Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors

• US 7,071,181 B2
• Filed: 09/19/2002
• Issued: 07/04/2006
• Est. Priority Date: 01/26/2001
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Picard, Gilles J., Veltri, Enrico P., Strony, John T., Kosoglou, Teddy, Davis, Harry R., Ress, Rudyard J.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Krishnan, Ganapathy
• Application Number:
  US10/247,099
• Publication Number:
  US 20040214811A1
• Time in Patent Office: 1,384 Days
• Field of Search: 536/17.2, 536/17.4, 536/18.1, 514/210.02, 514/210, 514/25, 514/23, 514/79, 540/200
• US Class Current: 514/210.02
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention provides methods of treating diabetes and associated conditions by administering a composition including at least one sterol or 5α-stanol absorption inhibitor or compositions or therapeutic combinations including: (a) at least one antidiabetic medication; and (b) at least one sterol or 5α-stanol absorption inhibitor.

Claims

1. A composition comprising:

(a) at least one antidiabetic medication selected from the group consisting of sulfonylurea, meglitinide, biguanide, thiazolidinedione, alpha-glucosidase inhibitor;

peptide for increasing insulin production, and combinations thereof for reducing blood glucose levels in a subject; and

(b) at least one sterol absorption inhibitor or at least one 5α

-stanol absorption inhibitor, or a pharmaceutically acceptable salt or solvate thereof.

2. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (I);

3. The composition according to claim 2, wherein the sterol or 5α

-stanol absorption inhibitor is represented by Formula (II) below;

4. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (III);

5. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (IV);

6. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (V);

7. The composition according to claim 1, where the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (VI);

8. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (VIIA) or (VIIB);

9. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (VIII);

10. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (IX);

11. The composition according to claim 1, wherein the sulfonylurea is selected from the group consisting of acetohexamide, chlorpropamide, gliamilide, gliclazide, glimepiride, glipizide, glyburide, glibenclamide, tolazamide, tolbutamide, and combinations thereof.

12. The composition according to claim 1, wherein the meglitinide is selected from the group consisting of repaglinide, nateglinide and combinations thereof.

13. The composition according to claim 1, wherein the biguanide is selected from the group consisting of mefformin, buformin, and combinations thereof.

14. The composition according to claim 1, wherein the alpha-glucosidase inhibitor is selected from the group consisting of acarbose, miglitol, camiglibose, voglibose, and combinations thereof.

15. The composition according to claim 1, wherein the peptide is selected from the group consisting of amlintide, pramlintide, exendin, GLP-1 agonistic peptides, and combinations thereof.

16. The composition according to claim 1, wherein the at least one antidiabetic medication is administered to a subject in an amount ranging from about 0.1 to about 1000 milligrams of antidiabetic medication per day.

17. The composition according to claim 1, wherein the at least one sterol or 5α

-stanol absorption inhibitor is administered to a subject in an amount ranging from about 0.1 to about 1000 milligrams of sterol or 5α

-stanol absorption inhibitor per day.

18. The composition according to claim 1, wherein the at least one antidiabetic medication is orally administrable insulin or insulin composition for intestinal delivery thereof in a therapeutically effective amount.

19. A pharmaceutical composition for the treatment of diabetes and lowering a concentration of a sterol or 5α

-stanol in plasma of a subject, comprising a therapeutically effective amount of the composition of claim 1, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition for the treatment of type 1 or type 2 diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject, comprising a therapeutically effective amount of the composition of claim 19 and a pharmaceutically acceptable carrier.

21. A method of treating diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of the composition of claim 1.

22. A method of treating type 1 or type 2 diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of the composition of claim 18.

23. A therapeutic combination comprising:

(a) a first amount of at least one antidiabetic medication selected from the group consisting of sulfonylurea, meglitinide, biguanide, thiazolidinedione, alpha-glucosidase inhibitor;

peptide for increasing insulin production, and combinations thereof for reducing blood glucose levels in a subject; and

(b) a second amount of at least one sterol or 5α

-stanol absorption inhibitor;

wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment of diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject.

24. The therapeutic composition according to claim 23, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (l);

25. The therapeutic composition according to claim 23, wherein the at least one sterol or 5α

-stanol absorption inhibitor is represented by Formula (II);

26. A therapeutic combination according to claim 23, wherein the at least one antidiabetic medication is administered concomitantly with the at least one sterol or 5α

-stanol absorption inhibitor.

27. A therapeutic combination according to claim 23, wherein the at least one antidiabetic medication and the at least one sterol or 5α

-stanol absorption inhibitor are present in separate treatment compositions.

28. A method of treating diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of the therapeutic combination of claim 23.

29. A composition comprising:

(a) at least one antidiabetic medication selected from the group consisting of sulfonylurea, meglitinide, biguanide, thiazolidinedione, alpha-glucosidase inhibitor;

peptide for increasing insulin production, and combinations thereof; and

(b) at least one substituted azetidinone compound or a pharmaceutically acceptable salt thereof or a solvate thereof.

30. A pharmaceutical composition for the treatment of diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject, comprising a therapeutically effective amount of the composition of claim 29 and a pharmaceutically acceptable carrier.

31. A method of treating diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject, comprising the step of administering to a subject in need of such treatment an effective amount of the composition of claim 29.

32. A therapeutic combination comprising:

(a) a first amount of at least one antidiabetic medication selected from the group consisting of sulfonylurea, meglitinide, biguanide, thiazolidinedione, alpha-glucosidase inhibitor;

peptide for increasing insulin production, and combinations thereof for reducing blood glucose levels in a subject; and

(b) a second amount of at least one substituted azetidinone compound or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment of diabetes or lowering a concentration of a sterol or 5α

-stanol in plasma of a subject.

33. A method of treating diabetes in a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one sterol or 5α

-stanol absorption inhibitor.

34. A method of treating diabetes in a subject, comprising the step of administering to a subject in need of such treatment an effective amount of a composition comprising at least one sterol or 5α

-stanol absorption inhibitor represented by Formula (II) below;