Compositions 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 - 10 . (canceled) 
     
     
         11 . A method of treating a human subject for a neurological condition selected from the group consisting of Alzheimer's disease and dementia, comprising orally administering once a day to said human subject a pharmaceutical composition in a unit dosage form comprising:
 a) a first drug selected from the group consisting of memantine and a pharmaceutically acceptable salt thereof in an amount of 22.5 mg to 33.75 mg;   b) a second drug selected from the group consisting of donepezil and a pharmaceutically acceptable salt thereof in an amount of 1 mg to 10 mg; and   c) at least one excipient that modifies release of said first drug to provide an extended release form of said first drug,   wherein said pharmaceutical composition provides a ratio of a maximum plasma concentration (Cmax) of memantine to average plasma concentration (Cmean) of memantine of about 1.6 to 2.5 wherein Cmax and Cmean are determined over a period from about 1.5 hours to 12 hours after oral administration of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study.   
     
     
         12 . The method of  claim 11 , wherein the amount of the first drug in the pharmaceutical composition is 25 mg to 30 mg. 
     
     
         13 . The method of  claim 12 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         14 . The method of  claim 11 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         15 . The method of  claim 11 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         16 . The method of  claim 13 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         17 . The method of  claim 15 , wherein said pharmaceutical composition has a Tmax of at least 13 hours for memantine as determined from a fasted single dose human pharmacokinetic study. 
     
     
         18 . The method of  claim 16 , wherein said pharmaceutical composition has a Tmax of at least 13 hours for memantine as determined from a fasted single dose human pharmacokinetic study. 
     
     
         19 . The method of  claim 11 , wherein said pharmaceutical composition provides a maximum steady state plasma concentration of memantine of about 4.5 ng/ml per mg of said first drug as determined from a multiple dose human pharmacokinetic study. 
     
     
         20 . The method of  claim 11 , wherein the neurological condition is Alzheimer's disease. 
     
     
         21 . The method of  claim 11 , wherein the amount of the first drug in the pharmaceutical composition is 28 mg. 
     
     
         22 . The method of  claim 11 , wherein the first drug is memantine hydrochloride. 
     
     
         23 . The method of  claim 11 , wherein said pharmaceutical composition provides an average ratio of Cmax to Cmean of about 1.6 to 2.5 as determined from human subjects of a single dose human pharmacokinetic study, wherein Cmax and Cmean are determined over a period from about 1.5 to 12 hours after oral administration of said pharmaceutical composition to said human subjects of said single dose human pharmacokinetic study. 
     
     
         24 . The method of  claim 15 , wherein said pharmaceutical composition provides an average ratio of Cmax to Cmean of about 1.6 to 2.5 as determined from human subjects of a fasted single dose human pharmacokinetic study, wherein Cmax and Cmean are determined over a period from about 1.5 to 12 hours after oral administration of said pharmaceutical composition to said human subjects of said fasted single dose human pharmacokinetic study. 
     
     
         25 . A method of treating a human subject for a neurological condition selected from the group consisting of Alzheimer's disease and dementia, comprising orally administering once a day to said human subject a pharmaceutical composition in a unit dosage form comprising:
 a) a first drug selected from the group consisting of memantine and a pharmaceutically acceptable salt thereof in an amount of 22.5 mg to 33.75 mg;   b) a second drug selected from the group consisting of donepezil and a pharmaceutically acceptable salt thereof in an amount of 1 mg to 10 mg; and   c) at least one excipient that modifies release of the first drug to provide an extended release form of said first drug,   wherein said pharmaceutical composition provides a ratio of a maximum plasma concentration (Cmax) of memantine to average plasma concentration (Cmean) of memantine of about 1.5 to 2.5 wherein Cmax and Cmean are determined over a period from about 2 hours to 12 hours after oral administration of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study.   
     
     
         26 . The method of  claim 25 , wherein said pharmaceutical composition provides a ratio of Cmax to Cmean of about 1.6 to 2.0 wherein Cmax and Cmean are determined over a period from about 2 hours to 12 hours after oral administration of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study. 
     
     
         27 . The method of  claim 25 , wherein the amount of the first drug in the pharmaceutical composition is 25 mg to 30 mg. 
     
     
         28 . The method of  claim 27 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         29 . The method of  claim 25 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         30 . The method of  claim 25 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         31 . The method of  claim 28 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         32 . The method of  claim 30 , wherein said pharmaceutical composition has a Tmax of at least 13 hours for memantine as determined from a fasted single dose human pharmacokinetic study. 
     
     
         33 . The method of  claim 25 , wherein said pharmaceutical composition provides a maximum steady state plasma concentration of memantine of about 4.5 ng/ml per mg of said first drug as determined from a multiple dose human pharmacokinetic study. 
     
     
         34 . The method of  claim 25 , wherein the neurological condition is Alzheimer's disease. 
     
     
         35 . The method of  claim 25 , wherein the amount of the first drug in the pharmaceutical composition is 28 mg. 
     
     
         36 . The method of  claim 25 , wherein the first drug is memantine hydrochloride. 
     
     
         37 . The method of  claim 25 , wherein said pharmaceutical composition provides an average ratio of Cmax to Cmean of about 1.5 to 2.5 as determined from human subjects of a single dose human pharmacokinetic study, wherein Cmax and Cmean are determined over a period from about 2 to 12 hours after oral administration of said pharmaceutical composition to said human subjects of said single dose human pharmacokinetic study. 
     
     
         38 . The method of  claim 30 , wherein said pharmaceutical composition provides an average ratio of Cmax to Cmean of about 1.5 to 2.5 as determined from human subjects of a fasted single dose human pharmacokinetic study, wherein Cmax and Cmean are determined over a period from about 2 to 12 hours after oral administration of said pharmaceutical composition to said human subjects of said fasted single dose human pharmacokinetic study. 
     
     
         39 . A method of reducing the potential for an adverse effect in a human subject being treated for a neurological condition selected from the group consisting of Alzheimer's disease and dementia, comprising orally administering once a day to said human subject a pharmaceutical composition in a unit dosage form comprising:
 a) a first drug selected from the group consisting of memantine and a pharmaceutically acceptable salt thereof in an amount of 22.5 mg to 33.75 mg;   b) a second drug selected from the group consisting of donepezil and a pharmaceutically acceptable salt thereof in an amount of 1 mg to 10 mg; and   c) at least one excipient that modifies release of the first drug to provide an extended release form of said first drug,   wherein said pharmaceutical composition provides a ratio of a maximum plasma concentration (Cmax) of memantine to average plasma concentration (Cmean) of memantine of about 1.5 to 2.5 wherein Cmax and Cmean are determined over a period from about 2 hours to 12 hours after administration of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study.   
     
     
         40 . The method of  claim 39 , wherein said pharmaceutical composition provides a ratio of Cmax to Cmean of about 1.6 to 2.0 wherein Cmax and Cmean are determined over a period from about 2 hours to 12 hours after administration of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study. 
     
     
         41 . The method of  claim 39 , wherein the amount of the first drug in the pharmaceutical composition is 25 mg to 30 mg. 
     
     
         42 . The method of  claim 41 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         43 . The method of  claim 39 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         44 . The method of  claim 39 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         45 . The method of  claim 42 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         46 . The method of  claim 44 , wherein said pharmaceutical composition has a Tmax of at least 13 hours for memantine as determined from a fasted single dose human pharmacokinetic study. 
     
     
         47 . The method of  claim 39 , wherein said pharmaceutical composition provides a maximum steady state plasma concentration of memantine of about 4.5 ng/ml per mg of said first drug as determined from a multiple dose human pharmacokinetic study. 
     
     
         48 . The method of  claim 39 , wherein the neurological condition is Alzheimer's disease. 
     
     
         49 . The method of  claim 39 , wherein the amount of the first drug in the pharmaceutical composition is 28 mg. 
     
     
         50 . The method of  claim 39 , wherein the first drug is memantine hydrochloride. 
     
     
         51 . The method of  claim 39 , wherein said pharmaceutical composition provides an average ratio of Cmax to Cmean of about 1.5 to 2.5 as determined from human subjects of a single dose human pharmacokinetic study, wherein Cmax and Cmean are determined over a period from about 2 to 12 hours after oral administration of said pharmaceutical composition to said human subjects of said single dose human pharmacokinetic study. 
     
     
         52 . The method of  claim 44 , wherein said pharmaceutical composition provides an average ratio of Cmax to Cmean of about 1.5 to 2.5 as determined from human subjects of a fasted single dose human pharmacokinetic study, wherein Cmax and Cmean are determined over a period from about 2 to 12 hours after oral administration of said pharmaceutical composition to said human subjects of said fasted single dose human pharmacokinetic study.