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

• Published in: International journal of nanomedicine 2021-01, Vol.16, p.6297-6311
• Main Authors: Zhao, Jing, Zhao, Qing, Lu, Jing-Ze, Ye, Dan, Mu, Sheng, Yang, Xiao-Di, Zhang, Wei-Dong, Ma, Bing-Liang
• Format: Article
• Language: English
• Subjects: Acids; Analysis; Animals; Berberine; berberine hydrochloride; Bioavailability; Caco-2 Cells; Chinese medicine; Chromatography; Colorectal cancer; Coptis chinensis; Denaturation; Dogs; drug delivery system; Drug delivery systems; Drugs; Drugs, Chinese Herbal; herbal extract; Humans; Intestinal Absorption; Laboratory animals; Mass spectrometry; Medical research; Medicine, Botanic; Medicine, Herbal; Metabolites; Mice; natural nanoparticles; Oral administration; Original Research; Pharmaceuticals; pharmacokinetic synergy; Pharmacokinetics; Proteins; Quantitative analysis; Scientific imaging; Vehicles
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S323685

This study aimed to evaluate the pharmaceutical and pharmacokinetic effects of the natural nanoparticles (Nnps) isolated from extract on berberine hydrochloride (BBR) and systematically explore the related mechanisms. Firstly, Nnps were isolated from 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. 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 , 1182.3 vs 310.2 ng/mL) and exposure level (AUC , 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). The proteinaceous nanoparticles isolated from extract can form a natural nano-drug delivery system with BBR, thereby significantly improving the pharmacokinetics of oral BBR.