Simultaneously Inhibiting P-gp Efflux and Drug Recrystallization Enhanced the Oral Bioavailability of Nintedanib.

Abstract

Nintedanib (NDNB) is a novel triple-angiokinase inhibitor for the treatment of lung cancer. However, the oral bioavailability of NDNB is only 4.7% owing to the poor solubility and the efflux of P-glycoprotein (P-gp). The aim was to explore the potential applications of a hydrogel of NDNB/hydroxypropyl-β- cyclodextrin (HP-β-CD) complex combined with a strong P-gp inhibitor Itraconazole (ITZ) for augmenting the oral delivery of NDNB. The NDNB/HP-β-CD complex was prepared and characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and molecular simulation and was subjected to in vitro and in situ studies. Then the NDNB/HP-β-CD complex was dispersed in carbopol 934 hydrogel and the gel was evaluated for pharmacokinetic and pharmacodynamics studies. The HP-β-CD and NDNB formed complex by van der Waals and hydrogen bonding interaction forces by XRD, FT-IR, and molecular simulation studies. When the molar ratio of NDNB/HP-β-CD was 1:20, the complex exhibited high drug inclusion efficiency and excellent stability. The in situ perfusion results revealed that the permeability of the combination of complex and ITZ enhanced about 3.0-fold compared with the NDNB solution. The oral bioavailability of the sequential administration of ITZ and NDNB/HP-β-CD complex gels was increased 3.5-fold by preventing recrystallization, extending the residence time in the gastrointestinal tract, and inhibiting P-gp in comparison with NDNB soft capsules. The co-therapy with NDNB/HP-β-CD complex gels and ITZ exerted a strong anti-tumor effect. In conclusion, NDNB/HP-β-CD complex gels combined with P-gp inhibitor were a potential strategy for enhancing the oral bioavailability and anti-tumor effect of NDNB.