Method for generating nitric oxide gas and apparatus for use in the method for generating nitric oxide gas

Abstract

A method for generating nitric oxide gas for generating a constant concentration of nitric oxide gas and an apparatus for use in the method for generating nitric oxide gas are provided. The method for generating nitric oxide gas involves mixing a liquid drug with a solid drug and generating nitric oxide gas through a chemical reaction. The active ingredient of the solid drug is ferric nitrosodilator (Fe(NO) X Cl3,x≦3) or a hydrate thereof. The active ingredient of the liquid medicament is a carbonate salt of an alkali metal, an alkaline earth metal, or a transition metal, or a corresponding acid salt, base salt, or complex salt, or a mixture of the above compounds.

Description

[Technical Field]

[0001] The present invention relates to a method for generating nitric oxide gas and an apparatus for use in the method for generating nitric oxide gas, and more particularly to a method for generating nitric oxide gas at a constant concentration and an apparatus for use in the method for generating nitric oxide gas, and particularly to applications of the generation of nitric oxide gas in medical and other related fields. [Background technology]

[0002] Nitric oxide (NO) is a colorless gas that is slightly soluble in water. The lipid-solubility of nitric oxide allows it to act as a messenger molecule in the human body. It has been discovered that nitric oxide molecules can easily pass through cell membranes, causing smooth muscle cells around blood vessels to receive signals and expand, thereby dilating blood vessels. This makes NO useful in treating cardiopulmonary diseases and other conditions, and it also has certain health care benefits.

[0003] Currently, industrial methods for producing nitric oxide gas include direct synthesis, ammonia catalytic oxidation, and the reaction of sodium nitrite with dilute sulfuric acid, depending on the application. The resulting nitric oxide gas is typically stored in a pressurized cylinder. For use in medical procedures, the nitric oxide gas in the cylinder must be diluted to a certain concentration beforehand. Therefore, it is generally used in medical institutions and is not easily transported or used at home. Meanwhile, nitric oxide gas is chemically active and easily converted into nitrogen dioxide and nitrous oxide, making long-term storage undesirable. These nitric oxide gas generators are primarily produced using gas discharge technology, such as that disclosed in Chinese Patent Publication (CN113456966A), or gas discharge technology, such as that disclosed in Chinese Patent Publication (CN111636071A). However, these nitric oxide gas generators are not widely used due to the high requirements for use and maintenance. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] China patent ZL201610541447.9 [Patent Document 2] China patent ZL201910889947.5 [Patent Document 3] Special Publication 2018-525208 [Patent Document 4] Special Table 2022-510773 Summary of the Invention [Problem to be solved by the invention]

[0005] The inventors have disclosed a method (Chinese Patent ZL 201610541447.9 or ZL 201910889947.5) that utilizes the chemical reaction of ferric chloride with nitric oxide gas to obtain a product, which is nitrosoferric chloride (Fe(NO) X The present invention has developed a method for generating nitric oxide gas and a corresponding device using the compound discovered by the above invention. [Means for solving the problem]

[0006] This is a method for generating nitric oxide gas by contacting and mixing a liquid drug and a solid drug and causing a chemical reaction to occur, thereby generating nitric oxide gas at a constant concentration. The active ingredient in solid drugs is ,salt Ferric nitrosochloride (Fe(NO) X Cl3, x≦3) or its hydrate. A certain amount of auxiliary ingredients may be added to the solid pharmaceutical preparation. The auxiliary ingredients are generally acid salts, and may be sulfates and hydrochlorides of transition metals, such as ferric chloride (or ferrous chloride), aluminum chloride, ferric sulfate (or ferrous chloride), and aluminum sulfate. At least my 1 type of The amount of auxiliary ingredients to be added is determined as needed. One of the functions of auxiliary ingredients is to dilute the content of the active ingredient, and the other is to react with the liquid to generate carbon dioxide gas, which dilutes the generated nitric oxide gas. Liquid medication Active ingredientare carbonates of alkali metals, alkaline earth metals and transition metals Or its response Acid salts, basic salts or complex salts The compound is a compound or a mixture of compounds, The effect is equivalent to that of alkali metal carbonates, sodium carbonate or potassium carbonate is It is preferable.

[0007] When an alkaline solution or slurry is used as a liquid agent, the higher the pH value, the faster the reaction rate, but the pH value of the alkaline solution is preferably 10 to 12. When a carbonate solution is used as a liquid agent, a chemical reaction occurs when the carbonate is mixed with the active ingredient and sub-ingredients of the solid agent, and the carbon dioxide gas generated dilutes the nitric oxide gas, preventing the oxidation of nitric oxide and avoiding the generation of toxic nitrogen dioxide gas. The active ingredient of the solid agent is ferric nitroso chloride (Fe(NO) X Cl3), and ferric chloride is an auxiliary ingredient. When sodium carbonate solution is used in the liquid drug, the main reaction is as follows:

[0008] [ka]

[0009] Note that reaction formula (1) is the hydrolysis reaction of nitrosoferric chloride, and reaction formulas (2) and (3) are neutralization reactions. The active ingredient and auxiliary ingredients in the solid formulation can be blended as needed to control the amount and concentration of nitric oxide released. For medical use, the active ingredient content in the solid formulation is generally 10% or less, while the water content of the solid formulation is generally about 20% or less, with the remainder being auxiliary ingredients. Solid formulations are generally stored at temperatures below 50°C (if the temperature is too high, the formulation may melt), while liquid formulations are stored above freezing, generally above 0°C, and are generally used at room temperature to prevent freezing. When storing formulations, containers can be protected with an inert gas such as nitrogen.

[0010] For medical treatment, the gas should be diluted with air to a NO concentration of ≦100 ppm and a CO concentration of ≦2%, preferably in the range of 0.1-1%. The concentration and flow rate of the generated nitric oxide gas can be controlled by adjusting the carbonate content in the liquid preparation and the flow rate of the liquid preparation.

[0011] The liquid drug may be a mixed solution using a liquid such as glycerin that does not chemically react with the solid drug, or may be used for the purpose of slowing down the solid-liquid reaction rate, and the specific blending ratio can be set according to actual needs.

[0012] The device used in the method for generating nitric oxide gas comprises a solid drug container (2), an outer container (3), a connecting pipe (4), a filter layer (5), a liquid inlet valve (6), a liquid drug flow regulator (7), a liquid outlet valve (8), a liquid drug container (10), a vent valve (11), a gas release valve (12), and a gas conduit (13). A U-shaped solid drug container (2) is fixed to the bottom of an outer container (3), the solid drug placed in the solid drug container faces the opening of a connecting pipe (4), and a liquid drug container (10) is connected to the outer container (3) via the connecting pipe (4).

[0013] The solid agent container is a U-shaped cylinder with an open top. It is used to receive the liquid agent from the connecting tube, leaving a space at the top that is approximately 1 / 5 to 1 / 10 of the container's volume. The reaction liquid can be discharged from the top of the container or through holes in the container wall. The number and location of the holes can be determined as needed. Alternatively, a shield ring can be placed over the holes to prevent the influence of liquid flowing down from the holes at the top. The annular space between the solid agent container and the outer container is used to receive the reaction product, and its volume can accommodate all of the liquid produced. The outer container should be slightly larger to act as a buffer to dilute the generated gas.

[0014] The procedure for using the nitric oxide gas generator is as follows. first Outer container gas Open the gas release valve. Next Passing air valve ,liquid Body outlet valve ,liquid Open the body inlet valves in sequence. The liquid drug enters the solid drug container through the connecting tube, Solid Drugs and contact reaction Response do Nitric oxide and carbon dioxide mixture Gas Generate do. The gas produced is From gas pipelines be released . BookWhen the generator is used as emergency equipment, the generated nitric oxide gas is inhaled naturally with ambient air, calculated at a normal human ventilation rate of 5-10 L / min. The dilution ratio after inhalation is typically 50-200. After the generated gas is diluted with air, the NO concentration is less than 100 ppm and the CO2 concentration is generally ≤2%. The concentration and flow rate of the generated nitric oxide gas are achieved by adjusting the flow rate of the liquid agent.

[0015] The container space may be protected by an inert gas such as nitrogen gas, or may have dilution and protection functions. The amount and concentration of nitric oxide generated can be controlled by adjusting a liquid reagent flow regulator, and typically three flow rates (large, medium, and small) are available. Specifically, this can be set according to requirements. The release rate of nitric oxide can be controlled by changing the solid-liquid contact area by changing the reaction cross-sectional area of ​​the container in the solid reagent or by adding and mixing a certain amount of neutral material such as quartz sand to the solid reagent. Reducing the solid-liquid contact area by half reduces the solid-liquid reaction rate by approximately half. [Effects of the Invention]

[0016] The advantage of the present invention is that a solid drug and a liquid drug are sealed in separate containers, and after mixing and chemically reacting the solid drug and the liquid drug in predetermined amounts, a predetermined concentration of nitric oxide gas can be obtained. The carbon dioxide gas generated during the reaction can dilute the nitric oxide gas concentration to prevent the generation of toxic nitrogen dioxide gas, and can also have an auxiliary effect of enhancing breathing. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is a schematic diagram illustrating the configuration of an apparatus used in a method for generating nitric oxide gas.

[0018] The apparatus for generating nitric oxide gas is shown in Figure 1. The generator includes a solid drug 1, a solid drug container 2, an outer container 3, a connecting tube 4, a filter layer 5, a liquid inlet valve 6, a liquid drug flow regulator 7, a liquid outlet valve 8, a liquid drug 9, a liquid drug container 10, a vent valve 11, a gas release valve 12, and a gas conduit 13.

[0019] The solid drug container 2 and outer container 3 are located at the bottom of the device. The liquid drug container 10 is located at the top of the generator, and is equipped with a vent valve 11 at the top of the liquid drug container 10 and a liquid drug outlet at the bottom. The liquid drug outlet communicates with the solid drug container via a connecting pipe, which is equipped with a liquid drug flow regulator 7, a liquid inlet valve 6, and a liquid outlet valve 8 to control the liquid. The outer container 3 for the solid drug has a gas outlet at the top of its side, which is connected to a gas conduit 13 via a gas release valve 12, and a filter layer 5 is further installed at the top inside of the outer container 3 for the solid drug.

[0020] The solid drug container 2 has a U-shaped structure, with its lower end fixed to the bottom of the outer container and its upper end open. The solid drug 1 is placed in the solid drug container 2, with its upper end facing the opening of the connecting tube 4, leaving a space above the solid drug to receive the liquid drug 9, and there is a gap between the inner container and the outer container.

[0021] The generator is used by first opening gas release valve 12 at the gas outlet of outer container 3. Then, vent valve 11 on liquid drug container 10, liquid outlet valve 8 on the liquid drug container, and liquid inlet valve 6 on outer container 3 are opened in sequence, and solid drug container 2 and solid drug 1 come into contact and react via connecting tube 4, generating nitric oxide gas at a certain concentration. The gas then passes through filtration layer 5 and is discharged from gas release valve 12 at the gas outlet of outer container 3 and gas conduit 13 for use by the supplier. The concentration and flow rate of nitric oxide gas can be adjusted by adjusting liquid drug flow regulator 7.

[0022] Example 1 The nitric oxide gas generation apparatus is shown in Figure 1. The container was cylindrical and made of polyethylene plastic (HDPE), with silica gel tubes for the connecting and gas conduits. The upper liquid container was approximately 80 mm in diameter and 100 mm in height. The lower solid container was approximately 100 mm in diameter and 150 mm in height. The filter layer was made of absorbent cotton and approximately 20 mm thick (a 5 mm alumina particle layer in the middle removed acidic gases). The inner container was approximately 30 mm in diameter and 90 mm in height, and the gas conduit was 8 mm in diameter. The solid container was filled to a height of approximately 60 mm (condensed and solidified after installation in the slurry tank). The active ingredient, ferric nitrosoferric chloride (Fe(NO)Cl3), contained approximately 0.6% of the active ingredient, 10% of water, and the remainder was ferric chloride. The liquid was approximately 400 ml of sodium carbonate solution with a mass concentration of approximately 22% and prepared with deoxygenated water. The container was kept at a room temperature of approximately 25°C, and the interior space of the container was protected with atmospheric nitrogen. The liquid flow rate was approximately 8 mL / min. The average gas flow rate at the outlet of the nitric oxide generator at the outer port of the gas conduit was approximately 100 mL / min, the average concentration was 1900 ± 500 ppm, the concentration after 100-fold air dilution was 19 ± 5 ppm, the CO2 concentration was ≦1%, and the total release time was approximately 50 min.

[0023] Example 2 The active ingredient in the solid preparation was a homogeneously mixed mixture of approximately 0.3% nitrosoferric chloride, 20% quartz sand, approximately 10% water, approximately 20% iron sulfate, and the remainder ferric chloride. The liquid flow rate was approximately 4 mL / min, and other conditions were the same as in Example 1. The average nitric oxide concentration at the outlet of the gas conduit was in the range of 1200±300 ppm. The gas flow rate was approximately 50 mL / min, the concentration after 200-fold air dilution was 6±3 ppm, the CO2 concentration was ≤0.5%, and the total release time was approximately 100 min. [Explanation of symbols]

[0024] 1 solid drug 2. Solid drug containers 3 Outer container 4 Connecting pipe 5 filtration layer 6 Liquid inlet valve 7 Liquid drug flow regulator 8 Liquid Outlet Valve 9 Liquid medicines 10 Liquid drug container 11 Vent valve 12 Gas release valve 13 Gas pipelines

Claims

1. A method for generating nitric oxide gas, comprising contacting and mixing a liquid drug and a solid drug, and causing a chemical reaction to generate nitric oxide gas at a constant concentration, The active ingredient of the solid medicament is ferric nitrosodeoxycholic chloride (Fe(NO) x Cl 3 , x≦3) or its hydrate; A method for generating nitric oxide gas, characterized in that the active ingredient of the liquid medicine is a compound that is a carbonate of an alkali metal, alkaline earth metal, or transition metal, or its corresponding acid salt, basic salt, or complex salt, or a mixture of multiple such compounds.

2. 2. The method for generating nitric oxide gas according to claim 1, wherein the solid agent contains an acid salt as an auxiliary component including a sulfate and a hydrochloride of a transition metal.

3. A method for generating nitric oxide gas as described in claim 1, characterized in that the solid agent contains at least one compound selected from the group consisting of ferric chloride, ferrous chloride, aluminum chloride, ferric sulfate, ferrous sulfate and aluminum sulfate.

4. 2. The method for generating nitric oxide gas according to claim 1, wherein the alkali metal carbonate is sodium carbonate or potassium carbonate.

5. An apparatus for use in the method for generating nitric oxide gas according to claim 1, A solid drug container (2), an outer container (3), a connecting pipe (4), a filter layer (5), a liquid inlet valve (6), a liquid drug flow regulator (7), a liquid outlet valve (8), a liquid drug container (10), a vent valve (11), a gas release valve (12), and a gas conduit (13). Equipped with The U-shaped solid drug container (2) is fixed to the bottom of the outer container (3), the solid drug placed in the solid drug container faces the opening of the connecting pipe (4), and the liquid drug container (10) is connected to the outer container (3) via the connecting pipe (4), The method of using the device comprises the following steps: First, open the gas release valve (12) of the outer container (3), Next, the vent valve (11), the liquid outlet valve (8), and the liquid inlet valve (6) are opened in sequence, and the liquid drug passes through the connecting pipe (4) and enters the solid drug container (2), where it comes into contact with and reacts with the solid drug (1) to produce a mixed gas of nitric oxide and carbon dioxide; The apparatus for use in the method for generating nitric oxide gas is characterized in that the generated gas is released from the gas conduit (13).

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