Vaginal Ring for Preventing Bacterial Vaginosis

描述（由申请人提供）：细菌性阴道病（BV）是一种非常常见的阴道疾病，在这种情况下，阴道内强健的乳酸菌群被密集的多微生物过度生长所取代。在任何时候，大约三分之一的美国女性患有细菌性阴道炎；一半是无症状的，大多数有症状性细菌性阴道炎的妇女只有轻微的症状（分泌物增多，有腥味）。尽管没有这些症状或症状轻微，但细菌性阴道炎显著增加了不良出生结果（早产和死胎）的风险，并显著增加了性传播感染（sti）的风险。因此，细菌性阴道炎构成了一个尚未得到充分认识的重大公共卫生问题。是什么原因导致阴道菌群在乳酸菌和细菌性阴道炎之间波动不稳定尚不清楚。BV发作可以用抗生素（甲硝唑、克林霉素）短暂治疗，但经常复发。患有细菌性阴道炎的女性每个月经周期通常有2次发作。鉴于与细菌性阴道炎相关的风险显著增加，以及细菌性阴道炎的高流行率，对一种能够长期预防细菌性阴道炎的阴道产品的需求尚未得到满足，特别是在怀孕期间和性传播感染高风险妇女。健康的阴道乳酸杆菌不断产生乳酸，使阴道酸化至pH~4。我们最近发现乳酸能有效地灭活多种bv相关细菌。本STTR应用的目的是开发一种持续释放乳酸以预防BV的阴道环（“bvp环”）。该环将被设计成以与健康乳酸菌产生的乳酸相当的速度释放乳酸，从而不会使阴道过度酸化。当发生可能引发细菌性阴道炎的因素（如月经、性交）时，环将为乳酸菌提供一个“安全港”。通过提供一种天然的保护剂，环可能是安全无毒的，并且有很强的基础来预期它是有效的：乳酸在体外可以有效地灭活与细菌性阴道炎相关的细菌，并且含有乳酸的阴道凝胶，当多次使用数周后，临床显示可以减少细菌性阴道炎的复发。阴道环对于避孕和激素替代疗法是高度用户可接受的。因此，BVP-Ring可能是用户可接受的，比频繁使用阴道凝胶或频繁使用抗生素更容易接受。对于STTR I期，约翰霍普金斯大学的具体目标是：(1)确定乳酸菌在宫颈阴道液中产生乳酸的速率；(2)确定乳酸菌作用于BV女性阴道的乳酸通过阴道上皮扩散离开阴道腔的速率。这些测量将用于估计阴道环释放乳酸的速率，ReProtect公司的具体目标是(3)设计一个硅胶bvp -环，以目标1和2中确定的速率释放乳酸1个月，并生产准备在STTR二期体内测试的原型环。

DESCRIPTION (provided by applicant): Bacterial Vaginosis (BV) is an exceptionally common vaginal condition in which robust lactobacillus microflora in the vagina is replaced by a dense polymicrobial overgrowth. At any given time, about 1 in 3 women in the U.S. have BV; half are asymptomatic, and most women with symptomatic BV have only mild symptoms (increased discharge with a fishy smell). Despite these missing or mild symptoms, BV markedly increases risk of adverse birth outcomes (premature births and still births) and markedly increases risks of sexually transmitted infections (STIs). Thus BV poses a major and yet under-recognized public health problem. What causes the fluctuating instability of vaginal microflora between lactobacilli and BV is unknown. Episodes of BV can be treated transiently with antibiotics (metronidazole, clindamycin) but relapse occurs frequently. Women with BV typically have ~2 episodes per menstrual cycle. Given the markedly increased BV-associated risks, and the high prevalence of BV, there is a major unmet need for a vaginal product that will provide long-term prevention of BV especially during pregnancy and for women at high risk of STIs. Healthy vaginal lactobacilli continuously produce lactic acid at a rate that acidifies the vagina to pH~4. We recently discovered that lactic acid potently inactivates a broad range of BV-associated bacteria. The aim of this STTR application is to develop a vaginal ring that continuously releases lactic acid to prevent BV ("BVP-Ring"). The Ring will be designed to release lactic acid at a rate comparable to that produced by healthy lactobacilli and thus will not over-acidify the vagina. The Ring will provide a 'safe harbor' for lactobacilli whenever factors (e.g., menses, sexual intercourse) occur that might otherwise initiate an episode of BV. By supplying a naturally present protective agent the Ring will likely be safe and nontoxic, and there is a strong basis for expecting it to be effective: Lactic acid potently inactivates BV-associated bacteria in vitro, and vaginal gels with lactic acid, when applied frequently over many weeks, have been shown clinically to reduce BV relapse. Vaginal rings are highly user-acceptable for contraception and for hormone replacement therapy. Thus the BVP-Ring is likely to be user-acceptable, and much more acceptable than frequently applying a vaginal gel, or frequent doses of antibiotics. For STTR Phase I, Specific Aims at Johns Hopkins University are: (1) Determine the rate at which lactobacilli produce lactic acid in cervicovaginal fluid and (2) Determine the rate at which lactic acid applied to the vagina of women with BV leaves the vaginal lumen by diffusing through the vaginal epithelium. These measurements will be used to estimate the rate at which the vaginal ring should release lactic acid, The Specific Aim at ReProtect, Inc. is (3) Design a silicone BVP-Ring that releases lactic acid for 1 month at the rate determined in Aims 1 and 2, and produce prototype Rings ready to be tested in vivo in STTR Phase II. PUBLIC HEALTH RELEVANCE: Unfortunately, most women, most of the time, do not have robust vaginal lactobacilli that protect the vagina with lactic acid; at any given time about 1 in 3 women have bacterial vaginosis (BV), a condition that puts women at markedly increased risks of poor pregnancy outcomes and sexually transmitted infections. The aim of this STTR project is to develop a vaginal ring that releases lactic acid to prevent BV. The ring will likely be useful for women with frequent episodes of symptomatic BV, and especially useful for preventing BV during pregnancy. )