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

基本信息

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
项目类别：
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

项目摘要

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，可抑制保护性乳酸杆菌。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，我们不知道是什么引发了 BV 发作，但我们确实清楚 BV 会产生。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 的性活跃女性可能患有细菌性阴道炎。可以暂时缓解 BV 引起的恶臭分泌物，但不能阻止 BV 重复出现（有时频率高达每月两次）市场上没有产品可以提供。我们和其他人已经证明，LA 可以灭活多种类型的 BV。由于洛杉矶是性传播感染的相关细菌以及多种病原体。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。我们最近确定了健康乳酸杆菌持续产生的速度。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这使我们能够开发出一种可释放 LA 的阴道环 (LA-IVR)。 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乳酸杆菌。不同聚合物基质中 LA 的释放速率，并在此基础上实现 LA 的持续释放。有希望的试点工作，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、然后我们将制作一个猕猴LA-IVR，并在Aim 2中测试LA是否持续释放。通过这种 IVR 可以抑制猪尾猕猴中的 BV 样细菌种类，并成功证明了安全性和有效性。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 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）