Formulation Development, Optimization, and Characterization of Entrectinib-Loaded Supersaturable Self-Nanoemulsifying Drug Delivery Systems

Entrectinib is a novel potent anticancer drug with poor aqueous solubility. A supersaturable self-nanoemulsifying drug delivery system of entrectinib is developed using a super saturation promoter. The components of the isotropic mixture of SNEDDS were selected based on solubility and emulsification study. The optimum composition was identified using phase diagrams and further optimized by mixture design. The supersaturated SNEDDS was prepared using HPMC K4M as precipitation inhibitor. The droplet of sSNEDDS ranges from 118.42 ± 1.26 to 128.34 ± 0.63 nm with PDI values range from 0.112 to 0.204, which is significantly smaller than that observed with plain SNEDDS. The percent transmittance of the diluted formulation was found to be 98.78 ± 0.74. The viscosity was found to be 528 ± 32 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug.

The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. The drug release rate is directly proportional to the concentration of the drug. The drug release from the insoluble matrix is a square root of time-dependent Fickian diffusion process. The formulation was found to be stable and transparent at all pH values and the percent transmittance was more than 95%. No significant difference was observed with all the samples exposed at different storage conditions. This study demonstrated the feasibility of stabilizing and improving the in vitro performance of SNEDDS by incorporating HPMC K4M as precipitation inhibitor.