Nitric Oxide Releasing Topical Gel for Burn Wound Healing

释放一氧化氮的外用凝胶用于烧伤伤口愈合

• 批准号: 7326862
• 负责人: ANJAL C SHARMA
• 金额: $ 10万
• 依托单位: LYNNTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326862
• 关键词: Acids; Adverse effects; Air; Animals; Ascorbic Acid; Bacterial Antibiotic Resistance; Bacterial Infections; Biochemical; Biology; Body Surface; Burn injury; Caring; Cellulose; Cessation of life; Chemicals; Chemistry; Cicatrix; Clinical; Clinical Trials; Closure; Consult; Cosmetics; Cream; Data; Data Set; Debridement; Dermal; Device Designs; Devices; Diffusion; Disease; Dose; Drug Design; Drug Formulations; Ear; Effectiveness; Evaluation; Experimental Designs; Gases; Gel; Government; Healed; Hospitalization; Hospitals; Human; In Vitro; Infection; Inhalation Therapy; Injury; Investigational Drugs; Investigational New Drug Application; Investments; Lead; Left; Length of Stay; Licensing; Longevity; Marketing; Medical; Methodology; Methods; Modeling; Molecular; Mus; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Nitrogen Dioxide; Nitrogen Oxides; Nitrous Acid; Oryctolagus cuniculus; Other Therapy; Outcome; Pain; Pathway interactions; Patients; Performance; Permeability; Persons; Pharmacologic Substance; Phase; Phase I Clinical Trials; Play; Preparation; Primary Health Care; Principal Investigator; Process; Production; Protocols documentation; Purpose; Range; Rate; Reducing Agents; Regulation; Reporting; Rodent Model; Role; Science; Scientist; Sepsis; Skin graft; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Sodium Chloride; Sodium Nitrite; Solubility; Specialist; Syringes; System; Technology; Testing; Therapeutic; Thick; Time; Topical application; Tube; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; Wound Healing; antimicrobial; automobile accident; base; chemical synthesis; clinically relevant; commercialization; cost; cytotoxic; design; direct application; disability; healing; human NOS2A protein; in vivo; in vivo Model; maleic acid; microbial; organic acid; pathogen; pre-clinical; preclinical study; programs; size; wound

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.

描述（由申请人提供）：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（包括烧伤伤口）中发挥着重要作用。 NO 还被证明有希望作为一种抗菌治疗剂，并且对人类病原体具有广泛的功效。目前大多数一氧化氮疗法（吸入疗法除外）涉及全身或局部治疗，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 NOS 在伤口愈合中发挥作用外，还报道了外源性 NO 后伤口愈合的改善，包括直接应用 NO 气体或应用合成 NO 和其他细胞毒性氮氧化物（亚硝酸）的局部凝胶或乳膏。酸、NO2）。然而，在十几个或更多当前和悬而未决的基于NO的药物临床试验中，没有一个局部方法利用外源性NO产生凝胶，因此依赖NOS途径在局部产生微量NO。尽管由于 NO 在空气中不稳定且难以在临床环境中生产而使该方法变得复杂，但已经实现了直接输送更多治疗相关剂量的 NO 气体用于局部/皮肤应用。更合理的基于NO的伤口愈合治疗在临床环境中应用将是方便和安全的，具有可预测的剂量，并且不会产生化学杂质从而影响伤口愈合过程。 Lynntech 的团队开发了一种简单的化学合成方法，可以异位产生足够持续且高纯度的 NO，用于皮肤应用，从而可以将局部“凝胶”应用于伤口治疗（特别是烧伤）。这种以凝胶形式合成 NO 的专有化学方法有潜力用作部分厚度烧伤的机械多功能局部治疗剂，并有可能用于清创后和植皮前全层烧伤的伤口愈合。初步结果表明，这种化学物质能够以浓度依赖性方式有效产生持续量的 NO，并且将 NO 凝胶应用于啮齿动物模型中的全层烧伤也显示出愈合速度（伤口闭合）和愈合速度的显着提高。重新上皮化。在该项目的第一阶段，Lynntech 的团队（毒理学家、世界著名的 NO 专家、烧伤专家、NO 材料化学家、微生物学家和 NO 生物化学家）将进行分析、体外和体内研究，为将在第二阶段。第一阶段将重点关注化学和凝胶基质的表征和优化，这将允许对给定烧伤创面提供可预测的剂量。此外，该项目还将表征针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伤口的高剂量和低剂量治疗进行体内评估。一期和二期项目的目的是完成临床前试验，以支持向 FDA 提交 IND 并同时向制药行业营销该技术。在美国，每年约有 240 万人因烧伤而接受治疗，其中 650,000 例需要医疗专业人员护理，75,000 例需要住院治疗。这些患者是治疗费用最高的灾难性伤害之一；全身烧伤面积超过 30% 的患者可能需要 20 万美元以上的医院、药品和初级保健费用。通过使用单一、廉价且安全的外用凝胶来减少烧伤伤口愈合时间并防止感染，患者可以获得更好的愈合效果，缩短住院时间和医疗护理时间，并降低护理成本。