Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic study.
Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.
Wang
Jhi-Joung
JJ
Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.
Sung
K C
KC
Huang
Jeng-Fen
JF
Yeh
Chih-Hui
CH
Fang
Jia-You
JY
D000279:Administration, Cutaneous; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D000081005:Cyclohexane Monoterpenes; D053138:Cyclohexenes / Q000494:pharmacology; D016503:Drug Delivery Systems; D004355:Drug Stability; D004952:Esters; D006537:Heptanoates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006868:Hydrolysis; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D039821:Monoterpenes / Q000494:pharmacology; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019301:Oleic Acid / Q000494:pharmacology; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011422:Propionates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption
D000701:Analgesics, Opioid; D000081005:Cyclohexane Monoterpenes; D053138:Cyclohexenes; D004952:Esters; D006537:Heptanoates; D039821:Monoterpenes; D009022:Morphine Derivatives; D011355:Prodrugs; D011422:Propionates; C523260:morphine enanthate; C523259:morphine propionate; C016775:alpha-terpineol; D019301:Oleic Acid