Oleic acid: its effects on stratum corneum in relation to (trans)dermal drug delivery.
Calorimetric studies with porcine stratum corneum (SC) have shown that the lipid phase transitions associated with the intercellular bilayers are markedly affected by treatment with oleic acid. Specifically, the transition temperatures (Tm) and cooperativity are reduced, whereas no effect was observed on the endotherm associated with keratin denaturation, suggesting that oleic acid primarily affects the SC lipids. The decrease in the lipid-associated Tm's was further correlated with the amount of oleic acid taken up by the SC. Parallel experiments with silastic implied that the uptake is dependent on the thermodynamic activity of oleic acid in the vehicle itself. The in vitro transport of Piroxicam across human and hairless mouse skin (HMS) was significantly enhanced by oleic acid, as a function of the extent of oleic acid uptake, with an attendant change in Tm. These results emphasize the role of SC lipids in percutaneous absorption. Transport also depended on the donor concentration of ionized drug suggesting that the enhanced transport mechanism cannot be accounted for solely on the principles of the classical pH-partition hypothesis. Accordingly, a model of skin permeability enhancement involving solid-fluid phase separation within the SC lipids is proposed for oleic acid, consistent with the existing phospholipid literature. In conjunction with the use of oleic acid as an enhancer, very soluble hydrophilic salts were recognized as key factors in attaining maximum delivery. Oleic acid uptake, lipid delta Tm, and enhanced drug flux were all found to correlate, exhibiting a bell-shaped curve as a function of the ethanol vehicle concentration. Therefore, uptake and/or DSC experiments are useful for formulating enhanced topical delivery systems.
Francoeur
M L
ML
Pfizer Central Research, Groton, Connecticut 06340.
Golden
G M
GM
Potts
R O
RO
D000279:Administration, Cutaneous; D000818:Animals; D002021:Buffers; D002152:Calorimetry, Differential Scanning; D000431:Ethanol; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D051379:Mice; D008812:Mice, Hairless; D019301:Oleic Acid; D009829:Oleic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D010894:Piroxicam / Q000008:administration & dosage / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects*; D013552:Swine; D013696:Temperature; D014961:X-Ray Diffraction
D002021:Buffers; D009829:Oleic Acids; D010894:Piroxicam; D019301:Oleic Acid; D000431:Ethanol