SBIR-STTR Award

Pulmonary hypertension (PH) is a highly debilitating disease that affects about 1% of the global population, which increases up to 10% in individuals aged more than 65 years. The life expectancy for these patients is less than 10 years after diagnosis, and no specific drugs are available for pharmacologic treatment. Despite the introduction PDE5, prostacyclin analogs, and endothelin antagonists, mortality remains high and quality of life poor. Therefore, inhalation and aerosolization are the best options for administering drugs to treat/manage PH. In this context, inhaled nitric oxide (iNO), a pulmonary-specific vasodilator, has been shown to be the best option for treating PH without compromising systemic blood pressure. Current iNO therapy requires a complex and expensive (approximately $180/hour) system of gaseous NO storage cylinders, transportation, and devices to monitor and regulate the dilution and delivery of NO, O2, and nitrogen dioxide (NO2). Therefore, this therapy is only in intensive care units and operating rooms of established hospitals in developed countries. Consequently, the demand is high and the opportunity large for new, inexpensive technologies that are less complex and portable for use in and out of hospitals. Since 1999, when the FDA approved the use of iNO therapy, several start- up companies have worked to develop such devices, but none has yet reached the market. We intend to fill this gap with our technology. Low molecular weight S-nitrosothiols (SNO) can be generated easily by reacting acidified nitrite with thiols in the laboratory. These SNO are not stable and spontaneously decompose to NO and corresponding disulfides. Hence these SNO have special ability to store and release NO. Our idea is to use this NO as a source of iNO therapy. Our preliminary studies indicate that NO released from S-nitrosothiols can be removed successfully from the reaction vessel and then introduced into carrier gas. Manipulating the reaction conditions can sustain this NO for over 10 hours. The main goal of the phase 1 study is to build prototype portable devices and then evaluate the purity of NO gas, as these are major hindrance to developing any novel inhaled technologies and FDA approval. Nitrogen dioxide (NO2) that forms as result of NO reaction with carrier gas, oxygen is a major toxic contaminant, especially in noninvasive iNO therapy. This NO2 formation will be minimized by generating desired levels of NO (NO2 formation is favored at higher NO concentrations) under anaerobic conditions and deliver to patients without storage. NO2 formation will be measured at the pre-set and lung level by direct and indirect methods via chemiluminescence assay and electrochemical sensors, respectively. A benchtop noninvasive iNO delivery system that simulates iNO delivery to patients will be used to evaluate the purity of gas and function of devices. Establishing the purity of gas and prototype device functions are an imperative before investing time and money in developing a final full-scale product. In summary our technology will deliver sustained, tunable levels of iNO with portability, increased safety (minimum or none toxic gases), less expensively, without the use of bulky cylinders.

Public Health Relevance Statement:
PROJECT NARRATIVE Inhaled nitric oxide (iNO) therapy, a pulmonary specific vasodilator is a lifesaving drug for hypoxic lung failure associated with pulmonary hypertension (PH) and life-threatening PH and right heart failure. This treatment currently requires a complex iNO delivery system and is available only in the intensive care units and operating rooms in the major hospitals of developed countries. The goal of this investigation is to develop portable devices that use chemical reactions to generate NO locally for delivery to wider population of PH patients in and out of hospitals whenever and wherever it is needed.

Project Terms:
Acetylcysteine; Acute; Adult; aerosolized; Aerosols; Affect; aged; Anaerobic Bacteria; analog; Animal Model; Anti-Inflammatory Agents; Antibiotic Resistance; antimicrobial; Antioxidants; base; Biological Availability; Cessation of life; chemical reaction; Chemicals; Chemiluminescence assay; Child; Clinical; clinical diagnostics; Clinical Research; Clinical Trials; Complex; cost; design; Developed Countries; Devices; Diagnosis; Disease; Disulfides; Dose; drug inhalation; Endothelial Cells; Endothelin; Failure; FDA approved; Formulation; Gases; Goals; Gold; Heart failure; Home environment; Hospitals; Hour; Hypertrophy; Hypoxia; Individual; Inhalation; inhaled nitric oxide; Intensive Care Units; Investigation; Kinetics; Laboratories; Life; Life Expectancy; Liquid substance; Lung; Lung diseases; lung hypoxia; Lung infections; Malignant Neoplasms; Manufacturer Name; Measures; Medical; Methods; Molecular Weight; Monitor; mortality; neonate; Nitric Oxide; Nitrites; Nitrogen; Nitrogen Dioxide; Nose; novel; Operating Rooms; Oxygen; Ozone; patient population; patient response; Patients; persistent pulmonary hypertension; Pharmaceutical Preparations; Pharmacological Treatment; Phase; phase 1 study; Physiologic intraventricular pressure; Physiological; Population; portability; Powder dose form; preclinical study; premature; Premature Infant; Production; Prostaglandins I; prototype; pulmonary arterial hypertension; Pulmonary Circulation; Pulmonary Hypertension; Quality of life; Reaction; Respiratory Failure; respiratory hypoxia; S-Nitrosothiols; Safety; Secure; sensor; Site; SKIL gene; Source; Sulfhydryl Compounds; Survival Rate; System; Systemic blood pressure; Tablets; Technology; Testing; Therapeutic; Time; Transportation; Vasodilator Agents; Work

Patients with pulmonary hypertension (PH) experience low oxygen saturation, shortness of breath, low qualityof life, and a short life span (<10 years) following diagnosis. These patients frequently present to emergencyrooms, and many are admitted to intensive care units (ICUs), straining the health care system. Despite therapywith phosphodiesterase-5 inhibitors, prostacyclin analogs, and endothelin antagonists, mortality remains highand quality of life poor. With no specific drug available for curative treatment, inhaled nitric oxide (iNO), apulmonary artery-specific vasodilator, is the best option for treating PH without compromising systemic bloodpressure. Current tank-based iNO delivery systems are expensive and available only in operating rooms andICUs of established medical centers in developed countries. The need is great for simpler, portable, and lessexpensive iNO technologies. During phase 1, a proof-of-concept prototype was developed in partnership withthe University of Alabama at Birmingham. All the proposed goals in phase 1 were met and the technology wasfurther advanced through several innovations. First, the NO generation method was modified from the originalproposal of producing sustained release NO from its precursor molecule to producing a stock bulk amount in asingle-step chemical reaction to synthesize medical grade NO in a sealed container on demand. This methodwill 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 withsubsequent need for extensive purification steps. Second, it is proposed to mix this 100% NO directly withsupplemental oxygen to attain therapeutic doses while reducing co-delivery of NO2 to levels far below FDA safetylimits or diluting NO in inert nitrogen (N2) gas within the device prior to mixing with supplemental oxygen. Thesesystems avoid the need to dilute NO 1250-fold in N2 gas for storage in compressed cylinders and transport tohospitals, as is done with current systems. Third, an integrated gas sensor system for NO and NO2 measurementand electronic control systems for dispensing NO was developed. The assembled prototype is functioning welland as expected. Based on these encouraging results, iNOvodel, Inc. was formed to license, develop andcommercialize a full-scale product. In Aim 1, focus is centered on developing a fully functional hospital-basedand demonstrating feasibility for a portable iNO devices incorporating an optimized reusable NO-generatingcartridge. Aim 2 seeks to establish the chemical method for generating and storing NO in the cartridge to utilizeon-demand. Aim 3 is directed toward development of noninvasive and invasive interface systems that arecompatible with iNO devices for safe delivery of nitric oxide to patients. Further, the safety of the device to deliverNO using an in vitro benchtop NO delivery system that simulates the patient NO delivery system will be evaluatedfacilitating the pursuit of FDA regulatory approval.

Public Health Relevance Statement:
PROJECT NARRATIVE Inhaled nitric oxide ("iNO") has gained significant prominence in treating highly debilitating hypoxic lung failure in newborns, pulmonary arterial hypertension and pulmonary hypertension associated with pulmonary diseases. However, the market for iNO is limited due to the cost, complexity, and safety of the dominant tank-based delivery systems. The goal of this investigation is to develop a simpler, safer, compact, portable and more versatile means of generating and delivering iNO, offering the promise of lower cost and better treatment for existing iNO therapy, and the potential for a significant expansion of the patient population who can safely and effectively benefit from iNO therapy.

Project Terms:
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