Sustained release aminopyridine composition

• US 8,007,826 B2
• Filed: 12/13/2004
• Issued: 08/30/2011
• Est. Priority Date: 12/11/2003
• Status: Active Grant

• Current Assignee: Acorda Therapeutics Incorporated
• Original Assignee: Acorda Therapeutics Incorporated
• Inventors: Blight, Andrew R., Cohen, Ron
• Primary Examiner(s): Landau; Sharmila G.
• Assistant Examiner(s): BREDEFELD, RACHAEL EVA
• Application Number:
  US11/010,828
• Publication Number:
  US 20050276851A1
• Time in Patent Office: 2,451 Days
• Field of Search: 424/468
• US Class Current: 424/468
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A pharmaceutical composition which comprises a therapeutically effective amount of a aminopyridine dispersed in a release matrix, including, for example, a composition that can be formulated into a stable, sustained-release oral dosage formulation, such as a tablet which provides, upon administration to a patient, a therapeutically effective plasma level of the aminopyridine for a period of at least 12 hours, preferably 24 hours or more and the use of the composition to treat various neurological diseases.

Claims

1. A method for maintaining a therapeutically effective concentration of 4-aminopyridine in order to improve walking in a human with multiple sclerosis in need thereof, said method comprising:

orally administering to the human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a day; and

thereafter,

maintaining administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of at least two weeks, whereby an in vivo 4-aminopyridine C_maxSS;

C_minSS ratio of 1.0 to 3.5 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

2. The method of claim 1, whereby an increase in walking speed is obtained in said human.

3. The method of claim 1, whereby an improvement in lower extremity muscle strength is obtained in said human.

4. The method of claim 1, wherein the sustained release composition further comprises an additional active ingredient.

5. The method of claim 1, wherein the sustained release composition further comprises a pharmaceutically acceptable excipient.

13. The method of claim 1, further comprising a step of determining the C_maxSS:

C_minSS ratio or the C_avSS.

18. The method of claim 1, whereby an in vivo C_maxSS:

C_minSS ratio of 1.5 to 3.0 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

19. The method of claim 1, whereby an in vivo C_maxSS:

C_minSS ratio of 2.0 to 3.0 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

20. The method of claim 1 wherein the maintaining step comprises maintaining for a period of more than two weeks.

21. The method of claim 1 wherein the maintaining step comprises maintaining for a period of more than twelve weeks.

22. The method of claim 1 wherein said sustained release composition is a tablet.

6. A dosing regimen method for providing a 4-aminopyridine at a therapeutically effective concentration in order to improve walking in a human with multiple sclerosis in need thereof, said method comprising:

initiating administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a day without a prior period of 4-aminopyridine titration, and then,

maintaining administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily;

without a subsequent period of 4-aminopyridine titration,

whereby an in vivo C_maxSS;

C_minSS ratio of 1.0 to 3.5 and a C_avSS of 15 ng/ml to 35 ng/ml are maintained in the human.

7. The method of claim 6, whereby an increase in walking speed is obtained in said human.

8. The method of claim 6, whereby an improvement in lower extremity muscle strength is obtained in said human.

9. The method of claim 6, wherein the sustained release composition further comprises an additional active ingredient.

10. The method of claim 6, wherein the sustained release composition further comprises a pharmaceutically acceptable excipient.

23. The method of claim 6 wherein the maintaining step comprises maintaining for a period of at least a week.

24. The method of claim 6 wherein the maintaining step comprises maintaining for a period of at least two weeks.

25. The method of claim 6 wherein the maintaining step comprises maintaining for a period of more than two weeks.

26. The method of claim 6 wherein the maintaining step comprises maintaining for a period of more than twelve weeks.

27. The method of claim 6, whereby an in vivo C_maxSS:

C_minSS ratio of 1.5 to 3.0 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

28. The method of claim 6, whereby an in vivo C_maxSS:

C_minSS ratio of 2.0 to 3.0 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

29. The method of claim 6 wherein said sustained release composition is a tablet.

11. A method for maintaining a therapeutically effective concentration of 4-aminopyridine in a human with multiple sclerosis in need of an improvement in walking, in order to improve walking in the human, said method comprising:

orally administering twice daily to the human a sustained release composition comprising a pharmaceutically acceptable excipient and 4-aminopyridine, the 4-aminopyridine consisting of 10 milligrams of 4-aminopyridine, for one day; and

thereafter,

maintaining twice daily administration for a time period of greater than two weeks of a sustained release composition comprising a pharmaceutically acceptable excipient and 4-aminopyridine, the 4-aminopyridine consisting of 10 milligrams of 4-aminopyridine;

whereby an in vivo 4-aminopyridine C_maxSS;

C_minSS ratio of 1.0 to 3.5 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

12. The method of claim 11, wherein an improvement in lower extremity muscle strength is obtained in said human.

14. The method of claim 11, wherein the twice daily administration comprises b.i.d. administration or administration at 12-hour intervals.

15. The method of claim 11, whereby an in vivo C_maxSS:

C_minSS ratio of 1.5 to 3.0 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

16. The method of claim 11, whereby an in vivo C_maxSS:

C_minSS ratio of 2.0 to 3.0 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained in the human.

17. A method to improve walking by a human with multiple sclerosis in need thereof, said method comprising:

orally administering twice daily for one day to the human a sustained release composition of 10 milligrams of 4-aminopyridine and an agent selected from the group consisting of one or more additional active ingredients, one or more pharmaceutically acceptable excipients and a combination thereof; and

thereafter,

maintaining twice daily administration of 4-aminopyridine by orally administering twice daily to said human a sustained release composition of 10 milligrams of 4-aminopyridine and an agent selected from the group consisting of one or more additional active ingredients, one or more pharmaceutically acceptable excipients and a combination thereof for a time period of greater than two weeks;

whereby an in vivo 4-aminopyridine C_maxSS;

C_minSS ratio of 1.0 to 3.5 and a C_avSS of 15 ng/ml to 35 ng/ml are obtained and there is an improvement in walking by the human.

30. The method of claim 17 wherein said sustained release composition is a tablet.

31. A method of increasing walking speed in a human multiple sclerosis patient in need thereof comprising orally administering to said patient a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of greater than two weeks, wherein said sustained release composition provides a mean T_max in a range of about 1 to about 6 hours after administration of the sustained release composition to the patient.

32. The method of claim 31 wherein the sustained release composition elicits a C_maxSS:

C_minSS ratio of 1.0 to 3.5 when administered b.i.d. or administered at 12-hour intervals to a human.

33. The method of claim 31 wherein said time period is twelve weeks.

34. The method of claim 31 wherein said sustained release composition is a tablet.

35. The method of claim 31 wherein the step of administering comprises b.i.d. administering or administering at 12-hour intervals.

36. A method to improve walking in a patient with multiple sclerosis in need thereof by use of a sustained release composition of 4-aminopyridine, where sustained indicates that the composition achieves an in vivo 4-aminopyridine C_maxSS:

C_minSS ratio of 1.0 to 3.5 and a C_avSS of 15 ng/ml to 35 ng/ml in a human, said method comprising;

orally administering twice daily for one day to the patient an amount of the sustained release composition having only 10 milligrams of 4-aminopyridine; and

thereafter,

maintaining twice daily administration of 4-aminopyridine by orally administering to said patient an amount of the sustained release composition having only 10 milligrams of 4-aminopyridine for a time period of at least two weeks.

37. A method of increasing walking speed in a human multiple sclerosis patient in need thereof comprising orally administering to said patient a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of greater than two weeks, wherein said sustained release composition provides a mean T_max in a range of about 2 to about 5.2 hours after administration of the sustained release composition to the patient.

38. The method of claim 37 wherein the sustained release composition elicits a C_maxSS:

C_minSS ratio of 1.0 to 3.5 when administered b.i.d. or administered at 12-hour intervals to a human.

39. The method of claim 37 wherein said time period is twelve weeks.

40. The method of claim 37 wherein said sustained release composition is a tablet.

41. The method of claim 37 wherein the step of administering comprises b.i.d. administering or administering at 12-hour intervals.