Sustained release ranolazine formulations

• US 6,620,814 B2
• Filed: 09/27/2002
• Issued: 09/16/2003
• Est. Priority Date: 09/10/1998
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Palo Alto Incorporated (Gilead Sciences Inc.)
• Inventors: Baker, Fiona, Langridge, John, Wolff, Andrew A.
• Primary Examiner(s): Hartley, Michael G.
• Assistant Examiner(s): George, Konata M.
• Application Number:
  US10/256,993
• Publication Number:
  US 20030100566A1
• Time in Patent Office: 354 Days
• Field of Search: 424/465, 514/252.12
• US Class Current: 514/252.17
• 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 suffering from a cardiovascular disease selected from arrhythmias, variant and exercise-induced angina, and myocardial infarction by administering a sustained release ranolazine pharmaceutical dosage form having at least 50% by weight ranolazine to the human to maintain ranolazine plasma levels of from about 550 to about 7500 ng base/mL for at least 24 hours.

2. A method for treating a human suffering from a cardiovascular disease selected from arrhythmias, variant and exercise-induced angina, and myocardial infarction by administering at least one sustained release dosage form over a 24 hour period, wherein the dosage form comprises at least 50% by weight ranolazine, said dosage form when administered at least once over a 24 hour period provides a peak to trough plasma ranolazine level ratio that does not exceed 4:

1 over the 24 hour period.

3. The method of claim 2, wherein the peak to trough plasma ranolazine level ratio is less than 3:

1 over a 24 hour period.

4. The method of claim 2, wherein the peak to trough plasma ranolazine level ratio is less than 2:

1 over a 24 hour period.

5. A method for treating a human suffering from variant and exercise-induced angina by administering at least one sustained release dosage form over a 24 hour period, wherein the dosage form comprises at least 50% by weight ranolazine, said dosage form when administered periodically over a 24 hour period maintains a trough plasma ranolazine level minimum of about 550 ng base/mL over the 24 hour period.

6. A method for maintaining plasma ranolazine levels close to minimal effective levels without peak fluctuations comprising delivering to a human suffering from a cardiovascular disease at least one sustained release dosage form over a 24 hour period wherein said dosage form comprises at least 50% by weight ranolazine.

7. A method for treating a human suffering from variant and exercise induced angina by administering at least one sustained release dosage form over a 24 hour period, wherein the dosage form releases ranolazine slowly and continuously as the formulation passes through the stomach and gastrointestinal tract to maintain a trough plasma ranolazine level minimum of about 550 ng base/mL over the 24 hour period.

8. A method for treating a human suffering from variant and exercise induced angina by administering over a 24 hour period an immediate release ranolazine formulation to rapidly achieve a therapeutically effective plasma concentration of ranolazine in combination with or followed by at least one sustained release dosage form, wherein the trough ranolazine level is maintained at a minimum of about 550 ng base/mL over the 24 hour period.

9. A method for treating a human suffering from variant and exercise induced angina by administering at least one sustained release dosage form over a 24 hour period, wherein the dosage form releases ranolazine slowly and continuously as the formulation passes through the stomach and gastrointestinal tract to maintain a peak plasma ranolazine level that is not more than about 7500 ng base/mL over the 24 hour period.

10. A method for treating a human suffering from variant and exercise induced angina by administering over a 24 hour period an immediate release ranolazine formulation to rapidly achieve a therapeutically effective plasma concentration of ranolazine in combination with or followed by at least one sustained release dosage form, wherein the peak ranolazine level is maintained at not more than about 5000 ng base/mL over the 24 hour period.

11. A method for treating a human suffering from variant and exercise induced angina by administering at least one sustained release dosage form over a 24 hour period, wherein the dosage form comprises about 70 to about 80% by weight ranolazine, said dosage form when administered at least once over a 24 hour period provides a peak to trough plasma ranolazine level ratio that does not exceed 4:

1 over the 24 hour period.

12. The method of claim 11, wherein the peak to trough plasma ranolazine level ratio does not exceed 3:

1 over the 24 hour period.

13. The method of claim 11, wherein the peak to trough plasma ranolazine level ratio does not exceed 2:

1 over the 24 hour period.

14. A method for treating a human suffering from variant and exercise-induced angina by administering at least one sustained release dosage form over a 24 hour period, wherein the dosage form maintains a trough plasma ranolazine level at a minimum of about 550 ng base/mL over the 24 hour period.

15. A method for maintaining plasma ranolazine levels close to minimal effective levels without peak fluctuations comprising delivering to a human suffering from a cardiovascular disease at least one sustained release dosage form over a 24 hour period, wherein said dosage form comprises about 70 to about 80% by weight ranolazine.

16. A method for treating a human suffering from variant and exercise-induced angina by administering a ranolazine formulation, wherein the trough ranolazine plasma level is maintained at a minimum of about 550 ng base/mL over a 24 hour period.

17. A method for treating variant and exercise-induced angina in a human comprising administering to said human a sustained release ranolazine formulation that includes at least 50% by weight ranolazine, and an admixture of at least one pH-dependent binder and at least one pH-independent binder, wherein the sustained release ranolazine formulation includes an amount of ranolazine sufficient to maintain ranolazine plasma levels in the human patient of about 550 to about 7500 ng base/mL for at least 24 hours.

18. A method for treating variant and exercise-induced angina in a human comprising administering to said human a sustained release ranolazine formulation in an amount sufficient to maintain ranolazine plasma levels in the human patient of about 550 to about 7500 ng base/mL for at least 24 hours.

19. A method for treating variant and exercise-induced angina in a human comprising administering to said human a sustained release ranolazine formulation that includes an admixture of at least one pH-dependent binder and at least one pH-independent binder, wherein the sustained release ranolazine formulation includes an amount of ranolazine sufficient to maintain ranolazine plasma levels in the human patient of about 550 to about 7500 ng base/mL for at least 24 hours.

20. A method of treating angina in a mammal by administration of ranolazine comprising administration of at least one sustained release pharmaceutical dosage form comprising at least 50% by weight ranolazine that provides a peak to trough ranolazine level ration in plasma that does not exceed 4:

1 over a 24-hour period.

21. The method of claim 20, wherein the dosage form is administered at least once over a 24 hour period.

22. The method of claim 20, wherein the dosage form provides a peak to trough ranolazine level ratio in plasma that does not exceed 3:

1 over a 24-hour period.

23. The method of claim 20, wherein the dosage form provides a peak to trough ranolazine level ratio in plasma that does not exceed 2:

1 over a 24 hour period.

24. A method of treating arrhythmias in a mammal by administration of ranolazine, comprising administration of at least one sustained release pharmaceutical dosage form comprising at least 50% by weight ranolazine that provides a peak to trough ranolazine level ration in plasma that does not exceed 4:

1 over a 24-hour period.

25. The method of claim 24, wherein the dosage form is administered at least once over a 24 hour period.

26. The method of claim 24, wherein the dosage form provides a peak to trough ranolazine level ratio in plasma that does not exceed 3:

1 over a 24-hour period.

27. The method of claim 24, wherein the dosage form provides a peak to trough ranolazine level ratio in plasma that does not exceed 2:

1 over a 24 hour period.