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

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.

A Novel Berberine–Glycyrrhizic Acid Complex Formulation Enhanced the Prevention Effect to Doxorubicin-Induced Cardiotoxicity by Pharmacokinetic Modulation of Berberine in Rats

“…Many researchers has used PEG (Sujitha et al, 2020), liposome (Allijn et al, 2017), TCM extracts (Zhao et al, 2021), cremochylomicrons (Elsheikh et al, 2018), and pluronic P85 and tween 80 (Kwon et al, 2020) to improve the solubility and bioavailability of BBR. However, there is not enough evidence to prove these ingredients or extract meet the requirements of safety and stability.…”

Strategies and Mechanism in Reversing Intestinal Drug Efflux in Oral Drug Delivery

“…In Caco-2 monolayer and MRP2-MDCK/BCRP-MDCK monolayer, MRP2/BCPR inhibitors significantly decreased the efflux ratio of Silybin, which indicated that Silybin was the substrate of MRP2 and BCRP pumps [38]. Compared to free berberine hydrochloride (BBH, a P-gp substrate), the efflux ratio of BBH for the mixture of BBH and natural nanoparticles decreased from 25.8 to 17.1 in MDR1-MDCK monolayer, indicating that the nanoparticles could inhibit P-gp activity [60]. In addition, the application of MDCK monolayer to explore excipients of inhibiting efflux transporters activity is also advisable.…”

“…Finally, everted gut sac containing drugs solution is incubated at 37 • C in a 20 mL Krebs-Ringer buffer. The everted gut sac method was used to research the efflux of BBR-loaded natural nanoparticles (Nnps-BBR) and free BBR, and results showed the efflux of BBR significantly decreased for Nnps-BBR due to Nnps inhibiting P-gp activity [60]. According to the everted gut sac method, the efflux ratio of Red Globe Grape, Raspbeery and Blackberry was accurately measured to be 1.55, 0.98 and 1.38, respectively [62].…”

Injectable in situ intelligent thermo-responsive hydrogel with glycyrrhetinic acid-conjugated nano graphene oxide for chemo-photothermal therapy of malignant hepatocellular tumor

“…32,33 However, BH suffers from solid state instability, low aqueous solubility, and dissolution rate resulting in poor bioavailability, which limit its potential application in clinic. 34,35 To sum up, GA as target ligand was covalently conjugated to the surface of NGO, and BH as model drug was loaded into the GA-modified NGO, which were further dispersed into poloxamer 188 and poloxamer 407 solution to form an injectable in situ thermo-sensitive hydrogel (GA-BH-NGO-gel) shown in Figure 1. The physicochemical properties and anti-tumor activity of GA-BH-NGO-gel were studied.…”

“…32,33 However, BH suffers from solid state instability, low aqueous solubility, and dissolution rate resulting in poor bioavailability, which limit its potential application in clinic. 34,35…”