N,N-Dimethylacetamide Vaginal Self-nanoemulsifying Drug Delivery System for the Prevention or Preterm Birth

摘要 根据世界卫生组织的估计，每年的早产率(PTB)更高 在大多数国家，这一比例超过10%。妊娠37周前早产 是导致出生第一年死亡的主要原因，并与 终生的认知后果。与早产相关的急性和终生护理费用 对家庭有广泛和持续的影响，对社会造成巨大的代价。成因 肺结核的病因是多因素的，但最常见的单一原因是炎症。可悲的是， 目前还没有美国食品和药物管理局批准的药物 预防肺结核。翻译研究和药物开发在这方面的障碍之一 领域是与药物有关的毒性影响胎儿的风险。几年前，我们制作了 偶然发现，安全的药物溶剂N，N-二甲基乙酰胺(DMA)可以防止 在我们的小鼠模型中，PTB和拯救自然流产的幼鼠。在我们的学校继续深造 实验室发现，DMA抑制核转位和核因子的激活 Kappa B(核因子-kB)，一种调节免疫细胞介导的炎症的转录因子。在……里面 此外，我们还发现，DMA可抑制培养的人类细胞因子的分泌。 滋养层细胞和人类胎盘外植体。最近，我们的实验室与我们的 合作者开发一种阴道(PV)自纳米乳化给药系统(SNEDDS)， 它利用第一次子宫/宫颈通过效应将药物输送到 阴道腔直接进入宫颈和子宫，从而最大限度地减少全身毒性和 致畸性。当前项目的具体目标是：1)测试我们的光伏DMA的效果 SNEDDS对小鼠宫颈组织形态和炎症反应的影响 确定DMA抑制核因子-kB转录活性的分子机制；3) DMA SNEDDS的毒性和致畸作用与腹膜腔内给药的比较 DMA。为了实现这些目标，我们组建了一支由肺结核、宫颈组织形态学专家组成的团队 和药物配方。这个多学科团队将与我们的学生一起工作，他们 来自多元化和服务不足的人群。虽然肺结核是一个全球性的公共卫生问题， 在服务不足的人群中，肺结核的发病率要高得多。重新调整用途的新颖性 一种易于获得且价格低廉的预防肺结核的常用药物辅料，与 设计一种阴道配方，可供远离诊所或 医院，解决了肺结核药物开发领域的一个严重缺口。

ABSTRACT Based on World Health Organization estimates, the annual rate of preterm birth (PTB) is greater than 10% in the majority of countries. Premature birth before 37 completed weeks of gestation is the leading cause of mortality in the first year of life and is associated with morbidity that has life-long cognitive consequences. Acute and lifespan care costs associated with preterm births have broad and sustained effects on families and are enormously expensive for society. Causes of PTB are multifactorial, but the single most common cause of PTB is inflammation. Sadly, there is currently no United States Food and Drug Administration approved drug for the prevention of PTB. One of the hurdles in translational research and drug development in this field is the risk of drug related toxicity affecting the fetus. Several years ago, we made the fortuitous discovery that the safe pharmaceutical solvent, N,N-dimethylacetamide (DMA), prevents PTB and rescues pups from spontaneous abortion in our mouse model. Further studies in our laboratory revealed that DMA suppresses nuclear translocation and activation of nuclear factor kappa B (NF-kB), a transcription factor that regulates immune cell-mediated inflammation. In addition, we have shown that DMA attenuates cytokine secretion from cultured human trophoblasts and from human placental explants. Recently, our laboratory has teamed up with our collaborator’s to develop a vaginal (pv) self-nanoemulsifying drug delivery system (SNEDDS), which takes advantage of the first uterine/cervix pass effect to deliver drugs introduced into the vaginal cavity directly to the cervix and uterus, thereby minimizing risk of systemic toxicity and teratogenicity. The specific aims of the current project are to 1) test the effects of our pv DMA SNEDDS on histomorphology and inflammatory responses in the cervix in a murine model; 2) determine the molecular mechanism whereby DMA inhibits NF-kB transcriptional activity; and 3) compare toxic and teratogenic effects of a DMA SNEDDS to intraperitoneal administration of DMA. To accomplish these aims, we assembled a team of experts in PTB, cervix histomorphology and drug formulation. This multidisciplinary team will be working alongside our students, who come from a diverse and underserved population. Although PTB is a global public health problem, rates of PTB are significantly higher among underserved populations. The novelty of re-purposing a readily available and inexpensive common drug excipient to prevent PTB, together with designing a vaginal formulation that can be administered by patients remote from clinics or hospitals, addresses a critical gap in the field of drug development for PTB.