COLON-SPECIFIC DRUG DELIVERY

拟议研究的主要目标是继续 结肠特异性前药的开发和表征- 基于交付系统。 的亲水性前药衍生物 药物将以合成方式制备。 的 前药包括地塞米松和泼尼松龙糖苷， 5-氨基水杨酸的半琥珀酸盐。 这些化合物 在胃和小肠中吸收不良。 一旦 化合物到达大肠， 微生物酶，前体部分被设计为被水解 释放游离药物，然后可以被结肠吸收， 粘膜 这种输送系统在本地化的 治疗炎症性肠病（IBD）。 本研究将 评估的交付，释放和吸收的各个方面， 用这种输送系统输送药物， 和疾病模拟（角叉菜胶诱导的结肠炎）豚鼠。 此外，该递送系统治疗模拟IBD的能力在以下方面是显著的： 将对豚鼠进行评价。 前药在药物中的稳定性 溶液在几个pH水平（2.5，6.0和7.5）和肠道 将评价内容物（体外）。 前药（和相应的 母体药物）将同时给予正常和患病患者 动物胃插管。 动物们以后会 牺牲，和水解的位置和程度， 将测定胃肠道。 的任何差异 正常和患病动物之间的下肠递送 会被注意到。 在另一组实验中， 该递送系统的药代动力学特征将是 评估。 的生物利用度和平均吸收时间 来自其前药形式的游离药物（和作为游离药物）将被 测定了 结肠组织中游离药物浓度 将比较口服给药前药后 口服后游离药物的组织浓度 给予游离药物和静脉内给予游离药物 药 豚鼠将被给予3%降解的角叉菜胶 在他们的饮用水，以诱导盲肠溃疡， 结肠 这些动物将用于评价 相对于正常动物的药代动力学以及 相对于传统的治疗IBD， 途径（口服或游离药物给药）。

The principal objective of the proposed research is to continue development and characterization of a colon-specific, prodrug- based delivery system. Hydrophilic prodrug derivatives of antiinflammatory drugs will be prepared synthetically. The prodrugs include dexamethasone and prednisolone glycosides and the hemisuccinate of 5-aminosalicylate. These compounds are poorly absorbed in the stomach and small intestine. Once the compounds reach the large intestine and the high concentration of microbial enzymes, the promoiety is designed to be hydrolyzed releasing the free drug, which can then be absorbed by the colonic mucosa. This delivery system should be effective in the localized treatment of inflammatory bowel disease (IBD). This study will evaluate all aspects of the delivery, release, and absorption of antiinflammatory drugs with this delivery system in both normal and disease-simulated (carrageenan-induced colitis) guinea pigs. Also, the ability of this delivery system to treat simulated IBD in the guinea pig will be evaluated. The stability of the prodrugs in solution at several pH levels (2.5, 6.0, and 7.5) and intestinal contents (in vitro) will be evaluated. The prodrugs (and respective parent drugs) will be administered to both normal and diseased animals by gastric intubation. The animals will later be sacrificed, and the location and extent of hydrolysis in the gastrointestinal tract will be determined. Any differences in delivery to the lower bowel between normal and diseased animals will be noted. In a separate set of experiments, the pharmacokinetic characteristics of this delivery system will be evaluated. The bioavailability and mean absorption time of the free drugs from their prodrug forms (and as free drugs) will be measured. The concentration of free drug in colonic tissues following oral administration of the prodrugs will be compared with tissue concentrations of free drug following oral administration of free drug and i.v. administration of the free drug. Guinea pigs will be administered 3% degraded carrageenan in their drinking water to induce ulceration of the cecum and colon. These animals will be used to evaluate any changes in the pharmacokinetics relative to normal animals as well as the ability of this delivery system to treat IBD relative to the traditional route (oral of administration of the free drug).