Method and Composition for Administering an NMDA Receptor Antagonist to a Subject

• US 20110059169A1
• Filed: 07/20/2010
• Published: 03/10/2011
• Est. Priority Date: 11/23/2004
• Status: Abandoned Application

• Current Assignee: Adamas Pharmaceuticals, Inc. (Supernus Pharmaceuticals, Inc.)
• Original Assignee: Adamas Pharmaceuticals, Inc. (Supernus Pharmaceuticals, Inc.)
• Inventors: Burkoth, Timothy S., Fuitz, Timothy J., Porter, Seth, Meyerson, Laurence R., Went, Gregory T.
• Application Number:
  US12/840,132
• Publication Number:
  US 20110059169A1
• Time in Patent Office: Days
• US Class Current: 424/457
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 25/30 for treating abuse or dependence

Abstract

The invention provides methods and compositions for administering an NMDA receptor antagonist (e.g., memantine) to a subject.

Claims

1. A composition comprising a modified release coating or matrix and an N-methyl-D-aspartate (NMDA) receptor antagonist, wherein said NMDA receptor antagonist has an in vitro dissolution profile in water that is substantially identical to its in vitro dissolution profile in a dissolution medium having a pH of 1.2 and wherein said dissolution profile ranges between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, greater than or equal to 70% in 10 hours, and greater than or equal to 90% in 12 hours as measured using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C.

2. The composition of claim 1, wherein at least 95% of said NMDA receptor antagonist in said composition is provided in a controlled release dosage form.

3. The composition of claim 2, wherein at least 99% of said NMDA receptor antagonist in said composition is provided in a controlled release dosage form.

4. The composition of claim 3, wherein 100% of said NMDA receptor antagonist in said composition is provided in a controlled release dosage form.

5. The composition of claim 1, wherein said NMDA receptor antagonist is an aminoadamantine derivative.

6. The composition of claim 5, wherein said aminoadamantane derivative is memantine, rimantadine, or amantadine.

7. The composition of claim 6, wherein said aminoadamantane derivative is memantine.

8. The composition of claim of claim 1, wherein said NMDA receptor antagonist is not amantadine or dextromethorphan.

9. The composition of claim 1, wherein said composition is formulated for oral, topical, transepithelial, subdermal, or inhalation delivery.

10. The composition of claim 1, wherein said composition is formulated as a lotion or patch.

30. The method of claim 29, wherein said composition is the composition of any one of claims 1-28.

11. A composition comprising a modified release coating or matrix and memantine, wherein memantine has an in vitro dissolution profile ranging between 0-60% one hour, 0-86% in two hours, 0.6-100% in six hours, 3-100% in 10 hours, and 8-100% in 12 hours as measured using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in water.

12. The composition of claim 11, wherein memantine has an in vitro dissolution profile ranging between 0.1%-20% in one hour, 5%-30% in two hours, 40%-80% in six hours, 50% or more in 10 hours, and 90% or more in 12 hours as measured using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in water.

13. The composition of claim 11, wherein at least 95% of memantine in said composition is provided in a controlled release dosage form.

14. The composition of claim 13, wherein at least 99% of memantine in said composition is provided in a controlled release dosage form.

15. The composition of claim 14, wherein 100% of memantine in said composition is provided in a controlled release dosage form.

16. The composition of claim 11, wherein less than 15% of memantine is released at 15 minutes.

17. The composition of claim 11, wherein less than 15% of memantine is released at 30 minutes.

18. The composition of claim 11, wherein at least 60% of said memantine is released as measured at 6 hours using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in a dissolution medium having a pH of 1.2.

19. The composition of claim 11, wherein said composition is formulated for oral, topical, transepithelial, subdermal, or inhalation delivery.

20. The composition of claim 19, wherein said composition is formulated as a lotion or patch.

21. A composition comprising memantine and a sustained release coating or matrix, wherein the fraction of released memantine is greater or equal to 0.01(0.297+0.0153*e^(0.515*^t)) and less than 1−

e<sup>(−

10.9</sup>*^t) as measured using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in water, wherein t is the time in hours and wherein t is greater than zero and equal or less than 17.

22. The composition of claim 21, wherein the fraction of released memantine is greater or equal to 0.01(0.297+0.0153*e^(0.515*^t)) and less than or equal to 1−

e<sup>(−

0.972</sup>*^t) as measured using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in water, wherein t is the time in hours and wherein t is greater than zero and equal or less than 17.

23. The composition of claim 21, wherein at least 95% of memantine in said composition is provided in an extended release dosage form.

24. The composition of claim 23, wherein at least 99% of memantine in said composition is provided in an extended release dosage form.

25. The composition of claim 24, wherein 100% of memantine in said composition is provided in an extended release dosage form.

26. The composition of claim 21, wherein less than 5% of memantine is released in one hour.

27. The composition of claim 21, wherein said composition is formulated for oral, topical, transepithelial, subdermal, or inhalation delivery.

28. The composition of claim 21, wherein said composition is formulated as a lotion or patch.

29. A method of treating, preventing or reducing a neurologic or neuropsychiatric condition comprising administering to a subject at risk of having or having said condition a composition comprising an NMDA receptor antagonist provided in a modified release dosage form, wherein said subject is administered said NMDA receptor antagonist at a substantially identical dose from the start of therapy.

31. The method of claim 29, wherein said condition is selected from the group consisting of seizure disorders, pain syndromes, neurodegenerative diseases, dementias, cerebrovascular conditions, movement disorders, brain trauma, cranial nerve disorders, neuropsychiatric disorders, other disease neuropathies, fatigue syndromes, ataxic syndromes, and axonic brain damage.

32. The method of claim 29, wherein said condition is Parkinson'"'"'s disease, multiple sclerosis, epilepsy, pain, depression, agitation, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, or neuropathic pain.

33. The method of claim 29, wherein said composition is administered to said subject no more than once every 24 hours.

34. The method of claim 29, wherein said NMDA receptor antagonist reaches a therapeutically effective steady state plasma concentration in said subject within fifteen days of said administering.

35. The method of claim 29, wherein said NMDA receptor antagonist reaches a therapeutically effective steady state plasma concentration in said subject within five days of said administration.

36. The method of claim 29, wherein said composition is administered to said subject no more than once every 24 hours and wherein said NMDA receptor antagonist reaches a therapeutically effective steady state plasma concentration in said subject in less than 30 days.

37. The method of claim 29, wherein the mean plasma concentration profile of said NMDA receptor antagonist in said subject has an slope from 2 hours to 4 hours after administration less than 50% of that for an JR formulation of the same NMDA receptor antagonist at the same administered dose.

38. The method of claim 29, wherein said NMDA receptor antagonist is an aminoadamantane.

39. The method of claim 38, wherein said aminoadamantane is memantine, amantadine, or rimantadine.

40. The method of claim 39, wherein said aminoadamantane is memantine.

41. The method of claim 40, wherein memantine is administered at a daily dose ranging between 5 and 100 mg.

42. The method of claim 41, wherein memantine is administered at a daily dose ranging between 2 and 80 mg.

43. The method of claim 42, wherein memantine is administered at a daily dose ranging between 5 and 80 mg.

44. The method of claim 43, wherein the daily dose of memantine ranges between 5 and 40 mg.

45. The method of claim 43, wherein the daily dose of memantine ranges between 20 and 50 mg.

46. The method of claim 45, wherein the daily dose of memantine ranges between 20 and 40 mg.

47. The method of claim 29, wherein said subject has not been administered said NMDA receptor antagonist, within one week of onset of therapy, at a dose that is lower than said dose used during therapy.

58. The method of claim 57, wherein said composition is manufactured according to claim 46.

48. A method of preparing a pharmaceutical composition for the treatment of a condition associated with a deregulation in NMDA receptor activity by providing a matrix or coated core to provide sustained release of a NMDA receptor antagonist, wherein said NMDA receptor antagonist is present in sufficient quantity to treat said condition, using a therapy that involves administering to a subject substantially identical doses of said NMDA receptor antagonist from the onset of said therapy.

49. The method of claim 48, further comprising providing a mixture containing a NMDA receptor antagonist to provide an immediate release of a NMDA receptor antagonist, wherein the weight of said mixture is less than 5% than the total weight of said matrix or coated core and mixture.

50. The method of claim 48, wherein said NMDA receptor antagonist is memantine.

51. The method of claim 48, wherein said NMDA receptor antagonist is not amantadine or dextromethorphan.

52. The method of claim 48, wherein said matrix core is a wax, insoluble matrix polymer, water soluble matrix materials, or mixtures thereof.

53. The method of claim 48, wherein said coated core is a core of NMDA receptor antagonist coated with a pharmaceutically acceptable polymer including diffusion barrier polymers with or without porosity enhancers selected from the group consisting of ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials, sugars, lactose, sucrose, fructose and mannitol, salts, sodium chloride, potassium chloride, organic acids, fumaric acid, succinic acid, lactic acid and tartaric acid and mixtures thereof, enteric polymers, hydroxypropyl celluose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups.

54. The method of claim 48, further comprising compressing said core and said mixture into a tablet form and wherein said core and said mixture are dispersed throughout said tablet.

55. The method of claim 48, wherein said core and said mixture are combined and compressed into a tablet form such that said core and said mixture form a multilayer tablet form.

56. The method of claim 48, wherein said core and said mixture are combined into a capsule or a patch.

57. A method of treating, preventing or reducing a neurologic or neuropsychiatric condition comprising administering to a subject at risk of having or having said condition a composition comprising an NMDA receptor antagonist provided in a modified release dosage form, wherein said subject is administered said NMDA receptor antagonist at a substantially identical dose from the start of therapy, no more than once every 24 hours.