Optimizing Entrectinib Nanosuspension: Quality by Design for Enhanced Oral Bioavailability and Minimized Fast-Fed Variability

The objective of this study was to decrease fast-fed variability, increase oral bioavailability, and enhance the solubility of entrectinib (ENT), a BCS class II drug. We developed the ENT formulation's nanosuspension (NS) utilizing the sonoprecipitation-ultrasonication technique. A three-factor, three-level Box-Behnken design (BBD) was utilized to optimize the formulation with poloxamer 188 as a stabilizing agent. The sizes of the formulations ranged from 83.2 to 258.2 nm, with corresponding polydispersity indices (PdI) ranging from 0.055 to 0.258. Using scanning electron microscopy (SEM), distinct spherical nanoparticles were seen. The drug was highly compatible with the stabilizing agent as verified by differential scanning calorimetry (DSC) and Fourier-Transform Infrared Spectroscopy (FTIR). Stability experiments revealed that the formulation exhibits rapid stability. When compared to the standard drug (plain drug), ENT-NS showed a 19.38-fold improvement in solubility. Improved solubility at intestinal pH was shown by the formulation, which helped to lower precipitation and boost absorption in the intestinal area. Compared to pure drug, the nanosuspension exhibited increased Cmax (3.59-fold and 3.51-fold) and AUC0-t (2.39-fold and 2.23-fold) in the fed and fasting phases, respectively. Significant pharmacokinetic differences were observed between the fed and fasted states during in vivo investigations using the drug suspension. The formulation displayed no significant difference in the pharmacokinetics in fasting and fed states. These encouraging findings demonstrate the potential of nanosuspension as a strategy for improving solubility and absorption and reducing fast-fed variability.