Nitric oxide generating systems

Abstract

To eliminate the need for nitric oxide tanks (i.e., NO in compressed gas cylinders) in a nitric oxide (NO) generating system.SOLUTION: A nitric oxide (NO) generating system is provided which includes an NO generating formulation and an inhalation device in operative contact with the NO generating formulation. The NO generating formulation comprises a stable NO donor / adduct, a hydrophilic binder, and an additive. The additive is to control a rate of release of NO from the NO donor / adduct after the formulation is exposed to an effective amount of water, water vapor, or blue or ultraviolet (UV) light. This eliminates the need for nitric oxide tanks (i.e., NO in compressed gas cylinders) in the nitric oxide (NO) generating system, thereby simplifying the systems / devices and thus reducing the cost of the systems / devices.SELECTED DRAWING: Figure 26

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 891,129, filed Aug. 23, 2019, the content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] In the human body, nitric oxide (NO) can be produced by any of several isoforms of the enzyme nitric oxide synthase (NOS). NO forms the core of the mammalian immune response or immune defense and is a cytotoxic substance in the mechanism used by macrophages to kill several bacterial species, including L. major, M. bovis, and M. tuberculosis. NO is also an effective antiviral agent, having activity against rhinoviruses that cause the common cold. NO is produced from L - arginine in the airways (e.g., upper airways) by immune cells (macrophages, neutrophils, lymphocytes, etc.) and airway epithelial cells (e.g., conductive respiratory epithelial cells), mainly via inducible nitric oxide synthase (iNOS). Deficiency in NO production may reduce the immune response and / or microbial biofilm formation. Deficiency in nasal NO levels has been associated with diseases such as primary ciliary dyskinesia and chronic rhinosinusitis (CRS), and potentially with a lack of ability to fight viral agents that cause the common cold. Some of the physiological properties of NO include its use as an anti - inflammatory agent, an anticoagulant, and / or an antibacterial agent.

[0003] The use of NO in inhalation therapy has also been studied. Inhaled nitric oxide has been used to treat lung failure and has been found to promote pulmonary vasodilation and reduce pulmonary vascular resistance. Inhaled nitric oxide has also been approved by the U.S. Food and Drug Administration (FDA) for treating neonates with hypoxic respiratory failure. It has also been found to improve oxygenation and reduce the need for extracorporeal membrane oxygenation therapy.

Summary of the Invention

[0004] An example of a nitric oxide (NO) generating system includes a NO generating formulation comprising a stable NO donor / adduct, a hydrophilic binder, and an additive, wherein the additive is adapted to control the rate of NO release from the NO donor / adduct after the formulation is exposed to an effective amount of water, water vapor, or blue or ultraviolet (UV) light, a NO generating formulation, and an inhalation device operably in contact with the NO generating formulation. 1. A nitric oxide (NO) generating system, comprising: A NO generating formulation, A stable NO donor / adduct, A hydrophilic binder, and An additive wherein the additive is for controlling the rate of NO release from the NO donor / adduct after the formulation is exposed to an effective amount of water, water vapor, or blue or ultraviolet (UV) light, a NO generating formulation; and An inhalation device operably in contact with the NO generating formulation, A nitric oxide (NO) generating system. 2. The NO generating system according to 1., wherein the NO generating formulation further comprises a lubricant. 3. The stable NO donor / adduct is an S-nitrosothiol (RSNO) powder present in an amount of about 3 wt% to about 12 wt% of the NO generating formulation, The hydrophilic binder is present in an amount of about 15 wt% to about 82 wt% of the NO generating formulation, The lubricant is present in an amount of about 1 wt% to about 15 wt% of the NO generating formulation, and The additive is present in an amount of about 3 wt% to about 60 wt% of the NO generating formulation, The NO generating system according to 2. 4. The NO generating system according to 2., wherein the lubricant is a surfactant selected from the group consisting of sodium stearate, zinc stearate, magnesium stearate, sodium laurate, zinc laurate, sodium palmitate, zinc palmitate, ascorbyl palmitate, and combinations thereof. 5. The NO generation system according to 1., wherein the NO generation agent further comprises an inert material selected from the group consisting of sodium chloride, sodium bicarbonate, calcium chloride, microcrystalline cellulose, silicon dioxide, and combinations thereof. 6. The NO generation system according to 5., wherein the inert material is present in an amount of greater than about 0 wt% to about 50 wt% of the NO generation agent. 7. The NO generation system according to 1., wherein the ratio (mol / mol) of the NO donor / adduct to the additive is 1:0.5 to 1:10. 8. The NO generation system according to 1., wherein the NO generation agent comprises a single solid. 9. The NO generation system according to 1., wherein the inhalation device comprises a face mask. 10. The NO generation system according to 9., wherein the face mask comprises a housing for effectively holding the NO generation agent in close proximity to at least one of the user's mouth or nose. 11. The NO generation system according to 10., wherein the NO generation agent comprises a single solid. 12. The NO generation system according to 11., wherein the NO generation agent comprises a plurality of the single solids. 13. The NO generation system according to 10., wherein the housing selectively opens and closes. 14. The housing further comprises an air humidifier in operable contact with the NO generation agent, an air pump in fluid communication with the air humidifier, and a power source operably connected to the air humidifier and the air pump The NO generation system according to 10. 15. The housing partially defines a reservoir, and the system further comprises a reservoir wall or filter positioned between the interior of the face mask and the interior of the reservoir. The NO generation system according to 10. 16. The NO generation system according to 15., wherein the reservoir wall or the filter is impermeable to the hydration liquid and permeable to NO. 17. The NO generation system according to 15., wherein the reservoir is adapted to receive a predetermined volume of a hydrated solution in which the NO generating agent is dissolved. 18. The NO generation system according to 15., further comprising an absorbent material contained within the reservoir. 19. The system further includes the filter positioned between the interior of the face mask and the interior of the reservoir, and the filter is for scavenging nitrogen dioxide (NO 2 ) released by the NO generating agent, a reagent for converting the generated NO 2 back to NO, or a combination thereof. The NO generation system according to 15. 20. The NO generating agent is contained within a NO-permeable container, and the NO-permeable container is arranged within the face mask without being attached to the face mask. The NO generation system according to 9. 21. The inhalation device further includes an air pump operably connected to the face mask, an air humidifier in fluid communication with the air pump, a container for holding the NO generating agent, the container being in fluid communication with the air humidifier and the face mask, and the container The NO generation system according to 9. 22. The inhalation device further includes a gas mixer in fluid communication with the container, a second air pump operably connected to the gas mixer, a NO sensor operably connected between the gas mixer and the face mask, a feedback controller operably connected to the NO sensor and the gas mixer The moisture-activated NO generation system according to 21. 23. The NO generating system according to 1., wherein the stable NO donor / adduct is activatable by blue light or ultraviolet (UV) light, and the system further comprises a blue light source or a UV light source positioned to illuminate the NO generating formulation. 24. The NO generating system according to 23., wherein the NO generating formulation and the blue light source or the UV light source are positioned on or within the inhalation device. 25. The NO generating system according to 23., wherein the blue light source or the UV light source is a light emitting diode. 26. The NO generating system according to 23., wherein the blue light source or the UV light source emits light at a wavelength of about 300 nm to about 520 nm at various intensities. 27. Further, a control electronic element operably connected to the blue light source or the UV light source, and a battery operably connected to the control electronic element. The NO generating system according to 23. comprising the above. 28. The NO generating system according to 23., further comprising an NO sensor, a nitrogen dioxide sensor, or a combination thereof. 29. The inhalation device comprises an air pump, an air humidifier in fluid communication with the air pump, a container holding the NO generating formulation in fluid communication with the air humidifier, a nasal cannula or a ventilator in fluid communication with the container. The NO generating system according to 1. comprising an inhalation system including the above. 30. The NO generating system according to 29., wherein the NO generating formulation comprises a single solid or a plurality of single solids. 31. The inhalation system further comprises a gas mixer in fluid communication with the container, a second air pump operably connected to the gas mixer, an NO sensor operably connected between the gas mixer and the nasal cannula or the ventilator, A war record NO sensor and a feedback controller operably connected to the gas mixer, The NO generation system according to 29., comprising 32. The NO generation system according to 1., wherein the additive is selected from the group consisting of reduced glutathione, cysteine, ascorbic acid or ascorbate, ascorbyl palmitate, copper ions, zinc ions, zinc oxide particles, organic selenium species, and combinations thereof. 33. The NO generation system according to 32., wherein the organic selenium species is selected from the group consisting of selenocysteine and ebselen. 34. The NO generation system according to 1., wherein the stable NO donor / adduct is an RSNO powder selected from the group consisting of S-nitrosoglutathione (GSNO), S-nitroso-cysteine, S-nitroso-N-acetylpenicillamine, S-nitroso-penicillamine, and S-nitroso-albumin. 35. The NO generation system according to 1., wherein the stable NO donor / adduct is nitroprusside. 36. The NO generation system according to 1., wherein the hydrophilic binder is selected from the group consisting of polyvinyl acetate (PVA), poly(ethylene glycol) (PEG), polyacrylamide, acetate, polyethylene oxide (PEO), polyethyl acrylate (PEA), polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate (PVP-VA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, and combinations thereof. 37. The NO generation system according to 1., wherein the NO generation preparation further comprises a pH control material selected from the group consisting of sodium phosphate buffer, potassium phosphate buffer, and combinations thereof. 38. A nitric oxide (NO) generation system, comprising: An NO generation preparation, A stable NO donor / adduct, A hydrophilic binder, and An alkaline material selected from the group consisting of sodium carbonate, a mixture of sodium carbonate and sodium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof comprising, wherein the alkaline material raises the pH of the NO generating formulation to 8.5 or higher, thereby destabilizing the NO donor / adduct such that NO is released after the formulation is exposed to an effective amount of water vapor or a hydrating liquid, a NO generating formulation; An inhalation device operably in contact with the NO generating formulation, A nitric oxide (NO) generating system comprising. 39. A nitric oxide (NO) generating system, A NO-permeable container including an attachment mechanism; A NO generating formulation contained within a NO-permeable pouch, wherein the NO generating formulation comprises a stable NO donor / adduct that is activatable upon exposure to an effective amount of water vapor, a hydrating liquid, or blue or ultraviolet (UV) light, a NO generating formulation, A nitric oxide (NO) generating system comprising. 40. The NO generating formulation further comprises, A hydrophilic binder, An additive for controlling the rate of NO release from the NO donor / adduct after the formulation is exposed to an effective amount, The NO generating system according to 39., comprising. 41. The NO generating system according to 40., wherein the hydrophilic binder is selected from the group consisting of polyvinyl acetate (PVA), poly(ethylene glycol) (PEG), polyacrylamide, acetate, polyethylene oxide (PEO), polyethyl acrylate (PEA), polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate (PVP-VA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, and combinations thereof. 42. The NO generating formulation further comprises an absorbent for scavenging nitrogen dioxide (NO 2 ) generated by the NO generating formulation, the generated NO2 The NO generation system according to item 40, comprising a reagent for changing it back to NO, or a combination thereof. 43. The NO generation system according to item 40, wherein the NO generation preparation further comprises a lubricant. 44. The stable NO donor / adduct is an S-nitrosothiol (RSNO) powder present in an amount of about 1 wt% to about 30 wt% of the NO generation preparation, the hydrophilic binder is present in an amount of more than 0 wt% to about 82 wt% of the NO generation preparation, the lubricant is present in an amount of more than 0 wt% to about 15 wt% of the NO generation preparation, and the additive is present in an amount of about 1 wt% to about 60 wt% of the NO generation preparation. The NO generation system according to item 43. 45. The NO generation system according to item 40, wherein the NO generation preparation further comprises an inert material selected from the group consisting of sodium chloride, sodium bicarbonate, calcium chloride, microcrystalline cellulose, silicon dioxide, and combinations thereof. 46. The additive is selected from the group consisting of reduced glutathione, cysteine, ascorbic acid or ascorbate, ascorbyl palmitate, copper ions, zinc ions, zinc oxide particles, organic selenium species, and combinations thereof. The NO generation system according to item 40. 47. The NO generation system according to item 39, wherein the attachment mechanism comprises an adhesive covered by a release liner. 48. The NO generation system according to item 47, wherein the adhesive is a pressure-sensitive adhesive or a double-sided adhesive. 49. The NO generation system according to item 39, wherein the attachment mechanism comprises a clip. 50. The NO generation system according to item 39, wherein the NO-permeable container is porous. 51. The NO generation system according to item 39, wherein the NO-permeable container is selected from the group consisting of a woven fabric material, a non-woven fabric material, a plastic material, and a metal material. 52. Further, it includes a filter on the surface of the container or a filter positioned outside the container, and the filter is for scavenging nitrogen dioxide (NO 2 ) released by the NO generating preparation, a reagent for changing the generated NO 2 back to NO, or a combination thereof. The NO generating system according to 39. 53. The NO generating system according to 39., further including an inhalation device adapted to attach a NO-permeable container via the attachment mechanism. 54. The NO generating system according to 53., wherein the inhalation device is a face mask. 55. The inhalation device includes a housing to which a NO-permeable container is to be attached, a tube including a first end fluidly connected to the housing, an adapter provided at a second end of the tube distal to the first end, the adapter being adapted to be attached to a face mask, a nasal cannula, or a breathing tube. The NO generating system according to 53. 56. The NO generating system according to 55., further including a fan or a suction device for transporting the NO from the housing to the adapter. 57. The NO generating system according to 55., further including a blue light source or a UV light source for illuminating the NO-permeable container. 58. Further an air humidifier operably contacting the housing, an air pump in fluid communication with the air humidifier, a power source operably connected to the air humidifier and the air pump. The NO generating system according to 55. 59. A housing to which the NO-permeable container is attached, a blue light or ultraviolet (UV) light source positioned inside the housing for illuminating the NO-permeable container. A battery operably connected to the blue light or ultraviolet (UV) light source The NO generation system according to 39., further comprising . 60. An NO sensor positioned within the housing, A control electronic element positioned within the housing The NO generation system according to 59., further comprising . 61. The NO generation system according to 39., wherein the stable NO donor / adduct is an RSNO powder selected from the group consisting of S-nitrosoglutathione (GSNO), S-nitroso-cysteine, S-nitroso-N-acetylpenicillamine, S-nitroso-penicillamine, and S-nitroso-albumin. 62. The NO generation system according to 44., wherein the stable NO donor / adduct is nitropru side. 63. An NO generation system, A face mask, A housing fixed to the face mask, the housing including a reservoir having a NO-permeable wall positioned between the housing and the interior of the face mask, An NO generation formulation contained within the reservoir or adapted to be introduced into the reservoir, the NO generation formulation comprising nitrite that generates NO when exposed to an effective amount of an acidic buffer, The NO generation system comprising .

[0005] Another example of a nitric oxide (NO) generating system includes a NO generating formulation, a hydrophilic binder, and an alkaline material selected from the group consisting of sodium carbonate, a mixture of sodium carbonate and sodium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof, wherein the alkaline material raises the pH of the NO generating formulation to 8.5 or higher, thereby destabilizing the NO donor / adduct to release NO after the formulation is exposed to an effective amount of water vapor or a hydrating liquid. The NO generating system includes a NO generating formulation containing the alkaline material and an inhalation device operably in contact with the NO generating formulation.

[0006] Yet another example of a nitric oxide (NO) generating system includes a NO-permeable container including an attachment mechanism and a NO generating formulation contained within a NO-permeable pouch. The NO generating formulation includes a stable NO donor / adduct that is activatable upon exposure to an effective amount of water vapor, a hydrating liquid, or blue or ultraviolet (UV) light.

[0007] Yet another example of a NO generating system includes a face mask and a housing secured to the face mask, the housing including a reservoir having a NO-permeable wall positioned between the housing and the interior of the face mask, and a NO generating formulation contained within the reservoir or adapted to be introduced into the reservoir, the NO generating formulation including nitrite that generates NO upon exposure to an effective amount of an acidic buffer.

[0008] The features of the embodiments of the present disclosure will become apparent by referring to the following detailed description and the drawings. In the drawings, like reference numerals correspond to similar, but perhaps not identical, components. For the sake of brevity, reference numerals or features having functions described previously may or may not be described in connection with other drawings in which they appear. In some of the drawings (e.g., FIGS. 9-20), data of nitric oxide (NO) release profiles or kinetics (e.g., in parts per billion or parts per billion by volume, Y-axis) as a function of time (X-axis) corresponding to compressed pellets of various formulations are shown. In these drawings, the data show a wide range of values based on variations associated with non-uniform hydration of the pellets.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0044] Nitric oxide (NO) is a potential antithrombotic, anti-inflammatory, antibacterial, and antiviral agent. NO deficiency in vivo can be genetic or associated with polymorphisms, or can be caused by a pathology or pathogen that exploits upstream regulation of NO production. Deficiency in NO production reduces mucociliary function (mucociliary function is one of the primary innate immune defense mechanisms in the airway epithelium and is directly correlated with ciliary beat frequency), makes it easier to be infected by microorganisms, and / or promotes the persistence of antibiotic-resistant bacterial biofilms.

[0045] NO inhalation therapy introduces NO into the patient's lungs, thereby enhancing the mucociliary function, reducing the susceptibility to infection by microorganisms, and / or promoting the resistance of bacterial biofilms. NO has been found to be effective against the SARS coronavirus and may also be effective in the treatment of other viruses, such as COVID-19 or SARS-CoV-2. The use of inhaled nitric oxide can also be proven to be beneficial in other fields, such as during lung transplantation, for the treatment of pulmonary hypertension, as an inhaled disinfectant, and for the treatment of other systemic conditions including ischemic stroke, heart attack, thrombosis, and traumatic brain injury.

[0046] Examples of moisture (e.g., water vapor) activated, hydrating liquid activated, acidic buffer activated, or photoactivated nitric oxide gas generation systems / devices are disclosed herein. In this example of the device, nitric oxide (NO) gas is generated as needed from an inhalation device in contact with an example of a moisture activated, hydrating liquid activated, acidic buffer activated, or photoactivated NO generating formulation (herein also referred to as an NO releasing formulation).

[0047] An example of an NO generating formulation includes a stable NO donor / adduct (e.g., S-nitrosothiol (RSNO) powder, or nitroprusside). In addition to the stable NO donor / adduct, some examples of NO generating formulations further include a hydrophilic binder and an additive. The additive is adapted to control (promote) the release rate of NO from the stable NO donor / adduct after the formulation is exposed to an effective amount of water vapor, hydrating liquid, or blue light or ultraviolet (UV) light.

[0048] In some examples, the NO generating formulation is in the form of a solid (e.g., pellet / tablet / disk) comprising a stable NO donor / adduct (e.g., RSNO (GSNO)), an additive (e.g., reaction accelerator), and a hydrophilic binder. In some examples, a lubricant and / or an inert material and / or a pH control material may be included. In some other examples, when the NO generating formulation is alkaline (e.g., above pH 8.5), the additive / reaction accelerator is not included.

[0049] In other examples, the NO generating formulation is in the form of a solution or dispersion. In some of these examples, a solid form containing a stable NO donor / adduct (e.g., RSNO (GSNO)), and in some cases, additives and a hydrophilic binder, is mixed with a hydrating solution. In other examples, the liquid form of the NO generating formulation contains a nitrite and an acidic buffer. This formulation may also contain additives and / or an oxygen scavenger as described herein.

[0050] "Nitric oxide adduct" (NO adduct) and "NO donor" mean compounds and functional groups that can donate and / or release NO under typical conditions (e.g., humidity, hydration), or when exposed to light of a specific wavelength. As such, the expression "moisture-activated NO-releasing formulation" as used herein includes NO donors / adducts that can release NO gas molecules when exposed to an effective amount of water vapor and / or a hydrating solution (e.g., water). In one example, an appropriate amount of water vapor can be found under conditions ranging from about 40% relative humidity to a high relative humidity of 100% (see, e.g., FIG. 15B). Similarly, a "photoactivated NO-releasing formulation" includes NO donors / adducts that can release NO gas molecules when exposed to light of a specific wavelength at various intensities to produce a desired amount of NO. Some examples of NO donors / adducts disclosed herein can be activated by two or more of moisture, a hydrating solution, and light. Suitable NO adducts are also generally adducts that exhibit process preparation stability.

[0051] Furthermore, the term "acidic buffer-activated NO-releasing formulation" refers to a formulation containing a nitrite that produces NO gas molecules when exposed to an acidic buffer that brings the formulation to a pH above 4 to about 7.5. In some examples, the pH is from about 4.5 to about 7.0, from about 4.1 to about 6.9.

[0052] In some of the examples disclosed herein, an example of a nitric oxide generating formulation is specifically, for example, in solid form (e.g., a single solid or a single high-density filled solid mass using pressure (e.g., about 25 - 50 kn), e.g., pellets, tablets, or disks). The solid form generates gaseous NO over a wide range (from about 50 ppbv to over about 50,000 ppbv) when exposed to humid air (e.g., from the user's inhalation / exhalation, from an air humidifier, etc.). This range covers the range demonstrated to be therapeutically effective for inhalation therapy. As used herein, "high-density filled" is not essentially granular and is similar to the density of a crystalline material. The NO generating formulation enables the spontaneous delivery of NO over a long period of time when the user is in contact with an inhalation device example containing a moisture-activated type NO generating formulation.

[0053] In other examples disclosed herein, the nitric oxide generating formulation is in solid form and is contained inside a container. The container is either attached to or introduced into an inhalation device. In some cases, the container allows humid air and NO to pass through. This type of container enables humid air to contact the nitric oxide generating formulation and also enables the generated gaseous NO to be released from the container. In other cases, the container is transparent to visible blue and / or cyan light (wavelengths from about 400 nm to about 490 nm and / or from about 490 nm to about 520 nm) and / or ultraviolet light (wavelengths from about 10 nm to about 400 nm) and is NO permeable. This type of container enables light to contact the nitric oxide generating formulation and also enables the generated gaseous NO to be released from the container.

[0054] In other examples disclosed herein, the nitric oxide generating formulation is in solid form or powder form sealed within a package. The package prevents moisture from reaching the nitric oxide generating formulation from outside moisture and liquids until the formulation is returned and poured into a reservoir, e.g., the reservoir shown in Figure 25B.

[0055] In other examples disclosed herein, the nitric oxide generating agent is a coating or a powder. The coating or powder is added to an absorbent pad (e.g., a PIG® absorbent pad) and placed into a device as described in FIG. 25B. This device generates NO when moisture or liquid is added to the device.

[0056] The systems / devices disclosed herein are relatively compact and eliminate the need for a nitric oxide tank (i.e., NO in a compressed gas cylinder). This simplifies the systems / devices and reduces their cost.

[0057] Using the NO releasing agent examples disclosed herein to form inhaled nitric oxide is effective in fighting diseases, including the use of prophylactic agents, reduction of infectious agents (e.g., viruses, bacteria, fungi), treatment of lung failure, improvement of pulmonary vasodilation, and reduction of other conditions including pulmonary vascular resistance, and inflammation, coagulation, and infection. As described above, inhaled nitric oxide can also be used to treat neonates with hypoxic respiratory failure and can improve oxygenation and reduce the need for extracorporeal membrane oxygenation therapy. Using the NO releasing agent examples disclosed herein to generate inhaled nitric oxide is also clearly beneficial in other fields, such as during lung transplantation, for the treatment of pulmonary hypertension, as an inhaled disinfectant, for the disinfection of air, etc.

[0058] For example, using the NO-releasing formulations disclosed herein generally increases the external and internal NO levels in epithelial and immune cells. This can also help control the ciliary beat frequency. As such, the nitric oxide-generating formulations described herein can help repair / improve the mucociliary function (which directly correlates with the ciliary beat frequency as described above). The repaired / improved mucociliary function can enhance the defense against chronically established pathogens and reduce or prevent the perpetuation of the disease. In addition, the nitric oxide released from the NO-releasing formulations has direct bactericidal, antiviral, and antibacterial activities against most types of bacteria, viruses, and fungi that can infect the sinuses and other parts of the respiratory system. Therefore, it can be said that this example of a nitric oxide-generating formulation is beneficial for treating or preventing airway infections including upper respiratory tract infections such as CRS.

[0059] NO-generating formulation

[0060] Some examples of NO-generating formulations include stable NO donors / adducts. In some cases, these examples of NO-generating formulations include a stable NO donor / adduct, a hydrophilic binder, and an additive.

[0061] Examples of moisture-activated stable NO donors / adducts include, for example, S-nitrosothiol (RSNO) powder, or nitroprusside.

[0062] The moisture-activated RSNO selected for the nitric oxide-generating formulation is a species that occurs naturally in the human body or another living organism, or a species that can be decomposed into species that occur naturally in the human body, or a drug suitable for human use (i.e., ingestion, consumption, etc.). In any of the examples disclosed herein, the moisture-activated RSNO or RSNO powder is selected from S-nitrosoglutathione (GSNO, occurs naturally in the human body), S-nitrosocysteine (CYSNO, occurs naturally in the human body), S-nitroso-N-acetyl-penicillamine (SNAP, decomposes into the drug penicillamine), S-nitroso-penicillamine, and S-nitroso-albumin (occurs naturally in vertebrates).

[0063] S-nitrosoglutathione (GSNO) is an example of a NO-releasing S-nitrosothiol (RSNO) molecule. GSNO is formed by the reaction of NO (produced by epithelial cells, macrophages, nasal epithelial cells, etc.) with oxygen to form N 2 O 3 which is present in the human body. N 2 O 3 provides nitrosonium ions (NO + ), which react with the thiol group of glutathione to form GSNO. As such, the nitric oxide generating agents disclosed herein do not introduce any foreign substances or toxins into the nasal cavity / airway.

[0064] GSNO was prepared from glutathione (GSH) by acidifying a mixture of sodium nitrite / GSH with hydrochloric acid and then isolating the GSNO species (as solid crystals). Alternatively, GSNO may be a commercially available sample.

[0065] In some examples, moisture-activated S-nitrosothiol (RSNO) molecules other than GSNO can be used in the nitric oxide generating agent. Examples of these other S-nitrosothiols include S-nitroso-cysteine (CYSNO, occurring naturally in the human body), S-nitroso-N-acetyl-penicillamine (SNAP, decomposing to the drug penicillamine), S-nitroso-penicillamine, and S-nitroso-albumin (occurring naturally in the human body).

[0066] In one example of a moisture-activated formulation, the RSNO powder is selected from the group consisting of S-nitrosoglutathione (GSNO), S-nitroso-cysteine, S-nitroso-N-acetyl-penicillamine, S-nitroso-penicillamine, and S-nitroso-albumin.

[0067] In a further example of a moisture-activated formulation, the stable NO donor / adduct is nitroprusside.

[0068] Some examples of S-nitrosothiols are also photoactivatable / sensitive. Examples of photoactivatable / sensitive S-nitrosothiols include S-nitroso-N-acetyl-penicillamine (SNAP) crystals, S-nitrosoglutathione (GSNO) crystals, and combinations thereof.

[0069] In the examples of the NO-generating formulations of the present disclosure, it goes without saying that one or more hydrophilic materials can be used as hydrophilic binders. Some examples include polyvinyl acetate (PVA), poly(ethylene glycol) (PEG), polyacrylamide, acetate, polyethylene oxide (PEO), polyethyl acrylate (PEA), polyvinyl pyrrolidone (PVP), and modified forms thereof (e.g., polyvinyl pyrrolidone-vinyl acetate (PVP-VA)), for example, as physical blends or mixtures. Each polymer maintains its inherent scientific properties. Various other hydrophilic polymers, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, etc., and / or combinations thereof may also be used. It is also contemplated within the scope of the present disclosure to use any of various polymers / copolymers, or combinations of polymers / copolymers, or other hydrophilic materials to provide a hydrophilic binder with the desired properties.

[0070] In one example, the weight average molecular weight of the hydrophilic polymer used may be from about 5000 Mw to about 500,000 Mw, or from about 10,000 Mw to about 200,000 Mw.

[0071] In one example, the hydrophilic binder is selected from the group consisting of polyvinyl acetate (PVA), poly(ethylene glycol) (PEG), polyacrylamide, acetate, polyethylene oxide (PEO), polyethyl acrylate (PEA), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-vinyl acetate (PVP-VA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, and combinations thereof.

[0072] The selected additive can control the rate of nitric oxide release from the NO donor / adduct after the formulation has been exposed to an effective amount of water vapor, hydrating liquid, or light. By including the additive in the formulation, the NO release profile can be controlled over time. This can enhance the antibacterial activity and / or therapeutic benefit. In some cases, the additive accelerates the rate of nitric oxide release. In one example, the ratio (mol / mol) of the NO donor / adduct to the additive is from 1:0.5 to 1:10.

[0073] Needless to say, the additive is any suitable reducing agent. In one example of a NO-generating formulation, the additive is selected from the group consisting of reduced glutathione, cysteine, ascorbic acid or ascorbate, ascorbyl palmitate, copper ions, zinc ions, zinc oxide particles, organic selenium species, and combinations thereof. In one example, the organic selenium species are selected from the group consisting of selenocysteine and ebselen. One example of a combination of additives is reduced glutathione and ascorbic acid.

[0074] The following are some examples of how an additive can control or accelerate the rate of nitric oxide release from RSNO, specifically from GSNO. Glutathione can increase the rate of NO release from GSNO via the formation of initial N-hydroxysulfanamide species (e.g., GS-N(OH)-SG). The initial N-hydroxysulfanamide species then changes to the radical GS - which changes to the radical GS -By reacting with another GSNO molecule, it can release NO and form GSSG disulfide species. Cysteine can form CysNO by transnitrosation with GSNO. CysNO releases NO significantly faster than GSNO. Ascorbic acid or ascorbate can form a smaller threose structure (a 3-carbon sugar) by being easily oxidized. The natural oxidation of ascorbate can release NO and GSH by being linked to the reduction of GSNO. Furthermore, the oxidation product of ascorbate, namely the smaller threose structure, is also a reducing agent. This reducing agent can provide electrons to GSNO and thus contribute to directly reducing GSNO to NO. In one example, ascorbic acid or ascorbate can be oxidized in solution for up to 5 days, dried, and then incorporated into a nitric oxide generating formulation. The generation of NO from GSNO can be catalyzed by organic selenium species. Any trace amount of free thiol present in the GSH formulation can reduce copper or zinc ions to their +1 oxidation state, and the Cu(I) or Zn(I) ions can then reduce GSNO to NO and GSH.

[0075] In one example, the nitric oxide generating formulation further includes a lubricant. When a lubricant is included, an example thereof is a surfactant selected from the group consisting of sodium stearate, zinc stearate, magnesium stearate, sodium laurate, zinc laurate, sodium palmitate, zinc palmitate, ascorbyl palmitate, and combinations thereof. Needless to say, the lubricant is not necessary for the generation of NO. However, in some examples, the lubricant can make the pellets more robust and also modify (slow down) the NO release kinetics. However, when the solid / pellets are compressed at a high sufficient pressure (e.g., over 40 kn), the pellets without lubricating oil should remain agglomerated (although the resulting NO release can be slower in some cases as the press pressure increases).

[0076] Needless to say, the components of the NO generating formulation containing the NO donor / adduct may be present in any desired appropriate amount. However, in one example, the stable NO donor / adduct (e.g., S-nitrosothiol (RSNO) powder) is present in an amount of about 1 wt% to about 50 wt%, or about 1 wt% to about 30 wt%, or about 3 wt% to about 12 wt% of the NO generating formulation, the hydrophilic binder is present in an amount of about 15 wt% to about 90 wt%, or greater than 0 wt% to about 82 wt%, or about 15 wt% to about 82 wt%, or about 25 wt% to about 82 wt% of the NO generating formulation, the lubricant (when present in the formulation) is present in an amount of greater than 0 wt% to about 15 wt%, or about 1 wt% to about 15 wt% of the NO generating formulation, and the additive is present in an amount of about 0.5 wt% to about 65 wt%, or about 1 wt% to about 60 wt%, or about 3 wt% to about 60 wt% of the NO generating formulation. When zinc oxide particles are utilized as the additive, these may be present in an amount of about 1 wt% to about 90 wt% of the NO generating formulation.

[0077] In another example, the NO releasing formulation containing the NO donor / adduct is made alkaline (e.g., above pH 8.5) by adding an alkaline material. In this example, no additive / promoter is included. GSNO is unstable at high pH (above about 8.5), and NO is released without an additive / promoter. Examples of alkaline materials are selected from the group consisting of sodium carbonate, a mixture of sodium carbonate and sodium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof.

[0078] In one example, the NO generating formulation (including the NO donor / adduct) further includes an inert substance selected from the group consisting of sodium chloride, sodium bicarbonate, calcium chloride, microcrystalline cellulose, silicon dioxide, and combinations thereof. When an inert material is included in the formulation, it is present in an amount of greater than about 0 wt% to about 50 wt%, or about 5 wt% to about 25 wt% of the NO generating formulation. As used herein, "inert material" means a material that does not have a significant effect on NO release (i.e., a material with a rate of change in NO release rate of less than 10%). In the examples disclosed herein, the inert material can act, for example, as an anti-caking agent, a bulking agent, and / or a binder (although, needless to say, an inert material binder is not involved in water supply like a hydrophilic binder).

[0079] In one example, the NO generating formulation (including the NO donor / adduct) further includes a pH control material. Needless to say, any suitable pH control material can be used as desired. In one example, the pH control material is selected from the group consisting of sodium phosphate buffer, potassium phosphate buffer, and combinations thereof. Other suitable pH control materials include carbonates, other phosphates, or any other interfering material that does not react with nitric oxide. The pH of the NO generating formulation (including the NO donor / adduct) is greater than 9.5.

[0080] Some examples of the NO generating formulation (including the NO donor / adduct) further include an absorbent for scavenging nitrogen dioxide (NO 2 ) released by the NO generating formulation, a reagent for converting the generated NO 2 back to NO, or a combination thereof. By reacting O 2 with NO, NO 2 can be generated, and NO 2 can be toxic to the recipient or patient. Therefore, any generated NO 2 should be removed, any generated NO 2 should be converted back to NO, or any NO 2It is desirable to maintain it at an extremely low level. As an absorbent, a soda lime scrubber may be included. NO 2 If the content exceeds 1 - 3 ppm in the final gas phase, a soda lime scrubber can be used to remove the excess NO 2 from it. An example of a reagent or catalyst that can convert the generated NO 2 back to NO is silica particles impregnated with ascorbic acid.

[0081] In another example, when a deliquescent salt (e.g., calcium chloride) is used, for instance, the NO - generating formulation containing a NO donor / adduct may be a two - component system. Using a material with extremely high hydrophilicity (such as a deliquescent salt like calcium chloride) increases the amount of NO generated. This is because the pellets at least partially dissolve and thus behave like a solution.

[0082] The moisture, hydrating liquid, or photo - activated NO - generating formulation containing a NO donor / adduct may be in the form of a powder.

[0083] The moisture, hydrating liquid, or photo - activated NO - generating formulation containing a NO donor / adduct can also be adhered to the surface as a coating or film using an adhesive that does not interfere with NO generation.

[0084] In yet another example, the moisture, hydrating liquid, or photo - activated NO - generating formulation can be made into a solid of any suitable shape or size, such as pellets, tablets, disks, etc., by molding / forming / pressing, etc. In some examples, the formed solid may be up to about 50 mm in diameter x about 25 mm thick. In one example, the formed solid may be about 5 mm in diameter x about 25 mm in length. Sizes exceeding 50 mm x 25 mm may be undesirable in some cases because the surface area - to - volume ratio is a criterion to be considered in conjunction with the water supply tendency. The weight of the shaped solid may be from about 0.1 gram to about 5.0 grams, or from about 0.2 gram to about 0.5 gram.

[0085] In one example, the NO generating formulations 10, 10’ include a single molded solid (i.e., the components of the moisture-activated type formulation (e.g., each of RSNO, binder, additive) are present within a single pellet, unlike a two-component system). An example of the NO generating formulation 10 shown in FIG. 1A is in the form of two molded single pellets, each of these pellets including a plastic sheath (the plastic sheath may be added if desired for mechanical rigidity to reduce pellet fragility). Another example of the NO generating formulation 10 shown in FIG. 1B is in the form of a molded single pellet without a plastic sheath. In one example, the plastic sheath is polyethylene. An example of the sheath manufacturing method is to insert the shaped pellet into polyethylene and then fix the pellet in place by rupturing the sheath with a needle. The sheath may be of any suitable thickness as desired, for example about 150 μm thick.

[0086] Needless to say, one or more single pellets can be used together with a container and / or an inhalation device to provide a desired amount of gaseous NO.

[0087] By returning the solid and powder forms of the NO generating formulation containing the NO donor / adduct to a hydrating liquid, such as deionized water or purified water, an example of the liquid form of the NO generating formulation is generated.

[0088] Instead of the NO donor / adduct described herein, other examples of NO generating formulations include an acidic buffer and nitrite that generates NO molecules when exposed to a pH of 4.1 to 7.5. The nitrite can be maintained in a solid form (e.g., as a powder) or in an aqueous solution (e.g., dissolved in water) until it is desired to generate NO.

[0089] The powder form of this example of the NO generating formulation may include nitrite alone or in combination with an additive and / or an oxygen scavenger.

[0090] The nitrite may be any water-soluble inorganic nitrite. Some water-soluble inorganic nitrites include alkali metal and alkaline earth metal nitrites. Specific examples include nitrites of Li (lithium), Na (sodium), K (potassium), Rb (rubidium), Ca (calcium), and Mg (magnesium). Most other metal salts are also soluble in water, such as Al (aluminum) salts and Fe (iron) salts. One specific example of a nitrite is NaNO 2 is.

[0091] The nitrite may be present in the powder formulation in an amount of up to 75 wt%. Upon dissolution, the maximum nitrite concentration depends on the solubility of the salt. For example, the solubility limit of sodium nitrite is 12 mol / L at 25 °C, and the solubility limit of potassium nitrite is 36.7 mol / L at 25 °C. The lower limit of the dissolution range may be 10 μmol / L. In some examples, the recycled solution is 8 mol / L of NaNO 2 and 13 mol / L of KNO 2 contains.

[0092] Any example of an additive that is a reducing agent may be included. In one example, the additive is an ascorbate or ascorbic acid. In this formulation, the additive can reduce NO 2 generation.

[0093] Oxygen can be removed (NO can be generated by reacting with NO 2 ), and thus an oxygen scavenger that can reduce the amount of NO 2 generation may be used. An example of a suitable oxygen scavenger is sodium metabisulfite, hydrazine, carbohydrazide, tannin, diethylhydroxyamine (DEHA). The oxygen scavenger may be included in an amount of about 10 wt% or less.

[0094] In this example, nitrite, which is used alone or in combination with an additive and / or an oxygen scavenger, can be maintained in powder form until it is desirable to reconstitute the powder with an acidic buffer to produce a liquid form of the NO generating agent NO. The pH of the liquid form of the NO generating agent NO is greater than 4 to 7.5. The acidic buffer can be a moderate acid that can acidify the nitrite to generate NO. In one example, the acidic buffer is a monobasic and / or dibasic phosphate. Other examples of acidic buffers are monocitric acid, dibasic citric acid, acetic acid, bis-tris (2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol), MOPSO (β-hydroxy-4-morpholinepropanesulfonic acid), PIPES (1,4-piperazinediethanesulfonic acid), BES buffered saline, MOPS (3-(N-morpholino)propanesulfonic acid), TES (2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid), HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid), DIPSO (3-(N,N-bis[2-hydroxyethyl]amino)-2-hydroxypropanesulfonic acid), TRIZMA® (2-amino-2-(hydroxymethyl)-1,3-propanediol), maleate, or cacodylate.

[0095] In another example, a kit is used to produce a liquid form of a NO generating agent (including nitrite). One example of the kit includes a first solution containing nitrite in water and also includes a second solution containing an acidic buffer and an additive. Any example of nitrite can be used in the first solution. Any example of an acidic buffer and an example of an additive can be used in the second solution.

[0096] In this example, the first solution and the second solution can be maintained separately until it is desirable to generate NO. When combined, the first solution and the second solution form a liquid form of the NO generating agent NO. The pH of this example of the liquid form of the NO generating agent NO is also greater than 4 to 7.5.

[0097] Other kit examples include a powder formulation and a reconstitution solution. The powder formulation and the reconstitution solution can be maintained separately until it is desired to generate NO. When combining, the powder formulation and the reconstitution solution are mixed to form a liquid form of the NO-generating agent NO. In one example, the powder formulation includes an NO donor / adduct (and in some cases a hydrophilic binder), and the reconstitution solution includes a hydrating solution and an additive. In another example, the powder formulation includes a nitrite (and in some cases an oxygen scavenger), and the reconstitution solution includes an acidic buffer and a reducing agent additive.

[0098] In any of the NO-generating agents, a solid (such as a pellet / tablet / disk, etc.), or a reconstituted liquid (such as a pellet, tablet, or powder in a hydrating solution, or a liquid form containing nitrite and an acidic buffer) can be used within the system over a predetermined period of time (e.g., it can be informed to the user that NO at "x" ppm will be generated over "y" hours). Then, the user can be instructed to replace the pellet or introduce fresh liquid. In a further example, a NO detector can be used to indicate when the NO-generating agent no longer produces the expected amount of NO. In a further example, when the NO-generating agent no longer produces the expected amount of NO, the formulation can be made to dissolve the solid.

[0099] Container

[0100] Several different containers are considered here. Some container examples function as an outer package. The outer package protects the NO-generating agent from premature water vapor and / or light exposure and / or premature hydration, and this can be removed before use. Other container examples function to contain the NO-generating agent during use (and thus can be NO-permeable). In some of the examples disclosed herein, a container having the NO-generating agent is held inside an outer package container before use. Several different containers are described below.

[0101] Any NO-generating formulation disclosed herein may be contained within an outer package, such as foil, a plastic pouch (e.g., biaxially oriented polyethylene terephthalate, e.g., commercially available MYLAR®). This type of outer package serves to hermetically seal the NO-generating material from moisture and light. This can affect the efficacy and time-release characteristics of the NO-releasing formulation, as well as its shelf life. In some examples, the outer package hermetically seals the solid form of the NO-generating formulation. In these examples, the user will remove the solid NO-generating formulation in the form of pellets, disks, or tablets from the outer package prior to use. In some examples, the outer package hermetically seals a pouch or other holder containing the NO-generating formulation. In these examples, the NO-permeable pouch or holder will be removed from the outer package prior to use. In some instances, the outer package hermetically seals the powder of the NO-generating formulation. In these instances, when the outer package is opened, the powder can, in some cases, be hydrated or exposed to an acidic buffer inside the outer package itself. In yet another example, the outer package may be a single container having two chambers. One of these chambers is for the NO-generating formulation and the second chamber is for the hydrating liquid or acidic buffer. The components of the two chambers can be mechanically forced to blend with each other. Such a container can also have a hole or membrane for NO to escape after mixing. In yet another example, the outer package hermetically seals an absorbent pad that is coated with or contains the NO-generating formulation. In these examples, the absorbent pad is removed from the hermetically sealed outer container for moisture and / or liquid activation. Yet another approach is to supply the NO-generating formulation within a pre-mixed ampule. The ampule can be opened and poured into a device such as that shown in FIG. 26.

[0102] Other container examples function to contain the NO-generating formulation during use (and can thus be NO-permeable). A suitable container example is a pouch.

[0103] The NO-permeable container may be a woven or non-woven material (e.g., cloth, fabric, etc.). In some examples, the NO-permeable container is a rigid shell made of plastic, metal, or another material that does not interfere with NO generation and does not absorb / adsorb the generated NO. In one example, the NO-permeable container is selected from the group consisting of a woven material, a non-woven material, a plastic material, and a metal material.

[0104] The NO-permeable container may be porous. The pores may be nanopores (e.g., having a diameter of about 1 nm to less than 1000 nm), or micropores (e.g., having a diameter of about 1 μm to less than 1000 μm).

[0105] If the NO-generating agent is sensitive to water vapor, the container may be permeable to humid air and NO. This type of container allows humid air to contact the nitrogen oxide generating agent and allows the generated gaseous NO to be released from the container. Examples of materials suitable for air·NO permeable containers include polyethylene, polyamide, polytetrafluoroethylene (PTFE), polypropylene, polyvinylidene difluoride, and the like.

[0106] If the NO-generating agent is photosensitive, the container may be transparent to blue and / or UV light and NO-permeable. NO-permeable and optically transparent materials for the container include polycarbonates, such as polycarbonate track-etched membranes. Commercially available NO-permeable and optically transparent materials include WHATMAN® NUCLEPORE® Track-Etched Membranes (GE Healthcare) and TRAKETCH® (Sabeu). These membranes may be nanoporous (e.g., having a diameter of about 1 nm to less than 1000 nm), or microporous (e.g., having a diameter of about 1 μm to less than 1000 μm).

[0107] Some examples of NO-permeable containers include an attachment mechanism. The attachment mechanism can be used to fix the NO-permeable container (and the NO-generating preparation inside the container) inside or outside an inhalation device or another housing. Some examples of the attachment mechanism are shown in FIGS. 21-23.

[0108] In FIG. 21, the container 32 is a pouch, and the attachment mechanism includes an adhesive 42 covered by a release liner 44. The adhesive 42 is positioned on one surface of the container 32, and the release liner 44 covers the adhesive 42 until it is removed by the user. An example of the adhesive is a pressure-sensitive adhesive or a double-sided adhesive. When the release liner 44 is removed, the adhesive 42 can fix the container 32 inside an inhalation device such as a face mask 12 as shown in FIG. 22.

[0109] Another example of the attachment mechanism is a clip. The clip 46 is schematically shown in FIG. 23. A part of the clip 46 is attached to the container 32 (for example, a pouch), and another part of the clip 46 is attached to an inhalation device such as a face mask 12. Although the clip 46 is shown, it goes without saying that other mechanical attachment mechanisms can be used instead of the clip. Examples thereof include hooks, clamps, pins, or the like.

[0110] The container 32 can be prepared using any suitable method including a molding method, a 3D printing method, etc.

[0111] Some examples of the container 32 further include a filter located on the surface of the container 32 or positioned outside the container 32. The filter includes an absorbent for scavenging nitrogen dioxide (NO 2 ) released by the NO-generating preparation, a reagent for changing the generated NO 2 back to NO, or a combination thereof. In some examples, the filter is a nitrogen dioxide (NO 2 ) filter. NO 2The filter may be positioned to receive the output gas NO before it is inhaled by the patient. In some examples, NO 2 The filter may be positioned outside of the container 32 on a surface that will face the user's mouth and / or nose. In some NO 2 filter examples, at least some of the nitrogen dioxide is removed from the NO gas. By way of example, a silica gel filter (having pre-conditioned silica particles) or a soda lime scrubber can be used as the NO filter. These filters can reduce NO to physiologically non-relevant levels. Other NO 2 filters. 2 filter examples convert nitrogen dioxide back to nitric oxide. This conversion is desirable because the NO payload is not lost in the form of scavenged (absorbed) NO and is returned to NO by reduction. An example of this type of NO 2 filter is silica particles impregnated with ascorbic acid. 2

[0112] Inhalation device

[0113] In some examples, the nitric oxide (NO) generation system further includes an inhalation device in operative contact with the NO generating agent. Examples of inhalation devices include face masks, nasal cannulas, nose pillows (also referred to as "nasal vent plugs"), and ventilators.

[0114] In one example of the NO generation system, the inhalation device includes the face mask 12. FIGS. 2-7 show various examples of suitable face mask configurations. FIGS. 22-24 also show various examples of suitable face mask configurations. The examples shown in FIGS. 22-24 also include various different container 32 examples. In some of the face mask 12 examples, the NO generating agents 10, 10' are manufactured separately and then introduced into the face mask 12. In other face mask examples, the NO generating agents 10, 10' can be manufactured as part of the face mask.

[0115] ​A face mask 12 (also known as a filtering respirator) can be used to protect the respiratory system from particles or chemicals. The face mask 12 can be configured to minimize the spread of infectious diseases or to protect the respiratory system from toxic substances or allergens in the ambient atmosphere. Additionally, the face mask 12 can be used to protect against inhalation of industrial or urban dust or dirt, chemicals, allergens, etc. that may be present in the air. Using the face mask 12, a closed space can be maintained around the breathing orifices when a person is in close proximity to others or when undesirable airborne substances are present. Additionally, by wearing the face mask 12, an infected person can protect others who are near the pathogen. Needless to say, the face masks disclosed herein are described in the context of humans, but compatibility with the anatomical features of any respiratory organ is also contemplated and disclosed herein. For example, the face mask can be adapted for dogs, cats, and horses.

[0116] In one example, the NO generating agents 10, 10' can be arranged (e.g., in the form of solid disks, pellets, etc.) without being fixed or attached inside the face mask. In this example, the NO generating agents 10, 10' are left loose inside the face mask 12. In some embodiments, the NO generating agents 10, 10' are contained inside a NO permeable container 32, and the NO permeable container 32 can be arranged without being fixed or attached inside the face mask 12.

[0117] In another example, the face mask 12 includes a housing 14 (Figs. 2A - 2C and 3A - 3C) for effectively holding the NO generating agents 10, 10' in close proximity to at least one of the user's mouth or nose. Figs. 2C and 3C show the face mask 12 positioned at a predetermined location on the user's face and also show the NO generating agents 10, 10' (Figs. 2A - 2C and 3A - 3C) effectively in close proximity to at least one of the user's mouth or nose.

[0118] In the examples shown in FIGS. 2A - 2C and 3A - 3C, the housing 14 selectively opens and closes. FIGS. 2A and 3A show the door of the housing in the open position (e.g., used to introduce the NO - generating agents 10, 10' into the face mask 12), and FIGS. 2B and 3B show the door of the housing 14 in the closed position (e.g., used when it is desirable to introduce NO gas to the user).

[0119] The open configurations shown in FIGS. 2A and 3A show four single solid pellets / tablets provided within the door of the housing 14. Each individual single solid pellet / tablet is an example of the NO - generating agents 10, 10'. As such, the NO - generating agents 10, 10' include a single solid. Needless to say, any number of single pellets / tablets that generate the desired level of NO gas at a given time can be used as the NO - generating agents 10, 10'. As such, when a number of single solid pellets / tablets are used together, the multiple single solids may be collectively referred to as the NO - generating agents 10, 10'. In some examples in this case, the NO - generating agents 10, 10' include multiple single solids.

[0120] In the examples shown in FIGS. 2A and 3A, each single pellet / tablet (e.g., the NO - generating agents 10, 10') may be snap - fastened in a predetermined location of the door of the housing 14. In other examples, each single pellet / tablet (e.g., the NO - generating agents 10, 10') can be slid into each receptacle defined within the door of the housing 14. Other suitable mechanisms can also be used to hold the single solid form of the NO - generating agents 10, 10' within the housing 14.

[0121] Although the door is shown as being able to pivot about an existing hinge, it goes without saying that the door of the housing may be formed / designed to selectively open and close by any suitable type of motion, such as pivoting, sliding, flipping, etc. It goes without saying that the housing 14 shown in FIGS. 2A-2C and FIGS. 3A-3C is an example, and any suitable attachment structure or device may be used as the housing 14. For example, the housing of the face mask 12 may include a flap or pouch (inside or outside). The flap or pouch may be capable of receiving and holding the NO generating agents 10, 10'.

[0122] In the example of the face mask inhalation device (face mask 12) shown in FIG. 3A, the housing 14 further includes an air humidifier 22 in operative contact with the NO generating agents 10, 10' (RSNO tablets / pellets), an air pump 20 in fluid communication with the air humidifier 22, and a power source (shown as battery 24 in the figure) operatively connected to the air humidifier 22 and the air pump 20. As shown in FIG. 3A, the housing 14 has an air inlet 18 defined therethrough. The air pump 20 may be connected to the air inlet so as to transport any water vapor generated by the air humidifier 22 through the air inlet 18 and thus near the NO generating agents 10, 10'. It goes without saying that "fluid communication" should be construed broadly and includes, for example, liquids and gases.

[0123] As shown in FIG. 3B, the air humidifier 22 and the air pump 20 are small enough to be mounted on or within the housing 14. The power of the battery 24 may be sufficient to operate both the air humidifier 22 and the air pump 20, or separate batteries 24 may be operably connected to the air humidifier 22 and the air pump 20. The air humidifier 22 can be used in any of the examples disclosed herein to generate moisture (e.g., water vapor) regardless of the presence or absence of moisture from the user's exhalation. The air pump 20 can be used to transport the generated water vapor near the NO generating agents 10, 10', and can also transport the generated NO gas to the user.

[0124] No further examples of the face mask inhalation device are shown, but are similar to the system example shown in FIG. 8. In this example, the face mask inhalation device includes an air pump 20 operably connected to the face mask 12, an air humidifier 22 in fluid communication with the air pump 20, and a container 32 for holding the NO generating agents 10, 10', the container 32 being in fluid communication with the air humidifier 22 and the face mask 12. In yet another example, the inhalation device includes a gas mixer in fluid communication with the container, a second air pump operably connected to the gas mixer, a NO sensor operably connected between the gas mixer and the face mask, and a feedback controller operably connected to the NO sensor and the gas mixer. This example is similar to the system shown in FIG. 8 except that the nasal cannula 34 (FIG. 8) is replaced with the face mask 12. In this example, the face mask 12 may not have a housing 14 and may have an adapter for attaching a conduit (e.g., a tube) that is also in fluid communication with the container 32.

[0125] In yet other examples, the housing 14 of the face mask 12 may be formed to receive and contain a liquid that generates NO gas. In some examples, the housing 14 at least partially defines a reservoir. The reservoir is adapted to receive a predetermined volume of a hydrated solution in which the NO generating agents 10, 10' are dissolved (or dispersed). In these examples, the solid NO generating agents 10, 10' can be mixed with a defined / predetermined volume of water and then the spent solution can be poured into the housing 14. In another example, the housing 14 at least partially defines a reservoir. The reservoir is adapted to receive a predetermined volume of a liquid form of the NO generating agent in which nitrite is dissolved in an acidic buffer. In some of these examples, a powder containing nitrite can be mixed with a defined / predetermined volume of the acidic buffer and then the spent solution can be poured into the housing 14. In other ones of these examples, an aqueous solution of nitrite can be mixed with the acidic buffer and then the mixed solution can be poured into the housing 14. In yet other examples, the housing may contain an absorbent. The absorbent can be coated with the NO generating agent or can hold the liquid form of the NO generating agent.

[0126] One of these examples is shown in FIG. 26. In this example, the housing 14 partially defines a reservoir 60 and includes a reservoir wall 62 or a filter 64 positioned between the interior of the face mask 12 and the interior of the reservoir 60. The reservoir wall 62 or the filter 64 may be made of a porous NO-permeable material, such as polyurethane, poly(tetrafluoroethylene), etc. The reservoir wall 62 or the filter 64 made of this type of material allows NO gas to penetrate through it (e.g., penetrate into the face mask 12), but also resists leakage of the hydration liquid containing the solid NO generating agents 10, 10' or other examples of acidic buffer solutions in the liquid form of the NO generating agent. In other words, the reservoir wall 62 or the filter 64 is impermeable to the hydration liquid or the acidic buffer solution and is NO-permeable. As such, the reservoir wall 62 or the filter 64 allows the NO gas generated inside the reservoir 60 to be inhaled by the user without allowing the liquid to escape. When the filter 64 is positioned between the interior of the face mask 12 and the interior of the reservoir 60, the filter 64 may include an absorbent for scavenging nitrogen dioxide (NO 2 ) released by the NO generating agent, a reagent for converting the generated NO 2 back to NO, or a combination thereof.

[0127] In these examples, the housing 14 may include a sealable input port 66 that is not movable between an open position and a closed position (as shown, for example, in FIGS. 2A and 2B). At the input port, liquid can be introduced into the reservoir 60. A removable cap 68 can be used to seal the sealable input port 66.

[0128] Although not shown in FIG. 26, this example may further include an absorbent material within reservoir 60. The absorbent material absorbs liquid (e.g., a hydrated solution of an acidic buffer), but allows NO gas to exit the material and pass through reservoir wall 62 or filter 64. Examples of absorbent materials that may be included within reservoir 60 include cotton balls or compressed cotton, or similar materials that do not affect the production of NO. In these examples, a sealable input port 66 may be formed as a larger opening or door for introducing an absorbent pad and an example of a liquid form of the NO generating agent, or for introducing the NO generating agent and an activating liquid (e.g., water or an acidic buffer).

[0129] The reservoir 60 of FIG. 26 can also receive a container 32 containing solid NO generating agents 10, 10'.

[0130] Another configuration not shown in FIG. 26 is to use a fan for blowing NO generated by the NO generating agent from the reservoir and towards the user of the inhalation device.

[0131] Also not shown in FIG. 26, but of course this example device may include an additional filter. The additional filter contains a reagent or catalyst for converting any NO 2 to NO. By positioning this filter between reservoir wall 62 or filter 64 and the interior of face mask 12, NO 2 is prevented from reaching the user.

[0132] The example shown in FIG. 26 may include a diverter valve (not shown). The diverter valve channels exhalation from the device (e.g., face mask 12) without interacting with reservoir 60 containing the NO generating agent. The configuration of this valve allows inhalation to pass through the NO generating system and into the user's mouth and nose.

[0133] The example shown in FIG. 26 may include a chamber (fluidly connected to reservoir 60). In the chamber, NO released through the diverter valve can be accumulated during apnea and expiration times. Then, during inspiration, the stored NO becomes available as a pulsed concentration.

[0134] In any of the examples of face mask 12 that can receive a returned solution or dispersion (e.g., a hydrating solution containing NO generating agents 10, 10'), or in another example of a liquid form of the NO generating agent, housing 14 (and thus reservoir 60) may be integrally formed with face mask 12, or may be a separate housing 14 attached to face mask 12.

[0135] The examples shown in FIGS. 4 - 7 illustrate several additional forms for incorporating NO generating agents 10, 10' into face mask 12. FIGS. 4A and 4B show another example of how a plurality of single pellets / tablets of NO generating agent 10 can be arranged within housing 14. In this example, housing 14 may include individual receptacles for single pellets / tablets of NO generating agent 10. Alternatively, a single pellet / tablet of NO generating agent 10 may be secured to a cap ring that can be inserted into housing 14.

[0136] The configurations of FIGS. 5 - 7 also include check valves, such as an inhalation check valve 16 (FIGS. 2A - 2C and 5), an exhalation check valve 16' (FIG. 6), or both an inhalation check valve 16 and an exhalation check valve 16' (FIG. 7). Check valves 16, 16' can help prevent exhaled air from returning into NO generating agents 10, 10' because exhaled air can undesirably expel NO gas from the system.

[0137] The examples shown in FIGS. 5 and 7 also show a filter 26. This filter is positioned outside of face mask 12 adjacent to one - way check valve 16. This filter 26 may be an N95 or N99 filter.

[0138] In an example, the face mask 12 includes a filtering face mask. As used herein, a filtering face mask means a mask that covers at least the nose and mouth of the wearer and includes a filter element 19 for removing contaminants and / or particles from the air passing through the filter element 19. As shown in FIG. 4A, the mask body 13 is a filter element 19 molded to fit the contour of the wearer's face. As indicated by the air flow direction arrow 15, the filter element 19 is a two-way filter, and the two-way filter is adapted to filter the air during inhalation and exhalation. As shown in FIG. 4A, the housing 14 is placed through and attached to the mask body 13. As shown in FIGS. 4A and 4B, the NO generating agent 10 is distributed around the aperture 17 defined in the inner wall 21 of the housing 14. In the example shown in FIG. 4A, the outer wall 23 of the housing 14 may be made of the above-mentioned porous NO-permeable material. In another example, the outer wall 23 of the housing 14 may be made of a porous NO-impermeable material. As shown in FIG. 5, when the inhalation check valve 16 opens, air is allowed to flow through the outer wall 23 of the housing 14 in the inhalation direction. When the inhalation check valve 16 closes, it blocks the passage of air through the outer wall 23 of the housing 14 in the exhalation direction opposite to the inhalation direction. As shown in FIG. 5, a filter 26 may be connected to the housing 14 to filter the air before the air passes through the inhalation check valve 16. This filter 26 may have any desired filtering characteristics. For example, the filter 26 may be an N95 filter or an N99 filter. It is recognized that the filter 26 operates in parallel with the filter element 19. Therefore, the flow characteristics of the filter 26 and the filter element 19 are interdependent. For example, if it is extremely easy to draw air through the filter element 19 compared to the filter 26, most of the air will take the minimum resistance path through the filter element 19.

[0139] The example shown in FIG. 6 is similar to the example shown in FIG. 4B where the exhalation check valve 16' is attached on the mask body 13. When the exhalation check valve 16' opens, it enables air to flow through the mask body 13 in the exhalation direction 26. When the exhalation check valve 16' closes, it blocks air from passing through the check valve 16' in the inhalation direction opposite to the exhalation direction 27. Thus, the exhalation check valve 16' allows at least a part of the exhaled air to bypass the filter element 19, thereby reducing, for example, the moisture that may accumulate in the internal space 20 partitioned by the face mask 12 and the wearer's face 31 (see, for example, FIG. 3C). As shown in FIG. 7, the present exemplary embodiment may include a combination of an inhalation check valve 16 having the filter 26 shown in FIG. 5 and the exhalation check valve 16' shown in FIG. 6.

[0140] Referring now to FIG. 8, another example of an inhalation device includes an air pump 20, an air humidifier 30 (hydrator) in fluid communication with the air pump 22, a container 32 for holding a NO generating agent 10 (shown as some RSNO pellets / tablets inside the canister), where the container 32 is in fluid communication with the air humidifier 2230, the container 32 (e.g., canister), and a nasal cannula 34 (or a ventilator (not shown)) in fluid communication with the container 32. This example includes the form shown on the upper side of FIG. 8 but without a gas mixer 36 or a NO sensor 38. However, it goes without saying that the NO sensor 38 can also be used in this form if desired.

[0141] In another example, the inhalation system further includes a gas mixer 36 in fluid communication with the container 32, a second air pump 20' (shown on the lower side of FIG. 8) operably connected to the gas mixer 36, a NO sensor operably connected between the gas mixer 36 and the nasal cannula 34 (or ventilator), and a feedback controller 40 operably connected to the NO sensor 38 and the gas mixer 36.

[0142] The second air pump 20' introduces the oxygen-containing gas into the gas mixer. Here, by mixing the oxygen-containing gas with NO gas, an output gas is formed that is transported to the inhalation device (for example, nasal cannula 34, or in other examples, face mask 12 or ventilator). The oxygen-containing gas may be at least substantially pure oxygen gas O 2 , or air, or a hypoxic gas containing oxygen. Although the air pump 20' is shown in FIG. 8, the oxygen-containing gas may be delivered from any suitable gas source (for example, a compressed gas cylinder (not shown)). This gas source can control the flow rate of the oxygen-containing gas, or can be connected to a flow controller so as to control the inflow rate of the oxygen-containing gas into the gas mixer. Any suitable gas flow rate can be used. As an example, the flow rate of the oxygen-containing gas may be from about 50 mL / min to about 5 L / min. In another example, the flow rate of the oxygen-containing gas may be controlled such that the output gas stream contains from about 20% oxygen to about 99.99% oxygen. In one example, 100% air saturation can be used as the oxygen-containing gas. This corresponds to about 10 mg / L (ppm) of O 2 in the output gas stream.

[0143] Needless to say, the NO sensor 38 can be used to monitor the NO level in the output gas stream from container 32 (or from gas mixer 36 if present in the system). NO 2 (nitrogen dioxide. This can sometimes be generated from the reaction of O 2 with NO and may not be desirable for the recipient / patient) is desirable to monitor the NO level to avoid the formation of. Any suitable NO sensor 38 can be used.

[0144] In one example, the NO sensor 38 is a Shibuki style sensor (not shown). This sensor is based on the oxidation of NO to nitrate (NO 3 - ) at the position of the inner platinum (Pt) electrode behind the gas permeable membrane.

[0145] Another example of the NO sensor 38 is an amperometric NO sensor that exhibits a relatively rapid response time, and the large surface area of the working electrode produces a greater current than the Shibuki configuration.

[0146] Some examples also include a NO 2 sensor. The NO 2 sensor can be used to monitor the NO 2 level in the output gas stream from the container 32 (or from the gas mixer 36 if present within the system).

[0147] For example, the NO sensor data (i.e., the NO concentration in the output gas stream and / or the NO 2 concentration) can be used by the feedback controller 40 to control the system to obtain at least a substantially constant NO concentration at the delivery end.

[0148] The target NO level may be based on a given application in which NO is used. The target level may be extremely low or extremely high depending on the patient and the application. As an example, the target NO level for a newborn receiving inhaled therapy may be from about 10 ppm to about 70 ppm, and the target NO level to be generated to prevent platelet and other cell activation during bypass surgery may be from about 190 ppm to about 210 ppm. Further, for example, in antibacterial applications for lung infections, lower NO levels, such as levels from about 500 ppb to about 10 ppm, may be useful during inhaled therapy.

[0149] As described above, the sensor data can also be used to determine whether an undesirable amount of NO 2 is present in the output gas stream. If an undesirable amount of NO 2 is present, an alarm for the system can be activated. Further, immediately before the output gas stream is delivered to the patient via the nasal cannula 34, face mask 12, nasal vent plug (see FIGS. 25A - 25C), or ventilator (not shown), a soda lime scrubber or other NO 2It can include a scavenger. When the content rate exceeds 1 ppm to 3 ppm in the final gas phase, the soda lime scrubber can remove excess NO 2 .

[0150] In other examples similar to FIG. 8, a reservoir of a hydrating liquid (e.g., water) can be provided instead of the air humidifier 22. The reservoir can be formed to introduce a defined / predetermined volume of the hydrating liquid into the container 32 and thus bring it into contact with the NO generating agents 10, 10' contained therein. Inside the container 32, the hydrating liquid activates NO gas generation. In some examples, the NO generating agents 10, 10' are configured to release a defined volume of NO gas when it is mixed with the defined hydrating liquid. The NO gas can then be transported to the gas mixer 36. In the gas mixer, the NO gas is mixed with the oxygen-containing gas and delivered to the patient. In these examples, since the reservoir is refillable, fresh hydrating liquid can be introduced. In addition, since the container 32 is refillable, the used liquid can be removed and, after the NO gas generation cycle is carried out, fresh solid pellets / tablets of the NO generating agents 10, 10' can be introduced.

[0151] In still other examples similar to FIG. 8, a reservoir of acidic buffer solution (with or without additives and / or an oxygen scrubber) can be provided instead of the air humidifier 22. The reservoir can be configured to introduce a defined / predetermined volume of acidic buffer solution into the container 32 and thereby bring it into contact with the nitrite (in powder or aqueous solution form) contained therein. Inside the container 32, the acidic buffer solution acidifies the nitrite and activates NO gas generation. In some examples, the acidified nitrite is configured to release a defined volume of NO gas, for example, from about 1 ppm to about 250 ppm. The NO gas can then be transported to the gas mixer 36. In the gas mixer, the NO gas is mixed with the oxygen-containing gas and delivered to the patient. In these examples, since the reservoir is refillable, fresh acidic buffer solution can be introduced. Additionally, since the container 32 is refillable, the used solution can be removed and fresh nitrite (in powder form or aqueous solution form) can be introduced after the NO gas generation cycle has been carried out.

[0152] Although the face mask 12 and nasal cannula 34 are shown as examples of inhalation devices, it goes without saying that, in accordance with the examples of the present disclosure, a ventilator or any other device suitable for delivering an output gas stream to the airway of a user / patient can also be used.

[0153] In some examples, the NO generating agents 10, 10' are contained within an example of the container 32, and the container 32 is introduced into the inhalation device. In some examples, the container 32 may simply be placed inside the inhalation device. In other examples, such as those shown in FIGS. 21 and 22, the NO permeable container 32 is attached to the inhalation device via an attachment mechanism. In each of these examples, the inhalation device is the face mask 12.

[0154] In the example shown in FIG. 22, the inner surface of the face mask 12 contacts the adhesive 42 (after the liner 44 is removed) and holds the container 32 inside the face mask 12. The container 32, and thus the NO generating agent (activated by moisture in this example), is held in effective proximity to at least one of the user's mouth or nose.

[0155] In the example shown in FIG. 23, the inner surface of the face mask 12 includes a receiving portion. The receiving portion can secure the clip 46, and thus the container 32, to the face mask 12. Through the clip 46, the container 32, and thus the NO generating agents 10,10' (activated by moisture in this example), are held in effective proximity to at least one of the user's mouth or nose.

[0156] In the examples shown in FIGS. 22 and 23, the user's breath delivers sufficient moisture to release gaseous NO drawn into the nose and mouth during normal breathing. However, these examples can also include an air humidifier 22 and an air pump 20.

[0157] In other examples, the stable NO donor / adduct is activatable by blue light or ultraviolet (UV) light, and the NO generating system further includes a blue light source or a UV light source 50 positioned to illuminate the NO generating agents 10,10'. In some examples, the NO generating agents 10,10' and the blue light source or the UV light source 50 are positioned on or within an inhalation device in a configuration that effectively illuminates the NO generating agents 10,10' to produce nitrogen oxide.

[0158] FIG. 24A shows an example of a photoactivatable NO generating system 47 inside an inhalation device (e.g., face mask 12). In some examples, the photoactivatable NO generating system 47 includes NO generating agents 10,10' contained inside a pouch (or other container 32). The pouch is NO permeable and transparent to blue light and / or UV light. In other examples, the NO generating agents 10,10' may be chemically or physically attached to the inner wall of the housing 48 (without a container 32).

[0159] An example of the system 47 shown in FIG. 24A also includes a housing 48 to which a NO-permeable container 32 is attached, a blue or UV light source 50 positioned inside the housing 48 to illuminate the NO container 32, and a battery 24 operably connected to the blue or UV light source 50.

[0160] The housing 48 of the photoactivation-type NO generation system 47 can hold various components and allows the generated NO gas molecules to be released into the interior of the face mask 12 for inhalation by the user / patient. Although the example shown in FIG. 24A includes a housing 48 for a NO-permeable container (containing the NO generation agents 10, 10'), it goes without saying that the NO generation agents 10, 10' may alternatively be coated as a film on the surface of the inhalation device. In these examples, the coating / film of the NO generation agents 10, 10' will be adhered to the inner surface of the inhalation device, and the blue or UV light source 50 will be positioned inside the inhalation device to illuminate the coating / film.

[0161] Any blue or UV light source 50 can be used as long as it can emit light that initiates the photolysis of the solid photosensitive NO donor / adduct. In other words, any light source 50 can be used as long as it can emit light of a specific wavelength that releases nitric oxide from the NO donor / adduct. As such, the light source 50 can depend on the NO donor used and the desired NO release rate. Examples include that the light source 50 may be a high-intensity light-emitting diode (LED), a laser diode, a lamp, etc. In one example, the blue or UV light source 50 is a light-emitting diode. Suitable LEDs may have a nominal wavelength of, for example, about 340 nm to about 520 nm, such as 340 nm, or 385 nm, or 470 nm, or 500 nm. In one example, the blue or UV light source 50 emits light of a light wavelength of about 300 nm to about 520 nm at various intensities.

[0162] One or more light sources 50 can be used to release NO from the NO donor / additive. When multiple light sources 50 are used, the NO release amount can be further controlled. For example, if a higher NO level is desired, all of the light sources 50 (or the coating / film of the NO-donating formulation) facing the container 32 can be activated to emit light towards the NO donor / additive, and if a lower NO level is desired, a number of light sources less than all of the light sources 50 may be activated. In some examples, the NO-generating formulations 10, 10' are configured to release a defined volume of NO gas when exposed to light wavelengths of approximately 300 nm to approximately 520 nm at various intensities.

[0163] In some examples, the system 47 further includes a control electronic element 52 operably connected to a blue light source or a UV light source 50, and a battery 24 operably connected to the control electronic element 52. The battery 24 may be a coin battery or other power source suitable for the light source 50 and the control electronic element 52.

[0164] Some examples of the system 47 further include a NO sensor 38, a nitrogen dioxide (NO 2 ) sensor, or a combination thereof.

[0165] The example shown in FIG. 24A includes a NO sensor 38 positioned within the housing 48 and a control electronic element 52 positioned within the housing 48. An electronic circuit (e.g., the control electronic element 52) can be operably connected to the light source 50 to control the on-cycle time, intensity, output surface density, etc. when the light source 50 is turned on and off. In one example, the control electronic element 52 controls the output of the light source 50 to generate a defined volume of NO gas.

[0166] The control electronic element 52 may be part of a sensing / feedback system. The sensing / feedback system includes the NO sensor 38 and a feedback controller 40 (not shown in FIG. 24A). The sensing / feedback system is NO 2It may include a sensor (not shown in FIG. 24A). Using the feedback from the NO sensor 38 and the NO 2 sensor, at least a substantially constant NO concentration can be obtained at the delivery end by servo-controlling one or more parameters of the light source 50.

[0167] Although the photoactivated NO generation system 47 of FIG. 24A is shown as being mounted inside the face mask 12, it goes without saying that the photoactivated NO generation system of FIG. 24A may be incorporated into other inhalation devices. In one example, the photoactivated NO generation system 47 shown in FIG. 24A is separate from the inhalation device and in fluid communication therewith. In these examples, the photoactivated NO generation system 47 shown in FIG. 24A includes a tube having a first end fluidly connected to a housing 48 and an adapter provided at a second end of the tube distal to the first end, the adapter being adapted to be attached to the face mask 12, the nasal cannula 34, or the breathing tube (or ventilator). In this example, NO gas molecules are generated inside the housing 48 when exposed to blue and / or UV light, and then the NO gas molecules are transported through the tube to the inhalation device and then delivered to the user / patient. These examples may include a fan or suction device for transporting NO from the housing 47 to the adapter. In one specific example, the inhalation device shown in FIG. 8 may be modified to include the photoactivated NO generation system 47. In this specific example, instead of the container 34 and the air humidifier 22 shown in FIG. 8, the photoactivated NO generation system 47 shown in FIG. 24A can be used.

[0168] The tube and adapter are described with the photoactivatable NO generating system 47, but of course these components can equally well be used with the moisture-activatable systems disclosed herein. In some of these examples, an air humidifier 22, an air pump 20, and a power source will be included to introduce an effective amount of water vapor into the housing. The housing contains the container 32 and the NO generating agents 10, 10'.

[0169] When the NO donor / adduct is activatable by light and moisture, it goes without saying that moisture and / or a hydrating liquid and / or UV or blue light 50 can be used to activate the NO donor / adduct in the NO generating agent 10. An example of this hybrid system 70 is shown in FIG. 24B. In this example, the photoactivatable NO generating system 47 (FIG. 24A) can include an additional chamber 72 surrounding the container 32 (which contains the NO generating agents 10, 10'). Since this chamber 72 is liquid-impermeable, any liquid or moisture introduced will not interfere with the components of the photoactivatable NO generating system 47. This chamber 72 includes one wall (facing the light source 50) that is transparent to the emitted UV or blue light and another wall (facing the interior of the inhalation device) that is NO-permeable. The chamber 72 can receive a hydrating liquid. The hydrating liquid can activate the NO donor / adduct or can be operably connected to the air humidifier 22. The air humidifier can introduce sufficient moisture to activate the NO donor / adduct.

[0170] Still other examples of NO generation systems are shown in FIGS. 25A, 25B, and 25C. These system examples include a nasal vent plug or nose pillow. Each of the nasal vent plugs includes a nitric oxide (NO)-impermeable housing 54 having integrally formed walls 55A, 55B, 55C that define a partially enclosed inner portion 57, two nasal protrusions 58 that extend from one of the integrally formed walls 55A and are in fluid communication with the partially enclosed inner portion 57, an air vent 56 defined within another of the integrally formed walls 55C for introducing an air flow into the partially enclosed inner portion 57, and a receptacle 59 within the partially enclosed inner portion 57, the receptacle 59 containing a NO generating agent and being adapted to receive the NO generating agent.

[0171] The nitric oxide (NO)-impermeable housing 54 can be formed from any NO-impermeable material. The materials used to manufacture the housing 54 should not include silicone or other materials known to interact (e.g., absorb) with NO.

[0172] The integrally formed walls 55A, 55B, 55C of the housing 54 and the nasal protrusions 58 can be a single continuous piece of material formed by molding, 3D printing, or the like.

[0173] The nasal vent plug housing 54 includes an inlet vent 56. The vent 56 can be strategically positioned such that air is drawn into one of the nasal protrusions 58 through the NO generating agent. The vent 56 is preferably located on the side (wall 55C) or near the side of the housing 54, as opposed to the top surface of the housing 54. This arrangement can prevent NO from escaping through the vent 56. This arrangement can also help to form a headspace within the enclosed inner portion 57. In the headspace, a NO concentration can be formed during exhalation and during the pause times in the user's natural breathing cycle. The stored NO can then be available as a pulsed aggregate during inhalation (described further below).

[0174] Each vent 56 may operate in conjunction with fins (not shown). The fins are positioned to assist in guiding air through the vent 56 and into the enclosed interior portion 57.

[0175] The nose projection 58 may be shaped to be insertable into a user's nostril or may be shaped to be disposed outside but near the user's nostril. For example, the nose projection 58 may fit snugly just below the user's nostril. In the latter example, the housing 54 may include a head strap 74 (FIG. 25B) to hold the nose projection 58 in a desired position on the user's face. As such, some examples of the NO generation system further include a head strap 74 secured to the housing 54. The housing 54 may include additional holes or another attachment mechanism (such as a hook and loop fastener) for securing the head strap 74. The head strap 74 may be adjustable. Needless to say, the nose projection 58 may be flush with the wall 55A (and thus not a true projection), and the head strap 74 can be used to hold the nasal vent plug adjacent to the user's nostril.

[0176] The nasal vent plug further includes a receptacle 59 within the enclosed interior portion 57. Various different examples of the receptacle 59 are shown in FIGS. 25A - 25C. The receptacle 59 holds a NO generating agent (such as in powder form, liquid form, solid form, etc.) in effective proximity to the air vent 56 and the nose projection 58.

[0177] Specifically referring to FIG. 25A, receptacle 59 is adapted to receive container 32 having a solid form of NO generating agents 10, 10'. In one example, the NO generating agents 10, 10' include a single solid or a plurality of single solids within container 32. Container 32 may be positioned between introduction vent 56 and inhalation opening 58. This positioning allows moisture and / or air from vent 56 and in some cases from the user's exhalation to enter container 32 and activate the NO generating agents 10, 10' contained therein. This position also allows the generated NO gas molecules to be inhaled by the user through nasal passage 58.

[0178] During use, the user inhales and exhales through nasal passage 58. Moisture in the inhalation may be sufficient to activate the NO generating agents 10, 10'. In other examples, nasal vent plug housing 54 may include an air humidifier 22 fixed to housing 54, and the air humidifier generates moisture. As shown in FIG. 25A, the system may include a fan (e.g., air pump 20) fixed to housing 54. The fan pushes moisture (from vent 56 or air humidifier 20) towards the NO generating agents 10, 10'.

[0179] In the example shown in FIG. 25A, the NO generating agents 10, 10' include a stable NO donor / adduct that can be activated when exposed to an effective amount of water vapor. The NO generating agents 10, 10' are contained inside the NO permeable container 32, and receptacle 59 includes either a wall for attaching the NO permeable container 32 or a slot for holding the NO permeable container 32. The receptacle wall protrudes into the center of housing 54 and can receive, for example, an adhesive 42 (similar to the example shown in FIG. 22) or snap into a clip 46 (similar to the example shown in FIG. 23). The slot of the spectrum (shown in FIG. 25A) can fix container 32 in a predetermined position.

[0180] In one example, the container 32 is permanently affixed by the receptacle 59, and in another example, the container 32 is removably affixed by the receptacle 59. When the container 32 (and thus the NO generating agents 10, 10') is permanently fixed inside the housing 54 (e.g., via an adhesive 42 or a slot), the entire nasal vent plug may be disposable (e.g., after its useful life has ended). When the container 32 (and thus the NO generating agents 10, 10') is removably fixed inside the housing 54 (e.g., via a slot), the nasal vent plug is reusable. In these examples, a new container 32 (and new NO generating agents 10, 10') can be introduced into the housing 54 and fixed by the receptacle 59.

[0181] When the nasal vent plug is reusable, the housing 54 may further include a door 69 (at the top of the nasal vent plug) defined within one of the integrally formed walls 55C. The door 69 can be moved between a closed position and an open position that allows access to the receptacle 59. An example of the door 69 is shown in FIG. 25B.

[0182] Referring specifically to FIG. 25B here, some examples of the receptacle 59 include a reservoir 60 for receiving the liquid form 73 of the NO generating agent.

[0183] In one of these examples, the system may include a solid form of the NO generating agents 10, 10'. This solid form can be reverted in a hydration solution to generate the liquid form 73 before the liquid form 73 is introduced into the reservoir 60. In this example, the solid form of the NO generating agents 10, 10' includes a stable NO donor / adduct, a hydrophilic binder, and an additive for controlling the NO release rate from the NO donor / adduct after the formulation is exposed to an effective amount of a hydration solution (e.g., water). By adding the hydration solution to the solid form, the liquid form 73 can be generated. The liquid form is then introduced into the reservoir 60 through the door 69.

[0184] In another example of these examples, the system may include a solid form of the NO generating agent 10, 10'. This solid form can be reverted in an acidic buffer to produce the liquid form 73 before the liquid form 73 is introduced into the reservoir 60. In this example, the solid form of the NO generating agent includes a nitrite for generating NO when exposed to an effective amount of an acidic buffer, and an additive for controlling the NO release rate from the nitrite after the agent is exposed to an effective amount of the acidic buffer. In this example, the solid form of the NO generating agent further includes an oxygen scavenger. Such a solid form of the NO generating agent is a powder that can be reverted with an acidic buffer. By adding the acidic buffer to the solid form, the liquid form 73 can be produced. The liquid form is then introduced into the reservoir 60 through the door 69.

[0185] In yet another further example of these examples, the system can include a kit for producing the liquid form 73 of the NO generating agent. The kit includes a first solution containing nitrite in water, and also includes an acidic buffer and a second solution containing an additive for controlling the NO release rate from the nitrite after the agent is exposed to an effective amount of the acidic buffer. In this example, the first solution and the second solution can be mixed with each other and then added to the reservoir 60 / receptacle 59 through the door 69.

[0186] Other examples of the receptacle 59 include a reservoir 60, but may further include an absorbent pad 71 (such as cotton, compressed cotton, etc.). The absorbent pad is either one that is contained within the reservoir 60 and is adapted to be wetted with the liquid form of the NO-generating agent, or one that is wetted with the liquid form of the NO-generating agent and then introduced into the reservoir 60. In some examples, the absorbent pad 71 is incorporated into the reservoir 60, and then any example of the liquid form 73 is incorporated into the reservoir 60. In other examples, the absorbent pad 71 is wetted with any example of the liquid form 73 outside the nasal vent plug and then incorporated into the reservoir 60. In still other examples, the absorbent pad 71 contains the solid form of the NO-generating agent. This solid form can be reverted in a hydration solution or an acidic buffer solution. In this example, the solid form of the NO-generating agent includes S-nitrosothiol (RSNO) powder or nitroprusside, or nitrite. For example, the absorbent pad 71 may include a coating of the powder form of the NO-generating agent, and the absorbent pad 71 with this coating is incorporated into the reservoir 60. In some examples, the solid or powder is poured onto the absorbent pad 71 or placed into the reservoir 60 in front of (and thus under) the absorbent pad 71.

[0187] (Depending on the chemical properties of the NO-generating agent in the coating) The NO donor / adduct or nitrite is activated by then introducing a hydration solution or an acidic buffer solution into the reservoir 60.

[0188] In any of these examples, the absorbent pad 71 can stabilize the liquid form 73 of the NO-generating agent.

[0189] The receptacle 59 which is the reservoir 60 may include a wall that is impermeable to the hydration solution or the acidic buffer solution and is permeable to NO.

[0190] The receptacle 59 / reservoir 60 can be dimensioned such that a headspace is formed within the closed inner portion 57. In the headspace, the released NO can concentrate through an exhalation check valve (i.e., an air diverter valve) (e.g., during the user's apnea and during the time of exhalation). The exhalation check valve redirects the air flow around the closed inner portion 57, thereby allowing a higher concentration of NO to collect in the headspace. Then, during inhalation, the stored NO becomes available as a pulsed aggregate (further described below).

[0191] Specifically referring to FIG. 25C here, some examples of the receptacle 59 can receive a cartridge, such as the photoactivatable NO generation system 47, 70 described in FIGS. 24A or 24B. In this example, the NO generation agent is activatable by blue or UV light, and the NO generation system further includes a cartridge (e.g., system 47 or 70) that is inserted or is to be inserted into the receptacle 59, a cartridge containing the NO generation agent, a blue light source or UV light source 50 positioned to illuminate the NO generation agent, and a battery 24 operably connected to the blue light source or UV light source 50. The cartridge operates in the same manner as the system 47 shown and described in FIG. 24A and the system 70 shown and described in FIG. 24B. Briefly, the activated blue or UV light source generates NO molecules by illuminating the NO generation agent. The NO molecules are delivered to the user through the nasal projection 58.

[0192] The example shown in FIG. 25C can include an NO sensor 38 positioned within the cartridge and a control electronic element 52 positioned within the cartridge. This example can include an on / off switch 75 disposed external to the housing 54. The on / off switch turns the blue or UV light source 50 on or off. This example of the nasal vent plug can be disposable or reusable.

[0193] Any example of a nasal vent plug (including those shown in FIGS. 25A, 26B, and 25C) can also include an air diverter valve (expiratory check valve 16') for channeling exhaled air from the housing 54. This valve can keep exhaled air away from the NO generating agent, so the amount of NO introduced to the user is maximized. The air diverter valve can be controlled by a control electronic element 52 (such as an electronic controller). The electronic control device is connected to a sensor feedback loop and a NO sensor 38. Using the data from the sensor 38, the air can be diverted from the housing 54 or made to stay within the housing 54 so that the user receives an appropriate level of NO. The valve can also be controlled to a closed position, so that NO can be formed in the headspace of the closed inner portion 57 during exhalation and during the pause time in the user's natural breathing cycle. The control electronic element 52 can also force a pulsed aggregation during the user's inhalation by activating a fan or other mechanism.

[0194] Any example of the inhalation device disclosed herein may include nitrogen dioxide (NO 2 ) filter. The NO 2 filter can receive the output gas before it is inhaled by the patient, for example, by positioning it in a nasal cannula or a ventilator tube, or inside a face mask, or inside the nasal projection 58 of a nasal vent plug. Any of the NO 2 filter examples described herein can be used. As an example, any of the nasal vent plugs shown in FIGS. 25A-25C may include a filter positioned between the receptacle 59 and the nasal projection 58. The filter includes an absorbent for scavenging nitrogen dioxide (NO 2 ) released by the NO generating agent, a reagent for changing the generated NO 2 back to NO, or a combination thereof.

[0195] Furthermore, in any of the examples disclosed herein that utilize any of the liquid forms of the NO generating formulation, an additional NO permeable membrane can be positioned over reservoir 60. In some instances, aerosol droplets may be generated along with the NO gas. Aerosol droplets are undesirable for various medical applications. Needless to say, the NO permeable membrane prevents the generation of aerosol droplets and / or their exit from reservoir 60 along with the NO gas. Example types of NO permeable membranes that prevent the formation of aerosol droplets include porous polytetrafluoroethylene (PTFE), polypropylene, polyethylene, polyamide, polyvinylidene difluoride, and the like. Example types of NO permeable membranes that prevent the escape of aerosol droplets include polycarbonate, such as polycarbonate track etching membranes.

[0196] Another mechanism for preventing the transport of aerosol droplets along with the NO gas stream involves positioning a highly porous droplet catcher (e.g., gauze).

[0197] In any of these examples, this type of NO permeable membrane can be positioned at the opening of reservoir 60, or specifically within the nasal vent plug, between the opening of reservoir 60 and nasal projection 58, or within nasal projection 58.

[0198] The examples disclosed herein are capable of generating an effective amount of NO for delivery to a user / patient via inhalation. When the level of NO generated is increased, it becomes therapeutic and is sufficient to kill bacteria and viruses, disrupt bacterial biofilm formation, dissipate or prevent microbial biofilm formation (e.g., dissipate antibiotic-resistant biofilms), reduce platelet aggregation and thrombus formation, reduce inflammation, and increase ciliary beat frequency, and thus improve mucociliary clearance. An increase in NO production according to the examples of the present disclosure can be observed almost immediately and over an extended period of time (e.g., about 4 to 96 hours).

[0199] In some of the examples disclosed herein, the levels of gaseous nitric oxide in the nasal cavity / airway interior as a result of inhaling gaseous nitric oxide generated from a moisture-activated NO generating formulation may be in the range of 50 parts per billion by volume (ppbv) to about 7500 ppbv. In other examples among the examples disclosed herein, the NO generating formulation contained within a pouch or other container 32 releases a desired volume of NO, for example, on average 10 ppm, 20 ppm, or 30 ppm, and optionally the design range is from 1 ppm to 250 ppm over a time range of 0.5 to 3 hours or more. In the example of a nose pillow (nasal vent plug), the NO generating capacity of any example of the returned NO generating formulation (e.g., in liquid form 73) can be formed in the range of 5 ppm to 50 ppm, and optionally the design range is from 1 ppm to 250 ppm.

[0200] To further illustrate the present disclosure, examples are presented herein. Needless to say, these examples are provided for illustrative purposes and should not be construed as limiting the scope of the present disclosure.

[0201] Needless to say, the following NO release data, and with respect to FIG. 9 (see below), was generated from pellets without a plastic sheath.

Examples

[0202] Example 1

[0203] Formulation

[0204] Moisture-activated NO generating formulations were all prepared in the same manner. The components were thoroughly mixed with each other until the mixture appeared homogeneous. The mixture was then placed into a circular manual pill press, for example, a manual pill press with a diameter of 5 mm. By compressing the mixture, solid pellets were formed. The pellets were then removed by additionally pressing after removing the bottom stop. Thereby, pellets having a length of about 10 mm and a diameter of 5 mm were produced. The size of these pellets varied depending on the target gas generation capacity of this design.

[0205] NO release rate

[0206] The NO release rate of the formulation was measured at room temperature in an amber NOA cell using an electrochemical nitric oxide analyzer (NOA) while purging through a glass pipette with humidified nitrogen (approx. 80% relative humidity (RH)) at 50 mL / min.

[0207] Stability measurement

[0208] The stability of the formulation was tested via UV / Vis analysis and / or via an electrochemical NOA.

[0209] GSNO results

[0210] Figures 9 - 20 show the NO release kinetics of various test formulations.

[0211] For Formulation A, Figure 9, GSNO, ascorbic acid (3.5 wt%) as a promoter, and corn starch (71 wt%) as a hydrophilic binder were used together with an inert salt (a mixture of sodium chloride and sodium bicarbonate) (21.5 wt%). The pellets of this mixture disintegrated easily.

[0212] For Formulation B, Figure 10, GSNO (6.4 wt%), ascorbic acid (13.8 wt%) as a promoter, and a commercial excipient mixture (FIRMAPRESS® excipient) were used for the hydrophilic binder (79.8 wt%). This excipient mixture is representative of common mixtures used to manufacture pills for ingestion. This improved the cohesion of the pills.

[0213] For Formulation C, Figure 11, GSNO (10.6 wt%), ascorbic acid (22.9 wt%) as a promoter, and hypromellose (71 wt%) as a hydrophilic binder were used. Hypromellose is another common component in the manufacture of inoculable pills for commercial dosage forms. This formulation was not as mechanically robust as the previous Formulation B.

[0214] For formulation D, as shown in Figure 12, GSNO (8.1 wt%), ascorbyl palmitate (41.1 wt%) as a promoter (the palmitate acts as a lubricant), and hypromellose (50.8 wt%) as a hydrophilic binder were used. Compared with formulation C, this improved the pill pressing characteristics. This is because it lubricates the press. This also indicates that the addition of the lubricant reduces the NO release rate.

[0215] Figure 13 shows another batch of formulation D. This indicates that the NO release kinetics are similar between batches.

[0216] Formulation E, which contains only 1% GSNO in the formulation, with ascorbic acid (about 10 wt%) as a promoter and about 90% hydrophilic binder, generated about 50 ppbv of NO as shown in Figure 14.

[0217] For formulation F, GSNO (40 wt%), cysteine (25 wt%) as a promoter, and hypromellose (35 wt%) as a hydrophilic binder were used. The NO release by formulation F (high percentages of GSNO and cysteine) is shown in Figure 15A.

[0218] Formulation F, as shown in Figure 15B, shows the dependence of NO generation on percent relative humidity (%RH). At zero humidity, the NO generation rate is relatively low, less than 200 ppbv, which is thought to be due to a small amount of residual moisture in the system. At moderate humidity, about 44%RH, the rate is significantly higher, and at very high humidity, about 80%RH, the rate is three times that at 44%RH.

[0219] For formulation G, as shown in Figure 16, a very high percentage of promoter, 60% ascorbyl palmitate, can generate effective NO levels. Formulation G also contained 12 wt% GSNO and 25 wt% FIRMAPRESS® excipient as a hydrophilic binder.

[0220] Formulation H, Figure 17 shows that a very low percentage of accelerator, 0.8% copper sulfate, can produce an effective NO level. Formulation H also contained 8 wt% GSNO and 91 wt% hypromellose as a hydrophilic binder.

[0221] Formulation I, Figure 18 shows that the hydrophilic compound, calcium chloride (deliquescent salt) (62 wt%), is very effective in generating NO in combination with glutathione (30 wt%) as an accelerator. Formulation I also contained 8 wt% GSNO.

[0222] Formulation J, Figure 19 shows NO generation by a high level of salt, disodium hydrogen phosphate (46 wt%). Formulation J also contained 7 wt% GSNO, 15 wt% ascorbic acid as an accelerator, and a mixture of 32 wt% hypromellose (24 wt%) and FIRMAPRESS® excipient (8 wt%) as a hydrophilic binder.

[0223] Formulation K contained 8 wt% GSNO, 50 wt% disodium hydrogen phosphate, and 42 wt% FIRMAPRESS® excipient. Formulation K, Figure 20 shows that the base, disodium hydrogen phosphate (50 wt%), which brings an alkaline pH when dissolved, is effective as an accelerator (RSNO is relatively unstable under alkaline conditions). The GSNO instability, and thus the NO production amount, begins to increase above pH 8.5. The instability increases as the pH increases above 8.5.

[0224] Example 2

[0225] A nasal vent plug (or nasal pillow) similar to that shown in Figure 25B was prepared.

[0226] An NO donor formulation containing sodium nitrate, sodium ascorbate, sodium dihydrogen phosphate, and disodium hydrogen phosphate was prepared. 1.5 mL of deionized (DI) water was also added. Table 1 shows the components of the NO donor formulation.

Table 1

[0227] The NO generating agent was introduced into the reservoir of the nasal vent plug. A steady air flow was introduced through the vent at a flow rate of 7.5 L / min. The NO and NO 2 levels were measured at the nasal protrusion. The results are shown in Fig. 27. These results indicate that NO is generated at the desired level. By incorporating an oxygen scrubber and / or filter, the NO 2 level can be further reduced.

[0228] References throughout this specification to "one example", "another example", "example", etc., mean that the particular elements (e.g., features, structures, and / or characteristics) described in connection with that example are included in at least one example described herein, and may or may not be present in other examples. Additionally, unless the context clearly dictates otherwise, elements described in connection with any example can be combined in any suitable manner in various examples.

[0229] It goes without saying that the ranges provided herein include the recited range and any value or sub-range within the recited range. For example, a range of about 3 wt% to about 12 wt% should be construed to include not only the explicitly recited limits of about 3 wt% to about 12 wt%, but also individual values such as 5 wt%, 6.2 wt%, 9.85 wt%, etc., and sub-ranges such as about 4 wt% to about 10 wt%, etc. Further, "about" when used to describe a value is to be construed to include a slight variation (up to + / - 10%) from the recited value.

[0230] When describing and claiming the examples disclosed herein, the singular forms "a", "an", and "the" include the plural unless the context clearly dictates otherwise.

[0231] Although several examples have been described in detail, it goes without saying that the disclosed examples may be modified. Accordingly, the above description should be considered non-limiting.

Claims

1. 1. A nitric oxide (NO) generating system comprising: It is an NO generating formulation, Stable NO donors / adducts, A hydrophilic binder, and an alkaline material selected from the group consisting of sodium carbonate, a mixture of sodium carbonate and sodium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof; wherein said NO-generating formulation does not contain an additive to control the release rate of NO from said NO donor / adduct; an NO-generating formulation, wherein said alkaline material provides a pH of said NO-generating formulation above 8.5, thereby destabilizing a stable NO-donor / adduct to release NO after said formulation is exposed to an effective amount of water vapor or a hydration fluid; an inhalation device in operative contact with an NO-generating formulation; A nitric oxide (NO) generating system comprising:

2. The NO generating formulation comprises: 8 wt % S-nitrosoglutathione (GSNO) as the stable NO donor / adduct; 42 wt. % of a hydrophilic binder; and 50 wt% disodium hydrogen phosphate as alkaline material 2. The nitric oxide (NO) generating system of claim 1, comprising:

3. 2. The nitric oxide (NO) generating system of claim 1, wherein the hydrophilic binder is selected from the group consisting of polyvinyl acetate (PVA), poly(ethylene glycol) (PEG), polyacrylamide, acetate, polyethylene oxide (PEO), polyethyl acrylate (PEA), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate (PVP-VA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, and the like, and combinations thereof.

4. 2. The nitric oxide (NO) generating system of claim 1, wherein the inhalation device is a face mask.

5. 2. The nitric oxide (NO) generating system of claim 1, wherein the inhalation device is a nasal cannula.

6. 2. The nitric oxide (NO) generating system of claim 1, wherein the inhalation device is a nasal vent plug.

7. 2. The nitric oxide (NO) generating system of claim 1, wherein the stable NO donor / adduct is an RSNO powder selected from the group consisting of S-nitrosoglutathione (GSNO), S-nitroso-cysteine, S-nitroso-N-acetyl-penicillamine, S-nitroso-penicillamine, and S-nitroso-albumin.

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