Formation of the Ternary Inclusion Complex of Limaprost with α- and β-Cyclodextrins in Aqueous Solution
Formation of the Ternary Inclusion Complex of Limaprost with α- and β-Cyclodextrins in Aqueous Solution
复制标题
DOI：
10.1248/cpb.c14-00733
复制
发表时间：
2015-05-01
影响因子：
1.7
通讯作者：
Uekama, Kaneto
中科院分区：
文献类型：
--
作者：
Inoue, Yasuo;Sekiya, Noboru;Uekama, Kaneto
研究了利马前列素在α-和β-环糊精（CD）存在下的包合模式，以深入了解添加固态β-CD后利马前列素-阿尔法糖的稳定机制。通过核磁共振波谱和动力学方法研究了α-和β-环糊精的包合位点。随着α-和β-CD的加入，分别在药物的ω链和五元环中观察到前列腺素F-2 α（PGF（2 α））的C-13化学位移的位移。在添加α-CD和β-CD的情况下观察到类似的位移变化。在二维（2D）H-1-NMR光谱中，在PGF（2 α）的质子与α-CD和β-CD的质子之间观察到分子间相关峰，表明PGF（2 α）与α-CD和β-CD相互作用形成三元复合物，前者包括ω链，后者包括五元环。在水溶液中的动力学研究中，利马前列素降解为17 S，20-二甲基-反式-Delta（2）-PGA（1）（11-脱氧-Delta（10））和17 S，20-二甲基-反式-Delta（2）-8-iso-PGE 1（8-iso）。在这些条件下，α-CD的加入促进脱水为11-脱氧-δ（10），而β-CD促进异构化为8-异。在存在α-CD和β-CD的情况下，脱水和异构化也加速，支持利马前列素/α-CD/β-CD三元复合物的形成。
The inclusion mode of Limaprost in the presence of alpha- and beta-cyclodextrins (CDs) was investigated to gain insight into the stabilization mechanism of Limaprost-alfadex upon the addition of beta-CD in the solid state. The inclusion sites of a- and beta-CDs were studied by NMR spectroscopic and kinetic methods. With the addition of alpha- and beta-CDs, displacements in C-13 chemical shifts of prostaglandin F-2 alpha (PGF(2 alpha)) were observed in the omega-chain and the five-membered ring, respectively, of the drug. Similar shift changes were observed with the addition of both alpha- and beta-CDs. In two-dimensional (2D) H-1-NMR spectra, intermolecular correlation peaks were observed between protons of PGF(2 alpha) and protons of both alpha- and beta-CDs, suggesting that PGF(2 alpha) interacts with alpha- and beta-CDs to form a ternary complex by including the omega-chain with the former CD and the five-membered ring with the latter. In kinetic studies in aqueous solution, Limaprost was degraded to 17S,20-dimethyl-trans-Delta(2)-PGA(1) (11-deoxy-Delta(10)) and 17S,20-dimethyl-trans-Delta(2)-8-iso-PGE1 (8-iso). The addition of alpha-CD promoted the dehydration to 11-deoxy-Delta(10), while beta-CD promoted the isomerization to 8-iso, under these conditions. In the presence of both alpha- and beta-CDs, dehydration and isomerization were also accelerated, supporting the formation of the ternary Limaprost/alpha-CD/beta-CD complex.