JP2023031181A - Molecular hydrogen-containing composition for preventing and/or ameliorating pneumonia - Google Patents

Abstract

To provide a composition for preventing and/or ameliorating pneumonia.SOLUTION: Provided is a composition comprising molecular hydrogen as an active ingredient for preventing and/or ameliorating pneumonia and symptoms associated with pneumonia in a subject.SELECTED DRAWING: Figure 1

Description

The present invention provides molecular hydrogen-containing compositions for preventing and/or ameliorating pneumonia in a subject.

Pneumonia is a general term for inflammatory diseases of the lungs, and 450 million people (7% of the population) develop pneumonia annually in the world, of which 4 million die. In particular, from the end of 2019 to 2020, the infection of the new coronavirus (SARS-CoV-2) has spread all over the world, triggered by the outbreak in Wuhan, China, and has become a social problem as a global pandemic. As of February 26, 2020, there have been 81,006 confirmed cases of SARS-CoV-2 infection worldwide, of which 2,764 have died from respiratory diseases such as pneumonia caused by SARS-CoV-2 infection. However, no effective treatment has been found.
Hydrogen, which is the active ingredient of the present invention, has antioxidant reactivity that suppresses oxidative stress caused by reactive oxygen species, and there is a precedent of improving chronic bronchitis and obstructive pulmonary bronchitis in studies using mice. (Patent Document 1). However, there is no precedent that hydrogen has been confirmed to improve intractable pneumonia.

Patent No. 6628449

If pneumonia could be prevented and/or ameliorated, it would not only be possible to alleviate patient pain and improve quality of life, but would also contribute to the reduction of medical expenses. As described above, few ingredients or substances useful for preventing and/or ameliorating pneumonia are known.
Under these circumstances, it is an object of the present invention to prevent and/or ameliorate pneumonia and/or promote amelioration of symptoms associated with pneumonia by using molecular hydrogen.

That is, the present invention includes the following features.
(1) A composition for preventing and/or improving pneumonia and symptoms associated with pneumonia in a subject, comprising molecular hydrogen as an active ingredient.
(2) The composition according to (1), wherein the pneumonia is one or more selected from the group consisting of bacterial pneumonia, viral pneumonia, fungal pneumonia, radiation pneumonia, and drug-induced pneumonia. It is a thing.
(3) Symptoms related to pneumonia include sore throat, fever, cough, sneezing, sputum production, dyspnea, general malaise, nausea, fatigue, chest pain, shortness of breath, runny nose, decreased white blood cells, diarrhea, headache, lung The composition according to (1) or (2), wherein the symptom is one or more selected from the group consisting of decreased function, decreased cardiac function, and decreased kidney function. .
(4) The composition according to any one of (1) to (3), which is a liquid or gas containing molecular hydrogen.
(5) The composition according to (5), wherein the liquid containing molecular hydrogen has a hydrogen concentration of 1 to 10 ppm.
(6) The composition according to (4), wherein the gas containing molecular hydrogen has a hydrogen concentration greater than zero (0) and less than or equal to 18.5% by volume.
(7) The composition according to any one of (1) to (6), wherein the subject is a mammal including humans.
(8) The composition according to any one of (1) to (7), which is produced using a hydrogen gas generator, a hydrogen water generator, or a hydrogen gas addition device.

The present invention can prevent and/or ameliorate pneumonia in a subject. In addition, administration of the composition of the present invention to a subject can improve refractory sepsis.

1 shows CT photographs before and after hydrogen administration of a patient with interstitial pneumonia in Example 1. FIG. FIG. 2 shows CT photographs of the patient with interstitial pneumonia in Example 1 before and after administration of hydrogen at a location different from that in FIG.

The present invention will now be described in more detail.
1. Composition for Preventing and/or Ameliorating Pneumonia The present invention provides a composition for preventing and/or promoting amelioration of pneumonia and symptoms associated with pneumonia, which contains molecular hydrogen as an active ingredient.
As used herein, “pneumonia” is a general term for inflammatory diseases of the lungs (alveolar, interstitial) excluding bronchitis.
As used herein, "infectious pneumonia" is classified into bacterial pneumonia, viral pneumonia, and fungal pneumonia. In general, secondary pneumonia after the common cold/upper respiratory tract inflammation is bacterial pneumonia, but sometimes pneumonia/interstitial pneumonia caused by the virus itself may occur. Influenza virus pneumonia, coronavirus pneumonia, measles pneumonia, etc. Allergic hypersensitivity pneumonitis is a non-infectious pneumonia that is not caused by pathogens.
As used herein, "bacterial pneumonia" refers to acute lung inflammation (pneumonia) caused by bacterial infection, most of which is alveolar pneumonia.
As used herein, the term “bacteria causing bacterial pneumonia” refers to Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, atypical bacteria, acid-fast bacteria, mycoplasma, and the like.
As used herein, “viral pneumonia” refers to acute lung inflammation (pneumonia) caused by viral infection.
As used herein, the term "virus causing viral pneumonia" generally refers to rhinovirus, coronavirus, influenza virus, respiratory syncytial virus, adenovirus, parainfluenza virus, herpes simplex virus, cytomegalovirus, and the like. . It also includes new viruses with mutations in the genome sequences of these viruses.
As used herein, “fungal pneumonia” is acute lung inflammation (pneumonia) caused by fungal infection.
As used herein, the term "fungus" refers to Histoplasma capsulatum, Blastomyces, Cryptococcus, Pneumocystis, Coccidioides, and the like.
As used herein, the term "drug-induced pneumonia" refers to an unexpected adverse reaction to the lungs caused by infusion or oral administration of a drug, other than the original efficacy of the drug. All drugs (especially antineoplastic agents, interferons, antirheumatic agents, biologics, and targeted therapies), nutritional foods, and supplements can cause lung damage.
As used herein, “radiation pneumonitis” refers to lung damage caused by radiation. It refers to pneumonia caused by radiation injury that occurs during therapy.
As used herein, “refractory pneumonia” means that improvement and recovery are impossible or difficult even with modern medicine and all drugs manufactured and sold by the pharmaceutical industry, and the evidence for treatment methods is low and has not been established. refers to pneumonia.
As used herein, the term "subject" includes mammals such as primates including humans, pet animals such as dogs and cats, and ornamental animals such as zoos. Preferred subjects are humans.
In the present specification, "hydrogen", which is an active ingredient of the composition of the present invention, is molecular hydrogen (that is, gaseous hydrogen or hydrogen gas), and unless otherwise specified, simply "hydrogen" or "hydrogen gas" called. Also, the term "hydrogen" as used herein refers to H ₂ , D ₂ (deuterium), HD (hydrogen deuteride), or a mixture thereof by molecular formula. Although _D2 is expensive, it is known to have a stronger superoxide scavenging effect than _H2 . Hydrogen that can be used in the present invention is _H2 , _D2 (deuterium), HD (deuterium), or a mixture thereof, preferably _H2 , or instead of _H2 , or _D2 and/or HD may be used mixed with _H2 .
A preferred form of the composition of the present invention is a gas or liquid containing molecular hydrogen, preferably a gas containing molecular hydrogen.
The gas containing molecular hydrogen is preferably air containing hydrogen gas or a mixed gas containing hydrogen gas and oxygen gas. the concentration of hydrogen gas in the gas containing molecular hydrogen (i.e., the composition of the invention) is greater than zero (0) and up to 18.5% by volume, such as 0.5 to 18.5% by volume; Preferably 1 to 10% by volume, for example 2 to 10% by volume, 2 to 9% by volume, 2 to 8% by volume, 3 to 10% by volume, 3 to 9% by volume, 3 to 8% by volume, 3 to 7% by volume , 3-6 vol%, 4-10 vol%, 4-9 vol%, 4-8 vol%, 4-7 vol%, 4-6 vol%, 4-5 vol%, 5-10 vol%, 5 ~9% by volume, 5-8% by volume, 6-10% by volume, 6-9% by volume, 6-8% by volume, 6-7% by volume, and the like. In the present invention, the higher the hydrogen gas concentration below the explosion limit or the higher the daily hydrogen dosage, the greater the effect of promoting the prevention and / or improvement (e.g., suppression or reduction) of pneumonia tends to be. .
Since hydrogen is a flammable and explosive gas, in order to prevent and/or improve pneumonia, the composition of the present invention containing hydrogen should be administered to a subject under conditions that are safe for subjects such as humans. is preferred.
When the gas other than hydrogen gas is air, the concentration of air is, for example, in the range of 81.5-99.5% by volume.
When the gas other than hydrogen gas contains oxygen gas, the oxygen gas concentration is, for example, in the range of 21 to 99.5% by volume.
Nitrogen gas, for example, can be further contained as other main gas.
In ordinary hydrogen gas inhalation therapy, high-concentration hydrogen gas of 66% or 99% has finally been shown to improve disease (cancer). However, in the present invention, it is preferable that the composition of the present invention contains hydrogen under conditions that are safe for a subject such as a human and is administered to the subject. Even at a low concentration, it can show a sufficient improving effect on pneumonia.
The liquid containing molecular hydrogen is specifically an aqueous liquid in which hydrogen gas is dissolved, and here, the aqueous liquid includes, but is not limited to, water (e.g., purified water, sterilized water), physiological saline. , buffer solutions (eg, pH 4-7.4 buffer solutions), infusion solutions, infusion solutions, injection solutions, beverages (eg, tea beverages such as green tea and black tea, fruit juice, green juice, vegetable juice, etc.). The hydrogen concentration of the liquid containing molecular hydrogen is non-limiting, eg 1-10 ppm, preferably 1.2-9 ppm, eg 1.5-9 ppm, 1.5-8 ppm, 1.5-7 ppm, 1.5-7 ppm. 5-6 ppm, 1.5-5 ppm, 1.5-4 ppm, 2-10 ppm, 2-9 ppm, 2-8 ppm, 2-7 ppm, 2-6 ppm, 2-5 ppm, 3-10 ppm, 3-9 ppm, 3- 8 ppm, 3-7 ppm, 4-10 ppm, 4-9 ppm, 4-8 ppm, 4-7 ppm, 5-10 ppm, 5-9 ppm, 5-8 ppm, 5-7 ppm, and the like.
In the present invention, the higher the concentration of dissolved hydrogen below the explosive limit or the higher the daily dose of hydrogen, the greater the effect of preventing and/or improving pneumonia.
After the gas or liquid containing molecular hydrogen is blended so as to have a predetermined hydrogen gas concentration, it is placed in a pressure-resistant container (e.g., stainless steel cylinder, aluminum can, preferably the inside is laminated with an aluminum film, pressure-resistant container, etc.). It is filled in a plastic bottle (for example, a pressure-resistant PET bottle), a plastic bag, an aluminum bag, etc.). Aluminum has the property that it is difficult for hydrogen molecules to permeate through it. Alternatively, the molecular hydrogen-containing gas or molecular hydrogen-containing liquid may, at the time of administration, be supplied to a hydrogen gas generator, a hydrogen water generator, or a hydrogen gas addition device, such as a known or commercially available hydrogen gas supply device (molecular hydrogen-containing gas generation device), hydrogen addition device (hydrogen water generation device), non-destructive hydrogen-containing device (for example, for non-destructive addition of hydrogen gas to the inside of a biologically applicable liquid bag such as intravenous drip may be made in situ using equipment such as
The hydrogen gas supply device mixes the hydrogen gas generated by the reaction between the hydrogen generating agent (e.g., metal aluminum, magnesium hydride, etc.) and water and the diluent gas (e.g., air, oxygen, etc.) at a predetermined ratio. (Japanese Patent No. 5228142, etc.). Alternatively, hydrogen gas generated by electrolysis of water is mixed with a diluent gas such as oxygen or air (Japanese Patent No. 5502973, Japanese Patent No. 5900688, etc.). This makes it possible to prepare a gas containing molecular hydrogen with a hydrogen concentration in the range of, for example, 0.5 to 18.5% by volume.
The hydrogenation device is a device that generates hydrogen using a hydrogen generating agent and a pH adjuster and dissolves it in a biologically applicable liquid such as water (Japanese Patent No. 4756102, Japanese Patent No. 4652479, Japan Japanese Patent No. 4950352, Japanese Patent No. 6159462, Japanese Patent No. 6170605, Japanese Patent Application Laid-Open No. 2017-104842, etc.). Combinations of the hydrogen generating agent and the pH adjuster include, for example, metallic magnesium and a strongly acidic ion exchange resin or organic acid (eg, malic acid, citric acid, etc.), metallic aluminum powder and calcium hydroxide powder, and the like. As a result, a liquid containing molecular hydrogen with a dissolved hydrogen concentration of, for example, about 1 to 10 ppm can be prepared.
A non-destructive hydrogen adding device is a device or device that adds hydrogen gas to commercially available liquids such as intravenous fluids (for example, enclosed in a hydrogen-permeable plastic bag such as a polyethylene bag) from the outside of the package. and is commercially available from, for example, MiZ (http://www.e-miz.co.jp/technology.html). In this device, by immersing a bag containing a fluid applicable to a living body in saturated hydrogen water, hydrogen permeates the bag and aseptically dissolves hydrogen in the fluid applicable to a living body until concentration equilibrium is reached. The device is composed of, for example, an electrolytic cell and a water tank, and water in the water tank circulates through the electrolytic cell and the water tank, and can generate hydrogen by electrolysis. Alternatively, simple disposable instruments can be used for the same purpose (Japanese Patent Application Laid-Open No. 2016-112562, etc.). This device contains a plastic bag (hydrogen permeable bag, such as a polyethylene bag) containing a biologically applicable fluid and a hydrogen generating agent (such as metallic calcium, metallic magnesium/cation exchange resin, etc.) inside an aluminum bag. The hydrogen generating agent is wrapped in, for example, a non-woven fabric (eg, a water vapor permeable non-woven fabric). Hydrogen generated by wetting the hydrogen generating agent wrapped in the nonwoven fabric with a small amount of water such as steam is nondestructively and aseptically dissolved in the biologically applicable liquid.
Alternatively, a purified hydrogen gas cylinder, a purified oxygen gas cylinder, or a purified air cylinder may be prepared, and a gas or liquid containing molecular hydrogen adjusted to have a predetermined hydrogen concentration, oxygen, or air concentration may be produced.
Gases containing molecular hydrogen and liquids containing molecular hydrogen (e.g. water (e.g. purified water, sterilized water), physiological saline, intravenous fluids, etc.) prepared using the above devices or instruments may cause pneumonia. Subjects can be administered orally or parenterally.
Another form of the composition of the present invention includes a dosage form containing a hydrogen generating agent capable of generating hydrogen in the gastrointestinal tract (e.g., tablet , capsules, etc.). The hydrogen generating agent is preferably composed of ingredients approved as food or food additives, for example.
As a method for administering the composition of the present invention to a subject, when molecular hydrogen is used as an active ingredient, administration by inhalation, inhalation, etc., such as transpulmonary administration, is preferable. Oral administration or intravenous administration (including drip infusion) is preferable for the component. When a gas is inhaled, it can be inhaled through the mouth or nose through a nasal cannula or a mask-type device that covers the mouth and nose and is delivered to the lungs for systemic delivery via the blood.
Liquids containing molecular hydrogen to be administered orally may be administered to subjects as chilled liquids or liquids stored at room temperature. It is known that hydrogen dissolves in water at a concentration of about 1.6 ppm (1.6 mg/L) under normal temperature and normal pressure, and the solubility difference due to temperature is relatively small. Alternatively, when the liquid containing molecular hydrogen is, for example, in the form of a drip or an injection containing hydrogen gas prepared using the above-described nondestructive hydrogen containing device, intravenous administration, intraarterial administration, etc. may be administered to a subject by any parenteral route of administration.
Gas containing molecular hydrogen with the above hydrogen concentration or liquid containing molecular hydrogen with the above dissolved hydrogen concentration once or multiple times per day (for example, 2 to 3 times) for a period of 1 week to 3 months or more , eg, from 1 week to 6 months or longer (eg, 1 year or more, 2 years or more, etc.). When a gas containing molecular hydrogen is administered, it is preferred to inhale for at least 30 minutes each time. Since the longer the inhalation time, the better the effect, the administration can be performed, for example, for 30 minutes to 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, or longer. In addition, when a gas containing molecular hydrogen is administered through the lungs by inhalation or inhalation, it is performed under an atmospheric pressure environment, or, for example, at a pressure exceeding standard atmospheric pressure (about 1.013 atmospheres) and 7.0 atmospheres or less. High pressure within the range, for example 1.02 to 7.0 atmospheres, preferably 1.02 to 5.0 atmospheres, more preferably 1.02 to 4.0 atmospheres, more preferably 1.02 to 1.35 atmospheres The gas can be administered to the subject under a range of hyperbaric environments (including molecular hydrogen-containing gases).
2. Methods for Preventing and/or Ameliorating Pneumonia For compositions containing molecular hydrogen, pneumonia, symptoms associated with pneumonia, dosages, methods of administration, etc., see 1 above. As explained in
In the method of the present invention, the subject has a 8% by volume, 3 to 10% by volume, 3 to 9% by volume, 3 to 8% by volume, 3 to 7% by volume, 3 to 6% by volume, 4 to 10% by volume, 4 to 9% by volume, 4 to 8% by volume %, 4-7 vol%, 4-6 vol%, 4-5 vol%, 5-10 vol%, 5-9 vol%, 5-8 vol%, 6-10 vol%, 6-9 vol%, of molecular inhalation or inhalation of a hydrogen-containing gas (preferably air or oxygen) for, for example, 1 to 3 hours or more per day, for example, 1 to 3 months or more, 4 to 7 months or more, It can last from 1 to 3 years or longer.
Alternatively, in the methods of the present invention, the subject may be subjected to ~4ppm, 2-10ppm, 2-9ppm, 2-8ppm, 2-7ppm, 2-6ppm, 2-5ppm, 3-10ppm, 3-9ppm, 3-8ppm, 3-7ppm, 4-10ppm, 4-9ppm , 4-8 ppm, 4-7 ppm, 5-10 ppm, 5-9 ppm, 5-8 ppm, 5-7 ppm, etc., preferably 3-10 ppm, 4-10 ppm, 5-10 ppm, 5-9 ppm, 5-8 ppm, 5- A molecular hydrogen-containing liquid such as 7 ppm is administered in an amount of, for example, 200 to 500 mL per administration for intravenous administration, and for example, 500 to 1000 mL per administration for oral administration, for example, for 0.5 to 3 months or more. , 4-7 months or more, 1-3 years or more.
The methods of the present invention may also optionally be used in combination with therapeutic agents used to treat pneumonia. Combined use is expected to prevent and/or improve pneumonia.

The invention is further illustrated with reference to the following examples, but the invention is not intended to be limited by the examples.

<Cases of improvement of interstitial pneumonia by hydrogen inhalation>
A 58-year-old male patient diagnosed with interstitial pneumonia received hydrogen infusion (1 ppm hydrogen, 250 ml) and hydrogen gas inhalation for 30 to 60 minutes once a week for 8 weeks. For inhalation of hydrogen gas, MHG-2000α (hydrogen gas concentration 6-7%, 120 ml/min) manufactured by MiZ Co., Ltd. was used. It was confirmed that the interstitial pneumonia was significantly ameliorated by the administration of the hydrogen from the absence of ground-glass opacities in the CT findings. CT photographs before and after treatment are shown in FIGS. 1 and 2. FIG.

According to the present invention, pneumonia can be prevented and/or improved by administering a composition containing molecular hydrogen.

Claims (8)

A composition containing molecular hydrogen as an active ingredient,
wherein said composition is administered to a human by inhalation of hydrogen gas;
A composition for ameliorating pneumonia and symptoms associated with pneumonia, excluding bronchitis, in humans. 2. The composition of claim 1, wherein said composition is further administered to humans by hydrogen infusion. 3. The composition according to claim 1 or 2, wherein the pneumonia is one or more selected from the group consisting of bacterial pneumonia, viral pneumonia, fungal pneumonia, and drug-induced pneumonia. Symptoms associated with pneumonia include sore throat, fever, cough, sneezing, sputum production, dyspnea, general malaise, nausea, fatigue, chest pain, shortness of breath, runny nose, decreased white blood cells, diarrhea, headache, decreased lung function. 4. The composition according to any one of claims 1 to 3, wherein the symptom is one or more selected from the group consisting of , decreased cardiac function, and decreased kidney function. 5. The composition according to any one of claims 1 to 4, which is a liquid or gas containing molecular hydrogen. A composition according to claim 5, wherein the liquid containing molecular hydrogen has a hydrogen concentration of 1-10 ppm. 6. The composition of claim 5, wherein the gas containing molecular hydrogen has a hydrogen concentration greater than zero (0) and less than or equal to 18.5% by volume. The composition according to any one of claims 1 to 7, which is produced using a hydrogen gas generator, a hydrogen water generator, or a hydrogen gas addition device.

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