International Journal of Nanomedicine (Jun 2018)
Dual-functional Brij-S20-modified nanocrystal formulation enhances the intestinal transport and oral bioavailability of berberine
Abstract
Wei Xiong,1 Wei Sang,1 Ke Gang Linghu,1 Zhang Feng Zhong,1 Wai San Cheang,1 Juan Li,2 Yuan Jia Hu,1 Hua Yu,1,3,4 Yi Tao Wang1 1Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao SAR, China; 2Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu, China; 3Hong Kong Baptist University Shenzhen Research Center, Shenzhen, Guangdong, China; 4School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China Introduction: Berberine (BBR) is a plant-derived benzylisoquinoline alkaloid and has been demonstrated to be a potential treatment for various chronic diseases. The poor water solubility and P-glycoprotein (Pgp)-mediated drug efflux are the main challenges for its further application in a clinical setting. Materials and methods: In this study, a Brij-S20 (BS20)-modified nanocrystal formulation (BBR-BS20-NCs) has been developed and investigated with the purpose of improving the intestinal absorption of BBR. The physicochemical properties of the developed BBR-BS20-NCs were characterized and the enhancement of the BBR-BS20-NCs on BBR absorption were investigated both in vitro and in vivo. Results: The results indicated that BS20 could significantly enhance the intracellular uptake of BBR in MDCK-MDR1 cells via a short-term and reversible modulation on the Pgp function, accompanied by a marked increase in Pgp mRNA expression but without significant influence on the Pgp protein expression. Moreover, the morphology of the prepared BBR-BS20-NCs was observed to be prism-like, with a smooth surface and an average diameter of 148.0 ± 3.2 nm. Compared to raw BBR and physical mixture, BBR-BS20-NCs facilitated the dissolution rate and extent of release of BBR in aqueous solution, and further increased the absorption of BBR in MDCK-MDR1 monolayer by overcoming the Pgp-mediated secretory transport (Papp[BL-AP] values of 2.85 ± 0.04 × 10-6 cm/s, 2.21 ± 0.14 × 10-6 cm/s, and 2.00 ± 0.07 × 10-6 cm/s for pure BBR, physical mixture, and BBR-BS20-NCs, respectively). Significant improvements in the maximum concentration observed (Cmax) and area under drug concentration-time curve (AUC0–t) of BBR-BS20-NCs were obtained in pharmacokinetic studies compared to pure BBR, and the relative bioavailability of BBR-BS20-NCs to pure BBR was 404.1%. Conclusion: The developed BBR-BS20-NCs combine the advantages of nanocrystal formulation and functional excipient. The novel pharmaceutical design provides a new strategy to improve the oral bioavailability of those drugs with both poor water solubility and Pgp-mediated efflux. Keywords: berberine, poor water solubility, Pgp-mediated drug efflux, Brij, nanocrystals
