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 amantadine to a subject in need thereof, said method comprising orally administering an extended release (ER) composition comprising amantadine, or a pharmaceutically acceptable salt thereof, less than three hours before bedtime. 
     
     
         2 . The method of  claim 1 , wherein the method comprises reducing sleep disturbance in a human subject undergoing treatment with amantadine. 
     
     
         3 . The method of  claim 1 , wherein the method comprises treating levodopa induced dyskinesia in a patient with Parkinson's disease, said method comprising orally administering once daily an extended release (ER) composition comprising amantadine, or a pharmaceutically acceptable salt thereof, less than about three hours before bedtime. 
     
     
         4 . The method of  claim 1 , wherein administration occurs less than 1 hour before bedtime. 
     
     
         5 . The method of  claim 1 , wherein the composition is administered once daily. 
     
     
         6 . The method of  claim 1 , wherein, the amantadine has a single dose Tmax of 9 to 15 hours, and/or a steady state Tmax of 7 to 13 hours. 
     
     
         7 . The method of  claim 1 , wherein the amantadine has a Cmax/Cmin ratio of 1.5 to 2.0. 
     
     
         8 . The method of  claim 1 , wherein the ratio of C-ave-day/C-ave night at steady state is 1.2 to 1.6. 
     
     
         9 . The method of  claim 1 , wherein the average amantadine plasma concentration during the day (C-ave-day) at steady state is 500-2000 ng/ml. 
     
     
         10 . The method of  claim 1 , wherein the composition comprises 50 to 600 mg of amantadine, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 10 , wherein the composition is administered as one or two unit dosage forms each comprising 130 to 210 mg of extended release amantadine, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 1 , wherein oral administration of a single dose of the composition to a human subject in a fasted state provides a maximum plasma concentration (Cmax) of 1.6 to 2.4 ng/ml per mg of amantadine, and an AUC 0-inf  of 40 to 75 ng*h/mL per mg of amantadine. 
     
     
         13 . The method of  claim 1 , wherein once daily oral administration of a dose of the composition to a human subject provides a steady state plasma concentration profile characterized by:
 (i) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine,   (ii) a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine, and   (iii) an AUC 0-24  of 44 to 83 ng*h/mL per mg of amantadine.   (iv) no increase in plasma concentration of amantadine for at least one hour after the administration; and   (v) a Cmax/Cmin ratio of 1.5 to 2.0.   
     
     
         14 . A unit dosage form comprising amantadine comprising 130 to 210 mg of extended release amantadine pellets in a capsule. 
     
     
         15 . The unit dosage form of  claim 14 , where the capsule is of size #1 or smaller. 
     
     
         16 . A pharmaceutical composition for oral administration comprising a capsule for oral administration, said capsule containing a plurality of pellets, each pellet comprising:
 (a) a pellet core comprising amantadine, or a pharmaceutically acceptable salt thereof, and   (b) an extended release coating surrounding the pellet core.   
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the extended release coating comprises ethyl cellulose, at least one of povidone and hydroxypropyl methyl cellulose, and a plasticizer. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein the pellet core comprises amantadine, or a pharmaceutically acceptable salt thereof, and a binder coated onto a core seed. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein, based on the combined weight of the pellet core and extended release coating, the amantadine is present in amounts from 40 to 60 wt %, the binder is present in amounts from 8 to 25 wt %, the core seed is present in amounts from 1 to 15 wt %, the ethyl cellulose is present in amounts from 10 to 20 wt %, the povidone is present in amounts from 1 to 4 wt %, and the plasticizer is present in amounts from 1 to 4 wt %. 
     
     
         20 . A method of administering amantadine, or a pharmaceutically acceptable salt thereof, to a human subject in need thereof, said method comprising orally administering a composition of  claim 16 . 
     
     
         21 . A method of treating Parkinson's disease in a human subject in need thereof, said method comprising orally administering a composition of  claim 16 . 
     
     
         22 . A pharmaceutical composition suitable for once daily oral administration to a patient in need thereof said composition comprising a therapeutically effective amount of amantadine or a pharmaceutically acceptable salt thereof in an extended release form which can be administered as not more than two size 1 or smaller capsules in a single daily administration. 
     
     
         23 . The composition of  claim 22  comprising 110-220 mg of amantadine or pharmaceutically acceptable salt thereof. 
     
     
         24 . The pharmaceutical composition of  claim 22  having an in vitro dissolution profile of amantadine of not more than 25% at 2 hours, 55-85% at 6 hours, and at least 80% at 12 hours, using a USP Apparatus II (Paddles) at 50 rpm with 500 ml water at 37° C. as the dissolution medium. 
     
     
         25 . The pharmaceutical composition of  claim 22 , comprising a plurality of pellets, each pellet comprising: (a) a pellet core comprising amantadine, or a pharmaceutically acceptable salt thereof, and (b) an extended release coating surrounding the pellet core. 
     
     
         26 . The pharmaceutical composition of  claim 25  wherein the extended release coating comprises ethyl cellulose, at least one of povidone and hydroxypropyl methyl cellulose, and a plasticizer. 
     
     
         27 . The pharmaceutical composition of any one of  claims 25 , wherein the pellet core comprises amantadine, or a pharmaceutically acceptable salt thereof, and a binder coated onto a core seed. 
     
     
         28 . The pharmaceutical composition of  claim 25 , wherein, based on the combined weight of the pellet core and extended release coating, the amantadine is present in amounts from 40 to 70 wt %. 
     
     
         29 . The pharmaceutical composition of  claim 25 , wherein, the pellet core comprises a core seed comprising sugar or microcrystalline cellulose, which is between 100 and 500 microns in diameter. 
     
     
         30 . The pharmaceutical composition of  claim 25 , wherein the bulk density is between 0.5 and 1 gm/cm 3 . 
     
     
         31 . A method of treating Parkinson's disease in a human subject, said method comprising orally administering a composition of  claim 22  or  25 . 
     
     
         32 . A method of treating levodopa induced dyskinesia in a human subject, said method comprising orally administering a composition of  claim 22  or  25 . 
     
     
         33 . A method of treating traumatic brain injury in a human subject, said method comprising orally administering a composition of  claim 22  or  25 . 
     
     
         34 . A method of treating fatigue in a human subject, said method comprising orally administering a composition of  claim 22  or  25 .