固体自微乳化西罗莫司给药系统的优化配方。

Optimized formulation of solid self-microemulsifying sirolimus delivery systems.

机构信息

Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.

出版信息

Int J Nanomedicine. 2013;8:1673-82. doi: 10.2147/IJN.S43299. Epub 2013 Apr 26.

DOI:10.2147/IJN.S43299

PMID:23641156

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3639716/

Abstract

BACKGROUND

The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability.

METHODS

Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed.

RESULTS

In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocapry late (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune® oral solution).

CONCLUSION

The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration.

摘要

背景

本研究旨在开发一种优化的西罗莫司固体自微乳给药系统（SMEDDS）制剂，以提高其溶解度、稳定性和生物利用度。

方法

筛选了用于提高西罗莫司溶解度和稳定性的辅料。进行了相分离试验、乳化效率的目视观察和粒径分析。构建三元相图以优化液体 SMEDDS 配方。将选定的液体 SMEDDS 制剂制备成固体形式。分析了在大鼠中的溶出度和药代动力学特征。

结果

在油和助溶剂筛选研究的结果中，Capryol™丙二醇单辛酸酯（PGMC）和甘油糠醛分别显示出所有油和助溶剂中最高的溶解度。在表面活性剂筛选试验中，D-α-生育酚聚乙二醇 1000 琥珀酸酯（维生素 E TPGS）被确定为在 pH 1.2 模拟胃液中最有效地稳定西罗莫司的物质。通过三元相图构建确定的最佳配方是 T32（Capryol™PGMC:glycofurol:vitamin E TPGS=30:30:40 重量比）配方，平均粒径为 108.2±11.4nm。固体 SMEDDS 制剂由蔗糖酯 15 和甘露醇制备。与液体 SMEDDS 相比，再分散的固体 SMEDDS 的粒径没有显著差异。在溶解研究中，西罗莫司从 SMEDDS 制剂中的释放量明显高于原西罗莫司粉末。此外，在 pH 1.2 模拟胃液中，固体 SMEDDS 制剂比液体 SMEDDS 更稳定。药代动力学研究结果表明，SMEDDS 制剂的生物利用度明显高于原西罗莫司粉末或市售产品（雷帕霉素口服液）。