Dosage Form Design Strategies for Delivery of UC781 and Tenofovir

UC781 和替诺福韦的剂型设计策略

• 批准号: 7898231
• 负责人: Lisa Cencia Rohan
• 金额: $ 33.96万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898231
• 关键词: AIDS prevention; Address; Antiviral Agents; Attention; Biological; Clinic; Clinical Research; Coitus; Crystallization; Data; Degradation Pathway; Development; Dosage Forms; Drug Delivery Systems; Drug Formulations; Drug Stability; Economics; Ensure; Evaluation; Extravasation; Film; Future; Gel; Goals; HIV; Human; In Vitro; Lead; Methods; Monkeys; Nucleotides; Patients; Pharmaceutical Preparations; Production; RNA-Directed DNA Polymerase; Reporting; Research; Reverse Transcriptase Inhibitors; Safety; Series; Site; Social Environment; Solubility; Solvents; Techniques; Technology; Tenofovir; Thermodynamics; Tissues; Toxic effect; UC 781; Vagina; Vaginal Gel; Vaginal delivery procedure; Water; aqueous; base; combat; design; dosage; drug candidate; efficacy testing; improved; manufacturing process; melting; microbicide; non-nucleoside reverse transcriptase inhibitors; oxidation; pathogen; prevent; product development; programs; research clinical testing; scale up; success

Microbicide product development has become an essential focus in the HIV prevention field. These products are applied prior to sexual intercourse to prevent HIV acquisition have the potential to become the first line of defense in combating the spread of HIV. However, acceptable formulations of microbicide candidates are required if this approach is to succeed. Although a number of potential microbicide drug candidates have been identified, little attention has been given to product formulation. The reverse transcriptase inhibitors tenofovir (TFV) and UC781 have significant activity against HIV. Although gel vaginal products are currently being evaluated in the clinic for these candidates, ultimately, it may be necessary to develop multiple dosage platforms to provide users with products that they can readily use within the constraints of their social environment, personal choice, and environmental conditions. In this program, quick dissolve vaginal films will be developed for TFV, UC781, and a combination ofthe two. Film dosage forms are easily applied, are inexpensively manufactured, are easily transportable, and eliminate the need for product applicators. This project also addresses a formulation issue with UC781 which impacts all dosage form types. UC781 has very low aqueous solubility and undergoes oxidative degradation. This attribute makes formulation difficult. In this project, the use of complexation and co-crystallization as a means for solubilization and stabilization of UC781 will be explored. Successful solubilization/stabilization ofthis compound will provide a basis for more efficient incorporation of UC781 into a dosage form. Ultimately a panel of dispersed film and gel formulations and formulations implementing these delivery strategies will be evaluated in a thorough product comparison. The most promising formulations will be advanced to monkey safety and efficacy testing in Project 2 and ultimately scaled up through Core C and brought forward to human studies in Projects 3 and 4. This project also includes evaluation of the potential for the use of melt extrusion which provides certain benefit from a manufacturing and economic standpoint, for the production of TFV and UC781 film products. Manufacture by hot melt extrusion will be compared with aqueous solvent casting technology.

杀菌剂产品的开发已成为艾滋病预防领域的重要焦点。这些产品 在性交前应用以预防艾滋病毒感染有可能成为第一线 防御艾滋病毒的传播。然而，可接受的候选杀菌剂配方是 如果这种方法要成功，就必须这样做。尽管许多潜在的杀菌剂候选药物已 已确定，但很少关注产品配方。逆转录酶抑制剂 替诺福韦 (TFV) 和 UC781 具有显着的抗 HIV 活性。虽然目前凝胶阴道产品 在临床上对这些候选人进行评估，最终可能有必要开发多种剂量 为用户提供在其社交范围内可以轻松使用的产品的平台 环境、个人选择、环境条件。在这个程序中，快速溶解阴道薄膜 将为 TFV、UC781 以及两者的组合开发。薄膜剂型易于应用， 制造成本低廉，易于运输，并且不需要产品涂抹器。这 该项目还解决了 UC781 的配方问题，该问题影响所有剂型类型。 UC781有 水溶性极低并会发生氧化降解。这个属性使得制定变得困难。 在该项目中，使用络合和共结晶作为溶解和稳定化的手段 UC781将被探索。该化合物的成功溶解/稳定将为更多的研究奠定基础 将 UC781 有效掺入剂型中。最终形成分散薄膜和凝胶的面板 配方和实施这些交付策略的配方将在全面的产品中进行评估 比较。最有前途的配方将被推进到猴子安全性和功效测试中 项目 2 最终通过核心 C 进行了扩展，并在项目 3 和项目 4 中进行了人体研究。 该项目还包括对熔体挤出使用潜力的评估，这提供了某些 从制造和经济角度来看，用于生产 TFV 和 UC781 薄膜产品。 热熔挤出制造将与水性溶剂浇铸技术进行比较。