ng base/mL for at least 24 hours wherein the dose is administered at a frequency selected from once, twice and three times over 24 hours.

2. The method of claim 1 wherein the sustained release dosage form includes at least one pH dependent binder wherein the pH dependent binder inhibits the release of ranolazine from the sustained release dosage form when the sustained release dosage form is subjected to an aqueous environment having a pH of the stomach and wherein the pH dependent binder promotes the release of a therapeutic amount of ranolazine in an aqueous solution having a pH above about 4.5.

3. The method of claim 2 wherein the pH dependent binder is partially neutralized.

4. The method of claim 1 wherein the pharmaceutical dosage form is administered to the human patient at a frequency selected from once and twice over 24 hours.

5. The method of claim 1 wherein the pharmaceutical dosage form is administered to the human patient in two dosed over 24 hours wherein each dose consists of two tablets.

6. The method of claim 1 wherein the pharmaceutical dosage form includes between about 50% to about 95% by weight ranolazine.

7. The method of claim 1 wherein the pharmaceutical dosage form includes from about 70% to about 80% by weight ranolazine.

8. The method of claim 2 wherein the pH dependent binder is selected from methacrylic acid copolymers, hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate, phthalate, polyvinylpyrrolidine phthalate, and mixtures thereof.

9. The method of claim 2 wherein the pH dependent binder is a methacrylic acid copolymer.

10. The method of claim 9 wherein the methacrylic acid copolymer is methacrylic acid copolymer Type C USP.

11. The method of claim 2 wherein the pH dependent binder is from about 5 to about 12 wt % methacrylic acid copolymer Type C USP.

12. The method of claim 1 wherein the pH dependent binder is about 10 wt % methacrylic acid copolymer Type C USP.

13. The method of claim 1 wherein the pharmaceutical dosage form includes a pH-independent binder.

14. The method of claim 13 wherein the pH-independent binder is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, poly(meth)acrylate esters, poly-vinylpyrrolidone, and mixtures thereof.

15. The method of claim 13 wherein the pH-independent binder is hydroxypropyl methylcellulose.

16. The method of claim 15 wherein the pharmaceutical dosage form includes from about 1 to about 3 wt % hydroxypropyl methylcellulose.

17. The method of claim 15 wherein the pharmaceutical dosage form includes about 2 wt % hydroxypropyl methylcellulose.

18. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the human patient plasma ranolazine level ranges from 1000-5000 ng base/mL.

19. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the human patient plasma ranolazine level ranges from 1000-3800 ng base/mL.

20. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the human patient plasma ranolazine level ranges from 550-5000 ng base/mL.

21. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the human patient plasma ranolazine level ranges from 550-3800 ng base/mL.

22. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the human patient plasma ranolazine level ranges from 1000-2800 ng base/mL.

23. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the human patient plasma ranolazine level ranges from 1700-3900 ng base/mL.

24. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the human patient plasma ranolazine level ranges from 550-2000 ng base/mL.

25. The method of claim 23 wherein the dosage form includes from 650-850 mg ranolazine.

26. The method of claim 24 wherein the dosage form includes from 900-1100 mg ranolazine.

27. The method of claim 25 wherein the dosage form includes from 400-600 mg ranolazine.

28. The method of claim 22 or 23 or 24 or 25 or 26 or 27 wherein the peak to trough human patient plasma ranolazine levels is less than 4:

1 over a 24 hour period.

29. The method of claim 23 or 24 or 25 or 26 or 27 wherein the peak to trough human patient plasma ranolazine levels is less than 3:

1 over a 24 hour period.

30. The method of claim 24 or 28 wherein the peak to trough human patient plasma ranolazine levels is less than 2:

1 over a 24 hour period.

31. A pharmaceutical dosage form comprising at least about 50 wt % ranolazine and at least one pH dependent binder that inhibits the release of ranolazine from the sustained release dosage form when the sustained release dosage form is subjected to an aqueous environment having a pH of the stomach and that promotes the release of a therapeutic amount of ranolazine in an aqueous solution having a pH above about 4.5.

32. The pharmaceutical dosage form of claim 31 including no more than two tablets per dose.

33. The pharmaceutical dosage form of claim 32 wherein the pharmaceutical dosage form includes from about 50% to about 95% by weight ranolazine.

34. The pharmaceutical dosage form of claim 32 wherein the pharmaceutical dosage form includes from about 70% to about 80% by weight ranolazine.

35. The pharmaceutical dosage form of claim 31 wherein the pH dependent binder is selected from methacrylic acid copolymers, hydroxypropyl cellulose phthalate, hydroxxpropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl acetate. phthalate, polyvinylpyrrolidine phthalate, and mixtures thereof.

36. The pharmaceutical dosage form of claim 31 wherein the pH dependent binder is a methacrylic acid copolymer.

37. The pharmaceutical dosage form of claim 36 wherein the methacrylic acid copolymer is methacrylic acid copolymer Type C USP.

38. The pharmaceutical dosage form of claim 36 wherein pharmaceutical dosage form includes from about 5 to about 12 wt % methacrylic acid copolymer Type C USP.

39. The pharmaceutical dosage form of claim 36 wherein the pharmaceutical dosage form includes about 10 wt % methacrylic acid copolymer.

40. The pharmaceutical dosage form of claim 31 wherein the pharmaceutical dosage form includes a pH-independent binder.

41. The pharmaceutical dosage form of claim 40 wherein the pH-independent binder is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, poly(meth)acrylate esters, poly-vinylpyrrolidone, and mixtures thereof.

42. The pharmaceutical dosage form of claim 40 wherein the pH-independent binder is hydroxypropyl methylcellulose.

43. The pharmaceutical dosage form of claim 42 wherein the pharmaceutical dosage form includes from about 1 to about 3 wt % hydroxypropyl methylcellulose.

44. The pharmaceutical dosage form of claim 42 wherein the pharmaceutical dosage form includes about 2 wt % hydroxypropyl methylcellulose.

45. The pharmaceutical dosage form of claim 31 wherein the dosage form includes from about 650 to about 850 mg ranolazine.

46. The pharmaceutical dosage form of claim 31 wherein the dosage form includes from about 900 to about 1100 mg ranolazine.

47. The pharmaceutical dosage form of claim 31 wherein the dosage form includes from about 400 to about 600 mg ranolazine.

48. The pharmaceutical dosage form of claim 31 wherein the dosage form includes from about 300 to about 1000 mg ranolazine.

49. The pharmaceutical dosage form of claim 32 wherein the pharmaceutical dosage form is a compressed tablet.

50. A compressed tablet comprising from about 70 to about 80 wt % ranolazine, at least one pH dependent binder selected from methacrylic acid copolymers, hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate, phthalate, polyvinylpyrrolidine phthalate, and mixtures thereof, and at least one pH independent binder wherein the compressed tablet includes from about 350 to about 800 mg ranolazine.