共载姜黄素/小檗碱自微乳给药系统的制备及评价

Preparation and evaluation of curcumin/berberine co-loaded self-microemulsion drug delivery system

目的制备共载姜黄素/小檗碱的自微乳给药系统(CUR/BER-SMEDDS),并对其理化性质和体外抗肿瘤作用进行评价。方法以CUR、BER为模型药物,在筛选油相种类,乳化剂、助乳化剂及二者质量比优化范围的基础上,以粒径和载药量为评价指标,以油相的质量百分比、乳化剂与助乳化剂的质量比为因素,采用星点设计-效应面法优化其处方并验证;对优化所得CUR/BERSMEDDS的理化性质、体外溶出度、体外抗肿瘤作用进行评价。结果CUR/BER-SMEDDS最优处方的油相为中链甘油三酯(30.97%),乳化剂为聚氧乙烯40氢化蓖麻油(46.77%),助乳化剂为聚乙二醇400(22.26%),乳化剂与助乳化剂质量比为2.10∶1。验证实验表明,CUR/BER-SMEDDS的平均粒径为(58.90±5.41)nm,平均载药量为(94.94±3.87)mg/g,与预测值的相对偏差分别为-2.90%、-0.14%。按最优处方所制CUR/BER-SMEDDS加水乳化后为淡黄色澄清透明液体,其微粒呈圆球形。体外溶出实验结果显示,制成SMEDDS后,CUR在人工肠液、人工胃液,BER在人工肠液中的累积溶出度均明显高于对应原料药。体外抗肿瘤实验结果显示,CUR/BER-SMEDDS对PC-3、DU-145细胞的IC_(50)分别为(17.38±2.84)、(20.89±1.26)μmol/L,均显著低于CUR、EBR单药(P<0.05)。结论优化所得CUR/BER-SMEDDS制备工艺稳定、可行;所制CUR/BER-SMEDDS改善了药物的溶出速度,且具有更强的体外抗前列腺癌作用。

OBJECTIVE To prepare curcumin/berberine co-loaded self-microemulsion drug delivery system(CUR/BERSMEDDS)and evaluate its physicochemical properties and in vitro anti-tumor effects.METHODS Using CUR and BER as model drug,based on the screening of the type of oil phase,emulsifier,co emulsifier and their mass ratio,the formulation of CUR/BERSMEDDS were optimized by central composite design-response surface methodology,taking particle size and drug loading as evaluation parameters,with the mass percentage of oil phase and the mass ratio of emulsifier to co emulsifier as factors,and verification test was conducted.CUR/BER-SMEDDS prepared by optimized formulation were evaluated in terms of physicochemical properties,in vitro dissolution and in vitro anti-tumor effects.RESULTS The optimized formulation of CUR/BER-SMEDDS included that the oil phase was medium chain triglyceride(30.97%),the emulsifier was polyoxyl 40 hydrogenated castor oil(46.77%),the co emulsifier was polyethylene glycol 400(22.26%),and the mass ratio of emulsifier to co emulsifier was 2.10∶1.The validation experiments showed that mean particle size of CUR/BER-SMEDDS was(58.90±5.41)nm,the average drug loading was(94.94±3.87)mg/g,and the relative deviations from the predicted values were -2.90% and -0.14%,respectively.The CUR/BER-SMEDDS prepared by optimal formulation was light yellow,clear and transparent liquid after emulsified with water,and its particles were spherical.The results of dissolution test in vitro showed that after SMEDDS was made,the cumulative dissolution of CUR in artificial intestinal fluid and artificial gastric fluid and that of BER in artificial intestinal fluid were significantly higher than those of its raw material.Results of in vitro anti-tumor experiment showed that IC_(50)values of CUR/BER-SMEDDS for PC-3 cells and DU-145 cells were(17.38±2.84)and(20.89±1.26)μmol/L,which were all lower than those of CUR and EBR significantly(P<0.05).CONCLUSIONS The optimized preparation process of CUR/BER-SMEDDS is stable and feasible.The drug release of CUR/BER-SMEDDS is more complete than that of single drug,and has stronger anti-prostate cancer effect in vitro.