Pulmonary administration of chemically modified insulin

• US 20030216542A1
• Filed: 04/01/2003
• Published: 11/20/2003
• Est. Priority Date: 05/21/2001
• Status: Active Grant

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Blaine Bueche, Chester Leach, Harris J. Milton, John S. Patton, Kimberly Perkins, Mei-Chang Kuo
• Inventors: Harris, J. Milton, Bueche, Blaine, Patton, John S., Leach, Chester, Kuo, Mei-Chang, Perkins, Kimberly
• Granted Patent: US 6,890,518 B2
• Time in Patent Office: Days
• US Class Current: 530/303
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

The present invention provides active, hydrophilic polymer-modified derivatives of insulin. The insulin derivatives of the invention are, in one aspect, suitable for delivery to the lung and exhibit pharmakokinetic and/or pharmacodynamic properties that are significantly improved over native insulin.

Claims

1. An insulin composition for pulmonary administration, said composition comprising a conjugate of insulin covalently coupled to one or more molecules of a non-naturally occurring hydrophilic polymer.

2. The insulin composition of claim 1, wherein said conjugate is absent a lipophilic moiety.

3. The insulin composition of claim 1, wherein said non-naturally occurring hydrophilic polymer is a polyalkyene glycol.

4. The insulin composition of claim 1, wherein said non-naturally occurring hydrophilic polymer is polyethylene glycol.

5. The insulin composition of claim 2, wherein said non-naturally occurring hydrophilic polymer is polyethylene glycol.

6. The composition of claim 4, characterized by an absolute pulmonary bioavailability that is greater than that of native insulin.

7. The composition of claim 6, characterized by an absolute pulmonary bioavailability that is at least twice that of native insulin.

8. The composition of claim 4, characterized by an absolute pulmonary bioavailability greater than 15%.

9. The composition of claim 8, characterized by an absolute pulmonary bioavailability greater than 30%.

10. The composition of claim 4, which when administered to the lung, is characterized by a Tmax that is at least three times that of native insulin.

11. The composition of claim 10, which when administered to the lung, is characterized by a Tmax that is at least five times that of native insulin.

12. The composition of claim 4, wherein said polyethylene glycol is end-capped.

13. The composition of claim 12, wherein said polyethylene glycol is end-capped with an alkoxy group.

14. The composition of claim 4, wherein said polyethylene glycol is selected from the group consisting of linear polyethylene glycol, branched polyethylene glycol, forked polyethylene glycol, and dumbbell polyethylene glycol.

15. The composition of claim 14, wherein said polyethylene glycol comprises a biodegradable linkage.

16. The composition of claim 14, wherein said polyethylene glycol comprises a number of (OCH₂CH₂) subunits selected from the group consisting of from about 2 to 300 subunits, from about 4 to 200 subunits, and from about 10 to 100 subunits.

17. The composition of claim 14, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 10,000 daltons.

18. The composition of claim 14, wherein said polyethylene glycol is linear.

19. The composition of claim 17, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 5,000 daltons.

20. The composition of claim 17, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 2,000 daltons.

21. The composition of claim 17, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 1,000 daltons.

22. The composition of claim 4, wherein said insulin is native insulin.

23. The composition of claim 4, wherein said conjugate has a purity of greater than 90%.

24. The composition of claim 4, wherein said insulin is covalently coupled to polyethylene glycol at one or more of its amino sites.

25. The composition of claim 24, wherein at least about 75% of the B-1Phe sites on insulin are covalently coupled to polyethylene glycol.

26. The composition of claim 25, wherein at least about 90% of the B-1Phe sites on insulin are covalently coupled to polyethylene glycol.

27. The composition of claim 24, comprising a mixture of monomer and dimer conjugates of insulin.

28. The composition of claim 27, further comprising a trimer insulin conjugate.

29. The composition of claim 4, wherein said insulin is covalently coupled to polyethylene glycol via a linking moiety positioned at a terminus of said polyethylene glycol.

30. The composition of claim 4, wherein said polyethylene glycol, prior to coupling with insulin, possesses an activated linking moiety at one terminus suitable for covalent coupling with insulin.

31. The composition of claim 30, wherein said activated linking moiety is suitable for coupling with reactive insulin amino groups.

32. The composition of claim 31, wherein said activated linking moiety comprises a reactive functional group selected from the group consisting of N-hydroxysuccinimide active esters, active carbonates, aldehydes, and acetals.

33. The composition of claim 29, wherein insulin is covalently coupled to polyethylene glycol via an amide linkage.

34. The composition of claim 4 in aerosolized form.

35. The composition of claim 4 in liquid or dry form.

36. The composition of claim 4 further comprising a pharmaceutically acceptable excipient.

37. The composition of claim 4 in spray-dried form.

38. A method for delivering insulin to a mammalian subject in need thereof, said method comprising:

aerosolizing the insulin composition of claim 4, and

administering said aerosolized insulin composition by inhalation for deposition in and absorption from the lung of said subject.

39. A method for providing a substantially non-immunogenic insulin composition for administration to the lung of a subject in need thereof, said method comprising:

covalently coupling insulin to one or more molecules of a non-naturally occurring hydrophilic polymer to provide a composition comprising an insulin-hydrophilic polymer conjugate, and

administering said composition to the lung of a subject in need thereof by inhalation, whereby as a result of said administering, said insulin passes through the lung and enters into the blood circulation.

40. The method of claim 39, wherein said non-naturally occurring hydrophilic polymer is a polyalkylene glycol.

41. A method for providing a prolonged-effect insulin composition for administration to the lung of a subject in need thereof, said method comprising:

covalently coupling insulin to one or more molecules of a non-naturally occurring hydrophilic polymer to provide a composition comprising an insulin-hydrophilic polymer conjugate,

administering said composition to the lung of a subject in need thereof by inhalation, whereby as a result of said administering, (i) said insulin passes through the lung and enters the blood circulation, and (ii) elevated blood levels of insulin are sustained for at least 8 hours post administration.

42. The method of claim 41, wherein said non-naturally occurring hydrophilic polymer is a polyalkylene glycol.

43. The method of claim 42, wherein said non-naturally occurring hydrophilic polymer is polyethylene glycol.

44. The method of claim 43, whereby elevated levels of insulin are sustained for at least 10 hours post-administration.

45. The method of claim 43, whereby elevated levels of insulin are sustained for at least 12 hours post-administration.

46. The method of claim 43, whereby further as a result of said administering, glucose levels in said subject are suppressed for at least 10 hours post administration.

47. The method of claim 46, whereby further as a result of said administering, glucose levels in said subject are suppressed for at least 12 hours post administration.

48. The method of claim 43, wherein said administering step comprises administering said composition in aerosolized form.

49. The method of claim 43, further comprising the step of aerosolizing said composition prior to administering.

50. The method of claim 43, wherein said coupling step comprises covalently coupling insulin to polyethylene glycol in a site-specific fashion.

51. The method of claim 43, wherein said coupling step comprises covalently coupling insulin to polyethylene glycol in a random fashion.

52. The method of claim 43, wherein said conjugate when administered to the lung is further characterized by an absolute pulmonary bioavailability that is greater than that of native insulin.

53. The method of claim 43, wherein said coupling step comprises covalently coupling insulin to one or more molecules of end-capped polyethylene glycol.

54. The method of claim 43, wherein said coupling step comprises covalently coupling insulin to one or more molecules of polyethylene glycol selected from the group consisting of linear, branched, forked, and dumbbell polyethylene glycol.

55. The method of claim 43, wherein said conjugate is absent a lipophilic moiety.

56. The method of claim 43, wherein said composition is absent a lipophilic component.

57. The method of claim 43, wherein said coupling step comprises covalently coupling insulin to one or more molecules of polyethylene glycol comprising a biodegradable linkage.

58. The method of claim 43, wherein said polyethylene glycol comprises a number of (OCH₂CH₂) subunits selected from the group consisting of from about 2 to 300 subunits, from about 4 to 200 subunits, and from about 10 to 100 subunits.

59. The method of claim 43, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 10,000 daltons.

60. The method of claim 43, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 5,000 daltons.

61. The method of claim 43, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 2,000 daltons.

62. The method of claim 43, wherein said polyethylene glycol has a nominal average molecular weight from about 200 to about 1,000 daltons.

63. The method of claim 43, wherein said coupling comprises coupling polyethylene glycol to insulin at one or more of its reactive amino sites.

64. The method of claim 63, wherein said polyethylene glycol is coupled to insulin at more or more of its reactive amino sites via a bond selected from the group consisting of amide, urethane, and methylene amino.

65. The method of claim 63, wherein said coupling comprises reacting a polyethylene glycol having a terminal reactive group selected from the group consisting of N-hydroxysuccinimide active esters, active carbonates, aldehydes, and acetals with one or more reactive amino sites on insulin.

66. The method of claim 43, wherein said coupling results in a composition wherein at least about 75% of the B-1Phe sites on insulin are covalently coupled to polyethylene glycol.

67. The method of claim 43, wherein said coupling results in a composition wherein at least about 90% of the B-1Phe sites on insulin are covalently coupled to polyethylene glycol.

68. The method of claim 43, wherein said coupling results in a composition comprising a mixture of monomer and dimer conjugates of insulin.

69. The method of claim 68, wherein said coupling results in a composition further comprising a trimer conjugate of insulin.

70. The method of claim 43, wherein said polyethylene glycol comprises an activated linking moiety at one terminus suitable for covalent coupling with insulin.

71. The method of claim 43, wherein said activated linking moiety comprises a reactive functional group selected from the group consisting of N-hydroxysuccinimide active esters, active carbonates, aldehydes, and acetals.

72. The method of claim 70, wherein said linking moiety has a length of from about 2 to about 20 atoms.

73. The method of claim 43, wherein said administering step comprises administering said composition by dry powder inhaler.

74. The method of claim 43, wherein said administering step comprises administering said composition by a metered dose inhaler.

75. The method of claim 43, wherein said administering step comprises administering said composition by a nebulizer.

76. The method of claim 43, wherein said composition further comprises a pharmaceutically acceptable excipient.

77. The method of claim 43, whereby as a result of administering said conjugate composition, serum levels of insulin that are at least 2 times greater than basal levels are achieved within 1 hour post administration.