Gliko-Kabir I, Yagen B, Penhasi A, Rubinstein A
The Hebrew University of Jerusalem, School of Pharmacy, Israel.
Pharm Res. 1998 Jul;15(7):1019-25. doi: 10.1023/a:1011921925745.
(a) To reduce the swelling properties of guar gum (GG) by crosslinking it with glutaraldehyde (GA), while maintaining its degradation properties in the presence of typical colonic enzymes, (b) to characterize the modified GG and to examine its degradation properties in vitro and in vivo, and (c) to assess, by drug probes with different water solubilities, the potential of the crosslinked GG to serve as a colon-specific drug carrier.
GG was crosslinked with increasing amounts of GA under acidic conditions to obtain different products with increasing crosslinking densities. These products were characterized by measuring (a) their swelling properties in simulated gastric and intestinal fluids, (b) their crosslinking densities, (c) the release kinetics of three different drugs: sodium salicylate (SS), indomethacin (Indo) and budesonide (Bud) from the crosslinked products into buffer solutions, with or without a mixture of galactomannanase and alpha-galactosidase, and (d) their in vivo degradation in the cecum of conscious rats with and without antibiotic treatment.
Significant reduction in GG swelling properties, in both simulated gastric and intestinal fluids, was accomplished by its crosslinking with GA. The crosslinking density of the modified GG products was GA concentration-dependent. The release of SS from crosslinked GG discs was completed within 120 minutes. During the same period of time and for more than 10 hours the release of Indo and Bud was negligible. The release rate of the latter two drugs was enhanced when galactomannanase and alpha-galactosidase were added to the dissolution media. Discs made of the crosslinked GG were implanted in the cecum of rats and their degradation was assessed after 4 days. The extent of degradation was dependent on the amount of GA used for the crosslinking. After 4 days the same discs were recovered intact from rats exposed to antibiotic treatment and from simulated gastric and intestinal fluids.
Reducing the enormous swelling of GG by crosslinking it with GA resulted in a biodegradable hydrogel which was able to retain poorly water soluble drugs, such as Indo and BUD, but not highly water soluble drugs, such as SS, in artificial gastrointestinal fluids. A variety of hydrogels with increasing crosslinking densities were produced and tested for their potential use as colon-specific drug platforms in vitro and in vivo. Their performance did not depend on creating physical barriers by means of compression.
(a) 通过将瓜尔胶（GG）与戊二醛（GA）交联来降低其溶胀性能，同时在典型结肠酶存在的情况下保持其降解性能；(b) 对改性瓜尔胶进行表征，并在体外和体内研究其降解性能；(c) 通过使用不同水溶性的药物探针，评估交联瓜尔胶作为结肠特异性药物载体的潜力。
在酸性条件下，用逐渐增加量的GA使GG交联，以获得交联密度不断增加的不同产物。通过测量以下各项对这些产物进行表征：(a) 它们在模拟胃液和肠液中的溶胀性能；(b) 它们的交联密度；(c) 三种不同药物——水杨酸钠（SS）、吲哚美辛（Indo）和布地奈德（Bud）从交联产物释放到缓冲溶液中的释放动力学，释放过程中有无半乳甘露聚糖酶和α-半乳糖苷酶混合物；(d) 它们在有无抗生素治疗的清醒大鼠盲肠中的体内降解情况。
通过GG与GA交联，在模拟胃液和肠液中其溶胀性能均显著降低。改性瓜尔胶产物的交联密度与GA浓度相关。交联瓜尔胶圆盘在120分钟内完成了SS的释放。在相同时间段内，Indo和Bud的释放量在10多个小时内可忽略不计。当向溶解介质中添加半乳甘露聚糖酶和α-半乳糖苷酶时，后两种药物的释放速率加快。将交联瓜尔胶制成的圆盘植入大鼠盲肠，4天后评估其降解情况。降解程度取决于用于交联的GA量。4天后，从接受抗生素治疗的大鼠以及模拟胃液和肠液中完整回收相同的圆盘。
通过GG与GA交联降低其巨大的溶胀性，得到了一种可生物降解的水凝胶，该水凝胶在人工胃肠液中能够保留难溶性药物，如Indo和BUD，但不能保留高水溶性药物，如SS。制备了多种交联密度不断增加的水凝胶，并在体外和体内测试了它们作为结肠特异性药物平台的潜在用途。它们的性能并不依赖于通过压缩形成物理屏障。
