Nitric Oxide Releasing Topical Gel for Burn Wound Healing

说明(申请人提供)：一氧化氮(NO)气体已被证明在促进和调节各种伤口愈合过程中发挥重要作用，包括烧伤伤口。NO也被证明是一种有希望的抗菌治疗药物，对人类病原体具有广泛的疗效。目前的大多数一氧化氮疗法(吸入疗法除外)包括全身或局部治疗，使用旨在刺激细胞内诱导型一氧化氮合酶(NOS)的药物。除了内源性NO通过一氧化氮合酶在创面愈合中的作用外，也有研究报道外源性NO促进创面愈合，包括直接应用NO气体或使用合成NO和其他细胞毒性氮氧化物(亚硝酸，NO2)的局部凝胶或乳膏。然而，在十几个正在或即将进行的基于NO的药物临床试验中，没有一种局部方法利用外源NO产生凝胶，从而依赖于NOS途径在局部产生微量的NO。尽管这种方法因NO在空气中的不稳定性和难以在临床环境中生产而变得复杂，但直接输送更具治疗意义的剂量的NO气体用于局部/皮肤应用已经完成。一种更合理的以NO为基础的创面愈合治疗方法在临床上应用将是方便和安全的，具有可预测的剂量，并且不会有化学杂质从而影响创面愈合过程。Lynntech的团队已经开发出一种简单的化学合成方法，可以产生足够持续和高纯度的异地一氧化氮，用于真皮应用，从而允许在伤口治疗--特别是烧伤--中应用外用“凝胶”。这种以凝胶形式合成NO的专利化学方法有可能被用作机械上多功能的局部治疗方法，用于部分深度烧伤的机械多功能局部治疗，并有可能用于清创后和植皮前的全面烧伤的创面愈合。初步结果表明，这种化学物质能够以浓度依赖的方式有效地产生持续数量的NO，并将NO凝胶应用于啮齿动物模型的全面烧伤，在愈合率(伤口闭合)和再上皮化方面也显示出显著的改善。在这个项目的第一阶段，Lynntech的团队(毒物学家、世界知名的NO专家、烧伤创面专家、非材料化学家、微生物学家和没有生物化学家)将进行分析、体外和体内研究，为第二阶段进行的临床前试验做准备。第一阶段将专注于化学和凝胶基质的表征和优化，使给定的烧伤创面能够获得可预测的剂量。此外，该项目还将表征对临床烧伤相关病原体的抗菌效果，并将使用两种不同的剂量计时方案对烧伤创面的高剂量和低剂量治疗进行体内评估。第一阶段和第二阶段项目的目的是完成临床前试验，以支持向FDA提交IND，并同时向制药部门营销该技术。在美国，每年约有240万人因烧伤而接受治疗，其中65万人需要医疗专业人员的护理，7.5万人需要住院治疗。这些患者是治疗费用最高的灾难性伤害之一；一个患者烧伤面积超过其总体表的30%，可能需要超过20万美元的医院、药品和初级保健费用。通过使用一种单一、廉价和安全的局部凝胶来缩短愈合烧伤伤口和防止感染的时间，患者可以预期更好的愈合结果，缩短住院时间和医疗护理时间，并降低护理成本。

DESCRIPTION (provided by applicant): Nitric oxide (NO) gas has been shown to play a significant role in the promotion and regulation of diverse wound healing processes, including burn wounds. NO has also been shown to have promise as an antimicrobial therapeutic and has broad range of effectiveness against human pathogens. Most current nitric oxide therapies (other than inhalation therapies) involve systemic or topical treatments with drugs designed to stimulate inducible nitric oxide synthase (NOS) intracellularly. In addition to a role of endogenous NO in wound healing through NOS, improvement of wound healing following exogenous NO has also been reported, including direct application of NO gas or application of topical gels or creams that synthesize NO and other cytotoxic nitrogen oxide species (nitrous acid, NO2). However, of the dozen or more current and pending NO- based pharmaceutical clinical trials, none of the topical approaches utilize an exogenous NO producing gel and thus rely on NOS pathways to generate minute amounts of NO locally. The direct delivery of more therapeutically relevant doses of NO gas for topical/dermal applications has been accomplished, although the method is complicated by NO's instability in air and difficulty to produce in a clinical setting. A more rational NO-based wound healing treatment would be convenient and safe to apply in a clinical setting, have a predictable dose, and would not have chemical impurities thus impacting the wound healing process. Lynntech's team has developed a simple, chemical synthesis methodology for generating sufficiently sustained and high purities of NO ex-situ for dermal applications, and thus allows for application of a topical 'gel' to wound treatments - specifically burns. This proprietary chemical method for the synthesis of NO in a gel format has the potential to be used as a mechanistically multi-functional topical therapeutic for partial thickness burns, and potentially in wound healing for full thickness burns after debridement and also prior to skin grafting. Preliminary results have shown the ability of this chemistry to efficiently produce sustained amounts of NO in a concentration dependant manner, and application of the NO gel to full thickness burns in a rodent model has also shown significant improvements in rate of healing (wound closure) and re-epithelization. In Phase I of this project, Lynntech's team (toxicologist, world-renowned NO expert, burn wound specialist, NO materials chemist, microbiologist and NO biochemist) will pursue analytical, in vitro and in vivo studies in preparation of preclinical trials to be conducted in Phase II. Phase I will focus on characterization and optimization of the chemistry and gel matrix which will allow for a predictable dose on a given burn wound. Also, the project will characterize the antimicrobial effectiveness against clinically burn relevant pathogens and will conclude with in vivo evaluation of a high and low dose treatment of burn wounds using two different dose timing protocols. The purpose of the Phase I and II projects is to complete preclinical trials to support filing of a IND with the FDA and concurrent marketing of the technology to the pharmaceutical sector. Approximately 2.4 million people a year in the United States are treated for burn injuries, with 650,000 of these cases requiring care by a medical professional and 75,000 requiring hospitalization. These patients represent one of the most expensive catastrophic injuries to treat; a patient sustaining burns over 30% of their total body surface may require upwards of $200,000 in hospital, pharmaceutical, and primary care costs. By reducing the time to heal a burn wound and protect against infection by using a single, inexpensive and safe topical gel, patients can expect better healing outcomes, shortened hospital stays and medical care duration, and reduced cost for that care.