Rod-shaped nintedanib nanocrystals improved oral bioavailability through multiple intestinal absorption pathways

Yunjing Zhu; Yu Fu; Anan Zhang; Xiaolin Wang; Zhiqing Zhao; Yu Zhang; Tian Yin; Jingxin Gou; Yanjiao Wang; Haibing He; Xing Tang

doi:10.1016/j.ejps.2021.106047

Rod-shaped nintedanib nanocrystals improved oral bioavailability through multiple intestinal absorption pathways

Eur J Pharm Sci. 2022 Jan 1:168:106047. doi: 10.1016/j.ejps.2021.106047. Epub 2021 Oct 20.

Authors

Yunjing Zhu¹, Yu Fu², Anan Zhang¹, Xiaolin Wang², Zhiqing Zhao², Yu Zhang², Tian Yin³, Jingxin Gou², Yanjiao Wang², Haibing He⁴, Xing Tang²

Affiliations

¹ Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, China; Luye Pharmaceutical Group, Yantai,China.
² Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, China.
³ School of Functional food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁴ Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, China; Jiangsu Haizhihong Biomedical Co., LtdB, Nantong, China. Electronic address: hhb_emily@126.com.

PMID: 34687899
DOI: 10.1016/j.ejps.2021.106047

Abstract

Nintedanib (BIBF) is a biopharmaceutical classification system II (BCS II) drug that has a good therapeutic effect for the treatment of nonsmall cell lung cancer; however, it shows poor oral bioavailability due to low dissolution and intestinal absorption. This study aims to fabricate rod-shaped nanocrystals to enhance oral bioavailability by improving the dissolution and absorption of BIBF in the intestine. By prescription screening, BIBF nanocrystals (BIBF-NCs) with a particle size of 325.30 ± 1.03 nm and zeta potential of 32.70 ± 1.24 mV were fabricated by an antisolvent precipitation-ultrasound approach with a stabilizer of sodium carboxyl methyl cellulose (CMC-Na). BIBF-NCs exhibited a rod-shaped morphology by transmission electron microscopy (TEM). The results of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) showed that the crystal form of BIBF in BIBF-NCs was altered. The BIBF-NCs remarkably improved the saturation solubility and dissolution of BIBF compared with BIBF powder. According to the results of in situ single-pass intestinal perfusion (SPIP), BIBF-NCs showed improved absorption and membrane permeability, with K_a and P_app values in the jejunum of 0.21 ± 0.01 min^-1 and (4.34 ± 0.11) × 10^-4 cm/min, respectively. Further, the K_a and P_app values of BIBF-NCs were all reduced significantly after the addition of inhibitors colchicine, chlorpromazine and indomethacin, which demonstrated that BIBF-NCs could be absorbed by endocytosis mediated by caveolae and clathrin and micropinocytosis in the intestine. The cell evaluation results showed that BIBF-NCs could be taken up by macrophages and transported from Caco-2 monolayers. The in vivo pharmacokinetic results showed that the bioavailability of the BIBF-NCs was 2.51-fold higher than that of the BIBF solution (BIBF-Sol) after oral administration with a longer T_max (4.50 ± 1.00 h vs. 2.60 ± 1.92 h). In summary, rod-shaped BIBF-NCs could significantly improve oral bioavailability through multiple intestinal absorption pathways.

Keywords: Intestinal absorption; Nanocrystal; Nintedanib; Oral bioavailability; Rod-Shape.

MeSH terms

Administration, Oral
Biological Availability
Caco-2 Cells
Carcinoma, Non-Small-Cell Lung*
Humans
Indoles
Intestinal Absorption
Lung Neoplasms*
Nanoparticles*
Particle Size
Solubility

Substances

Indoles
nintedanib