摘要
目的：为了促进难溶性药物西罗莫司（sirolimus,SRL）的口服吸收,制备西罗莫司自微乳化微丸（SRL-SMEDDS pellets,SSP）,并对其进行体内外评价。方法：通过考察液态SRL-SMEDDS制成微丸前后所形成微乳的粒径和粒径分布变化、SSP的溶出度和物相结构特征,对制剂进行体外评价。采用高效液相色谱-串联质谱法（HPLC-MS/MS）测定全血样品中SRL浓度,以市售西罗莫司片（commercial sirolimus tablets,CST）为参比制剂,考察SSP在比格犬体内的药动学特征。结果：液态SRL-SMEDDS固体化前后形成微乳的粒径和粒径分布变化不大;SSP与CST在水中30 min的溶出度分别为94.2%和10.4%,在0.4%SDS溶液中2制剂溶出度相当,SRL在SSP中以非结晶态存在;SSP与CST在Beagle犬体内的Cmax分别为（18.44±1.97）和（12.72±0.36）ng·m L^-1;Tmax分别为（0.875±0.209）和（1.042±0.246）h;AUC0-48h分别为（131.65±7.81）和（96.17±8.45）ng·m L^-1·h;SSP的相对生物利用度F0→48h为136.9%。结论：SMEDDS能显著提高SRL在水中的溶出度和比格犬体内的口服生物利用度。
Objective： To enhance the oral absorption of the poorly water-soluble drug sirolimus（ SRL）,sirolimus self-microemulsifying pellets（ SSP） were prepared and evaluated in vitro and in vivo. Methods： The in vitro characteristics were evaluated by investigating the variance of particle size and its distribution of the microemulsion resulted from SRL-SMEDDS before and after solidification,and determining the dissolution and analyzing phase composition of SSP. The SRL concentration in whole blood was determined by HPLC-MS / MS, and pharmacokinetic behaviors of SSP were evaluated by comparing with commercial sirolimus tablets（ CST）. Results：There was no significant variation in particle size and particle size distribution when liquid SRL-SMEDDS were prepared into solid SSP. The accumulated dissolution percent of SSP and CST in water was 94. 2% and 10. 4% at30 min,respectively. The value of SSP was as much as that of CST in 0. 4% SDS solution. Phase compositionanalysis of SSP showed that SRL existed in non-crystalline state. The Cmaxof SSP and CST in Beagle dogs was（ 18. 44 ±1. 97） and（ 12. 72 ±0. 36） ng·m L^- 1; Tmaxof SSP and CST was（ 0. 875 ± 0. 209） and（ 1. 042 ± 0. 246） h;AUC0- 48 hof SSP and CST was（ 131. 65 ± 7. 81） and（ 96. 17 ± 8. 45） ng·m L^- 1·h; the relative bioavailability F0→48of SSP was 136. 9%. Conclusion： SMEDDS could enhance the dissolution of SRL in water and oral bioavailability of SRL in Beagle dogs.
作者
刘志宏
胡雄伟
张晶
黄爱文
宋洪涛
LIU Zhi-hong HU Xiong-wei ZHANG Jing HUANG Ai-wen SONG Hong-tao(Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou 350025, Chin)
出处
《中国新药杂志》
CAS
CSCD
北大核心
2016年第20期2369-2375,共7页
Chinese Journal of New Drugs
基金
福建省科技计划重点项目(2013Y0074)
福建省自然科学基金(2010J01218)
