Self-assembled Zanubrutinib-loaded lipid polymer hybrid nanoparticles for enhanced oral absorption by lymphatic uptake: in vitro, ex vivo and in vivo evaluations.

The application of zanubrutinib (ZBR) is limited by poor aqueous solubility (0.0103 mg/ml) and low oral bioavailability (15%) owing to extensive metabolism by CYP3A4 enzyme and P-glycoprotein efflux. Hence, self-assembled lipid-polymer hybrid nanoparticles (LPHNPs) were developed to overcome pitfalls by intestinal lymphatic transport. The ZBR loaded LPHNPs (ZBR-LPHNPs) were prepared by nanoprecipitation method using lipoid P-45, PLGA, and MPEG-2000 DSPE. The ZBR-LPHNPs showed a particle size of 98.17 ± 2.38 nm, a zeta potential of -30.5 ± 2.78 mV, and entrapment efficiency of 82.15 ± 3.70%. The lyophilization of ZBR-LPHNPs was carried out using trehalose at a 1:3 ratio. The DSC and XRD analyses displayed the conversion of ZBR into amorphous form. The particles were spherical, with a core-shell hybrid structure. The ZBR-LPHNPs showed 99.85 ± 2.37% release in phosphate buffer pH 6.8 at 72 h and followed the Higuchi model. The fluorescein isothiocyanate loaded LPHNPs accumulated in intestinal villi and Peyer's patches within 2 h. The bioavailability study revealed 36.11-fold increase in bioavailability with ZBR-LPHNPs as compared to free ZBR. The AUC_total of ZBR-LPHNPs was reduced by 60.37% in cycloheximide treated group of rats, indicating uptake by intestinal lymphatic system. Overall, this study establishes LPHNP-mediated intestinal lymphatic transport as an effective strategy to enhance oral bioavailability of ZBR.