甘草次酸衍生物受体靶向复方脂质体的制备及其体外释放研究

Preparation and in Vitro Release of Glycyrrhetinic Acid-tanshinone ⅡA-salvianolic acid B Compound Liposomes with Glycyrrhetinic Acid Derivative as Targeting Molecule

目的:合成两亲性导向分子甘草次酸衍生物3-琥珀酸-30-硬脂醇甘草次酸酯(18-GA-Suc),研究其掺入甘草次酸—丹参酮ⅡA—丹酚酸B复方脂质体(GTS-Lip)的制备工艺,并考察其体外释放规律。方法:采用1HNMR和13CNMR表征18-GA-Suc的结构,通过单因素考察确定18-GA-Suc的投料量,低速离心法测定其掺入比率,比较修饰前后复方脂质体的理化性质,以平衡透析法考察甘草次酸衍生物受体靶向的甘草次酸—丹参酮ⅡA—丹酚酸B复方脂质体(Suc-GTS-Lip)中3种成分的体外释放规律。结果:优化的处方工艺为:18-GA-Suc投料量为膜材的10%(mol·mol-1),掺入比率为96.58%。Suc-GTS-Lip形态圆整,分布均匀,其中甘草次酸(GA)、丹参酮ⅡA(TSN)和丹酚酸B(Sal B)的平均包封率分别为86.15%,81.70%,91.05%,平均粒径为128.7 nm,平均Zeta电位为-15.5m V。GA和TSN体外释放规律符合Higuchi方程,Sal B体外释放规律符合Hixon-crowell方程。结论:甘草次酸衍生物(18-GA-Suc)能在脂质体膜上成功表达,本脂质体制备工艺稳定,GA、TSN和Sal B 3种成分在体外均具有一定的缓释作用,为进一步研究其肝靶向性奠定了基础。

This article was aimed to study the preparation process of glycyrrhetinic acid（GA）-tanshinone IIA（TSN）-salvianolic acid B（Sal B） compound liposomes with 3-succinic-30-stearyl glycyrrhetinic acid（18-GA-Suc） which is one of amphiphilicglycyrrhetinic acid derivatives as targeting molecule. The structure of the targeting molecule was validated by ^1H-NMR and ^13C-NMR methods. The feed ratio of 18-GA-Suc was optimized through single factor test and the incorporation ratio of 18-GA-Suc was determined by low-speed centrifugation. Meanwhile, physicochemical properties between Suc-GTS-Lip and GTS-Lip were compared. In vitro release studies of three components in Suc-GTS-Lip were conducted by equilibrium dialysis method. The results showed that the optimum conditions were when the feed ratio of 18-GA-Suc was 10% lipid liposomal membrane（mol·mol^-1）. It revealed that the incorporation ratio of 18-GA-Suc was 96.58%, and the encapsulation efficiencies of GA, TSN, and Sal B were about 86.15%, 81.70%, and 91.05%, respectively. In addition, the Suc-GTS-Lip was spherical and uniformly dispersed with particle size of 128.7 nm and zeta potential of-15.5 m V. The release model of GA and TSN was fitted well with Higuchi equation, while Sal B was fitted well with Hixon-crowell equation. It was concluded that Glycyrrhetinic acid derivatives（18-GA-Suc） can be successfully expressed in the liposome membrane, and the optimal preparation method of Suc-GTS-Lip was stable. All three components encapsulated into liposomes had sustained-release effects, which laid a good foundation for its further study about liver-targeting.