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.

摘要 一氧化氮(NO)在广泛的身体功能中发挥着关键作用，包括血管扩张， 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0.1-80ppmv(通常为20ppmv)的一氧化氮(INO)已成为新生儿的一种常见治疗方法 患有持续性肺动脉高压(PPHN)。此外，NO还作为一种有效的内源性 抗菌/抗病毒药物，由巨噬细胞和副鼻窦产生，用于对抗呼吸道 感染。也有证据表明，囊性纤维化(CF)和慢性阻塞性肺疾病患者体内NO生成减少。 阻塞性肺疾病(COPD)，导致肺动脉高压和呼吸风险增加 细菌病原体的感染通常难以治疗生物被膜，因为它们对 抗生素。因为iNO疗法具有肺血管扩张和抗菌双重功能 活性/生物膜分散对慢性阻塞性肺疾病和慢性阻塞性肺疾病患者有很大的潜在益处。目前，正在进行的临床 试验正在评估iNO治疗慢性阻塞性肺疾病、慢性阻塞性肺疾病和下肺部感染(毛细支气管炎)的疗效。 最近的研究还表明，iNO疗法改善了中风后脑组织的再灌注，并 脑梗塞后的心脏。鉴于应用的多样性，对简单、低成本和 便携式系统，在ICU之外提供iNO治疗，用于住院、家庭护理和医疗运输。 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产品 LANOR™(光激活一氧化氮释放)iNO递送装置。第二阶段的研究将集中在生产 两种原型，一种是医院使用的专业型号，另一种是患者在家里和医院使用的低剂量型号 医疗运输。该专业型号专为训练有素的医务人员使用，将允许更高的剂量 以及在配置该系统以治疗各种疾病和状况方面具有更大的灵活性。这个 低剂量模式最终将针对慢性阻塞性肺疾病和慢性阻塞性肺疾病患者的长期治疗，并将阻止用户调整 设置为医生指定的设置。这两种型号都将使用定制设计的I/O PCB板和 大幅缩减电子产品的占地面积和成本。固定化S-亚硝硫酚的制备 将通过使用自动喷涂和薄膜涂层技术进一步改进和扩大薄膜，并 使用商业级加工设备。更先进的可更换胶片盒设计将是 采用3D打印开发，将设计制作成塑料注塑模具。一批批cGMP级 RSNO将来自使用cGMP流程的化学品制造商，GSNO将是 固定在医用级载体上。第二阶段的目标是将设备转换为正式的 开发并实施符合FDA发布的指南的质量体系 一氧化氮递送设备的上市前通知提交导致初始510K 提交PPHN，因为这是到目前为止最容易进入市场的监管途径。