Thermostable vaginal probiotic microbicide

描述（由申请人提供）：最近修订的统计数据显示，全球艾滋病毒感染者人数超过3300万，其中68%在撒哈拉以南非洲。目前的艾滋病毒预防方法，如使用避孕套、一夫一妻制和禁欲，并不总是可行的。改进艾滋病毒预防技术的必要性仍然十分紧迫。局部杀微生物剂的发展代表了预防性传播疾病的一个新的和令人兴奋的领域。其中，应用活益生菌杀微生物剂（PBM）代表了一种有前途的预防方法。我们的最终目标是开发有效的优化多菌株热稳定和易于交付的益生菌阴道局部杀微生物剂。为了实现这一目标，我们将稳定阴道益生菌，使其在高环境温度下长期储存，并在快速溶解膜制造所需的温度（60 ℃及以上）下短期存活。该提案的基石是：1）“汽化保存”（PBV）-一种在高温环境下干燥稳定益生菌和其他脆弱生物制剂的创新、正在申请专利的方法，以及2）快速溶解薄膜技术，该技术正在优化以提供传统的阴道杀微生物剂。该策略可以简单地描述为，为了占据阴道上皮并提供针对HIV、BV和STI获得的持久保护环境，将含有PBV阴道益生菌的小（10-50 μ m）玻璃状糖颗粒配制成利用水溶性聚合物基质的薄膜。薄膜提供了一个独特的传递平台，与其他剂型相比具有许多优点。在最近的一项研究中，比较了女性对薄膜、片剂和胚珠的偏好，薄膜剂型在所研究的女性中具有最大的可接受性。我们认为，女性更喜欢使用阴道膜而不是其他潜在的益生菌杀微生物剂递送方法，特别是如果细菌定植阴道上皮的长效作用允许不太频繁地使用。将使用阴道和宫颈上皮细胞培养模型表征PBM在环境温度下长期储存后的生物学特性。 与公共卫生的相关性：随着艾滋病毒感染者人数继续增加，女性感染艾滋病的人数正在增加。截至2007年底，妇女占全世界所有成年艾滋病毒感染者的50%，在撒哈拉以南非洲占61%。在新的艾滋病毒病例中，至少有一半是25岁以下的人，在13-19岁的人中，54%是少女。因此，迫切需要开发一种有效的女性控制的杀微生物剂产品，以防止感染艾滋病毒。先天性阴道植物群为感染提供了天然的防御屏障，因此益生菌杀微生物剂提供了有希望的预防策略。该项目旨在评估克服其成功应用的两个障碍的策略，即在相关环境条件下的长期细菌保存和用于阴道给药的用户可接受的稳定递送系统。通过蒸发和薄膜剂型与使用多菌株制剂的创新组合提供了一种独特的技术，可以用于克服现有的障碍，提供安全有效的益生菌杀微生物剂产品，以保护妇女免受艾滋病毒感染。

DESCRIPTION (provided by applicant): Recently revised statistics show the number of individuals living with HIV at over 33 million worldwide, with 68% being in sub-Saharan Africa. Current HIV prevention methods, such as condom use, monogamy and abstinence, are not always feasible. The need for improved HIV preventative technologies remains urgent. The development of topical microbicides represents a new and exciting field in the prevention of sexually transmitted diseases. Of these, application of live probiotic bacterial microbicides (PBM) represents a promising preventative method. Our ultimate goal is to develop potent optimized multistrain thermostable and easily deliverable probiotic vaginal topical microbicides. To achieve this goal we will stabilize vaginal probiotics for long-term storage at high ambient temperatures and short term survival at temperatures required for quick dissolve film manufacturing (60¿C and above). The cornerstones of this proposal are: 1) Preservation by Vaporization" (PBV) - an innovative, patent pending method of dry-stabilizing probiotics bacteria and other fragile biologicals at high ambient temperatures, and 2) Quick-dissolve thin film technology that is being optimized to deliver conventional vaginal microbicides. The strategy can be described briefly as, to occupy the vaginal epithelium and provide a long lasting protective environment against HIV, BV, and STI acquisition small (10-50 ¿m) glassy sugar particles containing PBV vaginal probiotic bacteria will be formulated into thin films which utilize a water soluble polymer base. Thin films offer a unique delivery platform which has a number of advantages over other dosage forms. In a recent study comparing women's preference between films, tablets and ovules, the film dosage form was shown to have greatest acceptability among women studied. We believe that women will prefer using a vaginal film over other potential methods of probiotic microbicide delivery especially if a long-acting effect of the bacteria colonizing vaginal epithelium allows for less frequent use. Biologic properties of PBM after long-term storage at ambient temperatures will be characterized using cell culture models of vaginal and cervical epithelium. PUBLIC HEALTH RELEVANCE: As the number of individuals living with HIV continues to rise and a feminization of the epidemic is occurring. At the end of 2007 women accounted for 50% of all adults living with HIV worldwide and 61% in sub-Saharan Africa. Of new HIV cases at least half are in individuals less than 25 years of age and of those aged 13-19 54% are teenage girls. For this reason there is a desperate need for the development of an effective female controlled microbicide product to protect against acquisition of HIV. The innate vaginal flora provide a natural defensive barrier to infection hence a probiotic microbicide provides a promising strategy for prevention. This project serves to evaluate a strategy to overcome two barriers to its successful application, long term bacterial preservation at relevant environmental conditions and a user acceptable stable delivery system for vaginal administration. The innovative combination of preservation by vaporization and thin film dosage forms with use of multi-strain formulations provides a unique technology which can serve to overcome existing barriers to provide a safe and effective probiotic microbicide product to protect women from acquisition of HIV.