根皮素磷脂复合物的制备、表征及体内外溶出行为评价  

Preparation,characterization and dissolution behavior evaluation in vivo and in vitro of phloretin phospholipid complex

作　　者：黄珊 翟秉涛 杨洁[1] 邹俊波[1] 程江雪[1] 张小飞[1] 史亚军[1] 郭东艳[1] HUANG Shan;ZHAI Bing-tao;YANG Jie;ZOU Jun-bo;CHENG Jiang-xue;ZHANG Xiao-fei;SHI Ya-jun;GUO Dong-yan(State Key Laboratory of Research&Development of Characteristic Qin Medicine Resources(Cultivation),Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research,Shaanxi University of Chinese Medicine,Xi’an 712046,China)

机构地区：[1]陕西中医药大学,秦药特色资源研究与开发国家重点实验室(培育)/陕西省中药基础与新药研究重点实验室,陕西西安712046

出　　处：《中草药》2021年第18期5543-5551,共9页Chinese Traditional and Herbal Drugs

基　　金：国家自然科学基金资助项目(81202905);陕西中医药大学学科创新团队(2019-YL11);陕西省教育厅科研项目(15JF015)。

摘　　要：目的制备根皮素磷脂复合物(PHL-PC)并探讨其形成机制,以改善根皮素的经皮渗透性,提高其生物利用度。方法采用溶剂挥发法制备PHL-PC,选择药脂比、药物浓度,反应温度作为Box-Behnken设计-响应面法考察因素,以复合率为指标优选最佳工艺;扫描电子显微镜(SEM)、差示扫描量热法(DSC)、X射线衍射(XRD)、红外光谱(FT-IR)法分析复合物的形成机制,并考察其溶解度、经皮渗透性及体内药动学特性。结果最佳制备工艺为以乙醇为复合溶剂,PHL的质量浓度为1.7 mg/mL,与磷脂质量比为1∶1.6,反应温度为56℃,验证实验得到复合率为(94.30±1.13)%;SEM、DSC、XRD和FT-IR的结构表征显示磷脂复合物的形成是由于根皮素分子与磷脂的极性末端存在弱的分子间作用力所致,根皮素以无定形状态分散在磷脂中,形成磷脂复合物;溶解度实验结果显示,与根皮素相比,PHL-PC在水和正辛醇中的溶解度分别提高了4.90、2.20倍,油水分配系数由1.22提高到2.03;溶出度实验结果显示制成磷脂复合物后,累积释药率由72.07%提高到86.34%;体外经皮渗透实验结果显示,PHL-PC在24 h内累积渗透药量(Qn)是根皮素的2.06倍;药动学研究显示PHL-PC的AUC0~∞是根皮素的2.15倍。结论制备的PHL-PC可显著改善根皮素的经皮渗透性,提高其生物利用度。Objective To prepare phloretin phospholipid complex(PHL-PC)and explore its formation mechanism to improve the transdermal permeability of phloretin and increase its bioavailability.Methods The drug-lipid ratio,drug concentration and reaction temperature were selected as the factors of the Box-Behnken design-response surface method in the preparation of PHL-PC by solvent volatilization,and the best process was optimized with the compound rate as the index.Scanning electron microscopy(SEM),differential scanning calorimetry(DSC),X-ray diffraction(XRD),infrared spectroscopy(FT-IR)methods were used to analyze the formation mechanism of the complex,and to investigate its solubility,transdermal permeability and in vivo pharmacokinetic properties Results The optimum preparation technology of PHL-PC was as follows:ethanol was used as compound solvent,the concentration of PHL was 1.7 mg/mL,the mass ratio of phospholipid to phloretin was 1.6:1,and the reaction temperature was 56℃and the recombination rate was(94.30±1.13)%.SEM,DSC,XRD and FT-IR structural characterization showed that the formation of phospholipid complex was due to the weak intermolecular force between the phloretin molecule and the polar end of the phospholipid,and the phloretin was dispersed in the phospholipid in an amorphous state.The solubility test results showed that compared with phloretin,the solubility of PHL-PC in water and n-octanol was increased by 4.90 and 2.20 times,respectively,and the oil-water partition coefficient was increased from 1.22 to 2.03.In vitro solubility test results showed that the cumulative percentage of drug release increased from 72.07%to 86.34%after making phospholipid complexes.The results of percutaneous permeation test showed that the cumulative permeation dose of PHL-PC within 24 h was 2.06 times higher than that of phloretin.Pharmacokinetic studies showed that the AUC0—∞of PHL-PC was 2.15 times of the phloretin.Conclusion The prepared PHL-PC can significantly improve the transdermal permeability of phloretin an

关 键 词：根皮素 磷脂复合物 Box-Behnken设计-响应面法 溶解度 经皮渗透 溶出 生物利用度 溶剂挥发法 

分 类 号：R283.6[医药卫生—中药学]