Rational design of a stable W/O lipid emulsion for enhanced oral delivery of vinblastine

The transition from intravenous to oral administration of vinblastine sulfate (VLB) poses a major clinical challenge, primarily due to its extremely low and variable oral bioavailability. To address these inherent limitations, we rationally designed a stable water-in-oil (W/O) lipid emulsion (VLB-LE) through systematic interfacial engineering. A comprehensive screening and optimization process identified coconut oil, with its superior emulsification region in pseudo-ternary phase diagrams, as the optimal oil phase and cholesterol as the most effective permeation enhancer. The formulation was precisely optimized via Response Surface Methodology, yielding an emulsion with a small, uniform droplet size (0.61 ± 0.06 μm), a high negative zeta potential (-64.8 ± 10.8 mV), and an encapsulation efficiency of 96.42%. The W/O structure conferred exceptional stability, significantly protecting VLB against chemical and biorelevant degradation. Furthermore, it provided a sustained, pH-independent release profile and markedly enhanced intestinal permeation ex vivo. In vivo pharmacokinetic studies in rats demonstrated a remarkable 7.26-fold improvement in oral bioavailability compared to the control solution, achieving a relative bioavailability of 49.9%. The enhanced absorption directly translated to superior therapeutic outcomes, with VLB-LE exhibiting a 6.0-fold increase in cytotoxic potency and promoting apoptotic in HepG2 cells, correlated with effective cellular uptake. This study validates the rationally designed W/O emulsion as a robust and promising colloidal platform for the oral delivery of VLB, effectively integrating interfacial stabilization, enhanced permeation, and protective encapsulation to overcome the key biopharmaceutical challenges associated with oral chemotherapy.