Combination HIV prevention in drug-eluting fibers: designing for efficacy and use

描述（由申请人提供）：我们已经开发了一种用于阴道药物递送的创新剂型，其使用通过静电纺丝制造的聚合物纤维。药物洗脱纤维具有独特的材料和加工特征，使其有别于现有的杀微生物剂产品。迄今为止，我们的工作已经显示了聚合物纤维的多功能性，用于快速和持续递送各种单独和组合的抗逆转录病毒药物，以制造不同微观结构的复合材料，并使用制造规模的静电纺丝工艺生产。然而，任何单一杀微生物剂药物递送系统的进一步进步和发展必须优先考虑产品体现影响用户感知的物理属性，而不损害生物功效的设计。虽然我们先前的结果推进了使用药物洗脱纤维作为局部递送用于HIV预防的组合ARV药物的新剂型的概念，但尚未证明这种新平台技术被设计用于针对阴道HIV挑战的化学预防保护功效同时表现出具有足够用户感知性（几何形状、质地、溶解时间和粘度）的散装材料性质的可行性。我们在这里提出了一个项目框架，以通知第一代基于纤维的局部杀微生物剂的设计，该设计受到用户感知和NHP安全性/PK研究的优先功能的限制。该提案整合了三个主要研究领域：（i）纤维DDS原型设计和配方;（ii）用户指导的产品设计和评估;以及（iii）NHP安全性/PK和功效测试。我们的框架是一个迭代过程，以设计、测试和选择针对用户感知（目标1）和生物安全性/PK（目标2）进行优化的领先候选纤维DDS原型，然后推进NHP的阴道挑战有效性研究（目标3）。我们选择了一种新的三联抗逆转录病毒药物组合，以证明纤维DDS的强度，以提供物理化学多样的药物，具有不同的抗HIV作用机制，并显示出瞬时抑制潜力，以阻止病毒复制。我们还建议设计纤维织物，调节药物释放的围和持续保护。最后，我们在临床前开发的早期纳入了切入产品可接受性研究 新的杀微生物剂产品，以帮助指导配方的生物物理和其他属性的设计，对用户的依从性产生最大的影响。这些研究将首次证实，纤维基杀微生物剂的设计可以优先考虑对用户体验至关重要的物理特性，同时优先考虑预防阴道HIV感染的功能特性。这些创新的广泛影响将支持纤维杀微生物剂快速推进首次人体临床试验。

DESCRIPTION (provided by applicant): We have developed an innovative dosage form for vaginal drug delivery using polymeric fibers fabricated by electrospinning. Drug-eluting fibers exhibit unique materials and processing features that distinguish them from existing microbicide products. Our work to date has shown the versatility of polymer fibers for rapid and sustained delivery of diverse ARV drugs alone and in combination, to fabricate composite materials of varying microstructure, and to be produced using a manufacturing-scale electrospinning process. However, the further advancement and development of any single microbicide drug delivery system must prioritize that the product embody physical attributes that impact user perceptions without compromising the design for biological efficacy. While our previous results advance the concept of using drug-eluting fibers as a new dosage form for topical delivery of combination ARV drugs for HIV prevention, the feasibility of this new platform technology to be designed for chemoprophylactic protective efficacy against vaginal HIV challenge while exhibiting bulk material properties with adequate user perceptibility (geometry, texture, dissolution time and viscosity) has not been demonstrated. We propose here a project framework to inform the design of a first-generation fiber-based topical microbicide that is constrained for functions prioritized from user perception and NHP safety/PK studies. This proposal integrates three primary research areas: (i) Fiber DDS prototype design and formulation; (ii) User-guided product design and evaluation, and (iii) NHP safety/PK and efficacy testing. Our framework is an iterative process to design, test, and select lead candidate fiber DDS prototypes that are optimized for user perceptions (Aim 1) and biological safety/PK (Aim 2), before advancing to a vaginal challenge efficacy study in NHPs (Aim 3). We selected a novel triple ARV drug combination to demonstrate the strength of the fiber DDS to deliver agents that are physico-chemically diverse, have differing mechanisms of action against HIV, and show instantaneous inhibitory potential in combination to halt virus replication. We also propose to design fiber fabrics that modulate drug release for both pericoital and sustained protection. Finally, we incorporate incisive product acceptability studies early in the preclinical development of a new microbicide product to help guide the design of the formulation's biophysical and other attributes to have the greatest impact on user adherence. These studies will be the first to confirm that fiber-base microbicides can be designed to prioritize physical properties that are critical to the user experience, while at the same time prioritizing functional properties that prevent vaginal HIV infection. The broader impact of these innovations will support the rapid advancement of a fiber microbicide to first-in-human clinical trials.