Patent Application
20250152903
Inhaled nitric oxide (iNO) is used as a pulmonary-specific vasodilator without compromising the systemic blood pressure. Inhaled nitric oxide is used to treat persistent pulmonary hypertension associated with hypoxic lung failure in infants and life-threatening pulmonary hypertension in children and adults. Current tank-based iNO therapy is complex, expensive, and generally only available in the intensive care units and operating rooms of established medical centers. To make this therapy available to a broader patient population, less complex, less expensive, and non-tank portable iNO therapy devices are needed that can be used in and out of hospitals whenever and wherever they are needed.
In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, embodiments of the present disclosure, in some aspects, relate to methods for delivering NO to patients, systems for delivering NO to patients, devices for generation and storage of NO, and methods for generating NO.
The present disclosure includes a device for on-demand generation of NO which can include a reaction vessel and a liquid storage component, wherein the reaction vessel comprises a liquid injection port and a gas exit port. The liquid injection port and a gas exit port are each fitted with a self-sealing plug connector that is pressure-tolerant up to 500 PSI, such that the reaction vessel is self-sealing and pressure-tolerant up to 500 PSI. The liquid storage component is removably coupled to the reaction vessel at the liquid injection port via a socket connector.
Embodiments of the present disclosure include a two-stage dilution system for delivering NO to a patient. The system can include a removable NO gas cartridge in fluid communication with a gas mixing chamber and a CPU. The gas mixing chamber can include a carrier gas inlet, an NO inlet, a mixing space, and a gas outlet, wherein the NO inlet comprises an NO nozzle having an internal diameter of about 10 μm to 50 μm. The concentrated NO gas is delivered from the NO gas cartridge to the gas mixing chamber via a gas manifold, and the pressure of the NO gas in the manifold is controlled by an electronic pressure regulator in communication with the CPU. A carrier gas selected from air or N2 flows into the carrier gas inlet at a fixed flow rate. The NO nozzle injects the NO into a stream of carrier gas to mix the gas in the mixing chamber to form a first diluted mixed gas comprised of NO diluted in the carrier gas. The mixed gas comprises less than 1000 ppm of NO and less than 25 ppb of NO2. In a second dilution step, an oxygen source is coupled to the gas outlet via a flow sensor. The flow sensor measures the flow rate of inspired O2 and communicates to the CPU to inject the desired NO dose of the first diluted mixed gas into the O2 for delivery of a second dilute gas to a patient via an inspiratory tube at a desired NO dose, and wherein the desired NO dose is about 1 ppm to 80 ppm.
Embodiments of the present disclosure also include a single-dilution system for delivering NO to a patient, the system as above, but wherein the NO nozzle injects the NO into a stream of carrier gas to mix the gas in the mixing chamber to form a mixed gas comprised of NO diluted in carrier gas, wherein the mixed gas comprises from 1 ppm to 1000 ppm, and wherein the mixed gas is delivered to the patient without the second dilution.
Other compositions, apparatus, methods, features, and advantages will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional compositions, apparatus, methods, features and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims.
Further aspects of the present disclosure will be more readily appreciated upon review of the detailed description of its various embodiments, described below, when taken in conjunction with the accompanying drawings.
The drawings illustrate only example embodiments and are therefore not to be considered limiting of the scope described herein, as other equally effective embodiments are within the scope and spirit of this disclosure. The elements and features shown in the drawings are not necessarily drawn to scale, emphasis instead being placed upon clearly illustrating the principles of the embodiments. Additionally, certain dimensions may be exaggerated to help visually convey certain principles. In the drawings, similar reference numerals between figures designate like or corresponding, but not necessarily the same, elements.
Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.
Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of anesthesiology, molecular medicine, chemistry, material science, and the like, which are within the skill of the art.
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the systems disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C., and pressure is at or near atmospheric. Standard temperature and pressure are defined as 20° C. and 1 atmosphere.
Before the embodiments of the present disclosure are described in detail, it is to be understood that, unless otherwise indicated, the present disclosure is not limited to particular materials, reagents, reaction materials, manufacturing processes, or the like, as such can vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It is also possible in the present disclosure that steps can be executed in different sequence where this is logically possible.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
As used herein, the following terms have the meanings ascribed to them unless specified otherwise. In this disclosure, “consisting essentially of” or “consists essentially” or the like, when applied to methods and compositions encompassed by the present disclosure refers to compositions like those disclosed herein, but which may contain additional structural groups, composition components or method steps (or analogs or derivatives thereof as discussed above). Such additional structural groups, composition components or method steps, etc., however, do not materially affect the basic and novel characteristic(s) of the compositions or methods, compared to those of the corresponding compositions or methods disclosed herein. “Consisting essentially of” or “consists essentially” or the like, when applied to methods and compositions encompassed by the present disclosure have the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
Proportional valve, as used herein, refers to programmable electronically-controlled valves in which the flow speed and directionality of fluid are controlled through electronic pulsing of the valve opening. These valves do not require a pressure drop to operate.
Carrier gas, as used herein, can refer to nitrogen, air, air blended with oxygen (e.g., 21 to 80), or oxygen (21 to 100%) administered to a patient according to need.
Nitric oxide (NO); inhaled nitric oxide (iNO); Nitrogen dioxide (NO2); N-acetylcysteine (NAC); S-nitroso-N-acetylcysteine (SNOAC); cuprous chloride (Cu(I)Cl; Cupric chloride (Cu(II)Cl2: Disodium biphosphate (Na2HPO4)
Pulmonary hypertension (PH) is a highly debilitating disease, and no specific drugs are available for pharmacologic treatment. Inhaled NO (iNO) is a gold standard to provide a pulmonary specific vasodilator without compromising systemic blood pressure for treating/managing acute PH. Several clinical studies show that iNO clearly improves the ventilation-perfusion matching and lowers the pulmonary vascular resistance, thereby improving the oxygenation of blood in pulmonary arterial hypertension (PAH) and several PH-associated lung diseases. Presently, iNO has been used for the treatment of persistent pulmonary hypertension/hypoxic lung failure in infants and managing hypoxic lung failure and life-threatening pulmonary hypertension for adults to avoid the need for more invasive and expensive Extracorporeal Membrane Oxygenation (ECMO) treatment.
Current iNO therapy requires a complex and expensive (approximately $180/hour) tank-based NO delivery systems. Therefore, this therapy is available only in the intensive care units and operating rooms of established hospitals. It is possible that impurities in NO and the use of statistically underpowered subjects in clinical trials may be responsible for not observing clinical benefits of chronic treatment. Hence, there is a need for developing iNO therapy devices that are portable, less complex, less expensive and a desired amount of on-demand medical grade NO generation systems. The present disclosure addresses this need and other needs.
Since the FDA approved NO gas as a pharmaceutical agent, efforts are being made to develop portable NO-generating systems. Nitrite can be converted to NO in aqueous solutions, using mildly acidic conditions, electrolysis, high temperature, UV irradiation, electrochemical reduction using of Cu(II) to Cu(I) and ascorbic acid as a reducing agent, The major problem in these procedures is removing NO gas from the reaction vessel without generating toxic gases before introducing it to carrier gas. Catalytic reduction of highly toxic liquid N2O4/NO2 to NO is also being developed as a source of iNO. Other investigators are actively pursuing converting atmospheric air (N2 and O2) to iNO using high electric discharge electrodes. This procedure also generates toxic gases like NO2, ozone, other reactive oxygen species, and particulate matter in addition to NO. These need to be removed completely before administering to patients. Other start-up companies like Bellerophon pulse Technologies, Warren, NJ, Nu-Med Plus, Inc. Salt Lake city. UT and Novoteris, Canada have been developing portable NO delivery devices using a concentrated NO (2500 to 5000 ppm) blended with N2 in mini-cylinders, which can last only for a few hours. In these systems NO2 is also expected to be a major contaminant during storage and diluting the stock NO to therapeutic doses. In addition, patients need to buy NO cylinders from pharmacies as they do prescription medicine. All of these obstacles add to the cost of treatment. As such, there is a need for development of better methods for generating NO as well as better systems for delivering NO.
Therefore, the technology of the present disclosure for NO generation is focused on simple methods for generation of on-demand NO that are inexpensive and without need for purification. The treatment can be available to a wider global population for use both in and out of hospital facilities. The systems and methods described herein can be used for such as ambulatory patients, in a patient's home, and in hospitals or clinics, including while patients are transporting within or between facilities.
The methods and systems described herein present improvements in iNO therapy. The systems provided simplify the both the process for diluting NO with supplemental oxygen to the therapeutic doses and the process for delivery. Amongst other improvements, the present system introduces an electronically controllable pressure regulator for dosing NO based on the pressure difference between NO and NO carrier gas.
Two types of iNO systems are described herein. In a first system, intended mainly as an alternative to existing systems used in clinical settings. This system uses a dual dilution process in which high concentration NO is first diluted in a carrier gas through a controlled nozzle and flow configuration that prevents the formation of toxic levels of NO2 gas. The diluted gas, also referred to as mixed gas, is then diluted a second time as it is mixed with inspired oxygen at the point of delivery to a patient. Advantageously, the system allows for diluted, accurate dosing of NO from highly concentrated NO stock on demand. The NO can be diluted by a factor of about 40,000 while minimizing the formation of NO2. The NO2 produced using the system is less than 100 ppb, which is approximately 10 times less than the maximum allowed amount by the FDA, resulting in a very safe delivery system.
In this system, toxic NO formation is reduced at two stages where NO2 formation can potentially formed. In any reaction, the mixing point of NO with O2 is the source of about 99% of NO2 formation, especially when mixing highly concentrated NO. However, the present system uses a controlled nozzle system in a mixing chamber to minimize the formation of NO2 by rapid dilution The NO is diluted in the mixing chamber into a carrier gas comprising either N2 or O2 (21 to 100%) O2 gas. The carrier gas is pumped into the mixing chamber at a fixed flow rate of carrier gas (N2 or air). A gas flow rate sensor in the inspiratory tube controls the desired NO dose from the exit of the mixing chamber into the oxygen flowing to the patient's inspiratory tube. The diluted NO (<1000 ppm) is injected into inspired into inspiratory tube through injector nozzle having an orifice from about 50 microns to about 500 microns. In some embodiments, NO is directly injected into the inspired oxygen in the mixing chamber. The gas exit from the mixing chamber is directly used for inhalation. In various embodiments, the system can also include a gas sampling line in communication with one or more gas analyzers to measure NO and//or NO2 to ensure patient safety.
In a second system, intended mainly to be used as a portable system for use outside of clinical settings (e.g., home use, during patient transportation, or in emergency situations), the high concentration NO or diluted NO is diluted in a single or two or three doses into inspired oxygen immediately prior to delivery to the patient. In this embodiment, the carrier gas used in the mixing chamber is mainly atmospheric air or O2 gas. The NO flow to the mixing chamber is controlled by electronically regulated pressure regulator or proportional valves placed between the NO cartridge and the mixing chamber.
In both systems, the dose administered to the patient remains constant through control of the pressure of NO gas entering the carrier gas stream through the NO nozzle. The dose can be set through a user interface connected to a CPU, and the CPU controls the pressure of NO exiting the nozzle via a series of sensors and pressure regulators.
In various embodiments, the NO is injected into the carrier gas stream inside a mixing chamber via an NO delivery nozzle having a micro-orifice. The carrier gas (air or N2 in the dual-dilution system, O2 in the single dilution system) enters the mixing chamber through a carrier gas inlet, forming a stream of carrier gas. NO is injected into the stream. The nozzle system is used as a means to minimize the nitrogen dioxide (NO2) formation as well as control the injection of NO in microliter volumes into NO carrier gas. These improvements and others disclosed herein make the device simpler, smaller, lighter weight and better able to provide precise dosing for use in and out of hospitals. In some embodiments, concentrated NO gas (such as from about 2% to about 100% concentration) can be delivered into the carrier gas stream by a nozzle having an exit diameter of about 2.5 μm to 100 μm (e.g., 2.5 μm, 5 μm, 10 μm, 25 μm, 50 μm). Advantageously, the small nozzle size creates a build up of NO pressure in the manifold so that the NO can be metered. The small nozzle size also mixes NO rapidly with O2 rapidly so that NO2 formation can be minimized.
In some embodiments, the mixed gas (e.g. the NO diluted in the carrier gas) has a concentration of about less than 0.1% and is delivered from the device by an outlet having an exit diameter of about 50 μm to 1000 μm (e.g., 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 500 μm, 750 μm, 1000 μm).
In some embodiments, the carrier gas can be delivered to the mixing chamber at a flow rate of about 2 L/min to 12 L/min, or about 5 L/min to 8 L/min.
In various embodiments, the NO dosing is controlled using the pressure difference between the carrier gas and the NO gas. In this manner, the dosing remains constant even where the carrier gas flow or pressure changes. Where the carrier flow increases, the pressure difference also increases. Given a specific NO dose for desired delivery to a patient, a known NO concentration provided the system, and a known carrier gas flow rate, a pressure difference is established. Should the carrier gas pressure or flow rate change, the pressure of the NO dose delivered to the carrier gas can be proportionately adjusted to maintain the NO dose. In an illustrative non-limiting example, where a health care provider prescribes a NO dose of 25 ppm, with a typical 8 L/min carrier gas flow, there is a pressure difference of 12 kPa between the NO pressure and the carrier gas pressure. If the carrier gas flow was then reduced to 5 L/min, a pressure difference of 5 kPa would be needed to maintain the 25 ppm dose rate. The system would adjust to reduce the pressure of NO to achieve the 5 kPA pressure difference, thereby delivering the 25 ppm dose to the patient despite the change in gas flow rate. So, in this way the system can compensate if the flow rate changes to keep the dose constant. Similarly, if the user adjusts the desired dosage amount, the system can adjust the proportion of NO needed to achieve the dosage based on the carrier gas flow rate.
Where NO dosing is controlled using the pressure difference method described above, the NO is delivered from the NO source (such as a cartridge as described below) via a gas manifold, through the NO nozzle into the mixing chamber. The pressure and flow rate are controlled by an electronic NO pressure regulator and a carrier gas flow rate and pressure sensor in communication with a CPU. In some embodiments, the carrier gas flow is further controlled by a solenoid valve.
In another embodiment, the NO dosing is controlled by an electronically controllable proportional valve. Here, an ultra-miniature proportional valve is used in conjunction with the small (e.g., 10 or 25 micron) delivery nozzles to deliver the NO to the mixing chamber. Instead of the dosing being based on pressure difference as above, the pressure of the NO in the gas manifold remains constant and higher than the carrier gas pressure. The manifold pressure is set at lowest possible value that maintains a positive differential pressure between manifold and mixing chamber (across all anticipated carrier gas pressures) and is maintained by a pressure regulator. The pressure can be maintained at a limit such as less than 30 psi. The dosing is controlled by the amount of NO emitted through proportional valve. The proportional valve pulse width determines the amount of NO, where a high pulse width delivers less NO and a low pulse width means that the valve is open longer and therefore delivers more NO. The valve pulse width time is proportional to the NO dose. The valve pulse width time is proportional to the carrier gas flow rate at the fixed, prescribed NO dose.
In various embodiments, a system equipped with a proportional valve can be operated based the pressure differential method as described above. When the proportional valve is left open, the system can function based on the pressure differential. In this way, the pressure in the manifold is no longer constant, but is instead managed by the pressure regulator.
In various embodiments, the mixing chamber includes a carrier gas inlet and an NO inlet entering a mixing space, and a gas exit port exiting the mixing space. In some embodiments, the mixing space can have a volume of about 10 mL to about 50 mL, or about 20 mL. The NO inlet extends into the mixing chamber via a nozzle assembly that includes a hypodermic stainless-steel tube. In some embodiments the tube can be a 13-gauge tube. The tube is fitted with a nozzle having an internal diameter of 2.5 μm to 50 μm. The NO nozzle can have, in some embodiments, a corundum orifice. In a particular embodiment, the NO nozzle has a 10 μm internal diameter opening. The NO inlet is configured such that the NO injected through the nozzle enters into a stream of carrier gas entering the mixing space through the carrier gas inlet. The now combined stream of NO and carrier gas then encounters an obstruction which diverts the combined gas around the mixing space to mix it further. The carrier gas inlet and the gas exit port have the same diameter, causing the mixing chamber to operate under steady-state pressure such that the pressure of the gases entering is the same as the pressure of the combined gas exiting through the exit port.
In general, the NO gas is provided to the systems described by a NO cartridge in which NO is both generated and stored. This cartridge is then inserted into the system such that the NO from the cartridge is mixed in a mixing chamber with carrier gas for delivery to a patient. The concentration and flow velocity of NO and flow velocity of carrier gas is precisely controlled while mixing them together such that the formation of toxic NO2 is minimized while providing the patient with a prescribed NO dosage.
The NO is delivered to the system from an NO cartridge. The cartridge includes two primary components. The first component is a reaction vessel, which is used for storage of NO-generating dry chemicals prior to reaction and for storage of the high concentrated NO gas generated by reacting the chemicals with water. It can be a pressure-resistant, nonreactive material such as stainless steel. The reaction vessel can have a capacity of about 50 mL to about 200 mL. The reaction vessel has two ports, one for injecting liquid and/or inserting the reagents, and one for gas exit when the reaction vessel is inserted into one of the systems above. Each of the ports can be fitted with self-sealing plug connectors that are pressure tolerant (e.g., to about 500 psi) such that the reaction vessel is self-sealing and pressure resistant.
The second component is a liquid storage component. The liquid storage component delivers a liquid reactant such as water to the reaction vessel through the liquid injection port and is then removed. Upon injection of the liquid, the NO reaction commences to form NO gas. The pressure from the gas pressurizes the reaction vessel. In some embodiments, the liquid storage component can be a pressure-resistant, gas-tolerant syringe for manual injection of the fluid. In other embodiments, the liquid storage component can be a pressure-resistant, gas-tolerant vessel where the liquid is added to the reaction vessel when the NO-generating chemicals are stored under vacuum. The liquid storage component can be removably coupled to the reaction vessel's injection port by a socket coupler (e.g., a luer lock or other suitable connector) that provides a gas-tight connection between the two components. The socket can couple with a plug connector on the reaction vessel injection port. Advantageously, the reaction vessel can be recycled or reused. The liquid storage component can be disposable or reusable. Advantageously, the liquid storage component can be pre-filled with an amount of liquid precisely measured for the reactants in the reactant vessel.
The NO gas in the cartridge can have a concentration of about 2% to about 100%. In some embodiments, the NO gas can be diluted to about 2% to 50% by N2 gas in the cartridge for use in such as portable systems, providing NO supply appropriate for short-term (e.g., 2 to 24 hours.) usage. In other embodiments, the NO gas can be stored undiluted in the cartridge at a high concentration such as 80%, 90%, or higher for use in the system.
Also provided herein are various methods for generating high-purity, high concentrations of NO gas. In a particular embodiment, reactants sodium nitrite, N-acetylcysteine powder and cuprous chloride crystals in a ratio of 1:1:0.2 are stored in the reaction vessel. Advantageously, the completely dry reactants can be stored in the completely moisture and O2 free conditions of the cartridge described above for up to two years without affecting stability. The NO-generating reaction is initiated by addition of water from the liquid storage component. The reaction occurs under anaerobic conditions. Advantageously, because the reactants in the vessel are in powder form, the reaction occurs without mixing or agitation. One hundred percent of the nitrite is converted to NO. About 80% of this generation occurs within one minute. The reaction can be generated under N2 pumped into the reaction vessel through the exit port to reduce potential reaction with O2 in the vessel. The presence of any trace oxygen reacts with NO to forms NO2, but this NO2 diffuses back into water and converts to nitrous acid and nitrite, resulting in the final NO generated in the reaction vessel being 99.7% pure. Advantageously, this fast, pure reaction can be initiated on-demand, such as where NO intervention is needed in emergency situations.
In some embodiments, the reactants include sodium nitrite, NAC, Cu(I) chloride and Na2HPO4 in a ratio of 1:1.25:0.2:1.25. The addition of Na2HPO4 increase the shelf-life and stability of the generated NO, although the yield is slightly lowered.
In other embodiments, the reactants can be sodium nitrate, NAC, and Cu(II) chloride, and a proton donor. In some embodiments, the proton donor is ascorbic acid. In other embodiments, the proton donor can be a carboxylic group of NAC, substrate itself. Other proton donors can include, but are not limited to, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, and phosphoric acid.
Now having described the embodiments of the disclosure, in general, the examples describe some additional embodiments. While embodiments of the present disclosure are described in connection with the example and the corresponding text and figures, there is no intent to limit embodiments of the disclosure to these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure.
Devices and methods for portable delivery of iNO are discussed in PCT/US2021/071242, herein incorporated entirely by reference. The present invention can be used for storing chemicals and generating NO gas on-demand in the NO-cartridge. The present invention provides improved chemical storage stability as well as NO gas stability after generation, more controlled metering (dosage) of NO into a carrier gas, and higher NO purity. The present disclosure provides for systems and methods for bulk concentrated (e.g., 90 to 98%) NO generation and delivery. In general, an NO-generating chemical reaction is performed in a cartridge. The cartridge can be immediately placed in the delivery system for delivery to a patient or can be stored for later use for an extended period (such as 3 months) in the delivery system. The following examples describe the cartridge and the chemistry for generating the NO as well as the system for delivering the generated NO. The chemistry, cartridge, and system work in tandem to deliver iNO therapy to the patient.
Here, the cartridge, has been modified and simplified. First, a known amount of 90 to 98% of NO is generated in a cartridge. The NO is also diluted with nitrogen to a desired percent level using high pressure nitrogen tanks. The assembly of the cartridge's reaction vessel with high pressure threading self-sealing NPT connectors makes it safe for generating on-demand NO. Then, the cartridge is inserted into a receptacle in the iNO system for passage of NO into a mixing chamber. Advantageously, the cartridge allows simple, safe generation of NO by any healthcare worker, patient, caregiver, or other non-technical individual. The cartridge is also recyclable. This cartridge improves chemical compatibility and pressure thresholds associated with the previously disclosed device. The cartridge described herein generates on-demand, pressurized NO with a purity of about 90% to 99.6% within the cartridge by a chemical method.
In embodiments, prior to NO generation, the atmospheric air in the cartridge is replaced with nitrogen and evacuated. The evacuation does not remove all of the nitrogen. About 0.3% (30 ml in 100 ml reaction vessel) nitrogen is retained in the cartridge. This nitrogen dilutes the generated NO gas, resulting in a percentage of NO about 90% to 98%. The percentage of dilution is dependent on how much NO is generated. Depending on need and the amount of reagents, about 0.27 L (50 psi) ml to 1.5 L (230 psi) may be generated. The self-sealing connectors allow for safe storage of concentrated NO at high pressure for subsequent dosing. Other non-tank delivery systems generate very low concentration NO (about 0.08% (800 ppm) on site. Any changes in the desired dose requires a change in the chemical synthesis of the NO (Vero-biotech, LLC, Atlanta, GA, Beyond Air, Inc. New York, and Nota labs. Inc. Ann Arbor, MI). In contrast, the present system allows for high concentration (10% to 100%) pressurized NO in which the dosage can be altered in seconds based on metering the NO with carrier gas flow rates.
In the previous disclosure, it was proposed that the NO-generating chemicals be formulated as a tablet or capsule to increase the stability and shelf-life and to enable storage in an aerated (21% O2) NO cartridge. A magnetic stirrer that was integrated within the device was used to promote dissolution of the solid chemicals into the liquid. The stirring also facilitated diffusion of NO2 from the reaction vessel headspace to the solution to convert back to NO. In the present modified device, we have omitted the magnetic stirrer and programmatically actuated mechanism for combining the chemicals with liquid and transferring NO to the reservoir. Instead, NO is generated in a cartridge (described below) before inserting the cartridge into a receptacle of the iNO for passage of NO into a reservoir or mixing chamber. In the present system, chemicals in fine powder form are used because they dissolve or suspend quickly in the aqueous solution to minimize the need for stirring. The moisture content is also reduced in the gas. Further details are provided in the examples below.
The cartridge 100 is a self-sealing, pressure resistant vessel for storage of NO-generating chemicals. Cartridge 100 includes a reaction vessel 110 that is configured to be self-sealing. Reaction vessel 110 can store either unreacted first reactants or fully reacted NO. Reaction vessel 110 is configured to removably couple with liquid storage component 120. Once water is injected from liquid storage component 120 to initiate a reaction in reaction vessel 110, liquid storage component 120 can be released from reaction vessel 110. Reaction vessel 110 self-seals such that the reaction can take place inside, creating a pressurized vessel. Advantageously, the cartridge is very safe; it can be dropped, handled, moved, etc. without releasing the contents or exposing the contents to air.
Example cartridges are illustrated in
Liquid storage component 120 is removably coupled to reaction vessel 110 by a socket coupler 122 that pairs with plug connector 114 when both components are fitted together. Socket coupler 122 is provided an airtight connection to the reactant vessel 110 by coupler 124. Socket coupler 122 can be released from reaction vessel 110 by release button 126. In an embodiment, coupler 124 is a luer lock that forms an airtight connection to the storage chamber 120, forming a custom modification for socket coupler 122.
Liquid storage component 120 can be prefilled with an appropriate amount of a liquid diluent. When NO is needed, the socket coupler 122 is snapped to the plug connector 114, creating a quick connection to make a passage between the reaction vessel 110 and liquid storage component 120. The socket coupler 122 can be disconnected quickly by pressing the release button 126. After injecting liquids, the gas is generated and pressurizes the reaction vessel. This pressure can push the syringe plunger of liquid storage component 120 to release NO out if the socket coupler 122 is not removed. In some embodiments, a plunger flange is made to lock the socket 122, so that the pressure does not push the plunger out to release gas.
Alternatively, the process of mixing liquid with the chemicals in the cartridge 100 can be automated after insertion of the cartridge 100 into an assigned receptacle of the larger iNO system, where the liquid storage component 120 is part of the iNO system. A small amount of liquid can remain in the plug connector 114 during the transfer of liquid into reaction vessel 110. Hence, liquid injection port 112 is not used as a dual-purpose gas exit port and liquid injection port to avoid liquid contamination in the gas. The moisture content in the NO collected from the gas exit port 116 is less than 0.2% because the stirring of reagents is not required to initiate the reaction. This cartridge 100 has the ability to make up to 1.5 L of 100% pure NO gas having a pressure of about 50 psi to about 230 psi based on the requirement. In addition, the NO generated in the reaction vessel 110 can be diluted (e.g., about 10% to 90%) with nitrogen gas to use in inhaled NO therapy.
Turning now to
The NO-generating chemical mixture (discussed in detail below) was placed in the reaction vessel and then subjected to N2 at standard atmospheric pressure (1 ATM), N2 at 70% vacuum (0.3 ATM) (
In the literature, S-nitroso-N-acetylcysteine (SNOAC) is prepared by dissolving NAC in HCl (0.2 to 0.6 M) and mixing it with sodium nitrite solution at a ratio of 1:1. Similarly Cu(I) ion-mediated degradation of S-nitrosothiols has been demonstrated by combining soluble cupric salt with a reducing agent of ascorbic acid or miscible form of cuprous salts. However, there are no reports of generating NO gas in bulk amounts by combining solutions of NAC, nitrite, and Cu(I) ions or reacting this chemical mixture with water as described here. For the first time, we have demonstrated in this disclosure that a highly pure form of NO gas can be generated within a few minutes by reacting water with the mixture of NAC, sodium nitrite, and cuprous chloride crystals. This method can advantageously be used for generating NO rapidly, such as for use in emergency situations. The main observation is that the rate of reaction between these chemicals to generate NO is faster and safer (e.g., containing less NO2) when water is added to the mixture of these three crystal chemicals rather than mixing the aqueous solution of these chemicals, as previously described in the literature. Seven reactions, shown below, are taking place simultaneously to generate NO. All these reactions occur under acidic conditions provided by a proton donor from the carboxylic group of NAC. Acidified nitrite reacts with NAC to generate SNOAC. Cu(I) degrades SNOAC to NO. Cu(I) ions reduces acidified nitrite to NO. Cu(II) is reduced back to Cu(I) by NAC. The final products are NO and disulfide acetylcysteine.
NAC—COOH→NAC—COO−+H+
NO2−+2H+↔HNO2+H+↔NO+—H2O
NO+—H2O+NACSH→SNOAC+H2O
NO+—H2O+Cu(I)→NO+Cu(II)+H2O
SNOAC+Cu(I)→NO+Cu(II)+′SNAC
NACSH+Cu(II)→NACS′+Cu(I)
NACS′+NACS′→NACSSCA
The generation of NO gas during the reaction solution form of these chemicals has been described in the literature. This NO is converted to nitrous acid and nitrite following the reaction with soluble oxygen. The method of combining the crystals of these chemicals and then reacting with water in the absence of O2 to generate a bulk amount of NO has not been previously described. The rate of this reaction for generation of reaction is very rapid without generating toxic amounts of NO2 as a byproduct. Therefore, this method represents a great advance in generation of NO for on-demand use in inhaled NO therapy.
In this modified process, 0.23 moles (3.75 g) of N-acetylcysteine (NAC), 0.23 moles (1.59 g) of nitrite, and 0.0045 moles (0.45 g) of Cu(I)Cl are placed in the reaction vessel 110 described above, which is closed with the self-sealing plug connector 114 (
Stability of NO during storage—In a series of experiments, the instability of NO was investigated and a method for increasing stability was discovered. NO undergoes redox interactions with metal ions to form nitrogen oxide species. These redox reactions are highly influenced by the acidic pH of the reaction mixture. Therefore, we investigated the stability of NO that is generated in the reaction vessel to determine how long it can be used for inhaled NO (iNO) therapy. NO content in the fixed volume of generated gas was measured by chemiluminescence assay at varying time intervals for 180 days. The chemiluminescence assay was specific for NO gas only and not for other nitrogen oxide gases such as NO2, nitrous oxide (N2O), etc. NO was generated in a septum-sealed reaction vessel at up to 50 psi pressure. Exactly 25 μL of gas was drawn with a gastight Hamilton syringe and then injected into the stream of nitrogen gas (3 L/min) that was drawn into an NO analyzer for measurement of NO gas. The area under the curve of NO signal from the NO analyzer is directly proportional to NO concentration. The initial peak area that was measured within an hour of NO generation was considered to be baseline NO concentration. The change in peak areas of subsequently injected samples at varying time intervals is shown in
2CuCl+2NO+2H++2Cl−→2CuCl2+N2O+H2O.
Next, we increased the pH of the reaction mixture from 3.95 to 6 and 7 using a basic disodium hydrogen phosphate (Na2HPO4). Any other basic compounds like sodium or potassium hydroxide and other alkaline solutions can also be used. The pH of the reaction mixture was raised from 3.9 to 6.0 and 7.0 by injecting a required amount of Na2HPO4 into the reaction vessel after NO generation. The stability of NO in the reaction vessel was measured at varying time intervals for 180 days. As shown in
In the aforementioned experiment, the pH was raised by injecting a desired amount of Na2HPO4 into the reaction vessel after NO gas generated. However, this procedure is not practical to use in the NO-cartridge because the vessel seals due to the pressure generated by the reaction; therefore, an additional reactant cannot be added to the airtight reaction vessel after generation. One option is to transfer the NO to another container after generation in the reaction vessel, but his would add an extra complication to the NO delivery systems. Instead, we have developed a system to increase the stability of NO in the reaction vessel itself. The reaction between nitrite, NAC, and Cu(I) chemicals to generate NO gas is very fast following the addition of water, even without stirring (
It is important to know the rate of NO generation in the cartridge to assess how quickly it can be delivered to patients. As discussed above, a pH of 7.0 provides stability of NO in the reaction vessel. The reaction of nitrite with NAC to generate SNOAC and the reduction of nitrite to NO by Cu(I) are largely dependent on the acidity of the reaction mixture. Inclusion of Na2HPO4 in the reaction mixture raises the pH and slows the rate of NO generation, as shown in
Since approximately 80% of the NO is generated within approximately one minute in the absence of Na2HPO4, NO gas generated without the Na2HPO4 is available for therapy within minutes of reaction initiation. However, the shelf-life of the cartridge after generation of NO is less than 48 hours. It can be used when NO intervention is needed quickly and for a short duration of treatment (<48 hours). Advantageously, in the presence of Na2HPO4, the NO cartridge can have a long shelf-life for a minimum of 6 months or more. FTIR studies investigating longer-term storage will be performed to establish the destabilization rates to prevent unwanted degradation resulting in NO2 and N2O.
We hypothesized that under appropriate conditions, the dry chemicals in the cartridge and the NO yield in the cartridge should remain stable for one to two years prior to reaction with water. The purpose of this experiment was to find conditions that increase the stability of chemicals and shelf-life of the cartridge. NAC, nitrite, and Cu(I)Cl are slightly hygroscopic at atmospheric humidity and temperature. NAC degrades to diacetylcysteine disulfide, nitrite oxidizes to nitrate, and Cu(I) oxidizes to Cu(II) over time in the presence of oxygen and moisture. This instability is accelerated when they are mixed together because intermediate products are formed, including SNOAC, NO, nitrogen dioxide, and Cu(II)Cl2. Completely eliminating the moisture content that is absorbed into chemicals as well as outside moisture could increase the compatibility and stability of this chemical mixture. The moisture content in the chemicals is stripped by exposing them to heat without affecting the chemical nature of the compounds and stored them in a desiccator. The moisture content was found to be 0.3% in NAC, 0.2% in sodium nitrite, and 0.25% in Cu(I)Cl. We are currently assessing the long-term stability of the dry mixture of NAC, sodium nitrite, and Cu(I)Cl under air, air evacuation (70%), nitrogen, and nitrogen evacuation in airtight sealed glass vials by measuring the amount of NO generation at 6-month interval for 2 years. Chemicals were stored at the ratio of 1:1:0.2 under the indicated conditions in sealed vials. The amount of NO generation was measured following the reaction with water. Values are expressed as mean±SD. N=3. The values are expressed as a percentage of baseline NO concentration.
In a separate experiment, we included moisture-absorbent calcium sulfate crystals (WA Hammond Drierite Co.) in the chemical mixture to study the stability of chemicals under atmospheric air. Calcium sulfate did not interact with NO-generating chemicals in crystal or solution state. If use of calcium sulfate works in the long-term, the cartridge will not need to be flushed with N2 before evacuation. It is anticipated that the calcium sulfate would not interact with Na2HPO4, allowing the shelf-stable NO generation to be performed without N2 flushing.
Table 1 shows the storage stability of the NO generating chemical mixture of sodium nitrite, NAC and Cu(I)Cl in the presence and absence of base Na2HPO4 under nitrogen in gas-tight vials. In the previous experiment (
The data show that the chemical mixture of NAC, nitrite, Cu(I)Cl and Na2HPO4 is stable under nitrogen in a sealed container for 6 months, with a slight reduction of NO at 6 months. This study will continue for another 18 months under the same conditions.
Ascorbic acid (RH) readily loses hydrogen ion (H+ ions) forming ascorbate anion. Hydrogen ions acidify the nitrite to nitrous acid, which has a nitrosonium ion character. Ascorbate anion readily reduces this nitrous acid to NO. Ascorbate anion also reduces Cu(II) to Cu(I). Cu(I) ions reduce nitrous acid to NO rapidly. Cu(II)/Cu(I) undergoes redox cycles as long as ascorbic acid is available. Both the ascorbate anions and Cu(I) convert nitrite to NO under acidic conditions. We used these reactions to make a bulk amount of NO gas. Addition of water to the mixture of 5 mmoles (0.345 g) sodium nitrite, 5 mmoles (0.881 g) ascorbic acid and 0.25 (0.0336 g) mmole Cu(II)Cl2 at the ratio of 1:1:0.05 under nitrogen in an airtight reaction vessel resulted in rapid generation of NO. As shown in
RH→R−+H+
NO2−+2H+↔HNO2+H+↔NO+—H2O
NO+—H2O+R−→NO+R′+H2O
RH+Cu(II)→R′+Cu(I)
NO+—H2O+Cu(I)→NO+Cu(II)+H2O
R′+R′═R—R
Any compounds that are an electron and proton donors (H+) can be used in place of ascorbic acid to convert nitrite to NO. Any electron donor compounds (reducing agents) in the presence of low pH conditions can be used in the place of ascorbic acid to convert nitrite to a bulk amount of NO. Cu(I) salts under acidic conditions also converts nitrite to NO to make bulk amount of NO gas. Any other metal ions that undergo redox cycling in the presence of reducing agents under acidic conditions can be used in place of Cu(I) or Cu(II) salts to convert nitrite to NO in bulk amounts.
An additional experiment was undertaken to increase the stability of NO in the reaction vessel generated by nitrite-ascorbic acid and Cu(II) CI. NO that is generated in the reaction vessel is unstable. It slowly converts to nitrous oxide with time under the acidic conditions of the reaction mixture. Therefore, the pH of the reaction mixture was raised from 5.4 to 7.0 by adding a basic solution of Na2HPO4 after generation of NO using an infusion pump into the reaction vessel via the quick connectors shown in
Mixing the generated NO with carrier gas:
In the depicted embodiment, an O-ring seals the two halves and ⅛″ OD tube compression fittings attach to the carrier gas inlet 310 and combined gas outlet 340 ports. The NO inlet 320 extends into the mixing chamber 300 via nozzle assembly that includes a 13 Birmingham Wire Gauge (BWG) hypodermic stainless-steel tube 322. The tube 322 is capped with a stainless-steel, press-in, insert with a nozzle 324 (
The carrier gas inlet 310 brings the carrier gas into the mixing chamber 300 to intersect with the end of the NO inlet 320 tube. The geometry of the passageway 320 is such that the 1/16″ ID channel cross-sectional area is reduced by 40% into a slot channel that is perpendicular to the ruby orifice surface (
In order to test the NO generated by the reaction of nitrite, NAC and Cu(I)Cl with water in the reaction vessel 110, the NO was transferred into mini-canisters and shipped to CONSCI, Ltd., which analyzed the total gas composition by the FTIR method. The CO2 levels were miniscule. A small percent of nontoxic NO2 (0.14%) was detected and likely formed during the transfer of NO gas into the canisters. Analysis by a CAPS NO2 analyzer (Aerodyne Research, Billerica, MA) showed that NO2 was 0.26% (26 ppb in 100 ppm NO) in NO collected from the air-evacuated reaction vessel. Thus, traces of NO2 formed during the handling of sample for analysis. These results confirm the synthesis of 99.9% pure NO using the cartridge. No further purification is required as it is with the technology of other companies.
Baseline NO2 formation was established using inert nitrogen gas as the NO carrier. The baseline NO2 levels before the pre-set at the NO exiting point from the device were less than 25 ppb. However, the post-set (tracheal) NO2 levels are an indicators of NO2 formed at the interface of nasal/facemask from the entrance of room air into the upper respiratory system in addition to the pre-set level. These NO2 levels are highly variable, as the interface between air mixing and inspired gas residence time is highly dependent on the flow rates of carrier gas and breathing mechanics. The post-set NO2 levels were higher than pre-set levels at these settings and needed a detailed investigation. Table 2 shows NO and NO2 levels at pre-set and post-set for two different NO doses (20 and 40 ppm) and varying carrier gas flow rates. NO2 generation was less than 0.17 ppm when air (21% O2) was used as the carrier gas and 0.5 ppm when 100% oxygen was used as the carrier gas. These values were less than the safety limit (1 ppm) set by the FDA for patient populations. The post-set NO values were significantly less than pre-set values and highly dependent on flow rates of inspired gas. The post-set NO2 values were highly dependent on the O2 saturation and flow rates of inspired gas, indicating that all these factors need to be considered in iNO therapies.
Unlike other systems where the NO dosage is controlled primarily by changing the concentration of NO provided to the system, the NO dosage provided by the current NO delivery system is based on the pressure difference between NO gas and inspired oxygen. The pressure difference between NO and carrier gas governs the NO dosing and is achieved by the nozzle system (NO inlet 320, nozzle tube 322, and NO delivery nozzle 324), where the nozzle 324 size can be changed according to need.
Stage 1 gas regulator 210 restricts the NO-cartridge outlet pressure to a maximum of 200 kPa. Stage 2 regulator 218 electronically controls the differential gauge pressure level from 0.25 kPa to 200 kPa in the NO-manifold 214. NO pressure in the cartridge 100 is in the range of 500 kPa to 1500 kpa. Using both stage 1 and 2 pressure regulators can reduce the cartridge NO pressure to a minimum level of 0.25 kPa at the delivery point of the nozzle 324 orifice. The isolation valve 216 electronically controls the NO exit from NO-manifold 214 to the mixing chamber 300, where the gas is delivered via nozzle assembly 320. The isolation valve also prevents the entry of carrier gas into the NO manifold 214. If the carrier gas pressure is higher than manifold pressure, the program automatically closes the isolation value 216. As an alternative to oxygen, the system 3000 can optionally use air as a carrier gas by integrating a small air pump to supply the source of air (not shown). An injector 376 that is combined with a gas flow sensor 260 (not shown) can be placed at the gas outlet of a ventilator inspiratory tube 370 or high flow nasal cannula (HFNC) to deliver the therapeutic mixed gas to the patient. The injector nozzle 376 orifice size is from 100 μm to 1000 μm to mix NO rapidly with inspired oxygen to minimize the NO2 formation. The flow sensor 260 determines the carrier gas flow rate in milliseconds and communicate to CPU 500. The concentrated NO is diluted in nitrogen stream or air (0.5 to 1 L/min) to a lower concentration (<1000 ppm) in the mixing chamber 300 prior to introducing it into inspiratory tube 370 through the injector 376.
Operation of system 3000: The pressurized NO-cartridge 100 is inserted into a cartridge receptacle in the system. The user sets the desired dose on a user interface connected to CPU 500. The flow sensor 260 measures the flow rate of inspired O2 and communicates to the CPU 500. The calculation for dosing of NO is as follows (see
Advantageously, the cartridge 100 without chemicals in it can be used to fill the medical grade NO to the concentration of 2 to 100% at the pressure of 50 to 500 psi. These pre-filled cartridges can be used in the device as a source of inhaled NO. The system can use cartridges 100 that are pre-filled with medical grade NO in the range of 2 to 100% concentration at the pressure of 50 to 500 psi. The efficiency of NO dosing is more efficient with diluted stock NO because the pressure difference between NO and carrier gas is high as a result it is easy to regulate the NO dosing with pressure regulator. In addition, the two stages dilution (e.g., in the mixing chamber and again when mixed with inspired O2) is not required for using diluted NO of 2 to 20% because the NO2 formation would be within the safety limits. The injector module 376 in the inspiratory tube can be replaced with a mixing chamber 300 that is integrated with a gas flow sensor.
To test NO dosing, a prototype was built based on the designs shown In
In our previous work, NO2 levels in the combined NO and O2 gas were measured upon exiting the mixing chamber from a 25-μm nozzle. The present system uses a 10-μm NO nozzle 324. NO2 and NO levels are measured simultaneously in the mixed gas that exits the mixing chamber. NO2 levels in the nitrogen carrier gas indicate the NO2 present in the stock NO and/or formed while transferring NO from the cartridge to the mixing chamber. Mixing NO gas with air and 100% O2 results in formation of NO2 with increasing NO concentration. NO2 formation is within the safety limits of <1 ppm even at the maximum permitted dose of 80 ppm NO. The rate of NO reaction with O2 to generate NO2 is the square of the NO concentration and proportional to the O2 concentration. As seen in the Table 3, increasing NO concentration from 20 ppm to 40 ppm and 80 ppm generates only 3-fold and 9-fold NO2, respectively, rather than 4-fold and 16-fold. The possible explanation for this result is that NO is delivered into the mixing chamber at the fixed orifice of the nozzle. As the NO injecting volume increases, the flow velocity of NO gas that is emerging from the nozzle's orifice also increases, thereby resulting in more rapid mixing with O2 (or other carrier gas). The more rapid mixing in turn decreases the dilution time, thereby decreasing NO reaction with O2 to generate NO2. Therefore, NO2 formation does not pose a problem even at higher doses of NO in pressure-mediated NO delivery because it does not increase exponentially with increasing the NO concentration. Table 3 shows the NO2 levels in the NO and carrier gas mixture.
Proportional valve NO delivery:
NO delivery increases with increasing the pulse width (valve held open longer per cycle) rate of the valve. In a particular embodiment, the carrier gas flow rate is set at 5 L/min and initiates the procedure. The mixing chamber gas pressure that indicates the carrier gas pressure is 17 psi at this flow rate. The default PW is always 0.4 milliseconds/cycle. It allows NO delivery when its threshold pressure limit is crossed. The manifold pressure (NO pressure) is increased by using the pressure regulator controls on the touchscreen until the NO signal is seen on the NO analyzer program. At these settings, the manifold threshold pressure for NO is 22 psi. The presumption is that all the doses of NO can be delivered at this fixed manifold pressure. The pressure difference between the carrier gas and NO gas is 5 psi, at which the NO dosing is <0.1 ppm. In this experiment, we increased PW frequency in a stepwise manner while continuously recording NO signals. As shown in
Portable iNO therapy system:
The present disclosure will be better understood upon reading the following numbered aspects, which should not be confused with the claims. Any of the numbered aspects below can, in some instances, be combined with aspects described elsewhere in this disclosure and such combinations are intended to form part of the disclosure.
Aspect 1. A device for on-demand generation of NO, the device comprising:
Aspect 2. The device according to aspect 1, wherein the liquid storage component is a gas-tight, pressure resistant syringe.
Aspect 3. The device according to aspect 1, wherein the liquid storage component is a gas-tight, pressure resistant vessel.
Aspect 4. The device according to claim any of the preceding aspects, wherein the reaction vessel is a stainless-steel vessel.
Aspect 5. The device according to any of the preceding aspects, wherein the reaction vessel further comprises one or more reactants in solid or powder form.
Aspect 6. The device according to aspect 5, wherein upon injection of a liquid from the liquid storage component into the reaction vessel to initiate formation of NO gas, the liquid storage component is decoupled from the reaction vessel such that the NO gas is sealed in the reaction vessel and the reaction vessel is pressurized by the NO gas.
Aspect 7. A mixing device (also referred to as a chamber) for mixing NO gas with a carrier gas, the device comprising:
Aspect 8. The mixing device according to aspect 7, wherein the NO inlet is fitted with a nozzle having an inner diameter of 10 μm to 50 μm.
Aspect 9. The mixing device according to aspect 7, wherein the NO inlet is fitted with a nozzle having an inner diameter of 10 μm.
Aspect 10. The mixing device according to aspects 7-9, further comprising an obstruction in the mixing space, wherein the obstruction diverts the mixed gas around the chamber to facilitate further mixing before the mixed gas exits through the gas outlet.
Aspect 11. The mixing device according to aspects 7-10, wherein the carrier gas inlet channel cross-sectional area is reduced by 40% into a slot channel that is perpendicular to the nozzle orifice surface to increase the flow velocity of carrier gas.
Aspect 12. A two-stage dilution system for delivering NO to a patient, the system comprising:
Aspect 13. The system according to aspect 12, further comprising an oxygen source coupled the gas outlet via a flow sensor, wherein the flow sensor measures the flow rate of inspired O2 and communicates to the CPU to inject the desired NO dose of the first diluted mixed gas into the O2 for delivery of a second dilute gas to a patient via an inspiratory tube at a desired NO dose, and wherein the desired NO dose is about 1 ppm to 80 ppm.
Aspect 14. The system according to aspect 12 or 13, wherein the pressure regulator regulates the NO gas flow based on instructions from the CPU, where the NO gas flow rate is based on a pressure difference between the carrier gas and the NO gas to result in a desired dilution of the concentrated NO gas.
Aspect 14b. The system according to any of aspects 12-14, further comprising a proportional valve controlling a flow of NO entering the mixing chamber, wherein the pressure regulator maintains a constant pressure of NO gas in the manifold, and wherein the CPU calculates a pulse width time of the proportional valve based on the desired NO dose and carrier gas flow rate.
Aspect 15. The system according to any of aspects 12-14, wherein the concentrated NO gas in the gas cartridge has a concentration of about 10% to 100%.
Aspect 16. The system according to any of aspects 12-15, further comprising an exhaust system, the exhaust system comprising a vacuum pump connected to the manifold.
Aspect 17. The system according to any of aspects 12-16, further comprising a gas sensor system connected to the inspiratory tube, wherein the gas sensor system measures NO, NO2 and % O2 content in the inspired gas.
Aspect 18. The system according to aspect 17, wherein the gas sensor system is in communication with the CPU and provides an alert or stops the system if the NO and NO2 content exceeds a predetermined threshold.
Aspect 19. The system according to any of aspects 12-18, wherein the pressure regulator regulates the pressure of the NO in the manifold between about 0.25 kPa and 200 kPA.
Aspect 20. The system according to any of aspects 12-19, wherein the NO pressure in the NO gas cartridge is about 50 psi to about 220 psi.
Aspect 21. A system for delivering NO to a patient, the system comprising:
Aspect 22. The system according to aspect 21, wherein the pressure regulator regulates the NO gas flow based on instructions from the CPU, where the NO gas flow rate is based on a pressure difference between the O2 and the NO gas to result in a desired dilution of the concentrated NO gas.
Aspect 23. The system according to aspects 21-22, further comprising a proportional valve controlling a flow of NO entering the mixing chamber, wherein the pressure regulator maintains a constant pressure of NO gas in the manifold, and wherein the CPU calculates a pulse width time of the proportional valve based on the desired NO dose and O2 flow rate.
Aspect 24. The system according to any of aspects 21-23, wherein the concentrated NO gas in the gas cartridge has a concentration of about 10% to 100%.
Aspect 25. The system according to any of aspects 21-24, further comprising an exhaust system, the exhaust system comprising a vacuum pump connected to the manifold.
Aspect 26. The system according to any of aspects 21-25, further comprising a gas sensor system connected to the gas exit, wherein the gas sensor system measures NO, NO2, and O2 content in the inspired gas.
Aspect 27. The system according to any of aspects 21-26, wherein the gas sensor system is in communication with the CPU and provides an alert or stops the system if the NO and NO2 content exceeds a predetermined threshold.
Aspect 28. The system according to any of aspects 21-27, wherein the pressure regulator regulates the pressure of the NO in the manifold between about 0.25 kPa and 200 kPA.
Aspect 29. The system according to any of aspects 21-2, wherein the NO pressure in the NO gas cartridge is about 50 psi to about 220 psi.
Aspect 30. The system according to any of aspects 21-29, wherein the system is a portable system.
It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a concentration range of “about 0.1% to about 5%” should be interpreted to include not only the explicitly recited concentration of about 0.1 wt % to about 5 wt %, but also include individual concentrations (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within the indicated range. In an embodiment, “about 0” can refer to 0, 0.001, 0.01, or 0.1. In an embodiment, the term “about” can include traditional rounding according to significant figures of the numerical value. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”.
Disjunctive language such as the phrase “at least one of X, Y, or Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to present that an item, term, etc., may be either X, Y, or Z, or any combination thereof (e.g., X, Y, and/or Z). Thus, such disjunctive language is not generally intended to, and should not, imply that certain embodiments require at least one of X, at least one of Y, or at least one of Z to each be present.
As used herein, the terms “about,” “approximately,” “at or about,” and “substantially equal” can mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, measurements, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In general, an amount, size, measurement, parameter or other quantity or characteristic is “about,” “approximate,” “at or about,” or “substantially equal” whether or not expressly stated to be such. It is understood that where “about,” “approximately,” “at or about,” or “substantially equal” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
Where a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y′, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y′, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.
It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.
It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations and are set forth only for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiments of the disclosure without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure.
Although embodiments have been described herein in detail, the descriptions are by way of example. The features of the embodiments described herein are representative and, in alternative embodiments, certain features and elements may be added or omitted. Additionally, modifications to aspects of the embodiments described herein may be made by those skilled in the art without departing from the spirit and scope of the present invention defined in the following claims, the scope of which are to be accorded the broadest interpretation so as to encompass modifications and equivalent structures.
This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 63/309,889, having the title “CHEMICAL-BASED NITRIC OXIDE GAS-GENERATING DRUG DEVICE FOR DELIVERY TO A PATIENT”, filed on Feb. 14, 2022, the disclosure of which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2023/062609 | 2/14/2023 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63309889 | Feb 2022 | US |
