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

药物洗脱纤维可按需提供长期的 HIV 保护

• 批准号: 10576394
• 负责人: Kim A. Woodrow
• 金额: $ 80.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-22 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576394
• 关键词: AIDS prevention; Adherence; Affect; Antiviral Agents; Biological; Biological Availability; Biopsy; Cells; Colposcopy; Cytology; Development; Disadvantaged; Dosage Forms; Dose; Drug Delivery Systems; Drug Kinetics; Drug resistance; Evaluation; Face; Female; Fiber; Formulation; Generations; Geometry; HIV; HIV/AIDS; Incidence; Integrase Inhibitors; International; Irrigation; Lead; Macaca nemestrina; Measurement; Measures; Modality; Monitor; Oral; Parents; Particulate; Performance; Pharmaceutical Preparations; Plasma; Population; Prevention; Prevention strategy; Prodrugs; Property; Prophylactic treatment; Protective Agents; Proteins; Safety; Shapes; Site; Solid; Solubility; Systemic infection; Tissues; Vagina; Vaginal Douching; Water; Woman; Work; amorphous solid; aqueous; cervicovaginal; cytokine; design; dosage; drug action; girls; innovation; microbicide; microbiota; nanocrystal; nonhuman primate; novel; pandemic disease; pre-exposure prophylaxis; prevent; primary outcome; protective efficacy; sexual HIV transmission; simian human immunodeficiency virus; standard measure; vaginal fluid; young woman

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.

抽象的 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 需要每日用药方案才能达到保护功效。1-3 女性口服 PrEP 的功效不成比例 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。因此，女童和年轻妇女对全世界艾滋病毒的应对做出了重大贡献 需要采取一套以女性为重点的预防战略，以对结束这种现象产生有意义的影响 艾滋病毒/艾滋病流行。这包括增加对现有有效口服和局部 PrEP 的获取和遵守 策略，以及寻求替代的艾滋病毒预防方案。按需预防策略 可以间歇性使用的至少 2-4 周的延长保护功效窗口将提供 当前产品未解决的独特预防方式。我们开发了一种创新的药物输送 局部 PrEP 平台使用静电纺丝纤维，显示出持续预防艾滋病毒的潜力。在这个 项目中，我们建议调查起源并延长我们药物的抗病毒药物输送持续时间 将纤维制剂洗脱到组织中。我们项目范围的科学前提基于几个关键 观察。首先，我们已经在美国和国际网站完成了最终用户研究 告知了基于纤维的杀菌剂的尺寸/形状、流变学和性能属性，用于现场 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 反映了最终用户的需求，并且按需预防产品是非常理想和首选的 每日口服或局部 PrEP。其次，我们在猪尾猕猴中进行了测量，单次阴道剂量的三倍剂量 抗逆转录病毒药物洗脱纤维可维持宫颈阴道组织浓度，从而预测生物活性 疗效至少两周。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特性 纳米晶体对其溶解和生物利用度很重要。最后，我们开发了一个整合酶 抑制剂前药，使我们能够通过 LC- 区分配制的前药和释放的母体药物 质谱/质谱。这种前药由于其低水溶性（log P>3)，且母药先前已被证明对暴露前 (PrEP) 和暴露后均有效 (PEP) 局部使用时的预防。根据这些观察，我们建议的工作范围将： 配制长效抗逆转录病毒药物纳米晶体的缓释纤维的设计（目标1），优化纤维 通过对非人类安全性和组织药代动力学的迭代评估来制备固体药物纳米晶体制剂 灵长类动物（目标 2），以及验证反复低剂量阴道 SHIV 攻击的保护功效（目标 3）。我们的 项目框架利用我们的药物洗脱纤维的创新属性来增强其开发 要求局部预防并延长保护时间。