摘要
目的制备西罗莫司(sirolimus,雷幅霉素,rapamycin,RAPA)自微乳化释药系统(RAPA-SMEDDS)以提高低水溶性药物-RAPA的生物利用度。方法用HPLC-UV测定RAPA含量;通过溶解度实验和伪三元相图筛选SMEDDS组分;采用星点设计和效应面法优化处方以获得自乳化后粒径小于50 nm的自微乳化制剂;考察并比较优化处方与市售口服液在大鼠体内的药动学行为。结果优化后RAPA-SMEDDS的处方为30%MCT、50%Cremopher EL和20%Labrasol,每1 g SMEDDS中载药2.0 mg;自乳化后形成乳滴的粒径和PDI分别为41.10 nm和0.247;不同稀释介质及不同稀释倍数对微乳粒径大小及其分布影响较小;单剂量灌胃给药后大鼠体内SMEDDS和Rapamune口服液的主要药动学参数:ρmax分别为(13.37±2.78)和(4.15±1.48)μg.L-1,tmax分别为(2.60±1.29)和(5.40±1.34)h,AUC0-48 h分别为(157.75±70.77)和(73.36±34.12)μg.h.L-1。结论优化所得处方自乳化后粒径小于50 nm,大鼠体内相对生物利用度为215.04%,RAPA-SMEDDS可明显提高药物的口服吸收。
OBJECTIVE To prepare self-microemulsifying drug delivery system（SMEDDS） for enhancing the oral bioavailability of the poorly water soluble drug, sirolimus （RAPA）. METHODS The compositions of RAPA-SMEDDS were selected by solubility assay and pseudo-teruary phase diagrams analysis. The SMEDDS formulation was optimized using central composite design/response surface methodology. The concentrations of RAPA in vitro were determined by HPLC-UV and the whole blood concentrations of RAPA were determined by HPLC-MS/MS. The pharmacokinetic behaviors of RAPA-SMEDDS in rats were evaluated comparing with Rapamune. RESULTS Optimized formulaion of SMEDDS for bioavailability assessment were 30% MCT, 50% Cremopher EL and 20% Labrasol. 1.0 g mixture contained 2. 0 mg of RAPA. SMEDDS formulation formed mieroemulsion in water. The average particle diameter of microemulsion was less than 50 nm. The relative bioavailability of RAPA-SMEDDS to the conventional oral solution （ Rapamune, rapamycin 1 g L^-1 ） was 215.04%. CONCLUSION The HPLC method has been proved to be selective, sensitive, rapid and suitable for the determination of rapamycin in vitro. The bioavailability of RAPA-SMEDDS were significantly higher than Rapamune. These results supported new opportunities to deliver rapamycin using SMEDDS by oral route.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2010年第3期193-198,共6页
Chinese Pharmaceutical Journal
基金
华中科技大学医科重点资助项目
关键词
西罗莫司
自微乳化释药系统
微乳
生物利用度
sirolimus
self-microemulsifying drug delivery system
microemulsion
bioavailability
