A self-nanoemulsifying drug delivery system loaded with esculin-phospholipid complex to improve oral absorption and anti-hyperuricemic efficacy of esculin

Hyperuricemia (HUA) is the second most prevalent metabolic disease with unmet clinical needs persisting in its pharmacotherapy. Esculin (ESC) is an active coumarin with anti-hyperuricemic effects. However, its poor solubility, low membrane permeability, and significant first-pass effect limit its oral absorption and application. Self-nanoemulsifying drug delivery system (SNEDDS) has attracted extensive attention as a versatile platform to improve the oral bioavailability of poorly soluble and low-permeability drugs. Herein, an ESC-phospholipid complex (EPC) was prepared to enhance the lipophilicity of ESC and consequently its compatibility with SNEDDS. Subsequently, an EPC-loaded SNEDDS (EPC-SNEDDS) was developed for the oral delivery of ESC. Its composition was screened via pseudo-ternary phase diagrams and further optimized via a Box-Behnken design. The optimal formulation consisted of Lauroglycol 90, Tween 80, and Transcutol P (21.6:41.4:37.2, w/w/w). After aqueous dispersion, EPC-SNEDDS rapidly formed nanoemulsions with a small droplet size (27.78 ± 0.71 nm), narrow particle size distribution (PDI = 0.149 ± 0.007), and high stability. Moreover, the formulation increased the oral bioavailability of ESC by 2.88-fold, which could be ascribed to improved stability, membrane permeability and lymphatic transport. In hyperuricemic mice, oral EPC-SNEDDS effectively suppressed serum and hepatic xanthine oxidase activity and promoted uric acid excretion, exhibiting superior urate-lowering efficacy compared with free ESC and EPC. Collectively, the integration of phospholipid complexes with SNEDDS provides a feasible strategy for efficient oral administration of ESC, and EPC-SNEDDS represents a promising therapeutic approach for HUA treatment.