Gliko-Kabir I, Yagen B, Baluom M, Rubinstein A
The Hebrew University of Jerusalem, School of Pharmacy, Faculty of Medicine, P.O. Box 12065, Jerusalem, Israel.
J Control Release. 2000 Jan 3;63(1-2):129-34. doi: 10.1016/s0168-3659(99)00180-7.
Targeting of drugs to the colon, following oral administration, can be accomplished by the use of modified, biodegradable polysaccharides as vehicles. In a previous study, a crosslinked low swelling guar gum (GG) hydrogel was synthesized by reacting it with trisodium trimetaphosphate (STMP). In the present study the functioning of GG crosslinked products (GGP) as possible colon-specific drug carriers was analyzed by studying (a) the release kinetics of pre-loaded hydrocortisone from GGP hydrogels into buffer solutions with, or without GG degrading enzymes (alpha-galactosidase and beta-mannanase) and (b) direct measurements of the polymers' degradation in the cecum of conscious rats. The effect of GG diet on alpha-galactosidase and beta-mannanase activity in the cecum of the rat and GGP degradation was also measured. It was found that the product GGP-0.1 (loosely crosslinked with 0.1 equivalents of STMP) was able to prevent the release of 80% of its hydrocortisone load for at least 6 h in PBS, pH=6.4. When a mixture of alpha-galactosidase and beta-mannanase was added to the buffer solution, an enhanced hydrocortisone release was observed. In-vivo degradation studies in the rat cecum showed that despite the chemical modification of GG, it retained its enzyme-degrading properties in a crosslinker concentration-dependent manner. Eight days of GG diet prior to the study increased alpha-galactosidase activity in the cecum of the rat three-fold, compared to its activity without the diet. However, this increase in the enzyme activity was unable to improve the degradation of the different GGP products. The overall alpha-galactosidase activity in the rat cecum was found to be extracellular, while the activity of beta-mannanase was found to be bacterial cell-wall associated. It is concluded that because CG crosslinked with STMP can be biodegraded enzymatically and is able to retard the release of a low water-soluble drug, this polymer could potentially be used as a vehicle for colon-specific drug delivery.
口服给药后，通过使用改性的可生物降解多糖作为载体，可实现药物靶向结肠。在先前的一项研究中，通过使交联低溶胀瓜尔胶（GG）与三偏磷酸钠（STMP）反应，合成了一种交联低溶胀瓜尔胶水凝胶。在本研究中，通过研究（a）预加载的氢化可的松从GGP水凝胶释放到含有或不含有GG降解酶（α-半乳糖苷酶和β-甘露聚糖酶）的缓冲溶液中的释放动力学，以及（b）直接测量聚合物在清醒大鼠盲肠中的降解，分析了GG交联产物（GGP）作为可能的结肠特异性药物载体的功能。还测量了GG饮食对大鼠盲肠中α-半乳糖苷酶和β-甘露聚糖酶活性以及GGP降解的影响。发现产物GGP-0.1（与0.1当量的STMP松散交联）能够在pH = 6.4的PBS中至少6小时内阻止其80％的氢化可的松负载释放。当将α-半乳糖苷酶和β-甘露聚糖酶的混合物添加到缓冲溶液中时，观察到氢化可的松释放增强。在大鼠盲肠中的体内降解研究表明，尽管GG进行了化学修饰，但其仍以交联剂浓度依赖性方式保留其酶降解特性。与未饮食相比，研究前八天的GG饮食使大鼠盲肠中的α-半乳糖苷酶活性增加了三倍。然而，这种酶活性的增加并不能改善不同GGP产物的降解。发现大鼠盲肠中的总体α-半乳糖苷酶活性是细胞外的，而β-甘露聚糖酶的活性是与细菌细胞壁相关的。结论是，由于与STMP交联的CG可以被酶促生物降解并且能够延缓低水溶性药物的释放，因此该聚合物有可能用作结肠特异性药物递送的载体。
