Amantadine compositions and methods of use

Abstract

Methods of nighttime administration of amantadine to reduce sleep disturbances in patient undergoing treatment with amantadine are described, as well as compositions of extended release amantadine that are suitable for nighttime administration.

We claim: 
     
         1 . A method of administering a dose of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof to a human subject orally, once daily at a time such that the drug does not interfere with sleep, wherein the dose consists of (i) 220 mg to 445 mg of the drug and at least one excipient, wherein at least one of said excipients modifies the release of the drug to provide an extended release form, and wherein administration of the dose provides a Tmax of 6 to 18 hours as measured in a single dose human pharmacokinetic study and once daily administration provides a C-ave-morning to C-ave-night ratio of 1.1 to 2.0 as determined in a multiple dose human pharmacokinetic study. 
     
     
         2 . A method of reducing sleep disturbances in a patient undergoing amantadine therapy comprising orally administering to said patient once daily, at a time such that the amantadine does not interfere with sleep, a dose consisting of (i) 220 mg to 445 mg of a drug selected from the group consisting of amantadine and pharmaceutically acceptable salts thereof and (ii) at least one excipient,
 wherein at least one of said excipients modifies the release of the drug to provide an extended release form, and wherein administration of the dose provides a Tmax of 6 to 18 hours as measured in a single dose human pharmacokinetic study and once daily administration provides a C-ave-morning to C-ave-night ratio of 1.1 to 2.0 as determined in a multiple dose human pharmacokinetic study.   
     
     
         3 . The method of  claim 1  or  claim 2 , wherein administration of the dose provides a Tmax of 6 to 9 hours as measured in a single dose human pharmacokinetic study. 
     
     
         4 . The method of  claim 1  or  claim 2 , wherein administration of the dose provides a Tmax of 8 to 18 hours as measured in a single dose human pharmacokinetic study. 
     
     
         5 . The method of  claim 4 , wherein administration is 0 to 4 hours before bedtime. 
     
     
         6 . The method of  claim 1  or  claim 2 , wherein administration of the dose provides a Cmax of 1.0 to 2.8 ng/ml per mg amantadine and
 an AUC0-inf of 40 to 75 ng*hr/ml per mg amantadine as determined in a single dose human pharmacokinetic study. 
 
     
     
         7 . The method of  claim 1  or  claim 2 , wherein once daily administration of the dose provides a steady state plasma concentration profile characterized by a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine as determined in a multiple dose human pharmacokinetic study. 
     
     
         8 . The method of  claim 1  or  claim 2 , wherein once daily administration of the dose provides a steady state plasma concentration profile characterized by a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine as determined in a multiple dose human pharmacokinetic study. 
     
     
         9 . The method of  claim 1  or  claim 2 , wherein once daily administration of the dose provides a steady state plasma concentration profile characterized by an AUC0-inf of 44 to 83 ng*hr/ml per mg of amantadine as determined in a multiple dose human pharmacokinetic study. 
     
     
         10 . The method of  claim 1  or  claim 2 , wherein at least some of the drug is in an immediate release form. 
     
     
         11 . The method of  claim 1  or  claim 2 , wherein at least 50% of the drug is in the extended release form. 
     
     
         12 . The method of  claim 1  or  claim 2 , wherein at least 75% of the drug is in the extended release form. 
     
     
         13 . The method of  claim 1  or  claim 2 , wherein at least 90% of the drug is in the extended release form. 
     
     
         14 . The method of  claim 1  or  claim 2 , wherein the dose provides a single dose AUC0-inf per mg amantadine that is equivalent to that of a 100 mg tablet of an immediate release formulation of amantadine HCl. 
     
     
         15 . The method of  claim 1  or  claim 2 , wherein once daily administration of the dose maximizes the daytime plasma exposure to amantadine while minimizing night plasma exposure at steady state. 
     
     
         16 . The method of  claim 1  or  claim 2 , wherein once daily administration of the dose provides maximum benefit in morning hours. 
     
     
         17 . The method of  claim 1  or  claim 2 , wherein the dose is therapeutically effective for the treatment of Parkinson's disease. 
     
     
         18 . The method of  claim 1 , wherein the human subject is being treated for Parkinson's disease. 
     
     
         19 . The method of  claim 2 , wherein the patient is being treated for Parkinson's disease. 
     
     
         20 . The method of  claim 1 , wherein the human subject suffers from dyskinesia. 
     
     
         21 . The method of  claim 2 , wherein the patient suffers from dyskinesia. 
     
     
         22 . The method of  claim 20  or  claim 21 , wherein the dyskinesia is levodopa induced dyskinesia. 
     
     
         23 . The method of  claim 20  or  claim 21 , wherein the method reduces the frequency or severity of dyskinesia. 
     
     
         24 . The method of  claim 1  or  claim 2 , additionally comprising administering to the subject or patient a pharmaceutically effective amount of levodopa. 
     
     
         25 . The method of  claim 1  or  claim 2 , wherein the dose is administered at a therapeutically-effective dose from the onset of therapy. 
     
     
         26 . The method of  claim 25 , wherein the therapeutically effective dose of amantadine or a pharmaceutically acceptable salt thereof is 220 mg to 445 mg per day. 
     
     
         27 . The method of  claim 1  or  claim 2 , wherein the extended release form is an osmotic dosage form. 
     
     
         28 . The method of  claim 1  or  claim 2 , wherein the drug is 40% to 65% of the dose.