度他雄胺固体自微乳给药系统的制备及评价

Preparation and evaluation of dutasteride solid self-microemulsions drug delivery system

目的:研究度他雄胺固体自微乳给药系统制备方法,评价其体内外性质。方法:考察固体载体对自微乳体系微观结构、载药量及体外分散沉淀的影响;采用冷冻干燥法制备度他雄胺固体自微乳给药系统,考察其外观、粒径等物理形态和体外溶出行为,比格犬体内对比考察度他雄胺固体自微乳给药系统和上市度他雄胺软胶囊(Avodart)的药动学。结果:固体载体对自微乳体系微观结构影响小,对载药量和体外分散沉淀影响较大;适宜的载体为阿拉伯胶和甘露醇(1∶1),与自微乳液体的质量比为1∶1;度他雄胺固体自微乳给药系统重分散后近球状,平均粒径80 nm,在4种介质中的溶出均显著高于已上市度他雄胺软胶囊,具有非p H依赖性和快速溶出行为。体内药动学研究表明,度他雄胺固体自微乳给药系统与度他雄胺上市软胶囊生物等效。结论:固体自微乳给药系统能较好的保持液体自微乳系统的特性,扩展了自微乳系统药剂学应用范围。

Objective ： To establish preparation methods of dutasteride solid self-microemulsion drug deliv- ery system （S-SMEDDS） , and to evaluate its qualities in vivo and in vitro. Methods： The effects of solid carriers on self-mieromulsion＇s internal rnicrostructure, drug loading, dispersion and precipitation in vitro were determined. S-SMEDDS of dutasteride was prepared by freeze-drying, and its physical properties, such as appearance, particle size and dissolution in vitro, were assessed. The pharmacokinetie behaviors of dutasteride S-SMEDDS were com- pared with those of Avodart in Beagle dogs. Results： The solid carriers had little effect on microstrncture of L- SMEDDS but largely affected drug loading, dispersion and precipitation in vitro. Proper carriers were arabic and mannitol with the weight ratio of 1 ： 1. The mean diameter of dutasteride solid self-microemulsion after re-dispersing was 80 nm in spherical form. The dissolution of S-SMEDDS was significantly higher than that of Avodart in four media. Its dissolution profile was demonstrated to be rapid and pH-independent. In vivo pharmacokinetic study showed that dutasteride S-SMEDDS was bioequivalent with its market soft-capsules. Conclusion： Dutasteride S-SMEDDS is able to well maintain L-SMEDDS characteristics, and extends the range of applications in pharmaceutics.