采用分子印迹膜构建手性药物对映体选择性释放的透皮制剂研究

Enantiomers of chiral drugs in vivo show inevitablely different pharmacological activity, metabolism and toxicity. If you have to use a single isomer for the chiral drug, it is necessary to get the eutomer before you take it. However, process of chiral resolution and asymmetric synthesis is complicated and expensive, it is urgent to need to develop a new solution to obtain efficiently a single isomer and to avoid chiral separation. We will construct amlodipine transdermal delivery system based on molecularly imprinted membrane using a new imprinting technology of “synchronously graft-polymerizing and imprinting”. Transdermal delivery system is loaded on the racemic drugs and releases eutomer selectively. Based on mechanical properties, expansibility, stability of imprinted membrane and the structure of imprinted cavities is investigated, recognition selectivity and its mechanism of imprinted membrane is studied in depth. Transdermal penetration performance of amlodipine passing imprinted membrane is mainly explored. The proposal may provide a new idea for enantioselective release of chiral drugs by transdermal delivery system.

手性药物对映异构体在体内表现出不同的药理活性、代谢及毒副作用，而必须用单一异构体的手性药物都是先获得优性异构体再服用，而手性拆分和不对称合成工艺复杂、成本高、分离困难，迫切需要一种技术能免于拆分而在体内高效获得单一对映异构体。为此，本项目采用 “接枝聚合与交联印迹同步进行”的新型分子印迹技术制备分子印迹接枝膜以构建氨氯地平透皮制剂，载有外消旋体药物，而可以选择性释放优性对映异构体S-氨氯地平。在考察分析印迹膜的力学性能、膨胀性和稳定性、印迹空穴结构的基础上，深入研究印迹膜对药物的识别选择性、结合亲合性及其机理，重点探索氨氯地平选择性通过印迹膜和透皮制剂的渗透选择性能和机理。以期为发展手性药物选择性释放优性对映体，减少毒副作用，提供新的研究思路。

手性药物对映异构体在体内表现出不同的药理活性、代谢及毒副作用，而必须用单一异构体的手性药物都是先获得优性异构体再服用，而手性拆分和不对称合成工艺复杂、成本高、分离困难，本项目制备了一种既能免于拆分又能高效释放优性对映异构体的透皮制剂。首先在最优条件下制备了接枝度为4.9 mg/cm2的接枝膜PVA-g-PMAA，凭借氢键相互作用，PVA-g-PMAA对氨氯地平显示出好的吸附能力。在此基础上，以S-ADP为模板，MBA为交联剂，-OH/Ce4+氧化还原表面引发体系作用下，基于“主客体相互作用”，采用“接枝聚合与交联印迹同步进行”的新型表面分子印迹技术，实施S-ADP在聚乙烯醇膜表面的分子印迹，去除模板分子后，成功制得S-ADP表面分子印迹膜S-ADP-SMIM。考察了印迹膜对S-ADP具有优良的结合亲和性和识别选择性，S-ADP-SMIM对S-ADP的结合量为1.85 mg/cm2，而对ADP的结合量仅为0.88 mg/cm2。S-ADP-SMIM印迹膜的选择性系数高达4.6，光学纯度达到80%。体外释放行为表明，外消旋体ADP通过印迹膜S-ADP-SMIM时，S-ADP的累积释放量高达1459 μg/cm2，而R-ADP的累积释放量仅为106.21 μg/cm2，且S-ADP的渗透速率明显高于R-ADP。在“门效应”、“屏障效应”及“扩散效应”的协同作用下，印迹膜S-ADP-SMIM对外消旋体ADP具有良好的选择渗透性能，经皮渗透量可达到1097 μg/cm2，R-ADP的累积渗透释放量达到95.6 μg/cm2。在基础上制备了S-ADP透皮制剂，当贮药库中ADP浓度为4 mg/mL、卡波姆为0.9%，促渗剂为1%油酸时S-ADP的累积渗透释放量为1550.21±56.5 μg/cm2，渗透速率为61.32±1.3 μg/cm2/h，释放率达到77.5%，透皮制剂显示出了良好的选择性释放优性对映异构体的能力。动物实验表明，使用了S-ADP-SMIM膜的透皮制剂2h后大鼠的血压明显降低，且在36h血压明显保持在正常值范围。研究结果表明，采用表面分子印迹技术构建的选择性释放优性对映异构体的透皮制剂具有明显地、高效地选择渗透性能。本项目为手性药物的选择性释放提供了强有力的技术支持，为手性药物的应用提供了一个新的方向，对手性药物的发展具有实际的推动作用。