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：一种基于阴道内环输送系统，另一种基于生物反应（智能）凝胶输送载体。这两种产品的设计都具有以下特性：(1)延长在阴道内的停留时间，这样它们的使用就不依赖于性交；(2)含有单一或联合抗hiv杀菌剂；(3)具有良好的女性接受度。智能凝胶在插入后会很好地扩散，然后在物理完整性上增加，并在原位保持至少24小时。阴道内环将在一个月或更长的时间内连续提供恒定剂量的杀微生物剂分子。三种新的活性成分系列将由新车开发和交付。这些分子靶向HIV感染和复制途径中的多个步骤，包括双作用嘧啶二酮（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抑制剂。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。采用凝胶或环的最佳配方策略将被设计和实施。提出的工作范围包括新的基础科学技术、临床前开发和探索性临床开发。候选的新型杀微生物剂将对野生型和耐药病毒的活性、稳定性和效力进行优化。药物化学将继续在单个或组合产品中提供具有增强抗病毒特性的化合物。新的杀菌剂科学和技术将填补该领域的关键空白，并促进在阴道部署和药物递送功能方面进行优化的新给药系统。同时，将扩展现有的凝胶和环的可接受性知识和评估方法，并设计这些车辆的物理属性，以共同优化行为可接受性和生物功能。产品开发将与HIV中和机制、递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科学认识同步进行。这一套新的实验方法和药代动力学和药效学模型旨在广泛应用于杀微生物剂管道。

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.