Nitric oxide generation system

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 priority benefit of U.S. Provisional Application No. 62 / 891,129, filed August 23, 2019. The content of the above application is hereby incorporated herein 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 mammalian immune responses or immune defenses, and is a cytotoxic agent in the mechanism used by macrophages to kill *L. major*, *M. bovis*, and *M. tuberculosis* among numerous bacterial species. NO is also an effective antiviral agent, which has activity against rhinoviruses that cause the common cold. NO is produced from L-arginine in the respiratory tract (e.g., in the upper respiratory tract) by immune cells (macrophages, neutrophils, lymphocytes, etc.) and airway epithelial cells (e.g., conductive respiratory epithelial cells), primarily via inducible nitric oxide synthase (iNOS). Impaired NO production may reduce immune response and / or microbial biofilm formation. Reduced nasal NO levels are associated with diseases such as primary ciliary dyskinesia and chronic rhinosinusitis (CRS), and potentially associated with impaired ability to fight against viral agents causing the common cold. Several physiological properties of NO include its use as an anti-inflammatory agent, anticoagulant, and / or antibacterial agent.

[0003] The use of NO in inhalation therapy has also been studied. Inhaled nitric oxide is used to treat pulmonary failure, and has been found to promote pulmonary vasodilation and reduce pulmonary vascular resistance. Inhaled nitric oxide is also approved by the U.S. Food and Drug Administration (FDA) for the treatment of 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) generation system includes an NO-generating formulation comprising a stable NO donor / adduct, a hydrophilic binder, and an additive, wherein the additive controls the rate of NO release from the NO donor / adduct after the formulation has been exposed to an effective amount of water, water vapor, or blue light or ultraviolet (UV) light; and an inhalation device operably in contact with the NO-generating formulation. 1. A nitric oxide (NO) generation system, which includes the following: It is a NO-generating preparation. Stable NO donor / adduct, Hydrophilic binder, and additives A NO-generating formulation comprising, where the additive is for controlling the rate of NO release from the NO donor / adduct after the formulation has been exposed to an effective amount of water, water vapor, or blue light or ultraviolet (UV) light; An inhalation device that is in operable contact with the NO generating preparation, A nitric oxide (NO) generation system that includes [the specified component]. 2. The NO generating system according to 1, wherein the NO generating preparation further comprises a lubricant. 3. The stable NO donor / adduct is S-nitrosothiol (RSNO) powder present in an amount of approximately 3 wt% to approximately 12 wt% of the NO generating preparation. The hydrophilic binder is present in an amount of approximately 15 wt% to approximately 82 wt% of the NO generating preparation. The lubricant is present in an amount of approximately 1 wt% to approximately 15 wt% of the NO generating formulation, and The aforementioned additive is present in an amount of approximately 3 wt% to approximately 60 wt% of the NO generating preparation. NO generation system as described in 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 generating system according to 1, wherein the NO generating 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. 6. The NO generating system according to 5, wherein the inert material is present in an amount of more than 0 wt% to about 50 wt% of the NO generating formulation. 7. The NO generation system described in 1., wherein the ratio (mol / mol) of NO donor / adduct to additive is 1:0.5 to 1:10. 8. The NO generating system according to 1., wherein the NO generating preparation comprises a single solid. 9. The NO generating system according to 1., wherein the inhalation device includes a face mask. 10. The NO generating system according to 9, wherein the face mask includes a housing for holding the NO generating preparation in effective proximity to at least one of the user's mouth or nose. 11. The NO generating system according to 10, wherein the NO generating preparation comprises a single solid. 12. The NO generating system according to 11, wherein the NO generating preparation comprises a plurality of the single solids. 13. The NO generation system according to 10, wherein the housing is selectively opened and closed. 14. The housing further, An air humidifier in operational contact with an NO-generating preparation, An air pump that is in fluid communication with the aforementioned air humidifier, A power source operably connected to the air humidifier and the air pump. NO generation system as described in 10. 15. The NO generating system according to 10, wherein the housing partially defines a reservoir, and the system further includes a reservoir wall or filter positioned between the inside of the face mask and the inside of the reservoir. 16. The NO generation system according to 15, wherein the reservoir wall or the filter is impermeable to hydrate and permeable to NO. 17. The NO generation system according to 15, wherein the reservoir is configured to receive a predetermined volume of hydrated solution in which the NO-generating preparation is dissolved. 18. The NO generation system according to 15, further comprising an absorbent material contained inside the reservoir. 19. The NO generating system according to 15, wherein the system further includes the filter positioned between the inside of the face mask and the inside of the reservoir, and the filter includes an absorbent for scavenging nitrogen dioxide (NO2) released by the NO generating formulation, a reagent for converting the generated NO2 back into NO, or a combination thereof. 20. The NO-generating preparation is contained inside a NO-permeable container, and The NO-permeable container is positioned inside the face mask without being attached to the face mask. NO generation system as described in 9. 21. The inhalation device further, An air pump operably connected to the face mask, An air humidifier that is in fluid communication with the aforementioned air pump, A container for holding an NO generating preparation, wherein the container is in fluid communication with the air humidifier and the face mask. NO generation system as described in 9. 22. The inhalation device further A gas mixer that is in fluid communication with the aforementioned container, A second air pump operably connected to the aforementioned gas mixer, An NO sensor is operably connected between the gas mixer and the face mask, A feedback controller operably connected to the NO sensor and the gas mixer. A moisture-activated NO generation system as described in 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 preparation. 24. The NO generating system according to 23., wherein the NO generating preparation and the blue light source or UV light source are positioned on or in 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 with a light wavelength of about 300 nm to about 520 nm at various intensities. 27. The NO generating system according to 23., further comprising 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 . 28. The NO generating system according to 23., further comprising a NO sensor, a nitrogen dioxide sensor, or a combination thereof. 29. The NO generating system according to 1., wherein the inhalation device comprises an inhalation system comprising an air pump, an air humidifier in fluid communication with the air pump, a container holding the NO generating preparation, the container being in fluid communication with the air humidifier, and a nasal cannula or a ventilator in fluid communication with the container . 30. The NO generating system according to 29., wherein the NO generating preparation 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, and a NO sensor operably connected between the gas mixer and the nasal cannula or ventilator a feedback controller operably connected to a NO sensor and said 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 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 methyl cellulose (HPMC), microcrystalline cellulose, corn starch, and combinations thereof. 37. The NO generation system according to 1., wherein the NO-generating 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: a NO-generating preparation, a stable NO donor / adduct, a hydrophilic binder, and Alkaline materials selected from the group consisting of sodium carbonate, mixtures of sodium carbonate and sodium bicarbonate, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, trisodium phosphate, and combinations thereof. A NO generating preparation comprising, where the alkaline material raises the pH of the NO generating preparation to 8.5 or higher, thereby destabilizing the NO donor / adduct so that the preparation releases NO after being exposed to an effective amount of water vapor or hydrate; An inhalation device in operational contact with an NO-generating preparation, A nitric oxide (NO) generation system that includes [unclear]. 39. Nitric oxide (NO) generation system, NO-permeable container including attachment mechanism; A NO-generating preparation contained in an NO-permeable pouch, wherein the NO-generating preparation includes a stable NO donor / adduct that can be activated when exposed to an effective amount of water vapor, hydrate, or blue light or ultraviolet (UV) light, A nitric oxide (NO) generation system that includes [unclear]. 40. The NO generating preparation further Hydrophilic binder, An additive for controlling the rate of NO release from the NO donor / adduct after the formulation has been exposed to an effective amount, NO generation system as described in 39. 41. The NO generation 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), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate (PVP-VA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, and combinations thereof. 42. The NO generating system according to 40, wherein the NO generating preparation further comprises an absorbent for scavenging nitrogen dioxide (NO2) released by the NO generating preparation, a reagent for converting the generated NO2 back into NO, or a combination thereof. 43. The NO generating system according to 40, wherein the NO generating preparation further comprises a lubricant. 44. The stable NO donor / adduct is S-nitrosothiol (RSNO) powder present in an amount of approximately 1 wt% to approximately 30 wt% of the NO generating preparation. The hydrophilic binder is present in an amount of more than 0 wt% to approximately 82 wt% of the NO generating formulation. The lubricant is present in an amount of more than 0 wt% to approximately 15 wt% of the NO generating formulation, and The NO generating system according to 43., wherein the additive is present in an amount of approximately 1 wt% to approximately 60 wt% of the NO generating preparation. 45. The NO generating system according to 40, wherein the NO generating 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 NO generation system according to 40, 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. 47. The NO generating system according to 39, wherein the attachment mechanism includes an adhesive covered by a peel-off adhesive liner. 48. The NO generating system according to 47, wherein the adhesive is a pressure-sensitive adhesive or a double-sided adhesive. 49. The NO generating system according to 39, wherein the attachment mechanism includes a clip. 50. The NO generation system according to 39, wherein the NO permeable container is porous. 51. The NO generation system according to 39, wherein the NO permeable container is selected from the group consisting of woven fabric material, nonwoven fabric material, plastic material, and metal material. 52. The NO generation system according to 39, further comprising a filter on the surface of the container or a filter positioned outside the container, wherein the filter comprises an absorbent for scavenging nitrogen dioxide (NO2) released by the NO generation preparation, a reagent for converting the generated NO2 back into NO, or a combination thereof. 53. The NO generating system according to 39, further comprising an inhalation device configured to attach an 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, The housing to which the NO permeable container is to be attached, A tube including a first end fluidly connected to the housing, An adapter provided at the second end of the tube distal to the first end, wherein the adapter is designed to be attached to a face mask, nasal cannula, or breathing tube. NO generation system as described in 53. 56. The NO generating system according to 55, further comprising a fan or suction device for transporting the NO from the housing to the adapter. 57. The NO generation system according to 55, further comprising a blue light source or a UV light source for illuminating the NO-permeable container. 58. Furthermore An air humidifier that is in operable contact with the housing, An air pump that is in fluid communication with the aforementioned air humidifier, A power source operably connected to the air humidifier and the air pump, NO generation system as described in 55. 59. A housing to which the NO permeable container is attached, A blue light or ultraviolet (UV) light source positioned inside the housing to illuminate the NO-transmitting container, A battery operably connected to the aforementioned blue light or ultraviolet (UV) light source and The NO generation system described in 39. further includes the NO generation system described in 39. 60. NO sensor positioned within the housing, A control electronic element positioned within the housing and The NO generation system described in 59. further includes the NO generation system described in 59. 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 a nitroprusside. 63. NO generation system, Face mask and, A housing fixed to the face mask, wherein the housing includes a reservoir having a NO-permeable wall positioned between the housing and the interior of the face mask, A NO generating preparation contained in or introduced into the reservoir, comprising a nitrite that generates NO when exposed to an effective amount of acidic buffer, NO generation system, including

[0005] Another example of a nitric oxide (NO) generating system includes an NO generating formulation comprising 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, wherein the alkaline material causes the pH of the NO generating formulation to be 8.5 or higher, thereby destabilizing the NO donor / adduct so that the formulation releases NO after being exposed to an effective amount of water vapor or hydrate; and an inhalation device operably in contact with the NO generating formulation.

[0006] Another example of a nitric oxide (NO) generating system includes an NO-permeable container with an attachment mechanism and an NO-generating formulation contained within an NO-permeable pouch. The NO-generating formulation comprises a stable NO donor / adduct that can be activated upon exposure to an effective amount of water vapor, hydrate, or blue or ultraviolet (UV) light.

[0007] Another example of an NO generating system includes a face mask, a housing fixed to the face mask, the housing comprising a reservoir having an NO-permeable wall positioned between the housing and the interior of the face mask, and an NO generating formulation contained in or introduced into the reservoir, the NO generating formulation comprising a nitrite which generates NO when the NO generating formulation is exposed to an effective amount of acidic buffer.

[0008] The features of embodiments of this disclosure will become clear by referring to the following detailed description and drawings. In the drawings, similar reference numerals correspond to similar, but possibly not identical, components. For brevity, reference numerals or features having functions previously described may or may not be described in relation to other drawings in which they appear. Some of the drawings (e.g., Figures 9–20) show data for nitric oxide (NO) release profiles or dynamics (e.g., PPB or PPBV, Y-axis) as a function of time (X-axis) for compressed pellets of various formulations. In these drawings, the data shows broad values ​​based on variations associated with the heterogeneous hydration of the pellets. [Brief explanation of the drawing]

[0009] [Figure 1A] Figure 1A is a photograph showing examples of NO-generating formulations, each formed as two single pellets within a plastic sheath.

[0010] [Figure 1B] Figure 1B is a photograph showing an example of an NO-generating formulation formed as a single pellet without a plastic sheath.

[0011] [Figure 2-1] Figures 2A and 2B are schematic diagrams showing an example of a face mask inhalation device with the NO-generating formulation holding housing in the open position (Figure 2A) and the closed position (Figure 2B).

[0012] [Figure 2-2] Figure 2C is a side view of the face mask inhalation device shown in Figure 2B, with the NO-generating preparation located in close proximity to the area where the user's nose and mouth will be positioned.

[0013] [Figure 3-1] Figures 3A and 3B are schematic diagrams showing another example of a face mask inhalation device with the NO-generating formulation holding housing in the open position (Figure 3A) and the closed position (Figure 3B).

[0014] [Figure 3-2] Figure 3C is a side view of the face mask inhalation device shown in Figure 3B, with the NO-generating preparation located in close proximity to the area where the user's nose and mouth will be positioned.

[0015] [Figure 4] Figure 4A is a schematic side view showing another example of a face mask inhalation device. Figure 4B is a cross-sectional view showing multiple NO-generating pellets within the housing, indicated by the line 4B-4B in Figure 4A.

[0017] [Figure 5] Figure 5 is a schematic side view and end view showing an example of the face mask inhalation device shown in Figure 2.

[0018] [Figure 6] Figure 6 is a schematic side view illustrating yet another example of a face mask inhalation device.

[0019] [Figure 7] Figure 7 is a schematic side view illustrating yet another example of a face mask inhalation device.

[0020] [Figure 8] Figure 8 is an inverse schematic diagram showing an example of an inhalation system inhalation device including a nasal cannula.

[0021] [Figure 9] Figure 9 is a graph showing the nitric oxide (NO) release profile from NO-generating formulations over time.

[0022] [Figure 10] Figure 10 is a graph showing the nitric oxide (NO) release dynamics of GSNO from another NO-generating preparation example.

[0023] [Figure 11]Figure 11 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0024] [Figure 12] Figure 12 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0025] [Figure 13] Figure 13 is a graph showing the nitric oxide (NO) release profile from the NO-generating formulation example in Figure 12 over time.

[0026] [Figure 14] Figure 14 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0027] [Figure 15A] Figure 15A is a graph showing the nitric oxide (NO) release profile from further NO-generating formulations over time.

[0028] [Figure 15B] Figure 15B is a graph showing the nitric oxide (NO) release dynamics of the GSNO formulation example shown in Figure 15A under various relative humidity conditions.

[0029] [Figure 16] Figure 16 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0030] [Figure 17] Figure 17 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0031] [Figure 18] Figure 18 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0032] [Figure 19] Figure 19 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0033] [Figure 20] Figure 20 is a graph showing the nitric oxide (NO) release profile from yet another NO-generating formulation example over time.

[0034] [Figure 21] Figure 21 is a schematic diagram showing an example of an NO generation system including a container, an adhesive which can be formed into a disc, tablet, or other shape, and a release liner.

[0035] [Figure 22] Figure 22 is a schematic diagram showing the NO generation system from Figure 21 attached to an inhalation device.

[0036] [Figure 23] Figure 23 is a schematic diagram showing another example of an NO generation system attached to an inhalation device.

[0037] [Figure 24] Figure 24A is a schematic diagram showing an example of a photoactivated NO generation system attached to an inhalation device. Figure 24B is a schematic diagram showing another example of a photoactivated NO generation system attached to an inhalation device.

[0039] [Figure 25-1] Figure 25A is a schematic perspective view showing a nasal vent plug containing a solid NO-generating preparation.

[0040] [Figure 25-2] Figure 25B is a schematic perspective view showing a nasal vent plug containing a reservoir for receiving a liquid NO-generating preparation. Figure 25C is a schematic perspective view showing a nasal vent plug containing a photoactivated NO-generating system.

[0042] [Figure 26] Figure 26 is a schematic diagram showing yet another example of an NO generation system attached to an inhalation device.

[0043] [Figure 27] Figure 27 is a graph showing NO levels (ppm, left Y-axis) and NO2 levels (ppm, right Y-axis) against time (hours, X-axis). [Modes for carrying out the invention]

[0044] Nitric oxide (NO) is a potential antithrombotic, anti-inflammatory, antibacterial, and antiviral agent. In vivo NO deficiency may be hereditary or associated with pleomorphism, or may be caused by pathologies or pathogens that exploit the upstream regulation of NO production. Deficiency in NO production impairs mucociliary function (mucociliary function is one of the primary innate immune defense mechanisms in the airway epithelium and is directly correlated with ciliary motility frequency), increases susceptibility to microbial infection, and / or promotes the persistence of bacterial biofilms that are resistant to antibiotics.

[0045] NO inhalation therapy introduces NO into the patient's lungs, thereby enhancing mucociliary function, reducing susceptibility to microbial infections, and / or promoting resistance to bacterial biofilms. NO has been shown to be effective against SARS coronavirus and may also be effective in treating other viruses, such as COVID-19 or SARS-CoV-2. The use of inhaled nitric oxide can also prove beneficial in other areas, 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-activated (e.g., water vapor), hydrate-activated, acid-buffer-activated, or photo-activated nitric oxide gas generating systems / devices are disclosed herein. In these device examples, nitric oxide (NO) gas is generated as needed from an inhalation device in contact with a moisture-activated, hydrate-activated, acid-buffer-activated, or photo-activated NO generating preparation (also referred to herein as an NO-releasing preparation).

[0047] An example of a 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 additives. The additives are designed to control (enhance) the rate of NO release from the stable NO donor / adduct after the formulation has been exposed to an effective amount of water vapor, hydrate, or blue or ultraviolet (UV) light.

[0048] In some cases, NO-generating formulations take the form of a solid (e.g., pellets / tablets / disks) containing a stable NO donor / adduct (e.g., RSNO (GSNO)), additives (e.g., reaction accelerators), and a hydrophilic binder. In some cases, lubricants and / or inert materials and / or pH-controlling materials may be included. In some other cases, if the NO-generating formulation is alkaline (e.g., pH greater than 8.5), additives / reaction accelerators are omitted.

[0049] In other examples, NO-generating formulations exist in the form of solutions or dispersions. In some of these examples, a stable NO donor / adduct (e.g., RSNO (GSNO)), and in some cases, a solid form containing additives and a hydrophilic binder, is mixed with a hydrate. 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 oxygen scrubbers as described herein.

[0050] "Nitric oxide adducts" (NO adducts) and "NO donors" refer to 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 used herein, the expression "moisture-activated NO-releasing formulation" includes NO donors / adducts that can release NO gas molecules when exposed to an effective amount of water vapor and / or hydration solution (e.g., water). In one example, a suitable amount of water vapor can be found under conditions ranging from approximately 40% relative humidity to a high relative humidity of 100% (see, for example, Figure 15B). Similarly, "photo-activated NO-releasing formulations" include 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 the following: moisture, hydration solution, and light. Preferred NO adducts are also, broadly speaking, adducts that exhibit process-preparation stability.

[0051] Furthermore, the term "acid buffer-activated NO-releasing formulation" refers to a formulation containing nitrite that generates NO gas molecules when exposed to an acid buffer that brings the formulation to a pH greater than 4 to approximately 7.5. In some examples, the pH is approximately 4.5 to 7.0, or approximately 4.1 to 6.9.

[0052] In some of the examples disclosed herein, examples of nitric oxide generating formulations are specifically formulated in solid form (e.g., a single solid or a single high-density packed solid mass using pressure (e.g., about 25–50 kN)), e.g., pellets, tablets, or discs). When exposed to humidified air (e.g., from the user's inhalation / exhalation, from an air humidifier, etc.), the solid form generates gaseous NO over a wide range (about 50 ppbv to over 50,000 ppbv). This range covers the range that has been demonstrated to be therapeutically effective for inhalation therapy. As used herein, “high-density packed” is not essentially granular, but rather analogous to the density of a crystalline material. NO generating formulations enable spontaneous delivery of NO over extended periods of time when the user is in contact with an inhalation device example containing a moisture-activated NO generating formulation.

[0053] In other examples disclosed herein, the nitric oxide generating preparation is in solid form and contained within a container. The container is attached to or introduced into an inhalation device. In some cases, the container is permeable to humidified air and NO. This type of container allows humidified air to come into contact with the nitric oxide generating preparation and also allows 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 of approximately 400 nm to 490 nm and / or approximately 490 nm to 520 nm) and / or ultraviolet light (wavelengths of approximately 10 nm to 400 nm) and NO-transmissive. This type of container allows light to come into contact with the nitric oxide generating preparation and also allows the generated gaseous NO to be released from the container.

[0054] In other examples disclosed herein, the nitric oxide generating formulation is in solid 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, for example, the reservoir shown in Figure 25B.

[0055] In other examples disclosed herein, the nitric oxide generating formulation is a coating or powder. The coating or powder is added to an absorbent pad (e.g., PIG® absorbent pad) and placed in a device as shown in Figure 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 costs.

[0057] The use of NO-releasing formulations disclosed herein to form inhaled nitric oxide is clearly effective in combating disease, including the use of prophylactic agents, reduction of infectious agents (e.g., viruses, bacteria, fungi), treatment of lung failure, improvement of pulmonary artery vasodilation, and reduction of pulmonary vascular resistance and other conditions including inflammation, coagulation, and infection. As described above, inhaled nitric oxide can also be used to treat neonates with hypoxic respiratory failure, improve oxygenation, and reduce the need for extracorporeal membrane oxygenation therapy. The use of NO-releasing formulations 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, and for air disinfection.

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

[0059] NO generating preparation

[0060] Some examples of NO-generating formulations include stable NO donors / adducts. In some cases, these NO-generating formulations include stable NO donors / adducts, hydrophilic binders, and additives.

[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 nitric oxide generating formulations is either a species that occurs naturally in the human body or another living organism, a species that can be broken down into a species that occurs naturally in the human body, or a drug suitable for use in humans (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, spontaneously occurring in the human body), S-nitroso-cysteine ​​(CYSNO, spontaneously occurring in the human body), S-nitroso-N-acetyl-penicillamine (SNAP, broken down into the drug penicillamine), S-nitroso-penicillamine, and S-nitroso-albumin (spontaneously occurring in vertebrates).

[0063] S-nitrosoglutathione (GSNO) is an example of an NO-releasing S-nitrosothiol (RSNO) molecule. GSNO exists in the human body as a result of NO (produced by epithelial cells, macrophages, sinus epithelial cells, etc.) reacting with oxygen to form N2O3. N2O3 is a nitrosonium ion (NO + By providing ), it reacts with the thiol group of glutathione to form GSNO. As such, the nitric oxide generating formulations disclosed herein do not introduce any foreign matter or toxins into the nasal cavity / airway.

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

[0065] In some cases, moisture-activated S-nitrosothiol (RSNO) molecules other than GSNO can be used in nitric oxide generating preparations. Examples of these other S-nitrosothiols include S-nitroso-cysteine ​​(CYSNO, spontaneously occurring in the human body), S-nitroso-N-acetyl-penicillamine (SNAP, broken down into the drug penicillamine), S-nitroso-penicillamine, and S-nitroso-albumin (spontaneously occurring 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-acetylpenicillamine, 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 photoactivated / sensitive. Examples of photoactivated / sensitive S-nitrosothiols include S-nitroso-N-acetyl-penicillamine (SNAP) crystals, S-nitrosoglutathione (GSNO) crystals, and combinations thereof.

[0069] In the NO-generating formulation examples of this 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), polyvinylpyrrolidone (PVP), and their variations (e.g., polyvinylpyrrolidone-vinyl acetate (PVP-VA)), for example, as physical blends or admixtures. Each polymer maintains its intrinsic chemical properties. Various other hydrophilic polymers, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, and / or combinations thereof may also be used. It is also conceivable within the scope of this disclosure to use any of the following polymers / copolymers, or polymer / copolymer combinations, or other hydrophilic materials to obtain a hydrophilic binder with desired properties.

[0070] In one example, the weight-average molecular weight of the hydrophilic polymer used may be approximately 5,000 Mw to approximately 500,000 Mw, or approximately 10,000 Mw to approximately 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), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-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, hydrate, or light. By including the additive in the formulation, the NO release profile can be controlled over time. This can enhance antimicrobial 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 NO donor / adduct to additive is 1:0.5 to 1:10.

[0073] Needless to say, the additive is any suitable reducing agent. In one example of a NO-generating preparation, 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 is selected from the group consisting of selenocysteine ​​and ebselenium. An example of an additive combination is reduced glutathione and ascorbic acid.

[0074] The following are some examples of how additives 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 through the formation of an initial N-hydroxysulfanamide species (e.g., GS-N(OH)-SG). The initial N-hydroxysulfanamide species then forms the radical GS - It changes to Radical GS. -It can react with another GSNO molecule to release NO and form a GSSG disulfide species. Cysteine ​​can transnitrosate with GSNO to form CysNO. CysNO releases NO significantly faster than GSNO. Ascorbic acid or ascorbates can be readily oxidized to form smaller threose structures (3-carbon sugars). The spontaneous oxidation of ascorbic acid can release NO and GSH in conjunction with the reduction of GSNO. Furthermore, the oxidation products of ascorbic acid, i.e., the smaller threose structures, are also reducing agents. This reducing agent can donate electrons to GSNO, and thus contribute to the direct reduction of GSNO to NO. In one example, ascorbic acid or ascorbic acid can be oxidized in solution for up to 5 days, dried, and then incorporated into a nitric oxide generating preparation. The generation of NO from GSNO can be catalyzed by organoselenide species. Any trace amount of free thiols present in the GSH preparation can reduce copper or zinc ions to their +1 oxidized state, and Cu(I) or Zn(I) ions can then reduce GSNO to NO and GSH.

[0075] In one example, the NO-generating formulation further includes a lubricant. If a lubricant is included, examples include surfactants 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, lubricants are not necessary for NO generation. However, in some cases, lubricants can make the pellets more robust and modify (slow down) the NO release kinetics. However, when solids / pellets are compressed at high and sufficient pressure (e.g., over 40 kN), pellets without lubrication should remain clumped together (although the resulting NO release may slow down in some cases as the press pressure increases).

[0076] Needless to say, the components of the NO-generating preparation, including the NO donor / adduct, may be present in any desired and appropriate amount. However, in one example, the stable NO donor / adduct (e.g., S-nitrosothiol (RSNO) powder) is present in an amount of approximately 1 wt% to 50 wt%, or approximately 1 wt% to 30 wt%, or approximately 3 wt% to 12 wt%, of the NO-generating preparation, and the hydrophilic binder is present in an amount of approximately 15 wt% to 90 wt%, or greater than 0 wt% to 82 wt%, or approximately 15 wt% to 82 wt%, or approximately 25 wt% to 82 wt%, of the NO-generating preparation. If present, lubricants (if present in the formulation) are present in amounts of more than 0 wt% to about 15 wt%, or about 1 wt% to about 15 wt%, of the NO generating formulation, and additives are present in amounts 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. If zinc oxide particles are used as additives, they may be present in amounts of about 1 wt% to about 90 wt%, of the NO generating formulation.

[0077] In another example, a NO-releasing preparation containing an NO donor / adduct is made alkaline (e.g., pH above 8.5) by adding an alkaline material. In this example, no additives / accelerators are included. GSNO is unstable at high pH (above approximately 8.5), and NO is released even without additives / accelerators. Examples of alkaline materials are selected from the group consisting of sodium carbonate, mixtures 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 comprises an inert substance selected from the group consisting of sodium chloride, sodium bicarbonate, calcium chloride, microcrystalline cellulose, silicon dioxide, and combinations thereof. Where the inert material is included in the formulation, it is present in an amount of more than 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 significantly affect NO release (i.e., a material that changes the rate of NO release by less than 10%). In the examples disclosed herein, the inert material may act, for example, as an anticaking agent, a filler, and / or a binder (although it goes without saying that an inert material binder does not participate in water supply in the same way as a hydrophilic binder).

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

[0080] Some examples of NO-generating preparations (including NO donors / adducts) further include absorbents for scavenging nitrogen dioxide (NO2) released by the NO-generating preparation, reagents for converting the generated NO2 back to NO, or combinations thereof. NO2 can be generated by reacting O2 with NO, and NO2 can be toxic to recipients or patients. Therefore, it is desirable to remove any generated NO2, convert any generated NO2 back to NO, or maintain the level of NO2 inhaled by the user at an extremely low level. A soda-lime scrubber may be included as an absorbent. If the NO2 content is greater than 1-3 ppm in the final gas phase, a soda-lime scrubber can be used to remove excess NO2. An example of a reagent or catalyst that can convert the generated NO2 back to NO is silica particles impregnated with ascorbic acid.

[0081] In another example, when a deliquescent salt (e.g., calcium chloride) is used, the NO-generating preparation containing the NO donor / adduct may be a two-component system. Using a highly hydrophilic material (e.g., a deliquescent salt such as calcium chloride) increases the amount of NO produced because the pellet dissolves at least partially and subsequently behaves like a solution.

[0082] The wet, hydrated, or photoactivated NO generating preparation containing the NO donor / adduct may be in the form of a powder.

[0083] A wetted solution, hydrated solution, or photoactivated NO-generating preparation containing an NO donor / adduct can also be applied to a surface as a coating or film using an adhesive that does not interfere with NO generation.

[0084] In further examples, the moisture, hydrate, or photoactivated NO generating preparation can be molded / formed / pressed into solids of any suitable shape or size, such as pellets, tablets, or discs. In some examples, the molded solids may be up to approximately 50 mm in diameter x 25 mm in thickness. In one example, the molded solids may be approximately 5 mm in diameter x 25 mm in length. Sizes exceeding 50 mm x 25 mm may be undesirable in some cases, as the surface area-to-volume ratio is a criterion that should be considered in conjunction with the water absorption tendency. The weight of the molded solids may be approximately 0.1 grams to 5.0 grams, or approximately 0.2 grams to 0.5 grams.

[0085] In one example, the NO-generating formulation 10,10' contains a single molded solid (i.e., the components of a moisture-activated formulation (e.g., RSNO, binder, and additives) are present in a single pellet, unlike a two-component system). An example of the NO-generating formulation 10 shown in Figure 1A is in the form of two pre-molded single pellets, each of which contains a plastic sheath (the plastic sheath may be added as desired for mechanical rigidity to reduce pellet brittleness). Another example of the NO-generating formulation 10 shown in Figure 1B is in the form of a pre-molded single pellet without a plastic sheath. In one example, the plastic sheath is polyethylene. An example of a sheath manufacturing method is to insert the molded pellet into polyethylene and then puncture the sheath with a needle to fix the pellet in place. The sheath may be of any suitable thickness as desired, approximately 150 μm thick.

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

[0087] An example of a liquid form of an NO-generating preparation is generated by reconstituting the solid and powder forms of an NO-generating preparation containing an NO donor / adduct with a hydrate solution, such as deionized water or purified water.

[0088] In addition to the NO donors / adducts described herein, other examples of NO-generating formulations include nitrites that generate NO molecules when exposed to acidic buffers and pH 4.1–7.5. The nitrites can be maintained in solid form (e.g., powder) until NO generation becomes desirable, or in aqueous solution (e.g., dissolved in water) until NO generation becomes desirable.

[0089] The powder form of this NO-generating preparation example may contain nitrite alone or in combination with an additive and / or an oxygen scrubber.

[0090] Nitrites can be any water-soluble inorganic nitrites. 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 NaNO2.

[0091] Nitrite may be present in the powder formulation in an amount of up to 75 wt%. During dissolution, the maximum nitrite concentration depends on the salt's solubility. 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 solubility range may be 10 μmol / L. In some examples, the reconstituted solution contains 8 mol / L of NaNO2 and 13 mol / L of KNO2.

[0092] Any reducing agent additive may be included. In one example, the additive is ascorbate or ascorbic acid. In this formulation, the additive can reduce NO2 generation.

[0093] An oxygen scavenger that can remove oxygen (by reacting with NO to produce NO2) and thereby reduce the amount of NO2 produced may be used. Examples of suitable oxygen scrubbers include sodium metabisulfite, hydrazine, carbohydrazide, tannin, and diethylhydroxyamine (DEHA). The oxygen scrubber may be included in an amount of approximately 10 wt% or less.

[0094] In this example, the nitrite used alone or in combination with an additive and / or oxygen scrubber can be maintained in powder form until it becomes desirable to return the powder to an acidic buffer to produce the liquid form of the NO generating preparation NO. The pH of the liquid form of the NO generating preparation NO is greater than 4 to 7.5. The acidic buffer may be a moderate acid capable of acidifying the nitrite to generate NO. In one example, the acidic buffer is a monobasic and / or dibasic phosphate. Other examples of acidic buffers include monocitric acid, dibasic citrate, acetic acid, bis-tris(2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol), MOPSO(β-hydroxy-4-morpholinepropanesulfonic acid), PIPES(1,4-piperazinedietanesulfonic acid), BES buffered saline, MOPS(3-(N-monophorino)propanesulfonic acid), TES(2-[[1,3-dihy The compounds are droxy-2-(hydroxymethyl)propane-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 an NO-generating preparation (containing nitrite). An example of a kit includes a first solution containing nitrite in water, and a second solution containing an acidic buffer and an additive. Any example of nitrite can be used in the first solution. Any example of acidic buffer and an example of an additive can be used in the second solution.

[0096] In this example, the first and second solutions can be kept separate until it becomes desirable to generate NO. When combined, the first and second solutions form the liquid form of the NO-generating preparation NO. The pH of this liquid form of the NO-generating preparation NO is also greater than 4 and between 7.5.

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

[0098] In any NO-generating preparation, a solid (e.g., pellets / tablets / disks) or a reconstituted liquid (e.g., pellets, tablets, or powder in a hydrate solution, or a liquid form containing nitrite and acidic buffer) can be used in the system for a predetermined period of time (for example, the user may be informed that x ppm of NO will be generated over y hours). The user may then be instructed to replace the pellet or introduce fresh liquid. In a further example, an NO detector may be used to indicate when the NO-generating preparation no longer generates the desired amount of NO. In a further example, the NO-generating preparation may be formulated to dissolve the solid once it no longer generates the desired amount of NO.

[0099] container

[0100] Several different types of containers are conceivable here. Some container examples function as outer packaging. The outer packaging protects the NO-generating preparation 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 preparation during use (and thus may be NO-permeable). In some of the examples disclosed herein, the container containing the NO-generating preparation is held inside the outer packaging before use. Several different containers are described below.

[0101] Any NO-generating formulation examples disclosed herein may be contained within an outer package, such as foil or a plastic pouch (e.g., biaxially oriented polyethylene terephthalate, e.g., commercially available MYLAR®). This type of outer package helps to airtightly seal the NO-generating material from moisture and light. This can affect the effectiveness and time-release characteristics of the NO-releasing formulation, as well as its effective lifespan. In some examples, the outer package airtightly seals the solid form of the NO-generating formulation. In these examples, the user removes the solid NO-generating formulation, which may be in the form of pellets, discs, or tablets, from the outer package before use. In some examples, the outer package airtightly seals a pouch or other holder containing the NO-generating formulation. In these examples, the NO-permeable pouch or holder is removed from the outer package before use. In some examples, the outer package airtightly seals the powder of the NO-generating formulation. In these examples, once the outer package is opened, the powder may be prepared for hydration or exposure to an acid buffer, possibly 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 hydrate or acidic buffer. The components of the two chambers can be mechanically forced to blend with each other. Such a container may also have holes or membranes for NO to escape after mixing. In yet another example, the outer package is airtightly sealed with or coated with the NO-generating formulation and an absorbent pad containing it. In these examples, the absorbent pad is removed from the airtightly sealed outer container for moisture and / or liquid activation. Yet another approach is to supply the NO-generating formulation into a pre-mixed ampoule. The ampoule can be opened and poured into a device such as the one shown in Figure 26.

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

[0103] NO permeable containers may be woven or nonwoven materials (e.g., cloth, fabric, etc.). In some examples, NO permeable containers are rigid shells 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, NO permeable containers are selected from the group consisting of woven materials, nonwoven materials, plastic materials, and metal materials.

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

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

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

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

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

[0109] Another example of an attachment mechanism is a clip. Clip 46 is schematically shown in Figure 23. Part of clip 46 is attached to a container 32 (e.g., a pouch), and the other part of clip 46 is attached to an inhalation device, e.g., a face mask 12. Although clip 46 is shown, it goes without saying that other mechanical attachment mechanisms can be used instead of a clip. Examples include hooks, clamps, pins, or similar.

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

[0111] Some container 32 examples 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 (NO2) released by the NO-generating preparation, a reagent for converting the generated NO2 back to NO, or a combination thereof. In some examples, the filter is a nitrogen dioxide (NO2) filter. The NO2 filter may be positioned to receive the output gas NO before it is inhaled by the patient. In some examples, the NO2 filter may be positioned outside the container 32 on a surface that will face the user's mouth and / or nose. Some NO2 filter examples remove at least some of the nitrogen dioxide from the NO gas. For example, a silica gel filter (having pre-conditioned silica particles) or a soda-lime scrubber can be used as an NO filter. These filters can reduce NO2 to physiologically irrelevant levels. Other NO2 filter examples convert nitrogen dioxide back to nitric oxide. This change is desirable because the NO payload is not lost in the form of scavenged (absorbed) NO2, but is reduced back to NO. An example of this type of NO2 filter is silica particles impregnated with ascorbic acid.

[0112] Inhalation device

[0113] In some examples, the nitric oxide (NO) generating system further includes an inhalation device that is in operable contact with the NO generating preparation. Examples of inhalation devices include face masks, nasal cannulas, nose pillows (also called “nasal vent plugs”), and ventilators.

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

[0115] A face mask 12 (also known as a filtration respirator) can be used to protect the respiratory system from particles or chemicals. The face mask 12 can be configured to minimize the transmission of infectious diseases or to protect the respiratory system from toxic substances or allergens in the surrounding atmosphere. In addition, 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. The face mask 12 can be used to maintain a closed space around the respiratory orifice when a person is in close proximity to another person or when undesirable airborne substances are present. In addition, by an infected person wearing a face mask 12, others in close proximity to pathogens can be protected. Needless to say, the face masks disclosed herein are described in the context of humans, but adaptations to the anatomical features of any respiratory organ are also conceivable and disclosed herein. For example, face masks can be adapted for dogs, cats, and horses.

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

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

[0118] In the examples shown in Figures 2A-2C and 3A-3C, the housing 14 is selectively opened and closed. Figures 2A and 3A show the housing door in the open position (for example, used to introduce NO generating preparations 10,10' into the face mask 12), and Figures 2B and 3B show the housing 14 door in the closed position (for example, used when it is desirable to introduce NO gas to the user).

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

[0120] In the examples shown in Figures 2A and 3A, each single pellet / tablet (e.g., NO-generating formulation 10, 10') may be snapped into place in a designated location on the door of the housing 14. In other examples, each single pellet / tablet (e.g., NO-generating formulation 10, 10') may be slid into each receptacle defined within the door of the housing 14. The single solid form of the NO-generating formulation 10, 10' can also be held within the housing 14 using other appropriate mechanisms.

[0121] Although the door is shown as being able to open and rotate around an existing hinge, it goes without saying that the door of the housing may be formed / designed to be selectively opened and closed by any appropriate type of action, such as swivel, slide, or flip. Needless to say, the housing 14 shown in Figures 2A-2C and 3A-3C is an example, and any appropriate attachment structure or device can be used as the housing 14. For example, the housing of the face mask 12 may include a flap or pouch (internal or external). The flap or pouch can receive and hold the NO generating preparation 10,10'.

[0122] In the example of a face mask inhalation device (face mask 12) shown in Figure 3A, the housing 14 further includes an air humidifier 22 operably in contact with NO-generating preparations 10,10' (RSNO tablets / pellets), an air pump 20 fluidly communicating with the air humidifier 22, and a power source (shown as battery 24 in the figure) operably connected to the air humidifier 22 and the air pump 20. As shown in Figure 3A, the housing 14 has an air inlet 18 defined through it. The air pump 20 may be connected to the air inlet to transport any water vapor generated by the air humidifier 22 through the air inlet 18 and thus to the NO-generating preparations 10,10'. Needless to say, “fluid communication” should be interpreted broadly and include, for example, liquids and gases.

[0123] As shown in Figure 3B, the air humidifier 22 and air pump 20 are small enough to be mounted on or inside 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) with or without moisture coming from the user's exhaled breath. The air pump 20 can be used to transport the generated water vapor near the NO generating preparations 10,10' and can also transport the generated NO gas to the user.

[0124] Further examples of face mask inhalation devices are not shown, but are similar to the system example shown in Figure 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 NO generating preparations 10,10', the container 32 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, an 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 Figure 8, except that the nasal cannula 34 (Figure 8) is replaced with the face mask 12. In this example, the face mask 12 does not need to have a housing 14, and the container 32 may also have an adapter for attaching a conduit (e.g., a tube) in fluid communication.

[0125] In further 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 defines at least partially a reservoir. The reservoir is configured to receive a predetermined volume of hydrate in which the NO generating preparation 10,10' is dissolved (or dispersed). In these examples, the solid NO generating preparation 10,10' can be mixed with a specified / predetermined volume of water, and the reconstituted solution can then be poured into the housing 14. In another example, the housing 14 defines at least partially a reservoir. The reservoir is configured to receive a predetermined volume of the NO generating preparation in liquid form in which nitrite is dissolved in an acidic buffer. In some of these examples, the nitrite-containing powder can be mixed with a specified / predetermined volume of acidic buffer, and the reconstituted solution can then be poured into the housing 14. In other examples, an aqueous solution of nitrite can be mixed with an acidic buffer, and the mixed solution can then be poured into the housing 14. In yet another example, the housing may contain an absorbent. The absorbent can be coated with an NO-generating preparation or retain the liquid form of the NO-generating preparation.

[0126] One of these examples is shown in Figure 26. In this example, the housing 14 partially defines a reservoir 60 and includes a reservoir wall 62 or filter 64 positioned between the interior of the face mask 12 and the interior of the reservoir 60. The reservoir wall 62 or filter 64 may be made of a non-porous NO-permeable material, such as polyurethane or poly(tetrafluoroethylene). A reservoir wall 62 or filter 64 made of this type of material allows NO gas to penetrate it (e.g., into the face mask 12), but also resists leakage of a hydrate containing a solid NO-generating formulation 10,10', or an acidic buffer of another example of the liquid form of the NO-generating formulation. In other words, the reservoir wall 62 or filter 64 is impermeable to the hydrate or acidic buffer, and NO-permeable. As such, the reservoir wall 62 or filter 64 allows NO gas generated inside the reservoir 60 to be inhaled by the user without allowing the liquid to escape. If the filter 64 is positioned between the inside of the face mask 12 and the inside of the reservoir 60, the filter 64 may include an absorbent for scavenging nitrogen dioxide (NO2) released by the NO generating agent, a reagent for converting the generated NO2 back into NO, or a combination thereof.

[0127] In these examples, the housing 14 may include a sealable input port 66 that is not movable between open and closed positions (as shown, for example, in Figures 2A and 2B). The input port allows liquid to be introduced into the reservoir 60. The sealable input port 66 can be sealed using a removable cap 68.

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

[0129] The reservoir 60 in Figure 26 can also receive a container 32 containing a solid NO generating preparation 10,10'.

[0130] Another configuration, not shown in Figure 26, involves using a fan to blow the NO generated by the NO-generating agent from the reservoir towards the user of the inhalation device.

[0131] Although not shown in Figure 26, it goes without saying that this device example may include an additional filter. The additional filter contains a reagent or catalyst for converting any NO2 to NO. This filter is positioned between the reservoir wall 62 or filter 64 and the inside of the face mask 12 to prevent NO2 from reaching the user.

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

[0133] The example shown in Figure 26 may include a chamber (fluidly connected to reservoir 60). In the chamber, released NO can be accumulated through a diverter valve during respiratory pause and exhalation. The stored NO is then made available as a pulsed concentration during inspiration.

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

[0135] The examples shown in Figures 4 to 7 illustrate several additional configurations for incorporating the NO-generating formulations 10, 10' into the face mask 12. Figures 4A and 4B show another example of how multiple single pellets / tablets of the NO-generating formulation 10 are arranged within the housing 14. In this example, the housing 14 may contain individual receptacles for the single pellets / tablets of the NO-generating formulation 10. Alternatively, the single pellets / tablets of the NO-generating formulation 10 may be fixed to a cap ring that can be loaded into the housing 14.

[0136] The configurations shown in Figures 5-7 also include check valves, such as an inspiratory check valve 16 (Figures 2A-2C and Figure 5), an expiratory check valve 16' (Figure 6), or both an inspiratory check valve 16 and an expiratory check valve 16' (Figure 7). The check valves 16, 16' can help prevent exhaled air from returning to the NO-generating preparations 10, 10', because exhaled air can undesirably eject NO gas from the system.

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

[0138] In the example, the face mask 12 includes a filtering face mask. In this specification, a filtering face mask means a mask that covers at least the wearer's nose and mouth and includes a filter element 19 for removing contaminants and / or particles from the air passing through the filter element 19. As shown in Figure 4A, the mask body 13 is the filter element 19 molded to fit the contours of the wearer's face. As indicated by the airflow direction arrow 15, the filter element 19 is a bidirectional filter, which is configured to filter inhaled and exhaled air. As shown in Figure 4A, the housing 14 is mounted and attached to the mask body 13, penetrating it. As shown in Figures 4A and 4B, the NO generating preparation 10 is distributed around an aperture 17 defined in the inner wall 21 of the housing 14. In the example shown in Figure 4A, the outer wall 23 of the housing 14 may be made of the non-porous NO permeable material. In another example, the outer wall 23 of the housing 14 may be made of a non-porous NO-impermeable material. As shown in Figure 5, when the intake check valve 16 is open, it allows air to flow through the outer wall 23 of the housing 14 in the intake direction. When the intake check valve 16 is closed, it blocks air from passing through the outer wall 23 of the housing 14 in the exhalation direction, opposite to the intake direction. As shown in Figure 5, a filter 26 may be connected to the housing 14 to filter the air before it passes through the intake check valve 16. This filter 26 may have any desired filtration 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, then most of the air will take the least-resistance path through the filter element 19.

[0139] The example shown in Figure 6 is similar to the example shown in Figure 4B, in which the exhalation check valve 16' is mounted on the mask body 13. When the exhalation check valve 16' is open, it allows air to flow through the mask body 13 in the exhalation direction 26. When the exhalation check valve 16' is closed, it blocks air from passing through the check valve 16' in the inhalation direction, opposite to the exhalation direction 27. In this way, the exhalation check valve 16' allows at least some of the exhaled air to bypass the filter element 19, thereby reducing moisture that may accumulate in the internal space 20 partitioned by, for example, the face mask 12 and the wearer's face 31 (see, for example, Figure 3C). As shown in Figure 7, the present disclosure may include a combination of the inhalation check valve 16 having the filter 26 shown in Figure 5 and the exhalation check valve 16' shown in Figure 6.

[0140] Referring here to Figure 8, another example of an inhalation device includes an inhalation system comprising an air pump 20, an air humidifier 30 (hydrator) fluidly communicating with the air pump 22, a container 32 for holding an NO generating preparation 10 (shown as several RSNO pellets / tablets inside a canister), the container 32 (e.g., a canister) fluidly communicating with the air humidifier 2230, and a nasal cannula 34 (or ventilator (not shown)) fluidly communicating with the container 32. This example includes the configuration shown on the upper side of Figure 8, but without a gas mixer 36 or NO sensor 38. Needless to say, however, the NO sensor 38 can also be used in this configuration if desired.

[0141] In another example, the inhalation system further includes a gas mixer 36 in fluid communication with a container 32, a second air pump 20' (shown on the lower side of Figure 8) operably connected to the gas mixer 36, an NO sensor operably connected between the gas mixer 36 and a 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 an oxygen-containing gas into the gas mixer. Here, the oxygen-containing gas is mixed with NO gas to form the output gas that is delivered to the inhalation device (e.g., a nasal cannula 34, or in other examples, a face mask 12 or a ventilator). The oxygen-containing gas may be at least substantially pure oxygen gas O2, or air, or a low-oxygen gas containing oxygen. Although the air pump 20' is shown in Figure 8, the oxygen-containing gas may be delivered from any suitable gas source (e.g., a compressed gas cylinder (not shown)). This gas source can control the flow rate of the oxygen-containing gas, or it may be connected to a flow controller to control the amount of oxygen-containing gas flowing into the gas mixer. Any suitable gas flow rate can be used. For example, the flow rate of the oxygen-containing gas may be about 50 mL / min to about 5 L / min. In another example, the flow rate of the oxygen-containing gas may be controlled so that the output gas flow contains about 20% oxygen to about 99.99% oxygen. In one example, 100% saturated air can be used as the oxygen-containing gas. This corresponds to approximately 10 mg / L (ppm) of O2 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 the container 32 (or from the gas mixer 36, if present in the system). It is desirable to monitor the NO level to avoid the formation of NO2 (nitrogen dioxide, which can be produced from the reaction of O2 with NO and can be undesirable for the recipient / patient). Any suitable NO sensor 38 may be used.

[0144] In one example, the NO sensor 38 is a Shibuki-style sensor (not shown). This sensor detects nitrates (NO3) from NO at the position of the inner platinum (Pt) electrode behind the gas-permeable membrane. - Based on oxidation to ).

[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 larger current than the Shibuki configuration.

[0146] Some examples also include NO2 sensors. Using a NO2 sensor, the NO2 level in the output gas stream from the container 32 (or from the gas mixer 36, if present in the system) can be monitored.

[0147] For example, the feedback controller 40 can use NO sensor data (i.e., NO concentration in the output gas stream and / or NO2 concentration in the output gas stream) to control the system so that at least a substantially constant NO concentration is obtained at the delivery end.

[0148] The target NO level may be based on a given use in which NO is used. The target level may be very low or very high depending on the patient and the use. For example, the target NO level for neonates receiving inhalation therapy may be about 10 ppm to about 70 ppm, and the target NO level to be generated to prevent the activation of platelets and other cells during bypass surgery may be about 190 ppm to about 210 ppm. Furthermore, for antimicrobial uses such as for lung infections, a lower NO level, for example, about 500 ppb to about 10 ppm, may be useful in inhalation therapy.

[0149] As described above, sensor data can also be used to determine whether an undesirable amount of NO2 is present in the output gas stream. If an undesirable amount of NO2 is present, the system alarm can be activated. Furthermore, a soda lime scrubber or other NO2 scavenger may be included in the inhalation device immediately before the output gas stream is delivered to the patient via the nasal cannula 34, face mask 12, nasal vent plug (see Figures 25A-25C), or ventilator (not shown). If the content exceeds 1 ppm to 3 ppm in the final gas phase, the soda lime scrubber can remove the excess NO2.

[0150] In other examples similar to Figure 8, a reservoir of hydrate (e.g., water) can be provided instead of the air humidifier 22. The reservoir can be configured to introduce a specified / predetermined volume of hydrate into a container 32, and thereby into contact with the NO-generating preparation 10,10' contained therein. Inside the container 32, the hydrate activates NO gas generation. In some examples, the NO-generating preparation 10,10' is configured to release a specified volume of NO gas when mixed with a specified hydrate. The NO gas can then be transported to a gas mixer 36. In the gas mixer, the NO gas is mixed with an oxygen-containing gas and delivered to the patient. In these examples, the reservoir is refillable so that fresh hydrate can be introduced. In addition, the container 32 is refillable so that used liquid can be removed, and after the NO gas generation cycle has been performed, fresh solid pellets / tablets of the NO-generating preparation 10,10' can be introduced.

[0151] In yet another example similar to Figure 8, an acidic buffer reservoir (with or without additives and / or an oxygen scrubber) may be provided instead of the air humidifier 22. The reservoir can be configured to introduce a specified / predetermined volume of acidic buffer into a container 32, and thereby into contact with the nitrite (in powder or aqueous solution form) contained therein. Inside the container 32, the acidic buffer acidifies the nitrite and activates NO gas generation. In some examples, the acidified nitrite is configured to release a specified volume of NO gas, for example, about 1 ppm to about 250 ppm. The NO gas can then be transported to a gas mixer 36. In the gas mixer, the NO gas is mixed with an oxygen-containing gas and delivered to the patient. In these examples, the reservoir is refillable so that fresh acidic buffer can be introduced. In addition, the container 32 is refillable so that used solution can be removed and fresh nitrite (in powder 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 a ventilator or any other device suitable for delivering an output gas stream to the user / patient's airway may also be used in accordance with the examples of this disclosure.

[0153] In some examples, the NO-generating preparation 10,10' is contained within an example of a container 32, which is then introduced into an inhalation device. In some examples, the container 32 is simply placed inside the inhalation device. In other examples, such as those shown in Figures 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 a face mask 12.

[0154] In the example shown in Figure 22, the inner surface of the face mask 12 comes into contact with the adhesive 42 (after the liner 44 is removed), and the container 32 is held inside the face mask 12. The container 32, and by extension the NO-generating preparation (activated by moisture in this example), is held in close proximity to at least one of the user's mouth or nose.

[0155] In the example shown in Figure 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 preparation 10,10' (activated by moisture in this example) are held in close proximity to at least one of the user's mouth or nose.

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

[0157] In other examples, the stable NO donor / adduct is activatable with blue light or ultraviolet (UV) light, and the NO generation system further includes a blue light source or UV light source 50 positioned to illuminate the NO generation formulation 10,10'. In some examples, the NO generation formulation 10,10' and the blue light source or UV light source 50 are positioned on or within the inhalation device in such a way that they effectively illuminate the NO generation formulation 10,10' to generate nitric oxide.

[0158] Figure 24A shows an example of a photoactivated NO generating system 47 inside an inhalation device (e.g., a face mask 12). In some examples, the photoactivated NO generating system 47 includes NO generating preparations 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 preparations 10,10' may be chemically or physically attached to the inner wall of a housing 48 (without a container 32).

[0159] The example of the system 47 shown in Figure 24A also includes a housing 48 to which an NO-permeable container 32 is mounted, a blue light source 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 light source or UV light source 50.

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

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

[0162] NO can be released from the NO donor / adduct using one or more light sources 50. Using multiple light sources 50 allows for further control of the amount of NO released. For example, if a higher NO level is desired, all of the light sources 50 facing the container 32 (or the coating / film of the NO donor preparation) can be activated to emit light toward the NO donor / adduct, and if a lower NO level is desired, fewer than the total number of light sources 50 may be activated. In some examples, the NO generating preparations 10,10' are configured to release a specified volume of NO gas when exposed to light wavelengths of approximately 300 nm to approximately 520 nm at varying 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 another power source suitable for the light source 50 and the control electronic element 52.

[0164] Some examples of system 47 further include an NO sensor 38, a nitrogen dioxide (NO2) sensor, or a combination thereof.

[0165] The example shown in Figure 24A includes an NO sensor 38 positioned within a 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 specified volume of NO gas.

[0166] The control electronic element 52 may be part of a detection and feedback system. The detection and feedback system includes a NO sensor 38 and a feedback controller 40 (not shown in Figure 24A). The detection and feedback system may also include a NO2 sensor (not shown in Figure 24A). By using feedback from the NO sensor 38 and the NO2 sensor to servo-control one or more parameters of the light source 50, at least a substantially constant NO concentration can be obtained at the delivery end.

[0167] Although the photoactivated NO generating system 47 in Figure 24A is shown installed inside the face mask 12, it goes without saying that the photoactivated NO generating system in Figure 24A may be incorporated into other inhalation devices. In one example, the photoactivated NO generating system 47 shown in Figure 24A is separate from the inhalation device and is in fluid communication with it. In these examples, the photoactivated NO generating system 47 shown in Figure 24A includes a tube with 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, such that the adapter is attached to the face mask 12, nasal cannula 34, or 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 the NO gas molecules are then 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 Figure 8 may be modified to include a photoactivated NO generation system 47. In this specific example, the photoactivated NO generation system 47 shown in Figure 24A can be used instead of the container 34 and air humidifier 22 shown in Figure 8.

[0168] The tubes and adapters are described in conjunction with the photoactivated NO generating system 47, but needless to say, these components can also be used in conjunction with the moisture-activated systems disclosed herein. Some of these examples will include an air humidifier 22, an air pump 20, and a power source to introduce an effective amount of water vapor into the housing. The housing contains a container 32 and NO generating preparations 10,10'.

[0169] If the NO donor / adduct is activatable by light and moisture, then, needless to say, the NO donor / adduct in the NO generating preparation 10 can be activated using moisture and / or hydrate and / or UV or blue light 50. An example of this hybrid system 70 is shown in Figure 24B. In this example, the photoactivated NO generating system 47 (Figure 24A) may include an additional chamber 72 surrounding the container 32 (containing the NO generating preparations 10, 10'). Since the chamber 72 is impermeable to liquid, any introduced liquid or moisture will not interfere with the components of the photoactivated NO generating system 47. The chamber 72 includes one wall transparent to emitted UV or blue light (facing the light source 50) and another wall transparent to NO (facing the inside of the inhalation device). The chamber 72 can receive a hydrate. The hydrate can activate the NO donor / adduct or may be operably connected to an air humidifier 22. An air humidifier can introduce enough moisture to activate NO donors / adducts.

[0170] Further examples of NO generating systems are shown in Figures 25A, 25B, and 25C. These system examples include nasal vent plugs or nose pillows. Each nasal vent plug includes a nitric oxide (NO) impermeable housing 54 having integrally formed walls 55A, 55B, and 55C defining a partially closed internal portion 57; two nasal projections 58 extending from one of the integrally formed walls 55A and in fluid communication with the partially closed internal portion 57; an air vent 56 defined in another of the integrally formed walls 55C for introducing airflow into the partially closed internal portion 57; and a receptacle 59 within the partially closed internal portion 57, the receptacle 59 containing and receiving an NO generating agent.

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

[0172] The integrally formed walls 55A, 55B, and 55C of the housing 54 and the nasal projection 58 may 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 may be strategically positioned so that air is drawn into one side of the nasal process 58 via the NO generating agent. Preferably, the vent 56 is located on the side (wall 55C) of the housing 54 or near the side, rather than on the top surface of the housing 54. This position can prevent NO from escaping through the vent 56. This position can also help to form a headspace within the closed internal portion 57. In the headspace, NO concentrations can be formed during exhalation and during pauses in the user's natural breathing cycle. The stored NO is then available as pulsed aggregates during inspiration (described further below).

[0174] Each vent 56 may be operated in conjunction with fins (not shown). The fins are positioned to help guide air through the vents 56 into the closed interior section 57.

[0175] The nasal projection 58 may be molded to be inserted into the user's nostrils, or it may be molded to be positioned outside, but close to, the user's nostrils. For example, the nasal projection 58 may fit snugly just below the user's nostrils. In the latter example, the housing 54 may include a head strap 74 (Figure 25B) to hold the nasal projection 58 in a desired position on the user's face. As such, some examples of NO generating systems further include a head strap 74 fixed to the housing 54. The housing 54 may include additional holes or another attachment mechanism (e.g., a hook-and-loop fastener) to secure the head strap 74. The head strap 74 may be adjustable. Needless to say, the nasal projection 58 may be flush with the wall 55A (and therefore not a true projection), and the head strap 74 can be used to hold the nasal vent plug adjacent to the user's nostrils.

[0176] The nasal vent plug further includes a receptacle 59 inside a closed internal portion 57. Various examples of the receptacle 59 are shown in Figures 25A-25C. The receptacle 59 holds an NO-generating formulation (in powder, liquid, or solid form, etc.) in close proximity to the air vent 56 and the nasal projection 58.

[0177] Specifically, referring to Figure 25A, the receptacle 59 is configured to receive a container 32 containing the NO-generating preparation 10,10' in solid form. In one example, the NO-generating preparation 10,10' contains a single solid or multiple single solids within the container 32. The container 32 may be positioned between the introduction vent 56 and the inhalation opening 58. This positioning allows moisture and / or air from the vent 56, and in some cases from the user's exhaled breath, to enter the container 32 and activate the NO-generating preparation 10,10' contained within the container. This position also allows the generated NO gas molecules to be inhaled by the user through the nasal passage 58.

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

[0179] In the example shown in Figure 25A, the NO generating preparation 10,10' comprises a stable NO donor / adduct that can be activated upon exposure to an effective amount of water vapor, the NO generating preparation 10,10' is contained within the NO permeable container 32, and the 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 the housing 54 and can receive, for example, an adhesive 42 (similar to the example shown in Figure 22) or can be snapped to a clip 46 (similar to the example shown in Figure 23). The spectral slot (shown in Figure 25A) can secure the container 32 in place.

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

[0181] If the nasal vent plug is reusable, the housing 54 may further include a door 69 (above 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 Figure 25B.

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

[0183] In one of these examples, the system may include a solid form of the NO-generating formulation 10,10'. This solid form can be returned in a hydrate 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 formulation 10,10' includes a stable NO donor / adduct, a hydrophilic binder, and additives for controlling the rate of NO release from the NO donor / adduct after the formulation has been exposed to an effective amount of hydrate (e.g., water). The liquid form 73 can be produced by adding the hydrate to the solid form. The liquid form is then introduced into the reservoir 60 through a door 69.

[0184] In another example among these, the system may include a solid form of the NO-generating formulation 10,10'. This solid form can be returned 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 formulation includes a nitrite for generating NO when exposed to an effective amount of acidic buffer, and an additive for controlling the rate of NO release from the nitrite after the formulation has been exposed to an effective amount of acidic buffer. In this example, the solid form of the NO-generating formulation further includes an oxygen scrubber. Such a solid form of the NO-generating formulation is a powder that can be returned in an acidic buffer. The acidic buffer can be added to the solid form to produce the liquid form 73. The liquid form is then introduced into the reservoir 60 through a door 69.

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

[0186] Other examples of the receptacle 59 include a reservoir 60, but further include an absorbent pad 71 (e.g., cotton, compressed cotton, etc.). The absorbent pad is either contained within the reservoir 60 and moistened with the liquid form of the NO-generating preparation, or moistened with the liquid form of the NO-generating preparation and then introduced into the reservoir 60. In some examples, the absorbent pad 71 is incorporated into the reservoir 60, and then one example of the liquid form 73 is incorporated into the reservoir 60. In other examples, the absorbent pad 71 is moistened with one example of the liquid form 73 outside the nasal vent plug and then incorporated into the reservoir 60. In yet another example, the absorbent pad 71 contains the solid form of the NO-generating preparation. This solid form can be restored in a hydrate or acidic buffer. In this example, the solid form of the NO-generating preparation includes S-nitrosothiol (RSNO) powder, nitroprusside, or nitrite. For example, the absorbent pad 71 may contain a coating of NO-generating preparation in powder form, and this coated absorbent pad 71 is incorporated into the reservoir 60. In some examples, the solid or powder is poured onto the absorbent pad 71 or placed in front of (and therefore beneath) the absorbent pad 71 into the reservoir 60.

[0187] (Depending on the chemical properties of the NO-generating preparation within the coating) the NO donor / adduct or nitrite is activated by introducing a hydrate solution or acidic buffer into the reservoir 60.

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

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

[0190] The receptacle 59 / reservoir 60 can be sized so that a headspace is formed within a closed internal portion 57. Within this headspace, released NO can be concentrated through an expiratory check valve (i.e., an air diverter valve) (for example, during the user's breathing pause and exhalation). The expiratory check valve redirects the airflow around the closed internal portion 57, thereby allowing higher concentrations of NO to accumulate in the headspace. The stored NO then becomes available as pulsed aggregates during inspiration (further described below).

[0191] Specifically, referring to Figure 25C, several examples of receptacles 59 can receive cartridges, for example, photoactivated NO generating systems 47, 70 as described in Figures 24A or 24B. In this example, the NO generating preparation is activatable by blue or UV light, and the NO generating system further comprises a cartridge (e.g., system 47 or 70) inserted into or to be inserted into the receptacle 59, which includes a cartridge containing the NO generating preparation, a blue or UV light source 50 positioned to illuminate the NO generating preparation, and a battery 24 operably connected to the blue or UV light source 50. The cartridge operates similarly to system 47 shown and described in Figure 24A, and system 70 shown and described in Figure 24B. In short, the activated blue or UV light source generates NO molecules by illuminating the NO generating preparation. The NO molecules are delivered to the user through the nasal projection 58.

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

[0193] Any example of a nasal vent plug (including those shown in Figures 25A, 26B, and 25C) may also include an air diverter valve (expiratory check valve 16') for channeling exhaled air from the housing 54. This valve keeps the exhaled air away from the NO-generating preparation, thereby maximizing the amount of NO introduced to the user. The air diverter valve can be controlled by a control electronic element 52 (e.g., an electronic controller). The electronic controller is connected to a sensor feedback loop and an NO sensor 38. Data from the sensor 38 can be used to divert air away from the housing 54 or to keep it in the housing 54 so that the user can receive 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 internal portion 57 during exhalation and during pauses in the user's natural breathing cycle. The control electronic element 52 can also force pulsed accumulation during the user's inspiration by activating a fan or other mechanism.

[0194] Any example of an inhalation device disclosed herein may include a nitrogen dioxide (NO2) filter. The NO2 filter can receive the output gas before it is inhaled by the patient by positioning it, for example, in the tubing of a nasal cannula or ventilator, inside a face mask, or within the nasal projection 58 of a nasal vent plug. Any example of an NO2 filter described herein can be used. For example, any of the nasal vent plugs shown in Figures 25A-25C may include a filter positioned between the receptacle 59 and the nasal projection 58. The filter may include an absorbent for scavenging nitrogen dioxide (NO2) released by an NO-generating agent, a reagent for converting the generated NO2 back into 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 on the reservoir 60. In some cases, 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 escape from the reservoir 60 along with the NO gas. Examples of NO-permeable membrane types that prevent the formation of aerosol droplets include porous polytetrafluoroethylene (PTFE), polypropylene, polyethylene, polyamide, polyvinylidene difluoride, etc. Examples of NO-permeable membrane types that prevent aerosol droplets from escaping include polycarbonate, such as polycarbonate track-etched membranes.

[0196] Other mechanisms to prevent aerosol droplets from being transported along with the NO gas stream include 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 the reservoir 60, or specifically within the nasal vent plug, between the opening of the reservoir 60 and the nasal protrusion 58, or within the nasal protrusion 58.

[0198] The examples disclosed herein can generate an effective amount of NO for delivery to the user / patient via inhalation. Increased levels of NO produced become therapeutic and 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 motility frequency, thereby improving mucociliary clearance. The increase in NO production by the examples disclosed herein can be observed almost immediately and over long periods (e.g., approximately 4–96 hours).

[0199] In some of the examples disclosed herein, the level of gaseous NO in the nasal cavity / airway as a result of inhaling gaseous nitric oxide produced from a moisture-activated NO-generating formulation may be at a level of 50 parts per billion volume (ppbv) to approximately 7500 ppbv. In other examples disclosed herein, the NO-generating formulation contained in a pouch or other container 32 releases a predetermined volume of NO, for example, an average of 10 ppm, 20 ppm, or 30 ppm, with a design range of 1 ppm to 250 ppm over a time range of 0.5 to 3 hours or more, if desired. 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., liquid form 73) can be formed in the range of 5 ppm to 50 ppm, with a design range of 1 ppm to 250 ppm as needed.

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

[0201] Needless to say, the NO emission data below, and related to Figure 9 (see below), was generated from pellets without plastic sheaths. [Examples]

[0202] Example 1

[0203] formulation

[0204] All moisture-activated NO generating formulations were prepared in the same manner. The components were thoroughly mixed until the mixture appeared homogeneous. The mixture was then placed in a circular manual pill press, for example, a manual pill press with a diameter of 5 mm. Solid pellets were formed by compressing the mixture. The pellets were then removed by further pressing after removing the bottom stop. This produced pellets approximately 10 mm long and 5 mm in diameter. The size of these pellets varied according to 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 with humidified nitrogen (approximately 80% relative humidity (RH)) at a rate of 50 mL / min through a glass pipette.

[0207] Stability measurements

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

[0209] GSNO results

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

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

[0212] Formulation B, Figure 10, used GSNO (6.4 wt%), ascorbic acid (13.8 wt%) as an accelerator, and a commercial excipient mixture (FIRMAPRESS® excipient) 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 pill.

[0213] Formulation C, Figure 11, used GSNO (10.6 wt%), ascorbic acid (22.9 wt%) as an accelerator, and hypromellose (71 wt%) as a hydrophilic binder. Hypromellose is another common ingredient in the manufacture of inoculated pills for commercial excipient formulations. This formulation was not as mechanically robust as the previous formulation B.

[0214] Formulation D, Figure 12, used GSNO (8.1 wt%), ascorbyl palmitate (41.1 wt%) as an accelerator (the palmitate acts as a lubricant), and hypromellose (50.8 wt%) as a hydrophilic binder. Compared to Formulation C, this improved the pill pressurization characteristics because it lubricates the press. This also indicates that the addition of a lubricant reduces the NO release rate.

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

[0216] Formulation E, which contains only 1% GSNO, along with ascorbic acid (approximately 10 wt%) as an accelerator and approximately 90% hydrophilic binder, produced approximately 50 ppbv of NO (Figure 14).

[0217] Formulation F contained GSNO (40 wt%), cysteine ​​(25 wt%) as an accelerator, and hypromellose (35 wt%) as a hydrophilic binder. NO release by formulation F (high percentage of GSNO and cysteine) is shown in Figure 15A.

[0218] Formulation F, Figure 15B, shows the dependence of NO production on percentage relative humidity (%RH). At zero humidity, the NO production 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, approximately 44%RH, the rate is significantly higher, and at extremely high humidity, approximately 80%RH, the rate is three times that of 44%RH.

[0219] Formulation G, Figure 16, shows that a very high percentage of accelerator, 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 generate effective NO levels. 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%), in combination with glutathione (30 wt%) as an accelerator, is extremely effective in generating NO. Formulation I also contained 8 wt% GSNO.

[0222] Formulation J, Figure 19, shows NO production 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%) as a hydrophilic binder and FIRMAPRESS® excipient (8 wt%).

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

[0224] Example 2

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

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

[0227] The NO-generating agent was introduced into the reservoir of a nasal vent plug. A steady airflow was introduced through the vent at a flow rate of 7.5 L / min. NO and NO2 levels were measured at the nasal protuberance. The results are shown in Figure 27. These results indicate that NO is generated at the desired level. The NO2 level can be further reduced by incorporating an oxygen scrubber and / or filter.

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

[0229] It goes without saying that ranges provided herein encompass the recited range and any value or subrange within the recited range. For example, a range of about 3 wt% to about 12 wt% should be interpreted 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%, and the like, as well as subranges such as about 4 wt% to about 10 wt%, and the like. Furthermore, when "about" is used to describe a value, it is intended to include slight variations (up to + / - 10%) from the stated value.

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

[0231] While several examples have been described in detail, it is to be understood that the disclosed examples may be modified. Therefore, the foregoing description is to be considered non-limiting.

Claims

1. A nitric oxide (NO) generation system, A face mask with an inner surface; A NO-permeable container comprising an attachment mechanism selected from the group consisting of adhesives and clips fixed to the inner surface and covered with a peelable adhesive liner, so as to be held in effective proximity to at least one of the user's mouth or nose; A moisture-activated NO generating preparation contained in the NO-permeable container, wherein the moisture-activated NO generating preparation includes a stable NO donor / adduct that can be activated when exposed to an effective amount of water vapor, A nitric oxide (NO) generation system that includes [unclear].

2. The aforementioned NO generating preparation further, Hydrophilic binder, An additive for controlling the rate of NO release from the stable NO donor / adduct after the formulation has been exposed to an effective amount, The NO generation system according to claim 1, including the above.

3. The NO generating system according to claim 2, 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, polyvinylpyrrolidone-vinyl acetate (PVP-VA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, corn starch, and combinations thereof.

4. The NO generating preparation further generates nitrogen dioxide (NO) released by the NO generating preparation. ２ Absorbent for scavenging, NO generated ２ The NO generation system according to claim 2, comprising a reagent for changing the substance back to NO, or a combination thereof.

5. The NO generating system according to claim 2, wherein the NO generating preparation further comprises a lubricant.

6. The stable NO donor / adduct is S-nitrosothiol (RSNO) powder present in the NO generating preparation in an amount of 1 wt% to 30 wt%, The hydrophilic binder is present in an amount of more than 0 wt% to 82 wt% of the NO generating preparation. The lubricant is present in an amount of more than 0 wt% to 15 wt% of the NO generating agent, and The NO generating system according to claim 5, wherein the additive is present in an amount of 1 wt% to 60 wt% of the NO generating preparation.

7. The NO generating system according to claim 2, wherein the NO generating 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.

8. The NO generating system according to claim 2, 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.

9. The NO generating system according to claim 1, wherein the attachment mechanism is an adhesive covered by a release adhesive liner, and the adhesive is a pressure-sensitive adhesive or a double-sided adhesive.

10. The NO generating system according to claim 1, wherein the attachment mechanism includes the clip, and the inner surface includes a receiving portion capable of fixing the clip.

11. The NO generation system according to claim 1, wherein the NO permeable container is porous.

12. The NO generating system according to claim 1, wherein the NO permeable container is selected from the group consisting of woven fabric material, nonwoven fabric material, plastic material, and metal material.

13. Furthermore, the container includes a filter on the surface of the container or a filter positioned outside the container, wherein the filter absorbs nitrogen dioxide (NO) released by the NO generating preparation. ２ Absorbent for scavenging, NO generated ２ The NO generation system according to claim 1, comprising a reagent for changing the substance back to NO, or a combination thereof.

14. A nitric oxide (NO) generation system, A NO-permeable container comprising an attachment mechanism selected from the group consisting of adhesives and clips covered with a peelable adhesive liner; A moisture-activated NO generating preparation contained in the NO-permeable container, wherein the moisture-activated NO generating preparation includes a stable NO donor / adduct that can be activated when exposed to an effective amount of water vapor, A nitric oxide (NO) generation system including, Inhalation device, A housing to which an NO-permeable container is attached via an attachment mechanism, A tube including a first end fluidly connected to the housing, An adapter provided at the second end of the tube distal to the first end, wherein the adapter is designed to be attached to a face mask, nasal cannula, or breathing tube. An air humidifier that is in operable contact with the housing, An air pump that is in fluid communication with the aforementioned air humidifier, A power source operably connected to the air humidifier and the air pump, NO generation system, including

15. The NO generating system according to claim 14, further comprising a fan or suction device for transporting the NO from the housing to the adapter.

16. The NO generation system according to 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-acetylpenicillamine, S-nitroso-penicillamine, and S-nitroso-albumin.

17. The NO generation system according to claim 6, wherein the stable NO donor / adduct is a nitroprusside.

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