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

摘要 肺动脉高压(PH)患者出现低氧饱和度、呼吸急促、低质量 寿命短，确诊后寿命短(&lt；10年)。这些病人经常出现在紧急情况下。 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，死亡率仍然很高。 生活质量也很差。由于没有特效药可供治疗，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。目前基于储罐的iNO输送系统价格昂贵，仅在手术室和 发达国家老牌医疗中心的ICU。对于更简单、更便携和更少的需求是很大的 昂贵的iNO技术。在第一阶段，与以下伙伴合作开发了概念验证原型 阿拉巴马大学伯明翰分校。第一阶段的所有拟议目标都已实现，并且技术 通过几项创新进一步推进。首先，对原始的NO生成方法进行了修改 从前体分子生产缓释NO到生产原料量的建议 一步化学反应，按需在密封容器中合成医用级NO。这种方法 将避免其他公司目前追求的无生成方法的陷阱，在这些方法中，二氧化氮 (NO2，一种有毒气体)被转化为NO，或大气空气被高压电火花氧化为NO 后续需要大量的提纯步骤。第二，建议将这种100%的NO直接与 补充氧气以达到治疗剂量，同时将NO2的联合输送减少到远低于FDA安全的水平 在与补充氧气混合之前，限制或稀释装置内惰性氮气中的NO。这些 系统无需在氮气中稀释1250倍的氮气以储存在压缩钢瓶中并运输到 医院，就像当前系统所做的那样。第三，用于测量NO和NO2的集成气体传感器系统 开发了NO点胶电子控制系统。组装好的样机运行良好 不出所料。基于这些令人鼓舞的结果，iNovodel，Inc.成立了许可证，开发和 将全尺寸产品商业化。在目标1中，重点是开发一个功能完善的以医院为基础的 以及展示了结合优化的可重复使用的NO生成器的便携式iNO设备的可行性 弹药筒。目的2寻求建立用于在盒中产生和存储NO的化学方法以利用 按需提供。目标3旨在开发非侵入性和侵入性接口系统，这些系统 与iNO设备兼容，可安全地向患者输送一氧化氮。此外，该设备的安全性要交付 使用模拟患者的体外台式无输送系统将不会进行评估 促进寻求FDA监管部门的批准。

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.