Method of treatment of diabetes and/or obesity with reduced nausea side effect

• US 20070207958A1
• Filed: 11/09/2006
• Published: 09/06/2007
• Est. Priority Date: 11/09/2005
• Status: Active Grant

• Current Assignee: ConjuChem LLC (Colabor Group, Inc.)
• Original Assignee: ConjuChem LLC (Colabor Group, Inc.)
• Inventors: Thibaudeau, Karen, Castaigne, Jean-Paul, Bridon, Dominique
• Granted Patent: US 8,039,432 B2
• Time in Patent Office: Days
• US Class Current: 514/5.300
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention provides methods of administering an insulinotropic peptide in an amount effective to treat a disorder or condition while reducing nausea side effect by administering to a subject in need thereof an insulinotropic peptide conjugated to albumin. The present invention also provides methods of selecting a subject for administration of a conjugated insulinotropic peptide. Exemplary disorders or conditions treatable with an insulinotropic peptide include obesity and type II diabetes.

Claims

1. A method of administering an insulinotropic peptide to a nausea-sensitive subject comprising administering to said nausea-sensitive subject the insulinotropic peptide conjugated to albumin, wherein the conjugated insulinotropic peptide reduces nausea compared to administration of the unconjugated insulinotropic peptide.

2. The method of claim 1 further comprising the step of selecting the nausea-sensitive subject prior to administering said insulinotropic peptide conjugated to albumin.

3. The method of claim 1 wherein said nausea sensitivity is a result of the administration of unconjugated insulinotropic peptide.

4. The method of claim 1 wherein said administering of the conjugated insulinotropic peptide prevents nausea in the subject.

5. The method of claim 1 wherein said administering of the conjugated insulinotropic peptide eliminates nausea in the subject.

6. The method of claim 1 wherein the amount of conjugated insulinotropic peptide administered is between 1000 and 4000 μ

g.

7. The method of claim 1 wherein the amount of conjugated insulinotropic peptide administered is between 1250 and 3750 μ

g.

8. The method of claim 1 wherein the amount of conjugated insulinotropic peptide administered is between 1250 and 2500 μ

g.

9. The method of claim 1 wherein the amount of the conjugated insulinotropic peptide administered is 1250 μ

g.

10. The method of claim 1 wherein the amount of the conjugated insulinotropic peptide administered is 2500 μ

g.

11. The method of claim 1 wherein the amount of the conjugated insulinotropic peptide administered is 3750 μ

g.

12. The method of claim 1 wherein said administering of the conjugated insulinotropic peptide is in an amount effective to treat a disease or disorder that is characterized by the fact that it is treated by the action of said unconjugated insulinotropic peptide.

13. The method of claim 12 wherein the disease or disorder is obesity or diabetes.

14. The method of claim 13 wherein the disease or disorder is obesity.

15. The method of claim 13 wherein the disease or disorder is diabetes.

16. The method of claim 15 wherein the disease or disorder is type II diabetes.

17. The method of claim 15 wherein the amount is effective to reduce average daily blood glucose in the subject by at least 10% over one week after a single administration.

18. The method of claim 1 wherein the subject is human.

19. The method of claim 1 wherein the conjugated insulinotropic peptide comprises albumin covalently linked to a maleimido-containing group coupled to said insulinotropic peptide.

22. The method of claim 1 wherein the insulinotropic peptide is selected from the group consisting of glucagon-like peptide 1, exendin-3, and exendin-4.

23. The method of claim 1 wherein the insulinotropic peptide is exendin-4(1-39).

24. The method of claim 1 wherein the albumin is human serum albumin.

25. The method of claim 1 wherein the albumin is recombinant serum albumin.

26. The method of claim 1 wherein the albumin is recombinant human serum albumin.

27. The method of claim 1 wherein the conjugated insulinotropic peptide comprises recombinant human serum albumin covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetamide linker on the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys⁴⁰.

28. The method of claim 1 wherein the conjugated insulinotropic peptide is purified.

29. The method of claim 1, wherein said administering is subcutaneous.

31. The method of claim 29, wherein said subject has experienced nausea as a result of the administration of unconjugated insulinotropic peptide.

42. The method of claim 23 wherein the conjugated insulinotropic peptide comprises albumin covalently linked to a [2-[2-[2-maleimidopropionamido(ethoxy)ethoxy]acetamide linker on the epsilon amino of a lysine that has been added to the C-terminus of exendin-4(1-39).

43. The method of claim 1, wherein said administering is oral, intranasal, intravascular, intraarterial, intramuscular, transdermal or rectal.

20. (canceled)

21. (canceled)

30. A method of selecting a subject for treatment with an insulinotropic peptide conjugated to albumin, comprising the step of identifying a nausea sensitive subject having a disease or disorder treatable with the insulinotropic peptide, wherein the subject is selected for treatment when the subject is prone to experiencing or is experiencing nausea.

32. A method of administering an insulinotropic peptide to a subject comprising (a) selecting a nausea sensitive subject having a disease or disorder treatable with the insulinotropic peptide;

and (b) administering to the subject the insulinotropic peptide conjugated to albumin wherein the conjugated insulinotropic peptide reduces nausea compared to administering the unconjugated insulinotropic peptide.

33. A unit dose pharmaceutical comprising 1250 μ

g of a conjugate according to the following;

34. A unit dose pharmaceutical comprising 2500 μ

g of a conjugate according to the following;

35. A unit dose pharmaceutical comprising 3750 μ

g of a conjugate according to the following;

37. The method of claim 35, wherein the disease is diabetes.

38. The method of claim 35, wherein the disease is obesity.

39. The method of claims 35, 36 or 37, wherein the insulinotropic peptide is exendin-4(1-39)Lys⁴⁰.

40. The method of claim 38, wherein the insulinotropic peptide is linked to recombinant albumin.

41. The method of claim 39, wherein a maleimido-containing group is coupled to the insulinotropic peptide and has reacted with recombinant albumin.

36. A method for the treatment of diabetes or obesity in a subject, comprising

a. selecting a nausea-sensitive subject in need of said treatment, and

b. administering an insulinotropic peptide linked to albumin to the selected subject,

wherein the administration of the insulinotropic peptide linked to albumin provides a reduced nausea side effect compared to the administration of the insulinotropic peptide alone.