A Dual Nanoapproach for the Treatment of Depression and Sleep Via a Novel Optimized Eugenol-Mucoadhesive Nanoemulsion

This study aimed to develop a chitosan (CHS)-coated eugenol (EUGE)-loaded nanoemulsion (CHS-EUGE-NE) to enhance brain bioavailability. A novel GC-MS/MS method was developed and validated for EUGE quantification in brain tissue and plasma alongside pharmacokinetic analysis. The nanoemulsion was optimized using a Box-Behnken design (BBD), with the final formulation containing 6.0% oil, 10% surfactant mix, and undergoing 6.5 min of ultrasonication at 30% intensity and 40 °C. The optimized CHS-EUGE-NE exhibited a globule size of 142.4 ± 11.31 nm, a polydispersity index of 0.1660 ± 0.0009, and a zeta potential of -16.20 ± 1.10 mV, which shifted to positive upon CHS coating, enhancing mucoadhesion. A linear range from 1.00 to 3000 ng/mL was established, with accuracy between 90.91% and 99.83%. Pharmacokinetic analysis demonstrated significantly increased <i>C</i> _max and AUC in the rat brain, correlated with behavioral improvements in the forced swimming test. No signs of toxicity were observed. These findings suggest that CHS-EUGE-NE is a promising nanoformulation for enhancing the brain-targeted delivery of eugenol for the treatment of depression and sleep disorders.