Methods and compositions for the treatment of CNS-related conditions

• US 8,293,794 B2
• Filed: 04/02/2010
• Issued: 10/23/2012
• 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., Meyerson, Laurence R.
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Carter, Kendra D
• Application Number:
  US12/753,769
• Publication Number:
  US 20100311697A1
• Time in Patent Office: 935 Days
• Field of Search: 514/597, 514/400, 424/400
• US Class Current: 514/597
• 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) 5 to 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) in a defined time period of 0 to 6 hours after administration, as measured in a single-dose human PK study, that is less than about 50% of the dC/dT provided by the same quantity of an immediate release form of memantine during said defined time period; and

(b) a therapeutically effective amount of an ACheI or a pharmaceutically acceptable salt thereof selected from the group consisting of donepezil, rivastigmine and galantamine.

2. A pharmaceutical composition of claim 1, wherein the ACheI is donepezil.

3. The composition of claim 1 wherein the concentration profile is further 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.

4. The composition of claim 1, wherein at least 98% of the memantine is in an extended release form.

5. The composition of claim 1, wherein the composition is a capsule and wherein the memantine, or pharmaceutically acceptable salt thereof, is formulated as pellets.

6. The composition of claim 5, wherein the pellets comprise an extended release coating.

7. The composition of claim 6, wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material.

8. The composition of claim 7, wherein the insoluble matrix polymer comprises ethyl cellulose and the water soluble material comprises polyvinylpyrrolidone.

9. The composition of claim 1 comprising 12.5-40 mg memantine or a pharmaceutically acceptable salt thereof.

10. The composition of claim 1 comprising 25-40 mg memantine or a pharmaceutically acceptable salt thereof.

11. The composition of claim 1, wherein the extended release memantine dosage form further comprises, ethyl cellulose, polyethylene glycol, hydroxypropylmethyl cellulose and polyvinylpyrrolidone.

12. The composition of claim 1, wherein the ACheI is donepezil or a pharmaceutically acceptable salt thereof.

13. The composition of claim 12 wherein the donepezil or pharmaceutically acceptable salt thereof is in an immediate release form.

14. The composition of claim 1, wherein said extended release memantine or pharmaceutically acceptable salt thereof has an in vitro dissolution of less than 30% in one hour, less than 40% in two hours and 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°

C. with water as a dissolution medium.

15. A pharmaceutical composition comprising:

(a) 5 to 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 provided by the same quantity of an immediate release form of memantine during said defined time period, 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 an ACheI or a pharmaceutically acceptable salt thereof selected from the group consisting of donepezil, rivastigrnine and galantamine.

16. A pharmaceutical composition of claim 15, wherein the ACheI is donepezil.

17. The composition of claim 15, wherein the concentration profile is further 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.

18. The composition of claim 15, wherein at least 98% of the memantine is in an extended release form.

19. The composition of claim 15, wherein the composition is a capsule and wherein the memantine, or pharmaceutically acceptable salt thereof, is formulated as pellets.

20. The composition of claim 19, wherein the pellets comprise an extended release coating.

21. The composition of claim 20, wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material.

22. The composition of claim 21, wherein the insoluble matrix polymer comprises ethyl cellulose and the water soluble material comprises polyvinylpyrrolidone.

23. The composition of claim 15, comprising 12.5-40 mg memantine or a pharmaceutically acceptable salt thereof.

24. The composition of claim 15, comprising 25-40 mg memantine or a pharmaceutically acceptable salt thereof.

25. The composition of claim 15, wherein the extended release memantine dosage form further comprises, ethyl cellulose, polyethylene glycol, hydroxypropylmethyl cellulose and polyvinylpyrrolidone.

26. The composition of claim 15, wherein the ACheI is donepezil or a pharmaceutically acceptable salt thereof.

27. The composition of claim 26, wherein the donepezil or pharmaceutically acceptable salt thereof is in an immediate release form.

28. The composition of claim 15, wherein said extended release memantine or pharmaceutically acceptable salt thereof has an in vitro dissolution of less than 30% in one hour, less than 40% in two hours and 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°

C. with water as a dissolution medium.