Nitric oxide generating compositions, kits, and combinations for use in the treatment, improvement, or prevention of respiratory diseases or disorders.

Abstract

The present invention relates to nitric oxide generating compositions, kits, and combinations for the treatment, improvement, or prevention of respiratory diseases or disorders, and to methods for treating, improving, or preventing such diseases or disorders using such compositions, kits, and combinations.

Description

[Technical Field]

[0001] The present invention relates to nitric oxide generating compositions, kits, and combinations for the treatment, improvement, or prevention of respiratory diseases or disorders, and to methods for treating, improving, or preventing such diseases or disorders using such compositions, kits, and combinations. [Background technology]

[0002] Nitric oxide (NO) and its precursors have been extensively studied as potential pharmaceuticals. Many problems remain regarding the efficient production and delivery of nitric oxide, other nitrogen oxides, and their precursors to organisms and cells for therapeutic purposes. The widely employed system for nitric oxide production relies on the initial production of nitrite (HNO2) by acidifying nitrite with an acid, which then readily decomposes into nitric oxide, nitrate ions, hydrogen ions, and water. This decomposition can be represented by the following equilibrium equation (1): 3HNO2 → 2NO + NO3 - +H + +H2O (1) Acids and nitrites are usually supplied as separate aqueous solutions at predetermined concentrations, and mixing them at the required time prevents the release of nitric oxide before it is needed.

[0003] The production of nitric oxide through the acidification of nitrites depends, at least in part, on the pH of the mixture. Generally speaking, the more acidic (lower pH) the acid solution mixed with the nitrite, the greater the amount of nitric oxide produced. As the pH of the acid solution increases, the amount of nitric oxide produced generally decreases. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] However, in physiological settings, for example, when nitric oxide production is required in the treatment of a disease or disorder, using acidic solutions with very low pH (highly acidic) can lead to tolerance problems. For example, highly acidic solutions can damage internal tissues (e.g., the lungs for the treatment of lower respiratory diseases).

[0005] Therefore, there is a need to provide a nitric oxide generation composition that efficiently generates nitric oxide under physiological conditions by acidifying nitrites. [Means for solving the problem]

[0006] The inventors have, surprisingly, discovered a more effective nitric oxide generating composition when used to produce nitric oxide under physiological conditions. The nitric oxide generating composition of the present invention comprises a buffer, the buffering capacity of which is higher than that of conventional buffer acids in nitric oxide generating compositions.

[0007] Generally, the acidity of a nitric oxide generating composition decreases after the acidification of the nitrite begins. Therefore, the efficient amount of nitric oxide produced from a nitric oxide generating composition decreases over time. While we do not wish to be bound by theory, we believe that by using a buffer with such buffering capacity, the nitric oxide generating composition can be sufficiently acidified by the acid in the buffer, and at the same time, the nitric oxide generating composition can be maintained at a pH suitable for nitric oxide production for a longer period than conventional compositions, especially under physiological conditions.

[0008] Generally, a buffer solution is a solution that can withstand pH changes caused by the addition of acidic or basic components. Because a buffer solution can neutralize small amounts of added acid or base, it can maintain a relatively stable pH level. Buffer solutions also typically maintain their pH level even with moderate dilution. Buffer solutions have a working pH range and buffering capacity, which define the amount of acid / base that can be neutralized before the pH changes, and the amount of pH change that results.

[0009] By increasing the buffering capacity of the buffer solution, the nitric oxide generating composition of the present invention maintains the generation of nitric oxide by acidification of nitrite, while resisting both the increase in pH due to the progress of acidification of nitrite and the increase in pH due to the physiological environment (typically accompanied by a physiological or biological buffer such as phosphate buffer and / or when the composition may be diluted).

[0010] In a first aspect, the present invention is a nitric oxide generating composition for the treatment, improvement or prevention of a respiratory disease or disorder, wherein the composition a) one or more nitrites, and b) a buffer system comprising at least one acid and at least one conjugate base, and water, the buffer system having a pH in the range of 4.6 to 6.0, and also the formula (2):

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[0011] The acid and its conjugate base used as the buffer may be monoprotic or polyprotic. When the acid is monoprotic, the

Number

Number

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[0012] Similarly, when the buffer contains a single acid and conjugate base pair as the buffering agent,

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[0013] [[ID=4,0]] Buffering to pH 4.6 to 6.0 and having a buffering capacity β of at least 0.06 as defined by formula (2) may result in a more effective nitric oxide generating composition under physiological conditions.

[0014] The inventors have also found that the useful range of buffering capacity can be varied depending on the pH of the buffer system, taking into account that the effectiveness of the composition decreases above pH 6. When the pH of the buffer is significantly lower than pH 6, a lower buffering capacity may be used. On the other hand, when the pH of the buffer is close to pH 6, a higher buffering capacity may be used. Therefore, the inventors refer to the measure of buffering capacity in the context of the present invention as the relevant useful buffering capacity (RUβ), where RUβ is the pH integral of β between the pH of the buffer system (pH_i) and pH 6.00, and β is the buffering capacity of the buffer system calculated by equation (2). RUβ may be expressed by equation (3).

number

[0015] In a second embodiment, the present invention relates to a nitric oxide generating composition for the treatment, improvement or prevention of respiratory diseases or disorders, wherein the composition comprises a) One or more nitrites, and b) A buffer system comprising at least one acid, at least one conjugate base, and water, wherein the buffer system has a pH in the range of 4.6 to 6.0, and the related useful buffering capacity RUβ of the buffer system is at least 0.04, where Ruβ is given by formula (3):

number

number

[0016] In a third embodiment, the present invention is a kit for providing a nitric oxide generating composition for the treatment, improvement or prevention of respiratory diseases or disorders, the kit comprising: a) Nitrite components containing one or more nitrites, b) Acidic component containing at least one acid, The kit further comprises, wherein the kit comprises at least one conjugate base that forms a buffer system with the acid component such that the buffer system has a pH of 4.6 to 6.0, wherein the buffering capacity β of the buffer system is given by formula (2):

number

[0017] In a fourth embodiment, the present invention is a kit for providing a nitric oxide generating composition for the treatment, improvement or prevention of respiratory diseases or disorders, the kit comprising: a) Nitrite components containing one or more nitrites, and b) Acidic component containing at least one acid, The kit further comprises, wherein the kit comprises at least one conjugate base that forms a buffer system with the acid component such that the buffer system has a pH of 4.6 to 6.0 and the associated useful buffering capacity RUβ of the buffer system is at least 0.04, where Ruβ is given by formula (3):

number

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[0018] In the kits of the third and fourth embodiments, the conjugate base(s) may be contained in the nitrite component, acid component, or conjugate base component. In certain embodiments, the conjugate base(s) may include the acid component having a buffer system comprising at least one acid and at least one conjugate base. As such, it is contained in the acid component. Water necessary to form a buffer system may be present in one or more of the nitrite component, acid component, or conjugate base component (if present). If water is present in either the nitrite component or the acid component, or in both the acid component and the nitrite component, the nitrite component and the acid component are separated as separate components in the kit. The nitrite and acid components can then be mixed at the time of use to initiate the acidification of the nitrite. Alternatively, the kits of the third and fourth embodiments may include instructions indicating the amount of aqueous medium (such as water) to be added to form a buffer system. If the acid component and nitrite component do not contain water (i.e., are solid components), the acid component and nitrite component can be a mixture of the acid component and nitrite component in the kit. The aqueous medium (e.g., water) can then be added at the time of use to initiate the acidification of the nitrite.

[0019] In a fifth embodiment, the present invention provides a nitric oxide generating composition for the treatment, improvement or prevention of respiratory diseases or disorders, the composition being formed from a kit of the third or fourth embodiment by mixing at least a nitrite component, an acid component, a conjugate base component (if separate from the nitrite component and / or acid component), and an aqueous medium (e.g., water) (if not present in other components in an amount sufficient to form a buffer system).

[0020] In a sixth embodiment, the present invention provides a method for treating, improving or preventing a respiratory disease or disorder, the method comprising administering a composition or kit according to the first to fifth embodiments to a subject.

[0021] In a seventh embodiment, the present invention provides for the use of compositions or kits according to the first to fifth embodiments, for the purpose of manufacturing pharmaceuticals for the treatment, improvement or prevention of respiratory diseases or disorders.

[0022] The present invention will be described in detail below with reference to examples and accompanying drawings. [Brief explanation of the drawing]

[0023] [Figure 1] The following plots show the buffering capacity of citrate / citrate buffer systems in the pH range of 4.0 to 6.0 at buffer concentrations of 0.025 M, 0.05 M, 0.10 M, 0.125 M, 0.15 M, and 0.20 M, calculated by formula (2) described herein. [Figure 2] The relevant useful buffering capacity (as the integral of buffering capacity with respect to pH, using the trapezoidal plot with a pH interval of 0.01 between the buffer system's pH (pH_i) and pH 6.00) is plotted for citrate / citrate buffer systems in the pH range of 4.0 to 6.0 at buffer concentrations of 0.025M, 0.05M, 0.10M, 0.125M, 0.15M, and 0.20M. [Figure 3] The microbial loss (Log10 CFU / mL) of Pseudomonas aeruginosa NCTC 13618 is shown in 6.25% dilutions of formulations containing various concentrations of citrate / citrate buffer, 0.15 M nitrite, 0.05 M mannitol, and pH values ​​of 4.8, 5.0, and 5.4. [Figure 4] The microbial loss (Log10 CFU / mL) of Pseudomonas aeruginosa NCTC 13618 is shown in 6.25% dilutions of formulations containing various concentrations of citrate / citrate buffer, 0.22 M nitrite, 0.05 M mannitol, and pH values ​​of 4.8, 5.0, and 5.4. [Modes for carrying out the invention]

[0024] For producing nitric oxide, optionally other nitrogen oxides, and / or optionally their precursors. Reactions between one or more nitrites and an acid are referred herein to as “NOx-producing reactions,” or “reactions for producing NOx,” or by such expressions, and “NOx” is used to refer individually and / or collectively in any combination to the products of the acidification of nitrites, in particular nitric oxide, other nitrogen oxides, and their precursors. It will be understood that each component of the NOx produced can be released as a gas, or can migrate into solution in the reaction mixture, or migrate into solution first and then released as a gas, or any combination thereof.

[0025] In this specification, the term "target molar concentration" is used to indicate the desired molar concentration of a given component at the time when the nitrite, acid, and aqueous components are first mixed to form the nitric oxide-producing composition.

[0026] In this specification, the term "approximately" is used to indicate that the numerical value is not strictly limited and may be higher or lower than the actual value within a range that a person skilled in the art would consider appropriate. The term "approximately" may mean within ±10% of the value.

[0027] Unless otherwise specified, particle sizes described herein refer to volume-average diameters (VMD).

[0028] buffer system The present invention comprises at least one acid, at least one conjugate base, and water, which are mixed or miscible to form a buffer system. The buffer system has a pH of 4.6 to 6.0 and is further defined by either buffering capacity or related useful buffering capacity.

[0029] Buffer capacity The buffering capacity β of the buffer system, as defined by equation (2), may be at least 0.06.

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[0030] As explained above, the buffering capacity of polybasic acids and / or acids containing pairs of multiple acids and their conjugate bases can be calculated using formula (2), similar to the system of monobasic acids and their conjugate bases. Since the pH of the buffer system does not change with slight dilution, the pH of the buffer system before the addition of nitrite is usually [H] of the buffer system in the nitric oxide generating composition. + It is used to indicate the value. The value of the water dissociation constant at 25°C is typically 1 × 10⁻⁶. -14 It is said that...

[0031] In some embodiments, the buffering capacity β of the buffering system defined by formula (2) is at least 0.065, at least 0.070, at least 0.075, at least 0.080, at least 0.085, at least 0.090, at least 0.095, or less It is at least 0.100. The effectiveness of the nitric oxide generating composition may be improved by increasing the buffering capacity defined by formula (2).

[0032] In some embodiments, the buffering capacity β of the buffering system defined by formula (2) is 1.0 and up to 1.0 (i.e., 1.0 or less), 0.95 and up to 0.95, 0.90 and up to 0.90, 0.85 and up to 0.85, 0.80 and up to 0.80, 0.75 and up to 0.75, 0.70 and up to 0.70, 0.65 and up to 0.65, 0.60 and up to 0.60, or 0.55 and up to 0.55.

[0033] In a particular embodiment, the buffering capacity β of the buffering system defined by formula (2) is in the range of 0.065 to 0.95, 0.070 to 0.90, 0.075 to 0.85, 0.080 to 0.80, 0.085 to 0.75, 0.090 to 0.70, 0.095 to 0.65, or 0.100 to 0.60. In a particular embodiment, the buffering capacity β of the buffering system defined by formula (2) is in the range of 0.060 to 0.20.

[0034] Related useful buffering capacity The relevant useful buffering capacity Ruβ of the buffer system may be at least 0.04, where RUβ is the integral of β with respect to pH, using the trapezoidal method with a pH interval of 0.01 between the pH (pH_i) of the buffer system and pH 6.00, as given by equation (3).

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[0035] The considerations for calculating buffering capacity β are the same as above (for example, when using polybasic acids or multiple acid / conjugated base pairs).

[0036] The trapezoidal rule for calculating integrals is well known. For example, the integral from 1 to 2 (on the x-axis) at 0.5 intervals is calculated as follows: Add the value on the y-axis at 1 and the value on the y-axis at 1.5 (0.5 intervals), divide by two, and find the average of the y-axis values. Next, multiply this average by the interval of 0.5 to obtain the first area value. Repeat this calculation for the values ​​on the y-axis at 1.5 and 2 to obtain the second area value. Then add the first and second area values ​​together. The first and second integral values ​​are determined using the trapezoidal method at 0.5 intervals. In the calculation of Ruβ according to this invention, this method is used together with the pH value on the x-axis, a pH interval of 0.01, and the buffering capacity β on the y-axis.

[0037] In some embodiments, the relevant useful buffering capacity Ruβ of the buffer system is at least 0.0425, at least 0.045, at least 0.0475, at least 0.050, at least 0.0525, at least 0.055, at least 0.0575, or at least 0.060, where Ruβ is the integral of β with respect to pH using the trapezoidal method of a pH interval of 0.01 between the pH (pH_i) of the buffer system and pH 6.00, and β is the buffering capacity of the buffer system calculated by equation (2).

[0038] In some embodiments, the relevant useful buffering capacity Ruβ of the buffer system is at most 0.75, at most 0.70, at most 0.65, at most 0.60, at most 0.55, at most 0.50, at most 0.45, at most 0.40, at most 0.35, at most 0.30, or at most 0.25, where Ruβ is the integral of β with respect to pH using the trapezoidal method of a pH interval of 0.01 between the pH (pH_i) of the buffer system and pH 6.00, and β is the buffering capacity of the buffer system calculated by equation (2).

[0039] In certain embodiments, the relevant useful buffering capacity Ruβ of the buffer system is in the range of 0.040 to 0.75, where Ruβ is the integral of β with respect to pH using the trapezoidal method with a pH interval of 0.01 between the pH of the buffer system (pH_i) and pH 6.00, and β is the buffering capacity of the buffer system calculated by equation (2). In other embodiments, the relevant useful buffering capacity Ruβ of the buffer system is in the range of 0.0425 to 0.70, 0.045 to 0.65, 0.050 to 0.60, 0.050 to 0.55, or 0.050 to 0.50, where Ruβ is the integral of β with respect to pH using the trapezoidal method with a pH interval of 0.01 between the pH of the buffer system (pH_i) and pH 6.00, and β is the buffering capacity of the buffer system calculated by equation (2).

[0040] acid The composition and kit contain at least one acid. The acid(s) may not only form part of the buffer system but may also be involved in the acidification of the nitrite to produce nitric oxide. In certain embodiments, the composition or kit contains at least one organic acid.

[0041] In some embodiments, the composition or kit comprises at least one acid having at least one pKa in the range of 4.0 to 6.2 at 25°C. The pKa values ​​of the acids are known by themselves. In certain embodiments, the composition or kit comprises at least one organic acid having at least one pKa in the range of 4.0 to 6.2 at 25°C.

[0042] In certain embodiments, the acid(s) are one or more organic carboxylic acids or organic non-carboxylic acid reducing acids.

[0043] In this specification, “organic carboxylic acid” means any organic acid containing one or more -COOH groups in its molecule. Organic carboxylic acids may be linear or branched. They may be saturated or unsaturated. They may be aliphatic or aromatic. They may be acyclic or cyclic. They may be vinyl carboxylic acids.

[0044] Organic carboxylic acids may have one or more substituents, for example, one or more hydroxyl groups. Examples of hydroxyl-substituted organic carboxylic acids that may be used in this disclosure include α-hydroxycarboxylic acids, β-hydroxycarboxylic acids, and γ-hydroxycarboxylic acids. It can be listed.

[0045] In this specification, “organic non-carboxylate reducing acid” refers to any organic reducing acid that does not contain a -COOH group in its molecule. Organic non-carboxylate reducing acids may be linear or branched. They may be saturated or unsaturated. They may be aliphatic or aromatic. They may be acyclic or cyclic. They may be vinyl derivatives.

[0046] Organic non-carboxylic acid reducing acids may have one or more substituents, such as one or more hydroxyl groups. Examples of hydroxyl-substituted organic non-carboxylic acid reducing acids that may be used in this disclosure include acidic reductones, such as reductic acid (2,3-dihydroxy-2-cyclopentanone).

[0047] One or more organic carboxylic acids may contain, be composed of, or be one or more reducing carboxylic acids. Organic carboxylic acids may be selected from, for example, salicylic acid, acetylsalicylic acid, acetic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, lactic acid, maleic acid, malic acid, benzoic acid, formic acid, propionic acid, α-hydroxypropanoic acid, β-hydroxypropanoic acid, β-hydroxybutyric acid, β-hydroxy-β-butyric acid, naphthoic acid, oleic acid, palmitic acid, pamoic acid (embonic acid), stearic acid, malonic acid, succinic acid, fumaric acid, glucoheptonic acid, glucuronic acid, lactobionic acid, cinnamic acid, pyruvic acid, orotic acid, glyceric acid, glycyrrhizic acid, sorbic acid, hyaluronic acid, alginic acid, oxalic acid, their salts, and combinations thereof.

[0048] Organic carboxylic acids may be citric acid or its salts.

[0049] Carboxylic acids may be polymers or polymerized carboxylic acids, such as polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, polylactic acid, polyglycolic acid, or copolymers of lactic acid and glycolic acid, or may include such polymers or polymerized carboxylic acids. In this specification, “organic carboxylic acid” also includes partial or complete esters of organic carboxylic acids, or partial or complete salts thereof (provided they can function as acids used in accordance with the present invention).

[0050] Organic non-carboxylic acid reducing acids may be selected from, for example, ascorbic acid, ascorbic acid-palmitic acid (ascorbyl palmitate), 3-O-ethyl ascorbic acid, other 3-alkyl ascorbic acids, 6-O-octanoyl ascorbic acid, 6-O-dodecanoyl ascorbic acid, 6-O-tetradecanoyl ascorbic acid, 6-O-octadecanoyl ascorbic acid, 6-O-dodecanoyl ascorbic acid, L-ascorbic acid 2-phosphate, and ascorbic acid derivatives such as 2-O-α-D-glucopyranosyl-L-ascorbic acid, acidic redactones such as reductic acid, erythorbic acid, their salts, and combinations thereof.

[0051] Organic non-carboxylic acid reducing acids may be ascorbic acid or its salts.

[0052] In certain embodiments, the composition or kit comprises at least one organic carboxylic acid having at least one pKa in the range of 4.0 to 6.2 at 25°C. In some embodiments, the composition or kit described herein may further comprise an additional acid suitable for acidifying nitrous acid.

[0053] pH of the buffer system The acid and its conjugate base may be provided in a ratio to achieve the desired pH of the buffer system. The buffer system has a pH between 4.6 and 6.0. In some embodiments, the buffer system has a pH between 4.6 and 5.6, between 4.6 and 5.4, between 4.6 and 5.2, or between 4.6 and 5.0. In alternative embodiments, the buffer system has a pH between 4.8 and 5.2. Typically, the pH of the buffer system can be determined before adding the nitrite to form the composition.

[0054] The conjugate base may be added separately, or it may be generated in situ from the acid by adjusting the pH with an acid and / or base, such as a mineral acid and / or mineral base.

[0055] Buffer concentration The buffer concentration depends on the required pH and buffering capacity, or the relevant useful buffering capacity, and can be determined from the above formula and calculation.

[0056] For the purposes of the above calculations, the buffer concentration is the concentration in the buffer system of the nitric oxide-producing composition immediately after the composition is formed (for example, immediately after mixing components such as acid and nitrite components). The composition may have buffer concentrations in the range of 0.01M to 1.5M, 0.05M to 1.0M, or 0.075M to 0.75M. In certain embodiments, the composition has a buffer concentration of at least 0.075M, at least 0.10M, at least 0.11M, at least 0.12M, at least 0.13M, at least 0.14M, or at least 0.15M. In certain embodiments, the composition has a buffer concentration of at most 0.75M, at most 0.70M, at most 0.65M, at most 0.60M, at most 0.55M, or at most 0.50M.

[0057] The kits described herein typically contain amounts of acid and conjugate base that, when mixed with other components to form a nitric oxide-producing composition, provide the required buffer concentration. The kits may contain amounts of acid and conjugate base that, when mixed with other components to form a nitric oxide-producing composition, provide target buffer concentrations in the range of 0.01 M to 1.5 M, 0.05 M to 1.0 M, or 0.075 M to 0.75 M. In certain embodiments, the kits contain amounts of acid and conjugate base necessary to provide target buffer concentrations of at least 0.075 M, at least 0.10 M, at least 0.11 M, at least 0.12 M, at least 0.13 M, at least 0.14 M, or at least 0.15 M when mixed with other components to form a nitric oxide-producing composition. In certain embodiments, the kit contains an amount of acid and conjugate base necessary to provide a target buffer concentration of at most 0.75 M, at most 0.70 M, at most 0.65 M, at most 0.60 M, at most 0.55 M, or at most 0.50 M when mixed with other components to form a nitric oxide generating composition.

[0058] It should be noted that aqueous solutions of acid and nitrite are diluted when the two separate solutions are combined to form a composition. Therefore, the molar concentrations of the acid solution and the nitrite solution will be higher than the overall desired (or target) molar concentration when the components are mixed, taking dilution into account.

[0059] Nitrite / Nitrite Components The present invention comprises one or more nitrites. The selection of nitrites is not particularly limited. The nitrites may be selected from one or more alkali metal nitrites or alkali metal nitrites. For example, one or more nitrites may be LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, AgNO2, Be( The nitrite may be selected from NO2)2, Mg(NO2)2, Ca(NO2)2, Sr(NO2)2, Mn(NO2)2, Ba(NO2)2, Ra(NO2)2, and any mixture thereof. The nitrite may be NaNO2 or KNO2. The nitrite may be NaNO2.

[0060] The nitrite may be of a pharmaceutically acceptable grade. In other words, the nitrite may conform to one or more current pharmacopoeia monographs relating to nitrites. For example, the nitrite may conform to one or more monographs relating to nitrites from the United States Pharmacopeia (USP), the European Pharmacopoeia, or the Japanese Pharmacopoeia.

[0061] Specifically, the nitrites used may have one or more properties as provided in paragraphs

[0032] to

[0060] and / or Table 1 of paragraph

[0204] of International Publication No. 2010 / 093746, the entire disclosure of which is incorporated herein by reference.

[0062] Molar concentration of nitrite The molar concentration of nitrite in the composition may be in the range of 0.001 M to 2.0 M. In some embodiments, the molar concentration of nitrite in the composition is in the range of 0.01 M to 1.5 M, 0.05 M to 1.0 M, or 0.075 M to 0.75 M. In certain embodiments, the molar concentration of nitrite in the composition is at least 0.075 M, at least 0.080 M, at least 0.085 M, at least 0.090 M, at least 0.095 M, or at least 0.100 M. In certain embodiments, the molar concentration of nitrite in the composition is at most 0.75 M, at most 0.70 M, at most 0.65 M, at most 0.60 M, at most 0.55 M, or at most 0.50 M.

[0063] In some embodiments, the ratio of the molar concentration of nitrite to the buffer concentration is about 1:1 in the composition. In other embodiments, the ratio of the molar concentration of nitrite to the buffer concentration is greater than 1:1 in the composition.

[0064] The target molar concentration of nitrite in the kit (i.e., the molar concentration after mixing the acid and nitrite components) may be in the range of 0.001 M to 2.0 M. In some embodiments, the target molar concentration of nitrite in the kit is in the range of 0.01 M to 1.5 M, 0.05 M to 1.0 M, or 0.075 M to 0.75 M. In certain embodiments, the target molar concentration of nitrite in the kit is at least 0.075 M, at least 0.080 M, at least 0.085 M, at least 0.090 M, at least 0.095 M, or at least 0.100 M. In certain embodiments, the target molar concentration of nitrite in the kit is at most 0.75 M, at most 0.70 M, at most 0.65 M, at most 0.60 M, at most 0.55 M, or at most 0.50 M.

[0065] In some embodiments, the ratio of the target molar concentration of nitrite to the target buffer concentration is approximately 1:1 in the kit. In other embodiments, the ratio of the target molar concentration of nitrite to the target buffer concentration is greater than 1:1 in the kit.

[0066] Form of the kit's components Acids and / or nitrites in aqueous solutions In some embodiments, one or both of the acidic and nitrite components are in an aqueous solution. In these embodiments, the acidic and nitrite components are typically stored as separate components until needed to prevent the nitrite from becoming acidic before it is required.

[0067] In certain embodiments, both the acid component and the nitrite are in aqueous solution. In this embodiment, the conjugate base may be contained within the acid component. In this way, the aqueous acid component forms a buffer system. There are cases where this occurs.

[0068] Acids and / or nitrites in solid form In other embodiments, the kit comprises an acid component and / or a nitrite component in solid form. In these embodiments, the kit further includes instructions indicating the volume of aqueous medium (e.g., water) to be added to form the nitric oxide generating composition described herein. In some embodiments, the kit includes a separate container having a certain volume of aqueous medium and instructions for adding a certain volume of aqueous medium to create a buffer system.

[0069] In some embodiments, the kit includes a solid powder composition such as those described in PCT / GB2022 / 53305 or PCT / GB2022 / 53307, the contents of which are incorporated herein by reference. The solid powder compositions described therein typically contain both an acid and a nitrite, which are effectively preserved until use by being kept in close proximity.

[0070] The solid powder composition may contain the following particles: (a) Particles containing both nitrite and acid, and / or (b) A particle aggregate comprising one or more nitrite particles containing a nitrite and one or more acid particles containing an acid.

[0071] In this way, acidic and nitrite components may be kept in close proximity. If a particle contains both acid and nitrite, it should be understood that the particle may contain both nitrite and acid within the same particle.

[0072] In this specification, “aggregate,” “aggregation,” and “aggregating together” refer to aggregates or collections of primary particles exhibiting identifiable collective behavior. In the present invention, primary particles may be nitrite particles containing nitrite, acid particles containing acid, or particles containing both nitrite and acid. In the present invention, identifiable collective behavior may be resistance to mechanical separation, i.e., adhesion between particles.

[0073] The particles or aggregates of the solid composition may have a particle size suitable for their desired use or application. The particles or aggregates of the solid composition may have a particle size of about 10 μm or less, for example, about 5 μm or less, about 4 μm or less, about 3 μm or less, about 2 μm or less, or about 1 μm or less.

[0074] Alternatively, the particles or aggregates of the solid composition may have a particle size greater than 5 μm. For example, the particles or aggregates of the solid composition may have particle sizes greater than 50 μm, greater than 100 μm, greater than 250 μm, greater than 500 μm, greater than 750 μm, or greater than 1000 μm.

[0075] The weight ratio of nitrite to acid in the solid composition may range from approximately 1:1 to approximately 1:99, for example, from approximately 1:4 to approximately 1:49, or from approximately 1:7 to approximately 1:24.

[0076] The solid powder composition may be substantially free of one or more binders, or it may further contain one or more binders. In this specification, “binder” means an agent that promotes particle adhesion, i.e., promotes the formation of particle aggregates.

[0077] Suitable binders may include sugars, natural binders, or synthetic or semi-synthetic polymer binders. Sugars may include, for example, sucrose or liquid glucose. Natural binders include, for example, acacia, tragacanth, gelatin, starch paste, and ze. The binder may include pre-latinized starch, alginic acid, or cellulose. Synthetic or semi-synthetic polymer binders may include, for example, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol, and polymethacrylate. The binder may be a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate (copovidone). The binder may be microcrystalline cellulose.

[0078] The binder may be incorporated into the composition at a %w / w concentration ranging from approximately 5% w / w to approximately 30% w / w. For example, the binder may be incorporated into the composition at a %w / w concentration ranging from approximately 10% w / w to approximately 25% w / w.

[0079] Particle aggregation may be achieved by any suitable means well known to those skilled in the art.

[0080] Particle aggregation may be achieved by mechanical means, such as mechanically pressing and binding particles together. Mechanical aggregation may be achieved by micronizing nitrite particles and acid particles. Alternatively, mechanical aggregation may be achieved by using substantially non-statically charged particles.

[0081] Particle aggregation may be achieved by chemical means, such as chemically accelerated adhesion or chemical coating. Chemical aggregation may be achieved by adhesion promoters, such as moisture. Alternatively, chemical aggregation may be achieved by coatings that bind together primary particles of nitrite and primary particles of acid. Suitable binders are described above, and suitable coating materials are described below in the section on "Coated Particles".

[0082] The solid powder composition may contain particles coated with a hydrophobic material (also referred to herein as coated particles).

[0083] Coated particles may contain nitrites and acids and may include single particles coated with a hydrophobic material.

[0084] Alternatively, the coated particles may be aggregates of particles coated with a hydrophobic material, and such aggregates of particles may include (a) particles containing nitrite and acid, and / or (b) a mixture of one or more nitrite particles containing nitrite and one or more acid particles containing acid.

[0085] In this way, the coated particles contain nitrite and acid within the same coating agent.

[0086] Hydrophobic materials may be any material having the ability to coat particles or aggregates such that the particles or aggregates are covered with a hydrophobic layer. Hydrophobic materials may be polymeric materials, such as organic polymeric materials. Hydrophobic materials may be surfactant-type species, such as amphiphilic species, such as nonionic, anionic, cationic, or amphoteric surfactant-type species. Hydrophobic materials may be inorganic mineral materials, such as inorganic mineral materials that form a three-dimensional skeleton. Hydrophobic materials may be biocompatible. Hydrophobic materials may include one or more of poly(lactic acid-co-glycolic acid) (PLGA), dipalmitoylphosphatidylcholine (DPPC), magnesium stearate, and mesoporous silica. Hydrophobic materials may include polymeric materials poly(lactic acid-co-glycolic acid) (PLGA) without acid-terminated groups, or polymeric materials poly(lactic acid-co-glycolic acid) (PLGA) with acid-terminated groups.

[0087] In this specification, "surfactant" means a substance that reduces the surface tension of a species in a medium, or the interfacial tension between media. This refers to surfactants that can lower the pH. Surfactants generally have a hydrophilic head and a hydrophobic tail.

[0088] Hydrophobic substances may adhere to particles or aggregates through chemical bonds, electrostatic forces, or intermolecular forces.

[0089] The coating of coated particles or aggregates may affect the reaction kinetics, such as reaction rate, of nitrite acidification when the coated particles or aggregates are exposed to an aqueous environment.

[0090] The coated particles or coated aggregates of the solid composition may have a particle size suitable for the desired use or application. The coated particles or coated aggregates of the solid composition may have a particle size of about 10 μm or less, for example, about 5 μm or less, about 4 μm or less, about 3 μm or less, about 2 μm or less, or about 1 μm or less. Alternatively, the coated particles or coated aggregates of the solid composition may have a particle size greater than about 5 μm. For example, the particles or aggregates of the solid composition may have a particle size greater than about 50 μm, about 100 μm, about 250 μm, about 500 μm, about 750 μm, or about 1000 μm.

[0091] The formation of such solid powder compositions can be carried out by many methods.

[0092] Formation of particles from a mixture containing nitrite solution and acid solution The particles of the solid powder composition may be formed from a mixture containing a nitrite solution and an acid solution. The particles thus formed should be created by mixing an aqueous nitrite solution with an aqueous acid solution and then removing the solvent within a short time (e.g., 30 seconds or less). Alternatively, the mixture may be placed under reaction delay conditions (e.g., a temperature below the freezing point of the solvent) after mixing the aqueous nitrite solution with the aqueous acid solution to remove the solvent. In this way, the solvent is removed from the mixture while minimizing the acidification of the nitrite. Therefore, the resulting powder composition may contain effective amounts of nitrite and acid.

[0093] When the solvent is to be removed quickly after mixing the nitrite solution and the acid solution, the solvent may be removed in 30 seconds or less after mixing. In some examples, the solvent is removed in 10 seconds or less, 5 seconds or less, 2 seconds or less, or 1 second or less after mixing the nitrite solution and the acid solution. In some examples, the solvent is removed in 500 milliseconds or less, 100 milliseconds or less, 50 milliseconds or less, or 10 milliseconds or less after mixing the nitrite solution and the acid solution.

[0094] In one embodiment, particles may be formed by spray-drying a mixture containing a nitrite solution and an acid solution. By spray-drying the mixture, the solvent may be removed within 30 seconds or less after mixing the nitrite solution and the acid solution. Spray-drying of materials is known in itself.

[0095] The mixture is typically a mixture of an aqueous solution of nitrite and an aqueous solution of acid. When using aqueous solutions, the time between mixing the two solutions should be minimized to suppress the acidification of the nitrite. The aqueous solutions of nitrite and acid may be mixed inline for about 1 to 10 milliseconds, for example, about 3 to 5 milliseconds, before spray drying is performed. Spray drying may be performed immediately after mixing the aqueous solutions of nitrite and acid. It is understood that by mixing and spray drying the mixture containing the nitrite solution and the acid solution as described, the potential reaction time between the acid and nitrite components is limited.

[0096] The particles formed by spray-drying a mixture containing a nitrite solution and an acid solution are approximately 10 μm or smaller, for example, approximately 5 μm or smaller, approximately 4 μm or smaller, approximately 3 μm or smaller, approximately 2 μm or smaller. Alternatively, the particle size may be approximately 1 μm or less.

[0097] Spray-drying a mixture containing a nitrite solution and an acid solution as described may result in a solid powder composition in which each particle contains the nitrite and acid components.

[0098] The particles formed by spray-drying a mixture containing a nitrite solution and an acid solution may be in any preferred form. For example, the particles formed by spray-drying a mixture containing a nitrite solution and an acid solution may be in a crystalline or amorphous form.

[0099] Additionally or alternatively, the mixture of the nitrite solution and the acid solution is placed under reaction-inhibiting conditions (e.g., a temperature below the freezing point of the solvent) to remove the solvent before, during, or immediately after mixing. In this way, the acidification of the nitrite is delayed until the solvent is removed. Specifically, the solvent may be an aqueous solvent.

[0100] A specific example of a reaction delaying condition is a mixture temperature lower than the freezing point of the solvent. In this way, the reaction rate of acidification by nitrite may be slowed while the solvent is removed. When the mixture temperature is lower than the freezing point of the solvent, the nitrite solution and the acid solution are usually mixed at a temperature above the freezing point of the solvent before the mixture temperature drops below the freezing point of the solvent. In this way, good mixing of the solutions may occur.

[0101] In some examples, solvent removal may be carried out under reduced pressure. In particular, solvent removal may be carried out under reduced pressure at a temperature below the freezing point of the solvent to be removed.

[0102] A particularly useful technique for removing solvents under reaction-inhibiting conditions is lyophilization (or freeze-drying).

[0103] It should be noted that in this specification, “solvent removal” and / or “drying” means achieving a solid powder composition. These terms include, but are not limited to, the complete removal of the solvent. In some examples, the solid powder composition may contain trace amounts of residual solvent. For example, the powder composition may contain up to about 10% residual solvent, up to about 5% residual solvent, up to about 3% residual solvent, or up to about 1% residual solvent. To provide a solid powder composition, additional drying techniques, such as vacuum drying, may be employed after the solvent has been initially removed.

[0104] Solid mixture for forming particle aggregates A solid powder composition may be formed by mixing a nitrite-containing solid with an acid-containing solid to form a particle aggregate, where the particle aggregate contains one or more particles containing nitrite and one or more particles containing acid.

[0105] Forming particle aggregates by mixing a nitrite-containing solid with an acid-containing solid can be achieved, for example, (a) by mixing one or more nitrite particles with one or more acid particles, where the nitrite particles are formed by spray-drying a nitrite solution and the acid particles are formed by spray-drying an acid solution; or (b) by forming one or more particles by pulverizing the nitrite solid together with the acid solid.

[0106] Mixed spray-dried nitrite particles and spray-dried acid particles The solid powder composition may be a mixture of nitrite particles and acid particles, where nitrite Acid particles are formed by spray-drying a nitrite solution, and acid particles are formed by spray-drying an acid solution. The spray-dried nitrite particles and spray-dried acid particles may be mixed together by means of providing a standard solid powder composition well known to those skilled in the art.

[0107] Spray-dried nitrite particles and spray-dried acid particles may be mixed in weight ratios of nitrite to acid ranging from approximately 1:1 to approximately 1:99, for example, approximately 1:4 to approximately 1:49, or approximately 1:7 to approximately 1:24.

[0108] The spray-dried nitrite particles and spray-dried acid particles may be mixed for a period of time ranging from approximately 5 to 60 minutes, for example, from approximately 10 to 40 minutes, or from approximately 15 to 30 minutes. The spray-dried nitrite particles and spray-dried acid particles may be mixed for a period of time ranging from approximately 20 minutes.

[0109] The particles formed by spray-drying the nitrite solution and the acid solution and mixing these components as described may have a particle size of approximately 10 μm or less, for example, approximately 5 μm or less, approximately 4 μm or less, approximately 3 μm or less, approximately 2 μm or less, or approximately 1 μm or less.

[0110] A solid powder composition containing particle aggregates may be obtained by spray-drying a nitrite solution, spray-drying an acid solution, and mixing these components as described. Herein, the aggregates contain one or more particles containing nitrite and one or more particles containing acid.

[0111] The particles formed by spray-drying a nitrite solution, spray-drying an acid solution, and mixing these components may be in any preferred form. For example, the particles formed by spray-drying a nitrite solution, spray-drying an acid solution, and mixing these components may be in a crystalline or amorphous form. The particles formed by spray-drying a mixture containing a nitrite solution and an acid solution may be amorphous.

[0112] Particles formed by pulverizing nitrite solids together with acid solids. Particles may be formed by pulverizing nitrite solids together with acidic solids.

[0113] In this specification, “micronization” refers to a process for reducing the average particle size of a solid composition to typically within the micrometer range. Micronization can be achieved by standard processes well known to those skilled in the art. For example, micronization may occur by grinding or abrading particles, or by utilizing supercritical fluids.

[0114] If the acid is a buffered acid system, the acid solid may consist of two components: a solid acid component and a solid conjugated base component. Nitrite solids and acid solids may be pulverized in ratios of approximately 1:1 to 1:99, for example, approximately 1:4 to 1:49, or in the range of approximately 1:7 to 1:24, for example, 1:9 w / w nitrite:acid.

[0115] The particles formed by pulverizing nitrite solids together with acid solids may have a particle size of approximately 10 μm or less, for example, approximately 5 μm or less, approximately 4 μm or less, approximately 3 μm or less, approximately 2 μm or less, or approximately 1 μm or less.

[0116] As described, by micronizing a nitrite solid together with an acid solid, a solid powder composition containing nitrite particles and acid particles may be obtained. As described, by micronizing a nitrite solid together with an acid solid, a solid powder composition containing aggregates containing nitrite particles and acid particles may be obtained.

[0117] The particles formed by pulverizing a nitrite solid together with an acid solid may be in any preferred form. For example, the particles formed by pulverizing a nitrite solid together with an acid solid may be in a crystalline or amorphous form. The particles formed by pulverizing a nitrite solid together with an acid solid may be in a crystalline form.

[0118] The particles formed by micronization may contain one or more of the above-mentioned additives (in addition to the acid and nitrite). Specifically, the particles formed by micronization may contain the above-mentioned binders. The binders may be micronized together with the nitrite solids and acid solids.

[0119] Any ingredient The compositions and kits of the present invention may contain one or more optional components.

[0120] Organic polyols The compositions or kits of the present invention may substantially contain one or more organic polyols.

[0121] Alternatively, the compositions or kits of the present invention may further comprise one or more organic polyols. In this specification, “organic polyol” refers to an organic molecule having two or more hydroxyl groups that is an acid (particularly for nitrite reactions) and is not a monosaccharide or polysaccharide (where “monosaccharide” and “polysaccharide” include oligosaccharides, glycans, and glycosaminoglycans). Therefore, organic polyols have a pKa1 of about 7 or more.

[0122] In this specification, “organic polyol” preferably excludes reducing agents. Examples of reducing agents, which are organic molecules having two or more hydroxyl groups and not being monosaccharides or polysaccharides, include thioglycerol (e.g., 1-thioglycerol), hydroquinone, butylated hydroquinone, ascorbic acid, ascorbate, erythorbic acid, and erythorbate. Since thioglycerol (e.g., 1-thioglycerol), hydroquinone, butylated hydroquinone, ascorbic acid, and erythorbic acid are reducing agents, they are therefore preferably excluded from the expression “organic polyol.” Ascorbic acid and erythorbic acid are acids, particularly for nitrite reactions, and are therefore excluded from the expression in any case.

[0123] Organic polyols may be cyclic or acyclic, or they may be mixtures of one or more cyclic organic polyols and one or more acyclic organic polyols. For example, one or more organic polyols may be selected from one or more alkanes substituted with two or more OH groups, one or more cycloalkanes substituted with two or more OH groups, one or more cycloalkylalkanes substituted with two or more OH groups, and any combination thereof. Organic polyols may not have substituents other than OH groups.

[0124] One or more organic polyols may be one or more acyclic organic polyols. One or more acyclic organic polyols may be selected from sugar alcohols having 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. One or more acyclic organic polyols may be selected from alditols, for example, alditols having 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. One or more organic polyols may not contain saponins, sapogenins, steroids, or steroid glycosides.

[0125] Alternatively, one or more organic polyols may be one or more cyclic organic polyols. One or more cyclic organic polyols may be cyclic sugar alcohols or cyclic alditols. For example, one or more cyclic polyols may be 4, 5, 6, 7, 8, These may be cyclic sugar alcohols having 9, 10, 11, or 12 carbon atoms, or cyclic alditols having 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. A specific example of a cyclic polyol is inositol.

[0126] One or more organic polyols may have seven or more hydroxyl groups. One or more organic polyols may be sugar alcohols or alditols having seven or more hydroxyl groups. One or more organic polyols may have nine or more hydroxyl groups. One or more organic polyols may be sugar alcohols or alditols having nine or more hydroxyl groups. One or more organic polyols may have 20 or fewer hydroxyl groups. One or more organic polyols may be sugar alcohols or alditols having 20 or fewer hydroxyl groups. One or more organic polyols may have 15 or fewer hydroxyl groups. One or more organic polyols may be sugar alcohols or alditols having 15 or fewer hydroxyl groups. One or more organic polyols may have a number of hydroxyl groups in the range of 7 to 20, for example, in the range of 9 to 15. One or more organic polyols may contain 9, 12, 15, or 18 hydroxyl groups.

[0127] One or more organic polyols may be, for example, sugar alcohol compounds containing one or more monosaccharide units and one or more acyclic sugar alcohol units. One or more organic polyols may include, for example, sugar alcohol compounds containing one or more linear monosaccharide units and one or more acyclic sugar alcohol units, or one or more branched monosaccharide units and one or more acyclic sugar alcohol units.

[0128] In this specification, “monosaccharide unit” means a monosaccharide covalently bonded to at least one other unit in a compound (whether another monosaccharide unit or an acyclic sugar alcohol unit). In this specification, “acyclic sugar alcohol unit” means an acyclic sugar alcohol covalently bonded to at least one other unit in a compound (whether another monosaccharide unit or an acyclic sugar alcohol unit). Units in a compound may be bonded via ether bonds. One or more monosaccharide units may be covalently bonded to other units of a compound via glycosidic bonds. Each monosaccharide unit may be covalently bonded to other units of a compound via glycosidic bonds. Sugar alcohol compounds may be glycosides having monosaccharides or oligosaccharide glycones and acyclic sugar alcohol aglycones.

[0129] Acyclic sugar alcohol units may be sugar alcohol units having 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Acyclic sugar alcohol units may be selected from the group consisting of erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, and boremitol units.

[0130] One or more monosaccharide units may be C5 or C6 monosaccharide units, i.e., pentose or hexose units. Each monosaccharide unit may be a C5 or C6 monosaccharide unit. One or more sugar alcohol units may be C5 or C6 sugar alcohol units. Each sugar alcohol unit may be a C5 or C6 sugar alcohol unit.

[0131] A sugar alcohol compound may contain, for example, n monosaccharide units and m acyclic sugar alcohol units, where n is an integer at least 1, m is an integer at least 1, and (n+m) is 10 or less. A sugar alcohol compound may contain, for example, n monosaccharide unit chains terminated by one acyclic sugar alcohol unit, where n is an integer between 1 and 9. The monosaccharide unit chains may be covalently bonded by glycosidic bonds. Each monosaccharide unit may be covalently bonded to another monosaccharide unit or acyclic sugar alcohol unit by glycosidic bonds. A sugar alcohol compound may contain, for example, one, two, or three monosaccharide units terminated by one acyclic sugar alcohol unit. The chain may contain cyclic alcohol units. One, two, or three monosaccharide units, or each monosaccharide unit, may be a C5 or C6 monosaccharide unit. Acyclic alcohol units may be C5 or C6 sugar alcohol units. Examples of sugar alcohol compounds include, but are not limited to, isomalt, maltitol and lactitol (n=1), maltotriitol (n=2), and maltotetraitol (n=3).

[0132] Such sugar alcohol compounds may be described as sugar alcohols derived from disaccharides or oligosaccharides. In this specification, “oligosaccharide” refers to sugars containing 3 to 10 monosaccharide units. Sugar alcohols derived from disaccharides or oligosaccharides may be synthesized from disaccharides, oligosaccharides, or polysaccharides (e.g., by hydrogenation) (e.g., by hydrolysis and hydrogenation), but are not limited to compounds synthesized from disaccharides, oligosaccharides, or polysaccharides. For example, sugar alcohols derived from disaccharides may be formed from the dehydration reaction of monosaccharides and sugar alcohols. One or more organic polyols may be sugar alcohols derived from disaccharides, trisaccharides, or tetrasaccharides. Examples of sugar alcohols derived from disaccharides include, but are not limited to, isomalt, maltitol, and lactitol. Examples of sugar alcohols derived from trisaccharides include, but are not limited to, maltotriitol. Examples of sugar alcohols derived from tetrasaccharides include, but are not limited to, maltotetraitol.

[0133] Organic polyols may be selected from erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, boremitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and any combination thereof. Glycerol may also be used, and if present, preferably one or more other organic polyols, such as erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, boremitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and any combination thereof.

[0134] Many organic polyols contain one or more chiral centers, and therefore stereoisomers exist. All stereoisomers, optical isomers, and mixtures of isomers of organic polyols are intended to be within the scope of this invention. Specifically, the D and / or L forms of all chiral organic polyols, and all mixtures thereof, may be used.

[0135] If the composition or kit is in solid form and contains one or more organic polyols, it is preferable that the organic polyols be added to the composition after any treatment involving the removal of the solvent (e.g., after a spray-drying or freeze-drying step). In other words, the polyols may be added to a composition containing one or more particles containing nitrite and / or acid, or to a composition containing one or more particles containing nitrite and / or one or more particles containing acid (either before or after the aggregation of these particles is formed).

[0136] Molar concentration of organic polyols The molar concentration of the organic polyol in the composition may be in the range of 0.001 M to 1.0 M. In some embodiments, the molar concentration of the organic polyol in the composition is in the range of 0.002 M to 0.5 M, 0.003 M to 0.1 M, or 0.005 M to 0.05 M. In certain embodiments, the molar concentration of the organic polyol in the composition is at least 0.005 M, at least 0.008 M, at least 0.01 M, or at least 0.012 M. In certain embodiments, the molar concentration of the nitrite in the composition is at most 0.05 M, at most 0.045 M, at most 0.035 M, or at most 0.025 M.

[0137] Specific Embodiments In certain embodiments, the kit comprises a nitrite component as an aqueous solution containing one or more nitrites, and an acid component as an aqueous solution containing one or more organic carboxylic acids and organic non-carboxylic acid reducing acids.

[0138] In a particular embodiment, the buffering capacity β of the buffer system, as defined by equation (2), is in the range of 0.060 to 0.20. In a particular embodiment, the related useful buffering capacity Ruβ of the buffer system is in the range of 0.040 to 0.75, where Ruβ is the integral of β with respect to pH, calculated using the trapezoidal method with a pH interval of 0.01 between the pH (pH_i) of the buffer system and pH 6.00, and β is the buffering capacity of the buffer system calculated by equation (2).

[0139] In some embodiments, the buffer system is selected so that a pH between 4.8 and 5.2, or between 4.6 and 5.0, is achieved when exposed to an aqueous environment.

[0140] In some embodiments, the buffer system includes citrate and citrate as the acid and conjugate base. In these embodiments, the target buffer concentration may be in the range of 0.025 M to 0.25 M (depending on the pH of the acid). The target molar concentration of nitrite may be in the range of 0.025 M to 0.25 M. In some embodiments, the ratio of the target molar concentration of nitrite to the target buffer concentration may be in the range of about 0.8:1 to about 2:1. In some embodiments, the ratio of the target molar concentration of nitrite to the target buffer concentration may be greater than 1:1. In other words, the target molar concentration of nitrite may be greater than the target buffer concentration. The target molar concentration of nitrite may be greater than the target buffer concentration if the pH of the buffer is greater than 5.2.

[0141] The composition or kit may further contain an organic polyol selected from the group consisting of erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, boremitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and any combination thereof. Such organic polyol may be contained in either a nitrite component or an acid component. In certain embodiments, the composition or kit contains mannitol.

[0142] Pharmaceutical composition One or more components of the compositions or kits disclosed herein may be included in a pharmaceutical composition, optionally together with one or more pharmaceutically acceptable carriers, excipients, and / or adjuvants. Such carriers, excipients, and / or adjuvants may be physiologically compatible if in vivo use is desired.

[0143] Examples of carriers and / or excipients, such as physiologically compatible carriers and / or excipients, include, but are not limited to, lactose, starch, dicalcium phosphate, magnesium stearate, sodium saccharin, talc, cellulose, cellulose derivatives, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, magnesium chloride, magnesium sulfate, and calcium chloride.

[0144] Generally speaking, depending on the intended mode of administration, the pharmaceutical composition contains about 0.005% to about 95% by weight, preferably about 0.5% to about 50% by weight, of the combination or composition of the present invention or its components. Practical methods for preparing such dosage forms are known or will be obvious to those skilled in the art.

[0145] Excipients may be selected from known excipients depending on the intended use or administration route in which the reactants and / or reaction products are to be delivered to the target site for nitric oxide delivery. Optional additional components may be selected from, for example, sweeteners, flavoring agents, humectants, lubricants, binders, emulsifiers, solubilizers, stabilizers, colorants, deodorizers, salts, coatings, antioxidants, pharmaceutically active agents, and preservatives. Such components are well known in the art and no detailed discussion is necessary for those skilled in the art. Examples of auxiliary substances such as humectants, emulsifiers, lubricants, binders, and solubilizers include, for example, sodium phosphate, potassium phosphate, acacia gum, polyvinylpyrrolidone, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, and triethanolamine oleate. Examples of sweeteners or flavoring agents include sugar, saccharin, aspartame, sucralose, neotame, or other compounds that have a beneficial effect on taste, aftertaste, perceived unpleasant saltiness, sourness, or flavor, thereby reducing the tendency of oral or inhaled formulations to irritate the recipient (e.g., by causing cough or sore throat, or other undesirable side effects, which could, for example, reduce the dose delivered or adversely affect the patient's adherence to the prescribed treatment regimen). Certain flavoring agents may form complexes with one or more nitrites.

[0146] Examples of pharmaceutically active agents that may be incorporated into or co-administered with the components and compositions according to the present invention include antibiotics, steroids, anesthetics (e.g., local anesthetics such as lignocaine (lidocaine), ametokine (tetracaine), xylocaine, bupivacaine, prilocaine, ropibuffacaine, benzocaine, mepivacaine, cocaine, and any combination thereof), analgesics, anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs)), anti-infective agents, vaccines, immunosuppressants, antispasmodics, antidementia agents, prostaglandins, antipyretics, antipsychotics, antipsoriasis agents, antivirals, vasodilators or vasoconstrictors, sunscreens (e.g., PABAs), antihistamines, hormones such as estrogen, progesterone, or androgens, antiseborrheic agents, alpha-blockers or beta-blockers, or cardiovascular agents such as Rogaine, vitamins, or any combination thereof.

[0147] Specific examples include analgesics such as ibuprofen, indomethacin, diclofenac, acetylsalicylic acid, paracetamol, propranolol, metoprolol, and oxycodone; sex hormones such as thyroid-releasing hormone, estrogen, progesterone, and testosterone; antihistamines such as insulin, verapamil, vasopressin, hydrocortisone, scopolamine, nitroglycerin, isosorbide dinitrate, and terfenadine; nonsteroidal immunosuppressants such as clonidine, nicotine, cyclosporine, methotrexate, azathioprine, mycophenate, cyclophosphamide, TNF-α antagonists, and antisteroidal immunosuppressants such as anti-IL5, anti-IL4Ra, anti-IL6, anti-IL13, anti-IL17, and anti-IL23 cytokine monoclonal antibodies; antispasmodics; and drugs for treating Alzheimer's disease, dementia, and / or Parkinson's disease, such as apamorphine and rivastigmine.

[0148] Treatment, improvement, or prevention of respiratory diseases or disorders The present invention provides compositions, kits, and combinations for the treatment, improvement, or prevention of respiratory diseases or disorders, and methods for the treatment, improvement, or prevention of respiratory diseases or disorders, the methods comprising administering therapeutically effective doses of a combination of components of a composition, pharmaceutical composition, or kit as disclosed herein.

[0149] Respiratory disease or disorder Conditions treatable using the present invention include, for example, viral infections such as influenza, SARS-CoV, or SARS-CoV-2, pulmonary arterial hypertension, pulmonary fibrosis of any cause, and bronchiectasis of any cause (cystic fibrosis and noncystic fibrotic bronchiectasis). These include interstitial pneumonia of any cause (including stenosis), chronic obstructive pulmonary disease (COPD) (especially emphysema and chronic bronchitis), severe asthma, asthma including exacerbations and refractory (irreversible) asthma caused by viruses and bacteria, pneumonia, tuberculosis, bacterial infections of the nasal cavity or lungs such as nontuberculous mycobacterial infections, and other bacterial, protozoan and viral lung infections (e.g., secondary bacterial infections following viral infections of the respiratory tract).

[0150] The vasodilatory properties of nitric oxide characterize several therapeutic methods using the compositions, combinations, or pharmaceutical compositions described herein and the NOx gases generated therefrom.

[0151] In some embodiments, respiratory diseases or disorders are associated with the presence of one or more microorganisms in the subject being treated. In other words, respiratory diseases or disorders may be associated with one or more microbial infections in the subject. NOx gas generated from compositions or pharmaceutical compositions may have potentially broad-spectrum biocidal or biosidal effects against a wide range of microorganisms, leading to many antimicrobial therapies. Microorganisms are, for example, one or more selected from bacterial cells, viral particles and / or fungal cells, or microparasites, and may also be individual cells, organisms, or colonies.

[0152] When microorganisms are present in bacterial, fungal, viral, or microparasitic infections in humans or other animals, the infection may be in the context of a disease such as the common cold, influenza, tuberculosis, SARS, COVID-19, pneumonia, or measles.

[0153] Bacteria can be pathogenic species. Microbial infections can be infectious diseases caused by pathogenic bacterial species, including Gram-positive and Gram-negative bacteria, aerobic and anaerobic bacteria, and antibiotic-susceptible and antibiotic-resistant bacteria.

[0154] Examples of bacterial species that can be targeted using the present invention include bacteria of the genera Actinomyces, Bacillus, Bartonella, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Corynebacterium, Enterococcus, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Ureaplasma, Vibrio, or Yersinia. Any combination of these can also be targeted by the present invention.

[0155] The microorganisms may be pathogenic species of Corynebacterium, Mycobacterium, Streptococcus, Staphylococcus, Pseudomonas, or any combination thereof.

[0156] The active ingredients are Actinomyces israelii, Bacillus anthracis, Bacteroides fragilis, Bordetella pertussis, Borrelia burgdorferi, Borrelia garinii, Borrelia afzelii, and Borrelia recurrent Brucella abortus , Brucella canis , Brucella melitensis , Brucella suis , Campylobacter jejuni , Chlamydia pneumoniae , Chlamydia trachomatis , Chlamydophila psitta ci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheria, Ehrlichia canis, Ehrlichia chaffeensis, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, e.g. Enterotoxigenic E.coli (ETEC), Enteropathogenic E.coli, Enteroinvasive E.coli (EIEC), Enterohemorrhagic (EHEC), E.coli O157:H7.Francisella tularensis, Haemophilus influenza, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira, Listeria monocytogenes, Mycobacterium leprosy、Mycobacterium tuberculosis、Mycobacterium abscessus、Mycobacterium ulcerans、Mycoplasma pneumoniae、Mycobacterium avium、Mycobacterium Kansai、Neisseria gonorrhoeae、Neisseria meningitides、Pseudomonas aeruginosa、Nocardia asteroids、Rickettsia rickettsia、Salmonella typhi、Salmonella typhimurium、Shigella sonnei、Shigella dysenteriae、Staphylococcus aureus、Staphylococcus epidermidis、Staphylococcus saprophyticus、Streptococcus agalactiae、Streptococcus pneumoniae、Streptococcus pyogenes、Streptococcus viridans、Treponema pallidum singular pallidum Vibrio cholera、Yersinia pestis, and the effects of these strains are incredible.

[0157] The microorganisms may be selected from Chlamydia pneumoniae, Bacillus anthracis, Corynebacterium diphtheriae, Haemophilus influenzae, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium ulcerans, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, or any combination thereof.

[0158] The microorganisms may be antibiotic-resistant or antibiotic-sensitive pathogenic bacterial species, or strains of antibiotic-resistant or antibiotic-sensitive bacterial species. The use of nitric oxide for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) is described, for example, in International Publication No. 02 / 20026, the disclosure of which is incorporated herein by reference. Examples of antibiotic-resistant or antibiotic-sensitive pathogenic bacterial species that can be sterilized or treated using the present invention include, thus, methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive Staphylococcus aureus (MSSA).

[0159] Microorganisms can be pathogenic fungal species. Microbial infections can be caused by pathogenic fungal species, including pathogenic yeasts.

[0160] Examples of fungal species that can be targeted using the present invention include Aspergillus, Blastomyces, Candida (e.g., Candida auris), Coccidioides, Paracoccidioides, Cryptosporidium, Cryptococcus (especially Cryptococcus neoformans or Cryptococcus gattii), Histoplasma, Mucormycetes, Pneumocystis (e.g., Pneumocystis jirovecii or carinii), Sporothrix, Talaromyces, or any combination thereof.

[0161] Examples of fungal infections include infections caused by pathogenic species of Candida, such as aspergillosis (including allergic bronchopulmonary aspergillosis), histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, mucormycosis, cryptococcosis, and candidiasis.

[0162] Microorganisms can be viral particles. Infectious diseases can be caused by pathogenic viruses.

[0163] Examples of viruses that may be targeted using the present invention include influenza viruses, parainfluenza viruses, adenoviruses, noroviruses, rotaviruses, rhinoviruses, coronaviruses, respiratory syncytial virus (RSV), astroviruses, and hepatitis viruses. Compositions of the present invention may be used to treat or prevent infections caused by one of the following groups selected from H1N1 influenza virus, infectious bovine rhinotracheitis virus, bovine respiratory syncytial virus, bovine parainfluenza-3 virus, SARS-CoV, SARS-CoV-2, or any combination thereof.

[0164] This invention may be applied to treat diseases or disorders caused by viral infections.

[0165] Respiratory viral infections include influenza, rhinovirus (i.e., common cold virus), respiratory syncytial virus, adenovirus, coronavirus infections such as COVID-19 and severe acute respiratory syndrome (SARS), cytomegalovirus, and HSV. Gastrointestinal viral diseases include norovirus infection, rotavirus infection, adenovirus infection, and astrovirus infection. Exanthematous viral diseases include measles, rubella, chickenpox, herpes zoster, roseola, smallpox, erythema infectiosum, and chikungunya virus disease. Hepatic viral diseases include hepatitis A, B, C, D, and E.

[0166] Microorganisms can be parasitic (microparasites). Infectious diseases can be caused by pathogenic parasitic microorganisms. Examples of parasitic microorganisms that can be targeted using the present invention include protozoa.

[0167] In particular, the present invention relates to Sarcodina (e.g., amoeba, e.g., Entamoeba, e.g., Entamoeba histolytica or Entamoeba) dispar), Mastigophora (for example, flagellates, for example Giardia) The target may be protozoa such as Leishmania, Ciliophora (e.g., ciliates, e.g., Balantidium), Sporozoa (e.g., Plasmodium and Cryptosporidium), or any combination thereof.

[0168] Parasitic infections treatable using the present invention include pulmonary malaria, pulmonary amoebiasis, pulmonary babesiosis, pulmonary toxoplasmosis, and pulmonary leishmaniasis (e.g., mucocutaneous leishmaniasis).

[0169] In particular, respiratory illnesses or disorders may be tuberculosis.

[0170] Method of administration The composition of the present invention is typically administered to a subject immediately after mixing the three components: nitrite, acid, and water. In this way, the subject may be exposed to the reaction product of nitrite acidification immediately after the reaction has started.

[0171] The kits described herein may include the acid and nitrite as separate components, in particular when either or both of the acid and nitrite are provided as aqueous solutions. Alternatively, the acid and nitrite may be in solid powder form and may be mixed in the kit. In these embodiments, the kit includes instructions indicating the volume of aqueous medium (e.g., water) to be added to the mixed solid powder. In some embodiments, the kit includes a separate container having a certain volume of aqueous medium and instructions for adding a certain volume of aqueous medium to create a buffer system.

[0172] Prior to administration, the composition of the present invention may be prepared by mixing a nitrite, an acid, and an aqueous medium. The resulting composition may then be administered to the target.

[0173] In certain embodiments, the composition is administered to a subject by inhaling an aerosol of the composition (for example, by spray inhalation).

[0174] subject The subject matter may be animals or humans. While the term “animal” as used herein may generally include humans, where the term “animal” appears in expressions such as “animal or human subject matter,” the context will be understood to refer specifically to animals other than humans, or the reference to “human” will be understood to simply specify the option that animals may be humans, in order to avoid ambiguity.

[0175] The subjects may be human. Human subjects may be infants or adults.

[0176] The subjects may be vertebrates. Vertebrates may belong to the classes Agnatha (jawless fish), Chondrichthyes (cartilaginous fish), Osteichthyes (bony fish), Amphibians (amphibians), Reptilia (reptiles), Aves (birds), or Mammalia (mammals). The subjects may be animals belonging to the classes Mammalia or Aves.

[0177] The subject may be a domesticated animal species. Domesticated animals may be any of the following: - Facultaturates that have adapted to the ecological niche of humans (e.g., dogs, cats, guinea pigs) - Animals for food or farming (e.g., cattle, sheep, pigs, goats), and - Animals primarily used for carrying loads (e.g., horses, camels, donkeys).

[0178] Examples of livestock include, but are not limited to, alpacas, adaxes, bison, camels, canaries, capybaras, cats, cattle (including Bali cattle), chickens, collared peccaries, deer (including fallow deer, sika deer, horned deer, and white-tailed deer), dogs, donkeys, pigeons, ducks, lands, moose, emus, ferrets, and gays. Al, goats, geese, guinea fowl, guinea pigs, kudus, horses, llamas, minks, moose, rats, mules, musk oxen, ostriches, parrots, pigs, pigeons, quail, rabbits, rats (including reed mice), reindeer, white oryx, sheep, turkeys, buffalo, yaks, and zebu cattle. [Examples]

[0179] Example 1: Calculation example of buffering capacity and related useful buffering capacity The buffering capacity β is calculated using formula (2) as described herein:

number

[0180] The relevant useful buffering capacity is calculated as described herein. In this example, the buffer volume and the relevant useful buffer volume of the citrate / citrate buffer system (having three pKa values) are calculated at different pH values ​​and buffer concentrations. w = 1 × 10 -14 Use this.

[0181] In the following calculation, the integer K w / [H + ] and [H + ] is calculated for each pH value, and is an integer

number

number

[0182] The buffering capacity was calculated using a pH interval of 0.01 by taking the integral of β with respect to pH, using the trapezoidal method with a pH interval of 0.01 between the pH (pH_i) of the buffer system and pH 6.00, in order to calculate Ruβ. The buffering capacity interval of 0.01 is calculated by taking the average value of the buffering capacity value at a given pH (e.g., 4.60) and the buffering capacity value at a pH 0.01 higher than the given pH (e.g., 4.61), and multiplying this average value by the interval value (i.e., 0.01). Subsequently, the integral values ​​between the pH value and 6.00 are added together to calculate the relevant useful buffering capacity value.

[0183] The table below shows only a portion of the calculation results in the pH range of 4.6 to 6.0. The calculation was performed for the entire interval from 4.60 to 6.01, providing relevant useful buffering capacity across the entire range.

[0184] Figure 1 shows plots of buffering capacity calculated by equation (2) as described herein for citrate / citrate buffer systems with buffer concentrations of 0.025 M, 0.05 M, 0.10 M, 0.125 M, 0.15 M, and 0.20 M over the pH range of 4.0 to 6.0. Buffering capacity increases with increasing buffer concentration. The buffering capacity of the 0.025 M citrate / citrate buffer system does not exceed 0.02 across the entire pH range. The buffering capacity of the 0.20 M citrate / citrate buffer system varies between approximately 0.10 and 0.14 over the pH range.

[0185] Figure 2 shows plots of the associated useful buffering capacity (as the integral of β with respect to pH, using a trapezoidal plot with a pH interval of 0.01 between the buffer system's pH and pH 6.00) for citrate / citrate buffer systems with buffer concentrations of 0.025 M, 0.05 M, 0.10 M, 0.125 M, 0.15 M, and 0.20 M, over the pH range of 4.0 to 6.0. The associated useful buffering capacity generally increases as the pH decreases. The associated useful buffering capacity at a given pH generally increases as the buffer concentration increases.

[0186] [Table 1]

[0187] [Table 2]

[0188] Example 2: Antimicrobial activity of NO-releasing formulation Numerous NO-releasing formulations were tested, and their antimicrobial activity against Psuedomonas aeruinosa NCTC 13618 was measured using the 96-well suspension method, as described below.

[0189] methodology 100 microliters of the sample, at twice the desired final concentration, were dispensed into the corresponding wells of a 1.96-well plate. Two concentrations of each formulation were tested in three wells on each plate. 2. Prepare the bacterial suspension in cation-adjusted Mueller Hinton II liquid medium (CA). MHIIB) Medium 1×10 8 ±5 × 10 7 CFUmL -1 It was prepared as follows. 3. Add the final concentration of 5 × 10⁻¹⁵ to the prepared 96-well drug plate. 5 ±3 × 10 5 CFUmL -1 To achieve this result, 100 μL of bacterial suspension was inoculated into each well, and the number of inoculum was counted. 4. Sterile controls, negative controls, and positive controls were included. 5. After inoculation, the plates were placed on a temperature-controlled plate reader for 24 hours. The optical density (OD) of the plate reader was measured at 0, 4, 8, 12, 20, and 24 hours. 6.24 hours later, the plate was removed from the plate reader, the suspension was mixed, and the results were quantified by serial dilution, yielding the following reported decrease in the number of samples.

[0190] [Table 3] [Table 4]

[0191] [Table 5] [Table 6]

[0192] Figures 3 and 4 show the microbial loss (Log10 CFU / mL) at 6.25% dilutions of formulations containing 0.15 M nitrite and 0.22 M nitrite, respectively.

[0193] Example 3: Antimicrobial activity of NO-releasing formulation A number of NO-releasing formulations were tested, and their antibacterial activities against Mycobacterium abscessus ATCC 19977 were measured using the 96-well suspension method as described below.

[0194] Methodology 1. Individual colonies of Mycobacterium abscessus ATCC 19977 were picked and resuspended in cation-adjusted Mueller Hinton II broth (CAMHIBB). The suspension was prepared to a final concentration of 5×10 7 ±3×10 7 CFU / mL -1 and adjusted. Serial 10-fold dilutions were made in phosphate-buffered saline (PBS), and the resulting suspensions were plated on Middlebrook agar supplemented with 10% OADC enrichment (MBA) to quantify the inoculum concentration. 2. Test agents were prepared according to the following formulations. Subsequently, clear test agents were diluted to a test agent concentration of 25.0%. 3. 100 μL of each prepared test agent concentration was dispensed into the corresponding wells of a 96-well plate and mixed with 100 μL of the bacterial suspension to a final test agent concentration of 12.5%. 4. Aseptic controls, negative controls, and positive controls were included. 5. After inoculation, the plates were placed in a temperature-controlled plate reader for 72 hours. The plate reader measured the optical density (OD) at 0, 4, 8, 12, 24, 48, and 72 hours. 6. After 72 hours, the plates were removed from the plate reader, the suspensions were serially diluted and quantified, and the following reduction numbers were reported as results. 7. The test was repeated 3 more times, and a total of 4 biological replicates were performed for each formulation.

[0195]

Table 7

[0196]

Table 8

Claims

1. A nitric oxide generating composition for use in the treatment, improvement or prevention of respiratory diseases or disorders, wherein the composition comprises a) One or more nitrites, and b) A buffer system comprising at least one acid and at least one conjugate base, and water, wherein the buffer system has a pH in the range of 4.6 to 6.0, and the buffering capacity β of the buffer system, calculated by formula (2), is at least 0.

06. [Math 1] (In the formula, K ｗ This is the dissociation equilibrium constant of water at 25°C. [H ＋ ] is the hydrogen ion concentration based on the pH of the buffer system, C ｂｕｆ This is the buffer concentration in the composition, K ａ (where is the dissociation constant of the acid at 25°C.) The composition comprising the above.

2. The nitric oxide generating composition for use according to claim 1, wherein the buffering capacity β of the buffer system is at least 0.075 when calculated by formula (2).

3. A nitric oxide generating composition for use in the treatment, improvement or prevention of respiratory diseases or disorders, wherein the composition comprises a) One or more nitrites, and b) A buffer system comprising at least one acid, at least one conjugate base, and water, wherein the buffer system has a pH in the range of 4.6 to 6.0, and the associated useful buffering capacity RUβ of the buffer system is at least 0.04, where Ruβ is given by formula (3): [Math 2] As shown above, β is defined as the integral value of β with respect to pH, using the trapezoidal method with a pH interval of 0.01 between the pH of the buffer system and pH 6.00, where β is given by equation (2): [Math 3] (In the formula, K ｗ This is the dissociation equilibrium constant of water at 25°C. [H ＋ ] is the hydrogen ion concentration based on the pH of the buffer system, C ｂｕｆ This is the buffer concentration in the composition, K ａ (where is the dissociation constant of the acid at 25°C.) The buffering capacity of the buffering system is calculated by the buffering system, The composition comprising the above.

4. The nitric oxide generating composition for use according to claim 3, wherein the related useful buffering capacity Ruβ of the buffer system is at least 0.

05.

5. A nitric oxide generating composition for use according to any one of claims 1 to 4, wherein the buffer system comprises at least one acid selected from one or more carboxylic acids and one or more organic non-carboxylic acid reducing acids.

6. The nitric oxide generating composition according to claim 5, wherein the one or more organic carboxylic acids are selected from salicylic acid, acetylsalicylic acid, acetic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, lactic acid, maleic acid, malic acid, benzoic acid, formic acid, propionic acid, α-hydroxypropanoic acid, β-hydroxypropanoic acid, β-hydroxybutyric acid, β-hydroxy-β-butyric acid, naphthoic acid, oleic acid, palmitic acid, pamoic acid (embonic acid), stearic acid, malonic acid, succinic acid, fumaric acid, glucoheptonic acid, glucuronic acid, lactobionic acid, cinnamic acid, pyruvic acid, orotic acid, glyceric acid, glycyrrhizic acid, sorbic acid, hyaluronic acid, alginic acid, oxalic acid, salts thereof, and combinations thereof.

7. The nitric oxide generating composition according to claim 5, wherein the one or more organic non-carboxylic acid reducing acids are selected from ascorbic acid, ascorbic acid-palmitic acid (ascorbyl palmitate), 3-O-ethyl ascorbic acid, other 3-alkyl ascorbic acid, 6-O-octanoyl ascorbic acid, 6-O-dodecanoyl ascorbic acid, 6-O-tetradecanoyl ascorbic acid, 6-O-octadecanoyl ascorbic acid, 6-O-dodecanoyl ascorbic acid, L-ascorbic acid 2-phosphate, and ascorbic acid derivatives such as 2-O-α-D-glucopyranosyl-L-ascorbic acid, acidic reductones such as reductic acid, erythorbic acid, salts thereof, and combinations thereof.

8. A nitric oxide generating composition for use according to any one of claims 1 to 6, wherein the buffer system comprises citric acid and a citrate.

9. A nitric oxide generating composition for use according to claim 8, wherein the buffer concentration is at least 0.075 M and optionally 0.5 M or less.

10. A nitric oxide generating composition for use according to any one of claims 1 to 6, wherein the composition further comprises an organic polyol selected from the group consisting of erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, boremitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and any combination thereof.

11. The one or more nitrites are the composition LiNO ２ , NaNO ２ , KNO ２ , RbNO ２ , CsNO ２ , FrNO ２ , AgNO ２ , Be(NO ２ ) ２ , Mg(NO ２ ) ２ , Ca(NO ２ ) ２ , Sr(NO ２ ) ２ , Mn(NO ２ ) ２ , Ba(NO ２ ) ２ , Ra(NO ２ ) ２ , and are selected from any of them and any mixtures thereof, the use according to any one of claims 1 to 10 A nitric oxide generating composition for use.

12. A nitric oxide generating composition for use according to any one of claims 1 to 11, wherein the molar concentration of the nitrite in the composition is in the range of 0.001 M to 2.0 M.

13. A kit for providing a nitric oxide generating composition for use in the treatment, improvement, or prevention of respiratory diseases or disorders, wherein the kit comprises: a) Nitrite components containing one or more nitrites, b) An acidic component containing at least one acid, The kit further comprises, wherein the kit comprises at least one conjugate base that forms a buffer system with the acid component such that the buffer system has a pH of 4.6 to 6.0, wherein the buffering capacity β of the buffer system is given by formula (2): [Math 4] (In the formula, K ｗ This is the dissociation equilibrium constant of water at 25°C. [H ＋ ] is the hydrogen ion concentration based on the pH of the buffer system, C ｂｕｆ This is the buffer concentration in the nitric oxide generating composition, K ａ (where is the dissociation constant of the acid at 25°C.) It is at least 0.06 when calculated by The aforementioned kit.

14. A kit for providing a nitric oxide generating composition for use in the treatment, improvement, or prevention of respiratory diseases or disorders, wherein the kit comprises: a) Nitrite components containing one or more nitrites, and b) An acidic component containing at least one acid, The kit further comprises, wherein the kit comprises at least one conjugate base that forms a buffer system with the acid component such that the buffer system has a pH of 4.6 to 6.0 and the associated useful buffering capacity RUβ of the buffer system is at least 0.04, wherein the Ruβ is formula (3): [Math 5] As shown above, β is defined as the integral value of β with respect to pH, using the trapezoidal method with a pH interval of 0.01 between the pH of the buffer system and pH 6.00, where β is given by equation (2): [Math 6] (In the formula, K ｗ This is the dissociation equilibrium constant of water at 25°C. [H ＋ ] is the hydrogen ion concentration based on the pH of the buffer system, C ｂｕｆ This is the buffer concentration in the nitric oxide generating composition, K ａ (where is the dissociation constant of the acid at 25°C.) The buffering capacity of the buffering system is calculated as follows: the kit.

15. The kit for use according to claim 13 or claim 14, wherein the nitrite source component is an aqueous solution containing one or more nitrites, and / or the acid component is an aqueous solution containing an acid.

16. A nitric oxide generating composition for use in the treatment, improvement or prevention of respiratory diseases or disorders, formed from a mixture of a nitrite component and an acid component of the kit according to any one of claims 13 to 16.

17. A method for treating, improving, or preventing a respiratory disease or disorder, comprising administering a composition or kit according to any one of claims 1 to 16.

18. Use of the composition or kit according to any one of claims 1 to 16 in the manufacture of a pharmaceutical product for the treatment, improvement or prevention of respiratory diseases or disorders.

19. The composition for use, kit for use, method or use according to any one of claims 1 to 18, wherein the respiratory disease or disorder is related to one or more microbial infections in the subject.

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