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

项目摘要 美国有数百万妇女患有细菌性阴道病（BV），这是一种由明显的阴道炎引起的阴道疾病。 可抑制保护性乳酸杆菌的多微生物细菌群体的过度生长。健康乳酸菌 分泌乳酸（LA），使阴道酸化，并作为一种广谱杀微生物剂， 针对许多类型的病原体，并且还可以抑制BV物种的多微生物群落， 产生很少或不产生乳酸。我们不知道是什么引发了BV发作，但我们知道BV强烈地 增加了包括艾滋病毒在内的许多性传播感染的风险，并增加了早产的风险。 在任何时候，美国和世界范围内约有1/3的性活跃女性患有BV。抗生素可以 暂时缓解BV引起的恶臭排出物，但不能防止BV 复发（有时频率高达每月两次）。市场上没有产品可以提供 持续保护BV。我们和其他人已经证明，LA可以有效地抑制许多类型的BV- 相关的细菌以及许多类型的病原体，导致性传播感染。因为LA是 丰富的健康阴道的妇女与保护乳酸杆菌，它有可能提供一个安全的 无毒的杀微生物剂我们最近测定了健康乳酸杆菌持续产生 LA，因此第一次知道了乳酸应供应到阴道以进行治疗的速率， 预防BV。这使我们能够开发一种LA释放阴道环（LA-IVR）， 以治疗和预防BV所需的速率持续释放LA超过30天，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，我们已经表明，我们可以调整 从各种聚合物基质中释放LA的速率，并实现LA的持续释放。充分发挥两国 有前途的试点工作，我们寻求在目标1，以优化我们的领导LA-IVR制定，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，我们将制作一个猕猴LA-IVR，并在目标2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。成功展示了安全性和 在这种高度相关的大型动物模型中的有效性将支持通过以下方式推进Mucommune的LA-IVR： 国家工业发展扶持活动。我们的LA-IVR设计的简单性确保了易于生产， 最终产品的制造成本，这反过来又应该最大限度地提高潜在的公共卫生影响， 该产品在美国和全球低收入和中等收入国家的商业可行性。 (26行）

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)