Methods and Compositions for the Treatment of CNS-Related Conditions

• US 20100311697A1
• Filed: 04/02/2010
• Published: 12/09/2010
• 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.
• Granted Patent: US 8,293,794 B2
• Time in Patent Office: Days
• US Class Current: 514/129
• 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 pharmaceutical composition comprising:

(a) an NMDAr antagonist;

(b) an acetylcholinesterase inhibitor (ACheI), wherein at least one of said NMDAr antagonist or said second agent is provided in an extended release dosage form and wherein the agent in said extended release dosage form has an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater than 40% in six hours, and greater than 85% in 12 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.

2. The pharmaceutical composition of claim 1, wherein said NMDAr antagonist has a dC/dT less than about 80% of the rate for the IR formulation.

3. The pharmaceutical composition of claim 1, wherein said NMDAr antagonist has a C_max/C_mean of approximately 1.6 or less approximately 2 hours to at least 12 hours after said composition is introduced into a subject.

4. The pharmaceutical composition of claim 1, wherein the relative Cratio.var of said NMDAr antagonist and said second agent is less than 100% from 2 hour to 12 hours after said composition is introduced into a subject.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a non-dose escalating, twice per day, once per day, or once every other day dosage form.

6. The pharmaceutical composition of claim 1, wherein the NMDAr antagonist is selected from the group consisting of memantine, amantadine, rimantadine, ketamine, eliprodil, ifenprodil, dizocilpine, remacemide, iamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, neramexane, spermine, spermidine, levemopamil, dextromethorphan, dextrorphan, and pharmaceutically acceptable salts thereof.

7. The pharmaceutical composition of claim 1, wherein said Achel is selected from the group consisting of donepezil, rivastigmine, tacrine, metrifonate, Huperzine-A, and pharmaceutically acceptable salts thereof.

8. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is formulated for oral, transnasal, parenteral, subtopical transepithelial, transdermal patch, subdermal, or inhalation delivery.

9. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is formulated as a suspension, capsule, tablet, suppository, lotion, or patch.

10. The pharmaceutical composition of claim 1, wherein the NMDAr antagonist is memantine and the ACheI is donepezil or pharmaceutically acceptable salts thereof.

11. The pharmaceutical composition of claim 6, wherein the NMDAr antagonist is memantine and wherein the composition is formulated to provide memantine in an amount of 2.5-80 mg per day, 20-67.5 mg per day, 22.5-57.5 mg per day or 42.5-80 mg per day.

44. The pharmaceutical composition of claim 1, wherein the NMDAr antagonist and the ACheI are formulated as pellets, and wherein the ratio of the active pharmaceutical ingredients and the quantities of active pharmaceutical ingredients may be varied by adjusting the quantities and ratios of pellets in the final dosage form.

45. The pharmaceutical composition of claim 44, wherein the ratio of NMDAr antagonist to ACheI ranges from 0.1:

100 to 100;

0.1.

46. The pharmaceutical composition of claim 45, wherein the ratio of NMDAr antagonist to ACheI ranges from 1:

100 to 100;

1.

12. A method of preventing or treating a CNS-related condition comprising administering to a subject in need thereof a therapeutically effective amount of:

(a) an NMDAr antagonist; and

(b) an acetylcholinesterase inhibitor, wherein at least one of said NMDAr antagonist or said second agent is provided in an extended release dosage form and wherein the agent in said extended release dosage form has an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater than 40% in six hours, and greater than 85% in 12 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.

13. The method of claim 12, wherein said CNS-related condition is Alzheimer'"'"'s disease or Parkinson'"'"'s disease.

14. The method of claim 12, wherein said NMDAr antagonist is provided in an extended release dosage form.

15. The method of claim 14, wherein said NMDAr antagonist is administered at a substantially identical daily dose.

16. The method of claim 15, wherein said NMDAr antagonist reaches a therapeutically effective steady state plasma concentration in said subject within fifteen days of said administering.

17. The method of claim 14, wherein said NMDAr antagonist has a dC/dT less than about 80% of the rate for the IR formulation.

18. The method of claim 14, wherein said NMDAr antagonist has a C_max/C_mean of approximately 1.6 or less approximately 2 hours to at least 12 hours after said composition is introduced into a subject.

19. The method of claim 12, wherein the relative Cratio.var of said NMDAr antagonist and said ACheI is less than 100% from 2 hour to 12 hours after said composition is introduced into a subject.

20. The method of claim 19, wherein the relative Cratio.var of said NMDAr antagonist and said ACheI is less than 70% of the corresponding IR formulation from 2 hour to 12 hours after said composition is introduced into a subject.

21. The method of claim 12, wherein said NMDAr antagonist is selected from the group consisting of memantine, amantadine, rimantadine, ketamine, eliprodil, ifenprodil, dizocilpine, remacemide, iamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, neramexane, spermine, spermidine, levemopamil, dextromethorphan, dextrorphan, and pharmaceutically acceptable salts thereof.

22. The method of claim 21, wherein said NMDAr antagonist is memantine or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the amount of memantine ranges between 10 and 80 mg per dose.

24. The method of claim 23, wherein the amount of memantine ranges between 20-60 mg per dose.

25. The method of claim 23, wherein the amount of memantine ranges between 40 and 80 mg per dose.

26. The method of claim 13, wherein said acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, tacrine, metrifonate, Huperzine-A, and pharmaceutically acceptable salts thereof.

27. The method of claim 12, wherein the NMDAr antagonist is memantine and acetylcholinesterase inhibitor is donepezil or pharmaceutically acceptable salts thereof.

28. The method of claim 12, wherein said NMDAr antagonist and said second agent are administered simultaneously or sequentially.

29. The method of claim 12, wherein said NMDA antagonist and said second agent are administered as a single composition.

30. A method of treating, preventing or reducing a condition associated with a deregulation in NMDAr activity comprising administering to a subject at risk of suffering or suffering from said condition a composition comprising an NMDAr antagonist provided in an extended release dosage form and a second agent, wherein said second agent ACheI selected from the group consisting of donepezil, rivastigmine, tacrine, metrifonate, Huperzine-A;

wherein said composition is administered at a substantially identical daily dose.

31. The method of claim 30, wherein said pharmaceutical composition is administered to said subject no more than once every 24 hours.

32. The method of claim 30, wherein said daily dose of said NMDAr antagonist ranges between 15 and 35 mg.

33. The method of claim 32, wherein said daily dose of said NMDAr antagonist ranges between 20 and 25 mg.

34. The method of claim 30, wherein said NMDAr antagonist reaches a therapeutically effective steady state plasma concentration in said subject within fifteen days of said administering.

35. The method of claim 30, wherein the mean plasma concentration profile of said NMDAr antagonist in said subject has an initial slope in a subject has an initial slope from 2 hours to 4 hours after administration less than 50% of that for an IR formulation of the same NMDAr antagonist at the same administered dose.

36. Use of an NMDAr antagonist and an acetylcholinesterase inhibitor in the manufacture of a combined preparation for preventing or treating a CNS-related condition wherein at least one of said NMDAr antagonist or said acetylcholinesterase inhibitor has an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater than 40% in six hours, and greater than 85% in 12 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.

37. The use according to claim 36 wherein the combined preparation comprises the NMDAr antagonist and the acetylcholinesterase inhibitor are as separate formulations.

38. The use according to claim 36 wherein the combined preparation comprises the NMDAr antagonist and the acetylcholinesterase inhibitor as a single formulation.

39. The use according to claim 38 wherein the single formulation is a non-dose escalating formulation.

40. Use of an NMDAr antagonist in the manufacture of a medicament for preventing or treating a CNS-related condition in a subject in need thereof by combination therapy wherein said combination therapy comprises administration of said NMDAr antagonist and an acetylcholinesterase inhibitor to the subject, and wherein at least one of said NMDAr antagonist or said ACheI has an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater than 40% in six hours, and greater than 85% in 12 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.

41. Use of an ACheI in the manufacture of a medicament for preventing or treating a CNS-related condition in a subject in need thereof by combination therapy wherein said combination therapy comprises administration of said ACheI and an NMDAr antagonist to the subject, and wherein at least one of said NMDAr antagonist or said ACheI has an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater than 40% in six hours, and greater than 85% in 12 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.

42. A kit comprising:

(a) an NMDAr antagonist;

(b) an acetylcholinesterase inhibitor selected from the group consisting of donepezil, rivastigmine, tacrine, metrifonate, Huperzine-A; and

(c) instructions for treating or preventing CNS related conditions such as Alzheimer'"'"'s disease,

and wherein at least one of said NMDAr antagonist or said ACheI has an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater than 40% in six hours, and greater than 85% in 12 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.

43. The kit of claim 42, wherein said NMDAr antagonist and said second agent are formulated as a single formulation.

47. A pharmaceutical composition comprising:

(a) memantine in a dose ranging between 20 and 30 mg; and

(b) donepezil in a dose ranging between 2 and 5 mg;

wherein memantine and donezepil are both provided in an extended release dosage form, said extended release dosage form having an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater than 40% in six hours, and greater than 85% in 12 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;

48. The pharmaceutical composition of claim 47, wherein the ratio of dosing of said composition reduces gastro-intestinal and cardiovascular side effects.

49. The pharmaceutical composition of claim 47, the release profile of memantine is substantially identical to the release profile of donepezil.