Methods of treating diabetes mellitus

• US 7,060,675 B2
• Filed: 02/13/2002
• Issued: 06/13/2006
• Est. Priority Date: 02/15/2001
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Ekwuribe, Nnochiri N., Price, Christopher H., Still, James Gordon, Filbey, Jennifer Ann
• Primary Examiner(s): Campell, Bruce R.
• Assistant Examiner(s): Kosar, Andrew D.
• Application Number:
  US10/075,097
• Publication Number:
  US 20030050228A1
• Time in Patent Office: 1,581 Days
• Field of Search: 514/3, 530/303
• US Class Current: 514/6.2
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Methods of treating diabetes mellitus in a patient in need of such treatment include administering an effective amount of an insulin drug to the patient in order to treat diabetes mellitus in the patient. Methods according to the present invention may “activate” the liver, potentially restoring normal glucose homeostasis to individuals suffering from diabetes mellitus.

Claims

1. A method of treating diabetes mellitus in a human patient in need of such treatment, said method comprising:

orally administering to the human patient between about 0.05 and 10 mg per kilogram body weight of an insulin polypeptide-oligomer conjugate comprising the structure of Formula III;

Insulin polypeptide-X(CH₂)_m(OC₂H₄)_nOR 

 

(III)

 

wherein;

X is a moiety which forms an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

m is between 1 and 24;

n is between 1 and 50; and

R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the human patient within one hour prior to ingestion of a meal or contemporaneously with ingestion of a meal by the human patient in order to treat diabetes mellitus in the human patient, wherein the effective amount of the conjugate of Formula III is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.

2. The method of claim 1, wherein the oral administration of the effective amount of the conjugate of Formula III provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.

3. The method of claim 1, wherein the oral administration of the effective amount of the conjugate of Formula III provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.

4. The method of claim 1, wherein the oral administration of the effective amount of the conjugate of Formula III stabilizes peripheral glucose concentration to within about +/−

50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.

5. The method of claim 1, wherein the conjugate of Formula III clears the bloodstream of the human patient within about 4 hours following administration.

6. The method of claim 1, wherein the administration of the effective amount of the conjugate of Formula III reduces hepatic glucose production in the human patient by at least about 25 percent when compared to hepatic glucose production in the human patient without administration.

7. The method of claim 6, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.

8. The method of claim 1, wherein the conjugate of Formula III is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the human patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the human patient.

9. The method of claim 1, wherein the conjugate of Formula III is orally administered less than about one hour prior to ingestion of a meal by the human patient.

10. The method of claim 1, wherein the conjugate of Formula III is orally administered substantially contemporaneously with the ingestion of a meal by the human patient.

11. The method of claim 1, wherein the conjugate of Formula III is orally administered less than about one hour after ingestion of a meal by the human patient.

12. The method of claim 1, wherein the insulin polypeptide is insulin.

13. The method of claim 12, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.

14. A method of claim 1, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly^A21 insulin, human;

Gly^A21 Gln^B3 insulin, human;

Ala^A21 insulin, human;

Ala^A21 Gln^B3 insulin, human;

Gln^B3 insulin, human;

Gln^B30 insulin, human;

Gly^A21 Glu^B30 insulin, human;

Gly^A21 Gln^B3 Glu^B30 insulin, human;

Gln^B3 Glu^B30 insulin, human;

Asp^B28 insulin, human;

Lys^B28 insulin, human;

Leu^B28 insulin, human;

Val^B28 insulin, human;

Ala^B28 insulin, human;

Asp^B28 Pro^B29 insulin, human;

Lys^B28 Pro^B29 insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human; and

Ala^B28 Pro^B29 insulin, human.

15. The method of claim 1, wherein the conjugate of Formula III is present as a substantially monodispersed mixture.

16. The method of claim 1, wherein the conjugate of Formula III is present as a monodispersed mixture.

17. The method of claim 1, wherein the conjugate of Formula III is amphiphilically balanced.

18. The method of claim 1, wherein the effective amount of the conjugate of Formula III is present in a pharmaceutical composition.

19. The method of claim 1, wherein m is between 3 and 16.

20. The method of claim 1, wherein m is between 4 and 14.

21. The method of claim 1, wherein m is between 5 and 10.

22. The method of claim 1, wherein n is between 3 and 18.

23. The method of claim 1, wherein n is between 4 and 14.

24. The method of claim 1, wherein n is between 5 and 10.

25. The method of claim 1, wherein R is lower alkyl.

26. The method of claim 1, wherein R is C₁ to C₃ alkyl.

27. The method of claim 1, wherein R is methyl.

28. The method of claim 1, wherein the insulin polypeptide-oligomer conjugate comprises the structure of Formula IV:

29. The method of claim 28, wherein the oral administration of the effective amount of the conjugate of Formula IV provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.

30. The method of claim 28, wherein the effective amount of the conjugate of Formula IV is between about 0.05 and about 10 mg per kilogram body weight.

31. The method of claim 28, wherein the oral administration of the effective amount of the conjugate of Formula IV provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.

32. The method of claim 28, wherein the oral administration of the effective amount of the conjugate of Formula IV stabilizes peripheral glucose concentration to within about +/−

50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.

33. The method of claim 28, wherein the conjugate of Formula IV clears the bloodstream of the human patient within about 4 hours following administration.

34. The method of claim 28, wherein the administration of the effective amount of the conjugate of Formula IV reduces hepatic glucose production in the human patient by at least about 25 percent when compared to hepatic glucose production in the human patient without administration.

35. The method of claim 34, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.

36. The method of claim 28, wherein the conjugate of Formula IV is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the human patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the human patient.

37. The method of claim 28, wherein the conjugate of Formula IV is orally administered less than about one hour prior to ingestion of a meal by the human patient.

38. The method of claim 28, wherein the conjugate of Formula IV is orally administered substantially contemporaneously with the ingestion of a meal by the human patient.

39. The method of claim 28, wherein the conjugate of Formula IV is orally administered less than about one hour after ingestion of a meal by the human patient.

40. The method of claim 28, wherein the insulin polypeptide is insulin.

41. The method of claim 40, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.

42. A method of claim 28, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly^A21 insulin, human;

Gly^A21 Gln^B3 insulin, human;

Ala^A21 insulin, human;

Ala^A21 Gln^B3 insulin, human;

Gln^B3 insulin, human;

Gln^B30 insulin, human;

Gly^A21 Glu^B30 insulin, human;

Gly^A21 Gln^B3 Glu^B30 insulin, human;

Gln^B3 Glu^B30 insulin, human;

Asp^B28 insulin, human;

Lys^B28 insulin, human;

Leu^B28 insulin, human;

Val^B28 insulin, human;

Ala^B28 insulin, human;

Asp^B28 Pro^B29 insulin, human;

Lys^B28 Pro^B29 insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human; and

Ala^B28 Pro^B29 insulin, human.

43. The method of claim 28, wherein the conjugate of Formula IV is present as a substantially monodispersed mixture.

44. The method of claim 28, wherein the conjugate of Formula IV is present as a monodispersed mixture.

45. The method of claim 28, wherein the conjugate of Formula IV is amphiphilically balanced.

46. The method of claim 28, wherein the effective amount of the conjugate of Formula IV is present in a pharmaceutical composition.

47. The method of claim 28, wherein m is between 3 and 16.

48. The method of claim 28, wherein m is between 4 and 14.

49. The method of claim 28, wherein m is between 5 and 10.

50. The method of claim 28, wherein n is between 3 and 18.

51. The method of claim 28, wherein n is between 4 and 14.

52. The method of claim 28, wherein n is between 5 and 10.

53. The method of claim 28, wherein R is lower alkyl.

54. The method of claim 28, wherein R is C₁ to C₃ alkyl.

55. The method of claim 28, wherein R is methyl.

56. A method of treating diabetes mellitus in a human patient in need of such treatment, said method comprising:

orally administering to the human patient an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III;

Insulin polypeptide-X(CH₂)_m(OC₂H₄)_nOR 

 

(III)

 

wherein;

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

m is between 1 and 24;

n is between 1 and 50; and

R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to treat diabetes mellitus in the human patient, wherein the effective amount of the insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.

57. A method of treating diabetes mellitus in a human patient in need of such treatment, said method comprising:

orally administering to the human patient an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III;

Insulin polypeptide-X(CH₂)_m(OC₂H₄)_nOR 

 

(III)

 

wherein;

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

m is between 1 and 24;

n is between 1 and 50; and

R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the human patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide-oligomer conjugate is administered so that it stabilizes peripheral glucose concentration to within about +/−

50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.

61. The method of claim 57 wherein the insulin polypeptide-oligomer conjugate comprises the structure of Formula IV:

58. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering to the human patient between about 0.05 and 10 mg per kilogram body weight of an insulin polypeptide-oligomer conjugate comprising the structure of Formula III;

Insulin polypeptide-X(CH₂)_m(OC₂H₄)_nOR 

 

(III)

 

wherein;

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

m is between 1 and 24;

n is between 1 and 50; and

R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the human patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide-oligomer conjugate is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the human patient without administration.

59. The method of claim 58, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.

60. A method of treating diabetes mellitus in a human patient in need of such treatment, said method comprising:

orally administering to the human patient between about 0.05 and 10 mg per kilogram body weight of an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III;

Insulin polypeptide-X(CH₂)_m(OC₂H₄)_nOR 

 

(III)

 

wherein;

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

m is between 1 and 24;

n is between 1 and 50; and

R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the human patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide-oligomer conjugate is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes of ingestion of the meal by the human patient.