Methods and compositions for the treatment of CNS-related conditions
View Patent ↗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.
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.