Nitric oxide sterilization device and method

Abstract

The sterilization systems and methods presented herein include a reaction vessel in which nitric oxide is generated on demand from a nitric oxide donor in solution, and the nitric oxide so generated is moved from the reaction vessel through a surge vessel into a sterilization chamber via a negative pressure gradient, where residual nitric oxide is then adsorbed or catalytically destroyed.

Description

Detailed Description of the Invention

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS]

[0001] This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 438,445, filed January 11, 2023, which is incorporated herein by reference.

[0002] [Field of the Invention]

[0002] The field of the invention is devices, systems, and methods for sterilizing objects using nitric oxide as a gaseous sterilant, and in particular, the invention relates to on-demand generation and delivery of nitric oxide at low or subatmospheric pressures.

[0003] [Background of the invention] The background discussion includes information that may be useful in understanding the present invention. No admission is made that any of the information provided herein is prior art or relevant to the invention claimed herein, or that any publication specifically or implicitly referenced is prior art.

[0004]

[0004] All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In the event that a definition or use of a term in an incorporated reference contradicts or is contrary to the definition of that term provided herein, the definition of that term provided herein shall apply and the definition of that term in the reference shall not apply.

[0005] Sterilization of medical devices and equipment is paramount to their safe use, and the most common sterilization methods include steam autoclaving and irradiation. However, not all medical devices, equipment, and biopharmaceuticals can withstand such harsh conditions, and other sterilization methods must be used. To avoid these challenges, sterilization can be performed using selected gases. Ethylene oxide is the most commonly used sterilization gas for items such as surgical kits, catheters, cardiac implants, stents, and IV sets. Unfortunately, ethylene oxide poses several physical and health hazards that require special precautions. According to the U.S. Department of Labor's Occupational Safety and Health Administration, acute exposure to ethylene oxide gas can result in respiratory irritation and lung damage, headache, nausea, vomiting, diarrhea, shortness of breath, and cyanosis. Chronic exposure has been linked to the development of cancer, reproductive toxicity, mutagenic changes, neurotoxicity, and sensitization. In fact, the Environmental Protection Agency classifies ethylene oxide as a carcinogen.

[0006] To avoid some of the problems associated with ethylene oxide, various alternative sterilization gases have been used. For example, formaldehyde can be produced from formalin, which has been used as a sterilization gas at relatively high concentrations (e.g., 8–16 mg / L). Although significantly less flammable than ethylene oxide, formaldehyde gas must be produced and used at operating temperatures of approximately 70–75°C, preventing its use with thermally sensitive materials or equipment. Alternatively, hydrogen peroxide vapor can be used as a sterilization gas. Hydrogen peroxide vapor is typically produced by vacuum evaporation. Among other benefits, hydrogen peroxide vapor typically has a rapid cycle time (e.g., 30–45 minutes), is effective at low temperatures (e.g., 20°C), and produces environmentally safe by-products (water, oxygen). In addition, hydrogen peroxide vapor generally has fairly good material compatibility and is easy to operate. However, hydrogen peroxide vapor can react with selected polymers and is not approved by the U.S. Food and Drug Administration for sterilization of medical devices. On the other hand, ozone can be used as a sterilizing gas, which is relatively effective even at low temperatures. Unfortunately, ozone is chemically very unstable and can react with biopharmaceuticals. Furthermore, producing sufficient quantities for sterilization typically requires specialized equipment.

[0007] More recently, sterilization using nitric oxide gas as a sterilant has also been reported, as described in International Publication WO 2022 / 164894. Here, nitric oxide is generated from a nitric oxide donor compound, which is then exposed to conditions that result in the release of nitric oxide. Typically, the donor compound is immobilized on or within a carrier in close proximity to the object to be sterilized. Notably, such systems and methods avoid many of the challenges associated with sterilization using hydrogen peroxide or ethylene oxide. However, the use of a donor compound in close proximity to the object is difficult to scale up to larger operations. To increase scale, theoretically, nitric oxide gas from a large-scale source could be used. However, because high-pressure nitric oxide readily dismutates to NO and NO, replacing the nitric oxide donor compound with commercially available compressed nitric oxide gas is undesirable.

[0008]

[0008] Thus, while various compositions and methods for sterilizing various objects using sterilizing gases, including nitric oxide, are known in the art, all or nearly all of them suffer from several drawbacks. Thus, there remains a need for improved devices, systems, and methods for sterilizing objects using nitric oxide as a gaseous sterilant.

[0009] [Summary of the Invention] The present subject matter is directed to various devices, systems, and methods for sterilizing objects using nitric oxide as a sterilizing gas, wherein the nitric oxide is generated under controlled reaction conditions from a precursor solution, the nitric oxide so generated is moved through a sterilization system including a sterilization chamber via a negative pressure gradient, and finally, residual nitric oxide after sterilization is destroyed or otherwise removed from the exhaust air of the sterilization system using a suitable filter or reactor.

[0010] In one aspect of the present subject matter, the inventors contemplate a nitric oxide generator including a reaction vessel configured to maintain a solution containing a nitric oxide donor and a metering system configured to provide to the solution the nitric oxide donor or one or more reagents that generate the nitric oxide donor in the solution. The contemplated nitric oxide generator further includes an energy source coupled to the reaction vessel and configured to provide a sufficient amount of energy to the solution to generate nitric oxide by decomposing the nitric oxide donor. A control circuit is operably coupled to the metering system and the one or more sensors, such that the control circuit controls operation of the sensors in response to the nitric oxide donor concentration in the solution, the one or more reagents, and / or the concentration or amount of generated nitric oxide.

[0011] In some embodiments, the nitric oxide generator is configured to protect the solution containing the nitric oxide donor from ambient light, and / or the container can be configured to introduce an inert gas to allow displacement of atmospheric oxygen from the container. It is further contemplated that the solution is an aqueous solution, which may or may not contain a metal ion chelator. Although not required, the solution preferably has a pH of 4.0 or less (e.g., pH 2-4 or 3-5). In further embodiments, the nitric oxide donor includes a nitrosothiol group, and / or the one or more reagents include an organic thiol compound and a nitrite, and the nitric oxide donor is generated in situ in the solution by reaction of the organic thiol compound with the nitrite.

[0012] If desired, the metering system can include a liquid pump or screw drive configured to dispense the nitric oxide donor or one or more reagents into the solution. In further contemplated embodiments, suitable energy sources include a light source, a heater, an ultrasound emitter, and / or an impeller, and suitable sensors include a pH sensor, a UV-VIS sensor, a nitric oxide sensor, and / or a gas flow meter.

[0013] Additionally, it is contemplated that the nitric oxide generator may be fluidly coupled to a source of inert gas (e.g., nitrogen gas) and / or that the generator may be fluidly coupled to a surge receptacle. It is further contemplated that the generator may be fluidly coupled to a sterilization chamber and / or that the generator may be fluidly coupled to a vacuum pump.

[0014]

[0014] Accordingly, the present inventors also contemplate a method of producing nitric oxide, the method comprising the steps of reacting an organic thiol compound and a nitrite salt in a vessel, whereby reacting the organic thiol compound and the nitrite salt produces a solution containing a nitric oxide donor, and the further step of providing energy to the solution in the reaction vessel to decompose at least a portion of the nitric oxide donor, whereby decomposing at least a portion of the nitric oxide donor produces nitric oxide. In a further step, the produced nitric oxide is then moved from the reaction vessel using a negative pressure gradient, and the nitric oxide donor is replenished by providing additional organic thiol compound and nitrite salt to the solution.

[0015] It is also contemplated that the solution may include a metal ion chelating agent and / or have a pH of 4.0 or less (e.g., pH 2-4 or 3-5). While not required, it is preferred that the headspace above the solution be flushed with an inert gas, and the solution is typically protected from ambient light. It is further contemplated that the energy in such methods may be provided in the form of light energy, thermal energy, mechanical energy, and / or ultrasonic energy. If desired, contemplated methods may further include the step of measuring the nitric oxide concentration in the reaction vessel.

[0016]

[0016] Most typically, the generated nitric oxide is moved from the reaction vessel into a surge receptacle and from the surge receptacle into the sterilization chamber. Furthermore, it is generally preferred that the generated nitric oxide be moved through at least a portion of the system using a vacuum pump. As will be readily appreciated, contemplated methods can further include measuring the concentration of nitric oxide, with the nitric oxide donor being replenished in response to the measured nitric oxide concentration in the solution. Furthermore, it is contemplated that residual nitric oxide may be adsorbed or catalytically destroyed after use as a sterilant.

[0017]

[0017] Accordingly, in yet another aspect of the inventive subject matter, the inventors also contemplate a sterilization system for sterilizing objects using gaseous nitric oxide, the sterilization system comprising a reaction vessel fluidly coupled to a surge receptacle and a sterilization chamber, such that nitric oxide produced in the reaction chamber moves from the reaction vessel through the surge receptacle to the sterilization chamber. Such a system includes an energy source coupled to the vessel and configured to provide a sufficient amount of energy to a solution in the vessel to produce nitric oxide by decomposing a nitric oxide donor in the solution, and further includes a vacuum pump fluidly coupled to the sterilization chamber, such that the vacuum pump draws nitric oxide from the vessel, the surge receptacle, and the sterilization chamber to the nitric oxide adsorbent or catalyst.

[0018]

[0018] Most typically, the reaction vessel includes one or more ports configured to receive the nitric oxide donor or one or more reagents that generate the nitric oxide donor, and / or suitable energy sources include a light source, heater, ultrasound emitter, or impeller. In further embodiments, contemplated sterilization systems may further include a plurality of nitric oxide sensors that measure nitric oxide concentrations in one or more of the reaction vessel, the sterilization chamber, and the vacuum pump exhaust, and / or a sensor that measures the concentration of the nitric oxide donor in the reaction vessel.

[0019]

[0019] Consequently, from a different perspective, the inventors have contemplated a method for sterilizing an object using nitric oxide, which method includes the steps of generating nitric oxide from a solution containing a nitric oxide donor in a reaction vessel, the further steps of using a negative pressure gradient to move the generated nitric oxide from the reaction vessel to a sterilization chamber, and the further steps of maintaining a sterilizing nitric oxide concentration in the sterilization chamber for a time sufficient to sterilize the object.

[0020] Typically, but not necessarily, the nitric oxide donor contains a nitrosothiol group and can be generated in solution from the reaction between an organic thiol compound and a nitrite. It is also contemplated that nitric oxide can be generated from the nitric oxide donor by photolysis of the nitric oxide donor, and that the nitric oxide so generated can be moved from the reaction vessel to the sterilization chamber via a surge receptacle (typically having a volume greater than the volume of the sterilization chamber).

[0021] In a further aspect of the present subject matter, the negative pressure gradient is generated using a vacuum pump downstream of the sterilization chamber. It is further contemplated that the sterilizing nitric oxide concentration is 1-50 ppb or greater and / or that the sterilizing nitric oxide concentration is maintained for a time period of 10-120 minutes and / or at a temperature of 0-50°C or 20-50°C. As noted above, it is also contemplated that residual nitric oxide is adsorbed or catalytically destroyed after use as a sterilant.

[0022] Various objects, features, aspects and advantages of the present subject matter will become more apparent from the following detailed description of preferred embodiments, taken in conjunction with the accompanying drawings, in which like numerals represent like elements. [Brief explanation of the drawings]

[0023] [Figure 1] 1 is an exemplary schematic diagram of a nitric oxide sterilization system in accordance with the present subject matter.

[0024] [Detailed explanation] The present inventors have discovered systems, devices, and methods for sterilizing objects using nitric oxide as a sterilant, where nitric oxide is generated on demand in a reaction vessel and the nitric oxide so generated is moved through a sterilization chamber using a negative pressure gradient. Residual nitric oxide after sterilization is then adsorbed or catalytically destroyed. Advantageously, the systems, devices, and methods presented herein are conceptually simple, effective, and economically attractive, while enabling large-scale rapid sterilization at low temperatures (e.g., 0-50°C or 0-70°C, or even higher) and short cycle times.

[0025] In one exemplary embodiment, shown schematically in Figure 1, the sterilization system comprises a reaction vessel 250 in which nitric oxide is generated on demand and then transferred via valve 170 to a surge receptacle (or nitrogen bladder) 180 from which the nitric oxide is then transferred to the sterilization chamber 200. Residual nitric oxide then leaves the sterilization chamber and is catalytically oxidized by a hopcalite filter 210. Residual odors can be removed in an activated carbon filter 230.

[0026] In this context, it should be appreciated that the nitric oxide-containing gas stream does not undergo compression, thus avoiding the significant problems associated with the disproportionation of nitric oxide (NO), 3NO → NO2 + NO2. Early kinetic studies by others have revealed that the disproportionation reaction is strongly dependent on the pressure of the nitric oxide. For example, at 200 atmospheres, the mole fraction of NO2 and NO2 can be as high as 12-13% only after 10 days (see, e.g., Free Radic Res. 2003 Feb;37(2):171-7). Instead, it is generally preferred that the nitric oxide be driven by a negative pressure gradient generated by a vacuum (or suction) pump 220 located downstream of the sterilization chamber. For example, in some embodiments, the negative pressure gradient is generated by a vacuum pump, as shown in FIG. 1, which at least temporarily reduces the pressure in the sterilization chamber to about 10 Torr, thus drawing the nitric oxide (typically in a carrier gas) from the reaction vessel into the sterilization chamber. As the nitric oxide leaves the sterilization chamber, it is drawn into a hopcalite filter for catalytic oxidation. The vacuum pump exhaust can then be passed through an activated carbon filter to remove odorous compounds.

[0027]

[0027] Without limiting the subject matter of the present invention, it is generally preferred to include a surge receptacle between the nitric oxide reaction vessel and the sterilization chamber that can act as a nitric oxide reservoir. Most typically, the surge receptacle has a capacity for nitric oxide that is at least equal to or significantly greater than the volume of the sterilization chamber (e.g., at least 1.5 times, or at least 2.0 times, or at least 3.0 times, or at least 5.0 times). In some embodiments, the surge receptacle has a capacity of at least 1 m 3 , or at least 3m 3 , or at least 5m 3 of internal volume, or 2m 3 Internal volume less than or equal to 10-500cm 3 internal volume, or 100 to 5,000 cm 3 The inner volume of the container can be 1000 volts.

[0028]

[0028] With further reference to Figure 1, nitric oxide is preferably generated on demand from a precursor solution 120 in a reaction vessel, and the precursor solution generally more preferably contains a nitrosothiol compound. Furthermore, the concentration of the nitrosothiol compound in the solution can preferably be maintained by generating the nitrosothiol compound in situ from reactants supplied to the solution. In some embodiments, the precursor solution can be an aqueous solution at a relatively acidic pH (e.g., pH 4.0) and can further include a metal ion chelator (e.g., EDTA), thereby increasing the chemical stability of the nitrosothiol compound. To that end, the solution can be buffered or the pH can be actively controlled using a control system that can supply acid or base to the solution as needed to maintain a set point or pH band for the solution.

[0029] Among other suitable reagents, contemplated nitrosothiol compounds can be generated from organic thiol compounds 100 and nitrites 140. For example, if the nitrosothiol compound is S-nitrosoglutathione or S-nitrosocysteine, the reactants can be glutathione or cysteine ​​for the thiol compound and sodium nitrite for the nitrite. As will be readily appreciated, the appropriate molar ratio for the thiol and nitrite reagents can be readily ascertained by one of ordinary skill in the art (e.g., a 1:1.1 ratio of thiol to nitrite), and appropriate amounts can be added to achieve the desired final concentration. Of course, it should be understood that the addition of reagents can be continuous or discontinuous (e.g., in response to a sensed amount of nitrosothiol compound). Most typically, the nitrosothiol compound has a concentration of 0.1 M to 1.0 M in solution.

[0030]

[0030] In a further desirable embodiment, as also illustratively shown in Figure 1, it should be appreciated that the concentration of the formed nitrosothiol compounds (RSNOs) can be monitored by UV-VIS spectroscopy 125 (e.g., using a point analysis method such as an Ocean Optics optical UV-VIS spectrometer). It should be noted that UV-VIS spectroscopy can also monitor the pH of the solution using a ratiometric measurement that can be enabled by a pH indicator (such as thymol blue or methyl orange) in the solution. Advantageously, such a ratiometric system does not require calibration. Consequently, it should be appreciated that these two feedback parameters (amount of nitrosothiol compound and pH of the solution) allow for the maintenance of a constant level of nitrosothiol compound to be maintained (via a control system that dispenses thiol and nitrite reagents in response to the determined amount of nitrosothiol compound).

[0031] Nitric oxide 130 can then be generated from the nitrosothiol compounds in the solution by the addition of energy, generally preferably light sources 150 and 160 (which may be adjustable in frequency and / or intensity to adjust for different nitrosothiol compounds and / or nitric oxide generation rates). As will be readily appreciated, the amount / concentration of nitric oxide in the headspace of the reaction vessel can be monitored by an electrochemical NO sensor 110 (such as the SGX-4NO-250 Nitric Oxide Gas sensor from Sensortech), which allows for real-time measurement of the nitric oxide concentration / amount when the solution is illuminated. In the most typical embodiment, an inert gas (e.g., nitrogen) is flowed and maintained throughout the nitric oxide flow path to reduce or even completely avoid the presence of oxygen in the flow path. One or more flow meters can then be used to monitor the gas flow rate entering the sterilization chamber. Finally, it is preferred that the solution containing the nitrosothiol compounds be protected from ambient light and that the solution can be sparged or purged with an inert gas. Thus, nitric oxide is only produced in response to the light of the illumination source.

[0032]

[0032] With respect to the sterilization cycle, it is contemplated that objects within the sterilization chamber can be exposed to a static atmosphere containing nitric oxide or a dynamic atmosphere containing nitric oxide. To that end, nitric oxide in a carrier gas can be delivered to a steady-state concentration within the sterilization chamber, and the carrier gas with nitric oxide is maintained within the chamber for a sufficient period of time. Alternatively, nitric oxide in a carrier gas can be delivered in a continuous flow throughout the sterilization cycle, with nitric oxide present in either case at a sterilizing nitric oxide concentration. Of course, it should be noted that articles for sterilization can be placed directly into the sterilization chamber, or the articles can be placed / sealed in a container containing a microbial barrier permeable to nitric oxide, as described in U.S. Provisional Patent Application No. 63 / 438,073, filed January 10, 2023, which is incorporated herein by reference.

[0033]

[0033] Accordingly, with further reference to Figure 1, it is contemplated that the sterilization chamber will include one or more sensors 190 to verify the presence and amount of nitric oxide within the sterilization chamber, and to assist the operator in verifying the absence of nitric oxide after the sterilization cycle is completed before opening the sterilization chamber. Most typically, after the sterilization cycle is completed, the nitric oxide flow path is purged with an inert gas, and any residual nitric oxide is driven from the system to an adsorbent or catalyst that breaks down the nitric oxide. In addition, an activated carbon filter may be included within the flow path to remove any odorous components from the gas exiting the sterilization chamber. Finally, an additional nitric oxide sensor 240 may be included in a distal portion of the flow path to verify the desired degree of adsorption or catalytic destruction of nitric oxide within the flow path (e.g., at least 95%).

[0034] In further contemplated embodiments, it should be understood that various modifications can be made to the exemplary system described above without departing from the inventive concepts presented herein. For example, while it is generally preferred that the nitric oxide and carrier gas be moved through the system at pressures below 1 atmosphere (e.g., a vacuum pump producing a reduced pressure of about 5-10 Torr, or about 10-50 Torr, or about 50-100 Torr, or about 100-300 Torr, or about 300-700 Torr), moderate positive pressure levels for moving the carrier are also contemplated as suitable for use herein, including pressures of 800-1,500 Torr, or 1,500-2,500 Torr, or 2,500-6,000 Torr, and possibly even higher. Moderate positive pressures may be particularly appropriate when the residence time of the nitric oxide in the flow path between the reaction vessel and the sterilization chamber is less than 48 hours, or less than 24 hours, or less than 12 hours, or even shorter.

[0035] Further, with regard to the generation of nitric oxide, it is noted that the generation of nitric oxide from the precursor solution may be discontinuous (especially if the surge receptacle has a relatively large volume relative to the sterilization chamber) or continuous, thereby producing a sterilizing nitric oxide concentration in the carrier gas. In most embodiments, the sterilizing nitric oxide concentration is a steady-state concentration of nitric oxide of 1 to 500 ppb, or 1 to 10 ppb, or 10 to 50 ppb, or 50 to 250 ppb, or 250 ppb to 500 ppb, or even higher. Thus, suitable sterilizing nitric oxide concentrations are 1 ppb, or at least 5 ppb, or at least 10 ppb, or at least 50 ppb, or at least 100 ppb, or at least 200 ppb, and even higher.

[0036] It should be further noted that the properties of the thiol and nitrite reagents can vary widely; indeed, it is contemplated that any reagent is suitable for use herein, so long as it allows for the formation of a nitric oxide donor in solution within the reaction chamber and is capable of generating nitric oxide by decomposing the nitric oxide donor. Additionally, it should be understood that in further contemplated aspects, the solution containing the nitric oxide donor can be replaced with solid particles that include the nitric oxide donor and release nitric oxide upon exposure to energy. For example, the solid particles can include a polymer surrounding the nitric oxide donor or a polymer to which the nitric oxide donor is attached. Suitable particle materials are described in WO 2022 / 164894, which is incorporated herein by reference. In such embodiments, the particles can be fed to the reaction vessel (e.g., by a screw or auger drive), and the used particles can then be discarded (either en bloc or continuously) from the reaction vessel. Regardless of the particular properties of the nitric oxide donor, it should be understood that the nitric oxide donor is an environmentally safe and chemically stable source of nitric oxide that can be easily replenished. Furthermore, the generation of nitric oxide is conceptually simple and does not require complex equipment. Finally, it should be understood that the systems and methods presented herein can be integrated into or at least partially formed by existing gas sterilization equipment. Viewed from another perspective, existing gas sterilization systems can be modified to include a nitric oxide generator, a surge receptacle, and a vacuum pump in a retrofit, thus adding an alternative form of gas sterilization or replacing an existing form of gas sterilization (e.g., using ethylene oxide or hydrogen peroxide).

[0037] It should be understood that in some embodiments, numbers expressing quantities of ingredients, properties such as concentrations, reaction conditions, and the like, used to describe and claim embodiments of the present invention are modified in some instances by the term "about." As used herein, the terms "about" and "approximately," when referring to a specified measurable value (parameter, amount, duration, etc.), are meant to encompass the specified value, as well as variations therefrom, for example, ±10% or less, alternatively ±5% or less, alternatively ±1% or less, or alternatively ±0.1% or less, to the extent that such variations are appropriate for practice in the disclosed embodiments. Accordingly, the value to which the "about" or "approximately" modifier refers is itself also specifically disclosed. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise stated herein, each individual value is incorporated herein as if individually set forth herein.

[0038] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein with respect to specific embodiments, or the use of exemplary language (e.g., "etc."), are intended only to better clarify the invention and do not pose a limitation on the scope of the invention as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element necessary to the practice of the invention.

[0039] As used throughout this description and the claims that follow, the meanings of "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Also, as used in this description, the meaning of "in" includes "in" and "on," unless the context clearly dictates otherwise. Also, as used herein, unless the context clearly dictates otherwise, the term "coupled to" is intended to include both direct coupling (two elements coupled to each other touch each other) and indirect coupling (at least one additional element is located between the two elements). Thus, the terms "coupled to" and "coupled with" are used interchangeably.

[0040] It should be apparent to those skilled in the art that many further modifications beyond those already described are possible without departing from the inventive concepts herein. Accordingly, the present subject matter should not be limited except as defined by the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced element, component, or step may be present, or may utilize, or may be combined with other elements, components, or steps not expressly referenced. When the specification or claims refer to at least one member selected from the group consisting of A, B, C, ..., and N, the sentence should be interpreted as requiring only one element of the group, rather than A and N, or B and N, etc.

Claims

1. a reaction vessel configured to hold a solution containing a nitric oxide donor; a metering system configured to provide the solution with the nitric oxide donor or one or more reagents that generate the nitric oxide donor in the solution; an energy source coupled to the reaction vessel and configured to provide a sufficient amount of energy to the solution to generate nitric oxide by decomposing the nitric oxide donor; a control circuit operably coupled to the metering system and one or more sensors, for controlling operation of the sensors in response to a concentration of a nitric oxide donor in the solution, the one or more reagents, and / or the concentration or amount of the generated nitric oxide; A nitric oxide generator comprising:

2. 10. The nitric oxide generator of claim 1, wherein the container is configured to protect the solution containing the nitric oxide donor from ambient light.

3. 10. The nitric oxide generator of claim 1, wherein the container is configured to allow introduction of an inert gas to allow displacement of atmospheric oxygen in the container.

4. 10. The nitric oxide generator of claim 1, wherein the solution is an aqueous solution, optionally containing a metal ion chelator.

5. 5. The nitric oxide generator of claim 4, wherein the solution has a pH of 4.0 or less.

6. 2. The nitric oxide generator of claim 1, wherein the nitric oxide donor comprises a nitrosothiol group.

7. 2. The nitric oxide generator of claim 1, wherein the one or more reagents comprise an organic thiol compound and a nitrite, and the nitric oxide donor is generated in situ in the solution by reaction of the organic thiol compound with the nitrite.

8. 2. The nitric oxide generator of claim 1, wherein the metering system comprises a liquid pump or screw drive configured to dispense the nitric oxide donor or the one or more reagents into the solution.

9. 10. The nitric oxide generator of claim 1, wherein the energy source is a light source, a heater, an ultrasound emitter, or an impeller.

10. The nitric oxide generator of claim 1 , wherein the sensor is a pH sensor, a UV-VIS sensor, a nitric oxide sensor, and / or a gas flow meter.

11. 10. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a source of inert gas.

12. 10. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a surge receptacle.

13. 10. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a sterilization chamber.

14. 10. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a vacuum pump.

15. 1. A method for producing nitric oxide, comprising: reacting an organic thiol compound and a nitrite in a container, the organic thiol compound and the nitrite reacting to produce a solution comprising a nitric oxide donor; providing energy to the solution in the reaction vessel to decompose at least a portion of the nitric oxide donor, whereby decomposition of at least a portion of the nitric oxide donor produces nitric oxide; using a negative pressure gradient to move the produced nitric oxide from the reaction vessel; replenishing the nitric oxide donor by providing additional organic thiol compound and nitrite to the solution; A method comprising:

16. The method of claim 15 , wherein the solution comprises a metal ion chelator.

17. 16. The method of claim 15, wherein the solution has a pH of 4.0 or less.

18. 16. The method of claim 15, wherein the headspace above the solution is flushed with an inert gas and / or the solution is protected from ambient light.

19. 16. The method of claim 15, wherein the energy is provided in the form of light energy, thermal energy, mechanical energy, and / or ultrasonic energy.

20. 16. The method of claim 15, further comprising measuring the concentration of nitric oxide in the reaction vessel.

21. 16. The method of claim 15, wherein the produced nitric oxide is transferred from the reaction vessel into a surge vessel.

22. 16. The method of claim 15, wherein the produced nitric oxide is moved from the reaction vessel into a sterilization chamber.

23. 16. The method of claim 15, wherein the generated nitric oxide is moved using a vacuum pump.

24. 16. The method of claim 15, further comprising measuring the concentration of said nitric oxide, wherein said nitric oxide donor is replenished in response to the measured concentration of nitric oxide in said solution.

25. 16. The method of claim 15, wherein residual nitric oxide is adsorbed or catalytically destroyed after use as a sterilant.

26. 1. A sterilization system for sterilizing an object using gaseous nitric oxide, comprising: a reaction vessel fluidly coupled to a surge receptacle and a sterilization chamber, wherein nitric oxide generated in the reaction chamber travels from the reaction vessel through the surge receptacle to the sterilization chamber; an energy source coupled to the container and configured to provide a sufficient amount of energy to a solution in the container to produce nitric oxide by decomposing the nitric oxide donor in the solution; a vacuum pump fluidly coupled to the sterilization chamber for drawing the nitric oxide from the reservoir, the surge reservoir, and the sterilization chamber to a nitric oxide adsorbent or catalyst; A sterilization system comprising:

27. 27. The sterilization system of claim 26, wherein the reaction vessel comprises one or more ports configured to receive a nitric oxide donor or one or more reagents for generating the nitric oxide donor.

28. 27. The sterilization system of claim 26, wherein the energy source is a light source, a heater, an ultrasound emitter, or an impeller.

29. 27. The sterilization system of claim 26, further comprising a plurality of nitric oxide sensors that measure nitric oxide concentrations in one or more of the reaction vessel, the sterilization chamber, and the vacuum pump exhaust.

30. 27. The sterilization system of claim 26, further comprising a sensor for measuring the concentration of the nitric oxide donor in the reaction vessel.

31. 1. A method of sterilizing an object using nitric oxide, comprising: generating nitric oxide from a solution containing a nitric oxide donor in a reaction vessel; using a negative pressure gradient to move the generated nitric oxide from the reaction vessel to a sterilization chamber; maintaining a sterilizing nitric oxide concentration in the sterilization chamber for a time sufficient to sterilize the object; A method comprising:

32. 32. The method of claim 31 , wherein the nitric oxide donor comprises a nitrosothiol group.

33. 32. The method of claim 31, wherein the nitric oxide donor is generated in the solution from a reaction between an organic thiol compound and a nitrite.

34. 32. The method of claim 31, wherein the nitric oxide is generated from the nitric oxide donor by photolysis of the nitric oxide donor.

35. 32. The method of claim 31 , wherein the nitric oxide is moved from the reaction vessel to the sterilization chamber via a surge receptacle.

36. The surge receptacle has a volume greater than the volume of the sterilization chamber and / or a volume of 10 cm ３ ~1,000 cm ３ 36. The method of claim 35, having an internal volume of

37. 32. The method of claim 31 , wherein the negative pressure gradient is generated using a vacuum pump downstream of the sterilization chamber.

38. 32. The method of claim 31, wherein the sterilizing nitric oxide concentration is between 1 and 50 ppb.

39. 32. The method of claim 31, wherein the sterilizing nitric oxide concentration is maintained for a time period of 10 to 120 minutes and / or at a temperature of 0 to 50°C.

40. 32. The method of claim 31, wherein residual nitric oxide is adsorbed or catalytically destroyed after use as a sterilant.

Images