Night-time oral insulin therapy

• US 7,384,914 B2
• Filed: 01/06/2004
• Issued: 06/10/2008
• Est. Priority Date: 01/06/2003
• Status: Active Grant

• Current Assignee: NOVO Nordisk North America Operations A/S
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Goldberg, Michael, Arbit, Ehud
• Primary Examiner(s): Lukton; David
• Application Number:
  US10/541,433
• Publication Number:
  US 20060178296A1
• Time in Patent Office: 1,617 Days
• Field of Search: 530/303, 514/3, 424/434, 424/439, 424/464, 424/489
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A method for protection of a mammal that has impaired glucose tolerance or early stage diabetes mellitus from developing overt or insulin dependent diabetes comprises administering an orally effective dose of a pharmaceutical formulation comprising insulin at nighttime, e.g., at or shortly before bedtime.

Claims

1. A method of treating a mammal which has impaired glucose tolerance or early stage diabetes mellitus, comprising orally administering to said mammal, at or shortly before bedtime, a therapeutically effective dose of a pharmaceutical formulation comprising insulin and the delivery agent 4-CNAB in an amount which facilitates absorption of said insulin from the gastrointestinal tract of said mammal.

2. The method of claim 1 wherein the treating comprises substantially reducing the incidence of beta cell death or dysfunction.

3. The method of claim 1 wherein the treating comprises long term reduction in the incidence of developing overt diabetes.

4. The method of claim 1 wherein the treating comprises delaying the onset of overt or insulin dependent diabetes.

5. The method of claim 1, wherein the mammal is a rodent, dog, cat, sheep, pig, cow, horse or human.

6. The method of claim 5, wherein the mammal is a human.

7. The method of claim 1, wherein the oral pharmaceutical formulation is administered on a chronic basis.

8. The method of claim 1, wherein the oral pharmaceutical formulation is administered nightly for at least two weeks.

9. The method of claim 5, which provides a lowering of morning or fasting insulin levels of at least about 20%.

10. The method of claim 5, which achieves a therapeutically effective reduction in blood glucose after oral administration to a human diabetic patient, and which provides a ratio of portal vein to peripheral blood insulin concentration from about 2.5:

1 to about 6;

1.

11. The method of claim 5, wherein the dose of the pharmaceutical composition is administered through a dosage form that is solid.

12. The method of claim 1, wherein the dose of insulin contained in the dosage form is from about 50 Units to about 600 Units.

13. The method of claim 1, wherein the dose of unmodified insulin is from about 100 Units to about 400 Units insulin.

14. The method of claim 1, wherein the dose of unmodified insulin is from about 150 Units to about 300 Units.

15. The method of claim 1, wherein the dosage form(s) begin delivering insulin into the portal circulation (via absorption through the mucosa of the gastrointestinal tract) to achieve peak levels within about 30 minutes or less.

25. The method of claim 1, wherein said oral administration provides an insulin t_max at a time point from about 0.1 to about 1.5 hours after said oral administration, such that a statistically significant decrease in C-peptide levels from baseline is achieved in said mammal when said C-peptide level is measured about 8 hours after said oral administration of insulin.

26. The method of claim 1, wherein plasma insulin levels are reduced by a statistically significant degree from baseline when measured about 8 hours after said oral administration of insulin.

27. The method of claim 1 wherein the treating comprises reducing beta cell function.

28. The method of claim 1, wherein the pharmaceutical formulation comprises about 300 mg of 4-CNAB.

30. The method of claim 1, wherein C-peptide levels of said mammal are decreased by a mean of about 24% when measured about 8 hours after said oral administration of insulin.

31. The method of claim 1, wherein plasma insulin levels of said mammal are reduced by a mean of about 33% when measured about 8 hours after said oral administration of insulin.

32. The method of claim 1, wherein blood glucose levels of said mammal are reduced by a mean of about 6% when measured about 8 hours after said oral administration of insulin.

16. A method of treating manimals having impaired glucose tolerance or early stage diabetes mellitus, comprising,

orally administering to said mammal, at or shortly before bedtime, insulin and the delivery agent 4-CNAB in an amount which facilitates absorption of said insulin from the gastrointestinal tract of said mammal such that a statistically significant decrease in C-peptide levels from a mean baseline level is achieved in said mammal when said C-peptide level is measured about 8 hours after said oral administration of insulin.

17. The method of claim 16, wherein said C-peptide levels when measured are decreased by a mean of about 24%.

18. The method of claim 16, wherein plasma insulin levels are reduced by a statistically significant degree from baseline when measured about 8 hours after said oral adnilnistration of insulin.

19. The method of claim 18, wherein said plasma insulin levels are reduced by a mean of about 33% from baseline when measured about 8 hours after said oral administration of insulin.

20. The method of claim 16, wherein blood glucose levels are reduced by a statistically insignificant degree from baseline when measured about 8 hours after said oral administration of insulin.

21. The method of claim 20, wherein said blood glucose levels are reduced by a mean of about 6% from baseline when measured about 8 hours after said oral administration of insulin.

22. The method of claim 16, wherein sald oral administration of insulin comprises a dose of from about 200 to about 400 units of insulin.

23. The method of claim 16, wherein the amount of 4-CNAB is about 300 mg.

33. The method of claim 16, wherein said mammal is a human.

24. A method of treating mammals having impafred glucose tolerance or early stage diabetes mellitus, comprising orally administering to said mammal, at or shortly before bedtime, an unmodified insulin and the delivery agent 4-CNAB in an amount which facilitates absorption of said insulin from the gastrointestinal tract such that a statistically significant decrease in C-peptide levels from a mean baseline level is achieved in said mammal when said C-peptide level is measured about 8 hours after said oral administration of insulin.

34. The method of claim 24, wherein said C-peptide levels when measured are decreased by a mean of about 24%.

35. The method of claim 24, wherein plasma insulin levels are reduced by a statistically significant degree from baseline when measured about 8 hours after said oral administration of insulin.

36. The method of claim 35, wherein said plasma insulin levels are reduced by a mean of about 33% from baseline when measured about 8 hours after said oral administration of insulin.

37. The method of claim 24, wherein blood glucose levels are reduced by a statistically insignificant degree from baseline when measured about 8 hours after sald oral administration of insulin.

38. The method of claim 37, wherein said blood glucose levels are reduced by a mean of about 6% from baseline when measured about 8 hours after said oral administration of insulin.

39. The method of claim 24, wherein said oral administration of insulin comprises a dose of from about 200 to about 400 units of insulin.

40. The method of claim 24, wherein said insulin comprises a dose of from about 100 to about 400 units of insulin.

41. The method of claim 24, wherein the amount of 4-CNAB is about 300 mg.

42. The method of claim 24, wherein the mammal is a human.

29. A method of treating a mammal which has impaired glucose tolerance or early stage diabetes mellitus, comprising orally administering to said mammal, at or shortly before bedtime, a therapeutically effective dose of a pharmaceutical formulation comprising an unmodified insulin and the delivery agent 4-CNAB in an amount which facilitates absorption of said insulin from the gastrointestinal tract of said mammal.

43. The method of claim 29, wherein the mammal is a human.

44. The method of claim 29, wherein the oral pharmaceutical formulation is administered on a chronic basis.

45. The method of claim 29, wherein the oral pharmaceutical formulation is administered nightly for at least two weeks.

46. The method of claim 29, which provides a lowering of morning or fasting insulin levels of at least about 20%.

47. The method of claim 29, which achieves a therapeutically effective reduction in blood glucose after oral administration to a human diabetic patient, and which provides a ratio of portal vein to peripheral blood insulin concentration from about 2.5:

1 to about 6;

1.

48. The method of claim 29, wherein the dose of the pharmaceutical composition is administered through a dosage form that is solid.

49. The method of claim 29, wherein the dose of insulin contained in the dosage form is from about 50 Units to about 600 Units.

50. The method of claim 29, wherein the dose of unmodified insulin is from about 100 Units to about 400 Units insulin.

51. The method of claim 29, wherein the dose of unmodified insulin is from about 150 Units to about 300 Units.

52. The method of claim 29, wherein the dosage form(s) begin delivering insulin into the portal circulation (via absorption through the mucosa of the gastrointestinal tract) to achieve peak levels within about 30 minutes or less.

53. The method of claim 29, wherein said oral administration provides an insulin t_max at a time point from about 0.1 to about 1.5 hours after said oral administration, such that a statistically significant decrease in C-peptide levels from baseline is achieved in said mammal when said C-peptide level is measured about 8 hours after said oral administration of insulin.

54. The method of claim 29, wherein plasma insulin levels are reduced by a statistically significant degree from baseline when measured about 8 hours after said oral administration of insulin.

55. The method of claim 29, wherein C-peptide levels of said mammal are decreased by a mean of about 24% when measured about 8 hours after said oral administration of insulin.

56. The method of claim 29, wherein plasma insulin levels of said mammal are reduced by a mean of about 33% when measured about 8 hours after said oral administration of insulin.

57. The method of claim 29, wherein blood glucose levels of said mammal are reduced by a mean of about 6% when measured about 8 hours after said oral administration of insulin.

58. The method of claim 29, wherein said formulation comprises from about 200 to about 400 units of insulin.

59. The method of claim 58, wherein the pharmaceutical formulation comprises about 300 mg of 4-CNAB.