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。
Abstract
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-ternary 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 microemulsion 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.
关键词
西罗莫司 /
自微乳化释药系统 /
微乳 /
生物利用度
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Key words
sirolimus /
self-microemulsifying drug delivery system /
microemulsion /
bioavailability
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孙明辉 翟雪珍 斯陆勤 李高 杨祥良.
西罗莫司自微乳化释药系统的制备及体内外评价[J]. 中国药学杂志, 2010, 45(3): 193-198
SUN Ming-hui;ZHI Xue-zhen;SI Lu-qin;LI Go;YNG Xing-ling.
Formulation Design and Evaluation of Self-Microemulsifying Drug Delivery System of Sirolimus[J]. Chinese Pharmaceutical Journal, 2010, 45(3): 193-198
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