Structure/Effect Studies of Fatty Acid Isomers as Skin Penetration Enhancers and Skin Irritants

Comparisons were made of branched vs unbranched saturated fatty acids and cis vs trans unsaturated fatty acids as skin penetration enhancers and primary skin irritants. Skin penetration studies used naloxone base as the diffusant, propylene glycol as the vehicle, and human skin. Maximum naloxone flux was with C_9–12-branched and unbranched fatty acids. For C_5–14 fatty acids, branched and unbranched isomers had similar effects. One branched C₁₈ fatty acid isomer (C₁₆-branched isostearic acid) was more effective in enhancing skin penetration than a differently branched (C₂-branched isostearic acid) or unbranched C₁₈ isomer (stearic acid). There was no significant difference between cis and trans unsaturated C_16–18 fatty acid isomers in their effects on naloxone flux, and all unsaturated fatty acids were more effective enhancers than the corresponding saturated isomers. Several of these fatty acid/propylene glycol vehicles were evaluated in a rabbit primary skin irritation test. Irritation indices were poorly correlated with the effectiveness of the vehicles in enhancing naloxone flux. It was possible to enhance naloxone skin penetration greatly with a vehicle with only minimal skin irritation potential.