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, 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 oral administration of a dose of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study provides a plasma concentration profile of memantine characterized by a change in plasma concentration of memantine as a function of time (dC/dT) that is less than about 50% of a change in plasma concentration of memantine as a function of time (dC/dT) determined for oral administration of an equal dose of an immediate release form of said first drug to a human subject of said single dose human pharmacokinetic study,   wherein the dC/dT for both said pharmaceutical composition and said immediate release form of said first drug are determined in a time period between 0 hour to 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to a human subject in the same single dose human pharmacokinetic study; and   wherein said neurological condition is selected from the group consisting of Alzheimer's disease and dementia.   
     
     
         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 11 , wherein said pharmaceutical composition provides a change in plasma concentration of memantine as a function of time of 2.1 ng/ml/hr or less in a human subject of a single dose human pharmacokinetic study determined in a time period between 0 hours and 4 hours after administration of said pharmaceutical composition to said subject of a single dose human pharmacokinetic study. 
     
     
         18 . The method of  claim 11 , wherein said pharmaceutical composition provides a change in plasma concentration of memantine as a function of time of 2.1 ng/ml/hr or less in a human subject of a single dose human pharmacokinetic study determined in a time period between 2 hours and 4 hours after administration of said pharmaceutical composition to said subject of a single dose human pharmacokinetic study. 
     
     
         19 . The method of  claim 11 , wherein said pharmaceutical composition has a Tmax of at least 13 hours for memantine as determined from a fasted single dose human pharmacokinetic study. 
     
     
         20 . 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. 
     
     
         21 . The method of  claim 11 , wherein the neurological condition is Alzheimer's disease. 
     
     
         22 . The method of  claim 11 , wherein the amount of the first drug in the pharmaceutical composition is 28 mg. 
     
     
         23 . The method of  claim 11 , wherein the first drug is memantine hydrochloride. 
     
     
         24 . The method of  claim 11 , wherein oral administration of a dose of said pharmaceutical composition provides a change in mean plasma concentration of memantine as a function of time that is less than about 50% of a change in mean plasma concentration as a function of time determined for oral administration of an equal dose of an immediate release form of said first drug,
 wherein the change in mean plasma concentration of memantine for said pharmaceutical composition and said immediate release form of said first drug are both determined in a time period between 0 hours and 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to human subjects in the same single dose human pharmacokinetic study.   
     
     
         25 . The method of  claim 11 , wherein oral administration of a dose of said pharmaceutical composition provides a change in mean plasma concentration of memantine as a function of time that is less than about 50% of a change in mean plasma concentration as a function of time determined for oral administration of an equal dose of an immediate release form of said first drug,
 wherein the change in mean plasma concentration of memantine for said pharmaceutical composition and said immediate release form of said first drug are both determined in a time period between 0 hours and 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to human subjects in the same fasted single dose human pharmacokinetic study.   
     
     
         26 . A method of treating a human subject for a neurological condition, 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 the release of said first drug to provide an extended release form of said first drug,   wherein oral administration of a dose of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study provides a plasma concentration profile of memantine characterized by a change in plasma concentration of memantine as a function of time (dC/dT) per mg of said first drug that is less than about 50% of a change in plasma concentration of memantine as a function of time (dC/dT) per mg of said first drug determined for oral administration of an immediate release form of said first drug to a human subject of said single dose human pharmacokinetic study,   wherein the dC/dT per mg for both said pharmaceutical composition and said immediate release form of said first drug are determined in a time period between 0 hours to 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to a human subject in the same single dose human pharmacokinetic study; and   wherein said neurological condition is selected from the group consisting of Alzheimer's disease and dementia.   
     
     
         27 . The method of  claim 26 , 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 26 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         30 . The method of  claim 26 , 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 26 , wherein said pharmaceutical composition provides a change in plasma concentration of memantine as a function of time of 2.1 ng/ml/hr or less in a human subject of a single dose human pharmacokinetic study determined in a time period between 0 hours and 4 hours after administration of said pharmaceutical composition to said subject of a single dose human pharmacokinetic study. 
     
     
         33 . The method of  claim 26 , wherein said pharmaceutical composition provides a change in plasma concentration of memantine as a function of time of 2.1 ng/ml/hr or less in a human subject of a single dose human pharmacokinetic study determined in a time period between 2 hours and 4 hours after administration of said pharmaceutical composition to said subject of a single dose human pharmacokinetic study. 
     
     
         34 . The method of  claim 26 , wherein said pharmaceutical composition has a Tmax of at least 13 hours for memantine as determined from a fasted single dose human pharmacokinetic study. 
     
     
         35 . The method of  claim 26 , 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. 
     
     
         36 . The method of  claim 26 , wherein the neurological condition is Alzheimer's disease. 
     
     
         37 . The method of  claim 26 , wherein the amount of the first drug in the pharmaceutical composition is 28 mg. 
     
     
         38 . The method of  claim 26 , wherein the first drug is memantine hydrochloride. 
     
     
         39 . The method of  claim 26 , wherein oral administration of a dose of said pharmaceutical composition provides a change in mean plasma concentration of memantine as a function of time per mg of said first drug that is less than about 50% of a change in mean plasma concentration as a function of time per mg of said first drug determined for oral administration of an immediate release form of said first drug,
 wherein the change in mean plasma concentration of memantine for said pharmaceutical composition and said immediate release form of said first drug are both determined in a time period between 0 hours and 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to human subjects in the same single dose human pharmacokinetic study.   
     
     
         40 . The method of  claim 26 , wherein oral administration of a dose of said pharmaceutical composition provides a change in mean plasma concentration of memantine as a function of time per mg of said first drug that is less than about 50% of a change in mean plasma concentration as a function of time per mg of said first drug determined for oral administration of an immediate release form of said first drug,
 wherein the change in mean plasma concentration of memantine for said pharmaceutical composition and said immediate release form of said first drug are both determined in a time period between 0 hours and 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to human subjects in the same fasted single dose human pharmacokinetic study.   
     
     
         41 . A method of reducing a potential for an adverse effect in a human subject being treated for a neurological condition, 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 oral administration of a dose of said pharmaceutical composition to a human subject of a single dose human pharmacokinetic study provides a plasma concentration profile of memantine characterized by a change in plasma concentration of memantine as a function of time (dC/dT) per mg of said first drug that is less than about 50% of a change in plasma concentration of memantine as a function of time (dC/dT) per mg of said first drug determined for oral administration of an immediate release form of said first drug to a human subject of said single dose human pharmacokinetic study,   wherein the dC/dT per mg for both said pharmaceutical composition and said immediate release form of said first drug are determined in a time period between 0 hours to 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to a human subject in the same single dose human pharmacokinetic study; and   wherein the neurological condition is selected from the group consisting of Alzheimer's disease and dementia, wherein the oral administration of the pharmaceutical composition to the human subject is less likely to cause an adverse effect of the first drug in the human subject than is oral administration of an equal dose of the immediate release form of the first drug.   
     
     
         42 . The method of  claim 41 , wherein the amount of the first drug in the pharmaceutical composition is 25 mg to 30 mg. 
     
     
         43 . The method of  claim 42 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         44 . The method of  claim 41 , wherein the amount of the second drug in the pharmaceutical composition is 5 mg to 10 mg. 
     
     
         45 . The method of  claim 41 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         46 . The method of  claim 43 , wherein said single dose human pharmacokinetic study is a fasted single dose human pharmacokinetic study. 
     
     
         47 . The method of  claim 41 , wherein said pharmaceutical composition provides a change in plasma concentration of memantine as a function of time of 2.1 ng/ml/hr or less in a human subject of a single dose human pharmacokinetic study as determined in a time period between 0 hours and 4 hours after administration of said pharmaceutical composition to said subject of a single dose human pharmacokinetic study. 
     
     
         48 . The method of  claim 41 , wherein said pharmaceutical composition provides a change in plasma concentration of memantine as a function of time of 2.1 ng/ml/hr or less in a human subject of a single dose human pharmacokinetic study as determined in a time period between 2 hours and 4 hours after administration of said pharmaceutical composition to said subject of a single dose human pharmacokinetic study. 
     
     
         49 . The method of  claim 41 , wherein said pharmaceutical composition has a Tmax of at least 13 hours for memantine as determined from a fasted single dose human pharmacokinetic study. 
     
     
         50 . The method of  claim 41 , 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. 
     
     
         51 . The method of  claim 41 , wherein the neurological condition is Alzheimer's disease. 
     
     
         52 . The method of  claim 41 , wherein the amount of the first drug in the pharmaceutical composition is 28 mg. 
     
     
         53 . The method of  claim 41 , wherein the first drug is memantine hydrochloride. 
     
     
         54 . The method of  claim 41 , wherein oral administration of a dose of said pharmaceutical composition provides a change in mean plasma concentration of memantine as a function of time per mg of said first drug that is less than about 50% of a change in mean plasma concentration as a function of time per mg of said first drug determined for oral administration of an immediate release form of said first drug,
 wherein the change in mean plasma concentration of memantine for said pharmaceutical composition and said immediate release form of said first drug are both determined in a time period between 0 hours and 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to human subjects in the same single dose human pharmacokinetic study.   
     
     
         55 . The method of  claim 41 , wherein oral administration of a dose of said pharmaceutical composition provides a change in mean plasma concentration of memantine as a function of time per mg of said first drug that is less than about 50% of a change in mean plasma concentration as a function of time per mg of said first drug determined for oral administration of an immediate release form of said first drug,
 wherein the change in mean plasma concentration of memantine for said pharmaceutical composition and said immediate release form of said first drug are both determined in a time period between 0 hours and 6 hours of administration of said pharmaceutical composition and said immediate release form of said first drug to human subjects in the same fasted single dose human pharmacokinetic study.