Abstract: Altrenogest (ALT) is oral progestin with poor solubility (~10 μg/mL) and rapid metabolism in vivo, which severely constraints on clinical effectiveness. Nanosuspension drug delivery systems (NS) can reduce the drug particles to nanometer size and improve the solubility and bioactivity of insoluble drugs. The factors and mechanism of altrenogest nanosuspension (ALT-NS) formation were analyzed and investigated using the anti-solvent precipitation method and its quality was evaluated. The preparation process and prescription composition were analyzed and optimized using single factor experiments and the central composite design-response surface methodology (CCD-RSM), and the experiments of characterization, chemical structure analysis, crystalline shape examination, physical stability and release experiments in vitro were applied to evaluate the quality of ALT-NS. The optimal prescription and process were determined as follows: altrenogest 0.4wt%, sodium dodecyl sulfate (SDS) 25 mg/mL, hypromellose (HPMC) 4 mg/mL, stirring speed of 1000 r/min, and stirring time of 10 minutes. The formulation was a light yellow clarified liquid, and the drug particles were in the form of spherical particles with an average particle size of 104.87±1.10 nm, PDI (particle size distribution index) of 0.19±0.01, and Zeta potential of -37.87±0.81 mV, the drug was transformed from crystalline to amorphous state, and the use of freeze-drying technology to make ALT-NS into freeze-dried powder could further improve its physical stability. The cumulative release of the preparation group in vitro was 98.4% at 72 h,which was about 1.54 times higher than that of the original group, showing high efficiency and smooth drug release. In conclusion, the optimization of the prescription composition and preparation process of ALT-NS using the anti-solvent precipitation method can significantly reduce the physical size and specific surface area of ALT, improve the dissolution and release efficiency of ALT, and the formulation has the efficient and fast drug release characteristics, which is expected to provide a reference for the clinical application of ALT-NS.

Key words: altrenogest, nanosuspension, central composite design-response surface methodology, drug crystal, release properties in vitro

摘要： 烯丙孕素(ALT)作为一种动物用口服孕激素，其水溶性极低(约10 μg/mL)，且在体内代谢快，这严重制约了其临床疗效的发挥。纳米混悬递送系统(NS)可以将药物颗粒减小至纳米尺寸，有效提升难溶性药物的溶出能力和生物活性。本研究采用反溶剂法制备了烯丙孕素纳米混悬剂(ALT-NS)，通过单因素实验及星点设计-效应面法(CCD-RSM)对制备工艺和处方组成展开优化，并深入分析了ALT-NS的形成机理及制备影响因素。结果显示，ALT-NS最优处方和工艺参数为：烯丙孕素含量0.4wt%、十二烷基硫酸钠(SDS)浓度25 mg/mL、羟丙基甲基纤维素(HPMC)浓度4 mg/mL、搅拌速度1000 r/min、搅拌时间10 min。所制备的ALT-NS为淡黄色澄清液体，扫描电镜下呈类球形颗粒，平均粒径为104.87±1.10 nm、粒径分布指数(PDI)为0.19±0.01、Zeta电位为-37.87±0.81 mV。分析表明，在ALT-NS制备过程中，ALT由结晶状转变为无定形态。体外释放度研究表明，ALT-NS在72 h的体外累计释放度为98.4%，约是原药组的1.54倍，展现出高效、快速的释药特性。综上，本研究制备的ALT-NS能够显著减小ALT的粒径，有效提高ALT的溶解和释放效率，这对于ALT在临床应用中的疗效具有重要意义。

关键词: 烯丙孕素, 纳米混悬剂, 星点设计-效应面法, 药物晶型, 体外释放