Drug-eluting fibers for on-demand and extended protection against HIV

摘要 口服暴露前预防（PrEP）已经改变了艾滋病毒预防领域，但严格遵守 每日药物方案需要达到保护效果。1 -3口服PrEP在女性中的疗效不成比例 这也导致了对已经因艾滋病毒感染率较高而处于不利地位的人群的更严格的依从性要求 全球发病率。女孩和年轻妇女对全世界艾滋病毒的传播作出了重大贡献， 因此，有必要制定一套以女性为重点的预防战略，以便对结束 艾滋病毒/艾滋病大流行。这包括增加现有有效的口服和局部PrEP的可及性和依从性 战略，以及寻求替代性艾滋病毒预防方案。按需预防战略， 至少2-4周的保护效力延长窗口，可以间歇使用， 目前的产品没有解决的独特预防模式。我们开发了一种创新的药物输送系统 该平台使用静电纺丝纤维，显示出持续预防艾滋病毒的潜力。在这 项目，我们建议调查的起源，并延长从我们的药物抗病毒药物输送的持续时间- 将纤维制剂洗脱到组织中。我们的项目范围的科学前提是基于几个关键 意见。首先，我们已经完成了美国和国际站点的最终用户研究， 通知的大小/形状，流变学和性能属性的纤维基杀微生物剂打算上， 要求预防艾滋病毒。这些研究和其他研究表明，设计基于纤维的剂型是可行的 这反映了最终用户的需要，按需提供的预防产品是非常可取和首选的 第二，我们在猪尾猕猴中测量了单次阴道剂量的三倍剂量的PrEP。 抗逆转录病毒药物洗脱纤维保持宫颈阴道组织浓度，这将是生物学的预测 药效至少两周。我们将调查这种持续药物释放的起源，并期望找到 我们的纤维剂量概括了长效药物的颗粒和无定形固体分散体性质， 纳米晶体对于它们的溶解和生物利用度是重要的。最后，我们开发了整合酶， 抑制剂前药，使我们能够区分配制的前药和释放的母体药物， 该前药由于其低水溶性（log）而成为研磨成纳米晶体的有希望的候选物 P>3），并且母体药物先前已被证明对暴露前（PrEP）和暴露后均有效 (PEP)局部使用时预防。根据这些观察，我们建议的工作范围将： 长效抗逆转录病毒药物纳米晶缓释纤维的设计（目的1），优化纤维 通过在非人中反复评价安全性和组织药代动力学的固体药物纳米晶体制剂 灵长类动物（目标2），以及重复低剂量阴道SHIV攻击的保护功效（目标3）。我们 项目框架利用我们的药物洗脱纤维的创新属性，以促进其在 需要局部预防并延长保护期。

ABSTRACT Oral pre-exposure prophylaxis (PrEP) has transformed the field of HIV prevention, but rigorous adherence to daily drug regiments is required to achieve protective efficacy.1-3 Disproportionate efficacy of oral PrEP in women has also led to more stringent requirements for adherence in a population already disadvantaged by higher HIV incidence rates globally. Girls and young women contribute significantly to the face of HIV worldwide thus necessitating a suite of prevention strategies focused on females to make a meaningful impact on ending the HIV/AIDS pandemic. This includes increasing access and adherence to existing effective oral and topical PrEP strategies, as well as pursing alternative HIV prevention options. On-demand prevention strategies with an extended window of protective efficacy of at least 2-4 weeks that could be used intermittently would offer a unique prevention modality not addressed by current products. We have developed an innovative drug delivery platform for topical PrEP that uses electrospun fibers that show potential for sustained HIV prevention. In this project, we propose to investigate the origins and extend the duration of antiviral drug delivery from our drug- eluting fiber formulations into tissue. The scientific premise for our project scope is based on several key observations. First, we have completed end-user studies both within the U.S. and at international sites that have informed the size/shape, rheological and performance attributes of a fiber-based microbicide intended for on- demand HIV prevention. These studies and others indicate that it is feasible to design a fiber-based dosage form that reflects the needs of end-users, and that on-demand prevention products are highly desirable and preferred to daily oral or topical PrEP. Second, we have measured in pigtail macaques that a single vaginal dose of a triple ARV drug-eluting fiber maintains cervicovaginal tissue concentrations that would be predicative of biological efficacy for at least two weeks. We will investigate the origin of this sustained drug release, and expect to find that our fiber dosages recapitulate the particulate and amorphous solid dispersion properties of long-acting drug nanocrystals that are important for their dissolution and bioavailability. Finally, we have developed an integrase inhibitor prodrug that allows us to differentiate between formulated prodrug and released parent drug by LC- MS/MS. This prodrug is a promising candidate for milling into nanocrystals due to it low aqueous solubility (log P>3), and the parent drug has been previously shown to be effective for both pre- (PrEP) and post-exposure (PEP) prophylaxis when used topically. Based on these observations, our proposed scope of work will: Iterate the design of extended-release fibers formulating long-acting ARV drug nanocrystals (Aim 1), Optimize fiber formulations of solid drug nanocrystals by iterative evaluation of safety and tissue pharmacokinetics in nonhuman primates (Aim 2), and Validate protective efficacy from a repeated low-dose vaginal SHIV challenge (Aim 3). Our project framework leverages innovative attributes of our drug-eluting fibers to enhance their development for on- demand topical prevention with an extended duration of protection.