Sustained release aminopyridine composition
View Patent ↗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.
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.
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.
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.
13. The method of claim 1 , further comprising a step of determining the C maxSS :C minSS ratio or the C avSS .
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.
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.
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.
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.