Human skin permeation of branched-chain 3-0-alkyl ester and carbonate prodrugs of naltrexone.
OBJECTIVE
Physicochemical characterization and in vitro human skin diffusion studies of branched-chain ester and carbonate prodrugs of naltrexone (NTX) were compared and contrasted with straight-chain ester and carbonate NTX prodrugs.


METHODS
Human skin permeation rates, thermal parameters, solubilities in mineral oil and buffer, and stabilities in buffer and plasma were determined. Partition coefficients between stratum corneum and vehicle were determined for straight- and branched-chain esters with the same number of carbon atoms.


RESULTS
Branched prodrugs had lower melting points, lower buffer solubilities, and higher mineral oil solubilities than NTX. The transdermal flux values from all of these branched prodrugs were significantly lower than flux values from the straight-chain ester and the methyl carbonate prodrugs. Straight-chain prodrugs had higher partition coefficient values and higher calculated thermodynamic activities than their branched-chain counterparts. The prodrug hydrolysis to NTX in buffer and plasma was slower for prodrugs with increased branching.


CONCLUSIONS
Branched-chain prodrugs with bulky moieties had smaller stratum corneum-vehicle partition coefficients and lower thermodynamic activities that resulted in smaller transdermal flux values than straight-chain prodrugs.
Vaddi
Haranath K
HK
Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, Kentucky, USA.
Hamad
Mohamed O
MO
Chen
Jianhong
J
Banks
Stan L
SL
Crooks
Peter A
PA
Stinchcomb
Audra L
AL
D000005:Abdomen / Q000473:pathology; D002254:Carbonates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D004952:Esters / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008899:Mineral Oil / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D009271:Naltrexone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology; D012995:Solubility; D044366:Transition Temperature
D002254:Carbonates; D004952:Esters; D011355:Prodrugs; D009271:Naltrexone; D008899:Mineral Oil