Abstract: In order to improve the solubility and oral bioavailability of altrenogest in vivo, a self-microemulsion drug delivery system (ALT-SMEDDS) was developed and characterized. The study delved into the influencing factors and self-emulsifying mechanism of ALT-SMEDDS. Experimentation involved saturation solubility tests to discern the drug-carrying capacity of various excipients, while physical and chemical compatibility experiments were employed to ascertain the judicious compounding of these excipients. The formulation composition and the excipient dosage range of ALT-SMEDDS were systematically screened using pseudo ternary phase diagrams, and the effects of the ratio of oil phases and the mass ratio of emulsifiers to co-emulsifiers (Km) on the formation of self-microemulsions were also investigated. Further refinement of the formulation was achieved through the application of central composite design-response surface methodology (CCD-RSM). Through the regression model, and results of variance analysis, it was obtained that the self-emulsifying time was greatly affected by Km, which increased with the Km, while the average particle size was greatly affected by the oil phase, and which increased with the proportion of the oil phase. When the oil phase is ethyl oleate (22.0wt%), the surfactant was Tween80 (54.2wt%) and the co-surfactant was Transcutol HP (23.8wt%), ALT-SMEDDS exhibited a clear and transparent appearance with excellent flowability. The self-emulsifying time of ALT-SMEDDS was 35.76±1.10 s. The droplets displayed a rounded and homogeneous structure, devoid of adhesion. The average particle size of ALT-SMEDDSD was 18.39±0.03 nm, the PDI was 0.083±0.090, and the Zeta potential was -1.12±0.12 mV, indicating stability within the range of 10~1000 fold dilution. ALT-SMEDDS showcased an impressive cumulative release of 91.41% at 48 h in vitro, signifying a substantial improvement compared to the original drug release of 32.42%. With its reliable prescription, high emulsification efficiency, uniform microemulsion particle size distribution, and overall stability, ALT-SMEDDS emerges as a promising candidate for enhancing the in vitro release of ALT. This sets a solid foundation for the prospective clinical application of ALT-SMEDDS in improving the therapeutic efficacy of ALT.

Key words: altrenogest, self-microemulsion drug delivery system, central composite design-response surface methodology, surfactant, pseudo-ternary phase diagram

摘要： 为改善烯丙孕素(ALT)的溶解度，提高其体内口服生物利用度，本实验制备了ALT的自微乳化给药系统(ALT-SMEDDS)，分析影响因素及其自微乳化机理，并对其质量进行评价。通过饱和溶解度实验考察辅料的载药能力，通过物理、化学相容性实验确定辅料之间配伍合理性。绘制伪三元相图筛选出ALT-SMEDDS的处方组成及辅料用量范围，并采用星点设计-效应面法(CCD-RSM)建立模型优化处方，通过ALT-SMEDDS体外表征、稳定性实验和体外释放度实验对其进行质量评价。当油相选用油酸乙酯(22.0wt%)、乳化剂选用吐温80 (54.2wt%)，助乳化剂选用二乙二醇单乙醚(23.8wt%)，制备得到的ALT-SMEDDS外观澄清透明，流动性良好，自微乳化时间为35.76±1.10 s，自微乳化后乳滴的外观圆整均一、无粘连，平均粒径为18.39±0.03 nm，多分散系数(PDI)为0.083±0.090，Zeta电位为-1.12±0.12 mV，在10~1000倍稀释范围内能保持稳定。ALT-SMEDDS在48 h体外累积释放度能够达到91.41%，相较于原药32.42%具有显著提升。ALT-SMEDDS制备处方可靠，乳化效率高，微乳粒径分布均匀，具有良好的稳定性，能够提高ALT的体外释放度，为ALT-SMEDDS的临床应用奠定了基础。

关键词: 烯丙孕素, 自微乳化给药系统, 星点设计-效应面法, 乳化剂, 伪三元相图