Spontaneous emulsions containing cyclosporine

• US 6,960,563 B2
• Filed: 08/31/2001
• Issued: 11/01/2005
• Est. Priority Date: 08/31/2001
• Status: Expired due to Fees

• Current Assignee: Wockhardt EU Operations (Swiss) AG (Wockhardt Limited)
• Original Assignee: Morton Grove Pharmaceuticals Incorporated (Wockhardt Limited)
• Inventors: Egbaria, Kamel F., Groves, Michael J.
• Primary Examiner(s): Weber, Jon
• Assistant Examiner(s): Mohamed, Abdel A.
• Application Number:
  US09/943,687
• Publication Number:
  US 20030049280A1
• Time in Patent Office: 1,523 Days
• Field of Search: 514/9, 514/11, 514/937, 514/938, 530/317, 424/451, 424/455, 424/465
• US Class Current: 514/20.5
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A pharmaceutical composition contains cyclosporine as the active ingredient. More specifically, the composition is an orally administered pharmaceutical formulation in the form of a spontaneous emulsion comprising cyclosporine, ethanol ethyl oleate and polyoxyethylene glycerol trioleate. A method for preparing an orally administered pharmaceutical composition involves first dissolving cyclosporine in ethanol. Polyoxyethylene glycerol trioleate and an oil component are then added, mixed and diluted in an aqueous media to form a spontaneous emulsion.

Claims

1. An orally administered pharmaceutical composition comprising a spontaneous emulsion of cyclosporine, ethanol, polyoxyethylene glycerol trioleate, and an oil component.

2. The pharmaceutical composition of claim 1, wherein said cyclosporine is cyclosporine A.

3. The pharmaceutical composition of claim 1, wherein said oil component is ethyl oleate.

4. The pharmaceutical composition of claim 1, wherein said polyoxyethylene glycerol trioleate is present at about 20 to about 50 v/v %.

5. The pharmaceutical composition of claim 1, wherein said cyclosporine is present at a concentration from about 5 to about 20% by weight.

6. The pharmaceutical composition of claim 5, wherein said cyclosporine is present at a concentration from about 8 to about 12% by weight.

7. The pharmaceutical composition of claim 5, wherein said cyclosporine is present at a concentration of 10% by weight.

8. The pharmaceutical composition of claim 1, wherein said ethanol is present at about 15 to about 40 v/v %.

9. The pharmaceutical composition of claim 8, wherein said ethanol is present at about 15 to about 25 v/v %.

10. The pharmaceutical composition of claim 8, wherein said ethanol is present at 20 v/v %.

11. The pharmaceutical composition of claim 1, wherein said oil component is present at about 40 to about 65 v/v %.

12. The pharmaceutical composition of claim 11, wherein said oil component is present at about 55 to about 65 v/v %.

13. The pharmaceutical composition of claim 11, wherein said oil component is present at 60 v/v %.

14. An orally administered pharmaceutical composition comprising a spontaneous emulsion of cyclosporine, ethanol, polyoxyethylene glycerol trioleate and ethyl oleate In a weight ratio of cyclosporine, pure ethanol, polyoxyethylene glycerol trioleate and ethyl oleate of about 5:

18;

25.9;

50.1 to about 15;

16;

23.1;

44.9.

15. The pharmaceutical composition of claim 14, wherein the weight ratio of cyclosporine, pure ethanol, polyoxyethylene glycerol trioleate and ethyl oleate is 10:

17.1;

24.5;

47.5.

16. The pharmaceutical composition of claim 15, wherein said composition upon dilution with an aqueous media at a ratio of 1 part composition to 100 parts aqueous media forms a spontaneous emulsion.

17. The pharmaceutical composition of claim 16, wherein said spontaneous emulsion comprises particles having a diameter of 50 to 185 nm.

18. The method of claim 17, wherein said spontaneous emulsion comprises particles having a diameter of 50 to 150 nm.

19. A method of preparing an orally administered pharmaceutical composition comprising the steps of:

dissolving cyclosporine in ethanol to form a solution;

combining polyoxyethylene glycerol trioleate and an oil component with the solution to form a mixture; and

diluting the mixture with an aqueous media to allow formation of a spontaneous emulsion.

20. The method of claim 19, further comprising the step of gently mixing the diluted mixture to disperse the emulsion.

21. The method of claim 19 wherein the step of diluting further comprises diluting 1 part of the mixture with 100 parts of aqueous media.

22. The method of claim 19, wherein said oil component is ethyl oleate.

23. The method of claim 19, wherein said cyclosporine is cyclosporine A.

24. The method of claim 19, wherein the cyclosporine is present at a concentration of 10% by weight.

25. The method of claim 19, wherein said ethanol is present at about 15 to about 40 v/v %.

26. The method of claim 19, wherein said polyoxyethylene glycerol trioleate is present at about 20 to about 50 v/v %.

27. The method of claim 19, wherein said oil component is present at about 40 to about 65 v/v %.

28. The method of claim 19, wherein said composition comprises cyclosporine, ethanol, polyoxyethylene glycerol trioleate and ethyl oleate in a weight ratio of cyclosporine, pure ethanol, polyoxyethylene glycerol trioleate and ethyl oleate of 10:

17.1;

24.5;

47.5.

29. The method of claim 28, wherein said spontaneous emulsion comprises particles having a diameter of 50 to 185 nm.

30. The method of claim 29, wherein said spontaneous emulsion comprises particles having a diameter of 50 to 150 nm.