Natural Nano-Drug Delivery System in Coptidis Rhizoma Extract with Modified Berberine Hydrochloride Pharmacokinetics

Jing Zhao; Qing Zhao; Jing-Ze Lu; Dan Ye; Sheng Mu; Xiao-Di Yang; Wei-Dong Zhang; Bing-Liang Ma

doi:10.2147/IJN.S323685

Natural Nano-Drug Delivery System in Coptidis Rhizoma Extract with Modified Berberine Hydrochloride Pharmacokinetics

Int J Nanomedicine. 2021 Sep 14:16:6297-6311. doi: 10.2147/IJN.S323685. eCollection 2021.

Authors

Jing Zhao^#¹, Qing Zhao^#¹, Jing-Ze Lu¹, Dan Ye¹, Sheng Mu¹, Xiao-Di Yang², Wei-Dong Zhang^{3

4}, Bing-Liang Ma¹

Affiliations

¹ Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.
² Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.
³ Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.
⁴ School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: This study aimed to evaluate the pharmaceutical and pharmacokinetic effects of the natural nanoparticles (Nnps) isolated from Coptidis Rhizoma extract on berberine hydrochloride (BBR) and systematically explore the related mechanisms.

Methods: Firstly, Nnps were isolated from Coptidis Rhizoma extract and then an Nnps-BBR complex was prepared. After qualitative and quantitative analysis in terms of size, Zeta potential, morphology, and composition of the Nnps and the Nnps-BBR complex, the effects of the Nnps on the crystallization of BBR were characterized. The effects of the Nnps on the solubility and dissolution of BBR were then evaluated. In addition, the effects of the Nnps on BBR in terms of cellular uptake, transmembrane transport, metabolic stability, and pharmacokinetics in mice were studied.

Results: The Nnps had an average size of 166.6 ± 1.3 nm and Zeta potential of -12.5 ± 0.2 mV. The Nnps were formed by denaturation of co-existing plant proteins with molecular weight < 30 kDa. The Nnps adsorbed or dispersed BBR, thereby promoting BBR transformation from crystal to amorphous form and improving its solubility and dissolution. The Nnps carried and promoted BBR uptake by human colonic adenocarcinoma (Caco-2) cells via caveolae-mediated endocytosis, reducing P-gp-mediated efflux of BBR in mice gut sacs and Madin-Darby canine kidney cells stably expressing the transporter P-gp (MDCK-MDR1) cells. Moreover, the Nnps improved BBR metabolic stability in mouse intestinal S9, promoting BBR intestinal absorption in mice, as shown by increased peak BBR concentration (C_max, 1182.3 vs 310.2 ng/mL) and exposure level (AUC_{0-12 h}, 2842.8 vs 1447.0 ng·h/mL) in mouse portal vein. In addition, the Nnps increased BBR exposure level in mouse livers (95,443.2 vs 43,586.2 ng·h/g liver).

Conclusion: The proteinaceous nanoparticles isolated from Coptidis Rhizoma extract can form a natural nano-drug delivery system with BBR, thereby significantly improving the pharmacokinetics of oral BBR.

Keywords: berberine hydrochloride; drug delivery system; herbal extract; natural nanoparticles; pharmacokinetic synergy.

MeSH terms

Animals
Berberine*
Caco-2 Cells
Coptis chinensis
Dogs
Drugs, Chinese Herbal*
Humans
Intestinal Absorption
Mice

Substances

Drugs, Chinese Herbal
Berberine
Coptidis rhizoma extract

Grants and funding

This work was financially supported by Natural Science Foundation of Shanghai (17ZR1430400).