To elucidate the molecular mechanism(s) by which methyl salicylate enhances the skin delivery of herbal ingredients with diverse lipophilicity.

The toxicity of methyl salicylate on skin cell lines was evaluated using the MTT assay. The Franz diffusion cell method was used to measure the permeability enhancing activities of methyl salicylate for five herbal ingredients with a range of lipophilicities. The interaction between methyl salicylate and the stratum corneum (SC) was observed by using an infrared spectroscopy technique. Moreover, the solubilities and SC-vehicle partition coefficient were determined to monitor the impact of methyl salicylate on the drug thermodynamic activities and partition into the SC layer, respectively.

Compared with azone (1-dodecylazacycloheptan-2-one), methyl salicylate showed lower toxicity to skin cells in terms of the IC₅₀ values. The in vitro skin permeation studies showed that methyl salicylate could greatly improve the cumulative amounts or steady state flux of the selected model drugs with the exception of osthole, which indicated that methyl salicylate was prone to promote the skin delivery of hydrophilic drugs. The Fourier transform infrared spectroscopy studies revealed that methyl salicylate mainly interacted with SC lipids, leading to the disruption of the orderly arrangement of the SC. In addition, methyl salicylate had no obvious effect on the drug thermodynamic activity and partition into the SC.

Methyl salicylate could effectively promote the skin delivery of relatively hydrophilic ingredients in externally used traditional Chinese medicines (TCM) without obvious cytotoxicity.