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: 10547397
• 负责人: Alexander Keith Wolf
• 金额: $ 92.85万
• 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/10547397
• 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; Computer software; Consultations; Custom; Cystic Fibrosis; Development; Development Plans; Device or Instrument Development; Devices; Diagnosis; Disease; Documentation; Dose; Electronics; Engineering; Ensure; Environment; Epoprostenol; Equipment; Feedback; Film; Frequencies; Gases; Generations; Goals; Healthcare; Heart; Home; Hospitalization; Hospitals; Hypoxemia; Immobilization; Infant; Infarction; Infection; Inhalation; Injections; Intensive Care; Laboratories; Life; Light; Liquid substance; Lung; Lung infections; Manufacturer Name; Maps; Medical; Medical Staff; Microbial Biofilms; Modeling; Molds; Monitor; Myocardial Infarction; Nebulizer; Newborn Infant; Nitric Oxide; Nitrogen Dioxide; Notification; Oxygen; Patients; Performance; Phase; Phase I/II Clinical Trial; Platelet Activation; Play; Population; Preparation; Process; Production; Publishing; Pulmonary Hypertension; Regulatory Pathway; Reperfusion Therapy; Reproducibility; Research; Resistance; Respiratory Tract Infections; Risk; Role; Running; S-Nitrosoglutathione; S-Nitrosothiols; Sinus; Source; Stroke; Surveys; System; Techniques; Thinness; Training; Transportation; Ultrasonics; United States; Vasodilation; Vasodilator Agents; Work; antimicrobial; base; brain tissue; combat; common treatment; cost; cost effective; cystic fibrosis patients; design; effective therapy; efficacy evaluation; experience; flexibility; implantation; improved; in-home care; inhaled nitric oxide; instrument; left ventricular assist device; light intensity; macrophage; 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) 在多种身体功能中发挥着关键作用，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跳动频率。 事实上，吸入 0.1 – 80 ppmv（通常为 20 ppmv）的一氧化氮 (iNO) 已成为新生儿的常见治疗方法 患有持续性肺动脉高压（PPHN）。此外，NO 还可以作为一种有效的内源性物质 由巨噬细胞和鼻旁窦产生的抗菌/抗病毒剂，用于对抗气道 感染。还有证据表明，囊性纤维化 (CF) 和慢性病患者的 NO 产生减少 阻塞性肺疾病（COPD），导致肺动脉高压并增加呼吸道疾病的风险 细菌病原体感染通常形成难以治疗的生物膜，因为它们对细菌具有高度抵抗力 抗生素。因为iNO疗法具有肺血管舒张和抗菌双重功能 活性/生物膜分散对于 CF 和 COPD 患者可能有很大好处。目前，正在进行临床 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 疗法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，对简单、低成本和 便携式系统，可在 ICU 之外的医院内、家庭护理和医疗运输过程中提供 iNO 治疗。 为了满足这些新兴需求，NOTA 实验室建议继续开发其专有技术 LANOR™（光激活一氧化氮释放）iNO 输送装置。第二阶段研究将集中于生产 两个原型，一个是供医院使用的专业模型，另一个是供患者在家和医院使用的较低剂量模型 医疗运输。专业模型供训练有素的医务人员使用，并允许更高剂量 以及配置系统以治疗各种疾病和病症的更大灵活性。这 低剂量模型最终将针对 CF 和 COPD 患者的长期治疗，并将阻止用户调整 按照医生规定设置一次的设置。两种型号都将使用定制设计的 I/O PCB 板和 显着缩小电子产品的占地面积和成本。固定化S-亚硝基硫醇(RSNO)的制备 通过使用自动喷涂和薄膜涂层技术，薄膜将得到进一步改进和规模化， 使用商业级加工设备。更先进的可更换胶片盒设计将 使用3D打印开发，并将设计制作成塑料注射模具。 cGMP级批次 RSNO 将来自使用 cGMP 流程的化学品制造商，而 GSNO 将来自 固定在医疗级载体上。第二阶段的目标是将设备转变为正式的 开发并实施符合 FDA 发布的指南的质量体系 提交一氧化氮输送装置的上市前通知可获得初始 510k 提交 PPHN，因为这是迄今为止最简单的市场监管途径。