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

An esculin-phospholipid complex-based self-nanoemulsifying drug delivery system (EPC-SNEDDS) was successfully developed and optimized. • As The first reported oral nanoformulation for ESC, EPC-SNEDDS significantly improved its oral bioavailability. • The mechanisms by which EPC-SNEDDS improved the oral absorption of ESC were elucidated, including improved stability, enhanced intestinal permeability, and promoted lymphatic absorption. • Oral administration of EPC-SNEDDS normalized serum uric acid (UA) levels in hyperuricemic mice and concurrently exhibited favorable renal protective effects. • Orally administered EPC-SNEDDS not only significantly inhibited UA production, but also potently promoted its excretion. 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. Download: Download high-res image (244KB) Download: Download full-size image