Chemical-based Nitric Oxide Gas-generating Drug Device for the Treatment of Pulmonary Hypertension

治疗肺动脉高压的化学一氧化氮气体发生药物装置

• 批准号: 10611768
• 负责人: Gary Lessing
• 金额: $ 146.8万
• 依托单位: INOVODEL, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-18 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611768
• 关键词: Accident and Emergency department; Acute; Admission activity; Adult; Affect; Air; Alabama; Antihypertensive Agents; Atmosphere; Biological Availability; Blood Circulation; Blood Vessels; Cessation of life; Chemicals; Child; Chronic; Compensation; Complex; Conduct Clinical Trials; Consumption; Developed Countries; Development; Device or Instrument Development; Devices; Diagnosis; Disease; Dose; Electronics; Endothelin; Extracorporeal Membrane Oxygenation; FDA approved; Formulation; Gases; Generations; Goals; Growth; Health; Healthcare Systems; Hospitals; In Vitro; Infant; Infection; Inflammation; Inhalation; Intensive Care Units; Intervention; Investigation; Licensing; Life; Longevity; Lung; Lung diseases; Marketing; Measurement; Medical; Medical center; Methods; Newborn Infant; Nitric Oxide; Nitrogen; Nitrogen Dioxide; Operating Rooms; Oxygen; Patient Admission; Patients; Persons; Pharmaceutical Preparations; Phase; Process; Prostaglandins I; Pulmonary Hypertension; Pulmonary artery structure; Pump; Quality of life; Reaction; Safety; Shortness of Breath; Signaling Molecule; Site; Syringes; System; Systemic blood pressure; Technology; Testing; Therapeutic; Time; Universities; Vascular resistance; Vasodilator Agents; analog; antagonist; antimicrobial; chemical reaction; commercialization; cost; curative treatments; detector; experience; improved; inhaled nitric oxide; inhibitor; injury and repair; innovation; lung failure; lung hypoxia; monitoring device; mortality; novel; patient home care; patient population; phosphodiesterase V; portability; premature; prevent; prototype; pulmonary arterial hypertension; pulmonary arterial pressure; right ventricular failure; seal; sensor; supplemental oxygen; voltage

SUMMARY Patients with pulmonary hypertension (PH) experience low oxygen saturation, shortness of breath, low quality of life, and a short life span (<10 years) following diagnosis. These patients frequently present to emergency rooms, and many are admitted to intensive care units (ICUs), straining the health care system. Despite therapy with phosphodiesterase-5 inhibitors, prostacyclin analogs, and endothelin antagonists, mortality remains high and quality of life poor. With no specific drug available for curative treatment, inhaled nitric oxide (iNO), a pulmonary artery-specific vasodilator, is the best option for treating PH without compromising systemic blood pressure. Current tank-based iNO delivery systems are expensive and available only in operating rooms and ICUs of established medical centers in developed countries. The need is great for simpler, portable, and less expensive iNO technologies. During phase 1, a proof-of-concept prototype was developed in partnership with the University of Alabama at Birmingham. All the proposed goals in phase 1 were met and the technology was further advanced through several innovations. First, the NO generation method was modified from the original proposal of producing sustained release NO from its precursor molecule to producing a stock bulk amount in a single-step chemical reaction to synthesize medical grade NO in a sealed container on demand. This method will avoid the pitfalls of current NO generation approaches pursued by other companies in which nitrogen dioxide (NO2, a toxic gas) is converted to NO, or atmospheric air is oxidized to NO by high voltage electric sparks with subsequent need for extensive purification steps. Second, it is proposed to mix this 100% NO directly with supplemental oxygen to attain therapeutic doses while reducing co-delivery of NO2 to levels far below FDA safety limits or diluting NO in inert nitrogen (N2) gas within the device prior to mixing with supplemental oxygen. These systems avoid the need to dilute NO 1250-fold in N2 gas for storage in compressed cylinders and transport to hospitals, as is done with current systems. Third, an integrated gas sensor system for NO and NO2 measurement and electronic control systems for dispensing NO was developed. The assembled prototype is functioning well and as expected. Based on these encouraging results, iNOvodel, Inc. was formed to license, develop and commercialize a full-scale product. In Aim 1, focus is centered on developing a fully functional hospital-based and demonstrating feasibility for a portable iNO devices incorporating an optimized reusable NO-generating cartridge. Aim 2 seeks to establish the chemical method for generating and storing NO in the cartridge to utilize on-demand. Aim 3 is directed toward development of noninvasive and invasive interface systems that are compatible with iNO devices for safe delivery of nitric oxide to patients. Further, the safety of the device to deliver NO using an in vitro benchtop NO delivery system that simulates the patient NO delivery system will be evaluated facilitating the pursuit of FDA regulatory approval.

总结 肺动脉高压（PH）患者会出现低氧饱和度、呼吸急促、低质量 诊断后寿命短（<10年）。这些病人经常出现急诊 许多人住进了重症监护室，使卫生保健系统不堪重负。尽管接受了治疗 使用磷酸二酯酶-5抑制剂、前列环素类似物和内皮素拮抗剂时，死亡率仍然很高 生活质量差。由于没有特定的药物可用于治愈性治疗，吸入一氧化氮（iNO）， 肺动脉特异性血管扩张剂，是治疗PH而不损害全身血液的最佳选择 压力目前基于罐的iNO递送系统是昂贵的并且仅在手术室中可用， 在发达国家建立的医疗中心的ICU。对更简单、便携和更少的需求是巨大的 昂贵的iNO技术在第一阶段，与以下机构合作开发了概念验证原型： 位于伯明翰的亚拉巴马大学。第一阶段提出的所有目标都得到了实现， 通过多项创新进一步推进。首先，对NO生成方法进行了改进， 从其前体分子产生持续释放NO到以 按需在密封容器中一步化学反应合成医用级NO。该方法 将避免其他公司追求的当前NO生成方法的陷阱， (NO2一种有毒气体）转化为NO，或者大气通过高压电火花氧化为NO， 随后需要大量的纯化步骤。第二，建议将该100%NO直接与 补充氧气以达到治疗剂量，同时将NO2的共同输送降低至远低于FDA安全水平 在与补充氧气混合之前，在装置内的惰性氮气（N2）中限制或稀释NO。这些 系统避免了需要在N2气体中稀释NO 1250倍，以存储在压缩气瓶中并运输到 医院，就像现在的系统一样。第三，用于NO和NO2测量的集成气体传感器系统 开发了一氧化氮的电子控制系统。组装好的样机运行良好 和预期的一样。基于这些令人鼓舞的结果，iNOvodel，Inc.成立的目的是许可、开发和 将一个完整的产品商业化。在目标1中，重点是开发一个功能齐全的医院为基础的 并证明了结合优化的可重复使用的NO生成的便携式iNO装置的可行性， 弹药筒目的2寻求建立在药筒中产生和储存NO的化学方法以利用 点播目标3是针对非侵入性和侵入性接口系统的开发， 与iNO器械兼容，可安全向患者输送一氧化氮。此外，输送装置的安全性 将评估使用模拟患者NO输送系统的体外台式NO输送系统的NO 促进FDA监管批准的追求。