Oral Administration of Neratinib Maleate-Loaded Lipid-Polymer Hybrid Nanoparticles: Optimization, Physical Characterization, and In Vivo Evaluation.

Abstract

Background: Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. Current oral therapy of NM suffers from low and variable bioavailability due to the solubility and permeability-related issues of the drug. To overcome the low oral bioavailability, the drug is recommended to be administered at high doses, causing severe gastrointestinal side effects leading to discontinuation of the drug therapy. Methods: In this work, NM-loaded lipid-polymer hybrid nanoparticles (NM-LPNs) were designed and optimized to improve the oral bioavailability of the drug. A systematic approach involving a screening design followed by an optimization design based on the principles of design of experiments (DoE) was used to prepare NM-LPNs. Minimum particle size (PS) ranging between 200 and 300 nm and maximum drug loading (DL (%)) were set as the target physicochemical properties. The optimized NM-LPNs, with a mean PS of 278.57 ± 21.16 nm and a DL (%) of 25.77 ± 1.11%, were further characterized for physicochemical properties, thermal and diffractometric analysis, stability, in vitro drug release, and oral pharmacokinetic studies. Results: The nanoparticles exhibited a burst release followed by a prolonged release up to 12 h in the in vitro drug release studies in pH 6.8 media. Conclusions: The mean C_max and the AUC_last values were found to increase significantly for NM-LPNs by 1.72 times (p < 0.01) and 1.58 times (p < 0.01), respectively, when compared to plain NM in the oral pharmacokinetic studies. The optimized NM-LPN formulation can reduce the oral dose of NM and, thereby, its dose-dependent side effects.