Pharmaceutical Technology Department, Faculty of Pharmacy, University of Coimbra, 300-548 Coimbra, Portugal; Chemistry Department, Faculty of Science and Technology, University of Coimbra, 3004-535 Coimbra, Portugal; Institute of Pharmaceutical Science, King's College London, SE1 9NH London, United Kingdom.
Pharmaceutical Technology Department, Faculty of Pharmacy, University of Coimbra, 300-548 Coimbra, Portugal.
Int J Pharm. 2014 May 15;466(1-2):349-58. doi: 10.1016/j.ijpharm.2014.03.035. Epub 2014 Mar 20.
This work provides a new insight on fundamental principles of the interaction mechanism between two forms of tetracaine - a potent local anesthetic - both in neutral (TC) and ionized (TC(+)) states, with beta- (β-CD) and hydroxypropyl-beta-cyclodextrin (HP-β-CD), and how such interactions affect the transport of tetracaine, at different concentrations, across a model membrane. The kinetics and mechanism of TC release from HPMC gels is also evaluated giving an insight on the role of cyclodextrin on the tetracaine transport. HPLC, fluorescence and NMR spectroscopies provided solid physicochemical knowledge of these systems and in vitro studies were performed to obtain relevant data on the transport and mechanism parameters. HPLC and fluorescence spectroscopy data revealed that tetracaine interacts with both cyclodextrins on a 1:1 stoichiometry but it is observed that neutral tetracaine forms more stables complexes (ca. 1050 M(-1) for both cyclodextrins) than in its ionized form (628 and 337 M(-1) for β-CD and HP-β-CD respectively). Despite of that, no host-guest interactions take place as seen by ROESY. This study clearly demonstrates that both forms of tetracaine are successfully released from the formulations at a controlled rate, following a Super-Case transport mechanism and the transport of tetracaine can be tuned by using cyclodextrins.
这项工作提供了一种新的见解，即两种形式的局部麻醉剂——强力局麻药——四卡因的相互作用机制的基本原理，包括中性（TC）和离子化（TC(+)）状态下，与β-环糊精（β-CD）和羟丙基-β-环糊精（HP-β-CD）的相互作用，以及这种相互作用如何影响不同浓度的四卡因通过模型膜的转运。还评估了 HPMC 凝胶中四卡因的释放动力学和机制，深入了解了环糊精对四卡因转运的作用。HPLC、荧光和 NMR 光谱学为这些系统提供了坚实的物理化学知识，进行了体外研究以获得有关转运和机制参数的相关数据。HPLC 和荧光光谱数据表明，四卡因与两种环糊精以 1:1 的化学计量比相互作用，但观察到中性四卡因比其离子形式形成更稳定的配合物（对于两种环糊精分别约为 1050 M(-1)和 628 和 337 M(-1)）。尽管如此，正如 ROESY 所示，没有主体-客体相互作用发生。这项研究清楚地表明，两种形式的四卡因都可以从制剂中以受控的速率释放，遵循超案例转运机制，并且可以通过使用环糊精来调节四卡因的转运。
