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WO2024024149A1 - Fatty liver disease inhibitor - Google Patents

Fatty liver disease inhibitor Download PDF

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Publication number
WO2024024149A1
WO2024024149A1 PCT/JP2023/007451 JP2023007451W WO2024024149A1 WO 2024024149 A1 WO2024024149 A1 WO 2024024149A1 JP 2023007451 W JP2023007451 W JP 2023007451W WO 2024024149 A1 WO2024024149 A1 WO 2024024149A1
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WIPO (PCT)
Prior art keywords
hydrogen
fatty liver
liver disease
less
powder
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PCT/JP2023/007451
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French (fr)
Japanese (ja)
Inventor
史郎 高原
直嗣 市丸
康 梨井
景樹 南部
Original Assignee
国立研究開発法人国立成育医療研究センター
株式会社アッチェ
史郎 高原
直嗣 市丸
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Application filed by 国立研究開発法人国立成育医療研究センター, 株式会社アッチェ, 史郎 高原, 直嗣 市丸 filed Critical 国立研究開発法人国立成育医療研究センター
Publication of WO2024024149A1 publication Critical patent/WO2024024149A1/en

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to a fatty liver disease inhibitor that is considered to be safe and has little harm while exhibiting an excellent fatty liver disease inhibitory effect.
  • NASH non-alcoholic steatohepatitis
  • EPL polyene phosphatidylcholine preparation
  • Patent Document 1 discloses a PPAR ⁇ (peroxisome proliferator-activated receptor ⁇ ) activator as a therapeutic agent for fatty liver.
  • PPAR ⁇ peroxisome proliferator-activated receptor ⁇
  • these drugs are synthetic drugs that are also used to treat diabetes itself, and are thought to have strong side effects.
  • fenofibrate which is listed as a PPAR ⁇ activator in Patent Document 1, is known to have side effects such as hepatomegaly.
  • the liver is said to be a silent organ, and there are almost no symptoms, especially in the early stages of each disease.
  • fatty liver there are no symptoms in the early stages, but as it progresses, common symptoms of liver disease such as getting tired easily, feeling sluggish, and loss of appetite appear. Misunderstanding it and leaving it untreated often makes it worse. Therefore, it can be said that a drug that is safe and can be used prophylactically is preferable.
  • an object of the present invention is to provide a fatty liver disease inhibitor that is considered to be safe and has little harm, while exhibiting an excellent fatty liver disease inhibitory effect.
  • the present inventors have conducted extensive research in order to solve the above problems. As a result, the present inventors have discovered that the hydrogen-carrying powder developed by the present inventors can effectively suppress fatty liver disease when administered orally, and have completed the present invention.
  • the present invention will be described below.
  • a hydrogen-carrying powder that has an average particle size of 1 ⁇ m or more and 100 ⁇ m or less, contains calcium magnesium carbonate, and generates hydrogen gas of 0.1 ⁇ L or more and 100 ⁇ L or less per gram upon contact with moisture.
  • a fatty liver disease inhibitor characterized by comprising: [2] The fatty liver disease inhibitor according to the above [1], wherein the fatty liver disease is non-alcoholic steatohepatitis. [3] The fat according to [1] or [2] above, wherein the hydrogen-supported powder has an absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopic analysis. Sexual liver disease inhibitor.
  • the average particle size is 1 ⁇ m or more and 100 ⁇ m or less, contains calcium magnesium carbonate, and produces hydrogen gas of 0.1 ⁇ L or more and 100 ⁇ L or less per 1 g upon contact with water.
  • the use of hydrogen-carrying powder to generate [8] The use according to [7] above, wherein the fatty liver disease is non-alcoholic steatohepatitis.
  • the hydrogen-supported powder has absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopic analysis. .
  • a method for treating fatty liver disease which has an average particle diameter of 1 ⁇ m or more and 100 ⁇ m or less, contains calcium magnesium carbonate, and produces 0.1 ⁇ L or more and 100 ⁇ L per 1 g upon contact with water.
  • the fatty liver disease is non-alcoholic steatohepatitis.
  • the fatty liver disease inhibitor according to the present invention has excellent safety because its active ingredient is a hydrogen-carrying powder whose main ingredient is calcium magnesium carbonate, which is also included in foods and supplements, and it is recommended for daily administration. is also possible. Further, since the hydrogen-carrying powder used in the present invention exhibits an excellent ability to generate hydrogen gas, the fatty liver disease inhibitor according to the present invention exhibits an extremely excellent fatty liver disease inhibitory effect. Furthermore, according to the experimental findings of the present inventors, it has been recognized that fatty liver disease can be effectively suppressed by oral intake of the fatty liver disease inhibitor according to the present invention. Therefore, the fatty liver disease inhibitor according to the present invention is very useful as it can effectively suppress fatty liver disease without causing pain to the recipient.
  • FIG. 1 is a graph showing the ratio of liver weight to body weight of rats in the untreated group, rats in the control group, and rats in the group ingesting the hydrogen-carrying powder according to the present invention.
  • FIG. 2 is a graph showing serum AST concentrations of untreated rats, control rats, and rats ingesting the hydrogen-carrying powder according to the present invention.
  • FIG. 3 is a graph showing the serum total cholesterol concentration of rats in the untreated group, rats in the control group, and rats ingested with the hydrogen-carrying powder according to the present invention.
  • FIG. 1 is a graph showing the ratio of liver weight to body weight of rats in the untreated group, rats in the control group, and rats in the group ingesting the hydrogen-carrying powder according to the present invention.
  • FIG. 2 is a graph showing serum AST concentrations of untreated rats, control rats, and rats ingesting the hydrogen-carrying powder according to the present invention.
  • FIG. 3 is a graph showing the serum total cholesterol concentration
  • FIG. 4 is a graph showing the relative ratio of SREBP-1c gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats.
  • FIG. 5 is a graph showing the relative ratio of Leptin R gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats.
  • FIG. 6 is a graph showing the relative ratio of TNF- ⁇ gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats.
  • FIG. 7 is a graph showing the relative ratio of CCR2 gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats.
  • the fatty liver disease inhibitor according to the present invention contains hydrogen-carrying powder as an active ingredient.
  • the average particle diameter of the hydrogen-supported powder is preferably 1 ⁇ m or more and 100 ⁇ m or less. If the average particle diameter is 100 ⁇ m or less, the specific surface area of the hydrogen-supported powder is sufficiently large, and it is considered that hydrogen can be effectively adsorbed. Further, if the particle size is 1 ⁇ m or more, excessive energy is not required for crushing.
  • the average particle diameter is more preferably 5 ⁇ m or more, even more preferably 10 ⁇ m or more, more preferably 50 ⁇ m or less, and even more preferably 20 ⁇ m or less. Note that in the present disclosure, the average particle diameter is measured using a laser diffraction particle size distribution analyzer, and the average particle diameter is based on a volume basis, a weight basis, a number basis, etc., but a volume basis is preferable.
  • calcium magnesium carbonate is preferable as the main component of the hydrogen-carrying powder.
  • the ionic radius of calcium and magnesium differs, causing distortion in the structure after substitution, and increasing the number of sites that can support hydrogen, resulting in a structure that does not contain magnesium. It is believed that a powder with a higher hydrogen carrying amount than pure calcium carbonate can be obtained.
  • the Ca:Mg ratio in calcium magnesium carbonate is preferably 30:70 to 99:1, more preferably 40:60 to 98:2, and even more preferably 60:40 to 95:5.
  • Mg is necessary to support a sufficient amount of hydrogen, the lower the Mg ratio, the more the amount of hydrogen supported tends to increase.
  • Calcium magnesium carbonate has, for example, a structure represented by formula (1), preferably at least one of a structure represented by formula (2) and a structure represented by formula (3), more preferably a structure represented by formula (2). It is preferable that it contains both the structure represented by the formula (3) and the structure represented by the formula (3).
  • (Mg x Ca y ) CO 3 ... (1) [In the formula, 0.01 ⁇ x ⁇ 0.15, 0.85 ⁇ y ⁇ 0.99, x+y 1, x is preferably 0.02 or more and 0.14 or less, and y is is preferably 0.86 or more and 0.98 or less. ]
  • Formula (1) is preferably formula (2) or formula (3).
  • (Mg x2 Ca y2 )CO 3 ... (2) [In the formula, 0.01 ⁇ x2 ⁇ 0.05, 0.95 ⁇ y2 ⁇ 0.99, x2+y2 1, x2 is preferably 0.02 or more and 0.04 or less, and y2 is preferably 0.96 or more and 0.98 or less.
  • (Mg x3 Ca y3 )CO 3 ... (3) [In the formula, 0.05 ⁇ x3 ⁇ 0.15, 0.85 ⁇ y3 ⁇ 0.95, x3+y3 1, x3 is preferably 0.10 or more and 0.14 or less, and y3 is preferably 0.86 or more and 0.90 or less. ]
  • the content of calcium magnesium carbonate in 100% by mass of the hydrogen carrying powder is preferably 70% by mass or more, more preferably 80% by mass or more, 85% by mass or more, or 90% by mass or more, 95% by mass or more or 98% by mass. The above is even more preferable, and 100% by mass is particularly preferable.
  • the composition of the hydrogen-supported powder can be confirmed by, for example, infrared spectroscopy (IR) or X-ray diffraction (XRD).
  • IR infrared spectroscopy
  • XRD X-ray diffraction
  • the hydrogen-supported powder used in the present invention can be confirmed by having absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopy. .
  • powder derived from at least one species selected from the group consisting of corals, shellfish, pearls, foraminifera, and crinoids contains calcium carbonate and calcium magnesium carbonate in a well-balanced manner, and is therefore optimal as a raw material for the present invention.
  • the hydrogen-carrying powder may be coated with an enteric polymer or granulated with an enteric polymer.
  • Enteric-coated polymers refer to polymers that do not dissolve in the strong acidity (pH 1-2) of the stomach, but dissolve in the weakly acidic to neutral range (pH 5-7) of the small intestine.
  • the enteric-coated polymer suppresses the release of hydrogen from the hydrogen-carrying powder in the stomach, and also suppresses the release of hydrogen from the hydrogen-carrying powder in the small intestine. release can be promoted.
  • Enteric polymers are not particularly limited, but include, for example, hypromellose phthalate, carboxymethylethyl cellulose, cellulose acetate phthalate, the following (meth)acrylate units (I), and alkyl (meth)acrylate units (II). ) (meth)acrylate copolymers containing.
  • R 1 to R 3 independently represent H or a C 1-6 alkyl group.
  • C 1-6 alkyl group refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 1 or more and 6 or less carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • R 1 is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, even more preferably methyl.
  • R 2 is preferably H or a C 1-4 alkyl group, more preferably H or a C 1-2 alkyl group, even more preferably H or methyl.
  • R 3 is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group.
  • the (meth)acrylate copolymer may contain only one type of alkyl (meth)acrylate unit (II), or may contain two or more types.
  • the number is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or 1.
  • the ratio of the (meth)acrylate unit (I) to the alkyl (meth)acrylate unit (II) for example, the molar ratio of the alkyl (meth)acrylate unit (II) to the (meth)acrylate unit (I) is It is preferable to adjust it to 0.5 or more and 1.5 or less.
  • the molar ratio is preferably 0.8 or more, more preferably 0.9 or more, preferably 1.2 or less, and even more preferably 1.1 or less.
  • Coating and granulation of the hydrogen-carrying powder with enteric polymer can be performed by conventional methods. For example, by spraying and drying a solution or dispersion of an enteric polymer while fluidizing the hydrogen-carrying powder in a granulation dryer, the hydrogen-carrying powder may be coated with an enteric polymer or granulated. Can be done.
  • the hydrogen-carrying powder used in the present invention has excellent hydrogen generation ability. Specifically, the amount of hydrogen generated per 1 g of hydrogen-supported powder is calculated from the hydrogen concentration in the gas phase of the closed container when the hydrogen-supported powder is put in a closed container together with water and shaken at 35°C for 24 hours. is 0.1 ⁇ L or more and 100 ⁇ L or less.
  • the Japanese Pharmacopoeia's elution test second liquid pH 6.8 may be used instead of water.
  • the amount of hydrogen generated is more preferably 0.2 ⁇ L or more, even more preferably 0.3 ⁇ L or more, and even more preferably 50 ⁇ L or less.
  • Amount of hydrogen gas generated per 1g of hydrogen-supported powder ( ⁇ L/g) A x 25 x 10 -3 /3 [In the formula, A represents the hydrogen gas concentration (ppm) in the gas phase of the closed container. ]
  • the oxidation-reduction potential of the moisture is preferably -400 mV or more and -30 mV or less. If the redox potential is within this range, it is thought that the hydrogen-carrying powder effectively exerts its reducing action and suppresses inflammation and the like.
  • the redox potential is more preferably -350 mV or more, even more preferably -300 mV or more, more preferably -70 mV or less, or -100 mV or less, even more preferably -150 mV or less.
  • the hydrogen-supported powder having the above characteristics can be used, for example, in a gas atmosphere where the temperature is above 450°C and below 900°C, the hydrogen concentration is between 5 vol% and 100 vol%, and the pressure is between 0.1 MPa and 1.5 MPa.
  • a high-temperature treatment step in which a calcium magnesium carbonate-containing powder is heat-treated to produce a hydrogen-supported powder precursor It can be produced by a method including a low temperature treatment step of heat-treating a hydrogen-supported powder precursor to produce a hydrogen-supported powder in a gas atmosphere of .1 MPa or more and 1.5 MPa or less.
  • the temperature in the high temperature treatment step is preferably 500°C or higher, more preferably 550°C or higher, even more preferably 600°C or higher, and in order to lower the redox potential, preferably 680°C or higher, preferably 880°C.
  • the temperature is more preferably 860°C or lower, and in order to increase the amount of hydrogen gas generated by contact with moisture, the temperature is preferably 650°C or lower. As the temperature increases, the redox potential tends to decrease, while as the temperature decreases, the amount of hydrogen gas generated tends to increase.
  • the temperature in the low-temperature treatment step is preferably 160°C or higher, more preferably 180°C or higher, even more preferably 200°C or higher, and preferably 380°C or lower, more preferably 360°C or lower.
  • the temperature is preferably 250°C or lower. As the temperature increases, the redox potential tends to decrease, while as the temperature decreases, the amount of hydrogen gas generated tends to increase.
  • the high temperature treatment step and the low temperature treatment step are performed in a gas atmosphere containing hydrogen gas, and the hydrogen concentration in the high temperature treatment step and the low temperature treatment step in the gas atmosphere is preferably 20 vol% or more, more preferably 50 vol% or more. , more preferably 80 vol% or more, even more preferably 90 vol% or more, particularly preferably 100 vol%.
  • the remainder other than hydrogen gas is preferably an inert gas such as nitrogen, argon, or carbon dioxide.
  • the pressure in the high temperature treatment step and the low temperature treatment step is preferably 0.2 MPa or more, more preferably 0.3 MPa or more, even more preferably 0.4 MPa or more, and preferably 1.2 MPa or less, more preferably 1.2 MPa or more. It is 1 MPa or less, more preferably 1.0 MPa or less. The higher the pressure, the better the performance of the hydrogen-supported powder produced.
  • the high temperature treatment step is carried out for preferably 0.5 hours or more, more preferably 0.75 hours or more, even more preferably 1 hour or more, preferably 2 hours or less, more preferably 1.75 hours or less, and even more preferably is preferably carried out for 1.5 hours or less.
  • the low temperature treatment step may be carried out for preferably 1 hour or more, more preferably 2 hours or more, even more preferably 3 hours or more, preferably 6 hours or less, more preferably 5.5 hours or less, even more preferably 5 hours or less. preferable.
  • the heat treatment may be performed while flowing a gas whose hydrogen concentration is controlled to be 5 vol% or more and 100 vol% or less.
  • the particle size of the obtained hydrogen-supported powder can be adjusted as appropriate by pulverization and/or classification.
  • the fatty liver disease inhibitor according to the present invention exhibits an extremely excellent fatty liver disease inhibitory effect. Specifically, it suppresses liver enlargement due to fatty liver disease and improves liver function.
  • the hydrogen-carrying powder which is an active ingredient, has excellent hydrogen generation ability and exhibits a reducing effect, it is thought that, for example, inflammation caused by active oxygen can be suppressed.
  • the active ingredient, hydrogen-carrying powder is mainly composed of calcium magnesium carbonate, which is also included in foods and supplements, so it is considered to be extremely safe and can be used on a regular basis. . Therefore, for example, it can be taken multiple times a day for the treatment of fatty liver disease, and it can also be taken constantly for the purpose of preventing fatty liver disease over a long period of time.
  • Fatty liver disease includes fatty liver and steatohepatitis.
  • Fatty liver is a condition in which excess neutral fat accumulates in liver cells
  • steatohepatitis is a disease in which inflammation and fibrosis occur in fatty liver. It is often manifested by deterioration in numerical values indicating liver function, and can progress from fatty liver to steatohepatitis, and further to cirrhosis and liver cancer.
  • Fatty liver disease is generally diagnosed as alcoholic fatty liver disease caused by drinking more than 2 medium bottles of beer or 2 cups of sake per day, and alcoholic fatty liver disease caused by drinking less than 400 mL of beer or 1 cup of sake per day.
  • Non-alcoholic fatty liver disease is classified as non-alcoholic fatty liver disease (NAFLD), which consists of mild simple fatty liver disease and non-alcoholic fatty liver disease that causes severe functional impairment in the liver due to inflammation. including inflammatory hepatitis (NASH).
  • NASH inflammatory hepatitis
  • the fatty liver disease inhibitor according to the present invention has an effect of improving symptoms in a rat model of non-alcoholic steatohepatitis.
  • the method for treating fatty liver disease according to the present invention includes the step of administering the hydrogen-carrying powder as an active ingredient to a patient with fatty liver disease.
  • the amount of the fatty liver disease inhibitor according to the present invention to be used should be appropriately adjusted depending on the condition, age, sex, etc. of the recipient, and is not particularly limited.
  • the amount of the fatty liver disease inhibitor according to the present invention may be adjusted as appropriate within the range where the fatty liver disease inhibitory effect is observed. It can be administered about once or more and about 5 times or less per day, so that the amount is about 100 mg or more and 5 g or less per day.
  • Subjects to whom the fatty liver disease inhibitor of the present invention should be administered include humans as well as non-human animals such as pets.
  • the dosage form of the fatty liver disease inhibitor according to the present invention is not particularly limited, but can be, for example, an internal medicine such as a tablet, capsule, liquid, granule, powder, syrup, or aerosol.
  • the fatty liver disease inhibitor according to the present invention may contain various additive components depending on the dosage form. For example, base materials, excipients, colorants, lubricants, flavoring agents, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizing agents, suspending agents, surfactants, Oxidizing agents, adjuvants, buffers, pH adjusters, sweeteners, flavors, etc. can be added.
  • the blending amount of these additives can be appropriately set as necessary, as long as the amount does not interfere with the effects of the present invention.
  • other medicinal ingredients may be added. It is preferably an oral formulation.
  • the fatty liver disease inhibitor according to the present invention may be an enteric-coated capsule containing a hydrogen-carrying powder.
  • the fatty liver disease inhibitor of the present invention can effectively suppress fatty liver disease caused by excessive intake of food. Furthermore, for example, even if the ratio of fatty cells to all hepatocytes once increases, it is possible to reduce that ratio. That is, the fatty liver disease inhibitor according to the present invention is not only a fatty liver disease preventive agent that suppresses the occurrence of fatty liver disease by constant intake, but also a fatty liver disease preventive agent that suppresses the occurrence of fatty liver disease once it has occurred. This concept also includes therapeutic agents for fatty liver disease. Therefore, the fatty liver disease inhibitor of the present invention can also be used constantly and continuously as a health food having a preventive effect on fatty liver disease.
  • Example 1 Treatment 54 6-month-old male F344 rats were arbitrarily divided into an untreated group (12 rats), a control group (20 rats), and a hydrogen-carrying powder administration group (22 rats). The administration group was fasted from 2 days before the start of the experiment. Next, the control group and the hydrogen-carrying powder administration group were given ad libitum feed for 3 days with no methionine/choline additives (manufactured by Nippon Clea Co., Ltd.), which can produce symptoms similar to those of non-alcoholic steatohepatitis (NASH). The animals were given normal feed ad libitum for the next 3 days.
  • Nippon Clea Co., Ltd. no methionine/choline additives
  • the hydrogen-carrying powder administration group received a suspension of hydrogen-carrying powder (manufactured by Acche) in purified water at 300 mg/kg of body weight.
  • the drug was administered intragastrically using a probe once a day for 6 days.
  • the untreated group was given free access to normal feed throughout the experimental period.
  • 12 animals from the untreated group, 10 animals from the control group, and 11 animals from the hydrogen-carrying powder administration group were randomly selected and euthanized with isoflurane, and on the 7th day from the start of the experiment.
  • the remaining rats were euthanized with isoflurane, weighed, the liver was removed and weighed, blood samples were collected, and serum was separated.
  • FIG. 1 shows the liver weight/body weight ratio of each group.
  • “*” indicates that a significant difference was observed at p ⁇ 0.05 in the Student t test
  • "**” indicates that a significant difference was observed at p ⁇ 0.01
  • "***” indicates that a significant difference was observed at p ⁇ 0.001
  • "****” indicates that a significant difference was observed at p ⁇ 0.0001
  • "D3" and “"D7” indicates mice on the 3rd and 7th day from the start of the experiment, respectively
  • “H 2 " indicates mice in the hydrogen-carrying powder administration group.
  • the ratio of liver weight to body weight increased significantly in the control group administered the methionine/choline-free feed compared to the untreated group, but in the control group administered the methionine/choline-free feed, the ratio of liver weight to body weight increased significantly compared to the untreated group. In the control group, the ratio of liver weight to body weight was significantly reduced, indicating that liver enlargement was significantly suppressed.
  • the serum AST (aspart aminotransferase) concentration of each group is shown in FIG. 2. As shown in the results shown in FIG. 2, the serum AST concentration was significantly higher in the control group to which methionine/choline-free feed was administered than in the untreated group. The reason for this is thought to be that the hepatocytes were destroyed and AST in the cells leaked into the blood. However, in the group that ingested the hydrogen-carrying powder according to the present invention, the serum AST concentration was significantly reduced compared to the control group, indicating that the destruction of hepatocytes was significantly suppressed.
  • the serum TC (total cholesterol) concentration of each group is shown in FIG.
  • the serum TC concentration was significantly higher in the control group to which methionine/choline-free feed was administered than in the untreated group. The reason for this is thought to be that the methionine/choline-free feed disrupted liver function and the metabolism in the liver was no longer carried out normally.
  • the serum TC concentration was significantly reduced compared to the control group, indicating that the liver function was close to normal.
  • SREBP-1c is a transcription factor that controls the synthesis of fatty acids and triglycerides in the liver. Increased expression and activation of SREBP-1c leads to the expression of fatty acid and triglyceride synthases, which are response genes, and the energy intake is reduced from fat. It is stored as Activation of SREBP-1c in the liver has been reported in insulin resistance model animals.
  • FIG. 4 shows the relative ratio of SREBP-1c gene mRNA expression level in liver tissue to that of the untreated group.
  • FIG. 5 shows the relative ratio of Leptin R gene mRNA expression level in liver tissue to that of the untreated group.
  • the expression of the leptin receptor gene in the liver was significantly increased in the control group due to the intake of the methionine/choline-free feed, whereas the expression of the leptin receptor gene in the liver was significantly increased in the control group. It is significantly suppressed compared to the group. Therefore, it is thought that the hydrogen-carrying powder according to the present invention can suppress fat accumulation and progression of fatty liver disease.
  • FIG. 6 shows the relative ratio of the expression level of TNF- ⁇ gene mRNA in liver tissue to that of the untreated group.
  • the blood TNF- ⁇ concentration increased significantly in the control group due to the intake of the regular feed following the methionine/choline-free feed, but in the group that ingested the hydrogen-carrying powder according to the present invention.
  • TNF- ⁇ concentration was significantly reduced compared to the control group. Since TNF- ⁇ is involved in inflammation, it is possible that hepatitis was suppressed by the hydrogen-carrying powder.
  • CCR2 CC chemokine receptor 2 CCR2
  • CC chemokine ligand 2 CCR2 CC chemokine receptor 2 (CCR2) and CC chemokine ligand 2 are involved in macrophage infiltration into the liver, and infiltrated macrophages are important for the production of TNF- ⁇ and the formation of pathological conditions by inducing Th1 cells. It is also known that CCR2 and CCR5 increase in the blood of hepatitis patients.
  • FIG. 7 shows the relative ratio of CCR2 gene mRNA expression level in liver tissue to that of the untreated group. As shown in FIG.
  • the blood CCR2 concentration increased significantly in the control group due to the intake of the normal feed following the methionine/choline-free feed, but the CCR2 concentration in the group ingesting the hydrogen-carrying powder according to the present invention increased significantly.
  • the concentration was significantly reduced compared to the control group. Since CCR2 is involved in hepatitis, it is possible that hepatitis was suppressed by the hydrogen-carrying powder.

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Abstract

The purpose of the present invention is to provide a fatty liver disease inhibitor that exhibits excellent fatty liver disease inhibitory action while being considered to be safe and less harmful. A fatty liver disease inhibitor according to the present invention is characterized by containing, as an active ingredient, hydrogen-carrying powder that has an average particle diameter of 1-100 μm, that contains calcium magnesium carbonate, and that generates hydrogen gas of 0.1-100 μL per 1 g by contact with moisture.

Description

脂肪性肝疾患抑制剤Fatty liver disease inhibitor
　本発明は、安全で害が少ないと考えられる一方で優れた脂肪性肝疾患抑制作用を示す脂肪性肝疾患抑制剤に関するものである。 The present invention relates to a fatty liver disease inhibitor that is considered to be safe and has little harm while exhibiting an excellent fatty liver disease inhibitory effect.
　肝臓中に脂肪が過度に蓄積する脂肪肝の患者数は増加傾向にある。脂肪肝はかつて良性の疾患と考えられていたが、肝線維化や肝がんに進行し得る非アルコール性脂肪性肝炎（ＮＡＳＨ：Ｎｏｎ－Ａｌｃｏｈｏｌ　ＳｔｅａｔｏＨｅｐａｔｉｔｉｓ）が知られるようになり、脂肪肝に対する認識が大きく変化した。近年、糖質がコカインよりも中毒を引き起こし易いとの実験結果が公表されている一方で、果糖ブドウ糖液糖が清涼飲料水などに大量に用いられるようになってきており、過栄養性のＮＡＳＨが大きな問題になっている。しかし、ＮＡＳＨに対する薬剤治療は確立しておらず、食事療法や運動療法に大きく依存しているのが現状である。 The number of patients with fatty liver disease, in which fat accumulates excessively in the liver, is on the rise. Fatty liver was once thought to be a benign disease, but as non-alcoholic steatohepatitis (NASH), which can progress to liver fibrosis and liver cancer, has become known, awareness of fatty liver has changed. has changed significantly. In recent years, experimental results have been published showing that carbohydrates are more likely to cause addiction than cocaine, while high-fructose glucose corn syrup has come to be used in large quantities in soft drinks and other beverages, leading to hypernutritional NASH. has become a big problem. However, drug treatment for NASH has not been established, and currently it is largely dependent on diet therapy and exercise therapy.
　現在、脂肪肝治療の保険薬として我国で認可されているのはポリエンフォスファチジルコリン製剤（ＥＰＬ）のみである。ＥＰＬの作用機序としては、ＥＰＬの摂取により肝臓でのトリグリセリドの輸送や燃焼が促進される結果、脂肪肝の抑制に繋がると考えられている。しかしながらＥＰＬによる薬剤治療は、脂肪肝の原因である原疾患の治療や食事療法、運動療法に加えて行われる補足的な治療方法として認識されている。ＥＰＬは１９６０年代に販売が開始された古典的な薬剤であるにもかかわらず、ＮＡＳＨが問題になってきたのは最近であることからも、ＥＰＬの効果が十分でないことが分かる。 Currently, only polyene phosphatidylcholine preparation (EPL) is approved in Japan as an insurance drug for the treatment of fatty liver. As for the mechanism of action of EPL, it is thought that ingestion of EPL promotes the transport and combustion of triglycerides in the liver, leading to the suppression of fatty liver. However, drug treatment using EPL is recognized as a complementary treatment method in addition to treatment of the primary disease causing fatty liver, diet therapy, and exercise therapy. Although EPL is a classic drug that was first marketed in the 1960s, the fact that NASH has only recently become a problem shows that EPL is not sufficiently effective.
　脂肪肝の治療薬としては、インスリン抵抗性や糖尿病治療用の薬剤が利用されることがある。例えば特許文献１には、脂肪肝の治療薬としてＰＰＡＲα（ペルオキソーム増殖因子活性化レセプターα；Ｐｅｒｏｘｉｓｏｍｅ　ｐｒｏｌｉｆｅｒａｔｏｒ－ａｃｔｉｖａｔｅｄ　ｒｅｃｅｐｔｏｒ　α）活性化剤が開示されている。ところがこのような薬剤は、糖尿病自体の治療などにも使われる合成医薬品であり副作用も強いと考えられる。例えば、特許文献１にＰＰＡＲα活性化剤として挙げられているフェノフィブラートには、かえって肝肥大などの副作用が知られている。 Drugs for treating insulin resistance and diabetes are sometimes used as therapeutic drugs for fatty liver. For example, Patent Document 1 discloses a PPARα (peroxisome proliferator-activated receptor α) activator as a therapeutic agent for fatty liver. However, these drugs are synthetic drugs that are also used to treat diabetes itself, and are thought to have strong side effects. For example, fenofibrate, which is listed as a PPARα activator in Patent Document 1, is known to have side effects such as hepatomegaly.
　また、肝臓は沈黙の臓器といわれるように、特に各疾患の初期にはほとんど自覚症状がない。脂肪肝の場合も初期には自覚症状がなく、進行に伴って、疲れ易い、体がだるい、食欲不振といった肝臓疾患の一般的症状があらわれるが、肝臓疾患と自覚することは少なく、風邪などと勘違いして放置することによりさらに悪化させることも多い。よって、安全なものであり、予防的な使用も可能な薬剤が好ましいといえる。 Also, the liver is said to be a silent organ, and there are almost no symptoms, especially in the early stages of each disease. In the case of fatty liver, there are no symptoms in the early stages, but as it progresses, common symptoms of liver disease such as getting tired easily, feeling sluggish, and loss of appetite appear. Misunderstanding it and leaving it untreated often makes it worse. Therefore, it can be said that a drug that is safe and can be used prophylactically is preferable.
　ところで、近年、体内の活性酸素が、炎症、アレルギー反応、生活習慣病の原因の一つであると指摘されていることから、還元作用を有する水素を含む水素水が健康食品として販売されている。しかし、２０℃、１気圧における水に対する水素の溶解度は僅か１．６２ｐｐｍであり、効果を十分に発揮できる量の水素を水が含んでいるとは言い難い。それに対して、本発明者らは、優れた水素発生能を有する水素担持粉末を開発している（特許文献２）。 By the way, in recent years, it has been pointed out that active oxygen in the body is one of the causes of inflammation, allergic reactions, and lifestyle-related diseases, so hydrogen water containing hydrogen that has a reducing effect has been sold as a health food. . However, the solubility of hydrogen in water at 20° C. and 1 atm is only 1.62 ppm, and it is difficult to say that water contains enough hydrogen to be effective. In response, the present inventors have developed a hydrogen-supporting powder that has excellent hydrogen generation ability (Patent Document 2).
特開２００２－２２０３４５号公報Japanese Patent Application Publication No. 2002-220345 特許第６３３７１９２号公報Patent No. 6337192
　上述したように、水素を含むことが謳われている健康食品は販売されている。しかし、従来の水素を含む健康食品の摂取により、水素が体内の問題箇所に送達され、還元作用を有効に発揮できるか否かは不明である。
　そこで本発明は、安全で害が少ないと考えられる一方で優れた脂肪性肝疾患抑制作用を示す脂肪性肝疾患抑制剤を提供することを目的とする。 As mentioned above, health foods that claim to contain hydrogen are on the market. However, it is unclear whether hydrogen can be delivered to problem areas in the body and effectively exert a reducing effect by ingesting conventional health foods containing hydrogen.
Therefore, an object of the present invention is to provide a fatty liver disease inhibitor that is considered to be safe and has little harm, while exhibiting an excellent fatty liver disease inhibitory effect.
　本発明者らは、上記課題を解決するために鋭意研究を重ねた。その結果、本発明者らが開発している水素担持粉末が、経口投与により脂肪性肝疾患を有効に抑制できることを見出して、本発明を完成した。
　以下、本発明を示す。 The present inventors have conducted extensive research in order to solve the above problems. As a result, the present inventors have discovered that the hydrogen-carrying powder developed by the present inventors can effectively suppress fatty liver disease when administered orally, and have completed the present invention.
The present invention will be described below.
　［１］　平均粒子径が１μｍ以上、１００μｍ以下であり、炭酸カルシウムマグネシウムを含み、且つ水分と接触することにより１ｇあたり０．１μＬ以上、１００μＬ以下の水素ガスを発生する水素担持粉末を有効成分として含むことを特徴とする脂肪性肝疾患抑制剤。
　［２］　前記脂肪性肝疾患が非アルコール性脂肪性肝炎である前記［１］に記載の脂肪性肝疾患抑制剤。
　［３］　前記水素担持粉末が、赤外分光分析において、５００ｃｍ-1以上、６００ｃｍ-1以下および９００ｃｍ-1以上、１０００ｃｍ-1以下に吸収を有する前記［１］または［２］に記載の脂肪性肝疾患抑制剤。
　［４］　前記水素担持粉末が７０質量％以上の炭酸カルシウムマグネシウムを含む前記［１］～［３］のいずれかに記載の脂肪性肝疾患抑制剤。
　［５］　前記水素担持粉末に接触した水分の酸化還元電位が－４００ｍＶ以上、－３０ｍＶ以下である前記［１］～［４］のいずれかに記載の脂肪性肝疾患抑制剤。
　［６］　経口投与されるものである前記［１］～［５］のいずれかに記載の脂肪性肝疾患抑制剤。 [1] As an active ingredient, a hydrogen-carrying powder that has an average particle size of 1 μm or more and 100 μm or less, contains calcium magnesium carbonate, and generates hydrogen gas of 0.1 μL or more and 100 μL or less per gram upon contact with moisture. A fatty liver disease inhibitor characterized by comprising:
[2] The fatty liver disease inhibitor according to the above [1], wherein the fatty liver disease is non-alcoholic steatohepatitis.
[3] The fat according to [1] or [2] above, wherein the hydrogen-supported powder has an absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopic analysis. Sexual liver disease inhibitor.
[4] The fatty liver disease inhibitor according to any one of [1] to [3] above, wherein the hydrogen-carrying powder contains 70% by mass or more of calcium magnesium carbonate.
[5] The fatty liver disease inhibitor according to any one of [1] to [4] above, wherein the redox potential of water in contact with the hydrogen-supported powder is -400 mV or more and -30 mV or less.
[6] The fatty liver disease inhibitor according to any one of [1] to [5] above, which is orally administered.
　［７］　脂肪性肝疾患を治療するための、平均粒子径が１μｍ以上、１００μｍ以下であり、炭酸カルシウムマグネシウムを含み、且つ水分と接触することにより１ｇあたり０．１μＬ以上、１００μＬ以下の水素ガスを発生する水素担持粉末の使用。
　［８］　前記脂肪性肝疾患が非アルコール性脂肪性肝炎である前記［７］に記載の使用。
　［９］　前記水素担持粉末が、赤外分光分析において、５００ｃｍ-1以上、６００ｃｍ-1以下および９００ｃｍ-1以上、１０００ｃｍ-1以下に吸収を有する前記［７］または［８］に記載の使用。
　［１０］　前記水素担持粉末が７０質量％以上の炭酸カルシウムマグネシウムを含む前記［７］～［９］のいずれかに記載の使用。
　［１１］　前記水素担持粉末に接触した水分の酸化還元電位が－４００ｍＶ以上、－３０ｍＶ以下である前記［７］～［１０］のいずれかに記載の使用。
　［１２］　前記水素担持粉末が経口投与されるものである前記［７］～［１１］のいずれかに記載の使用。 [7] For treating fatty liver disease, the average particle size is 1 μm or more and 100 μm or less, contains calcium magnesium carbonate, and produces hydrogen gas of 0.1 μL or more and 100 μL or less per 1 g upon contact with water. The use of hydrogen-carrying powder to generate
[8] The use according to [7] above, wherein the fatty liver disease is non-alcoholic steatohepatitis.
[9] The use according to [7] or [8] above, wherein the hydrogen-supported powder has absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopic analysis. .
[10] The use according to any one of [7] to [9], wherein the hydrogen-supported powder contains 70% by mass or more of calcium magnesium carbonate.
[11] The use according to any one of [7] to [10] above, wherein the oxidation-reduction potential of water in contact with the hydrogen-supported powder is -400 mV or more and -30 mV or less.
[12] The use according to any one of [7] to [11] above, wherein the hydrogen-carrying powder is orally administered.
　［１３］　脂肪性肝疾患を治療するための方法であって、平均粒子径が１μｍ以上、１００μｍ以下であり、炭酸カルシウムマグネシウムを含み、且つ水分と接触することにより１ｇあたり０．１μＬ以上、１００μＬ以下の水素ガスを発生する水素担持粉末を有効成分として脂肪性肝疾患の患者に投与する工程を含むことを特徴とする方法。
　［１４］　前記脂肪性肝疾患が非アルコール性脂肪性肝炎である前記［１３］に記載の方法。
　［１５］　前記水素担持粉末が、赤外分光分析において、５００ｃｍ-1以上、６００ｃｍ-1以下および９００ｃｍ-1以上、１０００ｃｍ-1以下に吸収を有する前記［１３］または［１４］に記載の方法。
　［１６］　前記水素担持粉末が７０質量％以上の炭酸カルシウムマグネシウムを含む前記［１３］～［１５］のいずれかに記載の方法。
　［１７］　前記水素担持粉末に接触した水分の酸化還元電位が－４００ｍＶ以上、－３０ｍＶ以下である前記［１３］～［１６］のいずれかに記載の方法。
　［１８］　前記水素担持粉末を経口投与する前記［１３］～［１７］のいずれかに記載の方法。 [13] A method for treating fatty liver disease, which has an average particle diameter of 1 μm or more and 100 μm or less, contains calcium magnesium carbonate, and produces 0.1 μL or more and 100 μL per 1 g upon contact with water. A method characterized by comprising the step of administering the following hydrogen-carrying powder that generates hydrogen gas as an active ingredient to a patient suffering from fatty liver disease.
[14] The method according to [13] above, wherein the fatty liver disease is non-alcoholic steatohepatitis.
[15] The method according to [13] or [14], wherein the hydrogen-supported powder has absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopic analysis. .
[16] The method according to any one of [13] to [15], wherein the hydrogen-supported powder contains 70% by mass or more of calcium magnesium carbonate.
[17] The method according to any one of [13] to [16], wherein the oxidation-reduction potential of the water in contact with the hydrogen-supported powder is -400 mV or more and -30 mV or less.
[18] The method according to any one of [13] to [17], wherein the hydrogen-carrying powder is orally administered.
　本発明に係る脂肪性肝疾患抑制剤は、食品やサプリメントにも配合されている炭酸カルシウムマグネシウムを主成分とする水素担持粉末を有効成分とするものであることから安全性に優れ、毎日の服用も可能である。また、本発明で用いる水素担持粉末は、優れた水素ガス発生能を示すことから、本発明に係る脂肪性肝疾患抑制剤は、極めて優れた脂肪性肝疾患抑制作用を示す。また、本発明者らによる実験的知見によれば、本発明に係る脂肪性肝疾患抑制剤の経口摂取により、脂肪性肝疾患を有効に抑制できることが認められている。従って、本発明に係る脂肪性肝疾患抑制剤は、服用者に苦痛を感じさせることなく、脂肪性肝疾患を効果的に抑制できるものとして、非常に有用である。 The fatty liver disease inhibitor according to the present invention has excellent safety because its active ingredient is a hydrogen-carrying powder whose main ingredient is calcium magnesium carbonate, which is also included in foods and supplements, and it is recommended for daily administration. is also possible. Further, since the hydrogen-carrying powder used in the present invention exhibits an excellent ability to generate hydrogen gas, the fatty liver disease inhibitor according to the present invention exhibits an extremely excellent fatty liver disease inhibitory effect. Furthermore, according to the experimental findings of the present inventors, it has been recognized that fatty liver disease can be effectively suppressed by oral intake of the fatty liver disease inhibitor according to the present invention. Therefore, the fatty liver disease inhibitor according to the present invention is very useful as it can effectively suppress fatty liver disease without causing pain to the recipient.
図１は、未処置群ラット、対照群ラット、及び本発明に係る水素担持粉末摂取群ラットの体重に対する肝臓重量比を示すグラフである。FIG. 1 is a graph showing the ratio of liver weight to body weight of rats in the untreated group, rats in the control group, and rats in the group ingesting the hydrogen-carrying powder according to the present invention. 図２は、未処置群ラット、対照群ラット、及び本発明に係る水素担持粉末摂取群ラットの血清中ＡＳＴ濃度を示すグラフである。FIG. 2 is a graph showing serum AST concentrations of untreated rats, control rats, and rats ingesting the hydrogen-carrying powder according to the present invention. 図３は、未処置群ラット、対照群ラット、及び本発明に係る水素担持粉末摂取群ラットの血清中総コレステロール濃度を示すグラフである。FIG. 3 is a graph showing the serum total cholesterol concentration of rats in the untreated group, rats in the control group, and rats ingested with the hydrogen-carrying powder according to the present invention. 図４は、未処置群ラット、対照群ラット、及び本発明に係る水素担持粉末摂取群ラットの未処置群ラットに対する肝臓組織中ＳＲＥＢＰ－１ｃ遺伝子ｍＲＮＡ発現量の相対比を示すグラフである。FIG. 4 is a graph showing the relative ratio of SREBP-1c gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats. 図５は、未処置群ラット、対照群ラット、及び本発明に係る水素担持粉末摂取群ラットの未処置群ラットに対する肝臓組織中Ｌｅｐｔｉｎ　Ｒ遺伝子ｍＲＮＡ発現量の相対比を示すグラフである。FIG. 5 is a graph showing the relative ratio of Leptin R gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats. 図６は、未処置群ラット、対照群ラット、及び本発明に係る水素担持粉末摂取群ラットの未処置群ラットに対する肝臓組織中ＴＮＦ－α遺伝子ｍＲＮＡ発現量の相対比を示すグラフである。FIG. 6 is a graph showing the relative ratio of TNF-α gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats. 図７は、未処置群ラット、対照群ラット、及び本発明に係る水素担持粉末摂取群ラットの未処置群ラットに対する肝臓組織中ＣＣＲ２遺伝子ｍＲＮＡ発現量の相対比を示すグラフである。FIG. 7 is a graph showing the relative ratio of CCR2 gene mRNA expression levels in liver tissues of untreated rats, control rats, and rats ingested with the hydrogen-carrying powder according to the present invention to untreated rats.
　本発明に係る脂肪性肝疾患抑制剤は、水素担持粉末を有効成分として含む。水素担持粉末の平均粒子径としては、１μｍ以上、１００μｍ以下が好ましい。当該平均粒子径が１００μｍ以下であれば、水素担持粉末の比表面積は十分に大きく、水素を有効に吸着できると考えられる。また、１μｍ以上であれば、粉砕のために過剰なエネルギーが必要無い。当該平均粒子径としては、５μｍ以上がより好ましく、１０μｍ以上がより更に好ましく、また、５０μｍ以下がより好ましく、２０μｍ以下がより更に好ましい。なお、本開示において平均粒子径は、レーザー回折式粒度分布測定装置により測定するものとし、平均粒子径の基準としては、体積基準、重量基準、数基準などがあるが、体積基準が好ましい。 The fatty liver disease inhibitor according to the present invention contains hydrogen-carrying powder as an active ingredient. The average particle diameter of the hydrogen-supported powder is preferably 1 μm or more and 100 μm or less. If the average particle diameter is 100 μm or less, the specific surface area of the hydrogen-supported powder is sufficiently large, and it is considered that hydrogen can be effectively adsorbed. Further, if the particle size is 1 μm or more, excessive energy is not required for crushing. The average particle diameter is more preferably 5 μm or more, even more preferably 10 μm or more, more preferably 50 μm or less, and even more preferably 20 μm or less. Note that in the present disclosure, the average particle diameter is measured using a laser diffraction particle size distribution analyzer, and the average particle diameter is based on a volume basis, a weight basis, a number basis, etc., but a volume basis is preferable.
　水素担持粉末の主成分としては、炭酸カルシウムマグネシウムが好ましい。炭酸カルシウムにおけるカルシウムの一部がマグネシウムに置換されることで、カルシウムとマグネシウムのイオン半径が異なることにより置換後の構造に歪みが生じ、水素担持可能なサイトが増加することによって、マグネシウムを含まない純粋な炭酸カルシウムに比べて水素担持量がより多い粉末が得られると考えられる。 As the main component of the hydrogen-carrying powder, calcium magnesium carbonate is preferable. When some of the calcium in calcium carbonate is replaced with magnesium, the ionic radius of calcium and magnesium differs, causing distortion in the structure after substitution, and increasing the number of sites that can support hydrogen, resulting in a structure that does not contain magnesium. It is believed that a powder with a higher hydrogen carrying amount than pure calcium carbonate can be obtained.
　炭酸カルシウムマグネシウムにおけるＣａ：Ｍｇ比は、好ましくは３０：７０～９９：１、より好ましくは４０：６０～９８：２であり、更に好ましくは６０：４０～９５：５である。十分量の水素の担持のためにＭｇは必要であるが、Ｍｇ比が低い程、水素担持量は増加する傾向にある。 The Ca:Mg ratio in calcium magnesium carbonate is preferably 30:70 to 99:1, more preferably 40:60 to 98:2, and even more preferably 60:40 to 95:5. Although Mg is necessary to support a sufficient amount of hydrogen, the lower the Mg ratio, the more the amount of hydrogen supported tends to increase.
　炭酸カルシウムマグネシウムは、例えば、式（１）で表される構造、好ましくは式（２）で表される構造および式（３）で表される構造の少なくとも一方、より好ましくは式（２）で表される構造および式（３）で表される構造の両方を含んでいることが好ましい。
　　（ＭｇxＣａy）ＣＯ3　・・・　（１）
［式中、０．０１≦ｘ≦０．１５、０．８５≦ｙ≦０．９９であり、ｘ＋ｙ＝１であり、ｘとしては、０．０２以上、０．１４以下が好ましく、ｙとしては、０．８６以上、０．９８以下が好ましい。］ Calcium magnesium carbonate has, for example, a structure represented by formula (1), preferably at least one of a structure represented by formula (2) and a structure represented by formula (3), more preferably a structure represented by formula (2). It is preferable that it contains both the structure represented by the formula (3) and the structure represented by the formula (3).
(Mg x Ca y ) CO 3 ... (1)
[In the formula, 0.01≦x≦0.15, 0.85≦y≦0.99, x+y=1, x is preferably 0.02 or more and 0.14 or less, and y is is preferably 0.86 or more and 0.98 or less. ]
　式（１）は、好ましくは式（２）または式（３）である。
　　（Ｍｇx2Ｃａy2）ＣＯ3　・・・　（２）
［式中、０．０１≦ｘ２≦０．０５、０．９５≦ｙ２≦０．９９であり、ｘ２＋ｙ２＝１であり、ｘ２としては、０．０２以上、０．０４以下が好ましく、ｙ２としては、０．９６以上、０．９８以下が好ましい。］
　　（Ｍｇx3Ｃａy3）ＣＯ3　・・・　（３）
［式中、０．０５＜ｘ３≦０．１５、０．８５≦ｙ３＜０．９５であり、ｘ３＋ｙ３＝１であり、ｘ３としては、０．１０以上、０．１４以下が好ましく、ｙ３としては、０．８６以上、０．９０以下が好ましい。］ Formula (1) is preferably formula (2) or formula (3).
(Mg x2 Ca y2 )CO 3 ... (2)
[In the formula, 0.01≦x2≦0.05, 0.95≦y2≦0.99, x2+y2=1, x2 is preferably 0.02 or more and 0.04 or less, and y2 is preferably 0.96 or more and 0.98 or less. ]
(Mg x3 Ca y3 )CO 3 ... (3)
[In the formula, 0.05<x3≦0.15, 0.85≦y3<0.95, x3+y3=1, x3 is preferably 0.10 or more and 0.14 or less, and y3 is preferably 0.86 or more and 0.90 or less. ]
　水素担持粉末１００質量％中、炭酸カルシウムマグネシウムの含有率としては、７０質量％以上が好ましく、８０質量％以上、８５質量％以上または９０質量％以上がより好ましく、９５質量％以上または９８質量％以上がより更に好ましく、１００質量％が特に好ましい。 The content of calcium magnesium carbonate in 100% by mass of the hydrogen carrying powder is preferably 70% by mass or more, more preferably 80% by mass or more, 85% by mass or more, or 90% by mass or more, 95% by mass or more or 98% by mass. The above is even more preferable, and 100% by mass is particularly preferable.
　水素担持粉末の組成は、例えば、赤外分光分析（ＩＲ）やＸ線回折（ＸＲＤ）により確認できる。具体的には、本発明で用いる水素担持粉末は、赤外分光分析において、５００ｃｍ-1以上、６００ｃｍ-1以下および９００ｃｍ-1以上、１０００ｃｍ-1以下に吸収を有することにより確認することができる。また、本発明で用いる水素担持粉末がカルシウムに加えてマグネシウムも含むことは、ＸＲＤにより確認することができる。 The composition of the hydrogen-supported powder can be confirmed by, for example, infrared spectroscopy (IR) or X-ray diffraction (XRD). Specifically, the hydrogen-supported powder used in the present invention can be confirmed by having absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopy. . Moreover, it can be confirmed by XRD that the hydrogen-supported powder used in the present invention also contains magnesium in addition to calcium.
　特に、サンゴ、貝類、真珠、有孔虫およびウミユリよりなる群から選択される少なくとも１種以上に由来する粉末は、炭酸カルシウムと炭酸カルシウムマグネシウムをバランス良く含むため、本発明の原料として最適である。 In particular, powder derived from at least one species selected from the group consisting of corals, shellfish, pearls, foraminifera, and crinoids contains calcium carbonate and calcium magnesium carbonate in a well-balanced manner, and is therefore optimal as a raw material for the present invention. .
　水素担持粉末は、腸溶性高分子によりコーティングされていたり、腸溶性高分子により顆粒化されたものであってもよい。腸溶性高分子とは、胃中の強酸性（ｐＨ１～２）では溶解せず、小腸における弱酸性から中性域（ｐＨ５～７）で溶解する高分子をいう。本発明では、水素は主に腸管から吸収されて肝臓に作用すると考えられるため、腸溶性高分子により胃における水素担持粉末からの水素の放出を抑制し、且つ小腸における水素担持粉末からの水素の放出を促進することができる。 The hydrogen-carrying powder may be coated with an enteric polymer or granulated with an enteric polymer. Enteric-coated polymers refer to polymers that do not dissolve in the strong acidity (pH 1-2) of the stomach, but dissolve in the weakly acidic to neutral range (pH 5-7) of the small intestine. In the present invention, since it is thought that hydrogen is mainly absorbed from the intestinal tract and acts on the liver, the enteric-coated polymer suppresses the release of hydrogen from the hydrogen-carrying powder in the stomach, and also suppresses the release of hydrogen from the hydrogen-carrying powder in the small intestine. release can be promoted.
　腸溶性高分子としては、特に制限されないが、例えば、ヒプロメロースフタル酸エステル、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、以下の（メタ）アクリレート単位（Ｉ）と、アルキル（メタ）アクリレート単位（ＩＩ）を含む（メタ）アクリレート共重合体が挙げられる。 Enteric polymers are not particularly limited, but include, for example, hypromellose phthalate, carboxymethylethyl cellulose, cellulose acetate phthalate, the following (meth)acrylate units (I), and alkyl (meth)acrylate units (II). ) (meth)acrylate copolymers containing.
Figure JPOXMLDOC01-appb-C000001
［式中、Ｒ1～Ｒ3は、独立して、ＨまたはＣ1-6アルキル基を示す。］
Figure JPOXMLDOC01-appb-C000001
[In the formula, R 1 to R 3 independently represent H or a C 1-6 alkyl group. ]
　「Ｃ1-6アルキル基」は、炭素数１以上、６以下の直鎖状または分枝鎖状の一価飽和脂肪族炭化水素基をいう。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ｎ－ペンチル、ｎ－ヘキシル等である。Ｒ1として好ましくはＣ1-4アルキル基であり、より好ましくはＣ1-2アルキル基であり、より更に好ましくはメチルである。Ｒ2として、好ましくはＨまたはＣ1-4アルキル基であり、より好ましくはＨまたはＣ1-2アルキル基であり、より更に好ましくはＨまたはメチルである。Ｒ3として好ましくはＣ1-4アルキル基であり、より好ましくはＣ1-2アルキル基である。 "C 1-6 alkyl group" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 1 or more and 6 or less carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like. R 1 is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, even more preferably methyl. R 2 is preferably H or a C 1-4 alkyl group, more preferably H or a C 1-2 alkyl group, even more preferably H or methyl. R 3 is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group.
　（メタ）アクリレート共重合体は、アルキル（メタ）アクリレート単位（ＩＩ）を１種のみ含んでいてもよいし、２種以上含んでいてもよい。当該数としては、５種以下が好ましく、３種以下がより好ましく、２種または１種がより更に好ましい。また、（メタ）アクリレート単位（Ｉ）とアルキル（メタ）アクリレート単位（ＩＩ）との比としては、例えば、（メタ）アクリレート単位（Ｉ）に対するアルキル（メタ）アクリレート単位（ＩＩ）のモル比を０．５以上、１．５以下に調整することが好ましい。当該モル比としては、０．８以上が好ましく、０．９以上がより好ましく、また、１．２以下が好ましく、１．１以下がより更に好ましい。 The (meth)acrylate copolymer may contain only one type of alkyl (meth)acrylate unit (II), or may contain two or more types. The number is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or 1. Further, as the ratio of the (meth)acrylate unit (I) to the alkyl (meth)acrylate unit (II), for example, the molar ratio of the alkyl (meth)acrylate unit (II) to the (meth)acrylate unit (I) is It is preferable to adjust it to 0.5 or more and 1.5 or less. The molar ratio is preferably 0.8 or more, more preferably 0.9 or more, preferably 1.2 or less, and even more preferably 1.1 or less.
　腸溶性高分子による水素担持粉末のコーティングや顆粒化は、常法により行うことができる。例えば、造粒乾燥機中、水素担持粉末を流動させつつ、腸溶性高分子の溶液または分散液を噴霧して乾燥することにより、水素担持粉末を腸溶性高分子によりコーティングしたり顆粒化することができる。 Coating and granulation of the hydrogen-carrying powder with enteric polymer can be performed by conventional methods. For example, by spraying and drying a solution or dispersion of an enteric polymer while fluidizing the hydrogen-carrying powder in a granulation dryer, the hydrogen-carrying powder may be coated with an enteric polymer or granulated. Can be done.
　本発明で用いる水素担持粉末は、優れた水素発生能を有する。具体的には、密閉容器に水と共に水素担持粉末を入れ、３５℃で２４時間振盪した場合における密閉容器の気相中における水素濃度から下記式により求められる、水素担持粉末１ｇあたりの水素発生量が、０．１μＬ以上、１００μＬ以下である。腸溶性高分子でコーティングまたは顆粒化された水素担持粉末の水素発生能を試験する場合には、水の代わりに日本薬局方の溶出試験第２液（ｐＨ６．８）を用いてもよい。当該水素発生量としては、０．２μＬ以上がより好ましく、０．３μＬ以上がより更に好ましく、また、５０μＬ以下がより好ましい。
　　水素担持粉末１ｇあたりの水素ガスの発生量（μＬ／ｇ）＝Ａ×２５×１０-3／３
［式中、Ａは密閉容器の気相中の水素ガス濃度（ｐｐｍ）を示す。］ The hydrogen-carrying powder used in the present invention has excellent hydrogen generation ability. Specifically, the amount of hydrogen generated per 1 g of hydrogen-supported powder is calculated from the hydrogen concentration in the gas phase of the closed container when the hydrogen-supported powder is put in a closed container together with water and shaken at 35°C for 24 hours. is 0.1 μL or more and 100 μL or less. When testing the hydrogen generation ability of a hydrogen-carrying powder coated or granulated with an enteric polymer, the Japanese Pharmacopoeia's elution test second liquid (pH 6.8) may be used instead of water. The amount of hydrogen generated is more preferably 0.2 μL or more, even more preferably 0.3 μL or more, and even more preferably 50 μL or less.
Amount of hydrogen gas generated per 1g of hydrogen-supported powder (μL/g) = A x 25 x 10 -3 /3
[In the formula, A represents the hydrogen gas concentration (ppm) in the gas phase of the closed container. ]
　本発明で用いる水素担持粉末が水分と接触した場合、その水分の酸化還元電位としては、－４００ｍＶ以上、－３０ｍＶ以下が好ましい。当該酸化還元電位がこの範囲にあれば、水素担持粉末により還元作用が有効に発揮され、炎症などが抑制されると考えられる。当該酸化還元電位としては、－３５０ｍＶ以上がより好ましく、－３００ｍＶ以上がより更に好ましく、また、－７０ｍＶ以下または－１００ｍＶ以下がより好ましく、－１５０ｍＶ以下がより更に好ましい。 When the hydrogen-supported powder used in the present invention comes into contact with moisture, the oxidation-reduction potential of the moisture is preferably -400 mV or more and -30 mV or less. If the redox potential is within this range, it is thought that the hydrogen-carrying powder effectively exerts its reducing action and suppresses inflammation and the like. The redox potential is more preferably -350 mV or more, even more preferably -300 mV or more, more preferably -70 mV or less, or -100 mV or less, even more preferably -150 mV or less.
　上記の特性を有する水素担持粉末は、例えば、温度が４５０℃超、９００℃以下、水素濃度が５ｖｏｌ％以上、１００ｖｏｌ％以下、且つ圧力が０．１ＭＰａ以上、１．５ＭＰａ以下であるガス雰囲気下において、炭酸カルシウムマグネシウム含有粉末を熱処理して水素担持粉末前駆体を製造する高温処理工程、及び、温度が１５０℃以上、４００℃以下、水素濃度が５ｖｏｌ％以上、１００ｖｏｌ％以下、且つ圧力が０．１ＭＰａ以上、１．５ＭＰａ以下であるガス雰囲気下において、水素担持粉末前駆体を熱処理して水素担持粉末を製造する低温処理工程を含む方法により製造することができる。 The hydrogen-supported powder having the above characteristics can be used, for example, in a gas atmosphere where the temperature is above 450°C and below 900°C, the hydrogen concentration is between 5 vol% and 100 vol%, and the pressure is between 0.1 MPa and 1.5 MPa. , a high-temperature treatment step in which a calcium magnesium carbonate-containing powder is heat-treated to produce a hydrogen-supported powder precursor; It can be produced by a method including a low temperature treatment step of heat-treating a hydrogen-supported powder precursor to produce a hydrogen-supported powder in a gas atmosphere of .1 MPa or more and 1.5 MPa or less.
　高温処理工程における温度は、好ましくは５００℃以上、より好ましくは５５０℃以上、更に好ましくは６００℃以上であり、酸化還元電位を下げるためには、好ましくは６８０℃以上であり、好ましくは８８０℃以下、より好ましくは８６０℃以下であり、水分との接触による水素ガスの発生量を増やすためには、好ましくは６５０℃以下である。前記温度が高くなる程、酸化還元電位は下がる傾向にあり、一方で前記温度が低くなる程、水素ガスの発生量は増える傾向にある。 The temperature in the high temperature treatment step is preferably 500°C or higher, more preferably 550°C or higher, even more preferably 600°C or higher, and in order to lower the redox potential, preferably 680°C or higher, preferably 880°C. Below, the temperature is more preferably 860°C or lower, and in order to increase the amount of hydrogen gas generated by contact with moisture, the temperature is preferably 650°C or lower. As the temperature increases, the redox potential tends to decrease, while as the temperature decreases, the amount of hydrogen gas generated tends to increase.
　低温処理工程における温度は、好ましくは１６０℃以上、より好ましくは１８０℃以上、更に好ましくは２００℃以上であり、好ましくは３８０℃以下、より好ましくは３６０℃以下であり、水分との接触よる水素ガスの発生量を増やすためには、好ましくは２５０℃以下である。前記温度が高くなる程、酸化還元電位は下がる傾向にあり、一方で前記温度が低くなる程、水素ガスの発生量は増える傾向にある。 The temperature in the low-temperature treatment step is preferably 160°C or higher, more preferably 180°C or higher, even more preferably 200°C or higher, and preferably 380°C or lower, more preferably 360°C or lower. In order to increase the amount of gas generated, the temperature is preferably 250°C or lower. As the temperature increases, the redox potential tends to decrease, while as the temperature decreases, the amount of hydrogen gas generated tends to increase.
　高温処理工程および低温処理工程は水素ガスを含むガス雰囲気下で実施され、前記ガス雰囲気中、高温処理工程および低温処理工程における水素濃度は、それぞれ、好ましくは２０ｖｏｌ％以上、より好ましくは５０ｖｏｌ％以上、更に好ましくは８０ｖｏｌ％以上、より更に好ましくは９０ｖｏｌ％以上であり、特に好ましくは１００ｖｏｌ％である。前記ガス雰囲気中、水素ガス以外の残部としては、窒素、アルゴン、二酸化炭素などの不活性ガスが好ましい。 The high temperature treatment step and the low temperature treatment step are performed in a gas atmosphere containing hydrogen gas, and the hydrogen concentration in the high temperature treatment step and the low temperature treatment step in the gas atmosphere is preferably 20 vol% or more, more preferably 50 vol% or more. , more preferably 80 vol% or more, even more preferably 90 vol% or more, particularly preferably 100 vol%. In the gas atmosphere, the remainder other than hydrogen gas is preferably an inert gas such as nitrogen, argon, or carbon dioxide.
　高温処理工程および低温処理工程における圧力は、それぞれ、好ましくは０．２ＭＰａ以上、より好ましくは０．３ＭＰａ以上、更に好ましくは０．４ＭＰａ以上であり、好ましくは１．２ＭＰａ以下、より好ましくは１．１ＭＰａ以下、更に好ましくは１．０ＭＰａ以下である。前記圧力が高い程、製造される水素担持粉末の性能が良好となる。 The pressure in the high temperature treatment step and the low temperature treatment step is preferably 0.2 MPa or more, more preferably 0.3 MPa or more, even more preferably 0.4 MPa or more, and preferably 1.2 MPa or less, more preferably 1.2 MPa or more. It is 1 MPa or less, more preferably 1.0 MPa or less. The higher the pressure, the better the performance of the hydrogen-supported powder produced.
　本発明では、高温処理工程を、好ましくは０．５時間以上、より好ましくは０．７５時間以上、更に好ましくは１時間以上、好ましくは２時間以下、より好ましくは１．７５時間以下、更に好ましくは１．５時間以下行うことが好ましい。 In the present invention, the high temperature treatment step is carried out for preferably 0.5 hours or more, more preferably 0.75 hours or more, even more preferably 1 hour or more, preferably 2 hours or less, more preferably 1.75 hours or less, and even more preferably is preferably carried out for 1.5 hours or less.
　また低温処理工程を、好ましくは１時間以上、より好ましくは２時間以上、更に好ましくは３時間以上、好ましくは６時間以下、より好ましくは５．５時間以下、更に好ましくは５時間以下行うことが好ましい。 Further, the low temperature treatment step may be carried out for preferably 1 hour or more, more preferably 2 hours or more, even more preferably 3 hours or more, preferably 6 hours or less, more preferably 5.5 hours or less, even more preferably 5 hours or less. preferable.
　前記高温処理工程と前記低温処理工程を十分な時間実施することにより、水分との接触により所望量の水素ガスを発生し、且つ、その水分の還元力の高い水素担持粉末が製造される。 By carrying out the high-temperature treatment step and the low-temperature treatment step for a sufficient period of time, a hydrogen-supported powder that generates a desired amount of hydrogen gas upon contact with moisture and has a high ability to reduce the moisture is produced.
　高温処理工程および低温処理工程のいずれにおいても、水素濃度の調整が容易なことから、熱処理は水素濃度が５ｖｏｌ％以上、１００ｖｏｌ％以下にコントロールされたガスを流通しながら行ってもよい。 Since the hydrogen concentration can be easily adjusted in both the high-temperature treatment step and the low-temperature treatment step, the heat treatment may be performed while flowing a gas whose hydrogen concentration is controlled to be 5 vol% or more and 100 vol% or less.
　得られた水素担持粉末の粒径は、粉砕および／または分級により適宜調整可能である。 The particle size of the obtained hydrogen-supported powder can be adjusted as appropriate by pulverization and/or classification.
　本発明に係る脂肪性肝疾患抑制剤は、非常に優れた脂肪性肝疾患抑制作用を示す。具体的には、脂肪性肝疾患による肝臓の肥大を抑制し、肝機能を改善させる。おそらく、有効成分である水素担持粉末が優れた水素発生能を有し、還元作用を示すことから、例えば活性酸素を原因とする炎症などを抑制できると考えられる。その一方で、有効成分である水素担持粉末は、食品やサプリメントにも配合されている炭酸カルシウムマグネシウムを主成分とするため、安全性が非常に高く、恒常的な使用も可能であると考えられる。よって、例えば、脂肪性肝疾患の治療のために一日あたり複数回の服用も可能であり、また、長期にわたる脂肪性肝疾患の予防などを目的として恒常的な服用も可能である。 The fatty liver disease inhibitor according to the present invention exhibits an extremely excellent fatty liver disease inhibitory effect. Specifically, it suppresses liver enlargement due to fatty liver disease and improves liver function. Presumably, since the hydrogen-carrying powder, which is an active ingredient, has excellent hydrogen generation ability and exhibits a reducing effect, it is thought that, for example, inflammation caused by active oxygen can be suppressed. On the other hand, the active ingredient, hydrogen-carrying powder, is mainly composed of calcium magnesium carbonate, which is also included in foods and supplements, so it is considered to be extremely safe and can be used on a regular basis. . Therefore, for example, it can be taken multiple times a day for the treatment of fatty liver disease, and it can also be taken constantly for the purpose of preventing fatty liver disease over a long period of time.
　脂肪性肝疾患には、脂肪肝と脂肪性肝炎が含まれる。脂肪肝とは、肝細胞に中性脂肪が過剰にたまった状態のことをいい、脂肪性肝炎は、脂肪肝に炎症と線維化が起こる疾患であり、いずれも自覚症状は無いか或いは低く、肝機能を示す数値の悪化により明らかになる場合が多く、脂肪肝から脂肪性肝炎へ、更には肝硬変や肝臓癌に進行し得る。脂肪性肝疾患は、一般的に、一日あたりビール中瓶を２本以上または日本酒を２合以上の飲酒を原因とするアルコール性脂肪性肝疾患と、一日あたりビール４００ｍＬ未満または日本酒１号未満でなる非アルコール性脂肪性肝疾患（ＮＡＦＬＤ）に分類され、更に非アルコール性脂肪性肝疾患には、軽度の単純性脂肪肝と炎症により、肝臓に強い機能性障害を起こす非アルコール性脂肪性肝炎（ＮＡＳＨ）が含まれる。本発明者らの実験的知見によれば、本発明に係る脂肪性肝疾患抑制剤は、非アルコール性脂肪性肝炎のモデルラットの症状を改善する作用を有する。 Fatty liver disease includes fatty liver and steatohepatitis. Fatty liver is a condition in which excess neutral fat accumulates in liver cells, and steatohepatitis is a disease in which inflammation and fibrosis occur in fatty liver. It is often manifested by deterioration in numerical values indicating liver function, and can progress from fatty liver to steatohepatitis, and further to cirrhosis and liver cancer. Fatty liver disease is generally diagnosed as alcoholic fatty liver disease caused by drinking more than 2 medium bottles of beer or 2 cups of sake per day, and alcoholic fatty liver disease caused by drinking less than 400 mL of beer or 1 cup of sake per day. Non-alcoholic fatty liver disease (NAFLD) is classified as non-alcoholic fatty liver disease (NAFLD), which consists of mild simple fatty liver disease and non-alcoholic fatty liver disease that causes severe functional impairment in the liver due to inflammation. including inflammatory hepatitis (NASH). According to the experimental findings of the present inventors, the fatty liver disease inhibitor according to the present invention has an effect of improving symptoms in a rat model of non-alcoholic steatohepatitis.
　本発明に係る脂肪性肝疾患の治療方法は、前記水素担持粉末を有効成分として脂肪性肝疾患の患者に投与する工程を含む。本発明に係る脂肪性肝疾患抑制剤の使用量は、服用者の状態、年齢、性別などに応じて適宜調整すべきであり、特に制限されない。例えば、本発明に係る脂肪性肝疾患抑制剤の使用量は、脂肪性肝疾患抑制作用が認められる範囲で適宜調整すればよいが、例えばヒトに対して、水素担持粉末の摂取量が１日あたり１００ｍｇ以上、５ｇ以下程度となるように、１日当たり１回以上、５回以下程度投与することができる。本発明に係る脂肪性肝疾患抑制剤を投与すべき対象者としては、ヒトの他、愛玩動物などヒト以外の動物が考えられる。 The method for treating fatty liver disease according to the present invention includes the step of administering the hydrogen-carrying powder as an active ingredient to a patient with fatty liver disease. The amount of the fatty liver disease inhibitor according to the present invention to be used should be appropriately adjusted depending on the condition, age, sex, etc. of the recipient, and is not particularly limited. For example, the amount of the fatty liver disease inhibitor according to the present invention may be adjusted as appropriate within the range where the fatty liver disease inhibitory effect is observed. It can be administered about once or more and about 5 times or less per day, so that the amount is about 100 mg or more and 5 g or less per day. Subjects to whom the fatty liver disease inhibitor of the present invention should be administered include humans as well as non-human animals such as pets.
　本発明に係る脂肪性肝疾患抑制剤の剤形は特に制限されないが、例えば、錠剤、カプセル剤、液剤、顆粒剤、散剤、シロップ剤、エアゾール剤などの内服剤とすることができる。本発明に係る脂肪性肝疾患抑制剤は、剤形に応じて様々な添加成分を配合してもよい。例えば、基材、賦形剤、着色剤、滑沢剤、矯味剤、乳化剤、増粘剤、湿潤剤、安定剤、保存剤、溶剤、溶解補助剤、懸濁化剤、界面活性剤、抗酸化剤、佐薬、緩衝剤、ｐＨ調整剤、甘味料、香料などを添加することができる。また、これら添加剤の配合量は、本発明の作用効果を妨げない様な量である限り、必要に応じて適宜設定することができる。さらに、他の薬効成分を添加してもよい。好適には経口製剤とする。また、本発明に係る脂肪性肝疾患抑制剤は、水素担持粉末を含む腸溶性カプセル剤であってもよい。 The dosage form of the fatty liver disease inhibitor according to the present invention is not particularly limited, but can be, for example, an internal medicine such as a tablet, capsule, liquid, granule, powder, syrup, or aerosol. The fatty liver disease inhibitor according to the present invention may contain various additive components depending on the dosage form. For example, base materials, excipients, colorants, lubricants, flavoring agents, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizing agents, suspending agents, surfactants, Oxidizing agents, adjuvants, buffers, pH adjusters, sweeteners, flavors, etc. can be added. Further, the blending amount of these additives can be appropriately set as necessary, as long as the amount does not interfere with the effects of the present invention. Furthermore, other medicinal ingredients may be added. It is preferably an oral formulation. Moreover, the fatty liver disease inhibitor according to the present invention may be an enteric-coated capsule containing a hydrogen-carrying powder.
　本発明の脂肪性肝疾患抑制剤は、食物の過剰摂取などを原因とする脂肪性肝疾患を効果的に抑制することができる。また、例えば全肝細胞に対する脂肪化細胞の割合がいったん高まっても、その割合を低減できる可能性もある。即ち、本発明に係る脂肪性肝疾患抑制剤は、恒常的な摂取により脂肪性肝疾患の発生を抑制する脂肪性肝疾患予防剤に加え、いったん生じた脂肪性肝疾患が正常な肝臓となる脂肪性肝疾患治療剤も含まれる概念である。よって、本発明の脂肪性肝疾患抑制剤は、脂肪性肝疾患の予防効果を有する健康食品として、恒常的に継続して使用することもできる。 The fatty liver disease inhibitor of the present invention can effectively suppress fatty liver disease caused by excessive intake of food. Furthermore, for example, even if the ratio of fatty cells to all hepatocytes once increases, it is possible to reduce that ratio. That is, the fatty liver disease inhibitor according to the present invention is not only a fatty liver disease preventive agent that suppresses the occurrence of fatty liver disease by constant intake, but also a fatty liver disease preventive agent that suppresses the occurrence of fatty liver disease once it has occurred. This concept also includes therapeutic agents for fatty liver disease. Therefore, the fatty liver disease inhibitor of the present invention can also be used constantly and continuously as a health food having a preventive effect on fatty liver disease.
　本願は、２０２２年７月２８日に出願された日本国特許出願第２０２２－１２０２０９号に基づく優先権の利益を主張するものである。２０２２年７月２８日に出願された日本国特許出願第２０２２－１２０２０９号の明細書の全内容が、本願に参考のため援用される。 This application claims the benefit of priority based on Japanese Patent Application No. 2022-120209 filed on July 28, 2022. The entire contents of the specification of Japanese Patent Application No. 2022-120209 filed on July 28, 2022 are incorporated by reference into this application.
　以下、実施例を挙げて本発明をより具体的に説明するが、本発明はもとより下記実施例によって制限を受けるものではなく、前・後記の趣旨に適合し得る範囲で適当に変更を加えて実施することも勿論可能であり、それらはいずれも本発明の技術的範囲に包含される。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by the Examples below, and modifications may be made as appropriate within the scope of the spirit of the preceding and following. Of course, other implementations are also possible, and all of them are included within the technical scope of the present invention.
　実施例１　
　（１）処置
　６月齢の雄性Ｆ３４４系統ラット５４匹を、未処置（Ｎａｉｖｅ）群１２匹、対照（Ｃｏｎｔｒｏｌ）群２０匹、水素担持粉末投与群２２匹に任意に分け、対照群と水素担持粉末投与群は、実験開始の２日前から断食させた。次いで、対照群と水素担持粉末投与群には、非アルコール性脂肪性肝炎（ＮＡＳＨ）の症状に似た症状をつくり出すことのできるメチオニン／コリン無添加飼料（日本クレア社製）を３日間自由摂取させ、次の３日間は通常飼料を自由摂取させた。水素担持粉末投与群には、メチオニン／コリン無添加飼料と通常飼料に加えて、水素担持粉末（アッチェ社製）を精製水に分散させた懸濁液を、３００ｍｇ／ｋｇ体重の水素担持粉末の量で、ゾンデを使って１日一回、６日間にわたって胃内投与した。未処置群には、実験期間を通じて通常飼料を自由摂取させた。
　実験開始から３日目に、未処置群１２匹と、対照群から１０匹、水素担持粉末投与群から１１匹を任意に選択し、イソフルランにより安楽死させ、また、実験開始から７日目に残りのラットをイソフルランにより安楽死させ、体重を測定し、肝臓を摘出して重量を測定し、また血液試料を採取し、血清を分離した。 Example 1
(1) Treatment 54 6-month-old male F344 rats were arbitrarily divided into an untreated group (12 rats), a control group (20 rats), and a hydrogen-carrying powder administration group (22 rats). The administration group was fasted from 2 days before the start of the experiment. Next, the control group and the hydrogen-carrying powder administration group were given ad libitum feed for 3 days with no methionine/choline additives (manufactured by Nippon Clea Co., Ltd.), which can produce symptoms similar to those of non-alcoholic steatohepatitis (NASH). The animals were given normal feed ad libitum for the next 3 days. In addition to methionine/choline-free feed and normal feed, the hydrogen-carrying powder administration group received a suspension of hydrogen-carrying powder (manufactured by Acche) in purified water at 300 mg/kg of body weight. The drug was administered intragastrically using a probe once a day for 6 days. The untreated group was given free access to normal feed throughout the experimental period.
On the 3rd day from the start of the experiment, 12 animals from the untreated group, 10 animals from the control group, and 11 animals from the hydrogen-carrying powder administration group were randomly selected and euthanized with isoflurane, and on the 7th day from the start of the experiment. The remaining rats were euthanized with isoflurane, weighed, the liver was removed and weighed, blood samples were collected, and serum was separated.
　（２）肝臓重量／体重比
　図１に、各群の肝臓重量／体重比を示す。以下の図中、「＊」はＳｔｕｄｅｎｔ　ｔテストにおいてｐ＜０．０５で有意差が認められたことを示し、「＊＊」はｐ＜０．０１で有意差が認められたことを示し、「＊＊＊」はｐ＜０．００１で有意差が認められたことを示し、「＊＊＊＊」はｐ＜０．０００１で有意差が認められたことを示し、「Ｄ３」および「Ｄ７」はそれぞれ実験開始から３日目および７日目のマウスであることを示し、「Ｈ2」は水素担持粉末投与群マウスを示す。
　図１に示される結果の通り、未処置群に対して、メチオニン／コリン無添加飼料を投与した対照群では体重に対する肝臓重量比が有意に増加したが、本発明に係る水素担持粉末を摂取した群では、対照群に対して体重に対する肝臓重量の比が有意に低減され、肝臓の肥大が有意に抑制されたことが示された。 (2) Liver weight/body weight ratio Figure 1 shows the liver weight/body weight ratio of each group. In the figures below, "*" indicates that a significant difference was observed at p<0.05 in the Student t test, "**" indicates that a significant difference was observed at p<0.01, "***" indicates that a significant difference was observed at p<0.001, "****" indicates that a significant difference was observed at p<0.0001, "D3" and ""D7" indicates mice on the 3rd and 7th day from the start of the experiment, respectively, and "H 2 " indicates mice in the hydrogen-carrying powder administration group.
As shown in the results shown in Figure 1, the ratio of liver weight to body weight increased significantly in the control group administered the methionine/choline-free feed compared to the untreated group, but in the control group administered the methionine/choline-free feed, the ratio of liver weight to body weight increased significantly compared to the untreated group. In the control group, the ratio of liver weight to body weight was significantly reduced, indicating that liver enlargement was significantly suppressed.
　（３）ＡＳＴ
　各群の血清中ＡＳＴ（アスパレート・アミノトランスフェラーゼ）濃度を図２に示す。
　図２に示される結果の通り、未処置群に対して、メチオニン／コリン無添加飼料を投与した対照群では血清中ＡＳＴ濃度が有意に高くなった。その理由としては、肝細胞が破壊されて細胞中のＡＳＴが血中に漏出したことによると考えられる。しかし、本発明に係る水素担持粉末を摂取した群では、対照群に対して血清中ＡＳＴ濃度が有意に低減され、肝細胞の破壊が有意に抑制されたことが示された。 (3) AST
The serum AST (aspart aminotransferase) concentration of each group is shown in FIG. 2.
As shown in the results shown in FIG. 2, the serum AST concentration was significantly higher in the control group to which methionine/choline-free feed was administered than in the untreated group. The reason for this is thought to be that the hepatocytes were destroyed and AST in the cells leaked into the blood. However, in the group that ingested the hydrogen-carrying powder according to the present invention, the serum AST concentration was significantly reduced compared to the control group, indicating that the destruction of hepatocytes was significantly suppressed.
　（４）ＴＣ
　各群の血清中ＴＣ（総コレステロール）濃度を図３に示す。
　図３に示される結果の通り、未処置群に対して、メチオニン／コリン無添加飼料を投与した対照群では血清中ＴＣ濃度が有意に高くなった。その理由としては、メチオニン／コリン無添加飼料により肝機能に乱れが生じて肝臓における代謝が正常に行われなくなったことによると考えられる。しかし、本発明に係る水素担持粉末を摂取した群では、対照群に対して血清中ＴＣ濃度が有意に低減され、肝機能が正常に近くなったことが示された。 (4) T.C.
The serum TC (total cholesterol) concentration of each group is shown in FIG.
As shown in the results shown in FIG. 3, the serum TC concentration was significantly higher in the control group to which methionine/choline-free feed was administered than in the untreated group. The reason for this is thought to be that the methionine/choline-free feed disrupted liver function and the metabolism in the liver was no longer carried out normally. However, in the group that ingested the hydrogen-carrying powder according to the present invention, the serum TC concentration was significantly reduced compared to the control group, indicating that the liver function was close to normal.
　（５）ＳＲＥＢＰ－１ｃ
　ＳＲＥＢＰ－１ｃは肝臓において脂肪酸やトリグリセリドの合成を支配する転写因子であり、ＳＲＥＢＰ－１ｃの発現上昇や活性化により、その応答遺伝子である脂肪酸やトリグリセリドの合成酵素群が発現し、摂取エネルギーが脂肪として蓄えられる。インスリン抵抗性モデル動物において、肝臓のＳＲＥＢＰ－１ｃの活性化が報告されている。
　図４に、未処置群に対する肝臓組織中ＳＲＥＢＰ－１ｃ遺伝子ｍＲＮＡ発現量の相対比を示す。
　図４に示される結果の通り、メチオニン／コリン無添加飼料に続く通常飼料の摂取により、対照群ではＳＲＥＢＰ－１ｃの発現が上昇する傾向が認められたが、本発明に係る水素担持粉末を摂取した群では対照群に対してそれが有意に抑制されている。よって、本発明に係る水素担持粉末により、脂肪の蓄積などを抑制できると考えられる。 (5) SREBP-1c
SREBP-1c is a transcription factor that controls the synthesis of fatty acids and triglycerides in the liver. Increased expression and activation of SREBP-1c leads to the expression of fatty acid and triglyceride synthases, which are response genes, and the energy intake is reduced from fat. It is stored as Activation of SREBP-1c in the liver has been reported in insulin resistance model animals.
FIG. 4 shows the relative ratio of SREBP-1c gene mRNA expression level in liver tissue to that of the untreated group.
As shown in the results shown in Figure 4, the expression of SREBP-1c tended to increase in the control group due to the intake of the normal feed following the methionine/choline-free feed, but when the hydrogen-carrying powder according to the present invention was ingested. It was significantly suppressed in the treated group compared to the control group. Therefore, it is thought that the hydrogen-carrying powder according to the present invention can suppress fat accumulation and the like.
　（６）Ｌｅｐｔｉｎ　Ｒ
　肝臓中のレプチン受容体（Ｌｅｐｔｉｎ　Ｒ）は、ＳＲＥＢＰ－１ｃと同様に脂肪の蓄積や脂肪性肝疾患に関与する。図５に、未処置群に対する肝臓組織中Ｌｅｐｔｉｎ　Ｒ遺伝子ｍＲＮＡ発現量の相対比を示す。
　図５に示される結果の通り、メチオニン／コリン無添加飼料の摂取により、対照群では肝臓におけるレプチン受容体遺伝子の発現が有意に上昇したが、本発明に係る水素担持粉末を摂取した群では対照群に対してそれが有意に抑制されている。よって、本発明に係る水素担持粉末により、脂肪の蓄積や脂肪性肝疾患の進行などを抑制できると考えられる。 (6) Leptin R
Like SREBP-1c, the leptin receptor (Leptin R) in the liver is involved in fat accumulation and fatty liver disease. FIG. 5 shows the relative ratio of Leptin R gene mRNA expression level in liver tissue to that of the untreated group.
As shown in Figure 5, the expression of the leptin receptor gene in the liver was significantly increased in the control group due to the intake of the methionine/choline-free feed, whereas the expression of the leptin receptor gene in the liver was significantly increased in the control group. It is significantly suppressed compared to the group. Therefore, it is thought that the hydrogen-carrying powder according to the present invention can suppress fat accumulation and progression of fatty liver disease.
　（７）ＴＮＦ－α
　図６に、未処置群に対する肝臓組織中ＴＮＦ－α遺伝子ｍＲＮＡ発現量の相対比を示す。
　図６に示される結果の通り、メチオニン／コリン無添加飼料に続く通常飼料の摂取により、対照群では血中ＴＮＦ－α濃度が有意に上昇したが、本発明に係る水素担持粉末を摂取した群のＴＮＦ－α濃度は対照群に比べて有意に低減されていた。ＴＮＦ－αは炎症に関与することから、水素担持粉末により肝炎が抑制された可能性が考えられる。 (7) TNF-α
FIG. 6 shows the relative ratio of the expression level of TNF-α gene mRNA in liver tissue to that of the untreated group.
As shown in Figure 6, the blood TNF-α concentration increased significantly in the control group due to the intake of the regular feed following the methionine/choline-free feed, but in the group that ingested the hydrogen-carrying powder according to the present invention. TNF-α concentration was significantly reduced compared to the control group. Since TNF-α is involved in inflammation, it is possible that hepatitis was suppressed by the hydrogen-carrying powder.
　（８）ＣＣＲ２
　Ｃ－Ｃケモカイン受容体２（ＣＣＲ２）とＣ－Ｃケモカインリガンド２がマクロファージの肝臓への浸潤に関与しており、浸潤したマクロファージがＴＮＦ－αの産生やＴｈ１細胞の誘導による病態の形成に重要な役割を果たし、また、肝炎患者の血液中にＣＣＲ２やＣＣＲ５が増加することが知られている。
　図７に、未処置群に対する肝臓組織中ＣＣＲ２遺伝子ｍＲＮＡ発現量の相対比を示す。
　図７に示される結果の通り、メチオニン／コリン無添加飼料に続く通常飼料の摂取により、対照群では血中ＣＣＲ２濃度が有意に上昇したが、本発明に係る水素担持粉末を摂取した群のＣＣＲ２濃度は対照群に比べて有意に低減されていた。ＣＣＲ２は肝炎などに関与することから、水素担持粉末により肝炎が抑制された可能性が考えられる。 (8) CCR2
CC chemokine receptor 2 (CCR2) and CC chemokine ligand 2 are involved in macrophage infiltration into the liver, and infiltrated macrophages are important for the production of TNF-α and the formation of pathological conditions by inducing Th1 cells. It is also known that CCR2 and CCR5 increase in the blood of hepatitis patients.
FIG. 7 shows the relative ratio of CCR2 gene mRNA expression level in liver tissue to that of the untreated group.
As shown in FIG. 7, the blood CCR2 concentration increased significantly in the control group due to the intake of the normal feed following the methionine/choline-free feed, but the CCR2 concentration in the group ingesting the hydrogen-carrying powder according to the present invention increased significantly. The concentration was significantly reduced compared to the control group. Since CCR2 is involved in hepatitis, it is possible that hepatitis was suppressed by the hydrogen-carrying powder.

Claims (18)

  1. 　平均粒子径が１μｍ以上、１００μｍ以下であり、炭酸カルシウムマグネシウムを含み、且つ水分と接触することにより１ｇあたり０．１μＬ以上、１００μＬ以下の水素ガスを発生する水素担持粉末を有効成分として含むことを特徴とする脂肪性肝疾患抑制剤。 Contains as an active ingredient a hydrogen-carrying powder that has an average particle size of 1 μm or more and 100 μm or less, contains calcium magnesium carbonate, and generates hydrogen gas of 0.1 μL or more and 100 μL or less per gram upon contact with moisture. A characteristic fatty liver disease inhibitor.
  2. 　前記脂肪性肝疾患が非アルコール性脂肪性肝炎である請求項１に記載の脂肪性肝疾患抑制剤。 The fatty liver disease inhibitor according to claim 1, wherein the fatty liver disease is non-alcoholic steatohepatitis.
  3. 　前記水素担持粉末が、赤外分光分析において、５００ｃｍ-1以上、６００ｃｍ-1以下および９００ｃｍ-1以上、１０００ｃｍ-1以下に吸収を有する請求項１に記載の脂肪性肝疾患抑制剤。 The fatty liver disease inhibitor according to claim 1, wherein the hydrogen-carrying powder has absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopy.
  4. 　前記水素担持粉末が７０質量％以上の炭酸カルシウムマグネシウムを含む請求項１に記載の脂肪性肝疾患抑制剤。 The fatty liver disease inhibitor according to claim 1, wherein the hydrogen-carrying powder contains 70% by mass or more of calcium magnesium carbonate.
  5. 　前記水素担持粉末に接触した水分の酸化還元電位が－４００ｍＶ以上、－３０ｍＶ以下である請求項１に記載の脂肪性肝疾患抑制剤。 The fatty liver disease inhibitor according to claim 1, wherein the redox potential of water in contact with the hydrogen-supported powder is -400 mV or more and -30 mV or less.
  6. 　経口投与されるものである請求項１～５のいずれかに記載の脂肪性肝疾患抑制剤。 The fatty liver disease inhibitor according to any one of claims 1 to 5, which is orally administered.
  7. 　脂肪性肝疾患を治療するための、平均粒子径が１μｍ以上、１００μｍ以下であり、炭酸カルシウムマグネシウムを含み、且つ水分と接触することにより１ｇあたり０．１μＬ以上、１００μＬ以下の水素ガスを発生する水素担持粉末の使用。 For treating fatty liver disease, the average particle size is 1 μm or more and 100 μm or less, contains calcium magnesium carbonate, and generates hydrogen gas of 0.1 μL or more and 100 μL or less per gram upon contact with water. Use of hydrogen-carrying powder.
  8. 　前記脂肪性肝疾患が非アルコール性脂肪性肝炎である請求項７に記載の使用。 The use according to claim 7, wherein the fatty liver disease is non-alcoholic steatohepatitis.
  9. 　前記水素担持粉末が、赤外分光分析において、５００ｃｍ-1以上、６００ｃｍ-1以下および９００ｃｍ-1以上、１０００ｃｍ-1以下に吸収を有する請求項７に記載の使用。 The use according to claim 7, wherein the hydrogen-supported powder has absorption in infrared spectroscopy at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less.
  10. 　前記水素担持粉末が７０質量％以上の炭酸カルシウムマグネシウムを含む請求項７に記載の使用。 The use according to claim 7, wherein the hydrogen-carrying powder contains 70% by mass or more of calcium magnesium carbonate.
  11. 　前記水素担持粉末に接触した水分の酸化還元電位が－４００ｍＶ以上、－３０ｍＶ以下である請求項７に記載の使用。 The use according to claim 7, wherein the oxidation-reduction potential of the water in contact with the hydrogen-supported powder is -400 mV or more and -30 mV or less.
  12. 　前記水素担持粉末が経口投与されるものである請求項７～１１のいずれかに記載の使用。 The use according to any one of claims 7 to 11, wherein the hydrogen-carrying powder is orally administered.
  13. 　脂肪性肝疾患を治療するための方法であって、平均粒子径が１μｍ以上、１００μｍ以下であり、炭酸カルシウムマグネシウムを含み、且つ水分と接触することにより１ｇあたり０．１μＬ以上、１００μＬ以下の水素ガスを発生する水素担持粉末を有効成分として脂肪性肝疾患の患者に投与する工程を含むことを特徴とする方法。 A method for treating fatty liver disease, wherein the average particle size is 1 μm or more and 100 μm or less, contains calcium magnesium carbonate, and produces hydrogen of 0.1 μL or more and 100 μL or less per gram upon contact with water. A method comprising the step of administering a gas-generating hydrogen-carrying powder as an active ingredient to a patient suffering from fatty liver disease.
  14. 　前記脂肪性肝疾患が非アルコール性脂肪性肝炎である請求項１３に記載の方法。 14. The method according to claim 13, wherein the fatty liver disease is non-alcoholic steatohepatitis.
  15. 　前記水素担持粉末が、赤外分光分析において、５００ｃｍ-1以上、６００ｃｍ-1以下および９００ｃｍ-1以上、１０００ｃｍ-1以下に吸収を有する請求項１３に記載の方法。 14. The method according to claim 13, wherein the hydrogen-carrying powder has absorption at 500 cm -1 or more and 600 cm -1 or less and 900 cm -1 or more and 1000 cm -1 or less in infrared spectroscopy.
  16. 　前記水素担持粉末が７０質量％以上の炭酸カルシウムマグネシウムを含む請求項１３に記載の方法。 The method according to claim 13, wherein the hydrogen-supported powder contains 70% by mass or more of calcium magnesium carbonate.
  17. 　前記水素担持粉末に接触した水分の酸化還元電位が－４００ｍＶ以上、－３０ｍＶ以下である請求項１３に記載の方法。 The method according to claim 13, wherein the oxidation-reduction potential of the water in contact with the hydrogen-supported powder is -400 mV or more and -30 mV or less.
  18. 　前記水素担持粉末を経口投与する請求項１３に記載の方法。 The method according to claim 13, wherein the hydrogen-carrying powder is orally administered.
PCT/JP2023/007451 2022-07-28 2023-03-01 Fatty liver disease inhibitor WO2024024149A1 (en)

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