WO2021199792A1 - Formulation pour la prévention ou le traitement de la pneumonie - Google Patents

Formulation pour la prévention ou le traitement de la pneumonie Download PDF

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Publication number
WO2021199792A1
WO2021199792A1 PCT/JP2021/006626 JP2021006626W WO2021199792A1 WO 2021199792 A1 WO2021199792 A1 WO 2021199792A1 JP 2021006626 W JP2021006626 W JP 2021006626W WO 2021199792 A1 WO2021199792 A1 WO 2021199792A1
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Prior art keywords
pneumonia
silicon
hydrogen
fine particles
less
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PCT/JP2021/006626
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English (en)
Japanese (ja)
Inventor
小林　光
悠輝 小林
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国立大学法人大阪大学
株式会社Ｋｉｔ
株式会社ボスケシリコン
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Priority to JP2022511658A priority Critical patent/JPWO2021199792A1/ja
Publication of WO2021199792A1 publication Critical patent/WO2021199792A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to a pharmaceutical product for the prevention or treatment of pneumonia.
  • the hydroxyl radical generated in the body disappears by reacting with some substances.
  • an antioxidant substance in the living body such as polyphenol, vitamin C, ⁇ -tocopherol, or glutathione is generally presumed.
  • these substances eliminate not only hydroxyl radicals but also active oxygen having a function in the body such as hydrogen peroxide, there is a possibility of causing adverse effects (side effects) such as a decrease in immunity.
  • side effects such as a decrease in immunity.
  • hydrogen can also extinguish hydroxyl radicals.
  • hydrogen reacts only with hydroxyl radicals in active oxygen, it does not have the above-mentioned adverse effects (side effects). Therefore, a hydrogen water generator containing hydrogen that eliminates hydroxyl radicals in the body has been proposed (for example, Patent Document 1).
  • an orallyable solid preparation containing silicon fine particles as a main component and having a high hydrogen generating ability is disclosed (Patent Document 3).
  • some of the present inventors have disclosed agents for kidney diseases, which include silicon fine particles capable of generating hydrogen, aggregates of the silicon fine particles, or silicon crystal grains.
  • the silicon microparticles and the silicon suboxide (SiO X , x in the formula is 1/2, 1, and 3/2) and / or the silicon sub covering at least a part of the surface of the silicon fine particles.
  • a composite material containing a mixed composition of oxide and silicon dioxide is disclosed (Patent Document 4).
  • a drug for a kidney disease which comprises silicon fine particles capable of generating hydrogen, an aggregate of the silicon fine particles, or silicon crystals.
  • silicon particles or silicon fine particles can serve as a preventive or therapeutic preparation for pneumonia.
  • the present invention is classified as an intractable disease that has not been realized so far by solving at least one of the above-mentioned technical problems and creating a new utilization method of the hydrogen generating ability of silicon particles or silicon fine particles. It can greatly contribute to the realization of preventive or therapeutic preparations for various pneumonia including idiopathic interstitial pneumonia and pulmonary fibrosis.
  • the present inventor has conducted extensive studies and analysis toward the realization of a pharmaceutical product for the prevention or treatment of human pneumonia by utilizing a substance having a high hydrogen generating ability (producing ability).
  • a substance having a high hydrogen generating ability producing ability
  • sicon fine particles in which particles having an average crystallite diameter of 1 nm or more and less than 1 ⁇ m are the main particles.
  • the present inventor tried to produce silicon particles or silicon fine particles by using a method different from the production methods adopted so far.
  • the different production method is a production method including a classification step for obtaining silicon particles having a relatively large constant particle size after a step of crushing silicon particles.
  • an effective preventive or therapeutic preparation for pneumonia can be realized by using silicon particles and / or silicon fine particles having a hydrogen generating ability. ..
  • silicon particles having the following characteristics (1) a higher hydrogen generating ability is generated as compared with the conventional one, and it is also useful as an oral preparation.
  • the ratio of the silicon fine particles having a crystallite diameter of less than 1 ⁇ m and the aggregates of the silicon fine particles to all the silicon particles, the silicon fine particles and their aggregates is 5% by mass or less. (More preferably 3% by mass or less, further preferably 1% by mass or less, further preferably 0.5% by mass or less, still more preferably 0.2% by mass or less).
  • the total amount of hydrogen generated (total amount of hydrogen produced) of the silicon particles is remarkably superior to those of the conventional silicon fine particles. The inventor found.
  • the silicon fine particles of the above (1) and the aggregates of the silicon fine particles are the silicon particles, the silicon fine particles and the aggregate. Since the abundance ratio of the silicon particles of less than 1 ⁇ m and the agglomerates to the whole of the agglomerates is low, the hydrogen generating ability can be maintained high, and the crystallite diameter is kept within a certain range. Stable hydrogen generation ability can be exhibited. In addition, in the case of oral ingestion, deterioration of human texture can be suppressed. In addition, it is possible to prevent the silicon particles from being directly absorbed and invading the blood vessels with high accuracy.
  • the present invention was created from each of the above viewpoints.
  • the "silicon fine particles” in the present application are mainly particles having an average crystallite diameter of 1 nm or more and less than 1 ⁇ m.
  • the "silicon fine particles” in the present application mainly consist of silicon nanoparticles having an average crystallite diameter of nano-level, specifically, a crystallite diameter of 1 nm or more and 500 nm or less.
  • the "silicon particles” in the present application are mainly particles having an average crystallite diameter of more than 500 nm (more narrowly, 1 ⁇ m or more) and 500 ⁇ m or less.
  • the "silicon fine particles” are not limited to those in which each silicon fine particles are dispersed, but also have a size of ⁇ m order (generally 0.1 ⁇ m or more) in which a plurality of silicon fine particles are aggregated. Includes those in the state of forming aggregates. Since each of the above-mentioned numerical ranges of "silicon fine particles” is only an example, the numerical range is not limited. Further, the crystallite diameter is appropriately selected according to the use, usage, required function, etc. of the "silicon fine particles” or "silicon particles”.
  • the "water-containing liquid” in the present application is water or an aqueous solution, and includes, for example, a human digestive tract liquid.
  • the "digestive tract fluid” refers to the fluid in the small intestine and the fluid in the large intestine.
  • the example of the "water-containing liquid” is not limited to the above-mentioned example.
  • the material of the "pH adjuster” in the present application is particularly limited as long as it is a drug (hereinafter, "alkaline agent") capable of adjusting the pH value to an alkaline range of more than 7 (typically, more than 7.4). Not done. It also includes its use on human skin.
  • alkaline agent approved as a drug
  • examples of alkaline agents include sodium hydrogen carbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydrogen carbonate, potassium carbonate, and other medicinal pH adjusters.
  • sodium hydrogen carbonate which is the most general-purpose product, is widely used as a pharmaceutical product, and has a plurality of advantages such as a pH value adjusting function required by the present invention and excellent safety and versatility.
  • any pH adjusting agent has a form that is not decomposed by an acid.
  • the pharmaceutical product for the prevention or treatment of pneumonia of the present application is orally ingested, it is preferable to form a form that is not decomposed by gastric acid or is hardly decomposed.
  • One of the prophylactic or therapeutic formulations for pneumonia of the present invention contains silicon particles capable of generating hydrogen. Then, in a preferred embodiment of the present invention, the ratio of the silicon particles having a crystallite diameter of less than 1 ⁇ m and the aggregates of the silicon particles to all the silicon particles, the silicon fine particles, and the aggregates thereof. However, it is 5% by mass or less.
  • the hydrogen generating ability of the silicon particles can contribute to the prevention or treatment of pneumonia including various intractable diseases.
  • pneumonia includes pneumonia caused by a new coronavirus infection (COVID-19), pneumonia caused by a mutated new coronavirus infection (COVID-19), and a disease designated as an intractable disease in Japan.
  • COVID-19 a new coronavirus infection
  • COVID-19 a mutated new coronavirus infection
  • a disease designated as an intractable disease in Japan Includes “idiopathic interstitial pneumonia", drug-induced pneumonia, chronic hypersensitive pneumonia, dust lung, and bacterial pneumonia.
  • One of the prophylactic or therapeutic formulations of pneumonia of the present invention can contribute to the prevention or treatment of pneumonia including various intractable diseases.
  • FIG. 1 is a photograph of a tablet showing an example of the pharmaceutical product 100 for preventing or treating pneumonia according to the present embodiment.
  • the formulation 100 for the prevention or treatment of pneumonia of the present embodiment is formed so as to be a solid formulation using silicon particles and / or silicon fine particles having a hydrogen generating ability as a starting material.
  • the outer diameter of the prophylaxis or therapeutic preparation 100 for pneumonia of the present embodiment is not limited as long as it has a size that can be adopted as a human oral tablet.
  • An example of a typical outer diameter is a cylindrical mass having a diameter of about 8 mm and a height of about 5 mm.
  • the silicon fine particles containing silicon particles and / or silicon fine particles and having a crystallite diameter of less than 1 ⁇ m and an aggregate of the silicon fine particles.
  • the ratio of all the silicon particles, the silicon fine particles and their aggregates to the aggregates is 5% by mass or less (more preferably 3% by mass or less, still more preferably 1% by mass or less, still more preferably 0. 5% by mass or less, more preferably 0.2% by mass or less).
  • ⁇ Crushing process> for example, commercially available high-purity silicon particle powder (particle size 300 ⁇ m or less, purity 99.999%, i-type silicon) is used as a part of the raw material of the pharmaceutical product 100 for the prevention or treatment of pneumonia.
  • silicon particle powder having a purity higher or lower than the above-mentioned purity can be adopted.
  • a crushing step is performed on the above-mentioned high-purity silicon particle powder by a crushing process using a cutter by a jet mill method.
  • an additional pulverization step (second pulverization step) using 0.5 mm ⁇ zirconia beads in ethanol is performed in the bead mill method. It is also an embodiment that it is possible to obtain silicon fine particles (silicon nanoparticles) having a typical crystallite diameter) of less than 500 nm.
  • a roller mill method instead of the first pulverization step, a roller mill method, a high-speed rotary pulverization method, or a container-driven mill method is used to form silicon particles having a crystallite diameter of 1 ⁇ m or more and 60 ⁇ m or less, or a typical crystallite diameter of 500 nm. It is also an aspect that it can be adopted to obtain silicon fine particles (silicon nanoparticles) having a diameter of less than.
  • a pulverization step (first pulverization step or second pulverization step) is followed by a classification step.
  • the ratio of the silicon fine particles having a crystallite diameter of less than 1 ⁇ m and the aggregates of the silicon fine particles to all the silicon particles, the silicon fine particles and their aggregates is 5% by mass or less. (More preferably 3% by mass or less, further preferably 1% by mass or less, further preferably 0.5% by mass or less, still more preferably 0.2% by mass or less) using the air flow method.
  • silicon particles having a crystallite diameter of less than 1 ⁇ m and aggregates of the silicon particles are substantially removed.
  • crystallite diameter used for silicon particles
  • crystal grain size is used as a term for the overall diameter of agglomerates of silicon particles.
  • the hydrogen-generating pneumonia preventive or therapeutic formulation 100 of the present embodiment contains silicon particles and / silicon fine particles, and the silicon fine particles having a crystallite diameter of less than 1 ⁇ m and an aggregate of the silicon fine particles.
  • the ratio of all the silicon particles, the silicon fine particles and their aggregates to the aggregates is 5% by mass or less (more preferably 3% by mass or less, still more preferably 1% by mass or less, still more preferably 0. 5% by mass or less, more preferably 0.2% by mass or less) has the effect that the accuracy is higher and the safety can be enhanced by preventing the silicon particles from passing through the cell membrane of the intestinal tract and between the cells. Can play.
  • the upper limit of the crystallite diameter of silicon particles and aggregates of silicon particles is not limited.
  • the ratio to the agglomerates is 5% by mass or less (more preferably 3% by mass or less, further preferably 1% by mass or less, still more preferably 0.5% by mass or less, still more preferably 0.2% by mass).
  • the classification process for classifying so as to be (below) can be adopted.
  • the hydrogen generating ability can be maintained high and the crystallite diameter can be kept in a certain range. By staying inside, more stable hydrogen generation ability can be exhibited.
  • deterioration of human texture can be suppressed.
  • the ratio of the silicon fine particles having a crystallite diameter of less than 1 ⁇ m and the aggregates of the silicon fine particles to all the silicon particles, the silicon fine particles and their aggregates is 5% by mass.
  • a collection is obtained.
  • silicon particles having a crystallite diameter of 1 ⁇ m or more and 60 ⁇ m or less (more preferably 1 ⁇ m or more and less than 45 ⁇ m) and an agglomerate of silicon particles can be obtained.
  • the pharmaceutical product 100 for preventing or treating pneumonia of the present embodiment is excellent from the viewpoint of suppressing deterioration of human texture or reducing the possibility of silicon particles invading blood vessels.
  • Example> [Effect of preventive or therapeutic preparations for pneumonia on pneumonia]
  • a tester male in his 60s who had a disease of interstitial pneumonia and participated in this example on his own initiative took 1 g / day of the preventive or therapeutic preparation 100 for pneumonia every day. Ingested orally. Since the above-mentioned 1 g means the mass of silicon particles, the mass of a material other than silicon particles (for example, excipients) is not included. The same applies to each of the following examples.
  • KL-6 is a glycoprotein antigen and is one of the glycoproteins belonging to MUC1 mucin, which is a transmembrane non-secretory mucin.
  • serum "KL-6" is known to be an effective index of interstitial pneumonia.
  • KL-6 is useful for differentiating between interstitial pneumonia and other disease groups between the interstitial pneumonia group and the non-interstitial pneumonia group (Kikuchi et al.) , “Examination of basic performance and clinical usefulness of new KL-6 measurement reagent” LZ test'Eiken'KL-6 "", Medical Examination, Vol. 66 (2017) No. 1), especially in this example, " The remarkable decrease in the value of "KL-6" in a short period of time indicates that the therapeutic preparation of the first embodiment is particularly useful for the treatment of interstitial pneumonia.
  • the preparation 100 for preventing or treating pneumonia is not only for idiopathic interstitial pneumonitis, but also for pneumonia caused by a new coronavirus infection (COVID-19) and a mutated new coronavirus infection (COVID-19). It can also contribute as a prophylactic or therapeutic formulation against the resulting pneumonia, drug-induced pneumonia, chronic hypersensitivity pneumonitis, dust lung, or bacterial pneumonia.
  • a modification step of modifying the surface of the silicon particles by further contacting the surface with hydrogen peroxide solution.
  • This modification step allows the silicon nanoparticles to be made hydrophilic when viewed macroscopically.
  • the silicon particles are immersed in a hydrogen peroxide solution (for example, about 10 ° C. to about 80 ° C., about 20 ° C. to about 50 ° C. from the viewpoint of realizing lower cost) contained in a known container. Thereby, the reforming step can be performed.
  • the same modification can be realized by immersing the silicon particles in ozone water and / or sodium percarbonate instead of the hydrogen peroxide solution.
  • similar modification can be achieved by contacting the silicon particles with at least one selected from the group of hydrogen peroxide solution, ozone water, and sodium percarbonate.
  • the tablet is an example of a lumpy preparation.
  • nanocapsules, microcapsules usually, which do not dissolve the preventive or therapeutic preparation 100 for pneumonia having a stable silicon suboxide and the pH adjuster such as sodium hydrogen carbonate separately under acidic conditions but dissolve under basic conditions.
  • Capsule or coating of the above is a preferred embodiment.
  • the pharmaceutical product 100 for preventing or treating pneumonia according to the above-mentioned first embodiment or modified examples (1) to (2) of the first embodiment can be utilized as, for example, a pharmaceutical product (medicinal product).
  • the application examples are not limited to tablets.
  • a capsule containing the preventive or therapeutic preparation 100 for powdery pneumonia is used instead of the tablet, the same effect as described above can be achieved.
  • the pharmaceutical product 100 for the prevention or treatment of pneumonia can generate more hydrogen when it is in the form of a powder having a large surface area rather than in the form of a lump. It will be easier.
  • the prophylaxis or therapeutic preparation 100 for pneumonia may be a granule preparation.
  • Granule preparations are powdery at an earlier stage after ingestion or anal ingestion compared to tablets and capsules.
  • gastric juice has a low pH value (about 1.5), so even if it reaches the stomach and immediately becomes powdery, it hardly generates hydrogen, and in the presence of water after passing through the stomach. To generate hydrogen.
  • the prophylaxis or therapeutic preparation 100 for pneumonia may be a powder.
  • An example of a coating layer applicable to a tablet is a known poorly soluble gastrointestinal enteric material, which is a coating agent covering the outermost layer of a tablet.
  • An example of a coating layer applicable to a capsule is the capsule itself produced from a known poorly soluble gastrointestinal enteric material containing the prophylaxis or therapeutic formulation 100 for pneumonia.
  • an example of a suitable formulation as an example of utilization of the preventive or therapeutic formulation 100 for pneumonia is a tablet or powdery pneumonia which is a lumpy formulation which is easy to take in a sufficient amount orally or through the anus.
  • a disintegrant may be further contained.
  • a known material can be adopted.
  • a more preferred example of a disintegrant is an organic acid, the most preferred example is citric acid.
  • the organic acid can also function as a binder that agglomerates the silicon particles.
  • the pneumonia preventive or therapeutic preparation 100 of the above-mentioned first embodiment or modifications (1) to (3) of the first embodiment is brought into contact with, for example, the pneumonia preventive or therapeutic preparation 100.
  • the “medium” hydrogen can be taken into the body (including the skin itself or the mucous membrane itself) percutaneously or transmucosally.
  • the medium of this modification is not particularly limited to materials or products. Any physiologically acceptable medium can produce the effects of this variant. Therefore, a product provided with the prophylaxis / therapeutic preparation 100 for pneumonia and the medium in contact with the prophylaxis / therapeutic preparation 100 for pneumonia can exert a function as a hydrogen supply material.
  • a human part comes into contact with water (or a water-containing liquid) or a medium containing the water (or a water-containing liquid) (hereinafter, collectively referred to as "medium").
  • suitable vehicles are at least one selected from the liquid, gel, cream, paste, emulsion, and mousse groups.
  • An example of another suitable medium is bath water (preferably alkaline bath water). Therefore, in one example of this modification, the production of the bath water is the method for producing the medium.
  • tap water is typically stored as bathing water in a general bathtub (including a public bathtub, a public bathtub, and an indoor or outdoor bathtub installed by an inn).
  • a general bathtub including a public bathtub, a public bathtub, and an indoor or outdoor bathtub installed by an inn.
  • hydrogen by placing or putting the above-mentioned hydroxyl radical inhibitor in the bathtub and performing a contact step of contacting the bath water as a medium with the preparation 100 for preventing or treating pneumonia).
  • H 2 is generated. Therefore, the prophylaxis or therapeutic preparation 100 for pneumonia of this variant can be adopted as a so-called bath agent.
  • hydrogen (H 2 ) generated by the above-mentioned contact step can be brought into contact with the human skin and / or mucous membrane to be bathed via bath water as a physiologically acceptable medium.
  • the prophylaxis or therapeutic formulation 100 of each of the above-mentioned first embodiment or each modification of the first embodiment has a diameter of ⁇ m level (for example, several tens of ⁇ m or more) by aggregating in a natural state.
  • the pH value is less than 7. It can be brought into contact with one water-containing liquid, and in the subsequent contact step (second contact step), it is brought into contact with a second water-containing liquid having a pH value of 7 or more, and hydrogen can be generated in the second contact step.
  • the pharmaceutical product 100 for preventing or treating pneumonia according to each of the above-described embodiments is remarkable when it comes into contact with a water-containing liquid having a pH value of 7 or more (more preferably more than 7 and more preferably 8.2 or more). It may have the ability to generate hydrogen.
  • the temperature conditions of the second water-containing liquid for hydrogen generation described above are not limited. Although it may depend on the pH of the second water-containing liquid, if the temperature of the second water-containing liquid is 80 ° C. or lower, the accuracy is high and hydrogen generation can be promoted. However, the upper limit of the temperature of the second water-containing liquid is not originally limited. For example, when the pharmaceutical product 100 for preventing or treating pneumonia in each of the above-described embodiments and variants thereof is used as an industrial drug, the temperature may exceed 50 ° C. However, the higher the temperature, the higher the heat resistance of the equipment (including the container) is required, and there are problems that care must be taken in handling. Therefore, even when used as an industrial chemical, it is preferably used at 100 ° C. or lower.
  • the prophylactic or therapeutic preparation for pneumonia of the present invention can be widely used in the pharmaceutical and medical industries utilizing hydrogen.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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Abstract

Une formulation pour prévenir ou traiter la pneumonie, selon la présente invention, contient des particules de silicium et/ou des particules fines de silicium ayant une capacité de génération d'hydrogène. Une formulation pour prévenir ou traiter une pneumonie, selon la présente invention, peut contribuer à la prévention ou au traitement de la pneumonie, y compris diverses maladies réfractaires.
PCT/JP2021/006626 2020-04-02 2021-02-22 Formulation pour la prévention ou le traitement de la pneumonie WO2021199792A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0459601A (ja) * 1990-06-26 1992-02-26 Asahi Chem Ind Co Ltd 水素の製造方法
JP2006526140A (ja) * 2002-12-24 2006-11-16 バイオサイト インコーポレイテッド 鑑別診断のためのマーカーおよびその使用方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0459601A (ja) * 1990-06-26 1992-02-26 Asahi Chem Ind Co Ltd 水素の製造方法
JP2006526140A (ja) * 2002-12-24 2006-11-16 バイオサイト インコーポレイテッド 鑑別診断のためのマーカーおよびその使用方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LAI CHIH-CHENG; SHIH TZU-PING; KO WEN-CHIEN; TANG HUNG-JEN; HSUEH PO-REN: "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges", INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, ELSEVIER, AMSTERDAM, NL, vol. 55, no. 3, 17 February 2020 (2020-02-17), AMSTERDAM, NL , XP086083692, ISSN: 0924-8579, DOI: 10.1016/j.ijantimicag.2020.105924 *
NISHIKAWA, Y., ET AL.: "Hydrogen gas inhalation ameliorates direct lung injury and indirect contralateral lung injury in a murine aspiration pneumonia model", EUROPEAN RESPIRATORY SOCIETY ANNUAL CONGRESS 2012, vol. 19, no. 3, 1 January 2014 (2014-01-01), pages 179, XP055935650 *
TERASAKI Y. ET AL.: "Pathomorphism analysis of lung lesions in D1CC mouse model of rheumatoid arthritis and effect of drinking water which high-concentration molecular hydrogen (H2) on lesions", COMMISSIONED PROJECT OF MINISTRY OF HEALTH, LABOR AND WELFARE SCIENTIFIC RESEARCH, 2015, pages 115 - 122 *

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