羟基红花黄色素A磷脂复合物自微乳给药系统的制备及其在大鼠体内的药动学研究

Preparation of Self-microemulsion Drug Delivery System of Hydroxysafflor Yellow A Phospholipid Complex and Its Pharmacokinetics in Rats

关键词:  羟基红花黄色素A|磷脂复合物|自微乳|生物利用度

Key words:  hydroxysafflor yellow A|phospholipid complex|self-microemulsion|bioavailability

摘要:

目的 探讨羟基红花黄色素A磷脂复合物自微乳给药系统（hydroxysafflor yellow A phospholipid complex self-microemulsion drug delivery system，HSYA-PC-SMEDDS）的制备方法，以提高羟基红花黄色素A（HSYA）的口服生物利用度，并为今后口服制剂开发提供一定研究思路与基础。方法 通过单因素试验，以复合率为评价标准，采用溶剂蒸发法制备磷脂复合物（PC），并考察不同反应溶剂、反应时间、反应温度、药物浓度以及药脂比下复合率，确定HSYA-PC的最佳制备条件，并进行理化性质确证，以粒径及载药量为响应值对HSYA-PC-SMEDDS制备工艺进行优化；同时测定HSYA-PC-SMEDDS在不同溶出介质中体外溶出度；并以HSYA水溶液为对照组，记录HSYA-PC-SMEDD在SD大鼠体内药动学特性。结果 ①当反应溶剂为无水乙醇、反应时间为2 h、反应温度为40℃、药物浓度为2 mg·mL^-1以及药脂比为1：3时，HSYA-PC的制备条件最优，最佳工艺下复合率为（98.14±0.95）%。②当油相为油酸乙酯、表面活性剂为吐温80、助表面活性剂为二乙二醇乙醚时，所组成的空白自微乳液能在水中快速形成均一、稳定且略带蓝色微乳光的澄清透明液体。③当HSYA-PC-SMEDDS自微乳分散于50倍的去离子水中后，其迅速溶解并形成黄色澄清液体；所得溶液的粒径与电位在24 h内几乎无变化，且外观上无肉眼可见物质析出，表明HSYA-PC-SMEDDS给药系统在24 h内性质稳定。④相比于HSYA对照组，HSYA-PC-SMEDDS组的C_max由（0.37±0.36）μg·mL^-1显著增大到（1.28±0.62）μg·mL^-1，并且药时曲线下面积AUC_0→t与AUC_0→∞也分别由（147.29±137.63）min·μg·mL^-1和（195.82±169.09）min·μg·mL^-1增大至（430.99±151.46）min·μg·mL^-1和（502.69±138.96）min·μg·mL^-1，差异均具有显著性。结论 HSYA制备成PC中间体可显著提高HSYA的脂溶性，进一步制备成HSYA-PC-SMEDDS能使其充分溶解在水性介质，且口服相对生物利用度显著提高。

Abstract:

OBJECTIVE To explore the preparation method of hydroxysafflor yellow A phospholipid complex self-microemulsion drug delivery system(HSYA-PC-SMEDDS) to improve the oral bioavailability of hydroxysafflor yellow A(HSYA), and to provide some research ideas and bases for the future development of oral preparation. METHODS The phosphatide complex(PC) was prepared by solvent evaporation method in a single factor experiment using compound rate as evaluation criterion. The optimum preparation conditions of HSYA-PC were determined by investigating different reaction solvents, reaction time, reaction temperature, drug concentration and drug-lipid ratio. The physical and chemical properties of HSYA-PC were confirmed. The preparation of HSYA-PC-SMEDDS was optimized by using particle size and drug loading as the response value; the dissolution of HSYA-PC-SMEDDS in different dissolution media in vitro was determined; the pharmacokinetic characteristics of HSYA-PC-SMEDDS in SD rats were studied by using HSYA aqueous solution as the control. RESULTS ①The optimum conditions for the preparation of HSYA-PC-SMEDDS were obtained when the usage of absolute ethanol as reaction solvent, reaction for 2 h under 40℃, the drug concentration was 2 mg·mL^-1 and the drug-lipid ratio was 1:3. The compound rate under optimum conditions was (98.14±0.95)%. ②When the oil phase was ethyl oleate, the surfactant was Tween 80 and the auxiliary surfactant was diethylene glycol ether, the blank self-microemulsion could rapidly form uniform, stable and clear transparent liquid with a little blue microemulsion in water. ③When HSYA-PC-SMEDDS self-microemulsion was dispersed in 50 times deionized water, it quickly dissolved and formed yellow clarifying liquid; HSYA-PC-SMEDDS showed good stability with almost no change in particle size and zeta potential, as well as no visible matter precipitation during 24 h. ④Compared with HSYA control group, C_max of HSYA-PC-SMEDDS group increased significantly to (1.28±0.62)μg·mL^-1 from (0.37±0.36)μg·mL^-1, and the AUC_0→t and AUC_0→∞ were separately increased to (430.99±151.46)min·μg·mL^-1 and (502.69±138.96)min·μg·mL^-1 from (147.29±137.63)min·μg·mL^-1 and (195.82±169.09)min·μg·mL^-1. CONCLUSION The preparation of HSYA as an intermediate of PC can significantly improved the liposolubility of HSYA. HSYA-PC-SMEDDS formed via HSYA-PC can further contribute to the sufficient dissolution in water, as well as significantly improve the oral relative bioavailability.