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.