Photochemical Generation of Gas Phase Nitric Oxide from Immobilized S-Nitrosothiols for Biomedical Applications

用于生物医学应用的固定化 S-亚硝基硫醇光化学生成气相一氧化氮

• 批准号: 10708845
• 负责人: Alexander Keith Wolf
• 金额: $ 80.17万
• 依托单位: NOTA LABORATORIES, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708845
• 关键词: 3D Print; Acute Respiratory Distress Syndrome; Advanced Development; Age; Ambulances; Antibiotic Resistance; Antibiotics; Antiviral Agents; Biological Sciences; Bronchiolitis; Cause of Death; Chemicals; Chronic; Chronic Obstructive Pulmonary Disease; Clinical Trials; Commercial grade; Computer software; Consultations; Custom; Cystic Fibrosis; Development; Development Plans; Device or Instrument Development; Devices; Diagnosis; Disease; Documentation; Dose; Electronics; Engineering; Environment; Epoprostenol; Equipment; Feedback; Film; Frequencies; Gases; Generations; Goals; Good Manufacturing Process; Healthcare; Heart; Home; Hospitalization; Hospitals; Hypoxemia; Immobilization; Infant; Infarction; Infection; Injections; Intensive Care; Laboratories; Life; Light; Liquid substance; Lung; Lung infections; Macrophage; Manufacturer; Maps; Marketing; Medical; Medical Staff; Microbial Biofilms; Modeling; Molds; Monitor; Myocardial Infarction; Nebulizer; Newborn Infant; Nitric Oxide; Nitrogen Dioxide; Notification; Oxygen; Patients; Performance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Platelet Activation; Play; Population; Predisposition; Preparation; Process; Production; Publishing; Pulmonary Hypertension; Reaction; Regulatory Pathway; Reperfusion Therapy; Reproducibility; Research; Resistance; Respiratory Tract Infections; Risk; Role; S-Nitrosoglutathione; S-Nitrosothiols; Sinus; Source; Specific qualifier value; Stroke; Surveys; System; Techniques; Thinness; Training; Transportation; Ultrasonics; United States; Vasodilation; Vasodilator Agents; Work; antimicrobial; brain tissue; combat; commercial prototype; common treatment; cost; cost effective; cystic fibrosis patients; design; effective therapy; efficacy evaluation; experience; fabrication; flexibility; implantation; improved; in-home care; inhaled nitric oxide; instrument; left ventricular assist device; light emission; light intensity; manufacture; manufacturing run; natural antimicrobial; neonatal pulmonary hypertension; neurotransmission; pathogenic bacteria; persistent pulmonary hypertension; photolysis; portability; pre-clinical; prevent; printed circuit board; prototype; research and development; respiratory; scale up; sensor; tyvek; wound healing

ABSTRACT Nitric oxide (NO) plays a critical role in a wide range of bodily functions, including vasodilation, neurotransmission, wound healing, suppression of platelet activation, and controlling ciliary beat frequency. Indeed, inhaled NO (iNO) at 0.1 – 80 ppmv (typically 20 ppmv) has become a common treatment for newborns with persistent pulmonary hypertension (PPHN). In addition, NO acts as a potent and endogenous antimicrobial/antiviral agent that is produced by macrophages and the paranasal sinuses to combat airway infections. Evidence also exists that NO production is decreased in patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), causing pulmonary hypertension and increased risk of respiratory infections with bacterial pathogens often forming hard to treat biofilms, as they are are highly resistant to antibiotics. Because iNO therapy has dual functionality of both pulmonary vasodilation and antimicrobial activity/biofilm dispersal it is potentially of great benefit to CF and COPD patients. Currently, ongoing clinical trials are evaluating the efficacy of iNO treatment for CF, COPD, and lower pulmonary infection (bronchiolitis). Recent research has also demonstrated that iNO therapy improves reperfusion of brain tissue after a stroke and the heart after infarct. Given the diversity of applications, there is an unmet need for a simple, low-cost and portable system to deliver iNO therapy beyond the ICU for in-hospital, in-home care and during medical transport. To meet these emerging needs, NOTA Laboratories proposes to continue development of its proprietary LANOR™ (Light Activated Nitric Oxide Release) iNO delivery device. Phase II research will focus on producing two prototypes, a professional model for hospital use and a lower dosing model for patient use at home and for medical transport. The professional model is intended for use by trained medical staff and will allow higher dosing and greater flexibility in configuring the system for treatment of a wide variety of diseases and conditions. The low dose model will ultimately target long-term CF and COPD patient treatment and will prevent user adjustments to the settings once set as prescribed by the doctor. Both models will use a custom designed I/O PCB board and significantly shrink the electronics footprint and cost. The preparation of the immobilized S-nitrosothiol (RSNO) film will be further improved and scaled up by using automated spray and thin-film coating techniques, and the use of commercial-grade processing equipment. A more advanced replaceable film cartridge design will be developed using 3D printing and the design will be made into aplastic injection mold. Batches of cGMP-grade RSNO will be sourced from a chemical manufacturer that uses a cGMP process, and the GSNO will be immobilized onto a medical grade carrier. The goal for Phase II is to transition the devices into formal development with implementation of a Quality System that complies with the FDA’s published guidance for Premarket Notification Submissions for a Nitric Oxide Delivery Apparatus leading to a to an initial 510k submission for PPHN as this is by far the easiest regulatory path to market.

抽象的 一氧化氮（NO）在包括血管舒张在内的广泛的身体功能中起着至关重要的作用 神经传递，伤口愈合，血小板激活的抑制和控制睫状节频率。 实际上，在0.1 - 80 ppmv（通常为20 ppmv）的遗传NO（INO）已成为新生儿的常见治疗方法 持续性肺动脉高压（PPHN）。另外，没有一个潜力和内生的作用 由巨噬细胞和旁那鼻窦抗击气道产生的抗菌/抗病毒剂 感染。还存在证据表明，囊性纤维化（CF）和慢性患者的产生降低 阻塞性肺疾病（COPD），导致肺动脉高压和呼吸道风险增加 细菌病原体的感染通常很难治疗生物膜，因为它们对 抗生素。因为INO疗法具有双重功能，同时具有肺血管舒张和抗菌剂 活性/生物膜扩散可能对CF和COPD患者具有很大的好处。目前，持续的临床 试验正在评估INO治疗CF，COPD和较低肺部感染（支气管炎）的效率。 最近的研究还表明，INO治疗可改善中风后脑组织的再灌注 梗塞后的心脏。鉴于应用的多样性，需要简单，低成本的需求 便携式系统，可在ICU以外提供INO治疗，用于住院内和医疗运输期间。 为了满足这些新兴需求，Nota实验室的提议继续开发其专有 LANOR™（光激活的一氧化氮释放）INO输送装置。第二阶段研究将重点放在生产上 两个原型，一种用于医院使用的专业模型，以及用于在家中使用的患者使用的较低剂量模型 医疗运输。专业模型旨在由训练有素的医务人员使用，将允许更高的给药 并在配置系统以治疗多种疾病和疾病的系统方面具有更大的灵活性。 低剂量模型最终将针对长期CF和COPD患者治疗，并防止用户调整 按照医生规定的设置。两种型号都将使用定制设计的I/O PCB板和 显着收缩电子占地面积和成本。固定的S-硝基硫醇（RSNO）的制备 通过使用自动喷雾和薄膜涂料技术以及 使用商业级处理设备。更先进的更可更换的胶卷墨盒设计将是 使用3D打印开发，并将设计制成相位注入模具。 CGMP级批次 RSNO将来自使用CGMP工艺的化学制造商，GSNO将是 固定在医疗级载体上。第二阶段的目标是将设备转换为正式 通过实施符合FDA已发布的指导的质量系统的开发 一氧化氮递送设备的预上市通知提交，导致最初510K PPHN的提交是迄今为止最简单的市场监管途径。