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Current Pharmaceutical Biotechnology

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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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Research Article

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

Author(s): Jiandong Wang, Shujuan Zhang, Chunli Tan, Qi Wei and Subin Xiong*

Volume 24, Issue 15, 2023

Published on: 12 May, 2023

Page: [1972 - 1982] Pages: 11

DOI: 10.2174/1389201024666230417091625

Price: $65

Abstract

Introduction: 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).

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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