Terpene-based eutectic mixtures for cutaneous delivery: Eutectic point vs. molar ratio - which matters more?

Eutectic mixtures (EMs) of small molecules are increasingly used as a platform for dermal and transdermal drug delivery. However, there is still limited knowledge about how their composition impacts their permeation-enhancing effect, with most studies focusing only on formulations corresponding to the eutectic points (EPs) of binary mixtures. To address this, we investigated the role of the EMs' molar composition on their potential as a delivery platform for the model drug clotrimazole (CLOT). We examined several molar ratios of four terpene-based EMs composed of menthol:β-citronellol, thymol:β-citronellol, menthol:camphor and menthol:thymol for their CLOT-solubilizing potential and viscosity. We also studied CLOT skin retention and permeation after applying the CLOT-containing EMs to porcine skin and observed changes in the skin barrier function. For EMs without thymol, the solubility of CLOT in the EMs was independent of the molar ratio between the terpenes. In contrast, the solubility in thymol-based EMs depended on the molar ratio between the terpenes, with the lowest solubilities found for the EMs at their EPs. The viscosity of pure EMs was dictated by their molar composition, and when saturated with CLOT, it was largely governed by the amount of the dissolved drug in the mixtures, also at their EPs. A small amount of CLOT permeated through the porcine skin, with larger quantities of the drug found in the epidermis and, to lesser extent, in the dermis. The amount of CLOT found in the skin did not correlate with the degree of skin impairment and disruption of the lipid packing in the stratum corneum. Importantly, EMs at their EPs did not show better CLOT retention and permeation than the other EMs. Instead, skin retention of CLOT was dependent on the content of terpenes in the EMs, viscosity of the mixtures, and to some extent the drug solubility, rather than a particular ratio between them.