John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, United States; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, United States; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, United States.
J Control Release. 2020 Jun 10;322:602-609. doi: 10.1016/j.jconrel.2020.03.018. Epub 2020 Mar 19.
Delivery of hydrophobic drugs is a significant challenge due to poor solubility and formulation difficulty. Here, we describe the potential of ionic liquids, in particular choline and geranic acid (CAGE), for oral delivery of a hydrophobic drug, sorafenib (SRF). CAGE provided excellent apparent solubility of SRF tosylate (> 500 mg/mL). Upon oral dosing in rats, CAGE increased peak blood concentrations of SRF by 2.2-fold. The elimination half-life of SRF was also increased by 2-fold and the mean absorption time was extended by 1.6-fold. Furthermore, SRF delivered by CAGE exhibited significantly different biodistribution compared to control formulations. Specifically, accumulation in lungs and kidneys improved 4.4-fold and 6.2-fold, respectively compared to control formulations. Mechanistic studies revealed that SRF-CAGE solution spontaneously formed a self-assembled structure (427 ± 41 nm), which is likely responsible for altered biodistribution in vivo. UPLC-MS studies confirmed the presence of choline-geranate species in blood indicative of micellar/emulsion structures which eventually dissociated into choline and geranic acid molecular species. These studies provide a simple, scalable strategy for oral delivery of hydrophobic drugs.
由于疏水性药物溶解度差和制剂困难，其传递是一个重大挑战。在这里，我们描述了离子液体（特别是胆碱和香叶酸（CAGE））在将疏水性药物索拉非尼（SRF）经口递送给的潜在应用。CAGE 为 SRF 对甲苯磺酸盐提供了极好的表观溶解度（> 500mg/mL）。在大鼠口服给药后，CAGE 将 SRF 的血药峰浓度提高了 2.2 倍。SRF 的消除半衰期也增加了 2 倍，平均吸收时间延长了 1.6 倍。此外，与对照制剂相比，CAGE 递送的 SRF 表现出明显不同的生物分布。具体而言，与对照制剂相比，肺和肾脏中的积累分别提高了 4.4 倍和 6.2 倍。机制研究表明，SRF-CAGE 溶液自发形成自组装结构（427±41nm），这可能是体内改变生物分布的原因。UPLC-MS 研究证实了血液中存在胆碱-香叶酸盐，表明存在胶束/乳剂结构，最终这些结构解离为胆碱和香叶酸分子。这些研究为疏水性药物的经口传递提供了一种简单、可扩展的策略。
