Pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same

• US 10,314,803 B2
• Filed: 12/05/2012
• Issued: 06/11/2019
• Est. Priority Date: 09/02/2008
• Status: Active Grant

• Current Assignee: Amarin Pharmaceuticals Ireland Limited (Amarin Corporation plc)
• Original Assignee: Amarin Pharmaceuticals Ireland Limited (Amarin Corporation plc)
• Inventors: Manku, Mehar
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Al-Awadi, Danah
• Application Number:
  US13/705,990
• Publication Number:
  US 20130095178A1
• Time in Patent Office: 2,379 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/202 having three or more double bonds, e.g. linolenic eicosanoids, e.g. leukotrienes A61K31/557
• CPC Class Codes: A61K 31/232 having three or more double bonds, e.g. etretinate
• CPC Class Codes: A61K 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention relates to, inter alia, pharmaceutical compositions comprising eicosapentaenoic acid and/or derivatives thereof and nicotinic acid, to methods of manufacturing such compositions, and to therapeutic methods for treating carious diseases and disorders.

Claims

1. A pharmaceutical composition comprising nicotinic acid in an amount of 350 mg to not more than 1200 mg and about 4 g of eicosapentaenoic acid or a derivative thereof, wherein the composition contains not more than 10%, by weight, docosahexaenoic acid, if any, wherein upon administration of the composition to a subject, the subject experiences no flushing or reduced flushing compared to a control subject receiving niacin but not eicosapentaenoic acid or a derivative thereof, and wherein the pharmaceutical composition contains no more than 3%, by weight, of total fatty acids present other than eicosapentaenoic acid and/or docosahexaenoic acid.

2. The composition of claim 1 wherein the composition contains substantially no docosahexaenoic acid.

3. The composition of claim 1 wherein the eicosapentaenoic acid or derivative thereof comprises an eicosapentaenoic acid ethyl ester.

4. The composition of claim 1 wherein the nicotinic acid is suspended in the eicosapentaenoic acid or derivative thereof to form a suspension.

5. The composition of claim 4 wherein the suspension is present in a capsule.

6. The composition of claim 1 wherein the composition further comprises a statin.

10. A method of treating or preventing cardiovascular-related disease or disorder in subject in need thereof, comprising:

administering to the subject a pharmaceutical composition according to claim 1.

7. A pharmaceutical composition comprising nicotinic acid in an amount of 350 mg to not more than 800 mg and about 4 g of eicosapentaenoic acid ethyl ester, wherein the composition contains substantially no amount of docosahexaenoic acid or derivative thereof, wherein upon administration of the composition to a subject, the subject experiences no flushing or reduced flushing compared to a control subject receiving niacin but not eicosapentaenoic acid ethyl ester, and wherein the pharmaceutical composition contains no more than 3%, by weight, of total fatty acids present other than eicosapentaenoic acid and/or docosahexaenoic acid.

8. A pharmaceutical composition comprising nicotinic acid in an amount of 350 mg to not more than 500 mg and 100 mg to 1000 mg of eicosapentaenoic acid ethyl ester, wherein the composition contains no docosahexaenoic acid, the nicotinic acid is suspended in the eicosapentaenoic acid ethyl ester, and the composition is present in a capsule, wherein upon administration of the composition to a subject in an amount sufficient to provide about 4 g of the eicosapentaenoic acid ethyl ester per day, the subject experiences no flushing or reduced flushing compared to a control subject receiving niacin but not eicosapentaenoic acid or a derivative thereof, and wherein the pharmaceutical composition contains no more than 3%, by weight, of total fatty acids present other than eicosapentaenoic acid and/or docosahexaenoic acid.

9. The composition of claim 8 wherein the nicotinic acid is present in an amount of 350 mg to 400 mg and the eicosapentaenoic acid ethyl ester is present in an amount of 300 to 800 mg.

11. A method of treating a cardiovascular-related disease or disorder in a subject in need thereof, comprising:

co-administering to the subject a first pharmaceutical composition comprising nicotinic acid in an amount of 350 mg to not more than 800 mg and a second pharmaceutical composition comprising about 4 g of eicosapentaenoic acid or a derivative thereof wherein said second pharmaceutical composition contains substantially no docosahexaenoic acid or derivative thereof, wherein upon administration of the composition to a subject, the subject experiences no flushing or reduced flushing compared to a control subject receiving niacin but not eicosapentaenoic acid or a derivative thereof, and wherein the pharmaceutical composition contains no more than 3%, by weight, of total fatty acids present other than eicosapentaenoic acid and/or docosahexaenoic acid.

12. The method of claim 11 wherein the co-administering step comprises administering the first and second pharmaceutical compositions to the subject within a period of about 24 hours.

13. The method of claim 11 wherein the co-administering step comprises administering the first and second pharmaceutical compositions to the subject within a period of about 12 hours.

14. The method of claim 11 wherein the co-administering step comprises administering the first and second pharmaceutical compositions to the subject substantially simultaneously.

15. The method of claim 11 wherein the subject does not ingest a non-steroidal anti-inflammatory agent within about 3 hours prior to or after said co-administration step.

16. The method of claim 11 wherein the eicosapentaenoic acid or a derivative thereof is present in the second pharmaceutical composition in an amount of 100 mg to 2000 mg.

17. The method of claim 11 wherein the eicosapentaenoic acid or a derivative thereof comprises eicosapentaenoic acid ethyl ester.

18. A method of decreasing serum low-density lipoprotein-C and serum triglyceride levels and increasing serum high-density-lipoprotein-C levels in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising:

(a) nicotinic acid in an amount of 350 mg to not more than 1000 mg and (b) an oil comprising about 4 g of eicosapentaenoic acid ethyl ester, wherein the ethyl eicosapentaenoic acid ethyl ester represents at least about 95%, by weight, of the oil;

wherein the pharmaceutical composition contains no docosahexaenoic acid or derivative thereof, wherein upon administration of the composition to a subject, the subject experiences no flushing or reduced flushing compared to a control subject receiving niacin but not eicosapentaenoic acid ethyl ester, and wherein the pharmaceutical composition contains no more than 3%, by weight, of total fatty acids present other than eicosapentaenoic acid and/or docosahexaenoic acid.

19. The method of claim 18 wherein the eicosapentaenoic acid ethyl ester is present in two or more capsules, each capsule comprising 100 mg to about 2000 mg of the eicosapentaenoic acid ethyl ester.

20. The method of claim 19 where the composition is administered to the subject in about 1 to about 4 dosage units per day.

21. A method of reducing risk of cardiac arrest in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising (a) nicotinic acid in an amount of 350 mg to not more than 1000 mg and (b) an oil comprising about 4 g of eicosapentaenoic acid ethyl ester, wherein the composition contains no docosahexaenoic acid or derivative thereof, wherein the ethyl eicosapentaenoic acid ethyl ester represents at least about 95%, by weight, of the oil, wherein upon administration of the composition to a subject, the subject experiences no flushing or reduced flushing compared to a control subject receiving niacin but not eicosapentaenoic acid ethyl ester, and wherein the pharmaceutical composition contains no more than 3%, by weight, of total fatty acids present other than eicosapentaenoic acid and/or docosahexaenoic acid.

22. A kit comprising a first pharmaceutical composition comprising nicotinic acid in an amount of 350 mg to not more than 1200 mg and a second pharmaceutical composition comprising about 4 g of eicosapentaenoic acid or a derivative thereof, wherein the second pharmaceutical composition contains not more than 10%, by weight, docosahexaenoic acid, if any, wherein upon administration of the first and second pharmaceutical compositions to a subject, the subject experiences no flushing or reduced flushing compared to a control subject receiving niacin but not eicosapentaenoic acid or a derivative thereof, and wherein the pharmaceutical composition contains no more than 3%, by weight, of total fatty acids present other than eicosapentaenoic acid and/or docosahexaenoic acid.