Vaginal ring for sustained release of lactic acid to prevent bacterial vaginosis and associated health risks

用于持续释放乳酸以预防细菌性阴道病和相关健康风险的阴道环

• 批准号: 10157763
• 负责人: RICHARD CONE
• 金额: $ 30.65万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157763
• 关键词: Adherence; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Atopobium vaginae; Bacteria; Bacterial Vaginosis; Blinded; Buffers; Chlamydia; Clindamycin; Clinical; Data; Development; Ecosystem; Effectiveness; Elasticity; Ensure; Formulation; Frequencies; Gardnerella vaginalis; Goals; Gonorrhea; HIV; Health; Human; Human Papillomavirus; Hydrophobicity; Lactic acid; Lactobacillus; Lead; Macaca; Macaca nemestrina; Measurement; Measures; Methods; Metronidazole; Microbe; Organism; Phase; Physiological; Placebos; Polymers; Population; Predisposition; Premature Birth; Preparation; Primates; Probiotics; Production; Prophylactic treatment; Public Health; Recurrence; Risk; Role; Safety; Sampling; Sexually Transmitted Diseases; Small Business Innovation Research Grant; Smell Perception; Surface; Swab; Testing; Time; Toxicology; Trichomonas Infections; Vagina; Vaginal Cream; Vaginal Drug Administration; Vaginal Gel; Vaginal Ring; Woman; Work; adverse birth outcomes; adverse pregnancy outcome; bacterial community; base; cost; density; design; dysbiosis; effective therapy; experience; in vivo; low and middle-income countries; mechanical properties; microbicide; microbiome; novel; pathogen; prevent; sexually active; vaginal fluid; vaginal microbiome; vaginal microbiota

Project Summary Millions of women in the U.S. suffer from bacterial vaginosis (BV), a vaginal condition initiated by marked overgrowth of polymicrobial bacterial populations that can suppress protective lactobacilli. Healthy lactobacilli secrete lactic acid (LA) that acidifies the vagina and acts as a broad-spectrum microbicide that protects against many types of pathogens and also can suppress polymicrobial communities of BV species that produce little or no lactic acid. We do not know what initiates episodes of BV, but we do know that BV strongly increases risks of many sexually transmitted infections including HIV, and increases risks of premature births. At any given time, about 1/3 of sexually active women in the U.S. and world-wide have BV. Antibiotics can provide transient relief from the foul-smelling discharge caused by BV but they do not prevent BV from recurring (sometimes at a frequency up to twice a month). There is no product on the market that can provide sustained protection against BV. We and others have shown that LA can potently inactivate many types of BV- associated bacteria as well as many types of pathogens that cause sexually transmitted infections. Since LA is abundant in the healthy vaginas of women with protective lactobacilli, it has the potential to provide a safe nontoxic microbicide. We have recently determined the rate at which healthy lactobacilli continuously produce LA and hence for the first time know the rate at which lactic acid should be supplied to the vagina to treat and prevent BV. This has enabled us to develop an LA-releasing intravaginal ring (LA-IVR) that can provide sustained release of LA over 30 days at the rate needed to treat and prevent BV while not suppressing healthy lactobacilli. Through careful selection of polymers and formulation design, we have shown that we can tune the release rates of LA from various polymeric matrices, and achieve sustained release of LA. Building on our promising pilot work, we seek in Aim 1 to optimize our lead LA-IVR formulation, and perform various characterizations including LA release rates over time, hydrophobicity, and mechanical properties (elasticity, compressibility). We will then fabricate a macaque LA-IVR, and in Aim 2 test whether sustained release of LA by this IVR can suppress BV-like bacterial species in pigtail macaques. Successful demonstration of safety and efficacy in this highly relevant large animal model would support advancing Mucommune’s LA-IVR through IND-enabling activities. The simplicity of our LA-IVR design ensures both ease of production and likely very low manufacturing costs of the eventual product, which in turn should maximize potential public health impact and commercial viability of the product both in the U.S. and in low and middle income countries worldwide. (26 lines)

项目概要 在美国，数以百万计的女性患有细菌性阴道病 (BV)，这是一种由明显的细菌引起的阴道疾病。 多种微生物菌群过度生长，可以抑制保护性乳酸杆菌。健康乳酸菌 分泌乳酸 (LA)，酸化阴道并充当广谱杀菌剂，保护阴道 对抗多种病原体，还可以抑制 BV 物种的多种微生物群落， 产生很少或不产生乳酸。我们不知道 BV 发作的原因是什么，但我们确实知道 BV 强烈 增加许多性传播感染（包括艾滋病毒）的风险，并增加早产的风险。 在任何特定时间，美国和世界范围内约 1/3 性活跃的女性患有 BV。抗生素可以 可以暂时缓解 BV 引起的恶臭分泌物，但不能阻止 BV 重复发生（有时频率高达每月两次）。市场上没有产品可以提供 针对 BV 的持续保护。我们和其他人已经证明，LA 可以有效灭活多种类型的 BV- 相关细菌以及引起性传播感染的多种病原体。由于洛杉矶是 女性健康的阴道中含有丰富的保护性乳酸菌，它有可能提供安全的阴道保护。 无毒杀菌剂。我们最近确定了健康乳酸菌持续产生的速率 洛杉矶因此第一次知道应向阴道供应乳酸以治疗和治疗的速率 预防 BV。这使我们能够开发出一种 LA 释放阴道环 (LA-IVR)，它可以提供 LA 在 30 天内以治疗和预防 BV 所需的速率持续释放，同时不抑制健康 乳酸杆菌。通过仔细选择聚合物和配方设计，我们已经证明我们可以调整 LA从各种聚合物基质中的释放速率，并实现LA的持续释放。建立在我们的 有前景的试点工作，我们在目标 1 中寻求优化我们的领先 LA-IVR 配方，并执行各种 表征包括 LA 随时间的释放速率、疏水性和机械性能（弹性、 压缩性）。然后我们将制作一只猕猴LA-IVR，并在Aim 2中测试是否持续释放LA 通过这种 IVR 可以抑制猪尾猕猴中的 BV 样细菌种类。安全性和安全性的成功示范 在这种高度相关的大型动物模型中的功效将支持通过以下方式推进 Mucommune 的 LA-IVR 支持 IND 的活动。我们的 LA-IVR 设计的简单性确保了易于生产并且可能非常低 最终产品的制造成本，这反过来又应最大限度地提高潜在的公共健康影响和 该产品在美国以及全球低收入和中等收入国家的商业可行性。 （26行）