大黄酚混合胶束的制备及其体内药动学研究

Preparation and in vivo pharmacokinetics of Chrysophanol mix micelles

关键词:  大黄酚  甘草酸  混合胶束  Box-Behnken 设计-效应面法  药辅合一  体内药动学  Hepg-2细胞

Key words:  chrysophanol  glycyrrhizic acid  mixed micelles  Box-Behnken design-response surface method  integration of medicine and adjuvant  pharmacokinetic  Hepg-2 cells

摘要:

目的 制备大黄酚-普朗尼克F127/甘草酸混合胶束(Chry-F127/GA),对其进行表征并考察其在大鼠体内的药动学。方法 采用溶剂蒸发法制备Chry-F127/GA,单因素试验结合响应面法优化处方,按最优处方制备Chry-F127/GA,并对其进行表征。将大黄酚原料药和Chry-F127/GA胶束溶液经尾静脉注射给药,于不同时间点采血,采用HPLC法测定大黄酚血药浓度。所得血药浓度数据用PK Solver 2.0程序进行拟合,得到药动学参数。结果 制备Chry-F127/GA的最优处方为大黄酚投药量为3 mg,药载比为1: 23,GA的百分含量为60 %,载体浓度为4 mg/mL。包封率、载药量、粒径、Zate电位分别为(84.99 ± 1.63)%、118.425 ± 1.76和(-22.03 ± 1.47)mv。通过透射电子显微镜观察到所制备的纳米胶束外观均一,呈球形。差示扫描量热法与傅里立叶-红外光谱法测定结果表明大黄酚以无定型形式存在于混合胶束中。细胞摄取实验结果表明,胶束剂型提高了Hepg-2细胞对Chry的摄取量。药动学结果显示,相较于大黄酚原料药组,Chry-F127/GA胶束组的AUC_0-t升高,CL降低,MRT延长。结论 制备得到的Chry-F127/GA胶束包封率高。在体内停留时间长,发挥作用时间延长,能够提高大黄酚的生物利用度。

Abstract:

ABSTRACT: OBJECTIVE To prepare Chry-F127/GA Mixed micelles, characterized and to investigate their in vivo pharmacokinetics. METHODS Chry-F127/GA was prepared by solvent evaporation method, and the single factor experiment combined with response surface method was used to optimize the prescription, and Chry-F127/GA was prepared according to the optimal prescription and characterized. The Chry solution and Chry-F127/GA micellar solution were administered via tail vein injection, and blood was collected at different time points to determine the blood concentration of Chry by HPLC. The obtained blood concentration data were fitted with PK Solver 2.0 program to obtain pharmacokinetic parameters. RESULTS The optimal prescription for the preparation of Chry-F127/GA was 3 mg of Chry dosage, 1: 23 drug loading ratio, 60 % of GA, and 4 mg/mL carrier concentration. The encapsulation rate, drug loading, particle size, and Zate potential were (84.99 ± 1.63) %, 118.425 ± 1.76, and (-22.03 ± 1.47) mv, respectively. The uniform appearance of the prepared nanocolloids was observed by transmission electron microscopy (TEM) it was observed that the prepared nanocolloids were homogeneous and spherical in appearance. Differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FTIR) measurements showed that Chry was present in the mixed micelles in an amorphous form. The results of cellular uptake assay showed that the micellar dosage form enhanced the uptake of Chry by Hepg-2 cells. Pharmacokinetic results showed elevated AUC0-t, decreased CL, and prolonged MRT in the Chry-F127/GA micelles group compared to the Chry solution group. CONCLUSION The Chry-F127/GA micelles obtained from the preparation had high encapsulation rate. The long residence time in vivo and prolonged action time, Chry-F127/GA can improve the bioavailability of Chry.