Takeda Junpei, Iwao Yasunori, Karashima Masatoshi, Yamamoto Katsuhiko, Ikeda Yukihiro
Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka Higashi, Fujisawa, Kanagawa 251-8555, Japan.
ACS Biomater Sci Eng. 2021 Feb 8;7(2):595-604. doi: 10.1021/acsbiomaterials.0c01324. Epub 2021 Jan 3.
Recently, choline and geranic acid (CAGE), an ionic liquid (IL), has been recognized to be a superior biocompatible material for oral and transdermal drug delivery systems (DDS). When CAGE is administered, CAGE would be exposed to various types of physiological fluids, such as intestinal and intradermal fluids. However, the effect of physiological fluids on the structure of CAGE remains unclear. In the present study, molecular structures of CAGE with different ratios of water were investigated using small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR). The SAXS pattern of CAGE showed an IL-specific broad peak derived from nanoscale aggregation until 17 vol % water. Meanwhile, narrow peaks were observed in samples with 25-50 vol % water, showing a transition to the lamellar phase. With more than 67 vol % water, CAGE was found to exist as micelles in water. The H NMR spectra indicated that protons of HO, OH in choline (CH), and COOH in geranic acid (GA) were observed as only one peak up to 17 vol % water. This peak shifted to a high magnetic field, and the integral values increased with the water content, speculating that water is localized close to the COOH and OH groups to allow proton exchange. The C NMR spectra showed that peaks related to the carboxyl group shifted with adding water. Moreover, only GA peaks were observed in the lamellar phase through C cross-polarization magic-angle spinning NMR, suggesting that the main rigid component of the lamellar phase was GA. Taken together, this study suggested that CAGE still maintained its IL structure up to 17 vol % water, then transitioned to the lamellar phase with 25-50 vol % water, and finally changed to the micellar phase with more than 67 vol % water. This information would be useful in the formulation and development of DDS using CAGE.
最近，胆碱与香叶酸组成的离子液体（CAGE）被认为是用于口服和透皮给药系统（DDS）的一种优质生物相容性材料。当给予CAGE时，它会接触到各种类型的生理流体，如肠液和皮内液。然而，生理流体对CAGE结构的影响仍不清楚。在本研究中，使用小角X射线散射（SAXS）和核磁共振（NMR）研究了不同水比例下CAGE的分子结构。CAGE的SAXS图谱显示，在水含量达到17体积%之前，有一个源自纳米级聚集体的离子液体特异性宽峰。同时，在水含量为25 - 50体积%的样品中观察到窄峰，表明向层状相转变。当水含量超过67体积%时，发现CAGE以胶束形式存在于水中。1H NMR光谱表明，在水含量达到17体积%之前，胆碱（CH）中的HO、OH质子和香叶酸（GA）中的COOH质子仅观察到一个峰。该峰向高磁场移动，积分值随水含量增加，推测水定位于COOH和OH基团附近以允许质子交换。13C NMR光谱显示，与羧基相关的峰随加水而移动。此外，通过13C交叉极化魔角旋转NMR在层状相中仅观察到GA峰，表明层状相的主要刚性成分是GA。综上所述，本研究表明，CAGE在水含量达到17体积%之前仍保持其离子液体结构，然后在水含量为25 - 50体积%时转变为层状相，最终在水含量超过67体积%时变为胶束相。这些信息将有助于使用CAGE的给药系统的制剂和开发。
