Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof

Abstract

Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise an amphetamine prodrug that provides enzymatically-controlled release of amphetamine or an amphetamine analog. The composition can further comprise an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of amphetamine or the amphetamine analog from the amphetamine prodrug so as to attenuate enzymatic cleavage of the amphetamine prodrug.

1 . A compound of formula AM-(I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and 
         R 2  is an acyl, substituted acyl, or an N-acyl derivative of a peptide; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         2 . A compound of formula AM-(II): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and 
         R 2  is an acyl, substituted acyl, or an N-acyl derivative of a peptide; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         3 . The compound of  claim 1  or  2 , wherein R 1  is a side chain of an amino acid, the configuration of the carbon atom to which R 1  is attached corresponding with that in an L-amino acid. 
     
     
         4 . The compound of  claim 1  or  2 , wherein R 1  is —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 1  is attached corresponding with that in an L-amino acid. 
     
     
         5 . The compound of  claim 1  or  2 , wherein R 2  is acetyl, benzoyl, malonyl, piperonyl or succinyl. 
     
     
         6 . The compound of  claim 1  or  2 , wherein R 2  is acetyl, malonyl, or succinyl. 
     
     
         7 . The compound of  claim 1  or  2 , wherein R 2  is a peptide of the formula (R 4 ) p , wherein p is an integer from 1 to 100 and each R 4  is an independently selected amino acid, wherein the R 4  at the terminal end of the peptide is N-acylated. 
     
     
         8 . A compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof. 
     
     
         9 . A compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof. 
     
     
         10 . A compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof. 
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any of  claims 1 - 10 . 
     
     
         12 . A composition comprising a GI enzyme inhibitor and a compound of formula AM-(I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and 
         R 2  is an acyl, substituted acyl, or an N-acyl derivative of a peptide; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         13 . A composition comprising a GI enzyme inhibitor and a compound of formula AM-(II): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and 
         R 2  is an acyl, substituted acyl, or an N-acyl derivative of a peptide; 
         or a salt, hydrate or solvate thereof. 
       
     
     
         14 . The composition of  claim 12  or  13 , wherein R 1  is a side chain of an amino acid, the configuration of the carbon atom to which R 1  is attached corresponding with that in an L-amino acid. 
     
     
         15 . The composition of  claim 12  or  13 , wherein R 1  is —CH 2 CH 2 CH 2 NH(C═NH)NH 2  or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 1  is attached corresponding with that in an L-amino acid. 
     
     
         16 . The composition of  claim 12  or  13 , wherein R 2  is acetyl, benzoyl, malonyl, piperonyl or succinyl. 
     
     
         17 . The composition of  claim 12  or  13 , wherein R 2  is acetyl, malonyl, or succinyl. 
     
     
         18 . The composition of  claim 12  or  13 , wherein R 2  is a peptide of the formula (R 4 ) p , wherein p is an integer from 1 to 100 and each R 4  is an independently selected amino acid, wherein the R 4  at the terminal end of the peptide is N-acylated. 
     
     
         19 . A composition comprising a GI enzyme inhibitor and a compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof. 
     
     
         20 . A composition comprising a GI enzyme inhibitor and a compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof. 
     
     
         21 . A composition comprising a GI enzyme inhibitor and a compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof. 
     
     
         22 . A composition comprising a GI enzyme inhibitor and a compound of formula AM-(III): 
       
         
           
           
               
               
           
         
         wherein 
         R is a GI enzyme-cleavable moiety. 
       
     
     
         23 . A composition comprising a GI enzyme inhibitor and a compound of formula AM-(IV): 
       
         
           
           
               
               
           
         
         wherein 
         R is a GI enzyme-cleavable moiety. 
       
     
     
         24 . A composition comprising:
 an amphetamine prodrug comprising amphetamine covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of the amphetamine, wherein the amphetamine prodrug is compound of formula AM-(I) or AM-(II); and   a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the amphetamine from the amphetamine prodrug following ingestion of the composition.   
     
     
         25 . A dose unit comprising the composition of  claim 24 , wherein
 the amphetamine prodrug and GI enzyme inhibitor are present in the dose unit in an amount effective to provide for a pre-selected pharmacokinetic (PK) profile following ingestion.   
     
     
         26 . The dose unit of  claim 25 , wherein the pre-selected PK profile comprises at least one PK parameter value that is less than the PK parameter value of amphetamine released following ingestion of an equivalent dosage of amphetamine prodrug in the absence of inhibitor. 
     
     
         27 . The dose unit of  claim 26 , wherein the PK parameter value is selected from an amphetamine Cmax value, an amphetamine exposure value, and a (1/amphetamine Tmax) value. 
     
     
         28 . The dose unit of  claim 25 , wherein the dose unit provides for a pre-selected PK profile following ingestion of at least two dose units. 
     
     
         29 . The dose unit of  claim 28 , wherein the pre-selected PK profile is modified relative to the PK profile following ingestion of an equivalent dosage of amphetamine prodrug in the absence of inhibitor. 
     
     
         30 . The dose unit of  claim 28 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a linear PK profile. 
     
     
         31 . The dose unit of  claim 28 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a nonlinear PK profile. 
     
     
         32 . The dose unit of  claim 28 , wherein the PK parameter value is selected from an amphetamine Cmax value, a (1/amphetamine Tmax) value, and an amphetamine exposure value. 
     
     
         33 . A composition comprising:
 a container suitable for containing a composition for administration to a patient; and   a dose unit comprising the composition of  claim 24  disposed within the container.   
     
     
         34 . The composition of  claim 24 , wherein the composition is a dose unit having a total weight of from 1 microgram to 2 grams. 
     
     
         35 . The composition of  claim 24 , wherein the composition has a combined weight of amphetamine prodrug and GI enzyme inhibitor of from 0.1% to 99% per gram of the composition. 
     
     
         36 . A method to treat a patient comprising administering a pharmaceutical composition or dose unit of any of the preceding claims to a patient in need thereof. 
     
     
         37 . A method of making a dose unit, the method comprising:
 combining in a dose unit:
 an amphetamine prodrug comprising amphetamine covalently bound to a promoiety cleavable by a GI enzyme, wherein cleavage of the promoiety by the GI enzyme mediates release of amphetamine from the amphetamine prodrug, wherein the amphetamine prodrug is compound of formula AM-(I) or AM-(II); and 
 a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of amphetamine from the amphetamine prodrug; 
   wherein the amphetamine prodrug and the GI enzyme inhibitor are present in the dose unit in an amount effective to attenuate release of amphetamine from the amphetamine prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of amphetamine.   
     
     
         38 . The method of  claim 37 , wherein said release of drug is decreased compared to release of drug by an equivalent dosage of prodrug in the absence of inhibitor. 
     
     
         39 . A method for identifying an amphetamine prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
 combining an amphetamine prodrug, a GI enzyme inhibitor, and a GI enzyme in a reaction mixture, wherein the amphetamine prodrug comprises amphetamine covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the GI enzyme mediates release of amphetamine, wherein the amphetamine prodrug is compound of formula AM-(I) or AM-(II); and   detecting amphetamine prodrug conversion,   wherein a decrease in amphetamine prodrug conversion in the presence of the GI enzyme inhibitor as compared to amphetamine prodrug conversion in the absence of the GI enzyme inhibitor indicates the amphetamine prodrug and the GI enzyme inhibitor are suitable for formulation in a dose unit.   
     
     
         40 . A method for identifying an amphetamine prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
 administering to an animal an amphetamine prodrug and a GI enzyme inhibitor, wherein the amphetamine prodrug comprises amphetamine covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of amphetamine, wherein the amphetamine prodrug is compound of formula AM-(I) or AM-(II); and   detecting amphetamine prodrug conversion, wherein a decrease in amphetamine conversion in the presence of the GI enzyme inhibitor as compared to amphetamine conversion in the absence of the GI enzyme inhibitor indicates the amphetamine prodrug and the GI enzyme inhibitor are suitable for formulation in a dose unit.   
     
     
         41 . The method of  claim 40 , wherein said administering comprises administering to the animal increasing doses of inhibitor co-dosed with a selected fixed dose of amphetamine prodrug. 
     
     
         42 . The method of  claim 40 , wherein said detecting facilitates identification of a dose of inhibitor and a dose of amphetamine prodrug that provides for a pre-selected pharmacokinetic (PK) profile. 
     
     
         43 . The method of  claim 40 , wherein said method comprises an in vivo assay. 
     
     
         44 . The method of  claim 40 , wherein said method comprises an ex vivo assay. 
     
     
         45 . A method for identifying an amphetamine prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
 administering to an animal tissue an amphetamine prodrug and a GI enzyme inhibitor, wherein the amphetamine prodrug comprises amphetamine covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of amphetamine, wherein the amphetamine prodrug is compound of formula AM-(I) or AM-(II); and   detecting amphetamine prodrug conversion, wherein a decrease in amphetamine prodrug conversion in the presence of the GI enzyme inhibitor as compared to amphetamine prodrug conversion in the absence of the GI enzyme inhibitor indicates the amphetamine prodrug and the GI enzyme inhibitor are suitable for formulation in a dose unit.