Development of biocompatible lipid-polymer hybrid nanoparticles for enhanced oral absorption of posaconazole: A mechanistic in vitro and in silico assessment

The current research focuses on the development of lipid-polymer hybrid nanoparticles (LPHNs) designed to enhance the solubility and bioavailability of posaconazole (PCZ). PCZ, an antifungal drug, faces challenges due to its poor water solubility, resulting in inconsistent absorption and limited bioavailability. LPHNs composed of stearic acid and poly-δ-decalactone (PDL) were successfully fabricated and characterized. The optimized formulation (P-LPHN4) exhibited a particle size of 104.0 nm, negative zeta potential (−38.9 mV), high drug loading (19.5 %), and efficient encapsulation (82.6 %). In vitro release studies demonstrated sustained drug release over 18 h, with P-LPHN4 displaying the highest drug release (92 %). Stability studies revealed good physical stability over 45 days with no significant changes in particle size, zeta potential, and PDI. In silico simulations using GastroPlus® predicted significantly improved intestinal absorption and systemic exposure for P-LPHN4 compared to the pure drug suspension in a simulated rat model. The model predicted a higher peak plasma concentration (C_max) for P-LPHN4 (∼0.012 μg/mL) compared to the PCZ suspension (∼0.0058 μg/mL). The model identified the duodenum and jejunum as primary absorption sites for both formulations, with P-LPHNs showing significantly higher overall absorption (84.5 %) compared to the suspension (47.5 %). Simulation results revealed a dose-dependent increase in both C_max and AUC with increasing oral P-LPHN4 dose, while T_max remained unaffected. In conclusion, the developed posaconazole-loaded lipid-polymer hybrid nanoparticles (P-LPHN4) showed promising results in terms of enhanced drug release, stability, and bioavailability.