COLON-SPECIFIC DRUG DELIVERY

结肠特异性给药

• 批准号: 3287354
• 负责人: DAVID R FRIEND
• 金额: $ 12.1万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3287354
• 关键词: Crohn's disease; O glycosidase; amides; antiinflammatory agents; azathioprine; carrageenan; colon disorder; dexamethasone; dosage; drug administration routes; drug delivery systems; drug metabolism; gastrointestinal disorder chemotherapy; gastrointestinal pharmacology; glycosides; hydrolysis; inflammatory bowel diseases; p aminosalicylate; pharmacokinetics; prednisolone; prodrugs; succinates; ulcerative colitis

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).

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 为基础的交付系统。 亲水性前药衍生物 将合成制备抗炎药。 这 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。 这些化合物是 在胃和小肠吸收不良。 一旦 化合物到达大肠并且高浓度 微生物酶，promoiety 被设计用于水解 释放游离药物，然后被结肠吸收 粘膜。 该交付系统应该在本地有效 治疗炎症性肠病（IBD）。 这项研究将 评估递送、释放和吸收的各个方面 具有这种输送系统的抗炎药物在正常情况下 和疾病模拟（角叉菜胶诱导的结肠炎）豚鼠。 此外，该输送系统能够治疗模拟 IBD 将对豚鼠进行评估。 前药的稳定性 多种 pH 值（2.5、6.0 和 7.5）的溶液和肠道 内容（体外）将被评估。 前药（以及各自的 母药）将被给予正常和患病的人 动物通过胃插管。 动物们稍后会 牺牲，以及水解的位置和程度 胃肠道将被确定。 任何差异 正常动物和患病动物之间的下肠输送 将会被注意到。 在一组单独的实验中， 该递送系统的药代动力学特征将是 评价。 生物利用度和平均吸收时间 来自其前药形式的游离药物（以及作为游离药物）将被 测量。 结肠组织中游离药物的浓度 口服前药后将进行比较 口服后游离药物的组织浓度 免费药物和静脉注射的管理自由的管理 药品。 豚鼠将被注射3%的降解角叉菜胶 在他们的饮用水中诱发盲肠溃疡 冒号。 这些动物将被用来评估任何变化 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 的这种递送系统 途径（口服或施用游离药物）。