Permeation dynamics of microemulsions according to the amount of deep eutectic solvent when applied to the stratum corneum

Deep eutectic solvents (DESs) can enhance the penetration of drug carriers in transdermal drug delivery systems. Previously, we showed that terpene-based DESs substantially enhance the penetration of drug carriers but cause skin damage. To retain the penetration-enhancing properties of DESs while mitigating their adverse effects on the skin, we incorporated small amounts of terpene-based DESs into the oil phase, formulating water-in-oil-type microemulsions (MEs). Stratum corneum (SC) lipid layers, which are sensitive to hydration levels, exhibit changes in spacing and regularity when interacting with DESs. Furthermore, DESs disrupt the lipid structure <i>via</i> unique mechanisms differing from those of traditional MEs. Herein, we investigated the effect of DES concentrations in the MEs on skin permeation under different hydration conditions. Utilizing synchrotron small-angle X-ray scattering and small-angle neutron scattering methods, we analyzed the molecular-scale interactions between the MEs and SC lipids to effectively understand their interaction behavior across hydration states. Overall, these findings highlight the importance of optimizing DES contents and SC hydration levels to achieve an efficient and safe transdermal drug delivery system.