COMPOSITIONS FOR THE TREATMENT OF CNS-RELATED CONDITIONS
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.