Pro-nanodispersion for the delivery of cyclosporin

• US 20060205639A1
• Filed: 02/28/2006
• Published: 09/14/2006
• Est. Priority Date: 12/30/1999
• Status: Active Grant

• Current Assignee: Dexcel Limited
• Original Assignee: Dexcel Limited
• Inventors: Pevzner, Victor, Avramoff, Avi, Domb, Abraham J.
• Granted Patent: US 7,732,404 B2
• Time in Patent Office: Days
• US Class Current: 514/20.500
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• 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: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics

Abstract

A novel cyclosporine formulation, which is a pro-nanodispersion at room temperature, featuring solid particles of a relatively large particle size (at least about 150 nm) and yet which is a nanodispersion at body temperature.

Claims

1. A composition for administering a cyclosporin compound, the composition comprising:

(a) a pro-nanodispersion characterized by being capable of forming, upon contact with an aqueous solution, particles of a size of less than about 100 nm at a temperature of at least about 30°

C., said pro-nanodispersion comprising;

(i) at least one surfactant; and

(ii) an amphiphilic solvent comprising a lower alkyl hydroxyalkanoic acid ester; and

(b) a pharmaceutically effective amount of the cyclosporin compound.

2. The composition of claim 1 wherein said lower alkyl hydroxy alkanoic acid ester comprises ethyl lactate.

3. The composition of claim 1, wherein said at least one surfactant is a combination of at least two surfactants, at least one surfactant of said combination being a hydrophilic surfactant, and at least one surfactant of said combination being a hydrophobic surfactant.

4. The composition of claim 3, wherein said hydrophilic surfactant has an HLB (hydrophilic/lipophilic balance) of at least about 10.

5. The composition of claim 4, wherein said hydrophilic surfactant has an HLB of at least about 14.

6. The composition of claim 4, wherein said hydrophobic surfactant has an HLB of less than about 5.

7. The composition of claim 3, wherein said hydrophobic surfactant comprises a sorbitan fatty acid ester.

8. The composition of claim 3, wherein said combination is a combination of polyoxyethylene (20) sorbitan monolaurate and sorbitan monooleate.

9. The composition of claim 3, further comprising:

(c) an ethoxylated fat.

10. The composition of claim 9, wherein said ethoxylated fat is selected from the group consisting of polyethyleneglycol-hydrogenated castor oils.

11. The composition of claim 10, wherein said ethoxylated fat is selected from the group consisting of Cremophor and Cremophor RH.

12. The composition of claim 9, further comprising:

(d) a phospholipid.

13. The composition of claim 12, wherein said phospholipid comprises lecithin.

14. The composition of claim 13, wherein said phospholipid is selected from the group consisting of egg phospholipid, bovine heart phospholipid and soy phospholipid.

15. The composition of claim 12, further comprising:

(e) a fatty acid ester.

16. The composition of claim 15, wherein said fatty acid ester is a solid fat at room temperature.

17. The composition of claim 16, wherein said fatty acid ester comprises triglyceride.

18. The composition of claim 1, wherein said particle size is less than about 60 nm at a temperature of at least about 30°

C.

19. The composition of claim 18, wherein said particle size is in a range of from about 5 nm to about 50 nm at a temperature of at least about 30°

C.

20. The composition of claim 1, wherein the cyclosporin compound is Ciclosporin.

21. A composition for administering a cyclosporin compound, the composition comprising a pharmaceutically effective amount of the composition of claim 1, and an aqueous solution as a diluent for said pharmaceutically effective amount of the composition of claim 1.

22. A composition for administering a cyclosporin compound, the composition comprising a lyophilized composition, said lyophilized composition being formed from a pharmaceutically effective amount of the composition of claim 1 and an aqueous solution as a diluent for said pharmaceutically effective amount of the composition of claim 1 to form a diluted solution, said diluted solution being lyophilized to form said lyophilized composition.

23. A composition for administering a cyclosporin compound, the composition comprising:

(a) a pro-nanodispersion characterized by being capable of forming, upon contact with an aqueous solution particles of a size of less than about 100 nm at a temperature of at least about 30°

C., said pro-nanodispersion comprising;

(i) an ethoxylated fat; and

(ii) an amphiphilic solvent comprising a lower alkyl hydroxyalkanoic ester or a lower alkyl ester of N-alkyl pyrrolidone; and

(b) a pharmaceutically effective amount of the cyclosporin compound.

24. The composition of claim 23, wherein said ethoxylated fat is selected from the group consisting of polyethyleneglycol-hydrogenated castor oils.

25. The composition of claim 24, wherein said ethoxylated fat is selected from the group consisting of Cremophor and Cremophor RH 60.

26. The composition of claim 23 wherein said amphiphilic solvent includes a lower alkyl hydroxy alkanoic acid ester.

27. The composition of claim 26, wherein said amphiphilic solvent includes ethyl lactate.

28. A composition for administering a cyclosporin compound, the composition comprising:

(a) a pro-nanodispersion characterized by being capable of forming, upon contact with an aqueous solution, a solid particulate suspension containing the cyclosporin compound, said particulate suspension containing particles of a size of less than about 100 nm at a temperature of at least about 30°

C., said pro-nanodispersion comprising;

(i) at least one surfactant; and

(ii) an amphiphilic solvent comprising a lower alkyl hydroxy alkanoic acid ester; and

(b) a pharmaceutically effective amount of the cyclosporin compound.

29. A cyclosporine formulation comprising ethyl lactate and a solid fat as carrier, and cyclosporine as active ingredient, characterized in that the formulation is a pro-nanodispersion at room temperature, featuring solid particles of at least about 150 nm, but is a nanodispersion at body temperature, featuring solid particles of less than about 100 nm.

30. A composition for administering a cyclosporin compound, the composition comprising:

(a) a pro-nanodispersion comprising;

(i) a solid fat;

(ii) ethyl lactate;

(iii) at least two surfactants comprising a low HLB surfactant and a high HLB surfactant, wherein a difference between the HLB values for said low and said high HLB surfactants is at least about 5 units; and

(iv) an ethoxylated fat; and

(b) a pharmaceutically effective amount of the cyclosporin compound.

31. The formulation of claim 30, further comprising a suitable diluent for administration to the eye.

32. A formulation for topical administration to the eye, comprising:

(a) a pro-nanodispersion comprising;

(i) a solid fat;

(ii) an amphiphilic solvent;

(iii) at least one hydrophilic surfactant; and

(b) a pharmaceutically effective amount of the cyclosporin compound;

wherein the components are adapted for administration to the eye.

33. The formulation of claim 32, wherein said cyclosporine is present in an amount of from about 0.01 to about 1.0% (w/v).

34. The formulation of claim 33, wherein said cyclosporine is present in an amount of about 0.1% (w/v).

35. The formulation of claim 32, wherein said hydrophilic surfactant comprises Polysorbate 20.

36. The formulation of claim 35, wherein said polysorbate 20 comprises from about 0.3 to about 4 mg per ml of the final formulation.

37. The formulation of claim 32, further comprising a low HLB surfactant, wherein a difference between the HLB values for said low HLB surfactant and said hydrophilic surfactant is at least about 5 units.

38. The formulation of claim 37, wherein said low HLB surfactant comprises sorbitan oleate.

39. The formulation of claim 38, wherein said sorbitan oleate is present in an amount of from about 0.3 to about 4 mg per ml of the final formulation.

40. The formulation of claim 37, wherein said solid fat comprises tricaprin or ethyl stearate, or a combination thereof.

41. The formulation of claim 40, wherein said solid fat comprises tricaprin.

42. The formulation of claim 41, wherein said tricaprin is present in an amount of from about 0.3 to about 3 mg per ml of the final formulation.

43. The formulation of claim 37, wherein said surfactant further comprises an ethoxylated fat.

44. The formulation of claim 43, wherein said ethyoxylated fat comprises macrogolglycerol hydroxystearate.

45. The formulation of claim 44, wherein said macrogolglycerol hydroxystearate is present in an amount of from about 0.1 to about 2 mg per ml of the final formulation.

46. The formulation of claim 37, wherein said solvent comprises ethyl lactate.

47. The formulation of claim 37, wherein said solvent comprises N-methyl pyrrolidone.

48. The formulation of claim 37, further comprising:

a phospholipid.

49. The formulation of claim 48, wherein said phospholipid comprises lecithin.

50. The formulation of claim 49, wherein said lecithin is present in an amount of from about 0.1 to about 2 mg per ml of the final formulation.

51. The formulation of claim 46, further comprising a suitable diluent.