ORAL DELIVERY OF A SUSTAINED ESTRADIOL DELIVERY SYSTEM

持续雌二醇递送系统的口服递送

• 批准号: 3508186
• 负责人: KERRY S ESTES
• 金额: $ 22.98万
• 依托单位: PHARMOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3508186
• 关键词: drug administration routes; drug delivery systems; estradiol

Based on the demonstrated feasibility shown in Phase I studies for oral administration of 17 beta-Estradiol (E2) using a novel redox system, Phase II studies are proposed which are designed to develop and test prototype formulations for bioavailability. The redox- based chemical delivery system (CDS) is based on an interconversion of a lipophilic dihydropyridine to a hydrophilic pyridinium salt, analogous to the NADH NAD+ coenzyme system. It permits enhanced and sustained E2 delivery to the central nervous system by hydrolysis of a "locked-in" charged precursor to E2 and the non- toxic carrier. Studies in rats showed sustained LH inhibition, decreased body weight gain and increased brain drug levels after i.v. treatment which were not associated with elevated serum E2 values. The E2-CDS was incorporated into a modified cyclodextrin inclusion complex which stabilized the labile drug and greatly improved water solubility. Significantly bioavailability was shown after oral dosing in rats which appears to be the result of oral mucosa or buccal absorption. The objectives of proposed studies i) screen CDS-E2 analog for improved oral bioavailability, ii) pharmaceutically evaluate formulations toward a prototype oral/buccal tablet, and iii) establish pharmacokinetics and bioavailability of the prototype formulation in a non-rodent model. Development of an oral or oral mucosa formulation for E2-CDS offers several advantages over currently available therapies including: i) delivery of a naturally occurring steroid, ii) decreased peripheral estrogen activity and iii) increased dosing interval.

根据I期研究中显示的可行性， 使用新的氧化还原酶口服给药17 β-雌二醇（E2） 第二阶段研究的目的是开发 并测试原型制剂的生物利用度。 氧化还原- 基于化学输送系统（CDS）是基于一个相互转换 亲脂性二氢吡啶转化为亲水性吡啶鎓盐， 类似于NADH NAD+辅酶系统。 它允许增强 并持续向中枢神经系统输送E2， 将“锁定”带电前体水解为E2， 有毒载体 对大鼠的研究显示持续的LH抑制， 体重增加减少，大脑药物水平增加， 与血清E2升高无关的静脉给药 价值观 将E2-CDS掺入到改性的环糊精中， 包合物，稳定了不稳定的药物， 改善的水溶性。 生物利用度显著 大鼠经口给药后， 粘膜或口腔吸收。 拟议研究的目标 i）筛选CDS-E2类似物以改善口服生物利用度，ii） 药物评估配方朝向原型 口服/口含片，和iii）建立药代动力学， 在非啮齿动物模型中原型制剂的生物利用度。 用于E2-CDS的口腔或口腔粘膜制剂的开发提供了 与目前可用的疗法相比有几个优势，包括： i）递送天然存在的类固醇，ii）减少 外周雌激素活性和iii）增加的给药间隔。