Biguanide formulations

• US 20040052848A1
• Filed: 05/20/2003
• Published: 03/18/2004
• Est. Priority Date: 05/23/2002
• Status: Abandoned Application

• Current Assignee: Andrx Corporation (Abbvie Incorporated)
• Original Assignee: Andrx Corporation (Abbvie Incorporated)
• Inventors: Chen, Chih-Ming, Jan, Steve, Cheng, Xiu-Xiu, Tian, Dacheng
• Application Number:
  US10/442,692
• Publication Number:
  US 20040052848A1
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

In certain embodiments, the invention is directed to a pharmaceutical dosage form consisting essentially of a single phase matrix comprising metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient; said dosage form providing a mean T_max of metformin from about 3 to about 12 hours after administration to human patients.

Claims

1. A pharmaceutical dosage form consisting essentially of a single phase matrix comprising metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient;

said dosage form providing a mean T_max of metformin from 3 to 12 hours after administration to human patients.

7. The dosage form of claims 1-6 wherein said single phase matrix is prepared from a dry granulation.

8. The dosage form of claims 1-6 wherein said single phase matrix is prepared from a wet granulation.

10. The dosage form of claims 1-6 further comprising a film coat.

11. The dosage form of claims 1 and 3-6 wherein said dosage form does not comprise a controlled release coating.

12. The dosage form of claims 1-5 wherein said dosage form providing the following in-vitro dissolution profile when tested in a USP type 2apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 6.8 phosphate buffer) and at 37°

C.;

greater than 25% to about 40% metformin or salt thereof released after 1 hour;

from about 30% to about 60% metformin or salt thereof released after 2 hours;

from about 40% to about 70% metformin or salt thereof released after 3 hours;

from about 50% to about 80% metformin or salt thereof released after 4 hours;

from about 60% to about 90% metformin or salt thereof released after 8 hours, and

from about 70% to about 99% metformin or salt thereof released after 10 hours.

13. The pharmaceutical dosage form of claims 1-6 comprising an effective amount of metformin or salt thereof for making said dosage form suitable for once-a-day dosing for type 2 diabetes in human patients.

15. The pharmaceutical dosage form of claims 1-6 which provides a mean T_max of metformin from about 4 to about 8 hours after administration to human patients.

16. The pharmaceutical dosage form of claims 1-6 which provides a mean T_max of metformin from about 5 to about 12 hours after administration to human patients.

17. The pharmaceutical dosage form of claims 1-6 which provides a mean T_max of metformin from about 5 to about 10 hours after administration to human patients.

18. The pharmaceutical dosage form of claims 1-6 and 14 which provides a mean C_max of metformin from about 500 to about 700 ng/ml with 500 mg metformin included therein.

19. The pharmaceutical dosage form of claim 18 which provides a mean C_max of metformin of about 600 ng/ml.

20. The pharmaceutical dosage form of claims 1-6, 14 and 18 which provides a mean AUC_0-48 of metformin from about 3,500 to about 7,500 ng·

hr/ml with 500 mg metformin included therein.

21. The pharmaceutical dosage form of claim 20 which provides a mean AUC_0-48 of metformin from about 3,500 to about 6,000 ng·

hr/ml in the fasted state.

22. The pharmaceutical dosage form of claim 20 which provides a mean AUC_0-48 of metformin from about 5,000 to about 7,500 ng·

hr/ml in the fed state.

23. The dosage form of claims 1-2 and 5-6 comprising less than 70% metformin or pharmaceutically acceptable salt thereof.

24. The dosage form of claims 1-6 comprising less than 65% metformin or pharmaceutically acceptable salt thereof.

25. The dosage form of claims 1-6 comprising less than 55% metformin or pharmaceutically acceptable salt thereof.

26. The dosage form of claims 1, 2 and 4-6 wherein said controlled release excipient is a polymer.

27. The dosage form of claims 26 wherein said polymer is a water soluble polymer.

28. The pharmaceutical dosage form of claim 26 comprising greater than 30% water soluble polymer.

29. The pharmaceutical dosage form of claim 26 comprising greater than 40% water soluble polymer.

30. The pharmaceutical dosage form of claims 3 and 26 comprising greater than 50% water soluble polymer.

31. The pharmaceutical dosage form of claims 27 wherein said single phase matrix comprises an additional pharmaceutically acceptable excipient.

32. The pharmaceutical dosage form of claim 31 wherein said excipient is selected from the group consisting of a hydrophobic material, a lubricant, an inert diluent and a combination thereof.

33. The pharmaceutical dosage form of claim 32 wherein said hydrophobic material is a cellulosic material.

34. The pharmaceutical dosage form of claim 33 wherein said cellulosic material is selected from the group consisting of ethyl cellulose, microcrystalline cellulose and a mixture thereof.

35. The pharmaceutical dosage form of claim 32 wherein said hydrophobic material is an acrylic polymer.

36. The pharmaceutical dosage form of claim 35 wherein said acrylic polymer is selected from the group consisting of polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, and mixtures thereof.

37. A method of treating type 2 diabetes in a patient in need thereof comprising administering to said patient a dosage form of claims 1-6.

2. A pharmaceutical dosage form comprising a single phase matrix comprising metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient;

said dosage form providing a mean T_max of metformin from 3 to 12 hours after administration to human patients, said dosage form not having a controlled release coating.

3. A pharmaceutical dosage form comprising a single phase matrix comprising less than 60% metformin or a pharmaceutically acceptable salt thereof and greater than 40% of a water soluble polymer.

14. The pharmaceutical dosage form of claims 3-6 which provides a mean T_Max of metformin from 3 to 12 hours after administration to human patients.

4. A pharmaceutical dosage form consisting essentially of a single phase matrix comprising less than 70% metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient.

5. A pharmaceutical dosage form comprising a single phase matrix comprising at least one controlled release excipient and a granulation consisting essentially of metformin or a pharmaceutically acceptable salt thereof.

9. The dosage form of claim 5 wherein said metformin granulation is prepared by wet granulation.

6. A pharmaceutical dosage form comprising a single phase matrix comprising metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient, said dosage form providing the following in-vitro dissolution profile when tested in a USP type 2 apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 6.8 phosphate buffer) and at 37°

C.;

greater than 25% to about 40% metformin or salt thereof released after 1 hour;

from about 30% to about 60% metformin or salt thereof released after 2 hours;

from about 40% to about 70% metformin or salt thereof released after 3 hours;

from about 50% to about 80% metformin or salt thereof released after 4 hours;

from about 60% to about 90% metformin or salt thereof released after 8 hours, and

from about 70% to about 99% metformin or salt thereof released after 10 hours.

38. A method of preparing a pharmaceutical dosage form comprising:

compressing a mixture comprising metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient into a single phase matrix, wherein said dosage form consists essentially of said matrix;

said dosage form providing a mean T_max of metformin from 3 to 12 hours after administration to human patients.

44. The method of claims 38-43 wherein said mixture is prepared by dry granulation.

45. The method of claims 38-43 wherein said mixture is prepared by wet granulation.

39. A method of preparing a pharmaceutical dosage form comprising:

compressing a mixture comprising metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient into a single phase matrix, wherein said dosage form does not have a controlled release coating;

said dosage form providing a T_max of metformin from 3 to 12 hours after administration to human patients.

40. A method of preparing a pharmaceutical dosage form comprising:

compressing a mixture comprising metformin or a pharmaceutically acceptable salt thereof and at least one water soluble polymer into a single phase matrix wherein said water soluble polymer comprises greater than 40% of said matrix.

41. A method of preparing a pharmaceutical dosage form comprising:

compressing a mixture comprising metformin or a pharmaceutically acceptable salt thereof and at least one water soluble polymer into a single phase matrix wherein said dosage form does not have a controlled release coating and said metformin comprises less than 70% of said matrix.

42. A method of preparing a pharmaceutical dosage form comprising:

compressing a mixture comprising at least one controlled release excipient and a granulation consisting essentially of metformin or a pharmaceutically acceptable salt thereof into a single phase matrix.

46. The method of claim 42 wherein said metformin granulation is prepared by wet granulation.

43. A method of preparing a pharmaceutical dosage form comprising:

compressing a mixture comprising metformin or a pharmaceutically acceptable salt thereof and at least one controlled release excipient into a single phase matrix, wherein said dosage form provides the following in-vitro dissolution profile when tested in a USP type 2 apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 6.8 phosphate buffer) and at 37°

C.;

greater than 25% to about 40% metformin or salt thereof released after 1 hour;

from about 30% to about 60% metformin or salt thereof released after 2 hours;

from about 40% to about 70% metformin or salt thereof released after 3 hours;

from about 50% to about 80% metformin or salt thereof released after 4 hours;

from about 60% to about 90% metformin or salt thereof released after 8 hours, and

from about 70% to about 99% metformin or salt thereof released after 10 hours.