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 pharmaceutical composition consisting of:
 (i) 110 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 said composition is suitable for once daily, oral administration to a human subject at a time such that the drug does not interfere with sleep, wherein at least one of said excipients modifies the release of the drug to provide an extended release form, and wherein administration of the composition provides a) a Tmax of 6 to 18 hours, b) a Cmax of 1.0 to 2.8 ng/ml per mg amantadine, and c) an AUC0-inf of 40 to 75 ng*hr/m1 per mg amantadine as measured in a single dose human pharmacokinetic study.   
     
     
         2 . The composition of  claim 1 , wherein administration of the composition provides a Tmax of 6 to 9 hours as measured in a single dose human pharmacokinetic study. 
     
     
         3 . The composition of  claim 1 , wherein administration of the composition provides a Tmax of 8 to 18 hours as measured in a single dose human pharmacokinetic study. 
     
     
         4 . The composition of  claim 3 , wherein the composition is suitable for administration is 0 to 4 hours before bedtime. 
     
     
         5 . The composition of  claim 1 , wherein once daily administration of the composition 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. 
     
     
         6 . The composition of  claim 1 , wherein once daily administration of the composition 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. 
     
     
         7 . The composition of  claim 1 , wherein once daily administration of the composition provides a steady state plasma concentration profile characterized by an AUC0-24 of 44 to 83 ng*hr/ml per mg of amantadine as determined in a multiple dose human pharmacokinetic study. 
     
     
         8 . The composition of  claim 1 , wherein at least some of the drug is in an immediate release form. 
     
     
         9 . The composition of  claim 1 , wherein at least 50% of the drug is in the extended release form. 
     
     
         10 . The composition of  claim 1 , wherein at least 75% of the drug is in the extended release form. 
     
     
         11 . The composition of  claim 1 , wherein at least 90% of the drug is in the extended release form. 
     
     
         12 . The composition of  claim 1 , wherein administration of the composition 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. 
     
     
         13 . The composition of  claim 1 , wherein once daily administration of the composition maximizes the daytime plasma exposure to amantadine while minimizing night plasma exposure at steady state. 
     
     
         14 . The composition of  claim 1 , wherein once daily administration of the composition provides maximum benefit in morning hours. 
     
     
         15 . The composition of  claim 1 , wherein the composition is therapeutically effective for the treatment of Parkinson's disease. 
     
     
         16 . The composition of  claim 1 , wherein the human subject has been diagnosed with Parkinson's disease. 
     
     
         17 . The composition of  claim 1 , wherein the human subject suffers from dyskinesia. 
     
     
         18 . The composition of  claim 17 , wherein the dyskinesia is levodopa induced dyskinesia. 
     
     
         19 . The composition of  claim 17 , wherein the composition reduces the frequency or severity of dyskinesia. 
     
     
         20 . The composition of  claim 1 , wherein the extended release form is an osmotic dosage form. 
     
     
         21 . The composition of  claim 1 , wherein the amantadine or pharmaceutically acceptable salt thereof is 220 to 445 mg. 
     
     
         22 . The composition of  claim 1 , wherein the drug is 40% to 65% of the composition.