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 from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a single amino acid or to a peptide comprising from 2 to 10 amino acids and having an amphetamine base amount of from 7.37 to 22.1 mg of said amphetamine, said prodrug providing at least two properties selected from the group consisting of a mean AUC 0-12 h  (ng h/mL) from 205.4±42.5 to 611.5±104.5, a mean AUC last  (ng h/mL) from 396.7±84.8 to 1237.0±194.0, a mean AUC inf  (ng h/mL) from 415.0±80.1 to 1259.5±191.3, a mean C max  (ng/mL) from 25.0±5.6 to 74.0±12.9, a mean T max  (hours) from 3.1±0.876 to 3.9±1.0, and a mean T 1/2  (hours) from 9.68±1.43 to 10.3±1.7 of amphetamine when orally administered to a human subject. 
     
     
         2 . 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. 
     
     
         3 . 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. 
     
     
         4 . A composition as defined in  claim 1 , 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. 
     
     
         5 . A composition comprising 25 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a single amino acid or to a peptide comprising from 2 to 10 amino acids and having an amphetamine base amount of 7.37 mg of said amphetamine, said prodrug providing at least two properties selected from the group consisting of a mean AUC 0-12 h  (ng h/mL) of 205.4±42.5, a mean AUC last  (ng h/mL) of 396.7±84.8, a mean AUC inf  (ng h/mL) of 415.0±80.1, a mean C max  (ng1 mL) of 25.0±5.6, a mean T max  (hours) of 3.1±0.876, and a mean T 1/2  (hours) of 9.68±1.43 of amphetamine when orally administered to a human subject. 
     
     
         6 . A composition as defined in  claim 5 , 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. 
     
     
         7 . A composition as defined in  claim 5 , 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 5 , 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 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a single amino acid or to a peptide comprising from 2 to 10 amino acids and having an amphetamine base amount of 22.1 mg of said amphetamine, said prodrug providing at least two properties selected from the group consisting of a mean AUC 0-12 h  (ng h/mL) of 611.5±104.5, a mean AUC last  (ng h/mL) of 1237.0±194.0, a mean AUC inf  (ng h/mL) of 1259.5±191.3, a mean C max  (ng/mL) of 74.0±12.9, a mean T max  (hours) of 3.9±1.0, and a mean T 1/2  (hours) of 10.3±1.7 of amphetamine when orally administered to a human subject. 
     
     
         10 . A composition as defined in  claim 9 , 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. 
     
     
         11 . A composition as defined in  claim 9 , wherein said composition is in a dosage form selected from the group consisting of a tablet, capsule, caplet, oral solution, and oral suspension. 3115353.1 1202887-USX 
     
     
         12 . A composition as defined in  claim 9 , 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. 
     
     
         13 . A composition comprising from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a single amino acid or to a peptide comprising from 2 to 10 amino acids and having an amphetamine base amount of from 7.37 to 22.1 mg of said amphetamine, said prodrug providing at least two properties selected from the group consisting of a mean AUC last  (ng h/mL) from 11.32±3.74 to 58.1±30.2, a mean AUC inf  (ng h/mL) from 13.5±3.40 to 59.5±29.9, a mean C max  (ng/mL) from 11.56±3.8 to 53.6±34.1, a mean T max  (hours) of 1.05±0.16, and a mean T 1/2  (hours) from 0.419±0.077 to 0.534±0.211 of intact prodrug when orally administered to a human subject. 
     
     
         14 . A composition as defined in  claim 13 , 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. 
     
     
         15 . A composition as defined in  claim 13 , wherein said composition is in a dosage form selected from the group consisting of a tablet, capsule, caplet, oral solution, and oral suspension. 
     
     
         16 . A composition as defined in  claim 13 , 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. 
     
     
         17 . A composition comprising 25 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a single amino acid or to a peptide comprising from 2 to 10 amino acids and having an amphetamine base amount of 7.37 mg of said amphetamine, said prodrug providing at least two properties selected from the group consisting of a mean AUC last  (ng h/mL) of 11.32±3.74, a mean AUC inf  (ng h/mL) of 13.5±3.40, a mean C max  (ng/mL) of 11.56±3.8, a mean T max  (hours) of 1.05±0.16, and a mean T 1/2  (hours) of 0.419±0.077 of intact prodrug when orally administered to a human subject. 
     
     
         18 . A composition as defined in  claim 17 , 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. 
     
     
         19 . A composition as defined in  claim 17 , wherein said composition is in a dosage form selected from the group consisting of a tablet, capsule, caplet, oral solution, and oral suspension. 
     
     
         20 . A composition as defined in  claim 17 , 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. 
     
     
         21 . A composition comprising 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a single amino acid or to a peptide comprising from 2 to 10 amino acids and having an amphetamine base amount of 22.1 mg of said amphetamine, said prodrug providing at least two properties selected from the group consisting of a mean AUC last  (ng h/mL) of 58.1±30.2, a mean AUC inf  (ng h/mL) of 59.5±29.9, a mean C max  (ng/mL) of 53.6±34.1, a mean T max  (hours) of 1.05±0.16, and a mean T 1/2  (hours) of 0.534±0.211 of intact prodrug when orally administered to a human subject. 
     
     
         22 . A composition as defined in  claim 21 , 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. 
     
     
         23 . A composition as defined in  claim 21 , wherein said composition is in a dosage form selected from the group consisting of a tablet, capsule, caplet, oral solution, and oral suspension. 
     
     
         24 . A composition as defined in  claim 21 , 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. 
     
     
         25 . 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 any of  claims 1 ,  5 ,  9 ,  13 ,  17 , and  21 .