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Improving The Oral Absorption Of Nintedanib By A Self-Microemulsion Drug Delivery System: Preparation And In Vitro/In Vivo Evaluation

Authors Liu H, Mei J, Xu Y, Tang L, Chen D, Zhu Y, Huang S, Webster TJ, Ding H

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
Tel +8601370656506
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

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