Comparative analysis of percutaneous absorption enhancement by d-limonene and oleic acid based on a skin diffusion model.
Percutaneous absorption-enhancing effects of d-limonene and oleic acid were investigated using three model drugs with different lipophilicities in in vitro diffusion experiments with guinea pig skin. Pretreatment of the skin with d-limonene resulted in a large penetration enhancement for the lipophilic butylparaben (BP) and amphiphilic 6-mercaptopurine (6-MP) but had little effect on the hydrophilic mannitol (MT). Oleic acid caused a large effect only on 6-MP penetration. The penetration profiles were analyzed with a two-layer skin diffusion model consisting of stratum corneum with polar and nonpolar routes and viable epidermis plus dermis. Through curve-fitting, six parameters corresponding to drug diffusivity and partitioning in these three regions of the skin were obtained, and the mechanisms of enhancers were assessed in comparison with those of 1-geranylazacycloheptan-2-one (GACH) reported previously. Increased penetration was caused mainly by modification of the barrier property of the nonpolar route in the stratum corneum in all cases. In the nonpolar route, d-limonene increased mainly drug diffusivity, while GACH enhanced predominantly drug partitioning. On the other hand, oleic acid moderately increased both parameters.
Koyama
Y
Y
Faculty of Pharmaceutical Science, Kyoto University, Japan.
Bando
H
H
Yamashita
F
F
Takakura
Y
Y
Sezaki
H
H
Hashida
M
M
D000818:Animals; D053138:Cyclohexenes; D004058:Diffusion; D006168:Guinea Pigs; D066298:In Vitro Techniques; D000077222:Limonene; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D015122:Mercaptopurine / Q000493:pharmacokinetics; D008954:Models, Biological; D019301:Oleic Acid; D009829:Oleic Acids / Q000493:pharmacokinetics*; D010226:Parabens / Q000493:pharmacokinetics; D012869:Skin Absorption / Q000502:physiology*; D013729:Terpenes / Q000493:pharmacokinetics*
D053138:Cyclohexenes; D009829:Oleic Acids; D010226:Parabens; D013729:Terpenes; D019301:Oleic Acid; D008353:Mannitol; C038091:butylparaben; D000077222:Limonene; D015122:Mercaptopurine