自微乳化药物递送系统（SMEDDS）在索拉非尼与姜黄素联合给药中的开发与优化

Development and optimization of a self micro-emulsifying drug delivery system (SMEDDS) for co-administration of sorafenib and curcumin

Drug Delivery and Translational Research

影响因子:5.5

分区:医学3区 / 医学：研究与实验3区药学3区

发表日期:2025 May

作者: Xingzhen Huang, Lizhen Feng, Xuefang Lu, Fan Yang, Shengjun Liu, Xueqian Wei, Jinping Huang, Yao Wang, Dongyi Huang, Tingting Huang

DOI: 10.1007/s13346-024-01699-3

摘要

本研究开发了一种新型的姜黄素与索拉非尼联合给药系统，采用自微乳化药物递送系统（SMEDDS），命名为索拉非尼-姜黄素自微乳化药物递送系统（SOR-CUR-SMEDDS）。通过星点设计-响应面法对配方进行了优化，并进行了体外细胞实验以评估姜黄素与索拉非尼组合的递送比例及抗肿瘤效果。结果显示，SOR-CUR-SMEDDS具有粒径分布小（13.48 ± 0.61 nm）、多分散性指数（PDI）低（0.228 ± 0.05）及负的Zeta电位（-12.4 mV）。SOR-CUR-SMEDDS对HepG2细胞（人肝细胞癌细胞）的半数抑制浓度（IC50）比单独药物低3倍（姜黄素）和5倍（索拉非尼）。透射电子显微镜（TEM）和粒径检测确认，该微乳滴为均匀的圆形，粒径范围在10-20 nm内。对SMEDDS的药物释放进行体外透析膜研究，发现姜黄素在联合递送系统中释放更完全，7天内在培养基中的体外最大释放率为79.20%，而索拉非尼的累积释放率较低，达到58.96%。体外药代动力学研究表明，SMEDDS显著提高索拉非尼（1239.88倍）及姜黄素（3.64倍）的口服生物利用度。上述结果表明，SMEDDS配方能够极大改善药物的溶解度，增强药物吸收，延长体内循环时间，从而提高索拉非尼和姜黄素的口服生物利用度。

Abstract

In this study, we developed a novel co-administration of curcumin and sorafenib using a Self micro-emulsifying Drug Delivery System (SMEDDS) called Sorafenib-Curcumin Self micro-emulsifying Drug Delivery System (SOR-CUR-SMEDDS). The formulation was optimized using star point design-response surface methodology, and in vitro cellular experiments were conducted to evaluate the delivery ratio and anti-tumor efficacy of the curcumin and sorafenib combination. The SOR-CUR-SMEDDS exhibited a small size distribution of 13.48 ± 0.61 nm, low polydispersity index (PDI) of 0.228 ± 0.05, and negative zeta potential (ZP) of - 12.4 mV. The half maximal inhibitory concentration (IC50) of the SOR-CUR-SMEDDS was 3-fold lower for curcumin and 5-fold lower for sorafenib against HepG2 cells (human hepatocellular carcinoma cells). Transmission electron microscopy (TEM) and particle size detection confirmed that the SOR-CUR-SMEDDS droplets were uniformly round and within the nano-emulsion particle size range of 10-20 nm. The SMEDDS were characterized then studied for drug release in vitro via dialysis membranes. Curcumin was released more completely in the combined delivery system, showing the largest in vitro drug release (79.20%) within 7 days in the medium, while the cumulative release rate of sorafenib in the release medium was low, reaching 58.96% on the 7 day. In vitro pharmacokinetic study, it demonstrated a significant increase in oral bioavailability of sorafenib (1239.88-fold) and curcumin (3.64-fold) when administered in the SMEDDS. These findings suggest that the SMEDDS formulation can greatly enhance drug solubility, improve drug absorption and prolong circulation in vivo, leading to increased oral bioavailability of sorafenib and curcumin.