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硫醇化聚合物——硫醚聚合物:壳聚糖-2-亚氨基硫杂环戊烷缀合物的合成及体外评价

Thiolated polymers--thiomers: synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates.

作者信息

Bernkop-Schnürch Andreas, Hornof Margit, Zoidl Theresa

机构信息

Center of Pharmacy, Institute of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.

出版信息

Int J Pharm. 2003 Jul 24;260(2):229-37. doi: 10.1016/s0378-5173(03)00271-0.

Abstract

The aim of this study was to improve the properties of chitosan as excipient in drug delivery systems by the covalent attachment of thiol moieties. This was achieved by the modification of chitosan with 2-iminothiolane. The resulting chitosan-4-thio-butyl-amidine conjugates (chitosan-TBA conjugates) displayed up to 408.9+/-49.8 micromol thiol groups per gram polymer. Because of the formation of disulfide bonds based on an oxidation process of the immobilized thiol groups under physiological conditions, chitosan-TBA conjugates exhibit in situ gelling properties. After less than 2h, 1.5% (m/v) chitosan-TBA conjugate solutions of pH 5.5 formed covalently cross-linked gels. The viscosity increased in positive correlation with the amount of thiol groups immobilized on chitosan. In addition, also the mucoadhesive properties were strongly improved by the covalent attachment of thiol groups on chitosan. The adhesion time of tablets based on the unmodified polymer on freshly excised porcine intestinal mucosa spanned on a rotating cylinder in an artificial intestinal fluid was extended more than 140-fold by using the thiolated version. Drug release studies out of tablets comprising the chitosan-TBA conjugate demonstrated that an almost zero-order release kinetic was achieved for the model drug clotrimazole within the first 6h. The modification of chitosan with 2-iminothiolane leads, therefore to thiolated polymers, which represent a promising tool for the development of in situ gelling and/or mucoadhesive drug delivery systems.

摘要

本研究的目的是通过硫醇部分的共价连接来改善壳聚糖作为药物递送系统中辅料的性能。这是通过用2-亚氨基硫杂环戊烷修饰壳聚糖来实现的。所得的壳聚糖-4-硫代丁基脒缀合物(壳聚糖-TBA缀合物)每克聚合物显示高达408.9±49.8微摩尔的硫醇基团。由于在生理条件下固定化硫醇基团的氧化过程形成二硫键,壳聚糖-TBA缀合物表现出原位凝胶化特性。不到2小时后,pH 5.5的1.5%(m/v)壳聚糖-TBA缀合物溶液形成共价交联凝胶。粘度与固定在壳聚糖上的硫醇基团数量呈正相关增加。此外,壳聚糖上硫醇基团的共价连接也极大地改善了粘膜粘附性能。基于未修饰聚合物的片剂在人工肠液中旋转圆筒上新鲜切除的猪肠粘膜上的粘附时间通过使用硫醇化版本延长了140多倍。包含壳聚糖-TBA缀合物的片剂的药物释放研究表明,模型药物克霉唑在前6小时内实现了几乎零级释放动力学。因此,用2-亚氨基硫杂环戊烷修饰壳聚糖会产生硫醇化聚合物,这是开发原位凝胶化和/或粘膜粘附药物递送系统的有前途的工具。

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