Hong Eon-Pyo, Kim Ju-Young, Kim Su-Hyeon, Hwang Kyu-Mok, Park Chun-Woong, Lee Hyo-Jung, Kim Dong-Wook, Weon Kwon-Yeon, Jeong Seo Young, Park Eun-Seok
College of Pharmacy, Kyung Hee University.
Chem Pharm Bull (Tokyo). 2016;64(8):1108-17. doi: 10.1248/cpb.c16-00035.
The purposes of the present study were to develop a self-microemulsifying drug delivery system (SMEDDS) containing bortezomib, a proteasome inhibitor. The solubility of the drug was evaluated in 15 pharmaceutical excipients. Combinations of oils, surfactants and cosurfactants were screened by drawing pseudo-ternary phase diagrams. The system exhibiting the largest region of microemulsion was considered optimal. Bortezomib SMEDDS spontaneously formed a microemulsion when diluted with an aqueous medium with a median droplet size of approximately 20-30 nm. In vitro release studies showed that the SMEDDS had higher initial release rates for the drug when compared with the raw drug material alone. Measurement of the viscosity, size, and ion conductivity indicated that a phase inversion from water in an oil system to oil in a water system occurred when the weight ratio of the water exceeded 30% of the entire microemulsion system. In a pharmacokinetics study using rats, the bortezomib microemulsion failed to improve the bioavailability of the drug. The reason was assumed to be degradation of the drug in the microemulsion in the gastrointestinal tract. However, bortezomib in Labrasol(®) solution (an aqueous solution containing 0.025% Labrasol(®)) showed significantly increased area under the curve from 0-24 h (AUC0-24 h) and maximum plasma concentration (Cmax) values compared to the drug suspension. The findings of this study imply that oral delivery of a bortezomib and colloidal system containing Labrasol(®) could be an effective strategy for the delivery of bortezomib.
本研究的目的是开发一种含有蛋白酶体抑制剂硼替佐米的自微乳化药物递送系统（SMEDDS）。在15种药用辅料中评估了该药物的溶解度。通过绘制伪三元相图筛选油、表面活性剂和助表面活性剂的组合。微乳液区域最大的系统被认为是最佳的。硼替佐米SMEDDS在用水性介质稀释时自发形成微乳液，中位液滴尺寸约为20 - 30 nm。体外释放研究表明，与原料药相比，SMEDDS对药物具有更高的初始释放速率。粘度、粒径和离子电导率的测量表明，当水的重量比超过整个微乳液系统的30%时，会发生从油包水体系到水包油体系的相转变。在一项使用大鼠的药代动力学研究中，硼替佐米微乳液未能提高该药物的生物利用度。原因推测是药物在胃肠道的微乳液中降解。然而，与药物混悬液相比，Labrasol®溶液（含0.025% Labrasol®的水溶液）中的硼替佐米0 - 24小时曲线下面积（AUC0 - 24 h）和最大血浆浓度（Cmax）值显著增加。本研究结果表明，口服含有Labrasol®的硼替佐米胶体系统可能是硼替佐米递送的有效策略。
