Methods of treating conditions responsive to nitric oxide therapy

Abstract

The present application relates to methods of treating conditions responsive to nitric oxide therapy. Compositions and methods for treating conditions responsive to nitric oxide (NO) therapy in a subject are disclosed and described. Such compositions can include a combination of a nitric oxide releasing compound, an acidifying agent, and a carrier in an amount that releases about 1 ppm*min / mL to about 500 ppm*min / mL NO based on 1 mL of the composition when measured by releasing NO from the composition into a substantially inert carrier gas stream at a flow rate of 1 liter / minute and a pressure of 1 atmosphere coupled to a chemiluminescence detector for a period of 30 minutes.

Description

[0001] This application is a divisional application. The original application was filed on July 16, 2021, with application number 2021800630339 and invention title "Method for treating conditions that respond to nitric oxide therapy".

[0002] Priority data This application claims the benefit of U.S. Provisional Application Serial No. 63 / 052,805, filed July 16, 2020, which is incorporated herein by reference. Background Technology

[0003] Nitric oxide (NO) is a diatomic molecule consisting of one nitrogen atom and one oxygen atom. NO molecules are highly unstable and exhibit properties similar to free radicals. NO is readily oxidized to nitrogen dioxide (NO2). Therefore, it can be difficult to produce, store, or use NO in controlled quantities. In the human body, nitric oxide can be produced by nitric oxide synthase (NOS). Many physiological and pathological processes in the body may involve NO. For example, low levels of NO in the blood can promote vasodilation to prevent ischemic injury, aid wound healing, and act as an effective antimicrobial agent. Conversely, high levels of NO in the blood can lead to tissue toxicity and inflammatory conditions such as septic shock, diabetes, and arthritis. Attached Figure Description

[0004] The features and advantages of this disclosure will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which collectively illustrate the features of this disclosure by way of example; and, wherein: Figure 1 It is a graph depicting the differences in exposure between naturally occurring NO inhalation, INOmax, nitric oxide (NO) nasal spray (NONS) prevention, and NONS treatment, based on examples; Figure 2a The illustration shows the application of a bacterial mixture to a pig object, according to an example. Figure 2b Concentrations of various bacterial types for control, nitric oxide release gel (NORG) treatment, and nitric oxide release solution (NORS) + NORG treatment, according to examples, are depicted. Figure 3a The example demonstrates how to begin treating warts on the forefoot; Figure 3b The image shows the fading of warts on the foot after treatment according to an example; Figure 3c The image shows warts on the foot on day 1 after starting treatment, according to the example. Figure 3d The image shows warts on the foot 7 days after the start of treatment, according to the example. Figure 3e The image shows warts on the foot 14 days after the start of treatment, according to the example. Figure 3f The image shows warts on the foot 28 days after the start of treatment, according to the example. Figure 4a The image shows nail fungus before the initial treatment, according to an example. Figure 4b The regression of nail fungus after treatment according to the example is shown; Figure 4c The toenail fungus before initial treatment is shown according to the example; Figure 4d The toenail fungus is shown after 1 day of treatment according to the example; Figure 4e The toenail fungus is shown 3 weeks after the initial treatment according to the example. Figure 4f The toenail fungus is shown 2 months after the start of treatment according to the example; Figure 4g The toenail fungus is shown 42 months after the start of treatment according to the example; Figure 4h The toenail fungus is shown 9 months after the start of treatment according to the example; Figure 4i The toenail fungus is shown after 1 day of treatment according to the example; Figure 4j The toenail fungus is shown 28 days after the start of treatment, according to the example. Figure 4k The toenail fungus is shown 63 days after the start of treatment, according to the example. Figure 4l The toenail fungus is shown 77 days after the start of treatment, according to the example; and Figure 4m The image shows the regression of toenail fungus 120 days after the start of treatment according to the example.

[0005] Reference will now be made to the exemplary embodiments shown, which will be described herein using specific language. However, it should be understood that the scope of the invention is not therefore limited. Detailed Implementation

[0006] While the following detailed description contains numerous details for illustrative purposes, those skilled in the art will appreciate that many variations and modifications can be made to these details and are to be considered as included herein. Therefore, the following embodiments are set forth without loss of generality and do not impose limitations on any of the claims set forth. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be restrictive. Unless otherwise defined, all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0007] In this written description, the singular forms “a,” “an,” and “the” provide explicit support for plural references unless the context clearly specifies otherwise. Thus, for example, a reference to “particle” includes multiple particles.

[0008] In this application, terms such as “comprises,” “comprising,” “containing,” and “having” may have the meanings conferred upon them by U.S. Patent Law, and may refer to “includes” and “including,” and are generally interpreted as open-ended terms. The term “consisting of” or “consists of” is a closed-ended term that includes only the components, structures, steps, etc., specifically listed with these terms, and content conforming to U.S. Patent Law. “consisting essentially of” or “consistsessentially of” has the meanings generally conferred upon them by U.S. Patent Law. In particular, such terms are generally closed-ended but allow for the inclusion of additional items, materials, components, steps, or elements that do not substantially affect the basic and novel characteristics or functions of the items(s) associated with the use. For example, trace elements present in the composition but not affecting the properties or characteristics of the composition are permitted if present under the language of “consisting essentially of,” even if the item following such a term is not explicitly listed. When open-ended terms such as “comprising” or “including” are used in this written description, it should be understood that, if explicitly stated, the language “consisting essentially of” and “consisting of” should also be directly supported, and vice versa.

[0009] The terms “first,” “second,” “third,” “fourth,” etc. (if present) in the specification and claims are used to distinguish similar elements and are not necessarily used to describe a particular order or chronological sequence. It should be understood that any terms thus used are interchangeable where appropriate, such that embodiments described herein can, for example, operate in an order different from the sequence shown or otherwise described herein. Similarly, if a method is described as comprising a series of steps, the presented order of these steps is not necessarily the only order in which they can be performed, and some said steps may be omitted and / or other steps not described herein may be added to the method.

[0010] The phrases “in one implementation” or “in one aspect” in this article do not necessarily refer to the same implementation or aspect.

[0011] As used in this article, “object” refers to a mammal that may benefit from the application of NORS or NO. On the one hand, mammals can be humans.

[0012] As used herein, the term "treat" (or "treatment") when used in conjunction with the administration of NORS or NO (including their compositions and dosage forms) refers to administration to an asymptomatic or symptomatic subject. In other words, "treat" (or "treatment") can be to reduce, improve, or eliminate symptoms associated with a condition present in the subject, or it can be preventative (i.e., to prevent or reduce the occurrence of symptoms in the subject). Such preventative treatment may also be referred to as condition prevention.

[0013] As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some respects, the terms “formulation” and “composition” can be used to refer to a mixture of one or more active agents with a carrier or other excipient. Compositions can take almost any physical state, including solid, liquid (i.e., solution), or gas. Furthermore, the term “dosage form” can include one or more formulations or compositions provided for administration to an object. In one example, the composition could be a solution that releases NO.

[0014] "Reagent kit" can refer to a package or container that includes a composition or dosage form and instructions for applying or administering the composition or dosage form according to a given regimen or within specified time and quantity parameters to treat one or more specific indications. For example, a reagent kit may include a specific volume or amount of a NORS composition or its components, along with a set of instructions on the appropriate administration of NORS to a subject to treat a given condition (e.g., an indication). The instructions may include guidance for a single type of administration or indication, or guidance for multiple types of administration and indications. Furthermore, the amount and form of the NORS composition in the reagent kit may be suitable for a single administration to treat a single indication, multiple administrations to create a regimen for one indication, or single or multiple administrations for multiple indications. For example, a composition or dosage form of the NORS composition may be provided in the reagent kit along with instructions for administration of a dosage form suitable for treating multiple indications, such as skin conditions like acne, wound healing, respiratory therapy, or further for enhancing immunity in the sinus and throat regions.

[0015] As used herein, “NORS” refers to a nitric oxide (NO)-releasing solution, composition, or substance, including acidified nitrite ions capable of releasing NO. On the one hand, the NO released from NORS can be a gas. NORS can be in various physical forms, such as liquids, creams, gels, or others.

[0016] As used herein, the terms “nitric oxide-releasing compound” and “nitric oxide-releasing agent” are used interchangeably, and it should be understood that the use of one phrase in this written description provides explicit support for the other. These terms refer to compounds, agents, or molecules that release nitric oxide upon reaction with another compound or agent, such as an acid. Nitric oxide (NO) can be released as a gas (e.g., gNO). Furthermore, the term “nitrite” as used in this written description may be used to refer generally to “nitric oxide-releasing compound” or “nitric oxide-releasing agent”, or may specifically refer to NO2 compounds conventionally known in the field of chemistry, and explicit support for the interchangeability of these terms is hereby included.

[0017] As used herein, a "therapeutic agent" is an agent that, when administered to a subject in an appropriate or effective amount, produces a beneficial or positive effect on the subject. On the one hand, NO can be a therapeutic agent. On the other hand, therapeutic agents can include physiologically active non-NORS agents, such as antibiotics, antihistamines, antiviral agents, antimicrobial agents, biomolecules (such as siRNA, cDNA), steroids, vasodilators, vasoconstrictors, analgesics, anti-inflammatory agents, etc. In some respects, the term "therapeutic agent" can be used interchangeably with "active agent" or "drug."

[0018] As used herein, an “effective amount” of an agent means an amount sufficient to accomplish the intended task or function required by the agent. A “therapeutic effective amount” of a composition, drug, or agent means a non-toxic but sufficient amount of the composition, drug, or agent to achieve a therapeutic outcome for treating or preventing a condition to which the composition, drug, or agent is known to be effective. It should be understood that various biological factors can affect a substance’s ability to perform its intended task. Therefore, in some cases, an “effective amount” or “therapeutic effective amount” may depend on such biological factors. Furthermore, while the achievement of a therapeutic effect can be measured by a physician, veterinarian, or other qualified medical professional using assessments known in the art, it should be recognized that individual variations and responses to treatment can make the achievement of a therapeutic effect a subjective determination. The determination of an effective amount or therapeutic effective amount is entirely within the scope of common techniques in the pharmaceutical and medical fields. See, for example, Meiner and Tonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographs in Epidemiology and Biostatistics Volume 8 (1986).

[0019] As used herein, a “dosing regimen” or “routine” such as a “therapeutic dosing regimen” or a “prophylactic dosing regimen” refers to how, when, how much, and for how long a subject may or should be given a dose of a composition to achieve the desired therapeutic or therapeutic effect.

[0020] As used herein, the terms “release” and “release rate” are used interchangeably to refer to the expulsion or release of a substance (including, but not limited to, therapeutic agents such as NO) from a dosage form or composition containing that substance, or the rate at which such a substance is released. In one example, the therapeutic agent may be released in vitro. On the other hand, the therapeutic agent may be released in vivo.

[0021] As used herein, “immediate release” or “once-in-time release” may be used interchangeably and refers to the immediate or near-immediate (i.e., uninhibited or unrestricted) release of an agent or substance (including therapeutic agents such as NO) from a composition or formulation.

[0022] As used herein, the term "controlled release" refers to the non-immediate release of an agent or substance (including therapeutic agents, such as NO) from a composition or formulation. Examples of specific types of controlled release include, but are not limited to, prolonged or sustained release and delayed release. Many control mechanisms or components can be used to produce a controlled release effect, including formulation ingredients or composition, formulation properties or states, such as pH, the environment in which the formulation is placed, or a combination of formulation ingredients and the environment in which the formulation is placed. In one example, prolonged release may include releasing the therapeutic agent at a level sufficient to provide a therapeutic effect or treatment for a non-immediately specified or anticipated duration.

[0023] As used in this article, the term "regulation" refers to any change in the state of an organism, i.e., increase, decrease, etc.

[0024] As used in this article, when describing gas mixtures, units such as "parts per million," "ppm," "parts per billion," and "ppb" are based on volume. Therefore, one part per million is equivalent to one volume part out of a total of one million volume parts.

[0025] As used herein, comparative terms such as “increase,” “decrease,” “better,” “worse,” “higher,” “lower,” “enhance,” “improve,” “maximize,” “minimize,” etc., refer to the nature of a device, component, composition, biological response, biological state, or activity that is significantly different from its original (e.g., untreated) or baseline state compared to other devices, components, compositions, biological responses, biological states, or activities in the surrounding or adjacent areas, in similar locations, in a single device or composition or in multiple equivalent devices or compositions, belonging to a family or class, or belonging to multiple families or classes of other devices, components, compositions, biological responses, biological states, or activities. For example, a composition that “increases” an immune response provides a higher level of response in a subject compared to a previous time point, such as a baseline level (e.g., before treatment), or compared to an earlier treatment using a different (e.g., a lower dose).

[0026] As used herein, the term "substantially" refers to the extent or degree of completeness or near-completeness of a behavior, characteristic, property, state, structure, item, or result. For example, a "substantially" closed object means that the object is either completely closed or nearly completely closed. In some cases, the exact permissible degree of deviation from absolute completeness may depend on the specific context. However, in general, the degree of near-completeness will be the same as the overall result of achieving absolute or complete completeness. The use of "substantially" also applies when used in a negative sense to refer to the complete or near-complete absence of a behavior, characteristic, property, state, structure, item, or result. For example, a composition "substantially free of" particles will either be completely free of particles or nearly completely free of particles such that the effect is the same as being completely free of particles. In other words, a composition "substantially free of" an ingredient or element may actually still contain such an item, provided that its measurable effect is absent.

[0027] As used herein, the term "about" is used to provide flexibility for the endpoint of a numerical range by indicating that a given value may be "slightly above" or "slightly below" the endpoint. Unless otherwise stated, the use of the term "about" in relation to a specific number or numerical range should also be understood to support such numerical terms or ranges where the term "about" is not used. For example, for convenience and brevity, the numerical range of "about 50 ml to about 80 ml" should also be understood to support the numerical range of "50 ml to 80 ml". Furthermore, it should be understood that in this specification, even where the term "about" is used, support for actual numerical values ​​is provided. For example, the statement "about" 30 should be interpreted as supporting not only values ​​slightly above and slightly below 30, but also the actual value of 30.

[0028] As used herein, for convenience, multiple items, structural elements, constituent elements, and / or materials may be listed in a general list. However, these lists should be interpreted as if each member in the list were individually identified as a separate and unique member. Therefore, without indication to the contrary, no single member in such a list should be construed as being substantially equivalent to any other member in the same list solely based on its presence in a common group.

[0029] Concentration, amount, and other numerical data may be expressed or presented in range format herein. It should be understood that this range format is used merely for convenience and brevity, and therefore should be flexibly interpreted to include not only the values ​​explicitly listed as the limits of the range, but also all individual values ​​or subranges contained within that range, as if each value and subrange were explicitly listed. For example, the numerical range “about 1 to about 5” should be interpreted to include not only the explicitly listed values ​​of about 1 to about 5, but also the individual values ​​and subranges within that indicated range. Thus, the numerical range includes individual values ​​such as 2, 3, and 4, and subranges such as 1-3, 2-4, and 3-5, as well as individually 1, 2, 3, 4, and 5, and further includes decimal or fractional values ​​such as 1.8, 2.3, 3.7, and 4.2.

[0030] The same principle applies to ranges that list only one numerical value as the minimum or maximum. Furthermore, this interpretation should apply regardless of the breadth of the range or characteristic being described.

[0031] Throughout this specification, references to "example" mean that a particular feature, structure, or characteristic described in connection with the example is included in at least one implementation. Therefore, the phrase "in the example" appearing in various places throughout this specification does not necessarily refer to the same implementation.

[0032] Preferred embodiments of the invention will now be described in detail. While the invention will be described in conjunction with preferred embodiments, it should be understood that this is not intended to limit the invention to these preferred embodiments. Rather, the invention is intended to cover alternatives, variations, modifications, and equivalents that may fall within the spirit and scope of the invention as defined by the appended claims.

[0033] Example Implementation The following provides an initial overview of embodiments of the present invention, followed by a detailed description of specific embodiments. This initial overview is intended to help the reader understand the technical concept more quickly, but is not intended to identify its key or essential features, nor is it intended to limit the scope of the claimed subject matter.

[0034] This disclosure describes methods and compositions that can be used to treat conditions responsive to NO treatment. The methods and compositions can be used to treat a variety of specific indications. These indications include, but are not limited to, wounds, skin infections, fungal infections, respiratory infections, bacterial infections, viral infections, athlete's foot, onychomycosis, influenza, sinusitis, throat infections, acne, diabetic foot ulcers, warts, the common cold, respiratory syncytial virus, coronaviruses, etc. In some examples, NORS can be administered to provide NO gas that can kill and / or inactivate pathogens such as fungi, bacteria, and viruses. In other examples, NO gas can provide additional therapeutic effects.

[0035] In some examples, a method for treating a condition in which a subject responds to nitric oxide (NO) treatment may include applying a volume of nitric oxide releasing solution (NORS) to the subject's application site for the duration of treatment, the NORS providing a therapeutically effective amount of NO. In other words, NO gas is exposed to the application site during the duration of treatment. In some cases, the application site may be a location on or inside the subject's body. In some examples, the application site may be a diseased area. In further examples, the application site may be a mucous membrane, such as the subject's nasal passages, sinuses, mouth, pharynx, lungs, or other areas of their respiratory system. In even further examples, the application site may be a skin area of ​​the subject, the subject's feet, or the subject's nails, such as toenails or fingernails.

[0036] Furthermore, NORS can be applied in various forms depending on its intended use. In one embodiment, NORS can be a spray, such as a nasal spray, sinus spray, throat spray, or topical spray for skin. In another embodiment, NORS can be a mouthwash or gargling solution. In a further embodiment, NORS can be a sinus wash. In another embodiment, NORS can be a liquid bath for soaking the application site, such as a foot bath. In yet another embodiment, NORS can be soaked in a cloth or substrate for use as a wipe. In yet another embodiment, NORS can be an aerosol. In a further embodiment, NORS can be a gel or cream. Almost any form suitable for application to a specific designated site can be used.

[0037] In some embodiments, NORS provides a prolonged release of gaseous nitric oxide (gNO) upon application to a site. "Prolonged release" refers to the release of an effective amount of NO gas from the formulation at a controlled rate, such that a therapeutically beneficial level of gNO is maintained (but below toxic levels) for an extended period of time. Specific examples of various NORS, including prolonged-release NORS, can be found in U.S. Patent No. 9,730,956, which is incorporated herein by reference. The benefit of prolonged-release NORS is that the solution can be applied to a site over a short period of time, while the release of NO from the solution continues after application.

[0038] The NORS described herein may include solutions of nitrite and acid. In some examples, the solution may become active—when nitrite and acid are mixed in brine or water, wherein the pH of the solution is below 4.0 and exhibits increased or elevated levels of nitric oxide gas production over an extended period of time. In one embodiment, the pH of the active state of the nitric oxide releasing solution is between a pH of about 1.0 and a pH of about 4.0. In another embodiment, the pH of the active state of the nitric oxide releasing solution is between a pH of about 3.0 and a pH of about 4.0. In one embodiment, the pH is about 3.2. In another embodiment, the pH is about 3.6. In another embodiment, the pH is about 3.7. In one embodiment, the pH is about 4.0. In another embodiment, the pH is below about 4.0. Because the nitric oxide releasing solution of the present invention is inactive before the acid in the liquid interacts with the nitrite ions, the nitrite solution can be pre-prepared, transported, and set up for administration in its dormant state (pH greater than 4.0) without producing any perceptible nitric oxide gas or losing its ability to produce an effective amount of nitric oxide gas. Then, when the user is ready to deliver or apply the solution to a human subject for treatment, the solution can be activated immediately before application to the human subject by adding acid (driving the pH below 4.0), thereby maximizing the amount of nitric oxide gas produced by the applied dose of solution.

[0039] In one embodiment, the pH of the solution can be lowered by adding at least one acidifying agent to the solution. The introduction of the acidifying agent drives the solution to react with the reactants, thereby lowering the pH (producing more acid), and consequently producing more nitric oxide gas.

[0040] For example, by introducing sodium nitrite (or other nitrites) into a saline solution, it produces nitric oxide gas very slowly, but in an amount undetectable (e.g., by chemiluminescence analysis with ppb sensitivity). The rate of NO production from the solution increases as the pH decreases, particularly below 4.0. NO is produced according to the following equilibrium equation: Therefore, acidifying agents (such as acids) can react with H. + Provided with nitrite (NO2) - The existence of H. + The more [hydrogen] present, the faster the reaction with HNO2, and the more NO is produced.

[0041] In one embodiment, the nitric oxide-releasing solution comprises at least one nitric oxide-releasing compound, such as nitrite, nitrite, or metal nitrite. In one embodiment, the solution is a salt-based solution. In one embodiment, the nitric oxide-releasing compound is nitrite, its salts, or any combination thereof. Non-limiting examples of nitrite include: salts of nitrite, such as sodium nitrite, potassium nitrite, magnesium nitrite, barium nitrite, and calcium nitrite; mixed salts of nitrite, such as orotic nitrite; nitrite esters, such as amyl nitrite; and metal nitrites, such as silver nitrite or copper nitrite. In one embodiment, the nitric oxide-releasing compound is selected from sodium nitrite and potassium nitrite, and any combination thereof. In another embodiment, the nitric oxide-releasing compound is sodium nitrite. In one embodiment, the solution comprises an aqueous solution of sodium nitrite. In another embodiment, the solution comprises an aqueous solution of potassium nitrite.

[0042] In one embodiment, the concentration of nitrite in the solution may be from about 0.1% w / v to about 1.5% w / v. In another embodiment, the concentration of nitrite may be between 0.07% w / v and about 0.5% w / v. In one embodiment, the concentration of nitrite in the solution is not greater than about 0.5% w / v. In another embodiment, the concentration of nitrite in the solution is not greater than about 0.8% w / v. In another embodiment, the concentration of nitrite in the solution is not greater than about 1% w / v. In yet another embodiment, the concentration of nitrite in the solution is between about 0.07% and 0.5% w / v. In another embodiment, the concentration of nitrite in the solution is from about 0.2% to about 0.4% w / v. In yet another embodiment, the concentration of nitrite in the solution is from about 0.4% to about 0.7% w / v. In yet another embodiment, the concentration of nitrite in the solution is from about 0.7% to about 0.9% w / v. In yet another embodiment, the concentration of nitrite in the solution is from about 0.9% to about 1.3% w / v. As used herein, the term “w / v” means (weight of solute in grams / volume of solution in milliliters) × 100%.

[0043] The solution of the present invention may also contain at least one acidifying agent. As described elsewhere herein, adding at least one acidifying agent to the solution of the present invention helps to increase NO production. The present invention contemplates any acidifying agent that provides increased NO production. In one embodiment, the acidifying agent is an acid. In some examples, the acid may be a weak acid. In other examples, the acid may be a strong acid. In further examples, the acid may include a mixture of strong and weak acids. In still further examples, the acid may be an organic acid. In other examples, the acid may be an inorganic acid. In further examples, the acid may include a combination of organic and inorganic acids. Non-limiting examples of acids include ascorbic acid, palmitic ascorbate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, and phosphoric acid. In one embodiment, the acid is selected from ascorbic acid, citric acid, malic acid, hydrochloric acid, and sulfuric acid, and any combination thereof. In one embodiment, the acid is citric acid.

[0044] As described above, the amount of acidifying agent present in the solution can affect the rate of NO production. In some embodiments, the amount of acidifying agent is from about 0.1% to about 4% w / v. In one embodiment, the amount of acidifying agent is no more than about 0.5% w / v. In another embodiment, the amount of acidifying agent is about 0.5% w / v. In another embodiment, the amount of acidifying agent is about 0.2% w / v. In one embodiment, the amount of acidifying agent is about 0.07% w / v. In another embodiment, the amount of acidifying agent is between about 0.07% and 0.5% w / v. In yet another embodiment, the amount of acidifying agent is from about 0.2% to about 0.4% w / v. In another embodiment, the amount of acidifying agent is from about 0.4% to about 0.7% w / v. In another embodiment, the amount of acidifying agent is from about 0.7% to about 0.9%. In yet another embodiment, the amount of acidifying agent is from about 0.9% to 1.3% w / v. In another embodiment, the amount of acidifier is about 1.3% to about 2% w / v. In another embodiment, the amount of acidifier is about 2% to about 3% w / v. In yet another embodiment, the amount of acidifier is about 3% to about 4% w / v.

[0045] As mentioned above, NO gas can be unstable and has a relatively short half-life. Therefore, in some examples, NO gas may be available for a limited time after NO is released from NORS. In various examples, NORS can be a two-part composition. In some embodiments, NORS can be prepared just before application to the treatment site by applying an acidifier to a standby solution. For example, as described elsewhere herein, applying an acidifier to the standby solution causes a decrease in the pH of the standby solution, thereby activating the nitric oxide releasing solution to be applied to the treatment site. The nitric oxide releasing solution provides prolonged nitric oxide production. In one embodiment, the nitric oxide releasing solution produces nitric oxide for a period between 1 minute and 24 hours. In one embodiment, the nitric oxide releasing solution produces nitric oxide for a period between 10 and 45 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 15 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 30 minutes. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 1 hour. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 4 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 8 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 12 hours. In yet another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 24 hours. Therefore, the applied nitric oxide releasing solution provides continuous delivery of nitric oxide to the treatment site of the subject.

[0046] In some examples, the rate of NO production by NORS can vary over time. For instance, NORS can be prepared by mixing an acidifying agent with a standby solution, and the NORS can immediately begin releasing NO gas at a specific rate. In some cases, the reaction that forms NO gas may have an initial ramp-up period, during which the rate of NO production can increase to a peak rate. After the peak rate, the NO production rate decreases over time until the reaction is eventually substantially complete. The initial rate of NO production, the peak NO yield, and the time it takes for the NO production rate to decrease can vary depending on the formulation of the NORS.

[0047] In some examples, the amount of NO produced by NORS can be measured and quantified using the methods and apparatus described in U.S. Patent Application Serial No. 16 / 541,084—published as U.S. Patent Application Publication No. 2020 / 0110067 (hereinafter referred to and as herein)—. In one example, NO produced by NORS can be measured by releasing NO from NORS into a carrier gas stream. The concentration of NO in the carrier gas can then be quantified using an NO gas detector. Any suitable detector type can be used, such as a chemiluminescence detector, an electrochemical detector, a fluorescence detector, a mass spectrometer, etc. In some examples, the NO detector can be a chemiluminescence detector. Chemiluminescence is an analytical technique that typically involves the emission of light resulting from a chemical reaction. More specifically, the decay of molecules in an excited state to a lower energy state can cause the emission of light, which can be detected by a chemiluminescence analyzer / detector. As an example, nitric oxide (NO) can react with ozone (O3) to produce excited NO, which subsequently decays to a lower energy state and emits photoelectrically detectable electromagnetic radiation. In some examples, the detector can measure the concentration of NO gas in a carrier gas stream. The unit of concentration can be, for example, parts per million (ppm) or parts per billion (ppb). In one example, the detector could be a Sievers™ Nitric Oxide Analyzer 280i or a Zysense™ Nitric Oxide Analyzer 280i available from Zysense (USA).

[0048] When measuring NO release from NORS, several parameters can be adjusted. For example, the carrier gas flow rate and pressure can be adjusted. When the rate of NO production by the NORS remains constant, increasing the carrier gas flow rate will result in a decrease in the NO concentration measured by the detector because NO mixes with a larger volume of carrier gas. Conversely, decreasing the carrier gas flow rate will have the opposite effect. In some examples, the carrier gas flow rate can range from about 0.025 liters per minute (L / min) to about 10 L / min. In some examples, a standard flow rate can be selected so that the NO release rates of different NORS formulations can be compared. In one example, the flow rate could be 1 L / min. In other examples, the flow rate could be 0.5 L / min, 2 L / min, 3 L / min, or 5 L / min.

[0049] Furthermore, in some examples, the carrier gas may be selected from a gas that is inert relative to NO. In some examples, the carrier gas may contain no or substantially no oxygen or other reactive gaseous substances. In further examples, the carrier gas may include nitrogen, rare gases, helium, argon, neon, krypton, xenon, radon, or combinations thereof.

[0050] In a further example, the amount of NO gas produced over time can be quantified by measuring the NO gas concentration at different time points and then multiplying that concentration by the time it took to produce that NO concentration. At a given carrier gas flow rate, the concentration of NO gas in the carrier gas can be proportional to the rate at which NO gas is produced from the NORS. For example, if the NORS produces a sufficient amount of NO gas at a concentration of 100 ppm, and this concentration remains stable at 100 ppm for 30 minutes, the total amount of NO produced can be given by multiplying 100 ppm by 30 minutes to give 3,000 ppm. The unit is "min" for quantification. If the carrier gas flow rate is known, then the unit is "ppm". "min" can correspond to the actual amount of NO generated.

[0051] In practice, NORS formulations may frequently produce NO at continuously varying rates. Therefore, it is impossible for NORS to produce NO at a stable concentration of 100 ppm for 30 minutes. To accurately quantify the amount of NO gas produced, the NO concentration in the carrier gas can be measured at numerous time points. These measurements form a curve representing the change in concentration data points over time. By integrating the area under this curve (AUC), the NO concentration at ppm can be determined. The unit is the total amount of NO, expressed as min. In other examples, different units may be used, such as different concentration measures and different time measures. Other examples of units may include, for example, ppb. min or ppb s or ppb The AUC can be calculated by integrating the curve of concentration data points using numerical integration methods, such as multiplying each concentration data point by the time interval between the data points and summing the products. In various examples, the time interval between data points can be any suitable time period, such as from 1 / 1000 of a second to 1 minute or longer. The shorter the time interval between measurements, the more data points can be generated, which in some examples provides a more accurate AUC. In some examples, measurements can be obtained using a computer connected to the NO detector, and the computer can be programmed to calculate the AUC.

[0052] In some examples, standard procedures can be followed to measure the concentration of NO produced by NORS. Standard methods can also be used to calculate various quantities, such as ppm of NO produced over a given time period. Minutes, or peak NO concentration, etc. NO produced by different NORS formulations can be quantified using the same standard method, allowing for comparison between different NORS formulations. In specific examples, a certain volume of NORS can be introduced into the sample chamber. Any volume of NORS can be used. In some examples, the volume can be 1 mL, 2 mL, 3 mL, 5 mL, or other amounts. In some examples, the sample chamber can be made of a material inert relative to NO. In other examples, the sample chamber can have an inert liner relative to NO. The carrier gas can flow through the sample chamber at a fixed flow rate. In one example, the flow rate can be 1 L / min at standard temperature and pressure. In another example, the carrier gas can be nitrogen. The NORS can release NO into the flowing carrier gas, and the mixture of carrier gas and NO gas can exit the sample chamber through an outlet. A chemiluminescence detector can be connected to the carrier gas flow mixed with NO flowing from the outlet. The chemiluminescence detector measures the concentration of NO in the gas mixture. Measurements can be performed at specified time intervals, such as once per minute, once per second, once every 1 / 10 of a second, or other time intervals. These measurements can be recorded as data points over a 30-minute time period. AUC can be calculated based on the data points. This quantity can be expressed in ppm. The unit is min, and this can represent the total amount of NO gas released from the NORS sample over a 30-minute period. In a further example, the amount of NO released from one mL of NORS can be expressed in ppm. Calculated in min / mL. If the volume of NORS introduced into the sample chamber is 1 mL, then AUC is expressed in ppm. The same value is expressed in min / mL. If a larger volume of NORS is used, such as 5 mL, then the AUC can be divided by the number of mL used to obtain the value in ppm. NO release amount measured in min / mL.

[0053] Using the same measurement procedure, the peak NO concentration can be obtained by taking the highest measurement value returned by the chemiluminescence detector. In some examples, the chemiluminescence detector can return the measurement value in ppm. Therefore, the peak NO concentration can be the highest instantaneous value in ppm measured within 30 minutes.

[0054] In some examples, when measured over a 30-minute period at a pressure of 1 atm and a carrier gas flow rate of 1 L / min, 1 mL of NORS can release the desired amount of NO gas, as described above. In some examples, the amount of NO released by NORS can be approximately 1 ppm. min / mL to approximately 500 ppm min / mL. In other examples, the amount of NO may be approximately 1 ppm. min / mL to approximately 100 ppm min / mL, or about 1 ppm min / mL to approximately 60 ppm min / mL, or about 5 ppm min / mL to approximately 100 ppm min / mL, or approximately 10 ppm min / mL to approximately 100 ppm min / mL, or approximately 20 ppm min / mL to approximately 100 ppm min / mL. In a further example, when 1 mL NORS is used to release NO gas into a carrier gas at 1 atm for 30 minutes at a rate of 1 L / min, the NORS can release NO gas at peak concentrations of about 0.1 ppm / mL to about 20 ppm / mL, as described above. In specific examples, the peak concentration of NO released from 1 mL NORS can be about 0.3 ppm / mL to about 15 ppm / mL or about 0.5 ppm / mL to about 12 ppm / mL.

[0055] NORS can be administered in a variety of forms. NORS can be administered as a liquid, spray, vapor, droplets, mist, gargle, lavage, aerosol, gel, cream, or any form that provides the release of nitric oxide from solution. In one embodiment, NORS is administered as a spray. The amount or volume of the administered nitric oxide-releasing solution can be varied to optimize the duration of nitric oxide production and delivery. In one embodiment, the amount of the administered nitric oxide-releasing solution is between about 0.1 mL and 5000 mL. In another embodiment, the amount of the administered nitric oxide-releasing solution is between about 10 mL and 1000 mL. In a further embodiment, the amount of NORS administered can be from about 0.1 mL to about 1 mL, or from about 0.1 mL to about 2 mL, or from about 0.1 mL to about 5 mL, or from about 0.5 mL to about 1 mL, or from about 0.5 mL to about 2 mL, or from about 5 mL to about 500 mL, or from about 100 mL to about 300 mL, or from about 500 mL to about 5000 mL. Some types of NORS formulations can be applied in relatively large quantities, such as those used for bathing, washing, etc. Other types of NORS formulations can be used in smaller volumes, such as gels or creams applied to small local areas, or nasal sprays. Some types of NORS formulations can be used in intermediate volumes, such as oral rinsings and sinus rinsings.

[0056] When the total dose of NORS is measured as described above by releasing NO from NORS into a carrier gas flow at 1 L / min and 1 atm for 30 minutes, the total amount of NO released can be expressed in ppm. Quantification is performed in min. In some examples, the amount of NO released from a given dose of NORS can be approximately 10 ppm. min to approximately 75,000 ppm min. In a further example, the amount of NO could be approximately 25,000 ppm. min to approximately 75,000 ppm min, or about 10 ppm min to approximately 100 ppm min, or about 20 ppm min to approximately 100 ppm min, or about 50 ppm min to approximately 200 ppm min, or about 100 ppm min to approximately 500 ppm min, or approximately 1,000 ppm min to approximately 10,000 ppm The peak NO concentration can be measured over a 30-minute period, depending on the volume of the dose and the formulation of the NORS. In a further example, a dose of NORS can release a peak NO concentration over a 30-minute measurement period. The peak concentration can be about 1 ppm to about 25,000 ppm, or about 2 ppm to about 10 ppm, or about 2 ppm to about 20 ppm, or about 20 ppm to about 100 ppm, or about 100 ppm to about 200 ppm, or about 200 ppm to about 500 ppm, or about 1,000 ppm to about 5,000 ppm, or about 15,000 ppm to about 25,000 ppm.

[0057] In some embodiments, the nitric oxide-releasing solution is applied directly to the subject's upper respiratory tract. For example, in one embodiment, the nitric oxide-releasing solution is sprayed into the subject's upper respiratory tract. The solution can be applied to the subject's upper respiratory tract once an hour, once a day, once a week, once every two weeks, once a month, once every two months, once a year, and anywhere in between, for the treatment of the subject. In one embodiment, the solution is sprayed once a week. In another embodiment, the solution is sprayed once a week for four consecutive weeks. The nitric oxide-releasing solution provides prolonged nitric oxide production, thereby providing a continuous delivery of therapeutic nitric oxide to the subject's upper respiratory tract infection.

[0058] The duration of application of the nitric oxide-releasing solution to the subject can be varied to optimize delivery. In one embodiment, the nitric oxide-releasing solution is applied over a period of less than 5 seconds. In another embodiment, the nitric oxide-releasing solution is applied over a period of about 5 seconds. In another embodiment, the nitric oxide-releasing solution is applied over a period of about 30 seconds. In yet another embodiment, the nitric oxide-releasing solution is applied over a period of about 1 minute to about 20 minutes. The nitric oxide-releasing solution can also be applied according to a dosing regimen that may include single or multiple doses administered at specific times. In some examples, the dose may be administered at a frequency of about once a day to about 5 times a day, or about once a day to about once every 50 days, or about once a day to about once a week.

[0059] It should be noted that the time period during which a dose of NORS is administered to a subject may differ from the time period used to characterize the NORS formulation by measuring the concentration of NO gas released from the NORS. As mentioned above, in some examples, standard procedures may be used to characterize the NORS formulation and quantify the amount of NO gas released by the NORS. Standard procedures may require measuring NO release over a period of time, such as 30 minutes. However, when administering the NORS formulation to a subject, the time period for administering a dose of NORS may vary. Similarly, the volume of NORS administered to the subject may differ from the volume used in the measurement procedure used to quantify the amount of NO released from the NORS. Therefore, the actual amount of NO delivered to the subject may differ from the amount released during a standard measurement.

[0060] Treating respiratory diseases according to the present invention includes delivering a nitric oxide-releasing solution into the upper respiratory tract of a subject. For example, in some embodiments, the nitric oxide-releasing solution may be injected, sprayed, inhaled, or instilled into the subject's respiratory tract. The nitric oxide-releasing solution may be applied to the subject's respiratory tract via the nasal cavity or oral cavity. In one embodiment, the nitric oxide-releasing solution is sprayed into the subject's upper respiratory tract. In one embodiment, the solution is applied intranasally to the subject. In one embodiment, the solution is applied to the sinuses. The nitric oxide-releasing solution provides prolonged nitric oxide production, thereby providing a continuous delivery of therapeutic nitric oxide to the subject's upper respiratory tract.

[0061] In other examples, the skin of a subject can be treated by applying a nitric oxide-releasing solution to a skin area. The nitric oxide-releasing solution can be a liquid bath, spray, cream, gel, or other form applicable to the skin. In some examples, the skin of the foot can be treated by applying a nitric oxide-releasing solution to the skin of the foot. In further examples, fingernails, toenails, or the skin around them can be treated by applying a nitric oxide-releasing solution to the fingernails, toenails, or the skin around them. In various examples, a specific dose of nitric oxide can be provided to the specific application site. The nitric oxide can be provided by a nitric oxide-releasing solution formulated to provide that specific dose of nitric oxide.

[0062] In one example, NORS can be used to treat athlete's foot. Athlete's foot can be treated by applying NORS formulated to provide a therapeutically effective dose of NO. In some examples, NO can be applied to the application site on the subject's foot. In a particular example, NORS can be in the form of a liquid solution. The liquid solution can be used as a foot bath. The subject's feet can be dipped or immersed in the foot bath for the duration of treatment.

[0063] In some examples, NORS used to treat athlete's foot releases a specific amount of NO gas—measured when this is done over a 30-minute period by releasing NO gas into an inert carrier gas stream at a flow rate of 1 L / min and a pressure of 1 atm. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 25,000 ppm. min to approximately 75,000 ppm In a further example, the amount of NO released from one mL of NORS can be approximately 5 ppm. min / mL to approximately 15 ppm In a further example, the volume of the NORS dose can be from about 500 mL to about 10,000 mL. In a further example, the NORS dose can release a peak NO concentration of from about 5,000 ppm to about 20,000 ppm.

[0064] NORS can be formulated to provide a therapeutic amount of NO for treating athlete's foot. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0065] In some examples, treatment of athlete's foot may include administering NORS according to a dosage regimen of soaking the feet in a foot bath containing NORS for 30 minutes. In further examples, a dosage regimen may include soaking the feet in a foot bath once every 4 days.

[0066] In another example, NORS can be used to treat onychomycosis. Onychomycosis can be treated by applying NORS formulated to provide a therapeutically effective dose of NO. In some examples, NO can be applied to the application site on the subject's toenail or fingernail. In specific examples, NORS can be in the form of a liquid solution, gel, or cream. Liquid solutions, gels, or creams can be applied to the subject's nails for the duration of treatment.

[0067] In some examples, NORS used to treat onychomycosis can release a specific amount of NO gas—measured when the release of NO gas into an inert carrier gas flow at a rate of 1 L / min and a pressure of 1 atm over a period of 30 minutes. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 25 ppm. min to approximately 75 ppm In a further example, the amount of NO released from one mL of NORS can be approximately 25 ppm. min / mL to approximately 75 ppm In a further example, the volume of the NORS dose can be from about 0.1 mL to about 2 mL. In a further example, the NORS dose can release a peak NO concentration of about 5 ppm to about 20 ppm.

[0068] NORS can be formulated to provide a therapeutic amount of NO for the treatment of onychomycosis. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0069] In some examples, treatment for onychomycosis may include administering NORS according to a dosage regimen that applies NORS to the nails daily for a period of 5 to 30 days.

[0070] In another example, NORS can be used to treat influenza. Influenza can be treated by administering NORS formulated to provide a therapeutically effective dose of NO. In some examples, NO can be administered to the nasal cavity of the subject. In specific examples, NORS can be in the form of a nasal spray. The nasal spray can be applied to the subject's nasal cavity for the duration of treatment.

[0071] In some examples, NORS used to treat influenza can release a specific amount of NO gas—measured when measured over a 30-minute period by releasing NO gas into an inert carrier gas flow at a rate of 1 L / min and a pressure of 1 atm. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentrations in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 1 ppm. min to approximately 15 ppm min or about 5 ppm min to approximately 10 ppm min. In a further example, the amount of NO released from one mL of NORS can be approximately 2 ppm. min / mL to approximately 30 ppm In a further example, the volume of the NORS dose may be from about 0.1 mL to about 2 mL or from about 0.1 mL to about 1 mL. In a further example, the NORS dose may release a peak NO concentration of about 0.5 ppm to about 5 ppm.

[0072] NORS can be formulated to provide a therapeutic amount of NO for the treatment of influenza. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0073] In some examples, methods of treating influenza may include administering NORS as needed, according to the dosage regimen for nasal sprays.

[0074] In another example, NORS can be used to treat respiratory viral infections. Respiratory viral infections, such as the common cold, respiratory syncytial virus, and coronaviruses, can be treated by administering NORS formulated to provide a therapeutically effective dose of NO. In some examples, NO can be administered to the nasal cavity of the subject at the application site. In specific examples, NORS can be in the form of a nasal spray. The nasal spray can be applied to the subject's nasal cavity for the duration of treatment.

[0075] In some examples, NORS used to treat respiratory viral infections can release a specific amount of NO gas—measured when this is done by releasing NO gas into an inert carrier gas stream at a flow rate of 1 L / min and a pressure of 1 atm for 30 minutes. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 1 ppm. min to approximately 15 ppm min or about 5 ppm min to approximately 10 ppm min. In a further example, the amount of NO released from one mL of NORS can be approximately 2 ppm. min / mL to approximately 30 ppm In a further example, the volume of the NORS dose may be from about 0.1 mL to about 2 mL or from about 0.1 mL to about 1 mL. In a further example, the NORS dose may release a peak NO concentration of about 0.5 ppm to about 5 ppm.

[0076] NORS can be formulated to provide a therapeutic amount of NO for the treatment of respiratory viral infections. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0077] In some examples, methods for treating respiratory viral infections may include administering NORS as needed, according to the dosage regimen for nasal sprays.

[0078] In another example, NORS can be used to treat sinusitis. Sinusitis can be treated by administering NORS formulated to provide a therapeutically effective dose of NO. In some examples, the NO can be administered to the application site within the sinus cavity of the subject. In specific examples, NORS can be in the form of a liquid lavage agent or flushing solution. In some examples, the liquid lavage agent or flushing solution may have a volume of about 240 mL or less.

[0079] In some examples, NORS used to treat sinusitis can release a specific amount of NO gas—measured when the release of NO gas into an inert carrier gas flow at a rate of 1 L / min and a pressure of 1 atm is performed over a period of 30 minutes. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 100 ppm. min to approximately 5,000 ppm min, or about 100 ppm min to approximately 500 ppm min, or about 500 ppm min to approximately 2,000 ppm min, or approximately 2,000 ppm min to approximately 5,000 ppm In a further example, the amount of NO released from one mL of NORS can be approximately 0.5 ppm. min / mL to approximately 30 ppm min / mL, or about 1 ppm min / mL to approximately 4 ppm min / mL, or about 4 ppm min / mL to approximately 10 ppm min / mL, or approximately 10 ppm min / mL to approximately 30 ppm In a further example, the volume of the NORS dose can be from about 150 mL to about 300 mL. In a further example, the NORS dose can release a peak NO concentration of from about 50 ppm to about 1,500 ppm.

[0080] NORS can be formulated to provide a therapeutic amount of NO for the treatment of (nasal)sinusitis. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0081] In some examples, treatment of influenza may include administering NORS according to a dosage regimen of daily administration of NORS for a period of approximately 10 to approximately 50 days.

[0082] In another example, NORS can be used to treat throat infections. Throat infections can be treated by administering NORS formulated to provide a therapeutically effective dose of NO. In some examples, the NO can be delivered to the application site, i.e., the subject's throat. In specific examples, NORS can be in the form of a mouthwash solution. The subject can gargle with the solution for the duration of treatment.

[0083] In some examples, NORS used to treat throat infections can release a specific amount of NO gas—measured when measured over a 30-minute period by releasing NO gas into an inert carrier gas stream at a flow rate of 1 L / min and a pressure of 1 atm. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 200 ppm. min to approximately 800 ppm min or approximately 400 ppm min to approximately 600 ppm min. In a further example, the amount of NO released from one mL of NORS can be approximately 10 ppm. min / mL to approximately 40 ppm In a further example, the volume of the NORS dose may be from about 5 mL to about 40 mL or from about 10 mL to about 30 mL. In a further example, the NORS dose may release a peak NO concentration of about 100 ppm to about 200 ppm.

[0084] NORS can be formulated to provide a therapeutic amount of NO for the treatment of throat infections. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0085] In some examples, treatment of throat infections may include administering NORS according to a dosage regimen of 1 to 3 times daily for approximately 1 to 5 days.

[0086] In another example, NORS can be used to treat acne. Acne can be treated by applying NORS formulated to provide a therapeutically effective dose of NO. In some examples, NO can be applied to an application site on a region of the subject's skin. In specific examples, NORS can be in the form of a gel or cream. NORS can be applied to the subject's skin for the duration of treatment.

[0087] In some examples, NORS used to treat acne can release a specific amount of NO gas—measured when the release of NO gas into an inert carrier gas flow at a rate of 1 L / min and a pressure of 1 atm over a period of 30 minutes. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 10 ppm. min to approximately 60 ppm min or approximately 20 ppm min to approximately 60 ppm In a further example, the amount of NO released from one mL of NORS can be approximately 5 ppm. min / mL to approximately 30 ppm In a further example, the volume of the NORS dose can be from about 1 mL to about 5 mL. In a further example, the NORS dose can release a peak NO concentration of from about 5 ppm to about 20 ppm.

[0088] NORS can be formulated to provide a therapeutic amount of NO for the treatment of acne. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0089] In some examples, methods of treating acne may include administering NORS according to a dosage regimen in which NORS is applied to the skin 1 to 3 times daily for a period of about 10 to about 50 days.

[0090] In another example, NORS can be used to treat diabetic foot ulcers. Diabetic foot ulcers can be treated by applying NORS formulated to provide a therapeutically effective dose of NO. In some examples, the NO can be applied to the application site on the subject's foot. In specific examples, NORS can be in the form of a liquid solution or gel in a foot bath. NORS can be applied to the subject's foot for the duration of treatment.

[0091] In some examples, NORS used to treat diabetic foot ulcers can release a specific amount of NO gas—measured when the release of NO gas into an inert carrier gas flow at a rate of 1 L / min and a pressure of 1 atm over a period of 30 minutes. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 100 ppm. min to approximately 75,000 ppm min, or about 100 ppm min to approximately 400 ppm min, or approximately 25,000 ppm min to approximately 75,000 ppm In a further example, the amount of NO released from one mL of NORS can be approximately 5 ppm. min / mL to approximately 80 ppm min / mL, or approximately 10 ppm min / mL to approximately 60 ppm In a further example, the volume of the NORS dose can be from about 5 mL to about 10,000 mL. In a further example, the NORS dose can release a peak NO concentration of from about 50 ppm to about 20,000 ppm.

[0092] NORS can be formulated to provide a therapeutic amount of NO for the treatment of diabetic foot ulcers. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0093] In some examples, methods of treating diabetic foot ulcers may include administering NORS according to a dosage regimen in which NORS is applied to the subject's foot 1 to 3 times daily for a period of about 10 to about 30 days.

[0094] In another example, NORS can be used to treat warts. Warts can be treated by applying NORS formulated to provide a therapeutically effective dose of NO. In some examples, NO can be applied to an application site on a region of the skin. In specific examples, NORS can be in the form of a gel or a liquid solution. NORS can be applied to the skin of a subject for the duration of treatment.

[0095] In some examples, NORS used to treat warts can release a specific amount of NO gas—measured when measured over a 30-minute period by releasing NO gas into an inert carrier gas stream at a flow rate of 1 L / min and a pressure of 1 atm. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 20 ppm. min to approximately 400 ppm min, or about 20 ppm min to approximately 80 ppm min, or about 200 ppm min to approximately 400 ppm min. In a further example, the amount of NO released from one mL of NORS can be approximately 10 ppm. min / mL to approximately 60 ppm In a further example, the volume of the NORS dose can be from about 0.5 mL to about 10 mL. In a further example, the NORS dose can release a peak NO concentration of from about 1 ppm to about 60 ppm.

[0096] NORS can be formulated to provide a therapeutic amount of NO for the treatment of warts. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0097] In some examples, methods of treating warts may include administering NORS according to a dosage regimen in which NORS is applied to the skin 1 to 3 times daily for a period of about 1 day to about 10 days.

[0098] In another example, NORS can be used to disinfect the skin of a subject. Skin can be disinfected by applying NORS formulated to provide a therapeutically effective dose of NO. In some examples, NO can be applied to an application site on a specific area of ​​the subject's skin. In certain examples, NORS can be in the form of a gel or cream. NORS can be applied to the subject's skin for the duration of treatment.

[0099] In some examples, NORS used for skin disinfection can release a specific amount of NO gas—measured when measured over a 30-minute period by releasing NO gas into an inert carrier gas flow at a rate of 1 L / min and a pressure of 1 atm. The concentration of NO in the carrier gas can be periodically measured using a chemiluminescence detector that measures concentration in ppm. The total amount of NO released over 30 minutes can be determined by calculating the area under the curve (AUC) of the measured NO concentration. In some examples, the amount of NO released from a given dose of NORS can be approximately 450 ppm. min to approximately 750 ppm In a further example, the amount of NO released from one mL of NORS can be approximately 5 ppm. min / mL to approximately 25 ppm In a further example, the volume of the NORS dose can be from about 50 mL to about 20 mL. In a further example, the NORS dose can release a peak NO concentration of from about 1 ppm to about 20 ppm.

[0100] NORS can be formulated to provide a therapeutic amount of NO for use in skin disinfection. In some examples, NORS may contain nitrite and an acidifying agent. In some examples, NORS may contain nitrite at a concentration of about 0.1 g / L to about 20 g / L, expressed in grams of nitrite per liter of NORS. In further examples, NORS may contain an acidifying agent at a concentration of about 0.1 g / L to about 60 g / L.

[0101] In some examples, methods of disinfecting the skin may include administering NORS according to a dosage regimen in which NORS is applied to the skin 1 to 3 times daily for a period of about 10 to about 20 days.

[0102] As described above, NORS can be prepared in various forms depending on the specific indication and treatment method. Some forms of NORS that can be prepared include liquid solutions, such as aqueous and saline solutions, mouthwashes, liquid baths, liquid irrigators, liquid rinses, sprays (such as nasal sprays or throat sprays), sinus washes, gels, creams, foams, ointments, lotions, pastes, emulsions, aerosols, etc. In various forms, the NORS composition may contain a combination of the above-mentioned components. In some examples, NORS may contain nitrite and an acidifier, water, and optionally other components such as inactive ingredients. Nitrite and the acidifier may be included in the required amount to produce the desired amount of NO gas. Various inactive ingredients may include stabilizers, carriers, preservatives, emollients, adjuvants, etc.

[0103] In some examples, NORS can be prepared as a liquid solution. As mentioned above, the liquid solution can take many specific forms, such as aqueous solutions, saline solutions, mouthwashes, liquid baths, liquid irrigators, liquid rinses, sprays, sinus washes, etc. In some examples, NORS can be prepared by mixing nitrite and an acidifying agent in water. Nitrite and the acidifying agent can be included in the desired amounts to produce the desired amount of NO gas. Examples of nitrite and acidifying agents, as well as example amounts of these components, have been described above. In some examples, NORS in liquid solution form may also contain stabilizers, carriers, preservatives, emollients, adjuvants, or combinations thereof.

[0104] In examples containing stabilizers, the stabilizer may be included in an amount from about 0.1 wt% to about 50 wt% relative to the total weight of NORS. In further examples, the amount of stabilizer may be from about 1 wt% to about 50 wt%, or from about 1 wt% to about 30 wt%, or from about 1 wt% to about 15 wt%, or from about 1 wt% to about 8 wt%. In some examples, the stabilizer may include oxygen scavengers, lipids, synthetic polymers, natural polymers, copolymers, or combinations thereof.

[0105] In a further example, NORS in liquid solution form may include a carrier, which may include water—including deionized water and / or deoxygenated water—a surfactant, a polymer, or a combination thereof. The surfactant may include lipophilic and hydrophilic surfactants. In some examples, lipophilic surfactants may include monoglycerides and diglycerides of fatty acids, such as mono-linoleic acid esters (e.g., Maisine® 35-1); monoglycerides and diglycerides of caprylic and capric acids (e.g., Capmul® MCM); monooleic acid esters; and reaction mixtures of alcohols or polyols with various natural and / or hydrogenated oils, such as PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g., Labrafil® M 2125 CS), PEG-6 almond oil (e.g., Labrafil® M 1966 CS), PEG-6 apricot kernel oil (e.g., Labrafil® M 1944 CS), PEG-6 olive oil (e.g., Labrafil® M 1980 CS), PEG-6 peanut oil (e.g., Labrafil® M 1969 CS), and PEG-6 hydrogenated palm kernel oil (e.g., Labrafil®).PEG-6 palm kernel oil (e.g., Labrafil® M 2130 BS), PEG-6 triolein (e.g., Labrafil® M 2735 CS), PEG-8 corn oil (e.g., Labrafil® WL 2609 BS), PEG-20 corn glyceride (e.g., Crovol® M40), PEG-20 almond glyceride (e.g., Crovol® A40); lipophilic polyoxyethylene polyoxypropylene block copolymers (e.g., Pluronic® L92, L101, L121, etc.); propylene glycol fatty acid esters, such as propylene glycol monolaurate (e.g., Lauroglycol FCC), propylene glycol ricinoleate (e.g., Propymuls), propylene glycol monooleate (e.g., Myverol P-O6), propylene glycol dicaprylate / dicaprate (e.g., Captex® 200), and propylene glycol dicaptanoate (e.g., Captex® 800), propylene glycol monocaprylate (e.g., Capryol® 90); propylene glycol oleate (e.g., Lutrol OP2000); propylene glycol myristate; propylene glycol monostearate; propylene glycol hydroxystearate; propylene glycol ricinoleate; propylene glycol isostearate; propylene glycol monooleate; propylene glycol dicaprylate / didecanoate; propylene glycol dicaprylate; propylene glycol caprylate-decanoate; propylene glycol dilaurate; propylene glycol distearate; propylene glycol dicaprylate; propylene glycol didecanoate; mixtures of propylene glycol esters and glycerides, such as mixtures of oleates of propylene glycol and glycerol (e.g., Arlacel®). 186); sterols and sterol derivatives, such as cholesterol, sterols, phytosterols, phytosterol fatty acid esters, PEG-5 soybean sterol, PEG-10 soybean sterol, PEG-20 soybean sterol, etc.; glyceryl palmitate stearate, glyceryl stearate, glyceryl distearate, glyceryl monostearate or combinations thereof; sorbitol fatty acid esters, such as sorbitol monolaurate (e.g., Arlacel). 20) Sorbitol monopalmitate (e.g., Span-40), sorbitol monooleate (e.g., Span-80), sorbitol monostearate and sorbitol tristearate, sorbitol monolaurate, sorbitol monopalmitate, sorbitol monooleate, sorbitol trioleate, sorbitol sesquioleate, sorbitol tristearate, sorbitol monoisostearate, sorbitol sesquistearate, etc.; fatty acids, such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidylcholine, bile salts, etc.; and mixtures thereof.

[0106] In other examples, the carrier may include a hydrophilic surfactant. Examples of hydrophilic surfactants include nonionic surfactants, ionic surfactants, and amphoteric surfactants. Specifically, hydrophilic surfactants include, but are not limited to, alcohol-oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulfates, dioctyl sulfosuccinate salts; polyethylene glycol fatty acid esters; mixtures of polyethylene glycol fatty acid monoesters and diesters; polysorbates, polyethylene glycol derivatives of tocopherol, etc. It should be noted that, unless explicitly specified, combinations of two or more hydrophilic surfactants from the same or different classes are also within the scope of this invention and may be collectively referred to as hydrophilic surfactants. Other examples of hydrophilic surfactants may include PEG-8 caprylic / capric glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, mixtures of polyethylene glycol fatty acid monoesters and diesters, polysorbate 80, polysorbate 20, polyethylene glycol 1000 tocopheryl succinate, phytosterols, phytosterol fatty acid esters, and mixtures thereof.

[0107] In some embodiments, the surfactant may include sterols and sterol derivatives. In various embodiments, these surfactants may be hydrophilic or lipophilic. Examples of hydrophilic sterol surfactants are lanosterol PEG-24 cholesterol ether (e.g., Solulan C-24, Amerchol), PEG-30 stigmasterol (e.g., Nikkol BPS-30, from Nikko), PEG-25 phytosterol (e.g., Nikkol BPSH-25, from Nikko), and PEG-30 cholesterol (e.g., Nikkol DHC, from Nikko). Examples of lipophilic sterol surfactants are cholesterol, sterols, phytosterols (e.g., the GENEROL series, from Henkel), PEG-5 stigmasterol (e.g., Nikkol BPS-S, from Nikko), PEG-10 stigmasterol (e.g., Nikkol BPS-10, from Nikko), and PEG-20 stigmasterol (e.g., Nikkol BPS-20, from Nikko).

[0108] In some examples, the surfactant may comprise about 1 wt% to about 20 wt% of the carrier. In other examples, the surfactant may comprise at least 20 wt% of the carrier. In further examples, the surfactant may comprise about 1 wt% to about 10 wt% of the carrier or about 1 wt% to about 5 wt% of the carrier.

[0109] In further examples, the NORS liquid solution composition may contain a preservative. Non-limiting examples of preservatives may include ascorbic acid, acetylcysteine, bisulfite, metabisulfite, monothioglycerol, phenol, m-cresol, benzyl alcohol, methylparaben, propylparaben, butylparaben, benzalkonium chloride, benzyl chloride, butylated hydroxyl toluene, myristyl gamma-picolimium chloride, 2-phenoxyethanol, phenylmercuric nitrate, chlorobutanol, thimerosal, tocopherol, etc., or combinations thereof.

[0110] In some examples, the NORS liquid solution may also contain emollients. Non-limiting examples of emollients include, but are not limited to, aloe vera, lanolin, urea, petrolatum, avocado oil, cocoa butter, mineral oil, paraffin wax, beeswax, squalene, jojoba oil, coconut oil, sesame oil, almond oil, cetyl alcohol, stearyl alcohol, olive oil, oleic acid, triethylhexanoin, glycerin, sorbitol, propylene glycol, cyclomethicone, dimethicone, etc., or combinations thereof. In some examples, the emollient may be included in an amount from about 0.1 wt% to about 20 wt% relative to the total weight of the NORS liquid solution. In further examples, the emollient may be included in an amount from about 0.1 wt% to about 10 wt% or from about 0.1 wt% to about 5 wt%.

[0111] In further examples, the NORS liquid solution may also contain an adjuvant. Some examples of adjuvants may include analgesic adjuvants, aluminum hydroxide, aluminum phosphate, hydroxyapatite, paraffin oil, detergents, plant saponins, cytokines, and combinations thereof. In some examples, the adjuvant may be included in an amount from about 0.1 wt% to about 20 wt% relative to the total weight of the NORS liquid solution. In further examples, the adjuvant may be included in an amount from about 0.1 wt% to about 10 wt% or from about 0.1 wt% to about 5 wt%.

[0112] In other examples, the NORS composition may be in the form of a gel, cream, ointment, lotion, liniment, or paste. Similar to the NORS liquid solution compositions described above, these formulations may also contain nitrite and an acidifying agent in amounts necessary to produce the desired amount of NO gas. Furthermore, these NORS formulations may also contain stabilizers, carriers, preservatives, emollients, adjuvants, or combinations thereof. These components may include those described above, in the amounts stated above.

[0113] In further examples, NORS in the form of gels, creams, ointments, lotions, liniments, or pastes may also contain thickeners, penetration enhancers, or combinations thereof. In some examples, the thickener may include polymers having thickening properties. Non-limiting examples of polymers having thickening properties include, but are not limited to, hydrophobically modified crosslinked acrylate copolymers (Carbopol® Ultrez20). Other polymers with similar properties may also be used. Non-limiting examples of polymers having thickening properties include PEG-150 distearate, PEG-7 glyceryl cocoate, PEG-200 hydrogenated glyceryl palmitate, PEG-120 methyl glucose dioleate, carboxymethyl polymers, carboxyvinyl polymers, acrylates, C10-C30 alkyl acrylate crosslinked polymers, and combinations thereof. Other example thickeners may include polyacrylic acid (e.g., Carbopols, for example), gelatin, pectin, tragacanth gum, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, HPMC, CMC, alginate, starch, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyoxyethylene and polyoxypropylene, polyethylene glycol, etc., or combinations thereof. In some examples, the thickener may be included in an amount of about 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, or about 5 wt% to about 15 wt% of the total weight of the NORS composition.

[0114] In other examples, the NORS may contain a penetration enhancer. Non-limiting examples of penetration enhancers include, but are not limited to, ethanol, propylene glycol, oleic acid and other fatty acids, azones, terpenes, terpenoids, bile acids, isopropyl myristate and other fatty esters, dimethyl sulfoxide, N-methyl-2-pyrrolidone and other pyrrolidones, or combinations thereof. In some examples, the penetration enhancer may be included in an amount of about 0.1 wt% to about 5 wt%, or about 0.1 wt% to about 3 wt%, or about 0.1 wt% to about 2 wt% of the total weight of the NORS composition.

[0115] In further examples, the NORS composition may also contain pyrolytic silica, mica, talc, titanium dioxide, kaolin, aluminum glycinate, ethylenediaminetetraacetic acid, fragrance, colorant, or combinations thereof. In some examples, these additional components may be included in amounts from about 1 wt% to about 20 wt%, or from about 1 wt% to about 10 wt%, or from about 1 wt% to about 5 wt%.

[0116] Experimental Examples Example 1: NO release measurement A series of example nitric oxide-releasing solution formulations were prepared. Individual formulations were formulated to treat specific conditions. Conditions to be treated included: athlete's foot, onychomycosis, influenza, respiratory viral infections such as the common cold, sinusitis, throat infections, acne, diabetic foot ulcers, and warts. Example NORS formulated for skin disinfection were also prepared.

[0117] NO release from the example NORS formulation was tested by measuring the amount of NO gas released from the formulation. The following procedure was used to measure the NO gas. 5 mL of the NORS formulation was introduced into a sample chamber having an inner surface inert to NO. Nitrogen was used as the carrier gas. Nitrogen flowed into the inlet of the sample chamber at a rate of 1 L / min and exited through the outlet. The outlet led to a chemiluminescence detector, which measured the concentration of NO in the gas stream in ppm. The chemiluminescence detector provided the concentration measurements to a computer programmed to record the concentration measurements at regular time intervals over a 30-minute period. The 30-minute period began when the NORS sample was introduced into the sample chamber. The computer was also programmed to calculate the area under the curve (AUC) of the concentration data points, thus deriving the NO concentration in ppm. min represents the total amount of NO released per unit. This value is then divided by a volume of 5 mL to obtain the amount of NO released from one mL of NORS, expressed in ppm. min / mL. The highest ppm concentration measurement was also selected as the peak NO concentration occurring during the 30-minute time interval. The measured peak NO concentration was divided by 5 mL to obtain the peak NO concentration per 1 mL of NORS formulation. The "per mL" value was calculated based on the assumption that the amount of NO released is proportional to the volume of NORS in the sample chamber.

[0118] Table 1 shows the amount of NO released by example NORS formulations based on one mL NORS and full-dose NORS, as well as example dose volumes and peak NO concentrations.

[0119] Table 1 Example 2: Exposure, safety and efficacy of NONS like Figure 1The tables described in the paper depict non-clinical pharmacokinetic (PK) and toxicological tests of NO by measuring NONS prevention and NONS treatment compared to natural NO and INOmax.

[0120] NO concentrations in exhaled gases were measured under various physiological conditions. The patient population included adults whose administration route included exhalation. Measured NO concentrations ranged from 0.02 ppm to 0.1 ppm. Daily exposure duration was approximately 8 hours, as exhalation time constitutes about one-third of total breathing time. NO concentrations were calculated using the area under the curve (AUC) in ppm. Daily NO exposure, calculated in hr units, was estimated to be between 0.16 and 0.8 ppm. Within the range of hr. This calculation of daily exposure is based on 0.02 ppm for 8 hours as the lower limit of the range, and 0.1 ppm for 8 hours as the upper limit of the range. Because the patient population's exhaled air is naturally generated, the exposure and safety levels provide a baseline for comparing the exposure, safety, and efficacy of various treatments.

[0121] INOmax is a treatment already administered to the neonatal patient population via inhalation. NO is administered in gaseous form at concentrations ranging from 5 to 20 ppm. Exposure time can extend up to 24 hours. Based on the 5 to 20 ppm administration range and 24-hour exposure time, AUC is used in ppm... Daily NO exposure, calculated in hrs, was estimated at 120 ppm. hr to 480ppm Within the hr range. INOmax processing time can be up to 4 days in Canada or up to 14 days in the United States.

[0122] NONS (e.g., NORS supplied as a nasal spray) can be used as a nasal spray for prophylactic treatment, and adults can use it for a duration of 28 days. For each 0.5 mL volume of NONS, the amount of NO concentration administered can be up to a maximum peak NO concentration of 1.5 ppm. Based on six treatments of 5 minutes each, using a volume of 0.5 mL per treatment, the duration of exposure can be up to 30 minutes. The maximum total exposure from 5 mL of NONS was measured to be 54 ppm. For a treatment volume of 0.5 mL, the concentration can be calculated as 5.4 ppm. Therefore, for a 5-minute treatment session with a treatment volume of 0.5 mL, the maximum total exposure is 5.4 ppm. min, which can be achieved by reducing 5.4 ppm min divided by 60 min / hr equals 0.1 ppm. hr. For a maximum exposure time of 5 minutes per treatment and twice-daily treatments, the total exposure time is 10 minutes per day. Each treatment provides 0.1 ppm. If the HR has NO exposure, then treatment twice a day results in 0.2 ppm. NO exposure for hr. Therefore, based on an application concentration of 1.5 ppm and an exposure time of 10 minutes, AUC was used to calculate the NO exposure in ppm. Daily NO exposure, calculated in hrs, was calculated to be 0.2 ppm. hr.

[0123] NONS is available as a nasal spray for adults, administered as a single treatment six times daily for seven days. Therefore, as calculated above, the maximum total exposure for a 0.5 mL treatment volume is 5.4 ppm for each 5-minute treatment. min, which can be achieved by reducing 5.4 ppm min divided by 60 min / hr equals 0.1 ppm. hr. For a maximum exposure time of 5 minutes per treatment and 6 treatments per day, the total exposure time is 30 minutes per day. Each treatment provides 0.1 ppm. If the HR has NO exposure, then 6 treatments per day would result in 0.6 ppm. NO exposure for hr. Therefore, based on an application concentration of 1.5 ppm and an exposure time of 30 minutes, AUC was used to calculate the NO exposure in ppm. Daily NO exposure, calculated in hrs, was calculated to be 0.6 ppm. hr.

[0124] like Figure 1 The tables depict the safety margins (safety limits) of NONS prevention and treatment, calculated to be 3.3 to 13 times safer than INOmax, for NO concentrations measured by NO application in ppm. For NONS prevention and treatment, calculated to be 57 times safer than INOmax, for NONS prevention, the safety margins are approximately 600 times safer than INOmax, and 200 times safer than INOmax, as described in the tables. Daily NO exposure is measured in hrs. Compared to INOmax, the duration of NONS prevention and treatment may be shorter in some cases and longer in others.

[0125] Example 3a: Infected wounds in pigs like Figure 2a and 2b As shown, a pig study was conducted to evaluate the antimicrobial activity of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) compared to untreated control wounds.

[0126] A pathogen-free, female, commercially raised Yorkshire-cross pig was the subject of this study, weighing approximately 55 kg (+ / - 5 kg). Figure 2a As shown, a partially thick wound with a custom-designed diameter of 2.0 cm is created. A bacterial inoculum (e.g., Fusobacterium spp.) is applied using a sterile irrigating bulb containing 60-80 mL of inoculum. fusobacterium sp Staphylococcus aureus (.) staphylococcus aureus (ATCC 6538) and Pseudomonas aeruginosa ( pseudomonas aeruginosa (swine isolate), and used to submerge gauze until the gauze was saturated with the bacterial mixture. Cover the gauze strips with a sealing layer (SC Johnson and Sons, Brantford, ON) and leave for 1 hour.

[0127] Wound intervention involves either treatment 1 or treatment 2. Treatment 1 uses approximately 2 to 5 mL of NORG, equivalent to 104 to 210 ppm. min and 52 ppm Exposure at min / mL. Following NORG treatment, gauze was soaked in 2 to 5 mL of NORS, equivalent to 26 to 65 ppm. min and 13 ppm The NORS treatment was followed by covering with a transparent sealing dressing and incubating for 7 hours.

[0128] Treatment 2 involved a 1 mL volume of NORS rinse, equivalent to 13 ppm. This is followed by a minimum exposure. This is then followed by approximately 2 to 5 mL of NORG, equivalent to 104 to 210 ppm. min and 52 ppm Exposure at min / mL. Following NORG treatment, gauze was soaked in 2 to 5 mL of NORS, equivalent to 26 to 65 ppm. min and 13 ppm The NORS treatment was followed by covering with a transparent sealing dressing and incubating for 7 hours.

[0129] The control group involved covering the wound with a sterile, saline-moistened, non-adhesive dressing (Curad) and securing it with Transpore tape, then incubating for 7 hours.

[0130] Figure 2b Results graphs are provided depicting the concentrations (Log CFU / mL) of different bacteria (Fusobacterium, Staphylococcus aureus, and Pseudomonas aeruginosa) in the wound 7.5 hours after treatment with NORS alone or washing with NORS followed by NORG.

[0131] In the case of Fusobacterium, the bacterial concentration in the control group was approximately 7.2 Log CFU / mL, the bacterial concentration with NORG alone was approximately 3.8 Log CFU / mL, and the bacterial concentration with NORS washing followed by NORG was approximately 3.7 Log CFU / mL. These results indicate that, compared with the control, NORG alone or NORS followed by NORG significantly reduced the concentration of Fusobacterium.

[0132] In the case of Staphylococcus aureus, the bacterial concentration in the control was approximately 7.2 Log CFU / mL, the bacterial concentration with NORG alone was approximately 3.9 Log CFU / mL, and the bacterial concentration with washing with NORS followed by NORG was approximately 4.1 Log CFU / mL. These results indicate that, compared with the control, using NORG alone or NORS followed by NORG significantly reduced the concentration of Staphylococcus aureus.

[0133] In the case of *Pseudomonas aeruginosa*, the bacterial concentration in the control group was approximately 6.0 Log CFU / mL, the bacterial concentration with NORG alone was approximately 3.5 Log CFU / mL, and the bacterial concentration with NORS washing followed by NORG was approximately 2.2 Log CFU / mL. These results indicate that NORG alone or NORS followed by NORG significantly reduced the concentration of *Staphylococcus aureus* compared to the control group. These results also indicate that treatment with NORS followed by NORG resulted in a greater reduction in *Staphylococcus aureus* concentration than treatment with NORG alone.

[0134] Example 3b: Warts like Figures 3a to 3f As shown, a study was conducted on human subjects to evaluate the effects of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) on warts. Warts appeared on the feet of the human subjects in three areas: (a) the underside of the big toe, (b) the lower left posterior side of the foot, and (c) the lower part below the big toe. The affected feet received a total of 3.5 hours of NORS foot baths (12.85 ppm) per week. Treatment with NORG (52 ppm) for two weeks. Affected feet were also treated daily with NORG (52 ppm). The treatment duration was one week (min / mL).

[0135] like Figure 3a As shown, the wart on the lower left side of the foot was quite large before treatment, but it was completely removed 28 days after treatment began. Figure 3b As shown. Figures 3c to 3f Day 1 is shown. Figure 3c Day 7 Figure 3d Day 14 Figure 3e ) and the 28th day ( Figure 3f The progress of treatment with NORS and NORG. These results indicate that treatment with NORS and NORG can remove warts on the feet within 28 days.

[0136] Example 3c: Nail fungi Case Study 3c-1 like Figure 4a and 4b As shown, a study was conducted on human subjects to evaluate the effects of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) on nail fungus. The human subjects had nail fungus on their fingers. 1 mL of NORG (52 ppm) was administered daily. The affected fingers were treated with a concentration of (min / mL) for a total of 2 weeks.

[0137] like Figure 4a As shown, before treatment began, the nail fungus covered approximately one-third of the fingernail, and was completely removed 60 days after treatment began. Figure 4b As shown in the figure. These results indicate that treatment with NORS and NORG can remove nail fungi from fingers over a 60-day period.

[0138] Case Study 3c-2 like Figures 4c to 4h As shown, a study was conducted on human subjects to evaluate the effects of nitric oxide-releasing solution (NORS) and nitric oxide-releasing gel (NORG) on nail fungus on toenails. The human subjects had nail fungus on their toes. 1 mL of NORG (52 ppm) was administered daily. The affected toes were treated with a concentration of (min / mL) for a total of 3 weeks.

[0139] like Figure 4c As shown, before treatment began, the nail fungus covered approximately half of the toenail, and was completely removed nine months after treatment began. Figure 4h As shown. Figures 4c to 4g Day 1 is shown. Figure 4d Day 21 Figure 4e ), the second month ( Figure 4f ) and the 4th month ( Figure 4gThe progress of treatment with NORS and NORG. These results indicate that treatment with NORS and NORG can remove nail fungi from the fingers over a period of 9 months.

[0140] Case study 3c-3.

[0141] like Figure 4i and 4m As shown, a study was conducted on human subjects to evaluate the effects of nitric oxide-releasing solution (NORS) and nitric oxide-releasing gel (NORG) on nail fungus on the second and fourth toes. Nail fungus was present on the second and fourth toes of the human subjects. 1 mL of NORG (52 ppm) was administered daily. The affected toes were treated with a concentration of min / mL for a total of 4 weeks.

[0142] like Figure 4i As shown, on day 1 of treatment, the nail fungus covered the entire nails of the second and fourth toes, and was completely removed 120 days after treatment began. Figure 4m As shown. Figures 4j to 4l Day 28 was shown. Figure 4j Day 63 Figure 4k ) and the 77th day ( Figure 4l The progress of treatment with NORS and NORG. These results indicate that treatment with NORS and NORG can remove nail fungi from the toes over a period of 120 days.

[0143] Example Implementation The following embodiments are specific technical implementations, and indicate specific features, elements or steps that can be used or otherwise combined to implement such embodiments.

[0144] In one example, a method is provided for identifying the condition in a patient who responds to nitric oxide (NO) treatment / therapy.

[0145] In one example, a method for treating a condition that responds to NO treatment / therapy may include administering a volume of nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of NO to the treatment site for the duration of treatment.

[0146] In one example, a method for treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be a NORS containing nitrite and an acidifying agent. In one example, when measured by releasing NO from the NORS into a substantially inert carrier gas stream coupled to a chemiluminescence detector at a flow rate of 1 L / min and a pressure of 1 atm for a period of 30 minutes, the amount of NO released by the NORS is approximately 0.05 ppm per mL of NORS. min to approximately 500 ppm min.

[0147] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be NORS, wherein the amount of NO released by the NORS is approximately 0.05 ppm per mL of NORS. min to approximately 10 ppm In one example, the volume of NORS can be from about 0.1 mL to about 10,000 mL. In one example, the total amount of NO released from the volume of NORS applied can be about 0.1 ppm. min to approximately 3,000 ppm min.

[0148] In one example, methods for treating conditions that respond to NO treatment / therapy may include conditions that can be wounds, skin infections, fungal infections, respiratory infections, bacterial infections, or viral infections.

[0149] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that could be athlete's foot. In one example, a method for treating athlete's foot is provided. In one example, the application site may be the foot of the subject. In one example, the amount of NO released by NORS is approximately 0.2 ppm per mL of NORS. min to approximately 5 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 1,000 ppm. min to approximately 5,000 ppm In one example, the volume of NORS applied may be from about 500 mL to about 10,000 mL. In one example, the volume of NORS applied may release a peak NO concentration from about 5,000 ppm to about 20,000 ppm.

[0150] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that can be onychomycosis. In one example, a method for treating a condition that may include onychomycosis is provided. In one example, the application site may be the nail of the subject. In one example, the amount of NO released by NORS is approximately 1 ppm per mL of NORS. min to approximately 2 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 1 ppm. min to approximately 4ppm In one example, the volume of NORS applied may be from about 0.5 mL to about 2 mL. In one example, the volume of NORS applied may release a peak NO concentration of from about 5 ppm to about 30 ppm.

[0151] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that could be influenza. In one example, a method for treating a condition is provided, which may include influenza. In one example, the treatment method may include an application site, which may be the nasal cavity of the subject. In one example, the amount of NO released by NORS is approximately 0.1 ppm per mL of NORS. min to approximately 10 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 5 ppm. min to approximately 10 ppm In one example, the volume of NORS applied may be from about 0.5 mL to about 1 mL. In one example, the volume of NORS applied may release a peak NO concentration from about 1 ppm to about 4 ppm.

[0152] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that could be a respiratory viral infection. In one example, a method for treating a condition that could be a respiratory viral infection is provided, and the application site may be the subject's nasal cavity or lungs. In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 15 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 5 ppm. min to approximately 10 ppm In one example, the volume of NORS applied may be from about 0.5 mL to about 1 mL. In one example, the volume of NORS applied may release a peak NO concentration from about 1 ppm to about 4 ppm.

[0153] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that could be sinusitis. In one example, a method for treating a condition is provided, where the condition may be sinusitis and the application site may be the sinus cavity of the recipient. In one example, the amount of NO that NORS can release is approximately 1 ppm per mL of NORS. min to approximately 15ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 400 ppm. min to approximately 3,200 ppm In one example, the volume of NORS applied may be from about 150 mL to about 300 mL. In one example, the volume of NORS applied may release a peak NO concentration from about 100 ppm to about 1,200 ppm.

[0154] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that could be a throat infection. In one example, a method for treating a condition is provided, where the condition may be a throat infection and the application site may be the throat of the subject. In one example, the amount of NO released by NORS is approximately 15 ppm per mL of NORS. min to approximately 30 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 400 ppm. min to approximately 600 ppm In one example, the volume of NORS applied may be from about 10 mL to about 20 mL. In one example, the volume of NORS applied may release a peak NO concentration of from about 100 ppm to about 200 ppm.

[0155] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition such as acne. In one example, a method for treating a condition is provided, where the condition may be acne and the application site may be a skin area of ​​the subject. In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 30 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 10 ppm. min to approximately 60 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 20 ppm. min to approximately 60 ppm In one example, the volume of NORS applied may be from about 1 mL to about 5 mL. In one example, the volume of NORS applied may release a peak NO concentration of from about 5 ppm to about 20 ppm.

[0156] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition such as diabetic foot ulcers. In one example, a method for treating a condition, such as diabetic foot ulcers, is provided, and the application site may be the subject's foot. In one example, the amount of NO released by NORS is approximately 5 ppm per mL of NORS. min to approximately 80 ppm In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 60 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 100 ppm. min to approximately 75,000 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 200 ppm. min to approximately 75,000 ppm In one example, the volume of NORS applied can be from about 5 mL to about 10,000 mL. In one example, the volume of NORS applied can release a peak NO concentration from about 50 ppm to about 20,000 ppm.

[0157] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that can be warts. In one example, a method for treating a condition is provided, where the condition can be warts and the application site can be a skin area of ​​the subject. In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 60 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 45 ppm. min to approximately 75 ppm In one example, the total amount of NO released by the volume of the applied NORS could be approximately 20 ppm. min to approximately 400 ppm In one example, the volume of NORS applied may be from about 0.5 mL to about 10 mL. In one example, the volume of NORS applied may release a peak NO concentration from about 1 ppm to about 60 ppm.

[0158] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be a NORS, which may include at least one NO-releasing compound and at least one acidifying agent. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In further examples, the acidifying agent includes ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof.

[0159] In one example, a method of treating a condition that responds to NO treatment / therapy may include a composition. In one example, the composition may be a NORS that provides prolonged release of NO.

[0160] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may include NORS, which may have an amount of NO released by the NORS, the amount of NO released being measured by: introducing a carrier gas flow into a sample holding chamber via a gas inlet; introducing the NORS into the sample holding chamber via a sample inlet to contact a continuous carrier gas flow; directing the carrier gas and any NO released from the sample holding chamber to a NO detector via an outlet; and quantifying the amount of NO released using the NO detector. In one example, the sample holding chamber may include an inner surface that is inert relative to NO.

[0161] In one example, a method of treating a condition that responds to NO treatment / therapy may include NORS, which may be administered as: intranasal spray, open-ended vessel bath, liquid sinus rinse, liquid mouthwash, inhaled formulation, aerosol, gel, foam, emulsion, liquid solution, cream, or a combination thereof.

[0162] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be a NORS, which may contain a pharmaceutically acceptable carrier. In one example, a pharmaceutically acceptable carrier may include water, saline, hydroxyethyl cellulose, xanthan gum, or a combination thereof.

[0163] In one example, a composition for treating conditions responsive to nitric oxide (NO) treatment may include a nitric oxide releasing solution (NORS). In one example, the NORS may contain at least one NO-releasing compound and at least one acidifying agent. In one example, when measured by releasing NO from the NORS into a substantially inert carrier gas stream coupled to a chemiluminescence detector at a flow rate of 1 L / min and a pressure of 1 atm for a period of 30 minutes, the amount of NO released by the NORS is approximately 0.05 ppm per mL of NORS. min to approximately 500 ppm min.

[0164] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to the feet of a subject to treat athlete's foot, and the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 15 ppm min.

[0165] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to the nails of a subject to treat onychomycosis, and the amount of NO released by NORS is approximately 45 ppm per mL of NORS. min to approximately 60 ppm min.

[0166] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to the nasal cavity of a subject to treat influenza, and the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 15 ppm min.

[0167] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to the nasal cavity or lungs of a subject to treat a respiratory viral infection, and the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 15 ppm min.

[0168] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to the sinus cavity of a subject to treat sinusitis, and the amount of NO released by NORS is approximately 1 ppm per mL of NORS. min to approximately 15 ppm min.

[0169] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to the throat of a subject to treat a throat infection, and the amount of NO released by NORS is approximately 15 ppm per mL of NORS. min to approximately 30 ppm min.

[0170] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to a skin area of ​​a subject to treat acne, and the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 30 ppm min.

[0171] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to a subject's foot to treat diabetic foot ulcers, and the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 60 ppm min.

[0172] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be formulated for application to a skin area of ​​a subject to treat warts, and the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 60 ppm In one example, the composition can be formulated for application to a skin area of ​​a subject to treat warts, and the amount of NO released by NORS is approximately 5 ppm per mL of NORS. min to approximately 80 ppm min.

[0173] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may be a NO-releasing compound, which may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or a combination thereof.

[0174] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may include an acidifying agent. In one example, the acidifying agent may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof.

[0175] In one example, a method of treating a condition that responds to NO treatment / therapy may include a composition. In one example, the composition may be a NORS that provides prolonged release of NO.

[0176] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may include NORS, wherein the amount of NO released by the NORS can be measured by: introducing a carrier gas flow into a sample holding chamber via a gas inlet; introducing the NORS into the sample holding chamber via a sample inlet to contact a continuous carrier gas flow; directing the carrier gas and any NO released from the sample holding chamber via an outlet to a NO detector; and quantifying the amount of NO released using the NO detector. In one example, the sample holding chamber may include an inner surface that is inert relative to NO.

[0177] In one example, a method of treating a condition that responds to NO treatment / therapy may include a composition. In one example, the composition may be formulated to be applied as: an intranasal spray, an open-top container bath, a liquid sinus rinse, a liquid mouthwash, a respiratory inhaler, an aerosol, a gel, a foam, an emulsion, a liquid solution, a cream, or a combination thereof.

[0178] In one example, a method of treating a condition responsive to NO treatment / therapy may include a composition. In one example, the composition may comprise a pharmaceutically acceptable carrier. In one example, a pharmaceutically acceptable carrier may include water, saline solution, hydroxyethyl cellulose, xanthan gum, or a combination thereof.

[0179] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that can be athlete's foot. In one example, a method for treating athlete's foot may include: applying a nitric oxide releasing solution (NORS) to the subject's foot to provide a therapeutically effective dose of nitric oxide (NO) gas for a duration of treatment, wherein the amount of NO released by the NORS is approximately 50,000 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter / minute and a pressure of 1 atmosphere. min to approximately 75,000 ppm In one example, the volume of NORS applied can be from approximately 1,000 mL to approximately 10,000 mL. In one example, the amount of NO released by the NORS is approximately 5 ppm per mL of NORS. min to approximately 15 ppm In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 15 ppm In one example, the amount of NO that NORS can release is approximately 25 ppm per mL of NORS. min to approximately 500 ppm In one example, the volumetrically releaseable peak NO concentration of the applied NORS is from about 5,000 ppm to about 20,000 ppm. In another example, the volumetrically releaseable peak NO concentration of the applied NORS is from about 15,000 ppm to about 20,000 ppm. In one example, the NORS may be applied as a liquid solution in a foot bath. In one example, the method includes applying the NORS according to a dosage regimen of soaking the feet in a foot bath for 30 minutes once every 4 days. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifying agent. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifying agent may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, NORS can provide extended release of NO.

[0180] In one example, a method for treating a condition responsive to NO treatment / therapy may include a condition that could be onychomycosis in the nails of a subject. In one example, the method may include: administering a nitric oxide releasing solution (NORS) to the nails of the subject for a duration of treatment providing a therapeutically effective dose of nitric oxide (NO) gas, wherein the amount of NO released by the NORS is approximately 45 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 60 ppm In one example, the volume of NORS applied can be from about 0.5 mL to about 2 mL. In one example, the amount of NO released by the NORS is about 25 ppm per mL of NORS. min to approximately 75 ppm In one example, the amount of NO released by NORS is approximately 45 ppm per mL of NORS. min to approximately 60 ppm In one example, the volumetric release of the applied NORS is from about 5 ppm to about 15 ppm. In one example, the NORS may be applied as a liquid solution, gel, or cream. In one example, the method may include applying the NORS according to a dosage regimen of applying the NORS to the nails once every 21 days. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifier. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifier may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0181] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that can be influenza. In one example, a method for treating a subject with influenza may include administering a nitric oxide releasing solution (NORS) to the subject's nasal cavity for a duration of treatment, wherein the amount of NO released by the NORS is approximately 5 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 10 ppm In one example, the volume of NORS applied can be from about 0.5 mL to about 1 mL. In one example, the amount of NO released by the NORS is about 2 ppm per mL of NORS. min to approximately 15 ppm In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 15 ppm In one example, the volumetric release of the applied NORS is from about 1 ppm to about 4 ppm. In one example, the NORS may be administered as a nasal spray. In one example, the method may include administering the NORS according to a dosage regimen for on-demand nasal spray administration. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifying agent. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifying agent may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0182] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that may be a respiratory viral infection. In one example, a method for treating a subject with a respiratory viral infection may include administering a nitric oxide releasing solution (NORS) containing an amount of therapeutically effective nitric oxide (NO) gas to the subject's nasal cavity or lungs for a duration of treatment, wherein the amount of NO released by the NORS is approximately 5 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 10 ppm In one example, the volume of NORS applied may be from about 0.5 mL to about 1 mL. In another example, the volume of NORS applied may be from about 0.5 mL to about 5 mL. In one example, the amount of NO released by the NORS is about 5 ppm per mL of NORS. min to approximately 15 ppm In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 15 ppm In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 30 ppm In one example, the volumetric release of the applied NORS is from about 1 ppm to about 4 ppm of peak NO concentration. In one example, the NORS may be administered as a nasal spray. In one example, the method may include administering the NORS according to a dosing regimen for an on-demand nasal spray. In one example, the respiratory viral infection may be the common cold, respiratory syncytial virus, or coronavirus. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifier. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifier may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0183] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that may be sinusitis. In one example, a method for treating sinusitis in a subject may include administering a nitric oxide releasing solution (NORS) to the sinus cavity of the subject for a duration of treatment, wherein the amount of NO released by the NORS is approximately 400 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 3,200 ppm In one example, the volume of NORS applied can be from approximately 150 mL to approximately 300 mL. In one example, the amount of NO released by the NORS is approximately 1 ppm per mL of NORS. min to approximately 15 ppm min. In one example, the amount of NO that NORS can release is approximately 1 ppm per mL of NORS. min to approximately 30 ppm In one example, the volumetrically releaseable peak NO concentration of the applied NORS is from about 50 ppm to about 500 ppm. In one example, the volumetrically releaseable peak NO concentration of the applied NORS is from about 100 ppm to about 1,200 ppm. In one example, the volumetrically releaseable peak NO concentration of the applied NORS is from about 100 ppm to about 5,000 ppm. In one example, the NORS may be applied as a rinsing agent, drenching agent, or spray. In one example, the method may include applying the NORS according to a dosage regimen of applying the NORS about once every 42 days. In one example, the method may include applying the NORS according to a dosage regimen of applying the NORS daily for a period of about 10 days to about 50 days. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifying agent. In one example, the NO-releasing compound may include nitrite. In one example, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or a combination thereof. In one example, the acidifying agent may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, NORS may provide prolonged NO release.

[0184] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that could be a throat infection. In one example, a method for treating a throat infection in a subject may include administering a nitric oxide releasing solution (NORS) to the subject's throat providing a therapeutically effective dose of nitric oxide (NO) gas for a duration of treatment, wherein the amount of NO released by the NORS is approximately 400 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 600 ppm In one example, the volume of NORS applied may be from about 10 mL to about 20 mL. In another example, the volume of NORS applied may be from about 5 mL to about 40 mL. In one example, the amount of NO released by the NORS is about 15 ppm per mL of NORS. min to approximately 30 ppm In one example, the amount of NO released by NORS is approximately 10 ppm per mL of NORS. min to approximately 40 ppm In one example, the volumetric release of the applied NORS is from about 100 ppm to about 200 ppm. In another example, the volumetric release of the applied NORS is from about 200 ppm to about 800 ppm. In one example, the NORS may be administered as a mouthwash solution. In one example, the method may include administering the NORS according to a dosage regimen of rinsing for 1.5 minutes every 3 days. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifier. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may include sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifier may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0185] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that may be acne. In one example, a method for treating a subject's acne may include: applying a nitric oxide releasing solution (NORS) to a skin area of ​​the subject to provide a therapeutically effective dose of nitric oxide (NO) gas for a duration of treatment, wherein the amount of NO released by the NORS is approximately 20 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 60 ppm In one example, the volume of NORS applied can be from about 1 mL to about 5 mL. In one example, the amount of NO released by the NORS is about 10 ppm per mL of NORS. min to approximately 30 ppm In one example, the volumetric release peak NO concentration of the applied NORS is from about 5 ppm to about 20 ppm. In one example, the NORS may be applied as a cream. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifying agent. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may include sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifying agent may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0186] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that could be a diabetic foot ulcer. In one example, a method for treating a diabetic foot ulcer may include administering a nitric oxide releasing solution (NORS) to the subject's foot, providing a therapeutically effective dose of nitric oxide (NO) gas, for a duration of treatment, wherein the amount of NO released by the NORS is approximately 200 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter / minute and a pressure of 1 atmosphere. min to approximately 75,000 ppm In one example, the volume of NORS applied can be from about 5 mL to about 10,000 mL. In one example, the amount of NO released by the NORS is about 10 ppm per mL of NORS. min to approximately 60 ppm In one example, the volumetric release of the applied NORS is from about 50 ppm to about 20,000 ppm peak NO concentration. In one example, the NORS may be administered as a liquid solution in a foot bath. In one example, the method may include administering the NORS according to a dosage regimen of soaking the feet in a foot bath for 30 minutes once every 12 days. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifying agent. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may include sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifying agent may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0187] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition that can be warts. In one example, a method for treating warts on a subject may include: applying a nitric oxide releasing solution (NORS) to a skin area of ​​the subject to provide a therapeutically effective dose of nitric oxide (NO) gas for a duration of treatment, wherein the amount of NO released by the NORS is approximately 45 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 75 ppm In one example, the volume of NORS applied can be from about 0.5 mL to about 10 mL. In one example, the amount of NO released by the NORS is about 10 ppm per mL of NORS. min to approximately 60 ppm In one example, the volumetric release of the applied NORS is from about 1 ppm to about 60 ppm of peak NO concentration. In one example, the NORS may be administered as a liquid solution in a bath. In one example, the method may include administering the NORS according to a dosage regimen of immersing the skin in a bath for 30 minutes once every 6 days. In one example, the method may include administering the NORS according to a dosage regimen of immersing the skin in a bath for 30 minutes daily for about 1 day to about 10 days. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifier. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifier may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0188] In one example, a method for treating a condition that responds to NO treatment / therapy may include a condition in which the skin is at risk of infection. In one example, a method for disinfecting the skin of a subject may include: applying a nitric oxide releasing solution (NORS) to the skin area of ​​the subject, providing a therapeutically effective dose of nitric oxide (NO) gas, for a duration of treatment, wherein the amount of NO released by the NORS is approximately 450 ppm when measured over a period of 30 minutes by releasing NO, to be quantified by a chemiluminescence detector, from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm. min to approximately 750 ppm In one example, the volume of NORS applied can be from approximately 50 mL to approximately 200 mL. In one example, the amount of NO released by the NORS is approximately 5 ppm per mL of NORS. min to approximately 25 ppm In one example, the volumetric release peak NO concentration of the applied NORS is from about 1 ppm to about 20 ppm. In one example, the NORS may contain at least one NO-releasing compound and at least one acidifying agent. In one example, the NO-releasing compound may include nitrite. In one example, nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotic nitrite, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite, or combinations thereof. In one example, the acidifying agent may include ascorbic acid, ascorbate palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one example, the NORS may provide prolonged NO release.

[0189] In one example, a method of treating a condition responsive to NO treatment / therapy may include using the composition provided herein. In one example, the use of the composition provided herein in the preparation of a medicament for treating a condition responsive to nitric oxide (NO) treatment may include administering a therapeutically effective amount of the composition to a subject. In one example, a composition for treating a condition responsive to nitric oxide (NO) treatment may include administering a therapeutically effective amount of the composition to a subject.

[0190] In one example, compositions such as nitric oxide-releasing compositions are provided.

[0191] In one example of the composition, the composition comprises a combination of the following amounts of nitric oxide-releasing compound, acidifier, and carrier: when measured by releasing NO from the composition into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm for a period of 30 minutes, approximately 1 ppm is released per mL of the composition. min / mL to approximately 500 ppm min / mL nitric oxide (NO).

[0192] In one example of the composition, a pharmaceutically acceptable carrier includes water, saline solution, hydroxyethyl cellulose, xanthan gum, or a combination thereof.

[0193] In one example of the composition, the composition is formulated for use as: an intranasal spray, an open immersion container bath, a liquid sinus rinse, a liquid mouthwash solution, a respiratory inhaler, an aerosol, a gel, a foam, an emulsion, a liquid solution, a cream, or a combination thereof.

[0194] In one example of the composition, the amount of NO released was approximately 1 ppm. min / mL to approximately 500 ppm min / mL.

[0195] While the foregoing examples illustrate the principles of this technology in one or more specific applications, it will be apparent to those skilled in the art that various modifications can be made to the form, usage, and details of the implementation without inventiveness and without departing from the principles and concepts of this technology.

Claims

1. Methods for determining the response of patients to nitric oxide (NO) treatment, including: A volume of a nitric oxide releasing solution (NORS) providing a therapeutically effective amount of NO is applied to the application site of the subject for a duration of treatment, wherein the NORS comprises a nitric oxide releasing compound and an acidifying agent, wherein the NORS releases NO at a rate of about 1 ppm*min / mL to about 500 ppm*min / mL based on 1 mL of the NORS when measured by releasing NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 L / min and a pressure of 1 atm and coupled to a chemiluminescence detector.

2. The method of claim 1, wherein the NORS releases NO at an amount of about 1 ppm*min to about 60 ppm*min per mL of the NORS.

3. The method of claim 1, wherein the volume of the NORS is from about 0.1 mL to about 10,000 mL.

4. The method of claim 1, wherein the total amount of NO released from the volume of the applied NORS is from about 6 ppm*min to about 75,000 ppm*min.

5. The method of claim 1, wherein the condition is a wound, skin infection, fungal infection, respiratory infection, bacterial infection, or viral infection.

6. The method of claim 1, wherein the condition is athlete's foot and the application site is the foot of the subject, and wherein the NORS releases NO at an amount of about 5 ppm*min / mL to about 15 ppm*min / mL based on 1 mL of the NORS.

7. The method of claim 6, wherein the total amount of NO released from the volume of the applied NORS is from about 25,000 ppm*min to about 75,000 ppm*min.

8. The method of claim 6, wherein the volume of the NORS applied is from about 500 mL to about 10,000 mL.

9. The method of claim 6, wherein the peak NO concentration released by the volumetric release of the applied NORS is from about 5,000 ppm to about 20,000 ppm.

10. The method of claim 1, wherein the condition is onychomycosis and the application site is the nail of the subject, and wherein the NORS releases NO in an amount of about 25 ppm*min / mL to about 75 ppm*min / mL based on 1 mL of the NORS.

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