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

摘要 口服暴露前预防(PrEP)改变了艾滋病毒预防领域，但严格遵守 需要每日服药方案才能达到保护效果1-3妇女口服PrEP的不成比例疗效 也导致了对已经因艾滋病毒升高而处于不利地位的人口的更严格的遵守要求 全球发病率。女孩和年轻妇女对全世界艾滋病毒的面貌做出了重大贡献 有必要采取一套以女性为重点的预防战略，对结束 艾滋病毒/艾滋病大流行。这包括增加对现有有效的口头和局部PrEP的接触和坚持 战略，以及寻求替代艾滋病毒预防方案。按需预防战略， 可间歇使用的至少2-4周的保护效力延长窗口将提供 独一无二的预防模式，目前的产品没有解决。我们已经开发出一种创新的药物输送方式 外用PrEP平台，使用电纺纤维，显示出持续预防艾滋病毒的潜力。在这 项目，我们建议调查我们的药物的来源和延长抗病毒药物的给药期限- 将纤维配方洗脱到组织中。我们项目范围的科学前提是基于几个关键 观察。首先，我们已经完成了在美国国内和国际站点的最终用户研究，这些站点具有 已告知一种纤维基杀微生物剂的大小/形状、流变性和性能属性 要求预防艾滋病毒。这些研究和其他研究表明，设计以纤维为基础的剂型是可行的 这反映了终端用户的需求，而且按需预防产品是非常可取和首选的 每日口服或外用PrEP。其次，我们在辫尾猕猴身上测量到，单次阴道剂量是三次 ARV药物洗脱纤维维持宫颈阴道组织的浓度，这将是生物学上的预测 药效至少两周。我们将调查这种持续药物释放的来源，并有望找到 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特性 对其溶解和生物利用度很重要的纳米晶体。最后，我们开发了一种整合酶 抑制剂前药，使我们能够通过LC区分配方前药和释放的母药- MS/MS这种前药由于其低的水溶解度(LOG)，是一种很有前途的研磨成纳米晶的候选药物 P&gt；3)，并且先前已证明母药对暴露前(PrEP)和暴露后都有效 (PEP)局部使用时的预防作用。基于这些观察，我们提议的工作范围将是：迭代 长效抗逆转录病毒药物纳米晶缓释纤维的设计(目标1)，优化纤维 迭代评价固体药物纳米晶的安全性和非人体组织药代动力学 灵长类动物(目标2)，并验证对重复低剂量阴道SIV攻击的保护效果(目标3)。我们的 项目框架利用我们药物洗脱纤维的创新属性来加强它们的开发，以实现 要求局部预防，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.