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: 10092098
• 负责人: Kim A. Woodrow
• 金额: $ 78.24万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092098
• 关键词: AIDS prevention; AIDS/HIV problem; Adherence; Adhesives; 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; 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; base; cervicovaginal; cytokine; design; dosage; 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; AIDS prevention; AIDS/HIV problem; Adherence; Adhesives; 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; 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; base; cervicovaginal; cytokine; design; dosage; 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 口服预防预防（PREP）已转化了预防HIV的领域，但严格遵守 每日药物需要达到保护效果。1-3口服准备的疗效不成比例 还导致对艾滋病毒已经处于不利地位的人口的依从性提出了更严格的要求 全球发病率。因此，女孩和年轻妇女在全球的艾滋病毒面孔中做出了重大贡献 必须采用一系列预防策略，专注于女性，以对结束结束产生有意义的影响 艾滋病毒/艾滋病大流行。这包括增加访问和遵守现有的有效口头和局部准备 策略以及寻求替代性艾滋病毒预防选择。按需预防策略 保护性疗效至少2-4周的扩展窗口可间歇使用将提供 当前产品未解决独特的预防方式。我们已经开发了一种创新的药物 使用电纺纤维的局部准备平台，这些纤维显示出预防HIV的潜力。在这个 项目，我们建议研究起源并从我们的药物中延长抗病毒药物的持续时间 将纤维制剂洗脱到组织中。我们项目范围的科学前提是基于几个关键 观察。首先，我们已经完成了美国境内和国际网站的最终用户研究 告知基于纤维的菌心的大小/形状，流变学和性能特性 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求，而按需预防产品是非常可取的，并且首选 每天口服或局部准备。其次，我们在辫子猕猴中测量了一个三重阴道剂量 ARV药物洗脱纤维保持宫颈阴道组织浓度，这将是生物学的鉴定 功效至少两个星期。我们将调查此持续药物释放的起源，并希望找到 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性能 纳米晶体对于它们的溶解和生物利用度很重要。最后，我们开发了一个集成酶 抑制剂前药，使我们能够通过LC-区分配方的前药和释放的母体药物 MS/MS。由于其水溶性低（日志） p> 3），并以前已证明母体对前（PREP）和暴露后有效 （PEP）局部使用时预防。基于这些观察，我们提出的工作范围将：迭代 延长释放纤维制定长效ARV药物纳米晶体的设计（AIM 1），优化纤维 通过迭代评估非人类的安全和组织药代动力学的固体药物纳米晶体制剂 灵长类动物（AIM 2），并从重复的低剂量阴道SHIV挑战（AIM 3）中验证保护性疗效。我们的 项目框架利用我们洗脱纤维的创新属性来增强其开发 要求局部预防，并延长保护持续时间。