Method and composition for administering an NMDA receptor antagonist to a subject
View Patent ↗The invention provides methods and compositions for administering an NMDA receptor antagonist (e.g., memantine) to a subject.
1. A solid pharmaceutical composition in a unit dosage form for once daily oral administration comprising an extended release formulation of 5 to 40 mg memantine or pharmaceutically acceptable salt thereof, wherein administration of a dose of the composition to a human subject provides a plasma memantine concentration profile, as measured in a single-dose human PK study, characterized by a change in memantine concentration as a function of time (dC/dT) that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the composition, wherein the dC/dT is measured between the time period of 0 to Tmax of the immediate release form of memantine.
2. The composition of claim 1 wherein the concentration profile is further characterized by a memantine Tmax of at least 19 hours.
3. The composition of claim 1 or 2 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 3 wherein the Cmax/Cmean is about 2.5 to 2 at 1 hour to at least 9 hours after administration.
5. The composition of claim 1 , wherein at least 98% of the memantine or pharmaceutically acceptable salt thereof is in an extended release form.
6. The composition of claim 1 , wherein the unit dosage form is a capsule and wherein the memantine or pharmaceutically acceptable salt thereof is formulated as pellets.
7. The composition of claim 6 , wherein the pellets comprise an extended release coating.
8. The composition of claim 7 , wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material.
9. The composition of claim 8 , wherein the insoluble matrix polymer comprises ethyl cellulose and the water soluble material comprises polyvinylpyrrolidone.
10. The composition of claim 1 comprising 12.5-40 mg memantine or pharmaceutically acceptable salt thereof.
11. The composition of claim 1 comprising 25-40 mg memantine or pharmaceutically acceptable salt thereof.
12. The composition of claim 1 having a memantine in vitro dissolution profile ranging between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, and 50-90% in 10 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±0.5° C., in 500 ml water.
13. The composition of claim 12 in which the dissolution profile is at least 70% in 10 hours and at least 90% in 12 hours.
14. The composition of claim 1 having a memantine in vitro dissolution profile ranging between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, and 50-90% in 10 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±0.5° C., in an acidic dissolution medium.
15. The composition of claim 1 , wherein the extended release formulation of memantine or pharmaceutically acceptable salt thereof comprises ethyl cellulose, polyethylene glycol, hydroxypropylmethyl cellulose and polyvinylpyrrolidone.