Sustained release GLP-1 receptor modulators

• US 20070099835A1
• Filed: 11/08/2006
• Published: 05/03/2007
• Est. Priority Date: 07/02/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lee, Ving, Qian, Feng, Zhu, Yeheng, Mapelli, Claudio, Ni, Nina, Naringrekar, Vijay, Ewing, William, Riexinger, Douglas, Sulsky, Richard, Burton, Lori, Haque, Tasir, Martinez, Rogelio
• Granted Patent: US 7,534,763 B2
• Time in Patent Office: Days
• US Class Current: 514/7.2
• CPC Class Codes: A61K 38/26 Glucagons

Abstract

The present invention provides novel pharmaceutical compositions comprising a human glucagon-like peptide-1 (GLP-1)-receptor modulator as an active ingredient in a sustained release formulation.

Claims

1. A pharmaceutical composition or a pharmaceutically-acceptable salt thereof, wherein said pharmaceutical composition comprises:

(a) an effective amount of a glucagon-like peptide-1 (GLP-1) receptor modulator, or salt thereof, as an active ingredient, wherein said GLP-1 receptor modulator comprises at least one phenyl-heteroaryl-alanine analog; and

(b) a metal ion, or a protamine vehicle, or a combination thereof.

2. The pharmaceutical composition of claim 1 wherein said GLP-1 receptor modulator is a compound selected from the group consisting of SEQ ID NOs:

9, 15, 118, 151, and 158.

3. The pharmaceutical composition of claim 1 wherein said metal ion is a divalent cation.

4. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises a protamine vehicle.

5. The pharmaceutical composition of claim 1, wherein said composition is prepared by spray drying, precipitation, or lyophilization.

6. The pharmaceutical composition of claim 1, wherein said metal ion is a divalent metal cation selected from the group consisting of zinc, manganese, and iron.

7. The pharmaceutical composition of claim 6 wherein said divalent metal cation is zinc.

8. A method for treating a patient afflicted with diabetes or a diabetes-associated condition comprising administering the pharmaceutical composition of claim 1 or 2 to a subject.

9. The method of claim 8, wherein said pharmaceutical composition is administered to a subject by subcutaneous injection or intramuscular injection.

10. The method of claim 8 wherein said composition is administered using a syringe.

11. A kit comprising the pharmaceutical composition of claim 1.

12. The kit of claim 11, further comprising a brochure containing product information.

13. The pharmaceutical composition of claim 1 wherein said GLP-1 receptor modulator is the compound of SEQ ID NO:

9.

14. The pharmaceutical composition of claim 1 wherein said GLP-1 receptor modulator is the compound of SEQ ID NO:

15.

15. The pharmaceutical composition of claim 1 wherein said GLP-1 receptor modulator is the compound of SEQ ID NO:

118.

16. The pharmaceutical composition of claim 1 wherein said GLP-1 receptor modulator is the compound of SEQ ID NO:

151.

17. The pharmaceutical composition of claim 1 wherein said GLP-1 receptor modulator is the compound of SEQ ID NO:

158.

18. The pharmaceutical composition of claim 2 further comprising a co-precipitated, lyophilized, or spray dried zinc adduct, in a Zn:

GLP-1 receptor modulator ratio of from about 1;

10 to about 50;

1.

19. The pharmaceutical composition of claim 2 further comprising a co-precipitated, lyophilized, or spray dried zinc adduct, in a Zn:

GLP-1 receptor modulator ratio of from about 1;

10 to about 50;

1, with a weight to volume ratio of surfactants, suspending agents, and/or thickening agents, of 0% to about 30%.

20. The pharmaceutical composition of claim 19 wherein the GLP-1 receptor modulator is the compound of SEQ ID NO:

9.

21. The pharmaceutical composition of claim 19 wherein the GLP-1 receptor modulator is the compound of SEQ ID NO:

158.

22. The pharmaceutical composition of claim 19 wherein the Zn:

GLP-1 receptor modulator ratio is about 0.5;

1 to about 10;

1, and the weight to volume ratio of surfactants, suspending agents, and/or thickening agents, is 0% to about 10%.

23. The pharmaceutical composition of claim 19 wherein the Zn:

GLP-1 receptor modulator ratio is about 1.5;

1 to about 5;

1 and the weight to volume ratio of surfactants is 0% to about 1%, suspending agents is 0% to about 5%, and/or thickening agents is 0% to about 1%.

24. The pharmaceutical composition of claim 23 wherein the GLP-1 receptor modulator is the compound of SEQ ID NO:

9.

25. The pharmaceutical composition of claim 23 wherein the GLP-1 receptor modulator is the compound of SEQ ID NO:

158.

26. The pharmaceutical composition of claim 1 further comprising a co-precipitated, lyophilized, or spray dried zinc adduct, in a Zn:

GLP-1 receptor modulator ratio of from about 1;

10 to about 50;

1, with a weight to volume ratio of surfactants, suspending agents, and/or thickening agents, of 0% to about 30%.

27. The pharmaceutical composition of claim 26 wherein the Zn:

GLP-1 receptor modulator ratio is about 0.5;

1 to about 10;

1, and the weight to volume ratio of surfactants, suspending agents, and/or thickening agents, is from about 0% to about 30%.

28. The pharmaceutical composition of claim 26 wherein the Zn:

GLP-1 receptor modulator ratio is about 1.5;

1 to about 5;

1 and the weight to volume ratio of surfactants is 0% to about 1%, suspending agents is 0% to about 5%, and/or thickening agents is 0% to about 1%.

29. A method for making a pharmaceutical composition comprising:

a) obtaining a GLP-1 receptor modulator comprising at least one phenyl-heteroaryl-alanine analog;

b) suspending said GLP-1 receptor modulator to form a GLP-1 suspension;

c) adjusting the pH of the GLP-1 suspension to about 8.5 to obtain a GLP-1 solution;

d) dissolving zinc acetate in a solution to obtain a zinc acetate solution;

e) adding the zinc acetate solution drop wise, with stirring, to the GLP-1 solution; and

f) obtaining a composition having a molar ratio of zinc;

GLP-1 receptor modulator of about 3;

1, and having a final pH of about 6.0.

30. The method of claim 29 further comprising the step of adding surfactants, suspending agents, and/or thickening agents.

31. The method of claim 29 wherein said GLP-1 receptor modulator is selected from the group consisting of SEQ ID NOs:

9, 15, 118, 151, and 158.

32. The method of claim 31 wherein said GLP-1 receptor modulator is SEQ ID NO:

9 or SEQ ID NO;

158.