Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, 6020 Innsbruck, Austria.
Faculty of Pharmacy, University of Medicine and Pharmacy, Hue University, 530000 Hue, Thua Thien Hue, Viet Nam.
ACS Biomater Sci Eng. 2020 Sep 14;6(9):5032-5039. doi: 10.1021/acsbiomaterials.0c00637. Epub 2020 Aug 11.
The aim of this study was to evaluate the potential of -octadecyl sulfate (SOS) as a counterion for hydrophobic ion pairing (HIP) with exenatide-a potent glucagon-like peptide-1 (GLP-1) analogue in the treatment of diabetes mellitus-to improve its oral bioavailability. Exenatide was ion-paired with SOS and docusate (DOC) serving as the gold standard followed by the incorporation in a self-emulsifying drug delivery system (SEDDS) comprising Capmul MCM EP, Captex 355, Kolliphor RH40, and propylene glycol at a mass ratio of 41:15:40:4. The hydrophobicity of exenatide-SOS and exenatide-DOC was characterized by determining the butanol-water partition coefficient (log ). Droplet size and zeta potential of the ion pair-loaded SEDDS were characterized followed by intestinal membrane permeability determination on freshly excised rat intestines compared to exenatide solution. Furthermore, the oral bioavailability of exenatide-SOS- and exenatide-DOC-loaded SEDDS was also evaluated in vivo in healthy male Sprague-Dawley rats. Hydrophobic ion pairing increased the log of exenatide from -1.9 to 2.0 for exenatide-SOS and to 1.2 for exenatide-DOC. SEDDSs loaded with 0.26% (m/m) exenatide-SOS and 0.17% (m/m) exenatide-DOC had mean droplet size less than 30 nm and negative zeta potential. Ex vivo permeation experiments revealed 3.5-fold and 6.4-fold improvement in membrane permeability of the exenatide-SOS-loaded SEDDS vs. the exenatide-DOC-loaded SEDDS and exenatide solution, respectively. The orally administered exenatide-SOS-loaded SEDDS and exenatide-DOC-loaded SEDDS resulted in relative oral bioavailability vs. subcutaneous injection (SC) of 19.6 and 15.2%, respectively. Within this study, the key role of counterions for oral peptide delivery via HIP could be confirmed, and SOS was identified as a promising surfactant for this purpose.
本研究旨在评估 -十八烷基硫酸酯（SOS）作为与 exenatide（一种治疗糖尿病的有效胰高血糖素样肽-1（GLP-1）类似物）进行疏水离子对（HIP）的抗衡离子的潜力，以提高其口服生物利用度。将 exenatide 与 SOS 和 docusate（DOC）离子配对，DOC 作为金标准，随后将其纳入自乳化药物递送系统（SEDDS）中，该系统由 Capmul MCM EP、Captex 355、Kolliphor RH40 和丙二醇以 41:15:40:4 的质量比组成。通过测定丁醇-水分配系数（log ）来表征 exenatide-SOS 和 exenatide-DOC 的疏水性。对载有离子对的 SEDDS 的液滴大小和zeta 电位进行了表征，然后在新鲜分离的大鼠肠段上进行肠膜通透性测定，与 exenatide 溶液进行比较。此外，还在健康雄性 Sprague-Dawley 大鼠体内评估了载有 exenatide-SOS 和 exenatide-DOC 的 SEDDS 的口服生物利用度。疏水离子配对将 exenatide 的 log 从 -1.9 增加到 2.0（对于 exenatide-SOS）和 1.2（对于 exenatide-DOC）。载有 0.26%（m/m）exenatide-SOS 和 0.17%（m/m）exenatide-DOC 的 SEDDS 的平均液滴尺寸小于 30nm，并且具有负 zeta 电位。离体渗透实验显示，载有 exenatide-SOS 的 SEDDS 的膜通透性分别比载有 exenatide-DOC 的 SEDDS 和 exenatide 溶液高 3.5 倍和 6.4 倍。口服给予载有 exenatide-SOS 的 SEDDS 和载有 exenatide-DOC 的 SEDDS 的相对口服生物利用度分别为皮下注射（SC）的 19.6%和 15.2%。在本研究中，可以确认抗衡离子在通过 HIP 进行口服肽递送上的关键作用，并且 SOS 被确定为该目的的有前途的表面活性剂。
