Facilitated transport of two model steroids by esters and amides of clofibric acid.
A series of novel dermal penetration enhancers, esters and amides of clofibric acid, was synthesized. The permeation parameters and skin retention of two steroids (hydrocortisone-21-acetate and betamethasone-17-valerate) in propylene glycol were studied with athymic nude mouse skin by in vitro diffusion cell techniques in the presence of the novel enhancer compounds. Isopropyl myristate, dimethyl lauramide, and 1-dodecylazacycloheptan-2-one (laurocapram, Azone) were used as control enhancers. The most satisfactory enhancement of both the ester and amide series was observed with clofibric acid octyl amide; coadministration increased skin retention of hydrocortisone acetate after 24 h by 3.5-fold and that of betamethasone valerate by 2.9-fold. Diffusion cell receptor concentrations increased 51.6- and 10.3-fold, respectively, during the same time period. However, the enhancer compound in this case was applied to the skin 1 h prior to each of the steroids. The amide analogues were more effective than the equivalent ester compounds of the same carbon chain length. The best enhancer compounds (2c, 3d, 3e, and 3f) were nonirritating to athymic mouse skin in vivo.
Michniak
B B
BB
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208.
Chapman
J M
JM
Seyda
K L
KL
D000818:Animals; D001624:Betamethasone Valerate / Q000493:pharmacokinetics*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004058:Diffusion; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010539:Permeability; D014677:Pharmaceutical Vehicles; D012869:Skin Absorption; D013256:Steroids / Q000737:chemistry / Q000493:pharmacokinetics*
D014677:Pharmaceutical Vehicles; D013256:Steroids; C021650:hydrocortisone acetate; D002995:Clofibric Acid; D001624:Betamethasone Valerate; D006854:Hydrocortisone