Methods for the Treatment of CNS-Related Conditions

Abstract

The invention provides methods for treating CNS-related conditions with amantadine and donepezil, in which the amantadine is in an extended release form, wherein the extended release amantadine formulation provides a change in plasma concentration as a function of time (dC/dT) that is less than 40% of the dC/dT of the same quantity of an immediate release form of amantadine.

1 . A method of treating a CNS-related condition comprising orally administering once a day to a human subject in need thereof:
 a. 200-500 mg amantadine or a pharmaceutically acceptable salt thereof provided in extended release dosage form, wherein said extended release amantadine or pharmaceutically acceptable salt thereof provides a change in plasma concentration as a function of time (dC/dT) that is less than 40% of the dC/dT of the same quantity of an immediate release form of amantadine, wherein dC/dT is measured in a single dose human PK study between the period of 0 to Tmax of the immediate release form of amantadine; and   b. a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt thereof, wherein the CNS-related condition is selected from a group consisting of Alzheimer's disease, dementia, Parkinson's disease, multiple sclerosis, traumatic brain injury, fatigue, and neuropsychiatric disorders.   
     
     
         2 . The method of  claim 1 , wherein the amount of amantadine or pharmaceutically acceptable salt thereof ranges between 300 to 500 mg per dose. 
     
     
         3 . The method of  claim 1 , wherein the extended release amantadine has an in vitro dissolution profile in water that is substantially identical to its in vitro dissolution profile in a dissolution medium having a pH of 1.2 and wherein said in vitro dissolution is less than 20% in one hour, less than 30% in two hours, 40-80% in six hours, and greater than or equal to 80% in 12 hours as measured using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37±0.5C. 
     
     
         4 . The method of  claim 1 , wherein at least 95% of the amantadine is in extended release form. 
     
     
         5 . The method of  claim 1 , wherein said amantadine or a pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are administered simultaneously. 
     
     
         6 . The method of  claim 1 , wherein said amantadine or a pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are administered as a single composition. 
     
     
         7 . A method of reducing the potential for an adverse effect in a human 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. 200-500 mg amantadine or a pharmaceutically acceptable salt thereof provided in extended release dosage form, wherein said extended release amantadine or pharmaceutically acceptable salt thereof provides a change in plasma concentration as a function of time (dC/dT) that is less than 40% of the dC/dT of the same quantity of an immediate release form of amantadine, wherein dC/dT is measured in a single dose human PK study between the period of 0 to Tmax of the immediate release form of amantadine; and   b. a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt thereof, wherein the CNS-related condition is selected from a group consisting of Alzheimer's disease, dementia, Parkinson's disease, multiple sclerosis, traumatic brain injury, fatigue, and neuropsychiatric disorders;   and further wherein said adverse event is related to amantadine.   
     
     
         8 . The method of  claim 7 , wherein the composition is in a unit dosage form comprising 300 to 500 mg amantadine or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 7 , wherein the donepezil or a pharmaceutically acceptable salt thereof is in an immediate release form. 
     
     
         10 . The method of  claim 7 , wherein the composition comprises 1 to 20 mg donepezil hydrochloride. 
     
     
         11 . The method of  claim 7 , wherein the dosage form is in a capsule. 
     
     
         12 . The method of  claim 7 , wherein said amantadine or a pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are provided in a unit dosage form. 
     
     
         13 . The method of  claim 7 , wherein the composition comprises 200 to 500 mg amantadine hydrochloride. 
     
     
         14 . The method of  claim 7 , wherein the composition comprises at least 200 mg amantadine hydrochloride and 1 to 20 mg donepezil hydrochloride. 
     
     
         15 . In a method of treating a subject for CNS-related condition comprising administering to said subject an amantadine drug selected from the group consisting of amantadine 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 amantadine drug is administered in an extended release dosage form, wherein said extended release amantadine 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 amantadine after administration, as measured in a single dose PK study, that is less than 40% of the change in plasma concentration (dC/dT) of the same quantity of said immediate release form of said amantadine drug during said defined time period; and   b. said amantadine drug is administered once daily in a range of 200 to 500 mg; wherein said CNS-related condition is selected from the group consisting of Alzheimer's disease, dementia, Parkinson's disease, multiple sclerosis, traumatic brain injury, fatigue, and neuropsychiatric disorders.   
     
     
         16 . The method of  claim 15 , wherein said amantadine drug daily dose is 300 to 500 mg. 
     
     
         17 . The method of  claim 15 , wherein said amantadine drug and said donepezil drug are administered as a composition. 
     
     
         18 . The method of  claim 16 , wherein said amantadine drug and said donepezil drug are administered as a unit dosage form. 
     
     
         19 . The method of  claim 17 , wherein said donepezil drug is administered as an immediate release form. 
     
     
         20 . The method of  claim 18 , wherein said donepezil drug is administered as an immediate release form.