Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions

• US 6,656,504 B1
• Filed: 09/09/1999
• Issued: 12/02/2003
• Est. Priority Date: 09/09/1999
• Status: Expired due to Fees

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Hovey, Douglas C., Ostrander, Kevin D., Bosch, H. William
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Pulliam, Amy E
• Application Number:
  US09/392,557
• Time in Patent Office: 1,545 Days
• Field of Search: 424/489, 424/501, 424/502, 514/11, 514/937
• US Class Current: 424/489
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection

Abstract

Nanoparticulate amorphous cyclosporine formulations, and nanoparticulate cyclosporine formulations comprising a mixture of amorphous and crystalline cyclosporine, having effective average particle sizes of less than about 2000 nm are described. The compositions exhibit increased bioavailability and increased consistency of bioavailability as compared to prior macro-sized cyclosporine and formulations. Methods of making and using the compositions are also described.

Claims

1. A nanoparticulate composition comprising:

(a) amorphous cyclosporin particles; and

(b) at least one non-crosslinked surface stabilizer adsorbed on the surface of the cyclosporin particles,

wherein;

(i) the cyclosporin particles have an effective average particle size of less than about 2000 nm, and (ii) the cyclosporin and at least one surface stabilizer are present in a ratio of about 10;

1 to about 1.5;

1 (w/w), cyclosporin to surface stabilizer and (iii) the nanoparticulate composition does no contain an alcohol solubilizing agent and (iv) wherein the nanoparticulate composition does not contain solvent residues resulting from solvent extraction, solvent precipitation, or solvent-mediated hydrosol formation.

2. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 1500 nm.

3. The composition of claim 1, wherein said composition is a solid dose formulation.

4. The solid dose composition of claim 3, wherein said composition has a drug to surface stabilizer ratio of at least 2:

1.

5. The composition of claim 1, wherein said composition is an liquid dispersion formulation.

6. The liquid dispersion of claim 5, wherein the solid content of said dispersion is about 40% to about 5% (w/w).

7. The composition of claim 5, wherein said composition is an injectable formulation.

8. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers, poloxamines, dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), and triblock copolymers of the structure -(-PEO)--(-PBO-)--(-PEO-)-.

9. The composition of claim 8, wherein the surface stabilizer is selected from the group consisting of:

(1) a block copolymer of ethylene oxide and propylene oxide, (2) a triblock copolymer of the structure -(-PEO)--(-PBO-)--(-PEO- and having a molecular weight of about 5000, (3) 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, (4) hydroxypropyl cellulose, and (5) sodium lauryl sulfate.

10. A pharmaceutical composition comprising the amorphous cyclosporine composition of claim 1 and a pharmaceutically acceptable excipient.

25. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 1000 nm.

26. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 800 nm.

27. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 700 nm.

28. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 600 nm.

29. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 500 nm.

30. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 400 nm.

31. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 300 nm.

32. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 200 nm.

33. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 100 nm.

34. The composition of claim 1, wherein the effective average particle size of the nanoparticulate composition is less than about 50 nm.

55. The composition of claim 1, comprising as at least one surface stabilizer dioctylsulfosuccinate.

56. The composition of claim 1, comprising as surface stabilizers dioctylsulfosuccinate and polyvinylpyrrolidone.

57. The composition of claim 1, comprising as surface stabilizers dioctylsulfosuccinate and HPC-SL.

58. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, colloidal silicon dioxide, phosphates, magnesium aluminum silicate, and triethanolamine.

11. A nanoparticulate composition comprising:

(a) a mixture of amorphous and crystalline cyclosporin particles; and

(b) at least one non-crosslinked surface stabilizer absorbed on the surface of the cyclosporin particles,

wherein;

(i) the cyclosporin particles have an effective average particle size of less than about 2000 nm, and (ii) the cyclosporin and at least one surface stabilizer are present in a ratio of about 10;

1 to about 1.5;

1 (w/w), cyclosporin to surface stabilizer and (iii) the nanoparticulate composition does no contain an alcohol solubilizing agent and (iv) wherein the nanoparticulate composition does not contain solvent residues resulting from solvent extraction, solvent precipitation, or solvent-mediated hydrosol formation.

12. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 1500 nm.

13. The composition of claim 11, wherein said composition is a solid dose formulation.

14. The solid dose composition of claim 13, wherein said composition has a drug to surface stabilizer ratio of at least 2:

1.

15. The composition of claim 11, wherein said composition is an liquid dispersion formulation.

16. The liquid dispersion of claim 15, wherein the solid content of said dispersion is about 40% to about 5% (w/w).

17. The composition of claim 11, wherein said composition is an injectable formulation.

18. The composition of claim 11, wherein the surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers, poloxamines, dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), and triblock copolymers of the structure -(-PEO)--(-PBO-)--(-PEO-)-.

19. The composition of claim 18, wherein the surface stabilizer is selected from the group consisting of:

(1) a block copolymer of ethylene oxide and propylene oxide, (2) a triblock copolymer of the structure -(-PEO)--(-PBO-)--(-PEO-)- and having a molecular weight of about 5000, (3) 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, (4) hydroxypropyl cellulose, and (5) sodium lauryl sulfate.

20. A pharmaceutical composition comprising the amorphous cyclosporine composition of claim 11 and a pharmaceutically acceptable excipient.

35. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 1000 nm.

36. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 800 nm.

37. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 700 nm.

38. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 600 nm.

39. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 500 nm.

40. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 400 nm.

41. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 300 nm.

42. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 200 nm.

43. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 100 nm.

44. The composition of claim 11, wherein the effective average particle size of the nanoparticulate composition is less than about 50 nm.

59. The composition of claim 11, wherein the surface stabilizer is selected from the group consisting of casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, colloidal silicon dioxide, phosphates, magnesium aluminum silicate, and triethanolamine.

21. A method of making a nanoparticulate composition comprising:

(a) amorphous cyclosporin particles; and

(b) at least one non-crosslinked surface stabilizer absorbed on the surface of the cyclosporin particles,

wherein;

(i) the cyclosporin particles have an effective average particle size of less than about 1000 nm, and (ii) the cyclosporin and the at least one surface stabilizer are present in a ratio of about 10;

1 to about 1.5;

1 (w/w), cyclosporin to surface stabilizer,

said method comprising contacting cyclosporin with at least one non-crosslinked surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate amorphous cyclosporin composition in which the cyclosporin particles have an average effective particle size of less than about 2000 nm and the composition has a drug to surface stabilizer ratio of about 10;

1 to about 1.5;

1 (w/w), cyclosporin to surface stabilizer and (iii) the nanoparticulate composition does no contain an alcohol solubilizing agent and (iv) wherein the nanoparticulate composition does not contain solvent residues resulting from solvent extraction, solvent precipitation, or solvent-mediated hydrosol formation.

22. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 1500 nm.

23. The method of claim 21, wherein said composition is obtained by milling.

24. The method of claim 23, wherein said milling is high energy milling.

45. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 1000 nm.

46. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 800 nm.

47. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 700 nm.

48. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 600 nm.

49. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 500 nm.

50. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 400 nm.

51. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 300 nm.

52. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 200 nm.

53. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 100 nm.

54. The method of claim 21, wherein the effective average particle size of the nanoparticulate composition is less than about 50 nm.