Tranexamic acid formulations

• US 8,022,106 B2
• Filed: 04/30/2009
• Issued: 09/20/2011
• Est. Priority Date: 03/04/2004
• Status: Active Grant

• Current Assignee: Amring Pharmaceuticals, Inc.
• Original Assignee: Ferring BV (Ferring Holding SA)
• Inventors: Moore, Keith A., Facemire, John W., Greiwe, Jeffrey S., Modest, Jason D., Heasley, Ralph A.
• Primary Examiner(s): Fetterolf; Brandon
• Assistant Examiner(s): Stone; Christopher R
• Application Number:
  US12/433,510
• Publication Number:
  US 20090209646A1
• Time in Patent Office: 873 Days
• Field of Search: 514/574, 514/561
• US Class Current: 514/574
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

Disclosed are modified release oral tranexamic acid formulations and methods of treatment therewith.

Claims

1. A tranexamic acid oral dosage form comprising:

tranexamic acid or a pharmaceutically acceptable salt thereof; and

a modified release material which provides for the modified release of the tranexamic acid or pharmaceutically acceptable salt thereof from the dosage form such that the dosage form is suitable for administration on a two or three times a day basis;

wherein the modified release material comprises a polymer selected from the group consisting of hydroxyalkylcelluloses, alkylcelluloses, cellulose ethers, partial esters thereof, and mixtures thereof;

wherein the modified release material is present in the formulation in an amount from about 10% to about 35% by weight of the formulation;

wherein said dosage form provides an in-vitro dissolution release rate of the tranexamic acid or pharmaceutically acceptable salt thereof, when measured by a USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C., of less than about 40% tranexamic acid or pharmaceutically acceptable salt thereof released at about 15 minutes, less than about 70% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 45 minutes and not less than about 50% by weight of said tranexamic acid or pharmaceutically acceptable salt thereof released by about 90 minutes; and

wherein each tranexamic acid oral dosage form provides a dose of about 650 mg of tranexamic acid.

2. The tranexamic acid oral dosage form of claim 1, wherein said dosage form provides an in-vitro dissolution release rate of the tranexamic acid or pharmaceutically acceptable salt thereof, when measured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C., of about 0% to about 40% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 15 minutes, from about 20% to about 60% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 30 minutes, from about 40% to about 65% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 45 minutes, from about 50% to about 95% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 60 minutes, and not less than about 60% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 90 minutes.

3. The tranexamic acid oral dosage form of claim 1, wherein the dosage form releases about 10% to about 25% by weight tranexamic acid or pharmaceutically acceptable salt thereof every 15 minutes when measured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C.

4. The tranexamic acid oral dosage form of claim 1, wherein the dosage form releases about 1% tranexamic acid or pharmaceutically acceptable salt thereof every minute when measured in-vitro utilizing the USP 27 Apparatus Type II paddle method at 50 RPM in 900 ml water at 37±

0.5°

C.

5. The tranexamic acid oral dosage form of claim 1, which provides a mean maximum plasma concentration (C_max) of tranexamic acid in a range from about 9 to about 14.5 mcg/ml after single dose oral administration of two of said tranexamic acid oral dosage forms to humans.

6. The tranexamic acid oral dosage form of claim 1, which provides a mean maximum plasma concentration (C_max) of tranexamic acid in a range from about 5 to about 25 mcg/ml after steady state oral administration of two of said tranexamic acid oral dosage forms to humans.

7. The tranexamic acid oral dosage form of claim 1, which provides a mean maximum plasma concentration (C_max) of tranexamic acid in a range from about 10 to about 20 mcg/ml after steady state oral administration three times daily of two of said tranexamic acid oral dosage forms to humans.

8. The tranexamic acid oral dosage form of claim 1, which provides mean time to maximum plasma concentration (T_max) at a time in a range from about 1.0 to about 5.5 hours after oral administration of one or more of said tranexamic acid oral dosage forms to humans.

9. The tranexamic acid oral dosage form of claim 1, wherein the dosage form provides a mean transit time of said tranexamic acid of 7.70±

0.72 hours when orally administered across a patient population.

10. The tranexamic acid oral dosage form of claim 1, wherein the dosage form provides a mean absorption time of said tranexamic acid of 4.18±

0.70 hours when orally administered across a patient population.

11. The tranexamic acid oral dosage form of claim 1, which provides for the reduction of at least one side effect selected from the group consisting of headache, nausea, vomiting, diarrhea, constipation, cramping, bloating, and combinations thereof, as compared to an immediate release oral dosage form containing an equivalent amount of tranexamic acid or pharmaceutically acceptable salt thereof, when administered across a same or different population of patients as said modified release dosage form, and wherein said immediate release dosage form releases all of said tranexamic acid or pharmaceutically acceptable salt thereof within about 45 minutes when measured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C.

12. The tranexamic acid oral dosage form of claim 1, which provides a mean transit time of said tranexamic acid which is at least about 20 minutes longer than an immediate release formulation of tranexamic acid when administered across a patient population.

13. The tranexamic acid oral dosage form of claim 1, which provides a mean absorption time of said tranexamic acid which is at least about 20 minutes longer than an immediate release formulation containing an equivalent amount of tranexamic acid or pharmaceutically acceptable salt thereof when administered across a patient population, wherein said immediate release dosage form releases all of said tranexamic acid or pharmaceutically acceptable salt thereof within about 45 minutes when measured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C.

14. The tranexamic acid oral dosage form of claim 1, wherein said dosage form provides less headache, nausea, or combination thereof in comparison to a therapeutically equivalent amount of tranexamic acid or pharmaceutically acceptable salt thereof administered intravenously in five minutes or less when administered across a patient population.

15. The tranexamic acid oral dosage form of claim 1, wherein said dosage form is selected from the group consisting of one or more tablets, capsules, granules, powders, pellets, dragees, troches, non-pareils, and pills.

16. The tranexamic acid oral dosage form of claim 1, wherein said dosage form provides a bioavailability of said tranexamic acid of greater than 40% when administered to humans.

17. The tranexamic acid oral dosage form of claim 1, wherein the dosage form is a matrix tablet which comprises a pre-granulated drug mixed together with the modified release material.

18. The tranexamic acid oral dosage form of claim 1, wherein the modified release material comprises a hydroxyalkylcellulose or a cellulose ether.

19. The tranexamic acid oral dosage form of claim 1, wherein the modified release material comprises hydroxypropylmethylcellulose.

20. The tranexamic acid oral dosage form of claim 1, wherein the modified release material is present in an amount of about 15% by weight of the formulation.

21. The tranexamic acid oral dosage form of claim 19, wherein the modified release material is present in an amount of about 15% by weight of the formulation.

22. The tranexamic acid oral dosage form of claim 19, wherein the hydroxypropylmethylcellulose is present in an amount of about 10% to about 35% by weight of the formulation.

23. The tranexamic acid oral dosage form of claim 22, wherein the hydroxypropylmethylcellulose is present in an amount of about 15% by weight of the formulation.

30. A method of treating menorrhagia comprising administering to a human subject in need of such treatment a dosage form according to claim 1.

31. The method of claim 30, wherein the dosage form is administered three times daily.

32. The method of claim 30, wherein two dosage forms are administered three times daily.

33. The method of claim 30, comprising administering a single dose of about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof.

34. The method of claim 33, comprising administering a single dose of about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof three times daily.

35. The method of claim 30, wherein said dosage form is selected from the group consisting of one or more tablets, capsules, granules, powders, pellets, dragees, troches, non-pareils, and pills.

36. The method of claim 30, wherein the dosage form is a tablet.

37. The method of claim 30, wherein a mean maximum plasma concentration (C_max) of tranexamic acid in a range from about 10 to about 20 mcg/ml is provided after steady state oral administration three times daily of about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof included in one or more of said modified release oral dosage form to humans.

38. The method of claim 30, which provides for the reduction of at least one side effect selected from the group consisting of headache, nausea, vomiting, diarrhea, constipation, cramping, bloating, and combinations thereof, as compared to an immediate release oral dosage form containing an equivalent amount of tranexamic acid or pharmaceutically acceptable salt thereof, when administered across a same or different population of patients as said modified release dosage form, and wherein said immediate release dosage form releases all of said tranexamic acid or pharmaceutically acceptable salt thereof within about 45 minutes when measured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C.

39. The method of claim 30, wherein the dosage form is a matrix tablet which comprises a pre-granulated drug mixed together with the modified release material.

40. The method of claim 30, wherein the modified release material comprises a hydroxyalkylcellulose or a cellulose ether.

41. The method of claim 30, wherein the modified release material comprises hydroxypropylmethylcellulose.

42. The method of claim 30, wherein the modified release material is present in an amount of about 15% by weight of the formulation.

43. The method of claim 30, wherein the modified release material is present in an amount of about 15% by weight of the formulation.

44. The method of claim 30, wherein the hydroxypropylmethylcellulose is present in an amount of about 10% to about 35% by weight of the formulation.

45. The method of claim 30, wherein the hydroxypropylmethylcellulose is present in an amount of about 15% by weight of the formulation.

24. A tranexamic acid oral dosage form comprising:

tranexamic acid or a pharmaceutically acceptable salt thereof; and

hydroxypropylmethylcellulose in an amount from about 10% to about 35% by weight of the dosage form;

wherein the formulation provides an in-vitro dissolution release rate of the tranexamic acid or pharmaceutically acceptable salt thereof, when measured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C. of less than about 40% tranexamic acid or pharmaceutically acceptable salt thereof released at about 15 minutes, less than about 70% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 45 minutes, and not less than about 50% by weight tranexamic acid or pharmaceutically acceptable salt thereof released by about 90 minutes;

and

wherein each dosage form provides a dose of about 650 mg of tranexamic acid.

25. The tranexamic acid oral dosage form of claim 24, wherein the hydroxypropylmethylcellulose is present in an amount of about 15% by weight of the formulation.

26. The tranexamic acid oral dosage form of claim 24, wherein the tranexamic acid or pharmaceutically acceptable salt thereof, is present in an amount from about 60% to about 90% by weight of the formulation.

46. A method of treating menorrhagia comprising administering to a human subject in need of such treatment a dosage form according to claim 24.

47. The method of claim 46, comprising administering a 1300 mg dose of tranexamic acid three times daily.

48. A method of treating menorrhagia comprising administering to a human subject in need of such treatment a dosage form according to claim 25.

49. The method of claim 48, comprising administering a 1300 mg dose of tranexamic acid three times daily.

50. A method of treating menorrhagia comprising administering to a human subject in need of such treatment a dosage form according to claim 26.

51. The method of claim 50, comprising administering a 1300 mg dose of tranexamic acid three times daily.

27. A tranexamic acid oral dosage form comprising:

tranexamic acid or a pharmaceutically acceptable salt thereof; and

hydroxypropylmethylcellulose in an amount from about 10% to about 35% by weight of the formulation;

wherein the formulation releases from about 10% to about 25% by weight tranexamic acid or pharmaceutically acceptable salt thereof every 15 minutes when measured in vitro utilizing the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37±

0.5°

C. such that not less than about 60% of the tranexamic acid or pharmaceutically acceptable salt thereof is released by about 90 minutes;

and

wherein the amount of tranexamic acid or pharmaceutically acceptable salt thereof included in the dosage form provides a dose of about 650 mg of tranexamic acid.

28. The tranexamic acid oral dosage form of claim 27, wherein the tranexamic acid or pharmaceutically acceptable salt thereof, is present in an amount from about 60% to about 90% by weight of the formulation.

29. The tranexamic acid oral dosage form of claim 27, wherein the hydroxypropylmethylcellulose is present in an amount of about 15% by weight of the dosage form.

52. A method of treating menorrhagia comprising administering to a human subject in need of such treatment a dosage form according to claim 27.

53. The method of claim 52, comprising administering a 1300 mg dose of tranexamic acid three times daily.

54. A method of treating menorrhagia comprising administering to a human subject in need of such treatment a dosage form according to claim 28.

55. The method of claim 52, comprising administering a 1300 mg dose of tranexamic acid three times daily.

56. A method of treating menorrhagia comprising administering to a human subject in need of such treatment a dosage form according to claim 29.

57. The method of claim 52, comprising administering a 1300 mg dose of tranexamic acid three times daily.