Quality by design-based development of ibrutinib polymer-lipid hybrid nanoparticles for enhanced lymphatic absorption...

Ibrutinib (IBR) is an active Bruton's tyrosine kinase inhibitor used for the treatment of Chronic Lymphocytic Leukemia (CLL). However, its therapeutic efficacy is constrained by poor aqueous solubility and less than 3% oral bioavailability due to extensive first-pass metabolism. This study aims to develop and optimize IBR-loaded polymer-lipid hybrid nanoparticles (IBR-PLHNs) to enhance oral bioavailability by improving pharmacokinetic and intestinal lymphatic uptake profile. IBR-PLHNs were formulated by nanoprecipitation-emulsification using PLGA and soy lecithin, based on Central Composite Design. In vitro release studies were conducted in simulated GI fluids and K562 leukemia cells were used to investigate cellular uptake and cytotoxicity. Ex vivo intestinal permeation and mucoadhesion were also investigated. In vivo pharmacokinetics were compared between IBR-PLHNs, and free IBR and lymphatic uptake was investigated indirectly using cycloheximide blockade. Optimized IBR-PLHNs showed better particle size (252.757 ± 0.4 nm), PDI (0.229 ± 0.01), zeta potential (-35.6 ± 1.8 mV), and encapsulation (95.1 ± 2.01%.). TEM analysis revealed spherical, monodisperse nanoparticles. Ex vivo studies demonstrated 5-fold increased intestinal permeability and 10-fold increased mucin binding, suggesting strong mucoadhesion. Cellular uptake increased by 2.4-fold compared to free drug and IC50 reduced by 2.58-fold. IBR-PLHNs showed 31-fold increased C max and 874% relative bioavailability compared to free IBR, with increased half-life and reduced clearance. Cycloheximide reduced systemic exposure by 131.6-fold, suggesting a predominant role of intestinal lymphatic transport. IBR-PLHNs significantly improved the oral bioavailability, lymphatic transport and anticancer efficacy of IBR, thus proving their potential as a promising oral nanocarrier system to overcome its biopharmaceutical limitations.