Improving The Oral Absorption Of Nintedanib By A Self-Microemulsion Drug Delivery System: Preparation And In Vitro/In Vivo Evaluation
Received 21 July 2019
Accepted for publication 22 October 2019
Published 6 November 2019 Volume 2019:14 Pages 8739—8751
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Phong A Tran
Hongfei Liu,1 Jiaao Mei,1 Ying Xu,1 Lei Tang,1 Daquan Chen,2 Yating Zhu,1 Shuguang Huang,1 Thomas J Webster,3 Hui Ding4
1College of Pharmacy, Jiangsu University, Zhenjiang 212013, People’s Republic of China; 2School of Pharmacy, Yantai University, Yantai 264005, People’s Republic of China; 3Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA; 4Department of Respiratory and Critical Care Medicine, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, People’s Republic of China
Correspondence: Hui Ding
Department of Respiratory and Critical Care Medicine, The Affiliated Yixing Hospital Of Jiangsu University, Yixing, Jiangsu 214200, People’s Republic of China
Thomas J Webster
Department Of Chemical Engineering, Northeastern University, Boston, MA 02115, USA
, Tel +1 617 373 6585
Objective: Nintedanib (NDNB) is a triple receptor tyrosine kinase inhibitor with poor solubility in neutral conditions and low bioavailability. A self-microemulsifying drug delivery system (SMEDDS) of NDNB was developed to improve drug solubility in physical conditions and absorption in vivo.
Methods: The NDNB-SMEDDS formulation was optimized via pseudo-ternary phase diagrams. The physicochemical properties of NDNB-SMEDDS, viz., morphological observation, droplet size, stability, compatibility and in vitro release were investigated. The permeability of NDNB-SMEDDS was detected using both a Caco-2 cell monolayer in vitro and an intestinal perfusion study in vivo. Furthermore, the pharmacokinetic characteristics of NDNB-SMEDDS were evaluated.
Results: The optimal formulation was composed of MCT as an oil phase, RH 40 as a surfactant and ethylene glycol as a co-surfactant. The average droplet size of the microemulsion was about 23 nm with good stability within 30 days. The formulation did not exhibit any obvious cytotoxic effect on Caco-2 cells. Permeability of nintedanib in a Caco-2 cell monolayer was enhanced by 2.8-fold upon incorporation in SMEDDS compared with the drug solution. The intestinal perfusion study demonstrated that the Papp of NDNB-SMEDDS increased by 3.0-fold in the entire intestine and 3.2-fold in the colon in comparison with the drug solution. The pharmacokinetics study showed that the AUC of the NDNB-SMEDDS increased significantly.
Conclusion: This study showed that the self-microemulsion formulations could improve the absorption of nintedanib, and can thus serve as a promising carrier for the oral delivery of nintedanib.
Keywords: nintedanib, self-microemulsion drug delivery system, solubility, permeability, Caco-2 cell, intestinal perfusion, pharmacokinetics, bioavailability
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]