Abuse-resistant amphetamine prodrugs

Abstract

The invention describes compounds, compositions, and methods of using the same comprising a chemical moiety covalently attached to amphetamine. These compounds and compositions are useful for reducing or preventing abuse and overdose of amphetamine. These compounds and compositions find particular use in providing an abuse-resistant alternative treatment for certain disorders, such as attention deficit hyperactivity disorder (ADHD), ADD, narcolepsy, and obesity. Oral bioavailability of amphetamine is maintained at therapeutically useful doses. At higher doses bioavailability is substantially reduced, thereby providing a method of reducing oral abuse liability. Further, compounds and compositions of the invention decrease the bioavailability of amphetamine by parenteral routes, such as intravenous or intranasal administration, further limiting their abuse liability.

1 . A composition comprising an amphetamine covalently bonded to a single non-naturally occurring amino acid or to a peptide comprising from 2 to 10 non-naturally occurring amino acids; or a salt thereof. 
     
     
         2 . A composition as defined in  claim 1 , wherein said non-naturally occurring amino acid is selected from the group consisting of aminohexanoic acid, biphenylalanine, cyclohexylalanine, cyclohexylglycine, diethylglycine, dipropylglycine, 2,3-diaminoproprionic acid, homophenylalanine, homoserine, homotyrosine, naphthylalanine, norleucine, ornithine, phenylalanine (4-fluoro), phenylalanine(2,3,4,5,6-pentafluoro), phenylalanine(4-nitro), phenylglycine, pipecolic acid, sarcosine, tetrahydroisoquinoline-3-carboxylic acid, and tert-leucine. 
     
     
         3 . A composition as defined in  claim 2 , wherein said non-naturally occurring amino acid is selected from the group consisting of non-naturally occurring amino acids having a C 1 -C 6  alkyl side chain. 
     
     
         4 . A composition as defined in  claim 1 , wherein said peptide is a homo-peptide. 
     
     
         5 . A composition as defined in  claim 1 , wherein said amphetamine is selected from the group consisting of methylphenidate, methamphetamine, a compound having the formula 
       
         
           
           
               
               
           
         
       
       a salt of any of the foregoing, or a combination of any of the foregoing. 
     
     
         6 . A composition as defined in  claim 5 , wherein said amphetamine comprises methylphenidate. 
     
     
         7 . A composition as defined in  claim 1 , wherein said composition is in a dosage form selected from the group consisting of a tablet, capsule, caplet, oral solution, and oral suspension. 
     
     
         8 . A composition as defined in  claim 7 , wherein said dosage form further comprises a pharmacological substance selected from the group consisting of amphetamines, antidepressants, anxiolytics, non-steroidal anti-inflammatory drugs, or any combination of any of the foregoing. 
     
     
         9 . A composition comprising an amphetamine covalently bonded to a single non-naturally occurring amino acid or to a peptide comprising from 2 to 10 non-naturally occurring amino acids; or a salt thereof, wherein said composition provides a therapeutically bioequivalent AUC of said amphetamine when compared to the AUC of said amphetamine when administered in a form in which said amphetamine is not covalently bonded to a single non-naturally occurring amino acid or to a peptide comprising from 2 to 10 non-naturally occurring amino acids. 
     
     
         10 . A composition as defined in  claim 9 , wherein said peptide is a homo-peptide. 
     
     
         11 . A method, in a subject in need thereof, of treating attention deficit hyperactivity disorder, said method comprising administering to said subject a composition as defined in  claim 1  or  9 .