Investigation of Controlled Release Molecular Mechanism of Oil Phase in Spilanthol Emulsion: Development and In Vitro, In Vivo Characterization

The aim of the present study was to develop a spilanthol emulsion and investigate the effect of oil and drug physicochemical properties on drug release and skin retention at molecular level. Formulation factors including oil, emulsifier, and humectant were investigated by in vitro skin retention/permeation study and the optimized formulation was evaluated in vitro and in vivo. In addition, the controlled release effect of oil was characterized using drug emulsion distribution study, drug release study, FT-IR, and molecular modeling. The optimized emulsion (squalane as oil phase) obtained the maximum skin retention (118.71 ± 10.30 μg/g), which significantly restored skin hydroxyproline content (23.99 ± 2.21 μg/g), compared with the positive group (14.75 ± 1.84 μg/g) and the negative group (15.55 ± 2.03 μg/g). It was caused by high drug release of squalene and good drug–skin miscibility. FT-IR and molecular modeling showed that spilanthol (SPI) interacted with squalene through Van der Waals force, which was weaker than a hydrogen bond formed with other oils, thus exhibited good drug release properties. And the released drug was stored in the skin due to good drug–skin miscibility, which was proved by miscibility calculation and molecular modeling. In conclusion, an effective emulsion was developed and the controlled release effect of oil phase was proved through drug–excipient interaction.