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

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.