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.

摘要 一氧化氮（NO）在广泛的身体功能中起关键作用，包括血管舒张， 神经传递、伤口愈合、抑制血小板活化和控制纤毛搏动频率。 事实上，0.1 - 80 ppmv（通常为20 ppmv）的吸入NO（iNO）已成为新生儿的常用治疗方法 持续性肺动脉高压（PPHN）此外，NO作为一种有效的内源性 由巨噬细胞和鼻旁窦产生的抗微生物/抗病毒剂， 感染.也有证据表明，在囊性纤维化（CF）和慢性炎症患者中， 阻塞性肺疾病（COPD），导致肺动脉高压和呼吸系统疾病风险增加 细菌病原体的感染通常形成难以治疗的生物膜，因为它们对细菌病原体具有高度抗性。 抗生素由于iNO治疗具有肺血管扩张和抗菌的双重功能， 活性/生物膜分散，这对CF和COPD患者潜在地具有很大的益处。目前，正在进行的临床 临床试验正在评估iNO治疗CF、COPD和下肺部感染（细支气管炎）的疗效。 最近的研究还表明，iNO治疗改善了中风后脑组织的再灌注， 心肌梗死后的心脏考虑到应用的多样性，存在对简单、低成本且 便携式系统，可在ICU以外的医院、家庭护理和医疗运输过程中提供iNO治疗。 为了满足这些新出现的需求，NOTA实验室建议继续开发其专有的 LANOR™（光激活一氧化氮释放）iNO输送装置。第二阶段的研究将集中在生产 两个原型，一个是医院使用的专业模型，一个是患者在家使用的低剂量模型， 医疗运输专业型号旨在由受过培训的医务人员使用，并允许更高的剂量 并且在配置用于治疗各种疾病和病症的系统方面具有更大的灵活性。的 低剂量模型将最终针对长期CF和COPD患者治疗，并将阻止用户调整 设置为医生规定的设置。两种型号都将使用定制设计的I/O PCB板， 显著地缩小了电子器件的占地面积和成本。固定化S-亚硝基硫醇的制备 薄膜将通过使用自动喷涂和薄膜涂层技术进一步改进和扩大规模， 使用商业级加工设备。一个更先进的可更换的电影墨盒设计将是 开发使用3D打印和设计将制成塑料注塑模具。cGMP级批次 RSNO将来自使用cGMP工艺的化学品制造商，GSNO将 固定在医用级载体上第二阶段的目标是将设备过渡到正式的 开发并实施符合FDA已发布指南的质量体系， 导致初始510 k的一氧化氮输送装置的上市前通知提交 提交PPHN，因为这是迄今为止最简单的监管上市途径。