Long Acting Acceptable Microbicides: Novel Delivery, Activity and Pharmacodynamic

将开发两种新的杀微生物剂原型产品：一种基于阴道环状给药系统，另一种基于生物响应性(智能)凝胶给药载体。这两种产品都将设计成具有以下特性：(1)延长其在阴道中的停留时间，使其使用不依赖性交；(2)体现单一或组合的抗艾滋病毒杀菌剂；以及(3)具有良好的妇女接受性。这种智能凝胶在植入后最初会很好地涂抹，然后增加物理完整性，并保持至少24小时。阴道内环将在一个月或更长的时间内持续输送恒定剂量的杀微生物剂分子。新车辆将开发和交付三个新的有效成分家族。这些分子针对HIV感染和复制途径中的多个步骤，包括双重作用的嘧啶二酮类(抑制病毒进入和逆转录)、ISIS 5320(抑制CD4-gp120介导的附着)和病毒灭活NCp7抑制物。总的来说，这些活性成分既针对无细胞病毒，也针对细胞相关病毒。将设计和实施使用凝胶或环的最佳配方策略。拟议的工作范围包括新的基础科学和技术、临床前开发和探索性临床开发。候选的新型杀微生物剂将在活性、稳定性和对野生型和抗药性病毒的效力方面进行优化。药物化学将继续在单一或组合产品中提供具有增强抗病毒性能的化合物。新的杀微生物剂科学和技术将填补该领域的关键空白，并培育在阴道部署和药物输送功能方面得到优化的新给药系统。同时，凝胶和环的可接受性的现有知识和评估方法将得到扩展，这些载体的物理属性将被设计为同时优化行为可接受性和生物功能。产品开发将与对艾滋病毒中和机制、输送系统生物材料和功能、杀微生物剂产品药代动力学和药效学以及人类感知和可接受性的新的科学理解同步进行。这套新的实验方法和药代动力学和药效学模型旨在可翻译为在杀菌剂管道中广泛使用。

Two new prototype microbicide products will be developed: one based on an intravaginal ring delivery system and one on a bioresponsive (smart) gel delivery vehicle. Both products will be designed to function with the following attributes: (1) extended residence in the vagina such that their use is not coitally dependent; (2) embody either single or combination anti-HIV microbicides; and (3) have favorable acceptability by women. The smart gel will spread well initially upon insertion, and then increase in physical integrity and remain in place for at least 24 hours. The intravaginal ring will deliver a constant dose of microbicide molecules continuously over a duration of one month or greater. Three new families of active ingredients will be developed and delivered by the new vehicles. These molecules target multiple steps in the HIV infection and replication pathway and include the dual acting pyrimidinediones (inhibit virus entry and reverse transcription), ISIS 5320 (inhibits CD4-gp120 mediated attachment) and the virus inactivating NCp7 inhibitors. Collectively, these active ingredients target both cell-free and cell-associated virus. Optimal formulation strategies employing either gels or rings will be designed and implemented. The proposed work scope integrates new basic science and technology, preclinical development and exploratory clinical development. The candidate novel microbicides will be optimized for activity, stability and potency against both wild type and drug-resistant viruses. Medicinal chemistry will continue to provide compounds with enhanced antiviral properties in single or combination products. The new microbicide science and technology will fill critical gaps in the field, and foster new delivery systems that are optimized with respect to vaginal deployment and drug delivery functions. Simultaneously, current knowledge and evaluation methods for acceptability of gels and rings will be expanded, and physical attributes of these vehicles will be designed to co-optimize both behavioral acceptability and biological functionality. Product development will progress in synchrony with the new scientific understanding of HIV neutralization mechanisms, delivery system biomaterials and functionality, microbicide product pharmacokinetics and pharmacodynamics, and human perception and acceptability. The set of novel new experimental methods and pharmacokinetic and pharmacodynamic models is intended to be translatable for widespread use in the microbicide pipeline.