Nitrogen-based gas discharge device

Abstract

A nitrogen-based gas discharge device 100 according to one aspect of the present invention includes: a green compact 111 containing a powder of a layered double hydroxide in which nitrite ions (NO2 -) are included between layers, and a powder of a reducing agent or a precursor thereof; and a gas discharge module 110 disposed so as to cover the green compact 111 and composed at least of a film 112 that is waterproof and has water vapor permeability and gas permeability. The solubility of the reducing agent in water at room temperature is 1 g / 30 mL or more and the pH of a 0.1 (w / v)% aqueous solution of the reducing agent at room temperature is 5.1 or less. The nitrogen-based gas discharge device 100 may also include a water-containing body 120 for supplying water vapor to the nitrogen-based gas discharge module 110.

Description

Nitrogen-based gas release device

[0001] The present invention relates to a nitrogen-based gas release device.

[0002] In this specification, nitrogen oxides such as nitric oxide (NO), nitrogen dioxide (NO ３ ), nitrous oxide (N ２ O), and dinitrogen trioxide (N ２ O ３ ), nitrogen (N ｘ ), ammonia (NH ２ ), and other inorganic molecular species containing nitrogen atoms and being gaseous at normal temperature and pressure, as well as vapors of oxoacids of nitrogen such as nitrous acid (HNO ３ ２ ２ ), nitric acid (HNO ３ ３ ), are collectively referred to as "nitrogen-based gases".

[0003] Nitrogen oxides (NO ｘ ｘ ), also known as NOx, are gas components contained in combustion gases generated from automobiles and factories, and are known as harmful gases that cause photochemical smog, acid rain, and respiratory diseases such as asthma. There are various chemical species in nitrogen oxides (for example, nitric oxide, nitrogen dioxide, nitrous oxide, dinitrogen trioxide, etc.).

[0004] In recent years, it has become clear that among nitrogen oxides, there are gases that exhibit specific physiological effects when applied to living organisms in trace amounts. Therefore, research on the effects of such nitrogen oxides on living organisms and tissues has been actively conducted, and the application of nitrogen oxides to a wide range of medical fields has been under consideration. In particular, nitric oxide has a high degree of attention, and various physiological activities are known.

[0005] However, since nitric oxide is a gas at normal temperature and pressure, it is often supplied from a pressure cylinder for its use. In such a usage mode, due to the volume and weight of the cylinder, transportation and installation are not easy, and incorrect control of the gas flow rate and concentration can lead to serious accidents. Therefore, the medical development of nitric oxide has been limited to hospitals with complete facilities. In general, there are various relevant laws and regulations for handling high-pressure gases, and their import and use are restricted.

[0006] In addition, since nitrogen atoms can exist in various oxidation states, attention must also be paid to the stability of nitrogen oxides. Nitric oxide, in particular, readily reacts with oxygen in the air to transform into harmful nitrogen dioxide. Therefore, when applying this to a medical setting, it is necessary to carefully adjust and monitor the concentrations of nitric oxide and nitrogen dioxide using advanced medical equipment.

[0007] Under these circumstances, development of nitric oxide-releasing agents has progressed as an alternative to pressure cylinders for supplying nitric oxide. Some of the inventors of the present invention have so far obtained a lightweight, compact, safe, and easy-to-use means of sustained-release of nitrogen-based gases by utilizing layered double hydroxides (NLDH) in which nitrite ions and / or nitrate ions are encapsulated between layers as a solid material for sustained-release of nitrogen-based gases in the atmosphere (Patent Document 1).

[0008] International Publication No. 2020 / 213398, JP 2008-525499

[0009] S. Ishihara et al., “Disposable NO generator based on a structurally deformed nitrite-type layered double hydroxide”, Inorganic Chemistry 2021, Vol. 60, 16008-16015.

[0010] The nitrogen-based gas sustained-release means disclosed in Patent Document 1 basically uses powdered NLDH and a reducing agent, so depending on the application, it is desirable to take measures to suppress their dispersion during use. As a measure to suppress the dispersion of NLDH and the reducing agent, if the NLDH and reducing agent powders are compressed and molded into compacts, gas diffusion is suppressed, and the generation and release of nitrogen-based gas may be reduced to a low concentration. Patent Document 2 describes the concentration of nitric oxide gas used for wound healing, and it can be seen that 1 ppm or higher is preferable.

[0011] Therefore, the object of the present invention is to provide a nitrogen-based gas release device suitable for releasing high concentrations of nitrogen-based gases in compacted powder at room temperature and in the atmosphere.

[0012] In the process of investigating the above problem, the inventors discovered that nitrite ions (NO) ２ － The inventors discovered that a compact containing a layered double hydroxide powder in which ) is interlayered, and a specific reducing agent powder, releases a sufficient concentration of nitrogen-based gas in an atmosphere containing water vapor. By organizing the above facts, the inventors found a compact composition suitable for releasing nitrogen-based gas and completed the present invention.

[0013] One aspect of the present invention that solves the above problems is the nitrite ion (NO ２ － A nitrogen-based gas release device comprising a compact containing a layered double hydroxide powder in which ) is interlayered, a reducing agent or a precursor thereof, and a gas release module comprising at least a waterproof, water vapor permeable, and gas permeable film arranged to cover the compact, wherein the reducing agent has a solubility in water of 1 g / 30 mL or more at room temperature, and the pH of a 0.1 (w / v)% aqueous solution at room temperature is 5.1 or less. This nitrogen-based gas release device may further include a water-containing body that supplies water vapor to the gas release module.

[0014] The reducing agent may have a pH of 1.0 or higher and 4.0 or lower when used as a saturated aqueous solution at room temperature.

[0015] The reducing agent may be at least one selected from the group consisting of ascorbic acid (including optical and stereoisomers) and its esters, organic acid salts, inorganic acid salts and derivatives of L-cysteine, inorganic and organic acid salts of divalent iron, polyphenols, vitamin E, and sodium hyposulfite, sodium pyrosulfite, potassium pyrosulfite, guaiaconic acid, eugenol, sesamolin, and phenolic diterpenes. The ascorbic acid and its esters may be at least one selected from the group consisting of L(+)-ascorbic acid, D(-)-isoascorbic acid, ascorbic acid stearate, ascorbic acid palmitate, and ascorbyl dipalmitate. The organic acid salts, inorganic acid salts and derivatives of L-cysteine ​​may be at least one selected from the group consisting of L-cysteine ​​hydrochloride monohydrate and N-acetyl-L-cysteine. The inorganic and organic acid salts of divalent iron may be at least one selected from the group consisting of ferrous gluconate and ferrous sulfate heptahydrate. The polyphenols may be at least one selected from the group consisting of ferulic acid, α-glucosylisoquercitrin, α-glucosylrutin, chlorogenic acid, glucosylcinapyr alcohol, carnosic acid, rutin, quercetin, rosmarinic acid, and tannic acid. The vitamin E may be at least one selected from the group consisting of tocotrienol, d-α-tocopherol, d-γ-tocopherol, d-δ-tocopherol, and dl-α-tocopherol. The reducing agent may be at least one selected from the group consisting of L(+)-ascorbic acid, D(-)-isoascorbic acid, L-cysteine ​​hydrochloride monohydrate, ferrous gluconate, ferrous sulfate heptahydrate, and tannic acid. The reducing agent may have a solubility in water at room temperature of less than 1 g / 1.0 mL. The reducing agent may have a pH of 3.0 or higher in a 0.1 (w / v) aqueous solution at room temperature. The mass percentage of the reducing agent powder relative to the layered double hydroxide powder in the compacted powder may be 10% or more and 10,000% or less. The powder compressibility of the compacted powder may be 55% or more.The nitrogen-based gas released from the nitrogen-based gas release device may contain nitric oxide (NO) gas. The layered double hydroxide may be represented by the following general formula (1). Q. ｘ R(OH) ２（ｘ＋１） {(NO ２ － ) ｄ Z ｊ}・nH ２ O ... (1) In equation (1), Q is a divalent metal ion, R is a trivalent metal ion, and Z is NO ２ － It is an anion other than . Also, x, d, and j in equation (1) are numbers satisfying 1.8 ≤ x ≤ 4.2, 0.01 ≤ d ≤ 2.0, and 0 ≤ j ≤ 1.0, respectively, and n is a number that changes depending on the humidity of the environment. In the above general equation (1), Q is Mg ２＋ And R is Al ３＋ The nitrogen-based gas release device may also be one that slowly releases nitrogen-based gas.

[0016] According to the present invention, it is possible to provide a nitrogen-based gas release device that utilizes compacted powder and is suitable for releasing nitrogen-based gases of sufficient concentration at room temperature and in the atmosphere.

[0017] This is a schematic diagram showing one aspect of a nitrogen-based gas release device according to one aspect of the present invention. The nitrogen-based gas release device according to one aspect of the present invention uses nitrite ions (NOx). ２ － ) is interlayered in a layered double hydroxide (NO ２ －This is a schematic diagram showing the structure of LDH. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Comparative Example 1. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Comparative Example 2. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Example 1. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Example 2. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Example 3. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Example 4. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Comparative Example 3. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Example 5. This is a graph showing the change over time of the total amount of nitrogen gas released from the nitrogen gas release device according to Example 6. This graph shows the time-dependent changes in the total amount of nitrogen-based gas released from the nitrogen-based gas release device according to Example 7. This graph shows the time-dependent changes in the total amount of nitrogen-based gas released from the nitrogen-based gas release device according to Comparative Example 4. This graph shows the time-dependent changes in the amount of nitric oxide, nitrogen dioxide, and the total amount of nitrogen-based gas released from the nitrogen-based gas release device according to Example 1. This graph shows the time-dependent changes in the amount of nitric oxide, nitrogen dioxide, and the total amount of nitrogen-based gas released from the nitrogen-based gas release device according to Example 2. This graph shows the time-dependent changes in the amount of nitric oxide, nitrogen dioxide, and the total amount of nitrogen-based gas released from the nitrogen-based gas release device according to Example 3. This graph shows the time-dependent changes in the amount of nitric oxide, nitrogen dioxide, and the total amount of nitrogen-based gas released from the nitrogen-based gas release device according to Example 4. This graph shows the time-dependent changes in the wound area when the nitrogen-based gas release device according to Example 8 is applied. This graph shows the time-dependent changes in the wound area when the nitrogen-based gas release device according to Example 9 is applied.

[0018] The following describes a nitrogen-based gas release device (hereinafter sometimes simply referred to as "nitrogen-based gas release device") relating to one aspect of the present invention, with reference to the attached drawings. However, the mechanism of action related to the release of nitrogen-based gas is based on estimations, and its accuracy does not limit the present invention.

[0019] In this disclosure, "release" of nitrogen-based gas means that when the measurement method (1) for nitrogen-based gas release testing, which will be described in detail in the examples below, is performed, a nitrogen-based gas of 0.5 ppm or more is detected continuously for 60 minutes or more. Furthermore, in this disclosure, when the measurement method (1) is performed, the detection of a nitrogen-based gas of 0.5 ppm or more for 24 hours or more continuously is defined as "sustained release" of nitrogen-based gas, and the property of "sustained release" of nitrogen-based gas is defined as "sustained release property" of nitrogen-based gas.

[0020] An example of the structure of a nitrogen-based gas release device is shown in Figure 1. The nitrogen-based gas release device 100 releases nitrite ions (NOx). ２ － The present invention comprises a compacted powder 111 containing a layered double hydroxide powder in which layers are interspersed, and a reducing agent or its precursor powder; a gas release module 110 consisting of at least a waterproof, water vapor permeable, and gas permeable film 112 arranged to cover the compacted powder 111; and a water-containing body 120 that supplies water vapor to the gas release module. In Figure 1, a water-containing body 120 is depicted, but when a nitrogen-based gas release device is applied to the skin or wound site, sweat, exudate, or pads that absorb them may function as a water-containing body, supplying water vapor to the gas release module even without actively installing a water-containing body. Therefore, nitrogen-based gas release devices without a water-containing body are also included in the technical scope of the present invention. In Figure 1, the film 112 and the water-containing body 120 are in contact, but they may be separated as long as water vapor can be supplied to the compacted powder 111.

[0021] The compacted powder 111 contains nitrite ions (NOx). ２ － ) is interlayered in a layered double hydroxide (hereinafter referred to as "NO") ２ ―It may be written as "LDH". Contains powder. NO ２ ― The structure of LDH is schematically shown in Figure 2. NO ２ ― LDH10 consists of layer 1 and anion 2 encapsulated between layer 1. Layer 1 is a positively charged metal hydroxide layer. Anion 2 is at least a nitrite ion (NO2). ２ － ) contains. Anion 2 is entirely composed of nitrite ions (NO ２ － ) may be, or it may contain other anions in addition to the nitrite ion.

[0022] NO ２ － LDH10 is preferably represented by the following general formula (1). Q ｘ R(OH) ２（ｘ＋１） {(NO ２ － ) ｄ Z ｊ}・nH ２ O ... (1)

[0023] In equation (1), Q is a divalent metal ion, R is a trivalent metal ion, and Z is an anion other than a nitrite ion. Furthermore, x, d, and j in equation (1) are numbers satisfying 1.8 ≤ x ≤ 4.2, 0.01 ≤ d ≤ 2.0, and 0 ≤ j ≤ 1.0, respectively, and n is a number that changes depending on the ambient humidity. ２ O is called interlayer water, and the anionic species { (NO ２ － ) ｄ Z ｊ It is enclosed between LDH layers, similar to the above. n is typically between 0 and 4.

[0024] In equation (1), "Z" is NO ２ － Raw materials or solvents used in the manufacture of LDH10, or NO ２ － Anions originating from the atmosphere during the manufacture or storage of LDH10, OH － , Cl － , Br － , I － F－ , NO ３ － , ClO ４ － , SO ４ ２－ , CO ３ ２－ , acetate anion (CH ３ COO － ), propionate anion (CH ３ CH ２ COO － ), lactate anion (CH ３ -CH(OH)-COO － ), and isethionate anion (HO C ２ H ４ SO ３ － ) etc. are exemplified.

[0025] In the NO ２ － LDH10 represented by the general formula (1), the Q is preferably one or more selected from the group consisting of Mg ２＋ , Mn ２＋ , Fe ２＋ , Co ２＋ , Ni ２＋ , Cu ２＋ , Zn ２＋ and Ca ２＋ , and more preferably Mg ２＋ . Also, the R is preferably one or more selected from the group consisting of Al ３＋ , Ga <000009%>, Cr [[ID=6i]] ３＋ , Mn ３＋ , Fe ３＋ , Co ３＋ and Ni [[ID=7i]] ３＋ , and more preferably Al ３＋ . [[ID=?5]] <00||0273> The MgAl-type layered double hydroxide composed of Mg and Al as constituent elements, which is the most common solid material among layered double hydroxides, can be synthesized at low cost and is industrially produced (for example, synthetic hydrotalcite of Kyowa Chemical Industry).

[0027] Regarding safety, it poses no problem even if it comes into contact with skin, and is used in gastrointestinal medicines (antacids), etc. Furthermore, it has a proven track record of medical applications, including research from a medical perspective as a carrier for drug delivery systems (DDS). For this reason, the basic structure is a layered double hydroxide of the MgAl type, where Q is Mg ２＋ And R is Al ３＋ NO ２ － LDH10 is considered to be particularly safe, even when used for medical purposes.

[0028] The above explanation of NO ２ － LDH10 can be manufactured by the methods described in Patent Document 1 and Non-Patent Document 1.

[0029] The compacted powder 111 contains a reducing agent or its precursor powder (not shown). In this disclosure, the reducing agent precursor means a substance that generates a reducing agent under the operating environment of the nitrogen-based gas release device 100, upon the action of other components contained in the compacted powder 111, or water entering the compacted powder 111 from the outside. The reducing agent has a solubility in water of 1 g / 30 mL or more at room temperature, and the pH of a 0.1 (w / v)% aqueous solution at room temperature is 5.1 or less. In this disclosure, room temperature means 20°C. Also, in this disclosure, water means purified water according to the Japanese Pharmacopoeia. The reducing agent or its precursor powder having the above-mentioned solubility and pH is NO ２ － When used in combination with LDH, it becomes possible to release a sufficient concentration of nitrogen-based gas from the compacted powder at room temperature and in the atmosphere. This is because the reducing agent, which has high solubility in water, retains an appropriate amount of moisture upon contact with water vapor, and the moisture-retaining reducing agent then releases NO ２ － This promotes the release of nitrite ions from the interlayers of LDH to the outside of the layer, and the reducing agent retaining moisture becomes acidic, causing NO to come into contact with the reducing agent. ２ － Due to factors such as the partial decay of LDH and the release of nitrite ions between the layers, NO ２ －It is presumed that the amount of nitrite ions released from LDH10 increases, and these nitrite ions react with a reducing agent to produce nitrogen-based gases. Furthermore, the reaction known to generate nitric oxide (NO) is between sodium nitrite and iron sulfate (FeSO4). ４ Since the reaction with ) generally takes place in an acidic aqueous solution, it can be inferred that the ability of a reducing agent that retains water to form a moderately acidic environment is advantageous for the generation of nitrogen-based gases.

[0030] The solubility of the reducing agent is not particularly limited to an upper limit as long as it is above the lower limit mentioned above. However, from the standpoint of allowing the nitrogen-based gas generation reaction to proceed slowly and sustaining the release of nitrogen-based gas from the compacted powder 111 for a long period of time, it is preferable that the solubility in water at room temperature be less than 1 g / 1.0 mL, and more preferably less than 1 g / 2.0 mL.

[0031] The pH of the aqueous solution of the reducing agent is not particularly limited as long as it is below the upper limit mentioned above. However, from the standpoint of allowing the nitrogen-based gas generation reaction to proceed slowly and sustaining the release of nitrogen-based gas from the compacted powder 111 for a long period of time, it is preferable that the pH of the 0.1 (w / v)% aqueous solution be 3.0 or higher.

[0032] Here, the determination of whether the solubility of the reducing agent in water at room temperature is 1 g / 30 mL or more is performed using the following procedure. First, 1 g of the reducing agent powder to be evaluated is weighed into a 50 mL centrifuge tube. Next, 30 mL of room temperature water is added to the centrifuge tube containing the reducing agent powder, the lid of the centrifuge tube is closed, and the mixture is stirred for 30 seconds using a vortex mixer. Next, the centrifuge tube is left to stand for 270 seconds after stirring, and the liquid is visually inspected to check for any undissolved particles. This stirring, standing, and visual inspection is repeated until no more undissolved particles are found, or until the sixth stirring and visual inspection are completed. If no undissolved particles of the reducing agent are found, the prepared reducing agent is determined to have a solubility of 1 g / 30 mL or more. On the other hand, if undissolved particles are still found in the centrifuge tube after the sixth stirring, the prepared reducing agent is determined to have a solubility of less than 1 g / 30 mL. Furthermore, to determine whether the solubility of the reducing agent powder in water at room temperature is less than 1 g / 1.0 mL, the procedure can be the same as above, except that the amount of water added to the centrifuge tube is changed to 1.0 mL. Similarly, to determine whether it is less than 1 g / V mL, the procedure can be the same as above, except that the amount of water added to the centrifuge tube is changed to V mL.

[0033] Furthermore, the pH of a 0.1 (w / v)% aqueous solution of the reducing agent at room temperature is determined by the following procedure. First, a three-point calibration of the pH meter is performed using standard solutions with pH values ​​of 4, 7, and 9, respectively. Next, 0.1 g of the reducing agent powder to be determined is weighed into a 150 mL bottle. Then, 100 mL of room temperature water is added to the bottle containing the reducing agent powder, and the mixture is stirred using a vortex mixer until no undissolved particles are visible. Next, the pH of the stirred aqueous solution is measured twice using the calibrated pH meter, and the average of the obtained values ​​is taken as the pH of the 0.1 (w / v)% aqueous solution of the reducing agent at room temperature.

[0034] The reducing agent is preferably one whose saturated aqueous solution has a pH of 1.0 to 4.0 at room temperature. By using a reducing agent whose saturated aqueous solution has a pH of 4.0 or less at room temperature, nitrogen-based gas can be efficiently released from the compacted powder 111. From the viewpoint of increasing the release concentration of nitrogen-based gas, it is more preferable to use a reducing agent whose saturated aqueous solution has a pH of 3.0 or less at room temperature, and even more preferable to use a reducing agent whose saturated aqueous solution has a pH of 2.0 or less at room temperature. On the other hand, by using a reducing agent whose saturated aqueous solution has a pH of 1.0 or higher at room temperature, the nitrogen-based gas generation reaction can proceed slowly, and the release of nitrogen-based gas from the compacted powder 111 can be sustained for a long period of time. Specifically, the closer the pH value is to a neutral value, the longer the release time of nitrogen-based gas can be extended.

[0035] Here, the pH of the saturated aqueous solution of the reducing agent at room temperature is determined by the following procedure.

[0036] [Preparation of Saturated Solution] First, weigh a predetermined amount of reducing agent powder into a 50 mL centrifuge tube, and add 50 mL of room temperature water to the centrifuge tube containing the reducing agent powder. After closing the lid of the centrifuge tube, stir with a vortex mixer until the reducing agent powder is completely dissolved. The amount of reducing agent powder to weigh here should be set so that the concentration of the solution after stirring is 1 g / 10 mL for reducing agents with a solubility in water at room temperature of 1 g / 30 mL or more and less than 1 g / 1.0 mL. For reducing agents with a solubility in water at room temperature of 1 g / 1.0 mL or more, the amount of reducing agent powder should be set so that the concentration of the solution after stirring is 1 g / 1.0 mL. Next, open the lid of the centrifuge tube after stirring and add 5 g of reducing agent powder. After closing the lid of the centrifuge tube, stir with a vortex mixer for 30 seconds. Next, let the centrifuge tube stand for 270 seconds after stirring, then visually inspect the liquid to check for any undissolved particles. If undissolved material is found through visual inspection, the stirring and standing process, along with visual inspection, should be repeated up to six times under the conditions described above. If undissolved material is found after the sixth visual inspection, the aqueous solution containing the undissolved material should be filtered to obtain a saturated aqueous solution. On the other hand, if no undissolved material is found by the sixth visual inspection, the lid of the centrifuge tube should be opened, 5 g of reducing agent powder should be added, and the mixture should be stirred and standing under the conditions described above, with visual inspection of the solution to obtain a saturated aqueous solution. This process should be repeated until undissolved material is found after the sixth visual inspection, and the aqueous solution containing the undissolved material should be filtered to obtain a saturated aqueous solution. If the solution becomes too large to fit in the centrifuge tube due to the addition of reducing agent powder, it should be transferred to a larger container as needed, and stirring, standing, and visual inspection should be continued.

[0037] [pH Measurement of Saturated Aqueous Solution] The pH of the obtained saturated aqueous solution of the reducing agent is measured using the same procedure as described above for determining the pH of a 0.1 (w / v)% aqueous solution at room temperature, and the obtained value is taken as the pH of the saturated aqueous solution of the reducing agent at room temperature.

[0038] Examples of usable reducing agents include ascorbic acid (including optical and stereoisomers) and its esters, organic acid salts, inorganic acid salts and derivatives of L-cysteine, inorganic acid salts and organic acid salts of divalent iron, polyphenols, vitamin E, and at least one selected from the group consisting of sodium hyposulfite, sodium pyrosulfite, potassium pyrosulfite, guaiaconic acid, eugenol, sesamolin, and phenolic diterpenes. Examples of ascorbic acid and its salts and esters include L(+)-ascorbic acid, D(-)-isoascorbic acid, ascorbic acid stearate, ascorbic acid palmitate, and ascorbyl dipalmitate. Examples of organic acid salts, inorganic acid salts, and derivatives of L-cysteine ​​include at least one selected from the group consisting of L-cysteine ​​hydrochloride monohydrate and N-acetyl-L-cysteine. Examples of the aforementioned divalent iron inorganic and organic acid salts include ferrous gluconate and ferrous sulfate heptahydrate. Examples of the aforementioned polyphenols include ferulic acid, α-glucosylisoquercitrin, α-glucosylrutin, chlorogenic acid, glucosylcinapyr alcohol, carnosic acid, rutin, quercetin, rosmarinic acid, and tannic acid. In addition, gallic acid, propyl gallate, and catechins (including catechin extracts such as tea catechins) can also be used as polyphenols. Examples of the aforementioned vitamin E include tocotrienol, d-α-tocopherol, d-γ-tocopherol, d-δ-tocopherol, and dl-α-tocopherol. Of the various reducing agents mentioned above, at least one selected from the group consisting of L(+)-ascorbic acid, D(-)-isoascorbic acid, L-cysteine ​​hydrochloride monohydrate, ferrous gluconate, ferrous sulfate heptahydrate, and tannic acid is preferred from the viewpoint of nitrogen gas release. The reducing agent is NO ２ － It may be mixed directly with LDH, or it may be mixed while supported on a solid inorganic material such as zeolite, silica gel, alumina, diatomaceous earth, or activated carbon.

[0039] Examples of reducing agent precursors include sodium L(+)-ascorbate, potassium L(+)-ascorbate, magnesium L(+)-ascorbate, calcium L(+)-ascorbate, sodium erythorbate, and sodium N-acetyl-L-cysteine. Sodium L(+)-ascorbate becomes L(+)-ascorbic acid in an acidic solution. Therefore, by including sodium L(+)-ascorbate together with a solid acid in the compacted powder 111, L(+)-ascorbic acid, which acts as a reducing agent, is generated upon contact with water vapor.

[0040] NO in compacted powder 111 ２ － The ratio of LDH10 powder to reducing agent powder is not particularly limited as long as it is within a range that allows for the release of nitrogen-based gases, but from the standpoint of nitrogen-based gas release, NO ２ － The mass percentage of the reducing agent powder relative to the LDH10 powder is preferably 10% or more and 10,000% or less, and more preferably 50% or more and 200% or less.

[0041] The density of the compacted powder 111 is not particularly limited as long as it can maintain its shape during handling and use, but the bulk density, i.e., the value obtained by dividing the mass of the compacted powder by its volume, should be 0.930 g / cm³. ３ More than 1.500g / cm ３ The following is preferable in terms of strength:

[0042] The powder compressibility of the compacted body 111 is preferably 55% or higher. A powder compressibility of this value ensures that the compacted body 111 maintains its shape well, suppressing damage to the compacted body 111, resulting in powder scattering and fluctuations in gas release characteristics when handling the nitrogen-based gas release device 100. For even better shape retention, a powder compressibility of 57% or higher is more preferable, and 59% or higher is even more preferable. While there is no particular upper limit to the powder compressibility of the compacted body 111, it may be set to approximately 90%, which can be obtained by incorporating excipients and binders and molding with a mechanical press. Furthermore, if nitrogen-based gas release performance is important, the powder compressibility of the compacted body may be 85% or lower, preferably 80% or lower.

[0043] Here, the compressibility of the compact is determined by the following procedure. First, the mass and volume of the compact are measured. If the compact is cylindrical, its volume can be calculated from the height and diameter measured for the compact. Next, the bulk density ρ of the compact is obtained by dividing the obtained mass of the compact by the obtained volume of the compact. Ｂ Next, calculate the bulk density ρ of the mixed powder. Then, crush the compacted powder using a pulverizer. A general-purpose pulverizer such as the LAB MILL manufactured by Osaka Chemical Co., Ltd. can be used. The crushing conditions should be set so that large, lumpy particles are no longer visible. As an example of crushing conditions, in the case of a compacted powder with a diameter of 10 mm in the example described later, the crushing can be done for 10 seconds using the LAB MILL. Next, the crushed powder is sieved through a 125 μm sieve, and the powder that passes through is collected. Next, the collected powder is dropped into a container of known volume and mass using a funnel, and the drop is stopped when the powder reaches the top of the container, and after leveling it off, the mass is measured. The container should always be kept still during the dropping and leveling of the powder, and no tapping should be performed. The value obtained by subtracting the mass of the container from the obtained mass is the mass of the powder. Then, the value obtained by dividing the mass of the powder by the volume of the container is the bulk density ρ of the mixed powder. Ｐ The bulk density ρ of the obtained compacted powder is calculated as follows. Ｂ and the bulk density ρ of the mixed powder Ｐ Therefore, the value calculated by the following formula (2) shall be defined as the powder compressibility C (%). C (%) = {(ρ Ｂ -ρ Ｐ ) / ρ Ｂ} × 100 ... (2)

[0044] The shape and size of the compacted powder 111 are not particularly limited and can be determined appropriately according to the application location and method of the nitrogen-based gas release module. Examples of compacted powder shapes include round, tablet-shaped compacts.

[0045] The compacted powder 111 is NO ２ － It can be manufactured by loading a mixed powder of LDH10 and a reducing agent (raw material powder) into a mold and applying pressure. Molding methods include uniaxial compression molding, biaxial compression molding, twin-screw compression molding, and cold isostatic pressing (CIP).

[0046] The particle size of the raw material powder is not particularly limited, but from the perspective of obtaining a compacted powder 111 with excellent strength, the median value of the particle size distribution D ５０ It is preferable that the particle size is 0.1 μm or more and 10 μm or less. Here, D ５０ This is calculated from the results of observing the raw material powder with a scanning electron microscope (SEM) and measuring the equivalent circle diameter or Ferret diameter for 500 or more constituent particles.

[0047] The raw material powder contains NO ２ － In addition to LDH10 and reducing agents, binders, plasticizers, release agents, etc., may be added, provided that they do not hinder the release of nitrogen-based gases from the compacted powder.

[0048] The waterproof, water vapor permeable, and gas permeable film 112 is positioned to cover the compacted powder 111, preventing the compacted powder 111 from coming into direct contact with liquid water, while allowing the supply of external water vapor to the compacted powder and the extraction of nitrogen-based gases released from the compacted powder 111 to the outside. The material of the film 112 is not particularly limited as long as it has low reactivity with the components of the compacted powder 111. Examples of usable films 112 include polyethylene film, polytetrafluoroethylene film with micropores, and polyurethane film.

[0049] The film 112 has a water vapor transmission rate of 10 cc / m². ２ - Preferably 24hr·atm or higher, and 100.0 cc / m ２ - More preferably 24hr·atm or higher, and 200.0 cc / m ２ - It is even more preferable that the humidity is 24hr·atm or higher. On the other hand, the water vapor transmission rate is 1000.0 cc / m³. ２ - Preferably, the humidity is 24hr·atm or less. Also, the film 112 has a nitrogen-based gas permeability of 1.0 cc / m². ２ - Preferably, the humidity is 24hr·atm or higher. For nitric oxide (NO) among nitrogen-based gases, the transmittance should be 1.0 cc / m³. ２ - Preferably 24hr·atm or higher, and 2.0 cc / m ２- More preferably 24hr·atm or higher, and 5.0 cc / m ２ - It is even more preferable that the humidity be 24hr·atm or higher. On the other hand, the transmittance of nitric oxide (NO) is 30.0 cc / m³. ２ - Preferably 24hr·atm or less. Among nitrogen-based gases, nitrogen dioxide (NOx) ２ Regarding the following, its transmittance is 1.0 cc / m³ ２ - Preferably 24hr·atm or higher, and 30.0 cc / m ２ - More preferably 24hr·atm or higher, and 50.0 cc / m ２ - It is even more preferable that the humidity is 24hr·atm or higher. On the other hand, the nitrogen dioxide (NO ２ The transmittance is 100.0 cc / m³. ２ - Preferably, the pressure is 24hr·atm or less. Ensuring that the permeability of water vapor and nitrogen-based gases is above the aforementioned lower limits makes it easier to secure the release amount of nitrogen-based gases.

[0050] The water-containing material 120 generates water vapor and supplies it to the gas release module 110, which is composed of a compacted powder 111 covered with a film 112. This water vapor permeates the film 112 and is supplied to the compacted powder 111, causing nitrogen-based gas to be released from the compacted powder 111. The water-containing material 120 is not particularly limited as long as it has low reactivity with the film 112. Suitable water-containing material 120 can be any substance that generates water vapor, such as hydrogels, humidified cotton wool, cleansing wipes, or water vapor generators.

[0051] The nitrogen-based gas released from the nitrogen-based gas release device 100 is not particularly limited, but it is preferable to include nitric oxide (NO) gas in order to obtain physiological effects on living organisms and tissues. In a low pH aqueous solution, nitrite ions are protonated to produce nitrite (HNO). ２ Therefore, the released nitrogen-based gas may also contain nitrite vapor. Nitrite (HNO ２ ) undergoes autooxidation reduction to produce nitric oxide (NO) and nitrogen dioxide (NO ２ ) Therefore, at the same time, nitrogen dioxide (NO ２) may also be included. In addition, nitric oxide (NO) is oxidized by oxygen in the atmosphere to form nitrogen dioxide (NO ２ ) is also produced simultaneously through the pathway that results in nitrogen dioxide (NO ２ ) may be included. Furthermore, as is known from the Saltzman process, nitrogen dioxide (NO) ２ When ) reacts with water, it produces nitric acid (HNO). ３ ) and nitrite (HNO) ２ ) can be converted into these nitrogenous gases, and therefore these nitrogenous gases may be present. Thus, even if only NO is present, various nitrogenous gases can coexist in an environment where oxygen and water are also present. Furthermore, nitroglycerin, which is used to alleviate angina, is metabolized in the body to nitric oxide (NO) and exhibits a vasodilatory effect, so an appropriate amount of nitrogenous gas (for example, nitrogen dioxide (NO)) may be present. ２ ) and nitrite gas (HNO ２ It is also possible that when )) acts on living organisms, physiological effects on living organisms and tissues as nitric oxide (NO) may be obtained.

[0052] The duration of nitrogen gas release in the nitrogen gas release device 100 is not particularly limited, but from the viewpoint of reducing the number of replacements when applied to the prevention or treatment of injury or illness, the time during which nitrogen gas at 80% or more of the maximum concentration is continuously detected is preferably 1 hour or more, more preferably 5 hours or more, and even more preferably 7 hours or more. Furthermore, the time during which nitrogen gas at 70% or more of the maximum concentration is continuously detected is preferably 2 hours or more, more preferably 5 hours or more, and even more preferably 9 hours or more. Furthermore, the time during which nitrogen gas at 60% or more of the maximum concentration is continuously detected is preferably 3 hours or more, more preferably 10 hours or more, and even more preferably 14 hours or more.

[0053] In addition to the components described above, the nitrogen-based gas release device 100 may also include, as necessary, components for converting the released nitrogen-based gas into other gases, means for purifying the released nitrogen-based gas, and means for controlling the amount of nitrogen-based gas released.

[0054] The nitrogen-based gas release device 100 can be used for the prevention and treatment of various injuries and illnesses using nitric oxide.

[0055] The nitrogen-based gas release device 100 can be made into various shapes and dosage forms depending on the application. Examples of dosage forms include topical preparations, and more specifically, transdermal patches. Examples of transdermal patches include adhesive bandages, compresses, surgical tapes, dressings, and athletic tape. When the nitrogen-based gas release device is used as a topical preparation, it is useful for wound treatment. Furthermore, the nitrogen-based gas release device 100 may be applicable as an antibacterial or disinfectant agent. In addition, nitrogen-based gas release devices 100 that release high concentrations of nitrogen-based gas may be applicable to the treatment of skin cancer.

[0056] The nitrogen-based gas release device relating to one aspect of the present invention will be described in more detail below based on examples. However, these examples are provided to aid in understanding the present invention and are not intended to limit it.

[0057] [NO ２ － [Synthesis of LDH] NO ２ － LDH was synthesized in accordance with the method described in Non-Patent Document 1. Specifically, carbonate-type LDH (manufactured by Kyowa Chemical Industry, DHT-6 (Mg ３ Al(OH) ８ (CO ３ ２－ ) ０．５ ・2H ２20 g of O)) was placed in two alumina crucibles, each containing 10 g, and heated from room temperature to 550°C at a rate of 10°C per minute in a muffle furnace (Denken Heidental, KDF 300-Plus) under a flow of dry nitrogen (2 liters per minute). After reaching 550°C, it was maintained at 550°C for 1 hour. After cooling to approximately 300°C while maintaining the flow of dry nitrogen, the muffle furnace was opened, the two crucibles were removed, and placed in a vacuum dryer. They were cooled further in a vacuum for 1 hour, and then cooled to approximately 50°C to obtain an LDH or calcined body. On the other hand, 4.57 g of sodium nitrite (98.5+%, Fujifilm Wako Pure Chemical Industries, Ltd.) was placed in a 1 L round-bottom flask, and then 600 mL of ultrapure water was poured in to dissolve the sodium nitrite and prepare an aqueous sodium nitrite solution. Ultrapure water was prepared using a pure water generator (ELGA, PURELAB Option-S7 / 15) and bubbling with dry nitrogen gas for 15 minutes. The obtained LDH or calcined material was added to an aqueous sodium nitrite solution and treated in a bath-type ultrasonic cleaner for 5 minutes to disperse the LDH or calcined material particles. The dispersion was then stirred for 24 hours using a magnetic stirrer and magnetic stirrer, and after stopping the stirring, it was allowed to stand for another 24 hours to allow the LDH to settle. The reaction solution after standing was filtered under nitrogen flow using a hydrophilic PTFE membrane filter (Merck Millipore, JGWP04700 (pore size = 0.2 μm, diameter = 47 mm)), washed three times with 10 mL of ultrapure water, and vacuum dried at 50°C for 18 hours. The obtained lumpy, dry white solid was stored in a 50 mL screw vial and the target NO ２ － LDH was obtained. The yield was 18.9 g. The lumpy, dry white solid was ground for 10 minutes at a rate of 30 revolutions per minute using an automatic mortar and pestle (manufactured by Ishikawa Factory Co., Ltd., D18S) under a dry nitrogen flow of 2 L per minute, and NO was obtained. ２ － LDH powder was obtained. The powder was stored in a 50 mL screw-top vial.

[0058] [Preparation of Gas Release Module] (Comparative Example 1) As a reducing agent, magnesium ascorbyl phosphate powder (manufactured by Combi-Blocks, product number: QC-1627) was prepared. The solubility of this magnesium ascorbyl phosphate powder in water at room temperature was determined to be less than 1 g / 30 mL by the method described above, and the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 8.19. The pH of the saturated aqueous solution of the magnesium ascorbyl phosphate powder used was determined to be 6.99 by the method described above. NO synthesized by the method described above ２ － LDH powder and reducing agent powder were weighed in a mass ratio of 1:1, totaling 18 mg, and dry-mixed using an agate mortar. The resulting mixed powder was sandwiched between two dressing materials (Kyowa Co., Ltd., Airwall® "Fuwa-ri") to obtain a gas release module according to Comparative Example 1. The water vapor transmission rate of the dressing material was 806.7 cc / m³. ２ • At 24 hours and atm, the nitric oxide (NO) transmittance was 3.0 cc / m³. ２ • At 24 hours and atm, the nitrogen dioxide transmittance was 91.3 cc / m³. ２ It was 24 hours at an ATM.

[0059] (Comparative Example 2) NO ２ － Except for increasing the amount of LDH powder and reducing agent powder without changing the mass ratio, the procedure was the same as in Comparative Example 1, NO ２ － A mixed powder of LDH and a reducing agent was obtained. The obtained mixed powder was filled to a height of 5 mm to 10 mm into a mold having a cylindrical space with a diameter of 10 mm, and an elliptical compact was produced as a tablet by uniaxial compression molding using a manual simple tablet molding machine (HANDTAB-100R, manufactured by Ichihashi Seiki Co., Ltd.) under a pressure of 5 kN. The mass of the obtained compact was 247.7 mg, and the bulk density was 1.236 g / cm³. ３ The powder compressibility was 69.5%. The obtained compacted powder was coated with a dressing material (Airwall® "Fuwa-ri" manufactured by Kyowa Co., Ltd.) to obtain a gas release module according to Comparative Example 2.

[0060] (Example 1) The reducing agent used was L(+)-ascorbic acid powder (manufactured by Fujifilm Wako Pure Chemical Industries, product number: 016-04805), NO ２ － Except for reducing the amounts of LDH powder and reducing agent powder without changing the mass ratio, using a mold with a cylindrical space of 5 mm in diameter for the production of the compacted powder, and setting the uniaxial compression molding pressure to 1.25 kN, the gas release module according to Example 1 was obtained using the same procedure as in Comparative Example 2. The L(+)-ascorbic acid powder used was determined to have a solubility of 1 g / 30 mL or more in water at room temperature by the method described above, and the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 3.26. Furthermore, according to the method described above, undissolved reducing agent was observed at a concentration of 1 g / 1.0 mL in water at room temperature. The pH of a saturated aqueous solution of the L(+)-ascorbic acid powder used was determined to be 1.78 by the method described above. The mass of the compacted powder obtained by molding the mixed powder was 62.0 mg, and the bulk density was 1.254 g / cm³. ３ 、 The powder compressibility was 61.9%.

[0061] (Example 2) A gas release module according to Example 2 was obtained using the same procedure as in Comparative Example 2, except that the reducing agent used was changed to L-cysteine ​​hydrochloride monohydrate powder (manufactured by Fujifilm Wako Pure Chemical Industries, product number: 039-05274). The L-cysteine ​​hydrochloride monohydrate powder used was determined to have a solubility of 1 g / 30 mL or more in water at room temperature by the method described above, and the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 2.37. Furthermore, according to the method described above, no undissolved reducing agent was observed even at 1 g / 1.0 mL in water at room temperature. The pH of a saturated aqueous solution of the L-cysteine ​​hydrochloride monohydrate powder used was determined to be -0.19 by the method described above. The mass of the compacted powder obtained by molding the mixed powder was 275.0 mg, and the bulk density was 1.326 g / cm³. ３ The powder compressibility was 65.5%.

[0062] (Example 3) A gas release module according to Example 3 was obtained using the same procedure as in Comparative Example 2, except that the reducing agent used was changed to iron(II) gluconate dihydrate powder (manufactured by Thermo Scientific, product number: B24561). The iron(II) gluconate dihydrate powder used was determined to have a solubility of 1 g / 30 mL or more in water at room temperature by the method described above, and the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 4.21. Furthermore, according to the method described above, undissolved reducing agent was observed at a concentration of 1 g / 1.0 mL in water at room temperature. The pH of a saturated aqueous solution of the iron(II) gluconate dihydrate powder used was determined to be 3.91 by the method described above. The mass of the compacted powder obtained by molding the mixed powder was 249.9 mg, and the bulk density was 1.228 g / cm³. ３ The powder compressibility was 68.2%.

[0063] (Example 4) A gas release module according to Example 4 was obtained using the same procedure as in Comparative Example 2, except that the reducing agent used was changed to iron(II) sulfate heptahydrate powder (manufactured by Fujifilm Wako Pure Chemical Industries, product number: 094-01082). The iron(II) sulfate heptahydrate powder used was determined to have a solubility of 1 g / 30 mL or more in water at room temperature by the method described above, and the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 4.78. Furthermore, according to the method described above, undissolved reducing agent was observed at a concentration of 1 g / 1.0 mL in water at room temperature. The pH of a saturated aqueous solution of the iron(II) sulfate heptahydrate powder used was determined to be 2.82 by the method described above. The mass of the compacted powder obtained by molding the mixed powder was 293.2 mg, and the bulk density was 1.458 g / cm³. ３ The powder compressibility was 67.8%.

[0064] (Comparative Example 3) A gas release module according to Comparative Example 3 was obtained using the same procedure as in Comparative Example 2, except that the reducing agent used was changed to L-cysteine ​​powder (manufactured by Fujifilm Wako Pure Chemical Industries, product number: 039-20652). The L-cysteine ​​powder used was determined to have a solubility of 1 g / 30 mL or more in water at room temperature by the method described above, but the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 5.30. The pH of a saturated aqueous solution of the L-cysteine ​​powder used was determined to be 5.14 by the method described above. The mass of the compacted powder obtained by molding the mixed powder was 315.2 mg, and the bulk density was 1.303 g / cm³. ３ The powder compressibility was 64.3%.

[0065] (Comparative Example 4) A gas release module according to Comparative Example 4 was obtained using the same procedure as in Comparative Example 1, except that the reducing agent used was L(+)-ascorbic acid powder used in Example 1.

[0066] (Example 5) A gas release module according to Example 5 was obtained using the same procedure as in Comparative Example 2, except that the reducing agent used was changed to tannic acid powder (Sigma-Aldrich, product number: 403040). The tannic acid powder used was determined to have a solubility of 1 g / 30 mL or more in water at room temperature by the method described above, and the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 3.97. Furthermore, according to the method described above, undissolved reducing agent was observed at a concentration of 1 g / 1.0 mL in water at room temperature. The pH of a saturated aqueous solution of the tannic acid powder used was determined to be 2.34 by the method described above. The mass of the compacted powder obtained by molding the mixed powder was 312.7 mg, and the bulk density was 1.268 g / cm³. ３ The powder compressibility was 59.4%.

[0067] (Example 6) A gas release module according to Example 6 was obtained using the same procedure as in Comparative Example 2, except that the reducing agent used was changed to D(-)-isoascorbic acid powder (manufactured by Fujifilm Wako Pure Chemical Industries, product number: 89-65-6). The D(-)-isoascorbic acid powder used was determined to have a solubility of 1 g / 30 mL or more in water at room temperature by the method described above, and the pH of a 0.1 (w / v)% aqueous solution at room temperature was determined to be 3.20. Furthermore, according to the method described above, undissolved reducing agent was observed at a concentration of 1 g / 1.0 mL in water at room temperature. The pH of a saturated aqueous solution of the D(-)-isoascorbic acid powder used was determined to be 1.76 by the method described above. The mass of the compacted powder obtained by molding the mixed powder was 359.0 mg, and the bulk density was 1.303 g / cm³. ３ The powder compressibility was 61.4%.

[0068] (Example 7) A gas release module according to Example 7 was obtained using the same procedure as in Comparative Example 2, except that the reducing agent used was changed to L(+)-ascorbic acid powder used in Example 1. The difference between the gas release module according to Example 7 and the gas release module according to Example 1 lies in the size and mass of the compacted material and the pressure of uniaxial compression molding. The mass of the obtained compacted material was 310.9 mg, and the bulk density was 1.298 g / cm³. ３ The powder compressibility was 61.2%.

[0069] Table 1 summarizes the types and characteristics of the reducing agents constituting the gas release modules in Examples 1 to 7 and Comparative Examples 2 and 3, as well as the bulk density and powder compressibility of the compacted powder.

[0070]

[0071] [Nitrogen-based gas release test] Using the gas release modules according to Examples 1 to 7 and Comparative Examples 1 to 4, nitrogen-based gas release devices according to each example and comparative example were fabricated, and the type and amount of nitrogen-based gas released were measured according to the following procedure.

[0072] (Measurement Method (1)) First, the sensor portion of the ToxiRAE Pro NO sensor (manufactured by RAE Systems) was covered with a polyurethane film (3M Tegaderm® Roll Transparent Film Roll), and the gas release module was placed on top of it. The polyurethane film has a water vapor transmission rate of 266.7 cc / m². ２ • At 24 hours and atm, the nitric oxide (NO) transmittance was 8.6 cc / m³. ２ • At 24 hours and atm, the nitrogen dioxide transmittance was 61.1 cc / m³. ２ The temperature was 24hr·atm. Next, an appropriate amount of Granugel® (manufactured by ConvaTec, Inc.) was dropped onto the top surface of the gas release module, i.e., the side not in contact with the polyurethane film, as a water-containing material. Next, a polyurethane film (3M Tegaderm® Roll Transparent Film Roll) was placed over the top surface of the gas release module where the water-containing material was placed, sealing the gas release module and the water-containing material between the polyurethane film. Next, the concentration of nitrogen oxide (NOx) gas detected by the sensor was measured and recorded every minute. The value obtained from this measurement is the concentration of nitrogen-based gas released from the nitrogen-based gas release device in terms of nitric oxide (NO), and this concentration also includes a response corresponding to the cross-sensitivity to other nitrogen-based gases.

[0073] (Measurement Method (2)) First, a cell strainer (Corning, Falcon® 70 μm) was prepared and placed upside down from its normal use, with the side from which the filtrate is discharged facing upwards. Next, a polyurethane film (3M, Tegaderm® Roll Transparent Film Roll) was attached to the top surface of the cell strainer. Next, a gas release module was placed on the polyurethane film, and an appropriate amount of Granugel® (ConvaTec, Inc.) was dropped onto its top surface as a water-containing material. Next, the polyurethane film (3M, Tegaderm® Roll Transparent Film Roll) was placed over the gas release module from the side with the water-containing material, and this was used as the measurement sample. The concentration of nitrogen-based gas released from the obtained measurement sample was measured as NOｘ NO ｘ -amines / NH ３ Using a measuring device (ECO PHYSICS AG, cCLD 844 Mf), measurements were taken and recorded every 10 minutes under an air flow rate of 0.3 L / min. This measurement utilized ozone chemiluminescence to detect nitric oxide (NO) and nitrogen dioxide (NO). ２ ) can be detected separately.

[0074] (Measurement Results) Figure 3 shows the measurement results for the nitrogen-based gas release device according to Comparative Example 1, using measurement method (1). Figure 4 shows the measurement results for the nitrogen-based gas release device according to Comparative Example 2, using measurement method (1). Note that in Figure 3, the measurement was stopped after 23 hours from the start of measurement, as the trend of the nitrogen-based gas concentration could be grasped at that point. A comparison of Figure 3 and Figure 4 shows that when magnesium ascorbyl phosphate powder is used as the reducing agent, NO ２ － It can be seen that even if a module that emits nitrogen-based gas is obtained in the state of a mixed powder with LDH, when a compact is formed from the mixed powder, the concentration of the emitted nitrogen-based gas decreases to the detection limit of the measuring instrument, and thus no longer constitutes the emission of nitrogen-based gas as described in this disclosure.

[0075] Figure 5 shows the measurement results for the nitrogen-based gas release device according to Example 1, using measurement method (1). Figure 6 shows the measurement results for the nitrogen-based gas release device according to Example 2, using measurement method (1). Figure 7 shows the measurement results for the nitrogen-based gas release device according to Example 3, using measurement method (1). Figure 8 shows the measurement results for the nitrogen-based gas release device according to Example 4, using measurement method (1). Figure 9 shows the measurement results for the nitrogen-based gas release device according to Comparative Example 3, using measurement method (1). Figure 10 shows the measurement results for the nitrogen-based gas release device according to Example 5, using measurement method (1). Figure 11 shows the measurement results for the nitrogen-based gas release device according to Example 6, using measurement method (1). Figure 12 shows the measurement results for the nitrogen-based gas release device according to Example 7, using measurement method (1). In Figure 6, the nitrogen gas concentration remained constant at 250 ppm around 6 hours after the start of measurement; in Figure 11, from about 1 hour after the start of measurement until just before 11 hours; and in Figure 12, from about 5 hours and 30 minutes after the start of measurement until just before 13 hours. This is because 250 ppm is the maximum detectable concentration of nitrogen gas, and it is estimated that nitrogen gas emissions exceeding 250 ppm are actually occurring.

[0076] From the comparison of Figures 5 to 8 and Figures 10 to 12 with Figures 4 and 9, it can be seen that if the reducing agent contained in the compacted powder has a solubility of 1 g / 30 mL or more in water at room temperature and the pH of a 0.1 (w / v)% aqueous solution at room temperature is 5.1 or less, sufficient nitrogen-based gas release is possible. On the other hand, if the reducing agent contained in the compacted powder has a solubility of less than 1 g / 30 mL in water at room temperature, or the pH of a 0.1 (w / v)% aqueous solution at room temperature exceeds 5.1, the release of nitrogen-based gas as described in this disclosure does not occur.

[0077] Based on the above results, NO ２ －In order to construct a gas release module capable of releasing nitrogen-based gas at a sufficient concentration using a compacted powder containing LDH and a reducing agent, it is essential to use a reducing agent that has a solubility of 1 g / 30 mL or more in water at room temperature and a pH of 5.1 or less in a 0.1 (w / v)% aqueous solution at room temperature.

[0078] From the comparison of Figures 7, 8, and 10 to 12 with Figure 6, it can be seen that among the nitrogen-based gas release devices according to each embodiment of the present invention, those composed of a compacted powder containing a reducing agent having a solubility in water at room temperature of 1 g / 30 mL or more and less than 1 g / 1.0 mL, and a pH of 0.1 (w / v)% aqueous solution at room temperature of 3.0 or more and 5.1 or less, show a more gradual decrease in nitrogen-based gas concentration after reaching its maximum value, and sustained nitrogen-based gas release for a longer period of time. Specifically, in Figure 6, the time during which nitrogen-based gas at 80% or more of the maximum concentration was continuously detected was 1 hour and 50 minutes, compared to 10 hours and 30 minutes in Figure 7, 14 hours and 30 minutes in Figure 8, 27 hours and 50 minutes in Figure 10, 10 hours and 40 minutes in Figure 11, and 11 hours and 40 minutes in Figure 12. Furthermore, the time for which nitrogen-based gas at a concentration of 70% or more of the maximum was continuously detected was 2 hours and 30 minutes in Figure 6, compared to 18 hours and 30 minutes in Figure 7, 18 hours and 50 minutes in Figure 8, 11 hours and 50 minutes in Figure 11, and 15 hours and 20 minutes in Figure 12. In addition, the time for which nitrogen-based gas at a concentration of 60% or more of the maximum was continuously detected was 3 hours and 20 minutes in Figure 6, compared to 25 hours and 50 minutes in Figure 7, 22 hours and 40 minutes in Figure 8, 12 hours and 30 minutes in Figure 11, and 18 hours and 20 minutes in Figure 12. Note that in Figure 10, nitrogen-based gas exceeding 70% of the maximum concentration was detected even 60 hours after the start of emission. In the examination of the detection time of nitrogen-based gas, the maximum concentration was set to 250 ppm in cases where the nitrogen-based gas concentration exceeded 250 ppm. From these results, it can be said that the preferred solubility of the reducing agent used in the compacted powder in water at room temperature is 1 g / 30 mL or more and less than 1 g / 1.0 mL, and the preferred pH of the 0.1 (w / v) % aqueous solution at room temperature is 3.0 or more and 5.1 or less.

[0079] From the comparison of Figures 7, 8, and 10 to 12 with Figure 6, it can be seen that among the nitrogen-based gas release devices according to each embodiment of the present invention, those composed of a compacted powder containing a reducing agent with a saturated aqueous solution pH of 1.0 to 4.0 exhibit a more gradual decrease in nitrogen-based gas concentration after reaching its maximum value, and sustain the release of nitrogen-based gas for a longer period of time. Specifically, in Figure 6, the time during which nitrogen-based gas at 80% or more of the maximum concentration was continuously detected was 1 hour and 50 minutes, compared to 10 hours and 30 minutes in Figure 7, 14 hours and 30 minutes in Figure 8, 27 hours and 50 minutes in Figure 10, 10 hours and 40 minutes in Figure 11, and 11 hours and 40 minutes in Figure 12. Furthermore, the time for which nitrogen-based gas at a concentration of 70% or more of the maximum was continuously detected was 2 hours and 30 minutes in Figure 6, compared to 18 hours and 30 minutes in Figure 7, 18 hours and 50 minutes in Figure 8, 11 hours and 50 minutes in Figure 11, and 15 hours and 20 minutes in Figure 12. In addition, the time for which nitrogen-based gas at a concentration of 60% or more of the maximum was continuously detected was 3 hours and 20 minutes in Figure 6, compared to 25 hours and 50 minutes in Figure 7, 22 hours and 40 minutes in Figure 8, 12 hours and 30 minutes in Figure 11, and 18 hours and 20 minutes in Figure 12. In Figure 10, the release of nitrogen-based gas at a concentration exceeding 70% of the maximum was confirmed even 60 hours after the start of release. When examining the detection time of nitrogen-based gas, in cases where the concentration of nitrogen-based gas exceeded 250 ppm, the maximum concentration was set to 250 ppm. From these results, it can be said that the preferred pH of a saturated aqueous solution of the reducing agent used in compacted powder at room temperature is between 1.0 and 4.0.

[0080] Figure 13 shows the measurement results for the nitrogen-based gas release device according to Comparative Example 4, using measurement method (1). Comparing Figure 5 and Figure 13, in the nitrogen-based gas release device according to Comparative Example, in which the gas release module is composed of powder, the nitrogen-based gas concentration reached its maximum value 2 hours and 20 minutes after the start of gas release, and then decreased rapidly, with the nitrogen-based gas concentration falling to 50% of the maximum value 6 hours after the start of gas release. In contrast, in the nitrogen-based gas release device according to the present invention, in which the gas release module is composed of compacted powder, the nitrogen-based gas concentration reached its maximum value 6 hours and 40 minutes after the start of gas release, but the decrease in concentration was gradual, with the nitrogen-based gas concentration falling to 50% of the maximum value 16 hours and 20 minutes after the start of gas release. From these results, the gas release module is NO ２ － By constructing a compacted powder containing LDH and a specific reducing agent, it can be said that a nitrogen-based gas release device can be obtained that continuously releases nitrogen-based gas over a long period of time.

[0081] Figure 14 shows the measurement results for the nitrogen-based gas release device according to Example 1, using measurement method (2). Figure 15 shows the measurement results for the nitrogen-based gas release device according to Example 2, using measurement method (2). Figure 16 shows the measurement results for the nitrogen-based gas release device according to Example 3, using measurement method (2). Figure 17 shows the measurement results for the nitrogen-based gas release device according to Example 4, using measurement method (2). As mentioned above, in measurement method (1), measurements are taken with the nitrogen-based gas release device and sensor sealed, whereas in measurement method (2), measurements are taken while air is flowing. For this reason, the concentration of nitrogen-based gas obtained in measurement method (2) is lower than that obtained in measurement method (1).

[0082] From the results in Figures 14 to 17, it can be seen that gas containing nitric oxide (NO) was released from the nitrogen-based gas release device according to each embodiment of the present invention. In Figures 14 to 17, after a predetermined time has elapsed from the start of nitrogen-based gas release, the concentration of nitrogen dioxide (NO) was higher than that of nitric oxide gas. ２The gas concentration is increasing. This is presumed to be because, immediately after the start of the reaction, the main nitrogen-based gas generation reaction is on the surface of the compacted material, but as time passes, the main nitrogen-based gas reaction is on the inside of the compacted material, and the generated nitric oxide is oxidized while remaining in the compacted material, and / or the generated nitric oxide is oxidized by the oxygen contained in the air flowing through the measurement system.

[0083] [Application of Nitrogen-Based Gas Release Device to Adhesive Patches] (Example 8) Adhesive patches were prepared using a nitrogen-based gas release device according to the following procedure, and the therapeutic effect on wounds was verified. A gas release module according to Example 8 was prepared using the same procedure as in Example 1. The compacted powder constituting the gas release module had a mass of 41.7 mg and a bulk density of 1.202 g / cm³. ３ Next, the backs of diabetic model mice (BKS.Cg-+Leprdb / +Leprdb / Jcl) were shaved using clippers and shavers, and a mark approximately 1.5 cm in diameter was made on the skin. The skin at the marked area was then excised in its entirety, and the area of ​​the excised skin (wound surface) was measured. Next, an appropriate amount of Granugel® (manufactured by ConvaTec, Inc.) was dropped onto one side of the gas release module according to Example 8 as a water-containing material. A polyurethane film was then placed over the side with the water-containing material to cover the wound surface, and this was designated as the intervention group. On the other hand, in the control group, the wound surface was covered with a polyurethane film. Next, 1 day, 3 days, 5 days, 8 days, 10 days, 12 days, and 15 days after skin excision, the polyurethane film was peeled off, and the area of ​​the wound surface was measured. After measurement, the polyurethane film was reapplied to the wound surface. In the intervention group, the gas release module was replaced with a new one, a water-containing material was placed, and then it was applied to the wound surface. Figure 18 shows the percentage of the wound surface area at each time point relative to the wound surface area at the time of skin excision. Note that the wound surface area is the average value for the four individuals.

[0084] Figure 18 shows that while there was no significant difference in the percentage of wound area three days after skin excision (116.4% in the control group and 107.5% in the intervention group), a significant difference was observed in the percentage of wound area 15 days after skin excision (91.3% in the control group and 23.6% in the intervention group). From these results, it can be said that the patch using the nitrogen-based gas release device according to the embodiment of the present invention has a wound healing effect.

[0085] (Example 9) A gas release module was prepared using the same procedure as in Example 4, and then the intervention group was prepared using the same procedure as in Example 8. The compacted powder constituting the gas release module had a mass of 293.2 mg and a bulk density of 1.458 g / cm³. ３ The results were as follows. A control group was prepared using the same procedure as in Example 8. Next, the polyurethane film was removed and the wound area was measured 1 day, 3 days, 6 days, 8 days, 10 days, 13 days, and 15 days after skin excision. After measurement, the polyurethane film was reapplied to the wound. In the intervention group, the gas release module was replaced with a new one, and a water-containing material was placed before application to the wound. Figure 19 shows the percentage of the wound area at each time point relative to the wound area at the time of skin excision. Note that the wound area is the average value of the four individuals.

[0086] Figure 19 shows a significant difference in the percentage of wound area three days after skin excision, with the control group at 113.2% and the intervention group at 93.6%. Furthermore, a remarkable difference was observed in the percentage of wound area 15 days after skin excision, with the control group at 78.2% and the intervention group at 37.1%. These results indicate that the patch using the nitrogen-based gas release device according to the embodiment of the present invention has a wound healing effect.

[0087] According to the present invention, a nitrogen-based gas release device suitable for releasing nitrogen-based gas at a sufficient concentration in a compacted powder at room temperature and in the atmosphere can be provided. The resulting nitrogen-based gas release device has a fixed shape, making it easy to handle, and is useful in that it can release nitrogen-based gas at a concentration suitable for the expression of physiological activity. In addition, according to a preferred embodiment of the present invention, nitrogen-based gas at a concentration suitable for the expression of physiological activity can be released for a long period of time, which is useful in that it can reduce the number of times the device needs to be replaced.

[0088] 100 Nitrogen-based gas release device 110 Gas release module 111 Compacted powder 1 layer 2 anions 10 Nitrite ions (NO ２ － ) is interlayered in a layered double hydroxide (NO ２ ― LDH) 112 Film 120 Water-containing material

Claims

1. Nitrite ion (NO ２ － A nitrogen-based gas emission device comprising a compact containing a layered double hydroxide powder in which ) are interlayered, a reducing agent or a precursor thereof, and a gas emission module comprising at least a waterproof, water vapor permeable, and gas permeable film arranged to cover the compact, wherein the reducing agent has a solubility in water at room temperature of 1 g / 30 mL or more, and the pH of a 0.1 (w / v)% aqueous solution at room temperature is 5.1 or less.

2. The nitrogen-based gas release device according to claim 1, further comprising a water-containing body for supplying water vapor to the gas release module.

3. The nitrogen-based gas emission device according to claim 1 or 2, wherein the reducing agent has a pH of 1.0 or more and 4.0 or less when used as a saturated aqueous solution at room temperature.

4. The nitrogen-based gas emission device according to any one of claims 1 to 3, wherein the reducing agent is at least one selected from the group consisting of ascorbic acid (including optical isomers and stereoisomers) and its esters, organic salts, inorganic salts and derivatives of L-cysteine, inorganic salts and organic salts of divalent iron, polyphenols, vitamin E, and sodium hyposulfite, sodium pyrosulfite, potassium pyrosulfite, guaiaconic acid, eugenol, sesamolin, and phenolic diterpenes.

5. The ascorbic acid and its esters are at least one selected from the group consisting of L(+)-ascorbic acid, D(-)-isoascorbic acid, ascorbic acid stearate, ascorbic acid palmitate, dipalmitate ascorbyl, and erythorbic acid; the organic acid salts, inorganic acid salts, and derivatives of L-cysteine ​​are at least one selected from the group consisting of L-cysteine ​​hydrochloride monohydrate and N-acetyl-L-cysteine; the inorganic acid salts and organic acid salts of divalent iron are at least one selected from the group consisting of ferrous gluconate and ferrous sulfate heptahydrate; the polyphenols are at least one selected from the group consisting of ferulic acid, α-glucosylisoquercitrin, α-glucosylrutin, chlorogenic acid, glucosylcinapyl alcohol, carnosic acid, rutin, quercetin, rosmarinic acid, and tannic acid. The nitrogen-based gas emission device according to claim 4, wherein the vitamin E is at least one selected from the group consisting of tocotrienol, d-α-tocopherol, d-γ-tocopherol, d-δ-tocopherol, and dl-α-tocopherol.

6. The nitrogen-based gas emission device according to claim 4 or 5, wherein the reducing agent is at least one selected from the group consisting of L(+)-ascorbic acid, D(-)-isoascorbic acid, L-cysteine ​​hydrochloride monohydrate, ferrous gluconate, ferrous sulfate heptahydrate, and tannic acid.

7. The nitrogen-based gas release device according to any one of claims 1 to 6, wherein the reducing agent has a solubility in water at room temperature of less than 1 g / 1.0 mL.

8. The nitrogen-based gas emission device according to any one of claims 1 to 7, wherein the reducing agent has a pH of 3.0 or higher when used as a 0.1 (w / v)% aqueous solution at room temperature.

9. The nitrogen-based gas emission device according to any one of claims 1 to 8, wherein the mass percentage of the reducing agent powder to the layered double hydroxide powder in the compacted powder is 10% or more and 10,000% or less.

10. The nitrogen-based gas release device according to any one of claims 1 to 9, wherein the powder compressibility of the compacted powder is 55% or more.

11. A nitrogen-based gas emission device according to any one of claims 1 to 10, wherein the emitted nitrogen-based gas includes nitric oxide (NO) gas.

12. The nitrogen-based gas release device according to any one of claims 1 to 11, wherein the layered double hydroxide is represented by the following general formula (1). Q ｘ R(OH) ２（ｘ＋１） {(NO ２ － ) ｄ Z ｊ}·nH ２ O ··· (1) In the formula (1), Q is a divalent metal ion, R is a trivalent metal ion, and Z is an anion other than NO ２ － . Further, x, d, and j in the formula (1) are numbers satisfying 1.8 ≤ x ≤ 4.2, 0.01 ≤ d ≤ 2.0, and 0 ≤ j ≤ 1.0, respectively, and n is a number that varies depending on the humidity of the environment.

13. In the general formula (1) above, Q is Mg ２＋ And R is Al ３＋ The nitrogen-based gas release device according to claim 12.

14. A nitrogen-based gas release device according to any one of claims 1 to 13, which releases a nitrogen-based gas slowly.

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