Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, United Kingdom.
J Control Release. 2018 May 10;277:165-172. doi: 10.1016/j.jconrel.2018.03.018. Epub 2018 Mar 21.
The aim of the study was to develop an oral self-emulsifying drug delivery system (SEDDS) for exenatide and to evaluate its in vivo efficacy.
Exenatide was lipidised via hydrophobic ion pairing with sodium docusate (DOC) and incorporated in SEDDS consisting of 35% Cremophor EL, 25% Labrafil 1944, 30% Capmul-PG 8 and 10% propylene glycol. Exenatide/DOC was characterized in terms of lipophilicity evaluating the octanol/water phase distribution (logP). Exenatide/DOC SEDDS were characterized via droplet size analysis, drug release characteristics (log D determination) and mucus permeation studies. Furthermore, the impact of orally administered exenatide/DOC SEDDS on blood glucose level was investigated in vivo on healthy male Sprague-Dawley rats.
Hydrophobic ion pairing in a molar ratio of 1:4 (exenatide:DOC) increased the effective logP of exenatide from -1.1 to 2.1. SEDDS with a payload of 1% exenatide/DOC had a mean droplet size of 45.87 ± 2.9 nm and a Log D of 1.9 ± 0.05. Permeation experiments revealed 2.7-fold improved mucus diffusion for exenatide/DOC SEDDS compared to exenatide in solution. Orally administered exenatide/DOC SEDDS showed a relative bioavailability (versus s.c.) of 14.62% ± 3.07% and caused a significant (p < .05) 20.6% decrease in AUC values of blood glucose levels.
According to these results, hydrophobic ion pairing in combination with SEDDS represents a promising tool for oral peptide delivery.
本研究旨在开发一种用于艾塞那肽的口服自乳化药物传递系统（SEDDS），并评估其体内疗效。
通过与十二烷基硫酸钠（DOC）进行疏水离子配对将艾塞那肽进行脂质化，并将其纳入由 35%的 Cremophor EL、25%的 Labrafil 1944、30%的 Capmul-PG 8 和 10%的丙二醇组成的 SEDDS 中。通过评估辛醇/水相分配（logP）来表征艾塞那肽/DOC 的亲脂性。通过粒径分析、药物释放特性（log D 测定）和黏液渗透研究对艾塞那肽/DOC SEDDS 进行了表征。此外，还在健康雄性 Sprague-Dawley 大鼠体内研究了口服给予艾塞那肽/DOC SEDDS 对血糖水平的影响。
摩尔比为 1:4（艾塞那肽：DOC）的疏水离子配对将艾塞那肽的有效 logP 从-1.1 增加到 2.1。载药量为 1%的艾塞那肽/DOC SEDDS 的平均粒径为 45.87±2.9nm，Log D 为 1.9±0.05。渗透实验显示，与溶液中的艾塞那肽相比，艾塞那肽/DOC SEDDS 的黏液扩散性提高了 2.7 倍。口服给予艾塞那肽/DOC SEDDS 的相对生物利用度（与 sc 相比）为 14.62%±3.07%，并导致 AUC 值的血糖水平显著降低（p<.05）20.6%。
根据这些结果，疏水离子配对与 SEDDS 的组合代表了口服肽传递的一种有前途的工具。
