Nanoemulsion-based delivery system for enhanced oral bioavailability and Caco-2 cell monolayers permeability of berberine hydrochloride

Abstract

Berberine hydrochloride (BBH) has a variety of pharmacological activities such as antitumor, antimicrobial, anti-inflammation, and reduce irritable bowel syndrome. However, poor stability and low oral bioavailability limited its usage. Herein, an oil-in-water nanoemulsion system of BBH was developed to improve its stability and oral bioavailability. The pseudoternary phase diagrams were constructed for the determination of composition of various nanoemulsions. The nanoemulsions of BBH composed of Labrafil M 1944 CS (oil phase), RH-40 (surfactant), glycerin (co-surfactant), and water (aqueous phase). The O/W nanoemulsion of BBH showed a relative bioavailability of 440.40% compared with unencapsulated BBH and was stable in our 6-month stability study. Further, there was a significant increase in intestinal permeability of BBH as assessed by Caco-2 cell monolayers and a significant reduction in efflux of BBH by the multidrug efflux pump P-glycoprotein. This study confirmed that the nanoemulsion formulation could be used as an alternative oral formulation of BBH to improve its stability, oral bioavailability and permeability.ARTICLE HISTORY

The Quest to Enhance the Efficacy of Berberine for Type-2 Diabetes and Associated Diseases: Physicochemical Modification Approaches

“…In cellular models using HepG2 cells, targeting proprotein convertase subtilisin/kexin type 9 (PCSK-9) by this nanoparticle preparation to lower low-density lipoprotein cholesterol (LDL-C) has been presented. Nanoemulsion-based delivery systems with a significant increase in intestinal permeability as assessed by Caco-2 cell monolayers and a significant reduction in efflux have also been shown by Li et al [46]. The study by Xie et al [47] further showed that berberine nanoparticles were effective in ameliorating ischemia-reperfusion injury in renal tubular epithelial cells.…”

Self-nanoemulsifying system improves oral absorption and enhances anti-acute myeloid leukemia activity of berberine

“…The efflux ratio of BBR SNE was 2.47 ± 0.47, suggesting the presence of an efflux transporter. In addition, the apparent permeability coefficient (Papp) values of BBR from A-to-B transport and from B-to-A efflux were summarized [ 27 ]. The permeability coefficients of BBR and BBR SNE with verapamil, a P-glycoprotein inhibitor, were significantly lower than with BBR, which indicated that BBR SNE reduced BBR efflux in Caco-2 cell monolayers, and the drug was probably effluxed by P-glycoprotein.…”

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“…The previously reported reasons for poor membrane permeability, low bioavailability and poor stability of berberine were, low apparent oilwater partition coefficient (IgPapp = ˗ 1.08), presence of hydrophobic properties like two methoxy groups and a quaternary ammonium cation in its structure that shows high affinity to the multidrug efflux pump P-gp in gastrointestinal system. Berberine was reported to be a substrate of P-gp efflux pump 23,24 . In caco-2 cell line study, it was reported that, when synthetic P-gp inhibitors like cyclosporine and verapamil were coadministered with berberine, there was marked enhancement in the absorption of berberine, 18 indicating involvement of P-gp pump in the efflux of berberine into the intestinal lumen, leading to poor absorption and thus low bioavailability 24 .…”