基于体外溶出度与体内生物利用度的西罗莫司增溶技术研究  

Study on sirolimus solubilization technology based on in vitro dissolution and in vivo bioavailability

作　　者：张雪婷 云超 陈珍珍 陶春 宋洪涛 ZHANG Xueting;YUN Chao;CHEN Zhenzhen;TAO Chun;SONG Hongtao(Department of Pharmacy,Fuzong Clinical Medical College of Fujian Medical University,Fuzhou 350025,China;College of Pharmacy,Fujian Medical University,Fuzhou 350108,China)

机构地区：[1]福建医科大学福总临床医学院/第九〇〇医院药学科,福建福州350025 [2]福建医科大学药学院,福建福州350108

出　　处：《药学实践杂志》2020年第5期441-446,457,共7页Journal of Pharmaceutical Practice

基　　金：福建省自然科学基金面上项目(2018J01347);福建医科大学启航基金项目(2017XQ1202);福州总医院院立项目(2017Q06);福建省科技计划引导性项目(2019Y0071)。

摘　　要：目的评价不同增溶技术对西罗莫司(sirolimus,SRL)的体外溶出与体内吸收的影响。方法选取固体分散体(SD)、包合物(IC)、自微乳(SMEDDS)和纳米结构脂质载体(NLC)为SRL的增溶技术。SRL-SMEDDS和SRL-NLC已在前期研究中获得最优处方。另外,以包封率、体外溶出度等为指标,筛选SRL-SD和SRL-IC的处方工艺。分别采用0.4%SDS,水,及pH 1.2、pH 4.5、pH 6.8、pH 7.4缓冲液为溶出介质,考察市售制剂Rapamune®,以及自制的各增溶制剂的溶出曲线。采用比格犬体内药动学试验,考察上述制剂的体内吸收度。结果在0.4%十二烷基硫酸钠(SDS)中,各制剂在2 h的溶出度均超过80%。在pH 1.2的介质中,无法测得SRL-SD的溶出度,而IC、SMEDDS和NLC的溶出度呈先增大后减小的趋势。在其他介质中,SRL的溶出度均有所降低,而SRL-IC显示了最佳的溶出度,未出现明显的降低趋势。体内药动学试验结果显示,原料药、SRL-SD、SRL-IC、SRL-NLC和SRL-SMEDDS的相对生物利用度分别为9.1%、18.7%、33.2%、78.0%、97.6%。结论SD、SMEDDS、NLC、IC均可提高SRL的体外溶出度和体内吸收度,其中,SMEDDS对SRL的生物利用度改善最为明显。Objective To evaluate the effects of different solubilizing techniques on the in vitro dissolution and in vivo pharmacokinetics of Sirolimus(SRL).Methods Solid dispersions(SD),inclusion complex(IC),self-micro emulsifying drug delivery system(SMEDDS)and nano-structured lipid carrier(NLC)were selected as the solubilization technology for SRL.SRLSMEDDS and SRL-NLC have obtained the optimal prescription in the previous studies.Additionally,the formulation process of SRL-SD and SRL-IC was screened by using inclusion rate and dissolution profiles as indicators.0.4%SDS,water and buffer solutions with pH 1.2,4.5,6.8,7.4 were used as dissolution media.The dissolution profile of the commercially available formulation Rapamune®and the lab-made solubilized preparations were investigated.The in vivo absorption of the above preparations was examined using a pharmacokinetic test in Beagle dogs.Results In 0.4%SDS,the dissolution of each preparation exceeded 80%in 2 h.In the medium of pH 1.2,the dissolution of SRL-SD could not be measured while the dissolution of IC,SMEDDS and NLC increased first and then decreased.In other media,the dissolution of the SRL was reduced.The SRL-IC showed the best dissolution without a significant decrease.The relative bioavailability of APIs,SRL-SD,SRL-IC,SRL-NLC and SRLSMEDDS were 9.1%,18.7%,33.2%,78.0%,and 97.6%respectively in vivo pharmacokinetic tests.Conclusion SD,SMEDDS,NLC,and IC can improve the in vitro dissolution and in vivo absorption of SRL.Among them,SMEDDS has the most significant improvement in the bioavailability of SRL.

关 键 词：西罗莫司 固体分散体 包合物 自微乳 纳米结构脂质载体 溶出度 生物利用度 

分 类 号：R927[医药卫生—药学]