| 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 |
| 投稿时间：2019-10-10 修订日期：2020-01-03 点此下载全文 |
| 引用本文：张雪婷,云超,陈珍珍,陶春,宋洪涛.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[J].药学实践杂志,2020,38(5):441~446,457 |
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| 基金项目: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) |
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| 中文摘要: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。 |
| 中文关键词: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 |
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| Study on sirolimus solubilization technology based on in vitro dissolution and in vivo bioavailability |
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| Abstract: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. SRL-SMEDDS 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 SRL-SMEDDS 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. |
| keywords:sirolimus solid dispersion inclusion complex SMEDDS nano-structured lipid carrier dissolution bioavailability |
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