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 salt composition comprising a salt of a composition comprising an amphetamine covalently bonded to a single amino acid or to a peptide comprising from 2 to 10 amino acids. 
     
     
         2 . A salt composition as defined in  claim 1 , wherein said salt comprises an amphetamine covalently bonded to a salt of a single amino acid or to a salt of a peptide comprising from 2 to 10 amino acids. 
     
     
         3 . A salt composition as defined in  claim 2 , wherein said salt is selected from the group consisting of 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, finnarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, laurylsulphonate, malate, maleate, mandelate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthylate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, undecanoate, valerate salts, and any combination of any of the foregoing. 
     
     
         4 . A salt composition as defined in  claim 3 , comprising L-lysine-d-amphetamine diHCl. 
     
     
         5 . A salt composition as defined in  claim 3 , 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 salt composition as defined in  claim 2 , wherein said composition is in a dosage form selected from the group consisting of a tablet, capsule, caplet, oral solution, and oral suspension. 
     
     
         7 . A salt 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. 
     
     
         8 . A salt composition comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of a peptide comprising from 2 to 10 amino acids, wherein said salt 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 salt of a single amino acid or to a salt of a peptide comprising from 2 to 10 amino acids. 
     
     
         9 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 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. 
     
     
         10 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 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. 
     
     
         11 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 one property 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. 
     
     
         12 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 one property 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. 
     
     
         13 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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. 
     
     
         14 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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. 
     
     
         15 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 three 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. 
     
     
         16 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 three 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. 
     
     
         17 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 four 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. 
     
     
         18 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 four 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. 
     
     
         19 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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 five 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. 
     
     
         20 . A composition comprising amount of from 25 to 75 mg of a prodrug or a salt thereof, said prodrug comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of 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, wherein said prodrug 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 salt of a single amino acid or to a salt of a peptide comprising from 2 to 10 amino acids. 
     
     
         21 . A composition comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of a peptide comprising from 2 to 10 amino acids, wherein said salt is selected form the group consisting of benzenesulfonate (besylate), (+)-(1S)-camphor-10-sulfonic acid (camsylate), ethanesulfonic acid (esylate), 2-hydroxy-ethanesulfonic acid (isethionate), 2-naphthalene-2-sulfonic acid (napsylate), and p-toluenesulfonic acid (tosylate). 
     
     
         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 composition comprising an amphetamine covalently bonded to a salt of a single amino acid or to a salt of a peptide comprising from 2 to 10 amino acids, wherein said salt is selected form the group consisting of benzenesulfonate (besylate), (+)-(1S)-camphor-10-sulfonic acid (camsylate), ethanesulfonic acid (esylate), 2-hydroxy-ethanesulfonic acid (isethionate), 2-naphthalene-2-sulfonic acid (napsylate), and p-toluenesulfonic acid (tosylate), wherein said salt 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 said salt. 
     
     
         26 . A method, in a subject in need thereof, of treating attention deficit hyperactivity disorder, said method comprising administering to said patient a composition as defined in any of  claims 1 ,  2 ,  7 ,  8 ,  9 ,  10 ,  11 ,  12 ,  13 ,  14 ,  15 ,  16 ,  17 ,  18 ,  19 ,  20 , and  25 .