Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery

Abstract A small library of amino acid ester prodrugs of 6-β-naltrexol (NTXOL, 1 ) was prepared in order to investigate the candidacy of these prodrugs for microneedle-enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized ( 6a – f ). 6b , 6d , and 6e were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. The lead compound ( 6e ) exhibited the most rapid bioconversion to NTXOL in human plasma ( t 1/2  = 2.2 ± 0.1 h).