Bernkop-Schnürch Andreas, Guggi Davide, Pinter Yvonne
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens University Innsbruck, Innrain 52, Jösef Möller Haus, A-6020 Innsbruck, Austria.
J Control Release. 2004 Jan 8;94(1):177-86. doi: 10.1016/j.jconrel.2003.10.005.
It was the aim of this study to develop a mucoadhesive, permeation enhancing delivery system for orally administered poorly absorbed drugs. Chitosan was modified by the immobilisation of thiol groups utilising 2-iminothiolane (Traut's reagent). The permeation enhancing effect of the resulting chitosan-4-thio-butylamidine conjugate (chitosan-TBA conjugate) in combination with the permeation mediator glutathione (GSH) was evaluated in Ussing chambers on freshly excised small intestinal mucosa from guinea pigs using rhodamine 123 as marker for passive drug uptake. The mucoadhesive properties of the chitosan-TBA conjugate adjusted to pH 3, 5 and 7 were evaluated via the rotating cylinder method and via tensile studies. Release studies were performed with tablets comprising 10% cefadroxil used as model drug, 10% GSH and 80% chitosan-TBA conjugate pH 3 in 100 mM phosphate buffer pH 6.8 at 37 degrees C. Results showed a 3-fold higher permeation enhancing effect of the chitosan-TBA conjugate/GSH system in comparison to unmodified chitosan. Mucoadhesion studies revealed that the lower the pH of the thiolated chitosan is, the higher are its mucoadhesive properties. Release studies showed a sustained release of both cefadroxil and GSH over several hours. This delivery system might represent a promising novel tool in order to improve the therapeutic efficacy of various drugs which are poorly absorbed from the gastrointestinal tract.
本研究的目的是开发一种用于口服吸收不良药物的粘膜粘附、促进渗透的给药系统。利用2-亚氨基硫杂环戊烷（特劳特试剂）固定硫醇基团对壳聚糖进行修饰。使用罗丹明123作为被动药物摄取的标志物，在Ussing室中，对从豚鼠新鲜切除的小肠粘膜上，评估所得壳聚糖-4-硫代丁脒共轭物（壳聚糖-TBA共轭物）与渗透介质谷胱甘肽（GSH）联合使用时的渗透增强效果。通过旋转圆筒法和拉伸研究评估了pH值调节为3、5和7的壳聚糖-TBA共轭物的粘膜粘附性能。在37℃下，于pH 6.8的100 mM磷酸盐缓冲液中，对含有10%头孢羟氨苄作为模型药物、10% GSH和80% pH 3的壳聚糖-TBA共轭物的片剂进行释放研究。结果表明，与未修饰的壳聚糖相比，壳聚糖-TBA共轭物/GSH系统的渗透增强效果高3倍。粘膜粘附研究表明，硫醇化壳聚糖的pH值越低，其粘膜粘附性能越高。释放研究表明，头孢羟氨苄和GSH在数小时内持续释放。这种给药系统可能是一种有前景的新型工具，以提高各种从胃肠道吸收不良的药物的治疗效果。
