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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 sirolimus (rapamycin, rapamycin, RAPA) self-microemulsifying drug delivery system (RAPA-SMEDDS) to improve the bioavailability of low water-soluble drug-RAPA. Methods The content of RAPA was determined by HPLC-UV. The SMEDDS fraction was screened by solubility test and pseudo-ternary phase diagram. The self-microemulsifying preparation with self-emulsifying particle size less than 50 nm was obtained by the method of star point design and response surface methodology. The pharmacokinetics of the prescription and the commercially available oral solution in rats were compared. Results The optimal formulation of RAPA-SMEDDS was 30% MCT, 50% Cremopher EL and 20% Labrasol with 2.0 mg / 1 g SMEDDS. The diameter and PDI of the emulsion droplets after emulsification were 41.10 nm and 0.247, respectively. The main pharmacokinetic parameters of SMEDDS and Rapamune oral solution after single-dose intragastric administration were (ρmax, 13.37 ± 2.78, And (4.15 ± 1.48) μg.L-1, tmax were (2.60 ± 1.29) and (5.40 ± 1.34) h respectively, and AUC0-48 h were (157.75 ± 70.77) and (73.36 ± 34.12) μg.hL- . CONCLUSION: The optimized bioavailability of RAPA-SMEDDS after oral administration is less than 50 nm and the relative bioavailability in rats is 215.04%.