Skin permeation enhancement by terpenes for transdermal drug delivery

Abstract

Terpenes are components of essential oils. Their enhancing effects on human skin and interactions with skin lipids were studied. Firstly, mathematical and statistical models for in vitro permeation studies using both Franz and flow-through cells were derived and tested. For Franz cells, the model allowed the accumulation of chemicals in the receptor compartment and gave comparable results as those obtained from infinite outflow methods. For flow-through cells, the proposed model provided more precise estimates than the existing models. Secondly, based on the models, the enhancing efficacies of 49 terpenes were studied. For monoterpenes and sesquiterpenes, the enhancing efficacies increased as their lipophilicities increased. Melting points and boiling points were negatively correlated with their enhancing effects. Monoterpenes, sesquiterpenes and diterpenes were found to be effective enhancers and sesquiterpenes were better compared to monoterpenes. Terpenes with ester and aldehyde functional groups were found to be better than the others. Thirdly, the enhancing effects of two terpenes on the skin were found to be reversible and the permeability of skin recovered once the enhancers were removed from the excised skin. Fourthly, the drug and enhancers were incorporated into Small Molecule Gelling Agents (SMGA) gels without affecting the aesthetic properties. The novel SMGA gels are suitable for topical or transdermal delivery. Lastly, the solubilities of Stratum Corneum (SC) lipids and ligand binding studies suggest that the enhancing mechanism of farnesol could be due to lipid extraction and/or lipid phase transition in the SC lamella. In conclusion, terpenes are effective skin penetration enhancers with reversible effects in both solutions and gels, that can bind and solubilize stratum corneum intercellular lipids.