COLON-SPECIFIC DRUG DELIVERY

拟议研究的主要目标是继续 一种结肠特异的前药--的开发和鉴定 以交付系统为基础。阿司匹林亲水性前药衍生物 将合成抗炎药。这个 前药包括地塞米松和强的松龙糖苷和 5-氨基水杨酸的半琥珀酸单酯。这些化合物是 胃和小肠吸收不良。一旦 化合物到达大肠，高浓度的 微生物酶，促进剂是被设计用来水解的 释放游离药物，然后被结肠吸收 粘膜。这种递送系统应该在本地化的 治疗炎症性肠病(IBD)。这项研究将 评估药物的交付、释放和吸收的各个方面 抗炎药物与此给药系统均正常 和疾病模拟(卡拉胶诱导的结肠炎)豚鼠。 此外，该传递系统在治疗模拟IBD方面的能力 将对豚鼠进行评估。前药的稳定性考察 在几个pH水平(2.5、6.0和7.5)和肠道中的溶液 将对内容物(体外)进行评估。前药(和各自的 母体药物)将同时用于正常和患病患者 动物经胃管插管。这些动物稍后将被 被牺牲的，以及在 胃肠道将被确定。任何不同之处 正常和患病动物之间向下肠道的分娩 将会被注意到。在另一组单独的实验中， 该给药系统的药代动力学特征为 已评估。微球的生物利用度和平均吸收时间 前药形式的免费药物(以及作为免费药物)将 量过了。结肠组织中游离药物的浓度 在口服前药后，将进行比较 口服后组织中游离药物的浓度 免费药物和静脉注射的管理。免费的行政管理 毒品。将给豚鼠注射3%降解的卡拉胶 会导致盲肠溃疡和 冒号。这些动物将被用来评估 相对于正常动物的药代动力学以及能力 相对于传统的治疗IBD的递送系统 途径(免费药物的口服)。

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).