Enhanced in vitro permeability of curcuminoids and ar-turmerone using microemulsions of menthol-based hydrophobic deep eutectic solvents.

Curcumin has considerable therapeutic potential; however, its poor solubility and permeability limit its clinical applications. We evaluated menthol-based hydrophobic deep eutectic solvents (HDES) as oil phases in microemulsions to address these challenges. HDES were formulated by combining l-menthol with acids (lactic, decanoic, dodecanoic, and oleic acids) and incorporating them into microemulsions using surfactant mixtures of Cremophor RH40 (CrRH40) and diethylene glycol monoethyl ether or CrRH40 and Labrasol, with a 3 : 7 oil-to-surfactant ratio. Oleic acid, coconut oil, and medium chain triglyceride were used as the conventional oil phase. Physical properties, curcumin solubility in microemulsion, and their effects on in vitro permeability using synthetic membranes were assessed. Although oleic acid-based microemulsions (CLO) demonstrated higher curcumin solubility (54.5 mg mL-1) than HDES-based microemulsions (14.6-24.0 mg mL-1), curcumin permeation in oleic acid-based microemulsions was modest. In contrast, optimized HDES systems, particularly CL2MDO (menthol : dodecanoic acid, 2 : 1, as oil phase), achieved 116 µg cm-2 cumulative curcumin permeation over 12 h, significantly surpassing conventional formulations (CLO, achieving 20.0 µg cm-2 curcumin permeation) (p < 0.05). In oleic acid-menthol (HDES)-based formulations, increasing the menthol-to-oleic acid proportion enhanced permeation. CL2MO (menthol : oleic acid, 2 : 1) achieved 64.5 µg cm-2 cumulative curcumin permeation at 12 h, compared to 40.0 µg cm-2 in CLMO (menthol : oleic acid, 1 : 1) and lower at 37.2 µg cm-2 in CLM2O (menthol : oleic acid, 1 : 2). Enhanced permeability was correlated with a 2 : 1 menthol-to-acid ratio using CrRH40 and Labrasol as surfactant mixtures. The menthol-to-acid ratio critically influenced permeation efficiency. The combination of HDES with microemulsion technology provides a strategy for the transdermal delivery of hydrophobic compounds, outperforming conventional oils in permeation.