STABLE PHARMACEUTICAL COMPOSITION AND METHODS OF USING SAME

• US 20130004572A1
• Filed: 09/13/2012
• Published: 01/03/2013
• Est. Priority Date: 04/29/2009
• Status: Active Grant

• Current Assignee: Amarin Pharmaceuticals Ireland Limited (Amarin Corporation plc)
• Original Assignee: Amarin Pharmaceuticals Ireland Limited (Amarin Corporation plc)
• Inventors: Manku, Mehar, Osterloh, Ian, Wicker, Pierre, Braeckman, Rene, Soni, Paresh
• Granted Patent: US 8,501,225 B2
• Time in Patent Office: Days
• US Class Current: 424/456
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4825 Proteins, e.g. gelatin gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• 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 a polyunsaturated fatty acid and to methods of using the same to treat or prevent cardiovascular-related diseases.

Claims

1. A pharmaceutical composition comprising at least 95% EPA enclosed in a capsule shell, wherein the composition has a baseline peroxide value not greater than 5 Meq/kg and upon storage of the composition at 25°

C. and 60% RH for a period of 6 months, the composition has a second peroxide value not greater than 8 Meq/kg.

2. The pharmaceutical composition of claim 1 wherein the EPA is ethyl-EPA.

3. The pharmaceutical composition of claim 2 wherein the ethyl-EPA contains less than about 1% of any individual fatty acid other than ethyl eicosapentaenoate.

4. The pharmaceutical composition of claim 2 wherein the ethyl-EPA contains less than about 0.5% of any individual fatty acid other than ethyl eicosapentaenoate.

5. The pharmaceutical composition of claim 2 wherein the ethyl-EPA contains less than about 0.3% DHA, if any.

6. The pharmaceutical composition of claim 5 wherein the ethyl-EPA contains substantially no DHA.

7. The pharmaceutical composition of claim 1 wherein the ethyl-EPA comprises about 0.1% to about 1%, by weight, of an antioxidant.

8. The pharmaceutical composition of claim 7 wherein the antioxidant is tocopherol.

9. The pharmaceutical composition of claim 1 wherein upon storage of the composition at 25°

C. and 60% RH for a period of 6 months, the EPA has a second peroxide value not greater than 7 Meq/kg.

10. The pharmaceutical composition of claim 1 wherein upon storage of the composition at °

C. and 60% RH for a period of 6 months, the EPA has a second peroxide value not greater than 6 Meq/kg.

11. The pharmaceutical composition of claim 1 wherein upon storage of the composition at °

C. and 65% RH for a period of 6 months, the EPA has a second peroxide value not greater than 12 Meq/kg.

12. The pharmaceutical composition of claim 11 wherein upon storage of the composition at 30°

C. and 65% RH for a period of 6 months, the EPA has a second peroxide value not greater than 10 Meq/kg.

13. The pharmaceutical composition of claim 1 wherein upon storage of the composition at 30°

C. and 65% RH for a period of 6 months, the EPA has a second peroxide value not greater than 10 Meq/kg.

14. The pharmaceutical composition of claim 13 wherein upon storage of the composition at 30°

C. and 65% RH for a period of 6 months, the EPA has a second peroxide value not greater than 6 Meq/kg.

15. The pharmaceutical composition of claim 1 wherein the capsule shell comprises a film-forming material and at least one plasticizer.

16. The pharmaceutical composition of claim 15 wherein the at least one plasticizer comprises a hygroscopic plasticizer.

17. The pharmaceutical composition of claim 16 wherein the hygroscopic plasticizer comprises glycerol.

18. The pharmaceutical composition of claim 17 wherein the film-forming material comprises gelatin.

19. The pharmaceutical composition of claim 18 wherein the film-forming contains substantially no chemically modified gelatin.

20. The pharmaceutical composition of claim 19 wherein the film-forming contains substantially no succinated gelatin.

21. The pharmaceutical composition of claim 18 wherein the capsule shell has a weight ratio of gelatin to glycerol of about 2.5:

1 to about 10;

1.

22. The pharmaceutical composition of claim 18 wherein the capsule shell has a weight ratio of gelatin to glycerol of about 4:

1 to about 8;

1.

23. The pharmaceutical composition of claim 18 wherein the capsule shell further comprises a non-hygroscopic plasticizer.

24. The pharmaceutical composition of claim 21 wherein the non-hygroscopic plasticizer is selected from maltitol, lactitol, xylitol, hydrogenated starch hydrolysate and glucose syrup.

25. The pharmaceutical composition of claim 22 wherein the non-hygroscopic plasticizer comprises maltitol.

26. The pharmaceutical composition of claim 21 wherein the capsule shell has a hygroscopic plasticizer to non-hygroscopic plasticizer weight ratio of about 1:

1 to about 8;

1.

27. The pharmaceutical composition of claim 21 wherein the capsule shell has a hygroscopic plasticizer to non-hygroscopic plasticizer weight ratio of about 3:

1 to about 5;

1.

28. The pharmaceutical composition of claim 1 wherein the composition has a dissolution profile as measured by RDC wherein:

(1) at least about 20% of the E-EPA is dissolved by 10 minutes;

(2) at least about 45% of the E-EPA is dissolved by 30 minutes;

(3) at least about 80% of the E-EPA is dissolved by 60 minutes; and

/or (4) at least about 95% of the E-EPA is dissolved by 100 minutes.

29. The pharmaceutical composition of claim 28 wherein the composition has a dissolution profile as measured by RDC wherein:

(1) at least about 20% of the E-EPA is dissolved by 10 minutes;

(2) at least about 45% of the E-EPA is dissolved by 30 minutes;

(3) at least about 80% of the E-EPA is dissolved by 60 minutes; and

(4) at least about 95% of the E-EPA is dissolved by 100 minutes.

30. The pharmaceutical composition of claim 1 wherein upon administration of said composition to a human subject, the subject achieves an EPA T_max within at least 5.8 hours of said administration.