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Ester prodrug of scutellarin: synthesis, physicochemical property and degradation

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Author:: No author available

Journal Title:: ACTA PHARMACEUTICA SINICA

Issue:: 7

DOI:: 10.3321/j.issn:0513-4870.2006.07.004

Key Word:: 灯盏乙素;前药;合成;羟乙酰胺酯;理化性质;小肠降解;乳剂;包合物

Abstract：目的对口服难吸收中药活性成分灯盏乙素进行结构改造,为寻找和设计合理前药及其剂型提供依据.方法通过先成盐后酯化的方法合成灯盏乙素乙酯、苄酯并改进文献方法合成羟乙酰胺酯,用质谱和氢谱确证结构.研究3种前药在不同pH水溶液中的稳定性、溶解度、分配系数和在人血浆中的降解.制备灯盏乙素羟乙酰胺酯环糊精包合物和乳剂,比较包合物和乳剂在肠液中对该前药的保护作用,考察该前药在不同肠段黏膜匀浆中的降解情况.结果合成的3种前药经确证为目标物;灯盏乙素羟乙酰胺酯在缓冲液(pH 4.2)和水中的溶解度比灯盏乙素分别提高近10倍和35倍,分配系数也由原来的-2.56提高到1.48;该酯水溶液的稳定性较好(t1/2≈16 d,pH4.2),在人血浆的半衰期最短(t1/2≈7 min),但在肠黏膜匀浆中的降解可能影响酯的吸收,不同肠段黏膜匀浆降解羟乙酰胺酯的次序为:十二指肠＞回肠≥空肠＞结肠.乳剂在肠黏膜匀浆中对前药有显著的保护作用,包合物次之.结论与灯盏乙素乙酯和苄酯比较,羟乙酰胺酯的理化性质较好,但其在肠道中的稳定性有待提高,可以选择乳剂或结肠定位给药减少前药的降解.

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