Formulations of ladostigil tartrate

Abstract

The invention relates to a pharmaceutical composition of R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan ½ tartrate, at least one pharmaceutically acceptable excipient and up to 5% by weight of the composition of water. The composition is typically in a solid oral form which upon administration to a human subject provides a maximum blood plasma concentration of R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan of at least 0.7 nmol/mL.

1 . A pharmaceutical composition comprising R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan ½ tartrate, at least one pharmaceutically acceptable excipient and up to 5% by weight of the composition of water. 
     
     
         2 . The pharmaceutical composition of  claim 1 , comprising 2-5% water. 
     
     
         3 . The pharmaceutical composition of  claim 2 , comprising 2-3.5% water. 
     
     
         4 . An oral solid pharmaceutical composition according to  claim 1 , comprising 25-105 mg R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan ½ tartrate. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein no more than 0.5% by weight of the composition is sodium stearyl fumarate. 
     
     
         6 . The pharmaceutical composition of  claim 5 , free of sodium stearyl fumarate. 
     
     
         7 . The pharmaceutical composition of  claim 4 , wherein no more than 0.5% by weight of the composition is sodium stearyl fumarate. 
     
     
         8 . The pharmaceutical composition of  claim 7 , free of sodium stearyl fumarate. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the at least one pharmaceutically acceptable excipient is a first filler, a second filler, a disintegrant, a flow agent, a binder or a lubricant. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the lubricant is stearic acid. 
     
     
         11 . The pharmaceutical composition of  claim 10 , free of talc. 
     
     
         12 . The pharmaceutical composition of  claim 1  in the form of tablets, capsules, pills, powders, or granules. 
     
     
         13 . The pharmaceutical composition of  claim 1 , which upon administration to a human subject provides a maximum blood plasma concentration of R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan of at least 0.7 nmol/mL. 
     
     
         14 . A pharmaceutical composition comprising R(+)-6-(N-methyl, N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan ½ tartrate, at least one pharmaceutically acceptable excipient and no more than 0.5% by weight of the composition of magnesium stearate. 
     
     
         15 . A pharmaceutical composition comprising R(+)-6-(N-methyl, N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan ½ tartrate, at least one pharmaceutically acceptable excipient and no more than 1.5% by weight of the composition of sodium stearyl fumarate. 
     
     
         16 . A unit dosage form comprising R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan or a pharmaceutically active salt thereof in an amount selected from the group consisting of: 50 mg, 70 mg, 80 mg and 100 mg. 
     
     
         17 . A method for inducing in a human subject a maximum blood plasma concentration of R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan of at least 0.7 nmol/mL after one administration, comprising administering orally to the human subject a solid pharmaceutical composition comprising 25-105 mg R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan ½ tartrate and a pharmaceutically acceptable carrier so as to induce in the subject the blood plasma concentration. 
     
     
         18 . A method of treating a subject afflicted with Parkinson's disease, Alzheimer's disease or dementia, depression or a neurological disorder selected from the group consisting of epilepsy, narcolepsy, amyotrophic lateral sclerosis (“ALS”), memory disorders, panic, posttraumatic stress disorder (“PTSD”), sexual dysfunction, attention deficit and hyperactivity syndrome (“ADHD”), attention deficit disorder, and Tourette's syndrome comprising administering to the subject the pharmaceutical composition of  claim 1 . 
     
     
         19 . A process for making the pharmaceutical composition of  claim 1  comprising the step of wet granulation. 
     
     
         20 . The process of  claim 19 , comprising the step of wet granulation in the absence of water addition or in the absence of ethanol. 
     
     
         21 . The process of  19 , wherein the step of wet granulation is performed in the presence of isopropanol. 
     
     
         22 . A method of treating an individual who has been identified as having Alzheimer's disease comprising the step of: administering orally to said individual a therapeutically effective amount of R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan or a pharmaceutically active salt thereof, wherein said therapeutically effective amount is selected from the group consisting of: 70 mg per day, 140 mg per day, and 200 mg per day. 
     
     
         23 . The method of  claim 22 , wherein said therapeutically effective amount 200 mg per day administered in two 100 mg doses per day. 
     
     
         24 . The method of  claim 22 , wherein said therapeutically effective amount 140 mg per day administered in two 70 mg doses per day.