WO2022123567A1 - Système à oxyde nitrique - Google Patents

Système à oxyde nitrique Download PDF

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Publication number
WO2022123567A1
WO2022123567A1 PCT/IL2021/051463 IL2021051463W WO2022123567A1 WO 2022123567 A1 WO2022123567 A1 WO 2022123567A1 IL 2021051463 W IL2021051463 W IL 2021051463W WO 2022123567 A1 WO2022123567 A1 WO 2022123567A1
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WIPO (PCT)
Prior art keywords
nitric oxide
gas
filter
output
flow
Prior art date
Application number
PCT/IL2021/051463
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English (en)
Inventor
Dmitry Medvedev
Roman ILIEV
Boris MISLAVSKY
Michael Katz
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Innohale Therapeutics Ltd.
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Publication of WO2022123567A1 publication Critical patent/WO2022123567A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A61M16/12—Preparation of respiratory gases or vapours by mixing different gases
    • A61M16/122—Preparation of respiratory gases or vapours by mixing different gases with dilution
    • A61M16/125—Diluting primary gas with ambient air
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B21/00—Nitrogen; Compounds thereof
    • C01B21/20—Nitrogen oxides; Oxyacids of nitrogen; Salts thereof
    • C01B21/24—Nitric oxide (NO)
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B21/00—Nitrogen; Compounds thereof
    • C01B21/20—Nitrogen oxides; Oxyacids of nitrogen; Salts thereof
    • C01B21/24—Nitric oxide (NO)
    • C01B21/30—Preparation by oxidation of nitrogen
    • C01B21/32—Apparatus
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05H—PLASMA TECHNIQUE; PRODUCTION OF ACCELERATED ELECTRICALLY-CHARGED PARTICLES OR OF NEUTRONS; PRODUCTION OR ACCELERATION OF NEUTRAL MOLECULAR OR ATOMIC BEAMS
    • H05H1/00—Generating plasma; Handling plasma
    • H05H1/24—Generating plasma
    • H05H1/48—Generating plasma using an arc
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0051—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes with alarm devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0057—Pumps therefor
    • A61M16/0066—Blowers or centrifugal pumps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/021—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes operated by electrical means
    • A61M16/022—Control means therefor
    • A61M16/024—Control means therefor including calculation means, e.g. using a processor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/06—Respiratory or anaesthetic masks
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/08—Bellows; Connecting tubes ; Water traps; Patient circuits
    • A61M16/0816—Joints or connectors
    • A61M16/0841—Joints or connectors for sampling
    • A61M16/085—Gas sampling
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A61M16/105—Filters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/20—Valves specially adapted to medical respiratory devices
    • A61M16/201—Controlled valves
    • A61M16/202—Controlled valves electrically actuated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0003—Accessories therefor, e.g. sensors, vibrators, negative pressure
    • A61M2016/0027—Accessories therefor, e.g. sensors, vibrators, negative pressure pressure meter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0003—Accessories therefor, e.g. sensors, vibrators, negative pressure
    • A61M2016/003—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter
    • A61M2016/0033—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical
    • A61M2016/0039—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical in the inspiratory circuit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/02—Gases
    • A61M2202/0266—Nitrogen (N)
    • A61M2202/0275—Nitric oxide [NO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/18—General characteristics of the apparatus with alarm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/332—Force measuring means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3375—Acoustical, e.g. ultrasonic, measuring means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/50—General characteristics of the apparatus with microprocessors or computers
    • A61M2205/502—User interfaces, e.g. screens or keyboards
    • A61M2205/505—Touch-screens; Virtual keyboard or keypads; Virtual buttons; Soft keys; Mouse touches
    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05H—PLASMA TECHNIQUE; PRODUCTION OF ACCELERATED ELECTRICALLY-CHARGED PARTICLES OR OF NEUTRONS; PRODUCTION OR ACCELERATION OF NEUTRAL MOLECULAR OR ATOMIC BEAMS
    • H05H2245/00—Applications of plasma devices
    • H05H2245/10—Treatment of gases

Definitions

  • Nitric oxide has other possible applications in gene therapy.
  • genebased therapy is recognized as a powerful new therapeutic weapon for treating pulmonary arterial hypertension.
  • Genetic manipulation may be supplemental to standard pharmacotherapy or be used as a stand-alone treatment.
  • genetic material must be transferred into cells and expressed at a desired level to provide therapeutic benefits.
  • NO may play a role in improving gene transduction in gene therapies for treating PAH.
  • the apparatus further comprises an air input pump in the air inlet to the system.
  • the plasma generator comprises a plurality of electrodes across which an arc discharge is created upon application of a voltage across said plurality of electrodes.
  • the processor is further configured to change the voltage applied across the plurality of electrodes to generate a desired arc temperature.
  • the apparatus further comprises a heat exchanger positioned inline after and in fluid communication with the plasma generator.
  • the apparatus further comprises: an output line for outputting nitric oxide gas generated in the system; a nitrogen dioxide (NO2) filter in the output line for removing NO2 from the output gas; and an NO2 meter in the output line for measuring NO2 levels in the output gas.
  • NO2 nitrogen dioxide
  • the senor is a nitric oxide analyzer positioned in a measurement line comprising a pump and an outlet to vent measured gas from the system.
  • the nitric oxide analyzer comprises: an ozone source for oxidizing nitric oxide to form NO2 within the nitric oxide analyzer; and one or more light adsorption measurement systems for determining NO2 levels in gas in the nitric oxide analyzer before and after oxidizing.
  • the apparatus further comprises: a flow compensation output line comprising a valve, the processer further configured to remove a variable amount of circulating gas from the system using the valve; an output pump in the output line for delivering a desired level of nitric oxide gas, the processor further configured to vary the flow of output nitric oxide gas from the system, wherein the processor is further configured to vary the variable amount of circulating gas removed from the system through the flow compensation output line based on the flow of output nitric oxide gas from the system such that a sum of output flow rates from the flow compensation line and the output line is approximately equal to the flow rate of air into the system.
  • the apparatus further comprises a dryer positioned in the output line for removing moisture from the output nitric oxide gas.
  • the NO2 filter comprises a chemical filter comprising ascorbic acid.
  • the concentration of nitric oxide in the system further comprises varying a flow rate of air comprising nitrogen and oxygen into the system.
  • the flow rate of air into the system is controlled using one or more valves that create negative pressure in an air inlet to the system.
  • the power supplied to the plasma generator is varied by changing the voltage applied across the plurality of electrodes to generate a desired arc temperature.
  • the method further comprises cooling the circulating gas within the system using a heat exchanger positioned inline after the plasma generator.
  • the method further comprises outputting nitric oxide gas generated in the system through an output line. In another embodiment, the method further comprises removing NO2 from output gas using an NO2 filter in the output line.
  • the method further comprises measuring NO2 levels in output gas using an NO2 meter in the output line.
  • the sensor is a nitric oxide analyzer positioned in a measurement line comprising a pump and an outlet to vent measured gas from the system.
  • the method further comprises removing a variable amount of circulating gas from the system using a flow compensation output line comprising a valve.
  • the method further comprises varying the flow of output nitric oxide gas from the system using an output pump in the output line to deliver a desired level of nitric oxide gas and determining the flow of output nitric oxide gas based on the desired level of nitric oxide gas and the level of generated nitric oxide gas in the system.
  • the method further comprises removing droplets of condensed NO2 using filtration media within the two parallel cold traps. In another embodiment, the method further comprises removing moisture from output nitric oxide gas using a dryer positioned in the output line.
  • the NO2 filter comprises a chemical filter comprising ascorbic acid.
  • the ascorbic acid is coated onto a silica gel.
  • the method further comprises monitoring color change in the ascorbic acid to determine filter capacity.
  • the NO2 filter comprises one or more transparent surfaces wherein monitoring color change comprises directing a light at the ascorbic acid through the transparent surface and measuring reflected light.
  • an NO2 filter comprising: a plurality of parallel cold traps maintained at a temperature between the boiling points of nitric oxide and NO2 such that NO2 is condensed within the cold traps; and a valve for directing flow of gas into one or more of the plurality of parallel cold traps at a time.
  • the filter further comprises a drain in communication with the plurality of parallel cold traps for draining condensed NO2.
  • the plurality of parallel cold traps comprise a filter media therein for capturing droplets condensed NO2.
  • one or more of the plurality of parallel cold traps comprise removable units such that, while the valve directs flow through one or more of the plurality of parallel cold traps, the remaining parallel cold traps can be replaced without disrupting flow through the NO2 filter.
  • the temperature is about -178oC.
  • the filter further comprises a dryer for removing water from gas flowing into the filter.
  • the filter further comprises a liquid nitrogen source for maintaining the temperature.
  • the filter further comprises a temperature sensor.
  • the filter further comprises a processor coupled to a tangible, non- transitory memory in communication with the temperature sensor and the liquid nitrogen source and configured to change the flow of liquid nitrogen into the system based on input from the temperature sensor to maintain the temperature.
  • the liquid nitrogen source is in fluid communication with cooling jackets on the plurality of parallel cold traps.
  • an NO2 filter comprising: ascorbic acid; one or more transparent walls; a light source positioned to direct light through the one or more transparent walls onto the ascorbic acid; and a sensor positioned to receive light reflected off the ascorbic acid from the light source.
  • the filter comprises a plurality of sensors for measuring reflected light off the ascorbic acid at multiple positions within the NO2 filter.
  • the NO2 filter is a single pass filter.
  • the filter is a multi-pass filter comprising a plurality of channels and the multiple positions comprise a position in each of the plurality of channels.
  • the ascorbic acid is coated onto a filter material.
  • the filter material comprises silica gel.
  • the light source directs light in a blue-violet wavelength range.
  • the light source directs light in a wavelength of about 400 nm. In another embodiment, the light source comprises an LED.
  • the senor comprises a photo diode or a photo transistor.
  • each of the plurality of sensors are positioned together with a different light source on a compact chip.
  • the filter further comprises a processor coupled to a tangible, non- transitory memory configured to receive input from the sensor and determine filter capacity based on the input.
  • a sensor for measuring nitric oxide concentration in a sample comprising: an ozone source for oxidizing nitric oxide within a sample to form NO2; and one or more light adsorption measurement systems for determining NO2 levels in the sample in the nitric oxide analyzer before and after oxidizing.
  • the light adsorption measurement system comprises a light source positioned to pass light through the sample within the sensor.
  • the sensor further comprises a light sensor positioned to receive light from the light source passed through the sample within the sensor.
  • the senor comprises a transparent portion where the light from the light source is directed through the sample therein.
  • the sensor comprises a processor coupled to a tangible, non-transitory memory and configured to receive adsorption data from the one or more light adsorption measurement systems and determine an NO2 level therefrom.
  • a first light adsorption measurement system is positioned upstream of the ozone source and a second light adsorption measurement system is positioned downstream of the ozone source.
  • the processor is in communication with the ozone source and is configured to control ozone introduction to the sample through a valve or pump and to determine NO2 level before and after introducing ozone to the sample.
  • the senor comprises one or more mirrors for reflecting light to pass through the sample one or more times before entering the light sensor, thereby increasing the beam length for measurement of low concentrations of NO2.
  • a method for measuring nitric oxide concentration in a sample comprising: oxidizing nitric oxide within a volume of sample using ozone to form NO2; measuring light adsorption by NO2 within the sample to determine NO2 levels in the sample in the nitric oxide analyzer before and after oxidizing; and subtracting NO2 levels determined before oxidizing from NO2 levels determined after oxidizing to determine a nitric oxide concentration in the sample.
  • the method further comprises passing light through the sample from a light source within the sensor. In another embodiment, the method further comprises measuring light intensity in light from the light source passed through the sample within the sensor using a light sensor. [0056] In one embodiment, the light source emits light having a wavelength of about 350 nm to about 400 nm. In another embodiment, the light source comprises one or more LEDs.
  • the method further comprises passing light through the sample from a second light source within the sensor at the light intensity measured with the light sensor and measuring a second light intensity in light from the second light source using a second light sensor.
  • the method further comprises determining light adsorption by NO2 in the sample based on the second light intensity and a combined distance travelled by light through the sample between the light source and the light sensor and the second light source and the second light sensor.
  • determining nitric oxide levels is according to the formula C2*(C2N/C1N)-C1, where: C1N is the NO2 level from the first light adsorption measurement system before introduction of ozone; C2N is the NO2 level from the second light adsorption measurement system before introduction of ozone; Cl is the NO2 level from the first light adsorption measurement system after oxidation with ozone; and C2 is the NO2 level from the second light adsorption measurement system after oxidation with ozone.
  • x, y, and/or z means any element of the seven-element set ⁇ (x), (y), (z), (x, y), (x, z), (y, z), (x, y, z) ⁇ .
  • FIG. 1 diagrams a prior art nitric oxide generator.
  • FIG. 2 diagrams a nitric oxide generator where input air is controlled using an air intake valve, in accordance with some embodiments.
  • FIG. 3 diagrams a nitric oxide generator where input air is controlled using an air intake pump, in accordance with some embodiments.
  • FIG. 4 shows vapor pressures of NO and NO2 at various temperatures, in accordance with some embodiments.
  • FIG. 5 shows an exemplary cryogenic NO2 filter, in accordance with some embodiments.
  • FIG. 6 shows an exemplary cryogenic NO2 filter with an input air dryer, in accordance with some embodiments.
  • FIG. 7 shows an exemplary single pass chemical NO2 filter, in accordance with some embodiments.
  • FIG. 9 shows an exemplary ventilator system with a NO generator feed, in accordance with some embodiments.
  • FIG. 10A shows exemplary inhale and exhale tube flow rates for a system such as that illustrated in FIG. 9, in accordance with some embodiments.
  • FIG. 10B shows exemplary inhalation tube flow rates for a system such as that illustrated in FIG. 9, in accordance with some embodiments.
  • FIG. 10D shows exemplary NO concentrations in the inhalation tube for a system such as that illustrated in FIG. 9, in accordance with some embodiments.
  • FIG. 11 shows an exemplary ventilator system with a NO generator feed coupled to the system through a valve, in accordance with some embodiments.
  • FIG. 12A shows exemplary inhalation tube pressure for a system such as that illustrated in FIG. 11, in accordance with some embodiments.
  • FIG. 12D shows exemplary NO concentrations in the inhalation tube for a system such as that illustrated in FIG. 11, in accordance with some embodiments.
  • Systems and methods of the disclosure provide stable nitric oxide generation from air using feedback from sensors to vary both plasma generator power and gas flow rate through the plasma generator.
  • the air can be circulated through the plasma generator in a controlled system and, in certain embodiments, the flow of fresh air into the system can also be controlled to achieve a stable concentration of NO at a desired output flow rate.
  • the device of Montgomery comprises a: plasma generator of NO 10 comprising a pair of electrodes 15; a pair of flow meters 20; an air input terminal 25; an input filter 30; a pump 35; a pump dumping chamber 40; a photodiode 45; a controller 50; an NO2 filter 55; a programmable timer 60; an NO output terminal 65; and an applicator 70.
  • Plasma generator 10, electrodes 15, flow meters 20, air input terminal 25, input filter 30, pump 35, pump dumping chamber 40, photodiode 45, controller 50, NO2 filter 55, programmable timer 60, NO output terminal 65 and applicator 70 are illustrated herein for reference purposes only, and are not meant to limit similarly named devices of the present disclosure.
  • Systems and methods of the disclosure may use a computer system including, for example, a processor coupled to a tangible, non-transitory memory that is configured to receive data from a nitric oxide sensor and vary the flow rate of gas circulating through the plasma generator.
  • the computer system may also vary power provided to the plasma generator and/or fresh air entering the circulating system via an air inlet to achieve a desired NO level within the system and/or a desired output flow.
  • Fresh air flow can be regulated through control of an air input pump or control of negative pressure in the system using one or more valves.
  • Plasma generators may include a plurality of electrodes across which an arc discharge is created and the processor may be configured to control the voltage across the electrodes to generate a desired arc temperature.
  • systems and methods of the disclosure may include one or more heat exchangers inline after the plasma generator to cool the gas before and/or after output from circulation.
  • An output line may be included through which generated NO can be removed from circulation and directed to an end apparatus such as a ventilator or other medical device. Pumps and/or valves may be used to control the flow of gas through the output line.
  • An NO2 filter may be included in the system, for example, in the output line for removing NCh from output gas.
  • systems and methods of the disclosure may include a flow compensation output line comprising a valve through which the processer can control an amount of circulating gas to be removed from the system.
  • the flow compensation line and valve can be used to offset changes in output demand through the output line (e.g., to a medical device like a ventilator) such that a constant total NO outflow and production rate can be maintained for the system.
  • the total output of the system through both the flow compensation and device output lines can be controlled along with the input of fresh air into the system such that the flow rate of gas leaving the system is equal to the flow rate of air entering the system.
  • a dryer may be positioned in the system, preferably in the output line, to remove moisture from the output gas.
  • filters of the disclosure can provide predictable lifetimes, automatic regeneration without service disruption, and filter capacity monitoring in real time using optical sensors.
  • filters may include two or more parallel cold traps maintained at a temperature between the boiling points of nitric oxide and NO2 such that NO2 is condensed within the cold traps while nitric oxide remains in gaseous form. The condensed liquid NO2 can then be drained and removed from the system to regenerate the filter.
  • Filter media may be included within the cold trap providing increased surface area upon which the NO2 can condense for drainage and assisting in the capture of droplets in the gas.
  • Systems may include a valve for directing flow of gas into one or more of the parallel cold traps or other filters at a time in order to divert flow away from a filter during regeneration, removal, or replacement for example.
  • Temperature within the cold traps may be about -178°C.
  • the temperature may be maintained using, for example, liquid nitrogen passed through cooling jackets within or around the cold trap or a heat exchanger therein.
  • a dryer may be included before the filters in particular to remove water from gas flowing therein.
  • Temperature sensors may be included within or proximate to the NO2 filter to ensure the appropriate temperature for filter function is maintained.
  • a processor may receive data from such temperature sensors and act as a thermostat controlling the flow of liquid nitrogen to the cold trap to maintain the desired temperature.
  • Certain aspects of the disclosure may include an NO2 filter comprising ascorbic acid.
  • Such filters may use light sources and sensors to measure the reflectance of light by ascorbic acid within the filter. The measured reflectance can be used to monitor degradation of ascorbic acid in the filter (which may occur automatically) to determine filter capacity and to cue replacement at the appropriate time.
  • multiple filters may be run in parallel such that flow can be diverted away from one for replacement or service without disrupting NO supply.
  • Ascorbic acid filters may include one or more transparent walls, a light source positioned to direct light through the one or more transparent walls onto the ascorbic acid, and a sensor positioned to receive light reflected off the ascorbic acid from the light source.
  • NO2 filters may be single pass or multi-pass filters.
  • Multi-pass filters may comprise a plurality of channels with a sensor positioned in each of the plurality of channels.
  • the ascorbic acid can be coated onto a filter material such as silica gel.
  • the light source may direct light in a blueviolet wavelength range, for example, at about 400 nm.
  • the light source may include an LED and the sensor may include a photo diode or a photo transistor. Light sources and/or sensors can be positioned together on a compact chip.
  • Nitric oxide systems are also provided that are capable of communicating with external medical devices such as ventilators. Similar to the feedback from sensors within the NO generator itself, sensors in the medical device, (e.g., a ventilator tube) may provide NO concentration feedback used to control NO generation as discussed above.
  • Various NO generator control algorithms are provided including different operation modes with continuous and modulated NO flow for use with external medical devices.
  • Such medical devices may be an inhalation tube for delivering nitric oxide to a patient.
  • the inhalation tube may also be coupled to a ventilator.
  • a valve may be included in the output line that is configured to open during inhale cycles of the ventilator to allow output nitric oxide flow into the inhalation tube and to close during exhale cycles of the ventilator to restrict output nitric oxide flow into the inhalation tube.
  • the present disclosure provides stable and efficient nitric oxide generation from air with particular use in medical applications.
  • Systems and methods address variable flow rate demands while tightly regulating NO concentration in output gas by controlling various combinations of plasma generator power, air intake flow rate, gas circulation rate, and flow compensation channels.
  • NO sensors may provide rapid feedback on output gas NO concentration that may be used to regulate NO concentration.
  • Systems of the disclosure may include NO generators coupled to medical devices such as ventilators. Valved control of NO gas input can be programmed to correspond to inhale/exhale cycles to maintain desired NO concentrations.
  • filters may be included for the removal of NO2 from the output gas.
  • NO2 filters may manipulate the different vapor pressures of NO and NO2 to condense and remove NO2 while allowing NO gas to pass through.
  • Chemical NO2 filters may be used that rely on ascorbic acid to eliminate NO2 from gas passing therethrough.
  • Special light sensors may be used to measure filter capacity and provide alerts when a filter change is needed.
  • Multiple parallel filters may be used such that filters can be refreshed, serviced, or replaced without disrupting the flow of NO output gas.
  • FIG. 2 diagrams an exemplary NO generator 100 according to certain embodiments.
  • NO generators of the disclosure may use known plasma generator/plasmatron systems 110 to drive production of NO from nitrogen and oxygen present in air.
  • an internal circulation line 120 cycles air through the plasmatron 110 and a heat exchanger 130 for cooling gas after leaving the plasmatron 110.
  • the generation of NO from air through the use of electric discharges in a plasma reaction is well characterized as discussed in U.S. Pat. Nos. 4,287,040; 5,396,882; and Montgomery (discussed above, the contents of each of which are incorporated herein by reference).
  • plasmatron 110 air is passed through a gap between a plurality of electrodes across which a potential is applied to generate an electric discharge.
  • the gas passes through the gap, it is ionized at a high temperature to form a plasma in where oxygen and nitrogen break down and reform to produce nitric oxide.
  • the resulting product gas is too hot for use in most medical applications and is therefore passed through a heat exchanger or cooling chamber 130 to bring its temperature in line with use in the intended application (e.g., ventilator or other medical device). Cooling or quenching of the gas post plasmatron is also used to fix the generated nitric oxide.
  • Heat exchangers 130 are well known and any suitable device may be used with systems and methods of the disclosure.
  • an ethanol or ethanol/water cooled chamber may be used wherein the water/ethanol fluid is passed through cooling jackets to draw heat from the gas and then flowed away from the heat exchanger 130 to dissipate the collected heat.
  • a circulation pump 140 may be included to provide a desired flow rate through the system.
  • a valve 150 e.g., a chock valve
  • the valve 150 may be electronically controlled and in communication with a computer system (not shown) configured to control the valve 150.
  • the valve 150 can be used to create negative pressure to provide a desired flow rate of fresh air through the valve 150 and into the system.
  • a flow compensation output or flow compensation line 170 may be positioned along with another valve 175 configured to control the flow rate of gas leaving circulation through the flow compensation line 170. Again, any suitable valve 175 may be used.
  • valve 175 is also electronically controlled via the computer system.
  • Gas may also be outputted from circulation for use in an end device such a ventilator or other medical device.
  • Flow of output gas to such devices may be controlled via another valve or an output pump 180.
  • Either pump or valve may be electronically controlled.
  • NO2 filters 190 and sensors 195 may be included in the output line to ensure that NO2 levels are acceptable for the intended use of the output gas.
  • a separate measurement line 200 may be in communication with the circulation line 120 through which sample gas can be diverted for analysis.
  • a valve or pump 210 may be used to divert gas into the measurement line 200.
  • a nitric oxide sensor 220 may be included to analyze NO levels of samples diverted to the measurement line. Those sensors 220 as well as the measurement line valve or pump 210 may be in communication with the computer system as well.
  • the output pump 180 is off, the circulation pump 140 is activated, the input air valve 150 is opened, and gas is output through the flow compensation line 170 and measurement line 200.
  • the input air valve 150, circulation pump 140, and plasmatron 110 power levels are manipulated by the computer system in response to NO levels measured by the NO sensor 220 in the measurement line until the desired NO concentration is achieved.
  • the output pump 180 may be activated to deliver NO to the desired end device.
  • the flow compensation valve or pump 175 may be manipulated in response to the demands of the output pump 180 such that total gas output remains constant and NO concentration is stable. Because the total output flow rate (output line + flow compensation line outputs) remains constant despite fluctuations in output NO demand, the system can more easily maintain a desired NO concentration in the circulating gas without constant manipulation of circulation flow rate, plasmatron power, and/or intake air flow.
  • Such stability is particularly useful in applications where output flow demand is not constant such as experienced with variable back pressure in the output line to a ventilator (see FIG. 12).
  • a similar system 300 is depicted in FIG. 3, however input or intake air flow 160 is controlled by a pump 310 instead of a valve and negative pressure.
  • the output pump 180 is stopped and fresh air is injected into circulation by the input pump 310.
  • the 100% of the output is through the flow compensation line 170 and the measurement line 200.
  • NO concentrations inside the system 300 are stabilized at the desired level as produced by manipulating the plasmatron power, fresh air flow rate, and circulation rate, the gas is ready for output to the end device.
  • the output pump 180 may then be operated to deliver the desired NO capacity for use in the end device which is equal to the NO concentration in the output gas multiplied by the output gas flow rate.
  • constant total output flow rate can be maintained through automatic manipulation of the flow compensation valve to offset changes in demand through the output line.
  • various embodiments may include filters for removing NO2 from gas before output.
  • a particular challenge is the removal of unwanted NO2 without effecting NO concentration.
  • Two types of filters are described herein, cryogenic and chemical filters.
  • a cryogenic filter is used.
  • An example of such a filter system 400 is depicted in FIG. 5 and can operate continuously because it consists of two parallel cold traps 410. Output gas flow can be diverted through one or more of the parallel cold traps 410. When one cold trap 410 is working, the other can be automatically regenerated while flow through it is stopped. Such cold traps 410 can remove NO2 without changing NO concentration in the output gas.
  • the filters take advantage of the difference in vapor pressure between NO and NO2 as shown in FIG.4.
  • NO2 concentration is about 30 ppm and NO concentration is about 10,000 ppm. Accordingly, at that temperature NO will go through filter up to 10000 ppm while NO2 concertation will not be more than 30 ppm. After final diluting up to 100 times at, for example, a ventilator inhalation line, the NO concentration to the patient will be below 100 ppm while NO2 concentration will be below 0.3 ppm which is considered a safe level for the application. Condensed NO2 can be drained from the cold traps to enable automated regeneration without the need for removal of complex servicing. Exemplary cryogenic filters are shown in FIGS. 5 and 6.
  • output air containing NO from the NO generator can be fed into the filter system comprising one or more cryogenic filters 415.
  • the input gas is diverted into one or more of the filters through the use of input valves 450.
  • Flow rate can be controlled using the input valves and/or output valves 460 at the output lines exiting the filters.
  • the filters may include drain valves 470 for removing condensed liquid NO2 through drain lines for disposal. Temperature in the filters can be maintained through any known means.
  • liquid nitrogen is flowed through cooling jackets 480 around the filters.
  • a temperature sensor 490 provides feedback on filter temperature and valves and/or pumps 500 in the liquid nitrogen supply lines control the flow of liquid nitrogen from a liquid nitrogen reservoir 510 to maintain the desired temperature.
  • Both the valves/pumps 500, and the temperature sensors 490 can be in communication with a computing device (not shown) for controlling the temperature.
  • a pressure sensor 520 may also be included in the liquid nitrogen line to provide feedback to the computer.
  • a cryogenic filter system 600 may include an input air dryer 610. Drying of input fresh air can increase capacity of the NO2 cold traps by avoiding condensing/freezing water vapor along with NO2. Separation of water from air before input to the system can be readily achieved using known dryers and result in additional filter capacity for NO2.
  • the filter 615 may be filled with an appropriate filtration media to provide surface area for condensation and trapping of aerosol particles. Such filters may be run automatically with only electricity and liquid nitrogen supply required. Thus, continuous operation with, for example, a ventilator can be maintained.
  • a liquid nitrogen bypass valve 620 is coupled between the liquid nitrogen reservoir 510 and valves 500 to allow bypass of the air dryer 610.
  • a temperature sensor 630 is provided within the air dryer 610.
  • NO2 may be filtered using a chemical filter.
  • Chemical filters may be used alone or in combination with cryogenic or other filters.
  • Chemical filters may use an antioxidant reagent coated on a substrate such as silica gel coated with ascorbic acid.
  • Precise filter capacity monitoring can be performed by observing color changes in the antioxidant (in particular ascorbic acid) during the oxidation process. Oxidation products of ascorbic acid have a brown color and during oxidation ascorbic acid changes color from white to yellow and then to brown. This process is independent of the cause of ascorbic acid oxidation and, as such, takes into account all sources of oxidation. As such, optical monitoring is superior to oxidation estimation methods that do not account for general environmental parameters affecting filter capacity or rely on estimates thereof.
  • optical monitoring methods provide information about actual wear of the ascorbic acid in filter and help predict residual filter capacity and lifetime in real time.
  • An optical monitoring system is described herein for determining filter capacity of ascorbic acid systems.
  • Such systems may include a light source with wavelengths in the blue - violet range. For example, am approximately 400 nm LED may be used which can be directed onto the ascorbic acid coated media through a transparent filter wall or transparent window on the filter wall. The reflected light from the coated media can be measured using a sensor and is strongly dependent on surface color. Accordingly, changes in color can be accurately measured and used for ascorbic acid oxidation/wear calculation.
  • Exemplary light sensors include for example photo diodes and photo transistors. Such sensors can be paired with a light source such as LEDs in a compact chip and can be installed in various parts of the filter for precise calculation of actual filter wear throughout the filter.
  • a side wall 710 of the filter may be made from light transparent material.
  • LED/sensor pairs i.e. pairs of an LED 720 and an optical sensor 730
  • the initial sensor 730 can be used to provide information about initial and general wear of the filter 700 and the intermediate sensor 730 can provide information about the velocity of propagation of the color changing wave and allow for precise calculation of residual filter lifetime.
  • a respective buffer zone 760 and flow distributing layer 770 is provided between the input 740 and the filter material 780. In another embodiment, a respective buffer zone 760 and flow distributing layer 770 is provided between the output 750 and the filter material 780. Although 2 LED/sensor pairs are illustrated, this is not meant to be limiting in any way.
  • a multi-pass filter 800 may be provided as shown in FIGs. 8 A and 8B, where FIG. 8 A shows a perspective diagram of filter 800 and FIG. 8B shows an example of a cross-section of filter 800.
  • Filter 800 is in all respects similar to filter 700, with the exception that gas entering at input 740 is flowed back and forth through several separate channels 810 before being output at output 750.
  • the top and bottom walls 820 of filter 800 may be made from light transparent material. In that case, color changes in the ascorbic acid can be detected at each channel end point to determine propagation velocity and estimate filter lifetime.
  • NO generators of the disclosure may be in communication with other medical devices such as a ventilator to provide NO for patient or other medical applications.
  • the NO generator may be automatically controlled for operation with medical device to keep a desirable concertation of NO in the inhalation line which goes to the patient independently of any external parameters and accounting for variable flow rates needed by the device (see FIG. 10A).
  • the NO generator may provide a constant flow rate through an output pump 910 (see FIG.10C) to a ventilator inhalation tube 920 as depicted in device 900 of FIG. 9.
  • the output gas is passed through an NO2 filter 930 (as described above) and an NO2 measurement device 940 which checks NO2 concentration level to ensure patient safety.
  • the NO output gas can then be admixed into the air from the ventilator in the inhalation tube to achieve a desired NO concentration.
  • Flow rate in the inhalation tube depends on the ventilator cycle and during exhale time is at zero (FIG. 10B).
  • NO concentration goes up linearly.
  • concentration of NO goes down (FIG.10D).
  • the actual level of this concentration is determined by the NO generator capacity and the average inhale flow rate (FIG.10B) controlled by the ventilator.
  • the NO concentration is preferably measured continuously and NO capacity of the NO generator is adjusted.
  • the NO concentration within inhalation tube 920 is measured by an NO2 measurement device 950, via a sampling pump 960.
  • Sampling pump 960 is in fluid communication with to a port of the inhalation tube 920, an optional pressure sensor 970 is further provided between the inhalation tube 920 and the sampling pump 960.
  • the term "fluid communication”, as used herein, means that there is a path that allows fluid to flow between the components. Fluid can be liquid, gas and/or plasma.
  • the flow rate of NO provided by the output pump from the NO generator is modulated (FIG.12C) to the ventilator inhalation tube as shown in FIG. 11 using a valve or pump 980.
  • a solenoid valve 980 on the filter output is closed during exhale time.
  • a control system can close the solenoid valve 980 automatically in exhale time based on input from the ventilator or other medical device or based on a flow sensor.
  • the system can open the solenoid valve 980 during inhalation cycles as signaled by a pressure sensor in the inhalation tube (FIG.12A).
  • An advantage of this embodiment is the minimization of time it takes for the gas to go from the NO2 filter to the patient.
  • concentration of NO is somewhat stable because any NO2 produced in the filter is continuously reduced.
  • air containing NO outside of the filter, for example in the inhalation tube will continue to oxidize into NO2 and will no longer be filtered. Accordingly, minimization of the post-filter time is important for avoiding dangerous levels of NO2 for patients.
  • Control systems of the disclosure can indicate actual NO concentration in ppm using sensors and allow for appropriate manipulation of plasmatron power and input, output, and circulation flow rates.
  • Such systems of the disclosure can operate in manual or automatic modes. In manual mode, an operator may set the plasmatron power and output gas flow rate and wait to determine the resulting stationary NO concentration.
  • manual mode an operator may set the plasmatron power and output gas flow rate and wait to determine the resulting stationary NO concentration.
  • automatic mode a user may input a desired NO concentration and/or flow rate and the various intake, output, and circulation flow rates, as well as plasmatron power will be automatically controlled via electronic valves and/or pumps by the computer based on input from sensors as described above to achieve the desired NO concentrations and flow.
  • systems and methods of the disclosure may include computing devices that may include one or more of processor (e.g., a central processing unit (CPU), a graphics processing unit (GPU), etc.), computer-readable storage device (e.g., main memory, static memory, etc.), or combinations thereof which communicate with each other via a bus.
  • processor e.g., a central processing unit (CPU), a graphics processing unit (GPU), etc.
  • computer-readable storage device e.g., main memory, static memory, etc.
  • Computing devices may include mobile devices (e.g., cell phones), personal computers, and server computers.
  • computing devices may be configured to communicate with one another via a network.
  • Computing devices may be used to control the systems described herein including operation of valves and pumps and processing of sensor data from NO sensors, and filter-related sensors.
  • a processor may include any suitable processor known in the art, such as the processor sold under the trademark XEON E7 by Intel (Santa Clara, CA) or the processor sold under the trademark OPTERON 6200 by AMD (Sunnyvale, CA).
  • Memory preferably includes at least one tangible, non-transitory medium capable of storing: one or more sets of instructions executable to cause the system to perform functions described herein (e.g., software embodying any methodology or function found herein); data (e.g., data to be encoded in a memory strand); or both.
  • While the computer- readable storage device can in an exemplary embodiment be a single medium, the term “computer-readable storage device” should be taken to include a single medium or multiple media (e.g., a centralized or distributed database, and/or associated caches and servers) that store the instructions or data.
  • the term “computer- readable storage device” shall accordingly be taken to include, without limit, solid-state memories (e.g., subscriber identity module (SIM) card, secure digital card (SD card), micro SD card, or solid-state drive (SSD)), optical and magnetic media, hard drives, disk drives, and any other tangible storage media.
  • SIM subscriber identity module
  • SD card secure digital card
  • SSD solid-state drive
  • Cloud storage may refer to a data storage scheme wherein data is stored in logical pools and the physical storage may span across multiple servers and multiple locations. Storage may be owned and managed by a hosting company. Preferably, storage is used to store records as needed to perform and support operations described herein.
  • Input/output devices may include one or more of a video display unit (e.g., a liquid crystal display (LCD) or a cathode ray tube (CRT) monitor), an alphanumeric input device (e.g., a keyboard), a cursor control device (e.g., a mouse or trackpad), a disk drive unit, a signal generation device (e.g., a speaker), a touchscreen, a button, an accelerometer, a microphone, a cellular radio frequency antenna, a network interface device, which can be, for example, a network interface card (NIC), Wi-Fi card, or cellular modem, or any combination thereof.
  • Input/output devices may be used to enter desired NO concentration levels and flow rates and to alert users regarding sensor readings and the need for filter replacement.
  • systems and methods herein can be implemented using C++, C#, Java, JavaScript, Visual Basic, Ruby on Rails, Groovy and Grails, or any other suitable tool.
  • a computing device it may be preferred to use native xCode or Android Java.

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Abstract

La présente invention concerne un appareil de production d'oxyde nitrique, l'appareil étant constitué : d'un générateur de plasma comprenant une alimentation variable en électricité et étant en communication fluidique avec une pompe de circulation dans un système de circulation ; un capteur d'oxyde nitrique en communication fluidique avec le générateur de plasma ; et un processeur conçu pour faire varier le débit de la pompe de circulation et l'alimentation électrique du générateur de plasma sur la base d'une entrée provenant du capteur d'oxyde nitrique afin d'obtenir un taux d'oxyde nitrique souhaité dans le système de circulation.
PCT/IL2021/051463 2020-12-09 2021-12-09 Système à oxyde nitrique WO2022123567A1 (fr)

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US11833309B2 (en) 2017-02-27 2023-12-05 Third Pole, Inc. Systems and methods for generating nitric oxide
US11911566B2 (en) 2017-02-27 2024-02-27 Third Pole, Inc. Systems and methods for ambulatory generation of nitric oxide
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