Methods and compositions for the treatment of CNS-related conditions

• US 8,058,291 B2
• Filed: 04/06/2006
• Issued: 11/15/2011
• Est. Priority Date: 04/06/2005
• Status: Active Grant

• Current Assignee: Adamas Pharma, LLC (Supernus Pharmaceuticals, Inc.)
• Original Assignee: Adamas Pharmaceuticals, Inc. (Supernus Pharmaceuticals, Inc.)
• Inventors: Went, Gregory T., Fultz, Timothy J.
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Carter, Kendra D
• Application Number:
  US11/399,879
• Publication Number:
  US 20060252788A1
• Time in Patent Office: 2,049 Days
• Field of Search: 514/319, 514/579, 514/766, 546/192
• US Class Current: 514/319
• 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 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• 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 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2813 Inorganic compounds
• CPC Class Codes: A61K 9/282 Organic compounds, e.g. fats
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• 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
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides novel methods and compositions for the treatment and prevention of CNS-related conditions. One of the CNS-related conditions treated by the methods and compositions of the invention is Alzheimer'"'"'s disease.

Claims

1. A method of treating a CNS-related condition comprising orally administering once a day to a human subject in need thereof:

(a) 5-40 mg memantine or a pharmaceutically acceptable salt thereof provided in an extended release dosage form, wherein said extended release memantine or pharmaceutically acceptable salt thereof provides a change in plasma concentration as a function of time (dC/dT) that is less than about 50% of the dC/dT of the same quantity of an immediate release form of memantine, wherein the dC/dT is measured in a single dose human PK study between the time period of 0 to Tmax of the immediate release form of memantine; and

(b) a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt thereof, wherein the CNS-related condition is selected from the group consisting of Alzheimer'"'"'s disease and dementia.

2. The method of claim 1, wherein the amount of memantine or pharmaceutically acceptable salt thereof ranges between 10 to 40 mg per dose.

3. The method of claim 2, wherein the amount of memantine or pharmaceutically acceptable salt thereof ranges between 12.5 to 40 mg per dose.

4. The method of claim 1, wherein said memantine or a pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are administered simultaneously.

5. The method of claim 1, wherein said memantine or a pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are administered as a single composition.

22. The method of claim 1, wherein said extended release memantine or a pharmaceutically acceptable salt thereof has an in vitro dissolution profile less than 30% in one hour, less than 40% in two hours, greater than 40% in six hours as measured using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

with water as a dissolution medium.

23. The method of claim 1, wherein at least 80% of the memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended release form, with the remainder in an immediate release form.

24. The method of claim 1, wherein at least 95% of the memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended release forms, with the remainder in an immediate release form.

25. The method of claim 1, wherein the release of the memantine or pharmaceutically acceptable salt thereof is monophasic.

26. The method of claim 1, wherein the release of the memantine or pharmaceutically acceptable salt thereof is biphasic.

27. The method of claim 1, wherein the memantine further comprises one or more extended release excipients selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.

40. The method of claim 1, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 20 to 40 mg per dose.

41. The method of claim 5, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 12.5 to 40 mg per dose.

43. The method of claim 40, wherein said memantine or pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are administered in a unit dosage form.

45. The method of claim 41, wherein said donepezil or a pharmaceutically acceptable salt thereof is administered in an immediate release form.

46. The method of claim 43, wherein said donepezil or a pharmaceutically acceptable salt thereof is administered in an immediate release form.

47. The method of claim 41, wherein said donepezil or a pharmaceutically acceptable salt thereof is administered in an immediate release form.

48. The method of claim 1, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 22.5 mg to 40 mg per dose.

53. The method of claim 1, wherein the defined time period of 0 to Tmax of an immediate release form of memantine is the first 6 hours after administration.

56. The method of claim 48, wherein the defined time period of 0 to Tmax of an immediate release form of memantine is the first 6 hours after administration.

6. A method of reducing the potential for an adverse effect in a human subject being treated for a CNS-related condition comprising orally administering once a day to a human subject in need thereof a pharmaceutical composition comprising:

(a) 5-40 mg memantine or a pharmaceutically acceptable salt thereof in an extended release form, wherein said extended release memantine or pharmaceutically acceptable salt thereof provides a change in plasma concentration as a function of time (dC/dT) that is less than about 50% of the dC/dT of the same quantity of an immediate release form of memantine, wherein the dC/dT is measured in a single dose human PK study between the time period of 0 to Tmax of the immediate release form of memantine; and

(b) donepezil or a pharmaceutically acceptable salts thereof, wherein the CNS-related condition is selected from the group consisting of Alzheimer'"'"'s disease and dementia;

and further wherein said adverse effect is related to memantine.

7. The method of claim 6, wherein the composition is in a unit dosage form comprising 10 to 40 mg of the memantine or pharmaceutically acceptable salt thereof.

8. The method of claim 6, wherein the donepezil or pharmaceutically acceptable salt thereof is in an immediate release form.

9. The method of claim 6, wherein the memantine or pharmaceutically acceptable salt thereof is formulated as beads and/or pellets.

10. The method of claim 9, wherein the beads and/or pellets comprise an extended release coating.

11. The method of claim 10, wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material.

12. The method of claim 11, wherein the insoluble matrix polymer is ethyl cellulose.

13. The method of claim 11, wherein the insoluble matrix polymer is ethyl cellulose, and the water soluble material is selected from the group consisting of hydroxypropyl methyl cellulose and polyvinylpyrrolidone.

14. The method of claim 7, wherein the dosage form is in a capsule.

15. The method of claim 6, wherein the composition comprises 1 to 20 mg donepezil hydrochloride.

16. The method of claim 6, wherein administration of the composition to a human subject provides a shift in memantine T_max of at least 8 hours relative to an immediate release form of memantine.

17. The method of claim 6, wherein administration of the composition to a human subject provides a memantine T_max of at least 19 hours.

18. The method of claim 6, wherein administration of the composition to a human subject provides a plasma memantine concentration profile characterized by a maximum memantine plasma concentration to mean memantine plasma concentration ratio (Cmax/cmean) of about 2.5 to 2 at 1 hour to at least 6 hours after administration.

19. The method of claim 6, wherein said memantine or a pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are provided in a unit dosage form.

20. The method of claim 6, wherein the composition comprises at 12.5 mg to 40 mg memantine hydrochloride.

21. The method of claim 6, wherein the composition comprises at least 22.5 mg memantine hydrochloride and 1 to 20 mg of donepezil hydrochloride.

28. The method of claim 6, wherein the composition comprises 20 mg to 40 mg of memantine.

29. The method of claim 6, wherein at least 80% of the memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended release form, with the remainder in an immediate release form.

30. The method of claim 6, wherein at least 95% of the memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended release forms, with the remainder in an immediate release form.

31. The method of claim 6, wherein the release of the memantine or pharmaceutically acceptable salt thereof is monophasic.

32. The method of claim 6, wherein the release of the memantine or pharmaceutically acceptable salt thereof is biphasic.

33. The method of claim 6, wherein the memantine further comprises one or more extended release excipients selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.

42. The method of claim 6, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 10 to 40 mg per dose.

44. The method of claim 42, wherein said memantine or pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are administered in a unit dosage form.

49. The method of claim 6, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 22.5 mg to 40 mg per dose.

54. The method of claim 6, wherein the defined time period of 0 to Tmax of an immediate release form of memantine is the first 6 hours after administration.

57. The method of claim 49, wherein the defined time period of 0 to Tmax of an immediate release form of memantine is the first 6 hours after administration.

34. In a method of treating a subject for a CNS-related condition comprising administering to said subject a memantine drug selected from the group consisting of memantine and a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a donepezil drug selected from the group consisting of donepezil and a pharmaceutically acceptable salt thereof, the improvement comprising:

(a) said memantine drug is administered in an extended release dosage form, wherein said extended release memantine provides a change in plasma concentration as a function of time (dC/dT) in a defined time period of 0 to Tmax of an immediate release form of memantine after administration, as measured in a human single dose PK study, that is less than about 50% of the change in plasma concentration (dC/dT) of the same quantity of said immediate release form of said memantine drug during said defined time period; and

(b) said memantine drug is administered once daily in a dose range of 5 mg to 40 mg;

wherein said CNS-related condition is selected from the group consisting of Alzheimer'"'"'s disease and Parkinson'"'"'s disease.

35. The method of claim 34, wherein said memantine drug daily dose range is 10 mg to 40 mg.

36. The method of claim 34, wherein said memantine drug and said donepezil drug are administered as a composition.

37. The method of claim 35, wherein said memantine drug and said donepezil drug are administered in a unit dosage form.

38. The method of claim 36, wherein said donepezil drug is administered in an immediate release form.

39. The method of claim 37, wherein said donepezil drug is administered in an immediate release form.

50. The method of claim 34, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 12.5 mg to 40 mg per dose.

51. The method of claim 34, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 20 mg to 40 mg per dose.

52. The method of claim 34, wherein the amount of said memantine or pharmaceutically acceptable salt thereof ranges between 22.5 mg to 40 mg per dose.

55. The method of claim 34, wherein the defined time period of 0 to Tmax of an immediate release form of memantine is the first 6 hours after administration.

58. The method of claim 52, wherein the defined time period of 0 to Tmax of an immediate release form of memantine is the first 6 hours after administration.