Methods and compositions for the treatment of CNS-related conditions

• US 20050245617A1
• Filed: 01/31/2005
• Published: 11/03/2005
• Est. Priority Date: 01/29/2004
• Status: Abandoned Application

• Current Assignee: Neuromolecular Inc.
• Original Assignee: Neuromolecular Inc.
• Inventors: Went, Gregory T., Fultz, Timothy J., Meyerson, Laurence R.
• Application Number:
  US11/048,002
• Publication Number:
  US 20050245617A1
• Time in Patent Office: Days
• US Class Current: 514/649
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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

Abstract

The invention provides methods and compositions for the treatment of dementia-related conditions, such as Parkinson'"'"'s disease and Alzheimer'"'"'s disease.

Claims

1. A pharmaceutical composition comprising:

(a) an NMDA receptor antagonist;

(b) a second agent, wherein said agent is a monoamine oxidase (MAO) inhibitor or a GADPH inhibitor; and

(c) a pharmaceutically acceptable carrier

wherein said NMDA receptor antagonist, said second agent, or both are in an extended release dosage form.

2. The pharmaceutical composition of claim 1, wherein said NMDA receptor antagonist is provided in an extended release dosage form.

3. The pharmaceutical composition of claim 2, wherein said NMDA receptor antagonist has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 6 hours after said NMDA receptor antagonist is introduced into a subject.

4. The pharmaceutical composition of claim 1, wherein the relative Cratio of said NMDA receptor antagonist and said second agent is 0.4-2.5.

5. The pharmaceutical composition of claim 2, wherein at least 50% of said NMDA receptor antagonist in said pharmaceutical composition is provided in an extended release dosage form.

6. The pharmaceutical composition of claim 5, wherein 95% of said NMDA receptor antagonist in said pharmaceutical composition is provided in an extended release dosage form.

7. The pharmaceutical composition of claim 6, wherein essentially all of said NMDA receptor antagonist in said pharmaceutical composition is provided in an extended release dosage form.

8. The pharmaceutical composition of claim 2, wherein at least 99% of said NMDA receptor antagonist remains in said extended dosage form one hour following introduction of said pharmaceutical composition into a subject.

9. The pharmaceutical composition of claim 1, wherein said second agent is provided in an extended release dosage form.

10. The pharmaceutical composition of claim 9, wherein said second agent has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 6 hours after said second agent is introduced into a subject.

11. The pharmaceutical composition of claim 10, wherein said second agent has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 12 hours after said second agent is introduced into a subject.

12. The pharmaceutical composition of claim 11, wherein said NMDA receptor antagonist has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 6 hours after said NMDA receptor antagonist is introduced into a subject.

13. The pharmaceutical composition of claim 1, wherein said NMDA receptor antagonist and said second agent are both provided in an extended release dosage form.

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

15. The pharmaceutical composition of claim 14, wherein said aminoadamantine derivative is memantine (1-amino-3,5-dimethyladamantane), rimantadine (1-(1-aminoethyl)adamantane), or amantadine (1-amino-adamantane).

16. The pharmaceutical composition of claim 15, wherein said aminoadamantine derivative is memantine (1-amino-3,5-dimethyladamantane).

17. The pharmaceutical composition of claim 1, wherein said second agent is selegiline, rasagaline, desmethyldeprenyl, CGP3466, phenelzine, or tranycypromine.

18. The pharmaceutical composition of claim 17, wherein said second agent is selegiline.

19. The pharmaceutical composition of claim 1, wherein said NMDA receptor antagonist is memantine and said second agent is selegiline.

20. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is formulated for oral, intravenous, subtopical transepithelial, subdermal, or inhalation delivery.

21. The pharmaceutical composition of claim 20, wherein said pharmaceutical composition is formulated as a suspension, capsule, tablet, suppository, lotion, or patch.

22. The pharmaceutical composition of claim 1, wherein said NMDA receptor antagonist and said second agent are provided in a unit dosage form.

23. The pharmaceutical composition of claim 1, wherein the amount of said NMDA receptor antagonist in said pharmaceutical composition is less than the amount of NMDA receptor antagonist required in a unit dose to obtain the same therapeutic effect for treating CNS-related condition when the NMDA receptor antagonist is administered in the absence of said second agent.

24. The pharmaceutical composition of claim 1, wherein the amount of said second agent in said pharmaceutical composition is less than the amount of said second agent required in a unit dose to obtain the same therapeutic effect for treating CNS-related condition when said second agent is administered in the absence of the NMDA receptor antagonist.

25. The pharmaceutical composition of claim 1, wherein said NMDA receptor antagonist is present in said pharmaceutical composition at a dose that would be toxic to a human subject if said NMDA receptor antagonist were administered to said subject in the absence of said second agent.

26. The pharmaceutical composition of claim 1, wherein said second agent is present in said pharmaceutical composition at a dose that would be toxic to a human subject if said second agent were administered to said subject in the absence of said second agent.

36. The method of claim 25, wherein said second agent has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 6 hours after said second agent is introduced into a subject.

37. The method of claim 36, wherein said second agent has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 12 hours after said second agent is introduced into a subject.

27. A method of treating a CNS-related condition comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an NMDA receptor antagonist and a second agent, wherein said second agent is a MAO inhibitor or a GADPH inhibitor.

28. The method of claim 27, wherein said NMDA receptor antagonist is provided in an extended release dosage form.

29. The method of claim 28, wherein said NMDA receptor antagonist has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 6 hours after said NMDA receptor antagonist is introduced into a subject.

30. The method of claim 29, wherein said NMDA receptor antagonist has a C_max/C_mean of approximately 2 or less approximately 2 hours to at least 12 hours after said NMDA receptor antagonist is introduced into a subject.

31. The method of claim 27, wherein at least 50% of said NMDA receptor antagonist in said pharmaceutical composition is provided in an extended release dosage form.

32. The method of claim 31, wherein 95% of said NMDA receptor antagonist in said pharmaceutical composition is provided in an extended release dosage form.

33. The method of claim 32, wherein essentially all of said NMDA receptor antagonist in said pharmaceutical composition is provided in an extended release dosage form.

34. The method of claim 31, wherein at least 99% of said NMDA receptor antagonist is remains in said extended dosage form one hour following introduction of said pharmaceutical composition into a subject.

35. The method of claim 27, wherein said second agent is provided in an extended release dosage form.

38. The method of claim 27, wherein said NMDA receptor antagonist has a C_max/C_mean of approximately 2 or less, approximately 2 hours to at least 6 hours after said NMDA receptor antagonist is introduced into a subject.

39. The method of claim 27, wherein said NMDA receptor antagonist is a low affinity NMDA receptor antagonist.

40. The method of claim 27, wherein said NMDA receptor antagonist is an aminoadamantine derivative.

41. The method of claim 40, wherein said aminoadamantine derivative is memantine (1-amino-3,5-dimethyladamantane), rimantadine (1-(1-aminoethyl)adamantane), or amantadine (1-amino-adamantane).

42. The method of claim 41, wherein said aminoadamantine derivative is memantine (1-amino-3,5-dimethyladamantane).

43. The method of claim 27, wherein said second agent is selegiline, rasagaline, desmethyldeprenyl, CGP3466, phenelzine or tranycypromine.

44. The method of claim 27, wherein said NMDA receptor antagonist is memantine and said second agent is selegiline.

45. The method of claim 27, wherein said CNS-related condition is Parkinson'"'"'s disease, Alzheimer'"'"'s disease, or multiple sclerosis.

46. The method of claim 27, wherein said NMDA receptor antagonist is delivered orally, intravenouslly, subdermally, or by inhalation.

47. The method of claim 27, wherein said second agent is delivered orally, intravenouslly, subdermally, or by inhalation.

48. The method of claim 27, wherein said NMDA receptor antagonist and said second agent are administered simultaneously.

49. The method of claim 27, wherein said NMDA antagonist and said second agent are administered as a single composition

50. The method of claim 27, wherein said NMDA antagonist and said second agent are administered sequentially.

51. The method of claim 27, wherein said NMDA receptor antagonist and said second agent are administered within 24 hours of each other.

52. The method claim 27, wherein said NMDA receptor antagonist and said second agent are administered by the same route of administration.

53. The method of claim 27, wherein said NMDA receptor antagonist and said second agent are administered by different routes of administration.

54. The method of claim 27, wherein said NMDA receptor antagonist, said second agent, or both are administered to said subject once a day.

55. The method of claim 27, wherein said NMDA receptor antagonist, said second agent, or both are administered to said subject every three days.

56. The method of claim 27, wherein said subject is a human.