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WO2021206020A1 - Agent prophylactique ou thérapeutique contre le trouble de déficit de l'attention avec hyperactivité - Google Patents

Agent prophylactique ou thérapeutique contre le trouble de déficit de l'attention avec hyperactivité Download PDF

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Publication number
WO2021206020A1
WO2021206020A1 PCT/JP2021/014332 JP2021014332W WO2021206020A1 WO 2021206020 A1 WO2021206020 A1 WO 2021206020A1 JP 2021014332 W JP2021014332 W JP 2021014332W WO 2021206020 A1 WO2021206020 A1 WO 2021206020A1
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Prior art keywords
silicon
fine particles
silicon fine
therapeutic agent
hyperactivity disorder
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English (en)
Japanese (ja)
Inventor
昌一 島田
紀好 臼井
佳久 小山
近藤　誠
小林　光
悠輝 小林
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University of Osaka NUC
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Osaka University NUC
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Priority to JP2022514045A priority Critical patent/JP7759030B2/ja
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • the present invention relates to the prevention or treatment of attention deficit hyperactivity disorder.
  • Attention deficit hyperactivity disorder is a neurodevelopmental disorder or behavioral disorder whose three main symptoms are hyperactivity, impulsivity, and lack of attention. It is estimated to be about 2-2.5% in adulthood. In clinical practice, attention deficit hyperactivity disorder is classified into three types according to the characteristics of the person concerned: inattention-dominant type, hyperactivity / impulsivity-dominant type, and mixed type. There is no radical cure for attention deficit hyperactivity disorder, only symptomatic treatment. In drug therapy, as the first-stage treatment, a single agent of a central nervous system stimulant (methylphenidate hydrochloride, atomoxetine hydrochloride) is prescribed.
  • methylphenidate hydrochloride, atomoxetine hydrochloride methylphenidate hydrochloride, atomoxetine hydrochloride
  • Reactive oxygen species include superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and singlet oxygen.
  • Hydroxyl radicals are radicals with extremely high oxidizing power, and substances that are close to each other when generated in vivo, such as DNA and lipids, It is known to oxidize proteins and the like and damage radicals. Hydroxyl radicals are said to cause various diseases such as cancer and lifestyle-related diseases, and aging due to such actions.
  • Hydrogen is known as a substance that eliminates hydroxyl radicals generated in the body. It is water that hydrogen reacts with hydroxyl radicals and does not produce substances that are harmful to the body. Therefore, there are many reports on hydrogen water containing hydrogen that eliminates hydroxyl radicals in the body.
  • the saturated hydrogen concentration is 1.6 ppm at room temperature, and the amount of hydrogen contained in 1 liter of hydrogen water is only 18 ml (milliliter) in terms of gas even in the saturated state.
  • hydrogen has a small molecular size, hydrogen in hydrogen water passes through a container and diffuses into air, and it is difficult to maintain the amount of dissolved hydrogen in hydrogen water.
  • most of the hydrogen in the hydrogen water is gasified in the upper digestive tract such as the stomach, which may cause a belching symptom (so-called "belching"). Therefore, it is not easy to take in a sufficient amount of hydrogen into the body to react with hydroxyl radicals in the body by the method of ingesting hydrogen water.
  • hydrogen is absorbed and transported to each organ, its concentration returns to the concentration before ingestion of hydrogen water in about 1 hour. In addition, it is difficult to aspirate gaseous hydrogen in daily life.
  • Silicon fine particles can generate hydrogen in contact with water. This reaction hardly proceeds when it comes into contact with water having a pH of less than 5, and when it comes into contact with water having a pH of 7 or more, the reaction proceeds, and when it comes into contact with water having a pH of 8 or more, the reaction proceeds faster. Further, by surface-treating the silicon fine particles, the above reaction proceeds favorably. Further, the silicon fine particles continuously generate hydrogen for 20 hours or more while in contact with water, and depending on the conditions, 1 g of the silicon fine particles generate 400 ml or more of hydrogen (Patent Document 1, Patent Document 2, Non-Patent Document 2). Patent Document 1). 400 ml of hydrogen corresponds to hydrogen contained in 22 liters of saturated hydrogen water.
  • Patent Document 3 describes a solid preparation having a hydrogen generating ability containing silicon fine particles as a main component. However, it is not described that the silicon fine particles can prevent or treat the disease.
  • Patent Document 4 describes a hydrogen supply material including a medium containing silicon fine particles and water. It is described that the hydrogen supply material is used to supply hydrogen to the skin or mucous membranes. However, it is not described that the silicon fine particles can prevent or treat the disease.
  • Patent Document 5 describes the hydrogen peroxide solution treatment of silicon fine particles. However, it is not described that the silicon fine particles can prevent or treat the disease.
  • Patent Document 6 describes a formulation containing silicon fine particles, and is used in a "base material" such as an animal drug, a livestock or pet food, an animal feed, a plant drug, a plant fertilizer, or a plant compost.
  • base material such as an animal drug, a livestock or pet food, an animal feed, a plant drug, a plant fertilizer, or a plant compost.
  • Patent Document 7 mainly describes a silicon oxide film formed on the surface of silicon fine particles. As usage patterns, feeds, supplements, food additives, transdermal and / or transmucosal hydrogen uptake are described, and animal health promotion and / or disease prevention are also described. However, there is no description that silicon fine particles can prevent or treat diseases to the extent that they can be used as pharmaceuticals.
  • Kidney disease inflammatory disease (inflammatory bowel disease, arthritis, hepatitis, dermatitis), visceral discomfort, depression or depression, Parkinson's disease, autism spectrum disorder, memory loss, spinal cord injury, hearing loss, cerebral ischemia
  • inflammatory disease inflammatory bowel disease, arthritis, hepatitis, dermatitis
  • visceral discomfort depression or depression
  • Parkinson's disease autism spectrum disorder
  • memory loss spinal cord injury
  • hearing loss cerebral ischemia
  • An object of the present invention is to provide a medicine, a medical device, a food, a beverage, or the like for the prevention or treatment of attention deficit hyperactivity disorder.
  • silicon fine particles can prevent and / or treat attention deficit hyperactivity disorder, and have completed the present invention.
  • a preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon fine particles 2.
  • 3. The preventive or therapeutic agent according to item 1 or 2, wherein the silicon fine particles are fine particles containing silicon that can generate hydrogen in contact with water.
  • the silicon-containing fine particles are silicon-containing fine particles.
  • the preventive or therapeutic agent according to item 5 wherein the silicon oxide film is a silicon oxide film to which a hydroxyl group is added. 7.
  • the silicon fine particles are fine particles made of elemental silicon and have a silicon oxide film formed on the surface thereof.
  • the prophylactic or therapeutic agent according to any one of items 1 to 6 above, wherein the silicon fine particles are porous silicon particles. 10.
  • the preventive or therapeutic agent according to any one of items 1 to 9 above, wherein the silicon fine particles are hydrophilized silicon fine particles. 11.
  • An agent containing silicon fine particles for use in the prevention or treatment of attention deficit hyperactivity disorder 19.
  • 20. Use of silicone microparticles for the prevention or preparation of therapeutic agents for attention deficit hyperactivity disorder.
  • 21. Use of silicone microparticles for the preparation of therapeutic agents for attention deficit hyperactivity disorder.
  • the prophylactic or therapeutic agent of the present invention can prevent and / or treat attention deficit hyperactivity disorder.
  • the prevention or treatment with the therapeutic agent of the present invention can be one of the causative therapies for attention deficit hyperactivity disorder, and is excellent in effectiveness and safety. Since there was no fundamental treatment for attention deficit hyperactivity disorder and only symptomatic treatment was available, the discovery of causative treatment will greatly contribute to future medical care and health promotion.
  • the preventive or therapeutic agent of the present invention does not diffuse hydrogen before administration. This property contributes to maintaining the quality of products such as pharmaceuticals, and contributes to the convenience of manufacturers, sellers and users.
  • FIG. 1 is a photograph of silicon fine particles (mixture of silicon crystallites and aggregates thereof) taken with a scanning electron microscope (SEM) (Example 2).
  • FIG. 2 is a graph showing the amount of hydrogen (cumulative amount) per 1 g of silicon fine particles generated by contacting the silicon fine particles obtained in Example 2 with water at 36 ° C. and pH 8.2.
  • FIG. 3 is a photograph of silicon fine particles (aggregates of silicon crystallites) taken with a scanning electron microscope (SEM) (Example 3).
  • FIG. 4 is a graph showing the results of plasma antioxidant power (BAP test) of normal SD rats to which silicon fine particles were administered for 8 weeks. Con indicates a control group, and Si indicates a silicon fine particle administration group.
  • FIG. 1 is a photograph of silicon fine particles (mixture of silicon crystallites and aggregates thereof) taken with a scanning electron microscope (SEM) (Example 2).
  • FIG. 2 is a graph showing the amount of hydrogen (cumulative amount) per 1 g
  • FIG. 5 is a graph showing that, as a result of multivariate analysis of sulfur-related compounds contained in the large intestine, the control group and the silicon fine particle administration group can be distinguished by 10 types of sulfur-related compounds.
  • Con indicates a control group
  • Si indicates a silicon fine particle administration group.
  • FIG. 7 is a diagram showing a procedure for producing and experimenting with an attention deficit hyperactivity disorder model mouse.
  • FIG. 8 is a graph showing the results of a hyperactivity test using an open field.
  • the vertical axis shows the total distance traveled by the mouse in the open field for 10 minutes.
  • the distance traveled was improved to the same level as in the group in which physiological saline was administered to the normal diet, and hyperactivity was improved (most). right).
  • FIG. 9 is an immunohistochemical image of a coronal section of the forebrain of an attention deficit hyperactivity disorder model mouse showing the state of dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC). show.
  • VTA ventral tegmental area
  • SNC substantia nigra pars compacta
  • FIG. 10 is an immunohistochemical stained image of a coronary section of the midbrain of an attention deficit hyperactivity disorder model mouse, showing the state of dopaminergic neurons in the striatum.
  • the group in which 6-OHDA was administered to the normal diet had significantly reduced staining of tyrosine hydroxylase (TH) in the striatum, and dopaminergic neurons. (Center).
  • the stained image of TH was improved to the same extent as in the group in which physiological saline was administered to the normal diet (far right).
  • the silicon fine particles contained in the preventive or therapeutic agent of the present invention are fine particles containing silicon and can generate hydrogen in contact with water.
  • silicon-containing fine particles capable of generating hydrogen in contact with water continuously generate hydrogen when in contact with water at 36 ° C. and pH 8.2.
  • silicon fine particles capable of generating 10 ml or more of hydrogen per gram of silicon fine particles in 24 hours Preferably, it is 20 ml or more, 40 ml or more, 80 ml or more, 150 ml or more, 200 ml or more, and 300 ml or more.
  • the silicon-containing fine particles are preferably fine particles containing a simple substance of silicon.
  • the silicon simple substance is high-purity silicon.
  • the high-purity silicon is silicon having a purity of 99% or more, preferably 99.9% or more, and more preferably 99.99% or more.
  • the silicon fine particles contained in the preventive or therapeutic agent of the present invention are preferably silicon fine particles, aggregates of the silicon fine particles, and / or porous silicon particles (porous silicon particles).
  • the active ingredient of the prophylactic or therapeutic agent of the present invention is preferably at least one kind of particles selected from the group consisting of silicon fine particles, aggregates of the silicon fine particles, and porous silicon particles. That is, the preferable active ingredient may be silicon fine particles alone, agglomerates of silicon fine particles alone, or porous silicon particles alone. Further, two or more kinds of silicon fine particles may be contained as an active ingredient.
  • the prophylactic or therapeutic agent of the present invention preferably contains silicon fine particles and / or agglomerates of the silicon fine particles. More preferably, the main component is an aggregate of silicon fine particles.
  • the silicon fine particles in the present invention are preferably fine particles having a silicon oxide film formed on the surface.
  • the preferred silicon fine particles in the present invention are fine particles made of simple silicon, silicon fine particles having a silicon oxide film formed on the surface thereof, aggregates of the silicon fine particles, and particles made of porous silicon alone. It is at least one kind of particles selected from the group consisting of porous silicon particles having a silicon oxide film formed on the surface thereof.
  • the content of silicon in the silicon fine particles is preferably 10% by weight or more, more preferably 20% by weight or more, further preferably 50% by weight or more, and most preferably 70% by weight or more.
  • the silicon oxide film is preferably a silicon oxide film to which a hydroxyl group (-OH group) is added.
  • the silicon oxide film to which a hydroxyl group is added is a silicon oxide film that has been treated to increase the number of hydroxyl groups contained in the silicon oxide film.
  • a hydroxyl group can be added to the silicon oxide film by a hydrophilic treatment. Silicon fine particles on which a silicon oxide film to which a hydroxyl group is added have improved contact efficiency between the surface and water, promote a hydrogen generation reaction, and can generate a large amount of hydrogen.
  • the method of hydrophilic treatment is not particularly limited, and a known hydrophilic treatment method may be used.
  • hydrogen peroxide solution treatment and nitric acid treatment can be mentioned.
  • Hydrogen peroxide solution treatment is preferable.
  • the silicon fine particles to which the silicon oxide film to which the hydroxyl group is added are formed on the surface preferably have a hydroxyl group of 5 ⁇ 10 13 / cm 2 or more on the surface. More preferably, it has a hydroxyl group of 1 ⁇ 10 14 / cm 2 or more. More preferably, it has a hydroxyl group of 3 ⁇ 10 14 / cm 2 or more.
  • the particle surface is a surface of silicon fine particles, a surface of porous silicon particles, a surface of aggregates of silicon fine particles, and a surface of silicon fine particles forming the aggregates.
  • the specific method of hydrogen peroxide solution treatment is, for example, immersing silicon fine particles in hydrogen peroxide solution and stirring.
  • concentration of hydrogen peroxide is preferably 1 to 30%, more preferably 1.5 to 20%, still more preferably 2 to 15%, 2.5 to 10%, and most preferably 3 to 5%.
  • the time for immersing and stirring is preferably 5 to 90 minutes, more preferably 10 to 80 minutes, and even more preferably 20 to 70 minutes. Most preferably 30 to 60 minutes.
  • the hydrophilicity of the silicon fine particles can be improved by treating with hydrogen peroxide solution, but if the treatment time is long, the hydrogen generation reaction from the silicon fine particles proceeds and affects the thickness of the oxide film of the silicon fine particles.
  • the temperature of the hydrogen peroxide solution during the hydrogen peroxide solution treatment is preferably 20 to 60 ° C., more preferably 25 to 50 ° C., more preferably 30 to 40 ° C., and most preferably 35 ° C.
  • silicon fine particles There are no restrictions on the shape of silicon fine particles. Examples include amorphous, polygonal, spherical, elliptical, and columnar.
  • the silicon fine particles may be crystalline silicon fine particles having crystallinity. Further, it may be amorphous silicon fine particles having no crystallinity. As long as it has crystallinity, it may be single crystal or polycrystal. It is preferably crystalline silicon fine particles, and more preferably single crystal silicon fine particles.
  • the amorphous silicon fine particles may be amorphous silicon fine particles formed by a plasma CVD method, a laser ablation method, or the like.
  • the silicon oxide film formed on the surface of the silicon fine particles in the present invention may be a silicon oxide film formed by being naturally oxidized by being exposed to the atmosphere. Further, it may be a silicon oxide film artificially formed by a known method such as chemical oxidation with an oxidizing agent such as nitric acid.
  • the thickness of the silicon oxide film may be any thickness as long as the fine particles made of simple silicon are stable and enable efficient hydrogen generation. For example, it is 0.3 nm to 5 nm, 0.3 nm to 3 nm, 0.5 nm to 2.5 nm, 0.7 nm to 2 nm, 0.8 nm to 1.8 nm, and 1.0 nm to 1.7 nm.
  • the silicon oxide film may be a film containing oxides such as Si 2 O, SiO, Si 2 O 3 , and SiO 2 formed by combining silicon on the surface of fine particles made of elemental silicon with oxygen. Si 2 O, SiO, Si 2 O 3, etc. promote the hydrogen generation reaction.
  • the silicon fine particles may be crystalline silicon fine particles having crystallinity. Further, it may be amorphous silicon fine particles having no crystallinity. As long as it has crystallinity, it may be single crystal or polycrystal.
  • Preferred silicon fine particles are crystalline silicon fine particles, and more preferably single crystal silicon fine particles (hereinafter, also referred to as silicon crystallites).
  • the silicon fine particles may be fine particles in which at least two selected from the group consisting of single crystal silicon fine particles, polycrystalline silicon fine particles and amorphous silicon fine particles are mixed.
  • the silicon fine particles in the present invention can be silicon fine particles in which a silicon oxide film is naturally or artificially formed after the silicon fine particles are produced. More preferable silicon fine particles are fine particles in which a silicon oxide film is formed on the surface of silicon crystallites.
  • the silicon fine particles in the present invention may be particles obtained by crushing a lump of silicon simple substance (high-purity silicon) or particles obtained by crushing particles of elemental silicon.
  • a lump or particle of a simple substance of silicon is crushed to produce silicon fine particles, the surface of the silicon fine particles is naturally oxidized to form a silicon oxide film.
  • the particle size of the silicon fine particles in the present invention is preferably 0.5 nm or more and 100 ⁇ m or less, more preferably 1 nm or more and 50 ⁇ m or less, and more preferably 1. .5 nm or more and 10 ⁇ m or less, more preferably 2 nm or more and 5 ⁇ m or less, more preferably 2.5 nm or more and 1 ⁇ m or less, 5 nm or more and 500 nm or less, 7.5 nm or more and 200 nm or less, 10 nm or more and 100 nm or less.
  • the particle size is 500 nm or less, a suitable hydrogen generation rate and hydrogen generation amount can be obtained, and when the particle size is 200 nm or less, a more suitable hydrogen generation rate and hydrogen generation amount can be obtained.
  • the aggregate of silicon fine particles in the present invention is the aggregate of the silicon fine particles. It may be naturally formed or artificially formed. Preferably, it is an agglomerate in which silicon fine particles on which a silicon oxide film is formed are aggregated. Naturally formed aggregates are believed to remain aggregated in the gastrointestinal tract.
  • the preferred agglomerates have a structure having voids inside and allowing water molecules to infiltrate the agglomerates and react with the fine particles inside. Since the hydrogen generation rate of naturally formed aggregates does not depend on the size of the aggregates, the aggregates have voids inside and water molecules can infiltrate the aggregates and react with the fine particles inside. Has.
  • the particle size of the agglomerates of the preferable silicon fine particles is 10 nm or more and 500 ⁇ m or less. More preferably, it is 50 nm or more and 100 ⁇ m or less, and further preferably 100 nm or more and 50 ⁇ m or less.
  • the agglomerates can be formed to retain the surface area of the fine particles and can have sufficient surface area to achieve high hydrogen generation potential.
  • the particle size of the silicon fine particles constituting the aggregate of the silicon fine particles in the present invention is preferably 0.5 nm or more and 100 ⁇ m or less, more preferably 1 nm or more and 50 ⁇ m or less, and more preferably 1.5 nm or more and 10 ⁇ m or less. More preferably, it is 2 nm or more and 5 ⁇ m or less, more preferably 2.5 nm or more and 1 ⁇ m or less, 5 nm or more and 500 nm or less, 7.5 nm or more and 200 nm or less, 10 nm or more and 100 nm or less.
  • the silicon fine particles constituting the silicon aggregate may be crystalline silicon fine particles or amorphous silicon fine particles.
  • a preferable agglomerate is an agglomerate of silicon crystallites having a crystallite diameter of 1 nm or more and 10 ⁇ m or less.
  • it is an agglomerate in which silicon crystallites having a silicon oxide film formed on the surface are aggregated.
  • the prophylactic or therapeutic agent of the present invention is preferably a silicon crystallite having a crystallite diameter of 1 nm to 1 ⁇ m, more preferably a crystallite diameter of 1 nm or more and 100 nm or less, and a crystallite having a silicon oxide film formed on the surface thereof. And / or its aggregates. Preferably, it contains as a main component an aggregate of silicon crystallites having a silicon oxide film formed on the surface.
  • the prophylactic or therapeutic agent of the present invention is preferably a silicon crystallite having a crystallite diameter of 1 nm to 1 ⁇ m, more preferably a crystallite diameter of 1 nm or more and 100 nm or less, and a silicon oxide film having a hydroxyl group added is formed on the surface thereof.
  • a silicon crystallite having a crystallite diameter of 1 nm to 1 ⁇ m more preferably a crystallite diameter of 1 nm or more and 100 nm or less
  • a silicon oxide film having a hydroxyl group added is formed on the surface thereof.
  • the main component is an aggregate of silicon crystallites on which a silicon oxide film having a hydroxyl group added is formed on the surface.
  • Porous silicon particles can be a porous body of silicon particles. Further, it may be a porous body in which silicon fine particles are aggregated and processed.
  • the porous silicon particles are preferably particles made of a simple substance of porous silicon, and have a silicon oxide film formed on the surface thereof. More preferably, the silicon oxide film is a silicon oxide film to which a hydroxyl group is added.
  • the porous silicon particles can be porous silicon particles having crystallinity. Further, it may be amorphous porous silicon particles having no crystallinity. As long as it has crystallinity, it may be single crystal or polycrystal.
  • the size of the voids existing in the porous silicon particles is not limited, but usually can be 1 nm to 1 ⁇ m, and the porous silicon particles have a sufficient surface area to realize high hydrogen generating ability.
  • the size of the porous silicon particles is not particularly limited. It can be preferably 200 nm to 400 ⁇ m.
  • Agglomerates of silicon fine particles and porous silicon particles are particles suitable for oral administration because they have a large particle size as a whole and a large surface area. If the particles are large, they do not pass through the cell membranes and cells of the digestive tract, especially the intestinal tract, and silicon fine particles are not absorbed into the body, which is excellent from the viewpoint of safety.
  • the particle size distribution of silicon fine particles contained in the preventive or therapeutic agent of the present invention there are no particular restrictions on the particle size distribution of silicon fine particles contained in the preventive or therapeutic agent of the present invention, the particle size distribution of fine particles composed of silicon alone, or the crystallite size distribution. It may be polydisperse. It may be a preparation containing silicon fine particles having a specific range of particle size or crystallite size. Further, the size distribution of the aggregates of silicon fine particles is not particularly limited.
  • the hydrogen generation rate can be adjusted by the particle size, particle size distribution and / or the thickness of the silicon oxide film of the silicon fine particles.
  • the method for producing the silicon fine particles of the present invention is not particularly limited, but the silicon-containing particles can be produced by physically pulverizing the silicon-containing particles to the desired particle size.
  • the physical crushing method are a bead mill crushing method, a planetary ball mill crushing method, a shock wave crushing method, a high pressure collision method, a jet mill crushing method, or a crushing method in which two or more kinds thereof are combined.
  • a suitable crushing method is a physical crushing method.
  • a silicon oxide film may be artificially formed by a known method such as chemical oxidation with an oxidizing agent such as hydrogen peroxide solution or nitric acid.
  • the target particle size or particle size distribution can be obtained by appropriately changing the bead size and / or type. be able to.
  • the silicon-containing particles of the starting material are not limited as long as they are high-purity silicon particles.
  • high-purity silicon particle powder can be mentioned.
  • the silicon-containing particles of the starting material may be single crystal, polycrystalline, or amorphous.
  • the present application includes an invention relating to a preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon fine particles, an invention relating to a method for preventing or treating attention deficit hyperactivity disorder including administration of silicon fine particles, and silicon fine particles.
  • inventions relating to agents used for the prevention or treatment of attention deficit hyperactivity disorder and inventions relating to the use of silicon fine particles for the prevention or preparation of attention deficit hyperactivity disorder.
  • the description and embodiments of the invention relating to the preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon fine particles in the present specification are the description and embodiments of all these inventions.
  • the prophylactic or therapeutic agent for attention deficit hyperactivity disorder of the present invention includes an agent for preventing attention deficit hyperactivity disorder, an agent for treating attention deficit hyperactivity disorder, and an agent for preventing and treating attention deficit hyperactivity disorder. Includes agents.
  • the prophylactic or therapeutic agent of the present invention has effects on one or more symptoms related to attention deficit hyperactivity disorder, such as prevention of onset, improvement of symptoms, suppression of exacerbation of symptoms, prevention of recurrence of symptoms, and early recovery of symptoms.
  • Symptoms of attention deficit hyperactivity disorder include hyperactivity, impulsivity, and lack of attention.
  • the prophylactic or therapeutic agent of the present invention can be a prophylactic or therapeutic agent for hyperactivity in attention deficit hyperactivity disorder.
  • Symptoms of hyperactivity include high activity, inability to stay still, inability to stop talking, and restlessness in controlling behavior.
  • the prophylactic or therapeutic agent of the present invention can be a therapeutic agent for attention deficit hyperactivity disorder.
  • a therapeutic agent for attention deficit hyperactivity disorder For one or more symptoms related to attention deficit hyperactivity disorder, it has effects such as improvement of symptoms, suppression of exacerbation of symptoms, prevention of recurrence of symptoms, and early recovery of symptoms.
  • the prophylactic or therapeutic agent of the present invention can be a therapeutic agent for hyperactivity in attention deficit hyperactivity disorder.
  • Symptoms of hyperactivity include high activity, inability to stay still, inability to stop talking, and restlessness in controlling behavior.
  • the silicon fine particles in the present invention have the property of continuing to generate hydrogen for a long time (20 hours or more) in vitro.
  • the silicon fine particles of the present invention generate hydrogen when they come into contact with water having a pH of 7 or higher, and generate more hydrogen at a pH of 8 or higher. On the other hand, it has the property of generating almost no hydrogen at pH 5 or lower.
  • the silicon fine particles in the present invention When the silicon fine particles in the present invention are orally administered, it is considered that hydrogen is hardly generated in the stomach due to the above-mentioned properties, but hydrogen is generated in the intestine.
  • the silicon fine particles of the present invention were administered to normal mice, hydrogen generation was confirmed in the cecum, which is a part of the large intestine, and even if normal mice were fed a normal diet under the same conditions, hydrogen was below the detection limit. Since the residence time of food in the intestine is usually 20 hours or more in humans, the prophylactic or therapeutic agent of the present invention continuously generates hydrogen in the intestine for a long time when orally administered, and hydrogen in the body. It is thought that can be distributed.
  • hydrogen can be distributed into the body for a long time by percutaneous or transmucosal by indwelling silicon fine particles on the skin or mucous membrane for a long time.
  • One of the mechanisms of action in which attention deficit hyperactivity disorder is prevented and / or treated is that the silicon fine particles in the present invention continue to generate hydrogen for a long period of time, and the generated hydrogen is transported to blood and various organs. It is considered that hydrogen selectively reacts with hydroxyl radicals. In addition, since the antioxidant power in blood is improved, it is considered that it is due to the antioxidant substance produced in blood. Furthermore, since it shows a remarkable effect compared with hydrogen water in studies using disease model animals in which oxidative stress is involved, it is considered that there is another action that hydrogen water does not have.
  • the large intestine of the silicon fine particle-administered mice contained a large amount of glutathione monosulfide and cysteine monosulfide, which are involved in antioxidant action in vivo. This may be a peculiar action of silicon fine particles.
  • a protein containing a metal element such as cobalt that captures hydrogen in the initial state of development generated in the intestine by the reaction between silicon fine particles and water, or a hydrogen atom donates an electron, resulting in reducing power. It is considered that the protein that has become stronger is transported to each organ and reacts with the hydroxy radical to eliminate it.
  • the prophylactic or therapeutic agent of the present invention can be used in combination with other therapeutic agents for attention deficit hyperactivity disorder.
  • the mechanism of action of the prophylactic or therapeutic agent of the present invention is different from the mechanism of action of existing therapeutic agents for attention deficit hyperactivity disorder such as methylphenidate hydrochloride and atomoxetine hydrochloride. The effect is expected.
  • the prophylactic or therapeutic target of the prophylactic or therapeutic agent of the present invention is humans and non-human animals.
  • Preferred non-human animals include pets, livestock and the like.
  • One or more of the silicon fine particles in the present invention may be directly administered to humans or non-human animals, but if necessary, they are mixed with an acceptable additive or carrier and are well known to those skilled in the art. It can be formulated into a form and administered.
  • additives or carriers include, for example, pH adjusters (eg, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, citric acid, etc.), excipients (eg, sugar derivatives such as mannitol, sorbitol; corn starch, etc.
  • Steel derivatives such as potato starch; or cellulose derivatives such as crystalline cellulose; or lubricants (eg, metal stearate salts such as magnesium stearate; or talc, etc.), binders (eg, hydroxypropyl cellulose, hydroxypropyl). Methyl cellulose or polyvinylpyrrolidone, etc.), disintegrants (eg, cellulose derivatives such as carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), preservatives (eg, paraoxybenzoic acid esters such as methylparaben, propylparaben; or chlorobutanol, benzyl alcohol Alcohols, etc.).
  • These additives and carriers may be blended into silicon fine particles alone or in admixture of two or more.
  • Preferred additives include pH adjusters that can adjust the pH to 8 or higher.
  • Preferred pH adjusters include sodium hydrogen carbonate.
  • the administration route of the prophylactic or therapeutic agent of the present invention is not particularly limited, but preferred administration routes include oral, transdermal, and transmucosa (oral cavity, rectum, vagina, etc.).
  • Examples of the orally-administered preparation include tablets, capsules, granules, powders, syrups (dry syrups), and oral jellies.
  • Examples of the preparation for transdermal administration or transmucosal administration include patches, ointments and the like.
  • Tablets, capsules, granules, powders, etc. can be enteric-coated preparations.
  • tablets, granules and powders are coated with an enteric coating.
  • the enteric coating agent a gastric sparingly soluble enteric coating agent can be used.
  • Capsules can be made enteric by filling enteric capsules with the silicon fine particles of the present invention.
  • the prophylactic or therapeutic agent of the present invention can be administered to humans or non-human animals after being formulated into the above dosage form.
  • the content of silicon fine particles in the preventive or therapeutic agent of the present invention is not particularly limited, and examples thereof include 0.1 to 100% by weight, 1 to 99% by weight, and 5 to 95%.
  • the dose and frequency of administration of the silicon fine particles in the present invention are appropriately determined according to conditions such as the subject to be administered, the age, body weight, sex, purpose (preventive or therapeutic, etc.), severity of symptoms, dosage form, administration route, and the like. Can change.
  • the preferred dose of silicon microparticles is, for example, about 0.1 mg to 10 g, preferably about 1 mg to 5 g, more preferably about 1 mg to 2 g per day.
  • the number of administrations may be once or a plurality of times per day, or once every few days. For example, it may be 1 to 3 times, 1 to 2 times, or 1 time per day.
  • the preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon fine particles of the present invention can be used for pharmaceuticals, quasi-drugs, medical devices, foods, and beverages.
  • the present application also relates to the invention of a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder containing silicon fine particles.
  • the present application also relates to the invention of a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder containing silicon fine particles or for preventing or treating attention deficit hyperactivity disorder containing a therapeutic agent.
  • the pharmaceutical composition in the present invention also includes a composition having a mild action that corresponds to a quasi-drug. Examples of the embodiment of the pharmaceutical composition of the present invention include embodiments of the invention relating to the above-mentioned preventive or therapeutic agent.
  • the present application also relates to the invention of a medical device for preventing or treating attention deficit hyperactivity disorder containing silicon fine particles or for preventing or treating attention deficit hyperactivity disorder containing a therapeutic agent. It also relates to an invention of a medical device for preventing or treating attention deficit hyperactivity disorder containing the silicon fine particles.
  • the medical device in the present invention is a tool or device intended to be used for treating or preventing a disease of a human or non-human animal. Examples of medical devices include masks. By wearing the mask of the present invention, hydrogen can be directly supplied to the trachea or lungs. Another example is adhesive plasters.
  • the present application also relates to the invention of a food or beverage for preventing or treating attention deficit hyperactivity disorder containing silicon fine particles or for preventing or treating attention deficit hyperactivity disorder containing a therapeutic agent. It also relates to the invention of a food or beverage for preventing or treating attention deficit hyperactivity disorder containing the silicon fine particles.
  • Preferred examples of the food or beverage of the present invention include health foods, foods with functional claims, foods for specified health use and the like.
  • the health food, functional food, and food for specified health use are foods or beverages that can prevent the onset of symptoms of attention deficit hyperactivity disorder and / or prevent the recurrence of the symptoms.
  • There are no restrictions on the form of food or beverage for example, the form of a mixture mixed with existing foods and beverages and the form of a formulation can be mentioned. For example, tablets, capsules, powders, granules, jellies and the like can be mentioned.
  • Example 1 200 g of high-purity silicon powder (manufactured by High-Purity Chemical Laboratory, particle size distribution ⁇ 5 ⁇ m (however, silicon particles having a crystal particle size of more than 1 ⁇ m), purity 99.9%), 4 L (liter) of 99.5 wt% ethanol solution ), Add zirconia beads (capacity: 750 ml) of ⁇ 0.5 ⁇ m, and rotate for 4 hours using a bead mill device (IMEX Co., Ltd., horizontal continuous ready mill (model, RHM-08)). The particles were pulverized by pulverizing (one-step pulverization) at several 2500 rpm.
  • the ethanol solution containing the finely divided silicon particles was separated from the beads by a separation slit provided in the crushing chamber of the bead mill device, and then heated to 30 ° C. to 35 ° C. using a vacuum evaporator. By evaporating the ethanol solution, finely divided silicon particles (crystallites) were obtained.
  • the finely divided silicon particles (crystallites) obtained by the above method mainly had a crystallite diameter of 1 nm or more and 100 nm or less, and most of the crystallites formed aggregates.
  • the crystallites were coated with a silicon oxide film, and the thickness of the silicon oxide film was about 1 nm.
  • the mode diameter was 6.6 nm
  • the median diameter was 14.0 nm
  • the average crystallite diameter was 20.3 nm in the volume distribution. ..
  • the mixture of the obtained silicon crystallites on which the silicon oxide film is formed and the aggregates thereof is an embodiment of silicon fine particles which are the active ingredients of the present invention.
  • Example 2 The silicon crystallites and aggregates thereof obtained in Example 1 were mixed with hydrogen peroxide solution (3 wt%) in a glass container and stirred at 35 ° C. for 30 minutes. Silicon crystals and aggregates thereof treated with hydrogen peroxide solution were removed by solid-liquid separation treatment using a known centrifugal separation treatment apparatus. After that, the obtained silicon crystallites and aggregates thereof were mixed with an ethanol solution (99.5 wt%), and the mixture was sufficiently stirred. The silicon crystallites and their aggregates mixed with the ethanol solution were sufficiently dried after removing the highly volatile ethanol solution by a solid-liquid separation treatment using a known centrifugation device.
  • the obtained mixture of silicon crystals and aggregates thereof, which have been treated with hydrogen peroxide solution and have a silicon oxide film formed, is an embodiment of silicon fine particles which are the active ingredients of the present invention.
  • An electron scanning microscope (SEM) photograph of the obtained silicon fine particles is shown in FIG.
  • the hydrogen generation rate of the obtained agglomerates of silicon crystals did not depend on the agglomerate size.
  • the amount of hydrogen generated by the silicon fine particles (silicon crystallites and their aggregates) obtained in Example 2 was measured. 10 mg of silicon fine particles were placed in a glass bottle having a capacity of 100 ml (glass borosilicate glass, about 1 mm thick, Labran screw tube bottle manufactured by AS ONE). Water adjusted to pH 8.2 with sodium hydrogen carbonate was placed in this glass bottle, the liquid temperature was sealed under a temperature condition of 36 ° C., and the hydrogen concentration in the liquid in the glass bottle was measured. A portable dissolved hydrogen meter (manufactured by Toa DKK Corporation, model DH-35A) was used for measuring the hydrogen concentration. The amount of hydrogen generated per 1 g of silicon fine particles is shown in FIG.
  • Example 3 The silicon fine particles (silicon crystals and aggregates thereof) obtained in Example 1 were treated with hydrogen peroxide solution, mixed with an ethanol solution, and stirred in the same manner as in Example 2.
  • the silicon fine particles mixed with the ethanol solution were dried using a spray dryer (ADL311SA, manufactured by Yamato Scientific Co., Ltd.).
  • the obtained aggregate of silicon crystallites is an embodiment of silicon fine particles which are the active ingredients of the present invention.
  • An electron scanning microscope (SEM) photograph of the obtained silicon fine particles (aggregates of silicon crystals) is shown in FIG.
  • Example 4 One-step pulverization was performed in the same manner as in Example 1.
  • the ⁇ 0.5 ⁇ m zirconia beads (capacity: 750 ml) used for the one-step pulverization were automatically separated from the solution containing silicon crystals in the bead mill pulverization chamber.
  • 0.3 ⁇ m zirconia beads (capacity: 750 ml) were added, and the silicon crystals were further pulverized (two-step pulverization) at a rotation speed of 2500 rpm for 4 hours to make them finer.
  • the beads were separated from the solution containing silicon crystals as described above, and the obtained ethanol solution containing silicon crystals was heated to 40 ° C. using a vacuum evaporator as in Example 1. Ethanol was evaporated to give two-step pulverized silicon crystallites.
  • the silicon crystallite on which the silicon oxide film pulverized in two steps is formed is also an embodiment of the silicon fine particles which are the active ingredients of the present invention.
  • Example 5 A mixture of silicon crystals and aggregates thereof on which a hydrogen peroxide solution-treated silicon oxide film obtained in Example 2 was formed was filled in a commercially available capsule No. 3 to obtain a capsule preparation.
  • This capsule product contains agglomerates of silicon crystallites on which a hydrogen peroxide solution-treated silicon oxide film is formed as a main component, and further contains silicon crystallites on which a hydrogen peroxide solution-treated silicon oxide film is formed. contains.
  • ⁇ Test example> I Preparation of Silicon Fine Particle-Containing Food
  • the silicon fine particles (silicon crystallites and aggregates thereof) produced in Example 2 were mixed with a normal feed (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) so as to be 2.5 wt%. .. Further, an aqueous citric acid solution (pH 4) was added in an amount of about 0.5 wt% with respect to the total amount of the silicon fine particles and the feed, and kneaded using a known kneading device to obtain a silicon fine particle-containing food. ..
  • the silicon fine particle-administered group was given the above-mentioned silicon fine particle-containing diet, and the control group was given a normal feed (normal diet) (manufactured by Oriental Yeast Co., Ltd., model number AIN93M).
  • Blood was collected after 8 weeks of administration, and plasma antioxidant power was evaluated (BAP test) (free radical analyzer FREE Carrio Duo). The results are shown in FIG. It was shown that the antioxidant power was significantly increased in the silicon fine particle administration group.
  • B-2 Pretreatment for analysis Combine the frozen mouse colon samples (5) of the same group obtained in the first sample preparation, add methanol extract containing an internal standard compound (1 ml / g (organ)), and add. Grinded with pestle. Then, centrifugation was performed, and 100 ⁇ l of the supernatant was used as a sample. Sulfur compound labeling reagent and the like were added to 100 ⁇ l of the sample supernatant after centrifugation (130 ⁇ l in total) and suspended. The centrifuged supernatant (87 ⁇ l) was dried on a centrifugal evaporator.
  • the sulfur compounds contained in the prepared samples were analyzed by LC MSMS 8040 (manufactured by Shimadzu Corporation) using the sulfur index method. Specifically, among the compound species to be measured in Tables 1 and 2, all 61 sulfur-related compound species excluding the internal standard compound (No. 53; Camphorsulfonate) and the thiol group modifier (No. 40; Monobromobimane). Relative quantification was performed in. For the relative quantification, the peak area of the obtained mass chromatogram (standardized with an internal standard compound) was used. A total of 35 compounds were detected in the large intestine sample. Based on multivariate analysis based on the detected sulfur-related compound data, mapping analysis of similarity between samples (using R software vegan package) was performed.
  • FIG. 8 shows the results of multivariate analysis (the average value of the analysis results of each of the two samples) using the following 10 compounds in the silicon fine particle administration group and the control group.
  • Glutathione monosulfide (labeled) Systenylglycine (labeled) Thiosulfate ion (labeled) Hypotaurine 5-glutamylcysteine (labeled) Cysteine monosulfide (labeled) S-sulfocysteine sulfite ion (labeled) Serine taurine
  • the above compounds contain glutathione monosulfide, cysteine monosulfide, etc., which are involved in the antioxidant action in the living body, and are considered to play a part in the antioxidant action of the silicon fine particles. Since such a report has not been made for hydrogen, it may be one of the antioxidant effects peculiar to the preventive or therapeutic agent of the present invention.
  • C Pharmacological test in attention deficit hyperactivity disorder model C-1.
  • Preparation of Attention Deficit Hyperactivity Disorder Model Five-day-old newborn male mice (C57BL / 6JJmsSlc) were ventilated with desipramine (20 mg / kg), a selective noradrenaline reuptake inhibitor. Attention deficit hyperactivity disorder model was created by ventricular administration of 6-hydroxydopamine (6-OHDA) (25 ⁇ g), a neurotoxin that selectively degenerates dopaminergic neurons and noradrenalinergic neurons after 30 minutes. (Fig. 7).
  • 6-OHDA 6-hydroxydopamine
  • ventricles were 0.6 mm outside the sagittal suture, 2.0 mm rostral to the human suture, and 1.3 mm deep from the skin, and were injected into only one side, not both sides. See also: Bouchatta O. et al., Sci Rep, 2018; 8: 15349
  • the normal diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) and the silicon fine particle-containing diet obtained in I above were given in powder form without solidification so that mother mice and newborn mice could eat freely. ..
  • a normal diet or a diet containing silicon fine particles was fed to mother mice and neonatal mice from 3 days after birth to 24 days after birth until analysis was performed.
  • the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect on attention deficit hyperactivity disorder.
  • the present invention can be one of the causative therapies for attention deficit hyperactivity disorder, and will greatly contribute to future medical treatment and health promotion.

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Abstract

[Problème] L'invention vise à fournir un médicament, etc., capable de prévenir ou de traiter un trouble de déficit de l'attention avec hyperactivité. [Solution] Un trouble de déficit de l'attention avec hyperactivité peut être prévenu ou traité par administration par voie orale de fines particules de silicium ou par placement de fines particules de silicium sur la peau ou une muqueuse. Les fines particules de silicium sont des particules qui génèrent de l'hydrogène au contact de l'eau au pH de 7 ou plus. L'invention concerne un agent prophylactique ou thérapeutique contre un trouble de déficit de l'attention avec hyperactivité, une composition pharmaceutique, un instrument médical, un aliment ou une boisson, chacun contenant les fines particules de silicium. De préférence, les fines particules de silicium sont des microparticules de silicium qui ont un film d'oxyde de silicium portant un groupe hydroxyle ajouté à celui-ci et/ou des agrégats de ces microparticules de silicium.
PCT/JP2021/014332 2020-04-06 2021-04-02 Agent prophylactique ou thérapeutique contre le trouble de déficit de l'attention avec hyperactivité Ceased WO2021206020A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP4353241A4 (fr) * 2021-06-11 2024-09-18 Osaka University Agent préventif ou thérapeutique contenant des particules fines de silicium pour des maladies

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Publication number Priority date Publication date Assignee Title
WO2019235577A1 (fr) * 2018-06-07 2019-12-12 国立大学法人大阪大学 Agent prophylactique ou thérapeutique contre une maladie induite par le stress oxydatif

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Publication number Priority date Publication date Assignee Title
WO2019235577A1 (fr) * 2018-06-07 2019-12-12 国立大学法人大阪大学 Agent prophylactique ou thérapeutique contre une maladie induite par le stress oxydatif

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4353241A4 (fr) * 2021-06-11 2024-09-18 Osaka University Agent préventif ou thérapeutique contenant des particules fines de silicium pour des maladies

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