Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
Department of Organic Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, China.
Int J Pharm. 2024 Nov 15;665:124707. doi: 10.1016/j.ijpharm.2024.124707. Epub 2024 Sep 14.
Over 90 % of chiral drugs applied in transdermal drug delivery system (TDDS) are racemates, significantly increasing risks of side effects. Herein, we designed a chiral molecularly imprinted patch (CMIP) that achieved enantioselectively controlled release of S-enantiomers (eutomers) and inhibited the release of R-enantiomers (distomers) for transdermal drug delivery. It is composed of chiral pressure sensitive adhesive (PSA) and molecularly imprinted polymers (MIP), showing better transdermal delivery of S-enantiomers than that of R-enantiomers in vitro (1.86-fold) and in vivo (3.74-fold), significantly decreasing the intake of distomers. Additionally, synthesized fluorescent probe enantiomers visualized enantioselective process of CMIP. Furthermore, investigations of molecular mechanism indicated that dependence on spatial conformation was dominant. On one hand, imprinted cavity of MIP with D-isomer and stronger chiral interaction with R-enantiomers led to more specific adsorption. On the other hand, L-isomer of PSA controlled the release of S-enantiomers by multiple interaction including chiral H-bond, π-π interaction and Van der Waals force. Tthus, the innovatively designed transdermal patch with enantioselective ability released eutomers of racemate and simultaneously inhibited release of distomers, significantly improving therapeutical efficiency and avoiding overdose.
超过 90%的应用于经皮给药系统（TDDS）的手性药物为外消旋体，这显著增加了副作用的风险。在此，我们设计了一种手性分子印迹贴剂（CMIP），实现了对外消旋体 S-对映体（对映体）的手性控制释放，并抑制了 R-对映体（对映体）的释放，用于经皮给药。它由手性压敏胶（PSA）和分子印迹聚合物（MIP）组成，在体外（1.86 倍）和体内（3.74 倍）对 S-对映体的经皮传递优于 R-对映体，显著减少了对映体的摄入。此外，合成的荧光探针对映体可视化了 CMIP 的手性选择性过程。此外，对分子机制的研究表明，空间构象的依赖性占主导地位。一方面，MIP 的 D-异构体印迹腔与 R-对映体具有更强的手性相互作用，导致更特异的吸附。另一方面，PSA 的 L-异构体通过包括手性氢键、π-π相互作用和范德华力在内的多种相互作用控制 S-对映体的释放。因此，这种具有手性选择性的新型经皮贴片能够释放外消旋体的对映体，并同时抑制对映体的释放，显著提高治疗效率，避免药物过量。
