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

项目摘要 美国数以百万计的女性患有细菌性阴道病(BV)，这是一种由Mark引发的阴道疾病 可以抑制保护性乳酸菌的多菌群过度生长。健康乳酸菌 分泌乳酸(LA)，酸化阴道，起到广谱杀菌剂的作用，保护 对抗多种类型的病原体，还可以抑制BV物种的多微生物群落， 产生很少或根本不产生乳酸。我们不知道是什么引发了BV的发作，但我们确实知道BV强烈地 增加包括艾滋病毒在内的许多性传播感染的风险，并增加早产的风险。 在任何给定的时间，美国和全世界大约三分之一的性活跃女性都患有BV。抗生素可以 暂时缓解BV引起的恶臭排放，但它们不能阻止BV 复发(有时频率高达一个月两次)。市场上没有一种产品可以提供 对BV病毒的持续保护。我们和其他人已经证明，LA可以有效地灭活多种类型的BV- 相关细菌以及导致性传播感染的多种病原体。既然洛杉矶是 在具有保护性乳酸菌的妇女的健康阴道中大量存在，它有可能提供安全的 无毒杀微生物剂。我们最近测定了健康的乳酸菌持续产生 因此，第一次知道乳酸应该以多大的速率供应到阴道来治疗和 预防BV。这使得我们能够开发出一种释放LA的阴道内环(LA-IVR)，它可以提供 LA在30天内以治疗和预防BV所需的速度持续释放，同时不抑制健康 乳酸菌。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从各种聚合物骨架中的释放速率，并实现LA的持续释放。建立在我们的 有希望的试点工作，我们在目标1寻求优化我们的领先LA-IVR配方，并执行各种 表征包括LA随时间的释放率、疏水性和机械性能(弹性、 可压缩性)。然后我们将制作猕猴LA-IVR，并在Aim 2中测试LA的持续释放 通过这种IVR可以抑制辫尾猕猴体内类似BV的细菌种类。安全和安全的成功示范 这种高度相关的大型动物模型的有效性将支持通过以下方式推进MuComme的LA-IVR 促进工业发展的活动。我们LA-IVR设计的简单性确保了生产的简易性和可能的极低成本 最终产品的制造成本，这反过来又应该最大限度地发挥潜在的公共卫生影响，并 该产品在美国和全球中低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)