JP2020007300A - Prophylactic or therapeutic agents for depressive disorder or state - Google Patents

Abstract

To provide medicine that can prevent or treat depressive disorder or state.SOLUTION: Provided is a preventive or therapeutic agent, pharmaceutical composition, medical equipment, food or beverage for depressive disorder or state, containing silicon microparticles. Silicon microparticles, by oral administration or indwelling on the skin or mucous membranes, can prevent or treat depression or depression state, and its prophylactic and/or therapeutic effect is excellent. Silicon fine particles are fine particles containing silicon capable of generating hydrogen in contact with water.SELECTED DRAWING: Figure 4

Description

  The present invention relates to the prevention or treatment of depression or depression.

  Symptoms of depression include depressed mood, sleep disorders, loss of interest and pleasure, impaired appetite, reduced thinking, concentration, and decision-making, sense of neglect, self-responsibility, tiredness and weakness. The number of patients is increasing. Treatment for depression is a drug therapy centered on a selective serotonin reuptake inhibitor (SSRI), but the remission rate is less than 50%. I have.

  It is known that active oxygen is necessary for life support, while oxidizing and damaging cells constituting a living body. Active oxygen includes superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and singlet oxygen, but hydroxyl radicals are radicals with extremely high oxidizing power, and substances that come into close proximity when generated in a living body, such as DNA, lipids, It is known to oxidize proteins and the like and damage organs. The hydroxyl radical is said to cause various diseases such as cancer and lifestyle-related diseases and aging by such an action. It has also been reported that the oxidization of the cerebral nervous system causes injury and enhances inflammation.

  Hydrogen is known as a substance that annihilates hydroxyl radicals generated in the body. Hydrogen reacts with hydroxyl radicals to produce water, which does not produce any harmful substances to living organisms. Therefore, there are many reports on hydrogen water containing hydrogen that annihilates hydroxyl radicals in the body.

  However, the saturated hydrogen concentration is 1.6 ppm at room temperature, and the amount of hydrogen contained in one liter of hydrogen water is only 18 ml (milliliter) in gaseous state even in a saturated state. In addition, hydrogen has a small molecular size, and hydrogen in hydrogen water passes through a container and diffuses into the air, making it difficult to maintain the amount of dissolved hydrogen in the hydrogen water. Even if high-concentration hydrogen water is ingested, much of the hydrogen in the hydrogen water is gasified in the upper gastrointestinal tract such as the stomach, which may cause drunk symptoms (so-called "burp"). Therefore, it is not easy to take in a sufficient amount of hydrogen into the body by the method of ingesting hydrogen water to react with hydroxyl radicals in the body. Furthermore, even if hydrogen is absorbed and transported to each organ, its concentration returns to that before hydrogen water intake in about one hour. In addition, it is difficult to absorb gaseous hydrogen in daily life.

  Silicon (silicon, Si) is used in a wide range of fields such as semiconductor materials. The present inventors have variously studied the reactivity between silicon fine particles and water.

The present inventors have found that silicon fine particles can generate hydrogen in contact with water. The reaction is represented by the following formula.
Si + 2H ₂ O → SiO ₂ + 2H ₂
In addition, it was found that this reaction hardly proceeded in contact with water having a pH of less than 5, and that the reaction proceeded when contacted with water having a pH of 7 or more, and that the reaction proceeded more rapidly at a pH of 8 or more. In addition, it has been found that the above-described reaction proceeds favorably by surface treatment of silicon fine particles. Furthermore, it has been found that silicon fine particles continuously generate hydrogen for more than 20 hours while in contact with water, and that 1 g of silicon fine particles generate 400 ml or more of hydrogen depending on conditions (Patent Documents 1 to 6). Non-Patent Document 1). 400 ml of hydrogen corresponds to hydrogen contained in 22 liters of saturated hydrogen water.

JP 2016-155118 A JP 2017-104848 A International Publication No. 2017/130709 International Publication No. WO 2018/037752 WO2018 / 037818 WO2018 / 037819A

Shinsuke Matsuda et al., Water decomposition and hydrogen concentration by silicon nanoparticles, Proceedings of the 62nd JSAP Spring Meeting, 2015, 11a-A27-6

  An object of the present invention is to provide a medicine, a medical device, a food, a beverage, or the like for preventing or treating depression or a depressed state.

The present inventors have found that silicon microparticles can prevent and / or treat depression or a depressed state, and have completed the present invention.
1. A prophylactic or therapeutic agent for depression or depressive state containing silicon microparticles.
2. 2. The preventive or therapeutic agent according to the above 1, wherein the silicon fine particles are silicon-containing fine particles capable of generating hydrogen by contacting with water.
3. 3. The preventive or therapeutic agent according to the above 1 or 2, wherein the silicon fine particles are silicon fine particles and / or aggregates of the silicon fine particles.
4. 4. The preventive or therapeutic agent according to the above item 3, wherein the silicon fine particles are fine particles made of silicon alone and have a silicon oxide film formed on the surface thereof.
5. The preventive or therapeutic agent according to the above 3 or 4, wherein the silicon fine particles are fine particles obtained by crushing a lump or particles of silicon alone.
6. The prophylactic or therapeutic agent according to any one of the above items 3 to 5, wherein a particle diameter of the aggregate of the silicon fine particles is 10 nm or more and 500 μm or less.
7. 7. The preventive or therapeutic agent according to any one of the above items 3 to 6, wherein the silicon fine particles are silicon crystallites.
8. 3. The preventive or therapeutic agent according to the above 1 or 2, wherein the silicon fine particles are porous silicon particles.
9. 9. The preventive or therapeutic agent according to any one of items 1 to 8, wherein the silicon fine particles are silicon fine particles subjected to a hydrophilic treatment.
10. 10. The prophylactic or therapeutic agent according to the above item 9, wherein the hydrophilization treatment is a hydrogen peroxide solution treatment.
11. The prophylactic or therapeutic agent according to any one of Items 1 to 10, which is for oral administration.
12. A pharmaceutical composition for preventing or treating depression or depressive state, comprising silicon microparticles.
13. A medical device comprising the prophylactic or therapeutic agent according to any one of the above items 1 to 11.
14． A food or beverage containing the prophylactic or therapeutic agent according to any one of the above items 1 to 11.

  The preventive or therapeutic agent of the present invention can prevent and / or treat depression or depression. Its preventive and therapeutic effects are very good.

Silicon microparticles contained in the preventive or therapeutic agent of the present invention are microparticles capable of generating hydrogen. Since OH ^- ions act catalytically in the hydrogen generation reaction, hydrogen is efficiently generated under alkaline conditions for 20 hours or more. On the other hand, the residence time of food in the human intestine is usually 20 hours or more.

  The orally administered prophylactic or therapeutic agent of the present invention can continuously generate hydrogen in the intestine for a long time, and can continuously supply hydrogen to the body. In addition, if the prophylactic or therapeutic agent of the present invention is left on the skin or mucous membrane for a long time, it is considered that hydrogen can be continuously delivered to the body for a long time. It is thought that by continuously supplying hydrogen in this way, the antioxidant power in the body is improved, and the improved antioxidant power is maintained.

  Hydrogen water or gaseous hydrogen could not continuously supply hydrogen to the body for a long time, but the preventive or therapeutic agent of the present invention requires continuous supply of hydrogen to the body for a long time. Can be. In addition, it is considered that the preventive or therapeutic agent of the present invention has an action not found in hydrogen water.

  Prevention and treatment with the prophylactic or therapeutic agent of the present invention can be one of the causative treatments for depression or depression. Causal therapy is both effective and safe. Further, the prophylactic or therapeutic agent of the present invention is excellent in safety because the product generated by reacting with the hydroxyl radical is water. Depression or depression is a disease that has been increasing in recent years, the rate of remission is low, and the rate of relapse even after remission is high. It greatly contributes to medical care and health promotion.

  In addition, the preventive or therapeutic agent of the present invention does not cause diffusion of hydrogen before administration unlike hydrogen water. This property contributes to maintaining the quality of the product and to the convenience of manufacturers, sellers and users.

FIG. 1 is a graph showing the amount of hydrogen (cumulative amount) per gram of silicon fine particles generated by bringing the silicon fine particles obtained in Example 2 into contact with water at 36 ° C. and pH 8.2. FIG. 2 is a photograph of silicon crystallite aggregates taken by a scanning electron microscope (SEM). FIG. 3 is a graph showing the results of the antioxidant power (BAP test) of the plasma of normal SD rats to which silicon microparticles were administered for 8 weeks. Con indicates a control group, and Si indicates a silicon microparticle administration group. FIG. 4 is a graph showing the immobility time (second) in a tail suspension test of a depression model mouse (LPS) and a normal mouse (Sal). ■ indicates a group administered with silicon fine particles, and □ indicates a control group. FIG. 5 is a graph showing the immobility time (second) in the forced swimming test of the depression model mouse (LPS) and the normal mouse (Sal). ■ indicates a group administered with silicon fine particles, and □ indicates a control group. FIG. 6 is a graph showing the spontaneous activity of a depression model mouse (LPS) and a normal mouse (Sal). ■ indicates a group administered with silicon fine particles, and □ indicates a control group. Depression model mice (LPS) and normal mice (Sal) subjected to the tail suspension test and the forced swimming test show no difference in spontaneous activity regardless of the administration of silicon microparticles. FIG. 7 is a graph showing the concentration of inflammatory cytokines in the serum of a depression model mouse (LPS) and a normal mouse (Sal). Con indicates a control group, and Si indicates a silicon microparticle administration group. The vertical axis indicates the concentration of IL-6 (pg / ml) and the concentration of TNF-α (pg / ml).

  The silicon microparticles contained in the preventive or therapeutic agent of the present invention may be silicon-containing microparticles, and may be any silicon-containing microparticles capable of generating hydrogen in contact with water.

  The above-mentioned "fine particles containing silicon capable of generating hydrogen in contact with water" (silicon fine particles having a hydrogen generating ability) refer to the continuous generation of hydrogen when exposed to water at 36 ° C and pH 8.2. And 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 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 particle 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, an aggregate 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 preventive or therapeutic agent of the present invention preferably contains silicon fine particles and / or aggregates 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 composed of silicon alone, but when exposed to the atmosphere, the silicon fine particles have a surface oxidized to form a silicon oxide film. Therefore, the silicon fine particles in the present invention are preferably fine particles having a silicon oxide film formed on the surface. Preferred silicon fine particles in the present invention are fine particles composed of silicon alone, silicon fine particles having a silicon oxide film formed on the surface thereof, aggregates of the silicon fine particles, and particles composed of porous silicon alone. And 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 at least 10% by weight, more preferably at least 20% by weight, further preferably at least 50% by weight, and most preferably at least 70% by weight.

  The silicon simple substance is high-purity silicon. In this specification, high-purity silicon refers to silicon having a silicon purity of 99% or more, preferably 99.9% or more, more preferably 99.99% or more.

  There is no limitation on the shape of the silicon fine particles. Examples include irregular shapes, polygons, spheres, ellipses, and columns.

  The silicon fine particles may be crystalline silicon fine particles having crystallinity. Further, it may be amorphous silicon fine particles having no crystallinity. When it has crystallinity, it may be a single crystal or a polycrystal. Preferably, they are crystalline silicon fine particles, and more preferably, single crystalline silicon fine particles.

  The amorphous silicon fine particles may be amorphous silicon fine particles formed by a plasma CV 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 exposed to the atmosphere and naturally oxidized. Further, it may be a silicon oxide film artificially formed by a known method such as chemical oxidation using an oxidizing agent such as nitric acid.

The thickness of the silicon oxide film may be any thickness as long as fine particles composed of silicon alone are stable and efficient hydrogen generation is possible. For example, they are 0.3 nm to 3 nm, 0.5 nm to 2.5 nm, 0.7 to 2 nm, 0.8 nm to 1.8 nm, and 1.0 to 1.7 nm. The silicon oxide film is a film including silicon such as Si ₂ O, SiO, Si ₂ O ₃ , and SiO ₂ in which silicon on the surface of fine particles composed of silicon alone is combined with oxygen. Si ₂ O, SiO, Si ₂ O _{3 and the} like 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. When it has crystallinity, it may be a single crystal or a 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 may be silicon fine particles in which a silicon oxide film is formed naturally or artificially after the silicon fine particles are manufactured. More preferred silicon fine particles are fine particles in which a silicon oxide film is formed on the surface of a silicon crystallite.

  The silicon fine particles in the present invention may be particles obtained by pulverizing a lump of silicon alone (high-purity silicon) or particles obtained by pulverizing particles of silicon alone. When silicon fine particles are crushed to produce silicon fine particles, the surface of the silicon fine particles is naturally oxidized to form a silicon oxide film.

  The particle diameter of the silicon fine particles (crystallite diameter when the fine particles are silicon crystallites) in the present invention is preferably 0.5 nm or more and 100 μm or less, more preferably 1 nm or more and 50 μm or less, more preferably 1 nm or less. 0.5 nm or more and 10 μm or less, more preferably 2 nm or more and 5 μm or less, more preferably 2.5 nm or more and 1 μm 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. If the particle diameter is 500 nm or less, a suitable hydrogen generation rate and hydrogen generation amount can be obtained, and if it 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 silicon fine particles. It may be formed naturally or artificially. Preferably, it is an aggregate in which silicon fine particles on which a silicon oxide film is formed are aggregated. The naturally formed aggregates are believed to remain aggregated in the digestive tract. The preferred aggregate has a structure having voids therein so that water molecules can enter the aggregate and react with 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 a structure in which water molecules can enter the aggregates and react with fine particles inside. Having.

  The size of the aggregate of silicon fine particles is not particularly limited. A preferred particle diameter of the aggregate of silicon fine particles is 10 nm or more and 500 μm or less. More preferably, it is 50 nm or more and 100 μm or less, and still more preferably 100 nm or more and 50 μm or less. Agglomerates can be formed to retain the surface area of the fine particles, and can have sufficient surface area to achieve high hydrogen generation capacity.

  The particle diameter of the silicon fine particles constituting the aggregate of silicon fine particles in the present invention is preferably 0.5 nm or more and 100 μm or less, more preferably 1 nm or more and 50 μm or less, more preferably 1.5 nm or more and 10 μm or less, It is more preferably 2 nm or more and 5 μm or less, more preferably 2.5 nm or more and 1 μm or less, 5 nm or more and 500 nm or less, 7.5 nm or more and 200 nm or less, and 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 preferred aggregate is an aggregate of silicon crystallites having a crystallite diameter of 1 nm or more and 10 μm or less. Preferably, it is an aggregate in which silicon crystallites having a silicon oxide film formed on the surface are aggregated.

  The preventive or therapeutic agent of the present invention is preferably a silicon crystallite having a crystallite diameter of 1 nm to 1 μm, more preferably a crystallite diameter of 1 nm or more and 100 nm or less, a crystallite having a silicon oxide film formed on its surface, And / or an aggregate thereof. Preferably, it contains, as a main component, an aggregate of silicon crystallites having a silicon oxide film formed on the surface.

  Porous silicon particles (porous silicon particles) can be a porous body of silicon particles. Further, a porous body obtained by aggregating and processing silicon fine particles may be used. The porous silicon particles are preferably particles composed of porous silicon alone, and are particles having a silicon oxide film formed on the surface.

  The porous silicon particles may be crystalline silicon particles. Further, it may be amorphous porous silicon particles having no crystallinity. When it has crystallinity, it may be a single crystal or a polycrystal.

  The size of the voids present in the porous silicon particles is not limited, but may be usually 1 nm to 1 μm, and the porous silicon particles have a sufficient surface area to realize high hydrogen generating ability. There is no particular limitation on the size of the porous silicon particles. Preferably it can be 200 nm to 400 μm.

  The aggregate of silicon fine particles and the porous silicon particles are particles suitable for oral administration because they have a large particle diameter as a whole and a large surface area. If the particles are large, they do not pass through the gastrointestinal tract, especially the cell membrane and cells of the intestinal tract, and the silicon fine particles are not absorbed into the body, which is excellent from the viewpoint of safety.

  The silicon fine particles in the present invention are preferably silicon fine particles that have been subjected to a hydrophilic treatment. The silicon fine particles that have been subjected to the hydrophilization treatment can improve the contact efficiency between the surface and water, promote the hydrogen generation reaction, and generate a large amount of hydrogen. The method for the hydrophilic treatment is not particularly limited, and a known hydrophilic treatment method may be used. For example, a hydrogen peroxide solution treatment and a nitric acid treatment may be mentioned. Preferably, it is a peroxide water treatment. The hydrophilization treatment is preferably a treatment of removing the SiH groups of the silicon oxide film on the particle surface and adding a hydroxyl group to the particle surface. The particle surface is the surface of silicon fine particles, the surface of porous silicon particles, and the surface of silicon fine particles forming an aggregate of silicon fine particles.

  As a specific method of the hydrogen peroxide solution treatment, for example, silicon fine particles are immersed in a hydrogen peroxide solution and stirred. The 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%. The time for immersion and stirring is preferably 5 to 90 minutes, more preferably 10 to 80 minutes, and further preferably 20 to 70 minutes. The hydrophilicity of the silicon microparticles can be improved by treating with hydrogen peroxide water, which is most preferably 30 to 60 minutes. However, if the treatment time is long, the hydrogen generation reaction from the silicon microparticles proceeds and the oxidation of the silicon microparticles occurs. Affects film thickness. The temperature of the hydrogen peroxide solution during the treatment with the hydrogen peroxide solution is preferably from 20 to 60C, more preferably from 25 to 50C, more preferably from 30 to 40C, and most preferably 35C.

  There is no particular limitation on the particle size distribution of the silicon fine particles, the particle size distribution of the silicon fine particles, or the crystallite size distribution contained in the preventive or therapeutic agent of the present invention. It may be polydisperse. It may be a preparation containing fine silicon particles having a specific range of particle size or crystallite size. There is no particular limitation on the size distribution of the aggregates of silicon fine particles.

  The method for producing silicon fine particles of the present invention is not particularly limited, but can be produced by physically pulverizing silicon-containing particles to a target particle diameter. Preferable examples of the physical pulverization method include a bead mill pulverization method, a planetary ball mill pulverization method, a shock wave pulverization method, a high pressure collision method, a jet mill pulverization method, and a pulverization method combining two or more of these. It is also possible to adopt a known chemical method. From the viewpoint of production cost or ease of production control, a suitable pulverization method is a physical pulverization method. The fine particles composed of fine particles of silicon alone are exposed to the atmosphere to oxidize the surface and form a silicon oxide film. After the pulverization, a silicon oxide film may be artificially formed by a known method such as chemical oxidation using an oxidizing agent such as hydrogen peroxide solution or nitric acid.

  When the silicon-containing particles are manufactured by pulverizing the silicon-containing particles to a target particle diameter using a bead mill, the size or particle size distribution of the target particles is obtained by appropriately changing the size and / or type of the beads. be able to.

  The silicon-containing particles of the starting material are not limited as long as they are high-purity silicon particles. For example, commercially available high-purity silicon particle powder can be used. The silicon-containing particles of the starting material may be single crystal, polycrystalline, or amorphous.

  The silicon microparticles according to the present invention exhibit an excellent preventive and / or therapeutic effect on depression or depression. Symptoms of depression include depressed mood, sleep disorders, loss of interest and pleasure, impaired appetite, reduced thinking, concentration, and decision-making ability, sense of neglect, self-responsibility, tiredness, and reduced energy. As diagnostic criteria for depression, International Statistical Classification of Diseases and Related Health Problems (ICD) and Diagnostic and Statistical Manual of Mental Disorders (DSM) have been used. In the present invention, the depression or depression state includes, in terms of diagnostic criteria, a relatively mild state of symptoms that is not diagnosed as depression, and a depression state associated with another disease (for example, depression associated with anxiety disorder, cancer, etc.). Accompanying depression).

  The agent for preventing or treating depression or depression of the present invention includes an agent for preventing depression or depression, an agent for treating depression or depression, and an agent for preventing and treating depression or depression. It is.

  The prophylactic or therapeutic agent of the present invention exerts effects such as prevention of onset of symptoms, improvement of symptoms, suppression of symptom exacerbation, and prevention of recurrence of symptoms, for one or more symptoms related to depression or depression.

  The preventive or therapeutic agent for depression or depressive state of the present invention can preferably be a preventive or therapeutic agent for depression or depressive state accompanied by inflammation. The depression or depressive state accompanied by inflammation can be referred to as a depression or depressive state in which the amount of inflammatory cytokine produced is increased. Inflammatory cytokines include, for example, TNF-α and IL-6.

  The silicon fine particles in the present invention have a property of continuously generating hydrogen for a long time (20 hours or more) in vitro. In the preparation of one embodiment of the present invention, the silicon fine particles generate hydrogen when they come in contact with water having a pH of 7 or more, and generate more hydrogen at a pH of 8 or more. On the other hand, at a pH of 5 or less, it has a property of hardly generating hydrogen.

  When the silicon microparticles of the present invention are orally administered, it is considered that almost no hydrogen is generated in the stomach due to the above-mentioned properties, but hydrogen is generated in the intestine. When the silicon microparticles of the present invention were administered to normal mice, hydrogen generation was confirmed in the cecum, which is a part of the large intestine. Even when normal mice were fed a normal diet under the same conditions, hydrogen was below the detection limit. Since the retention time of food in the intestine is usually 20 hours or more in humans, the preventive or therapeutic agent of the present invention continues to generate hydrogen for a long time in the intestine by oral administration, and hydrogen in the body. Could be distributed.

  In addition, it is considered that hydrogen can be delivered to the body percutaneously or transmucosally for a long time by placing silicon fine particles on the skin or mucous membrane for a long time.

  In addition, the antioxidant power of the plasma was evaluated (BAP test) after administering the silicon microparticles to the rats, and it was confirmed that the antioxidant power was significantly increased in the silicon microparticle administration group.

  One of the mechanisms by which depression or depression is prevented and / or treated is that the silicon microparticles of the present invention continue to generate hydrogen over a long period of time, and the generated hydrogen is transported to the blood and organs. It is believed that the hydrogen selectively reacts with the hydroxyl radical. Further, since the antioxidant power in blood is improved, it is considered that the antioxidant is generated by antioxidants generated in blood. Furthermore, it is conceivable that the hydrogen water has another action that is not available. For example, nascent hydrogen generated in the intestine by the reaction between silicon microparticles and water, i.e., a hydrogen atom, is captured by a protein containing a metal element such as cobalt, or the hydrogen atom donates electrons, resulting in a strong reducing power. A possible mechanism is that the protein is transported to each organ, reacts with the hydroxyl radical, and disappears.

  The prophylactic or therapeutic agents of the prophylactic or therapeutic agent of the present invention are human and non-human animals. Preferred non-human animals include pets and livestock.

  One or more of the silicon microparticles in the present invention may be administered to a human or non-human animal as it is, but if necessary, mixed with an acceptable additive or carrier and known to those skilled in the art. It can be formulated and administered in a form. Such additives or carriers include, for example, pH adjusters (eg, sodium bicarbonate, sodium carbonate, potassium carbonate, citric acid, etc.), excipients (eg, sugar derivatives such as mannitol, sorbitol; corn starch, Starch derivatives such as potato starch; or cellulose derivatives such as crystalline cellulose, etc.); lubricants (eg, metal stearate such as magnesium stearate; or talc); binders (eg, hydroxypropyl cellulose, hydroxypropyl) Methylcellulose or polyvinylpyrrolidone, etc.), disintegrants (eg, cellulose derivatives such as carboxymethylcellulose, calcium carboxymethylcellulose), preservatives (eg, paraoxybenzoate such as methylparaben, propylparaben) Esters; or chlorobutanol, alcohols such as benzyl alcohol, etc.). These additives and carriers may be used alone or in combination of two or more to be blended with the silicon fine particles. Preferred additives include pH adjusters capable of adjusting the pH to 8 or more. Preferred pH adjusters include sodium bicarbonate.

  The administration route of the prophylactic or therapeutic agent of the present invention is not particularly limited, but preferred administration routes include oral, transdermal, transmucosal (oral, rectal, vaginal, etc.).

  Examples of the preparation for oral administration include tablets, capsules, granules, powders, syrups (dry syrups), oral jellies and the like. Examples of preparations for transdermal administration or transmucosal administration include patches and ointments.

  Tablets, capsules, granules, powders and the like can be made into enteric preparations. For example, tablets, granules, and powders are provided with an enteric coating. As the enteric coating agent, a gastric sparingly soluble enteric coating agent can be used. The capsule can be made enteric by filling the silicone particles of the present invention into an enteric capsule. Further, the generation rate of hydrogen can be adjusted by adjusting the particle size and particle size distribution of the silicon fine particles.

  After the prophylactic or therapeutic agent of the present invention is formulated into the above-mentioned dosage form, it can be administered to a human or non-human animal.

  The content of the 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 microparticles in the present invention are appropriately determined depending on conditions such as the subject of administration, the age, body weight, sex, purpose (for prevention or treatment), severity of symptoms, dosage form, and administration route. Can change. When administered to humans, 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. In addition, the number of administrations may be one or more times per day, or once every several days. For example, it may be 1-3 times, 1-2 times, or 1 time per day.

  The preventive or therapeutic agent for depression or depressive state containing the silicon microparticles 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 depression or depressive state, which contains silicon microparticles. The present application also relates to the invention of a pharmaceutical composition containing the agent for preventing or treating depression or depressive state containing the silicon microparticles. The pharmaceutical composition of the present invention also includes a composition having a moderate effect as a quasi-drug. Embodiments of the pharmaceutical composition of the present invention include embodiments of the present invention relating to the above-mentioned prophylactic or therapeutic agent.

  The present application also relates to the invention of a medical device containing the agent for preventing or treating depression or depressive state containing the silicon microparticles. In addition, the present invention relates to a medical device for preventing or treating depression or depressive state containing the silicon microparticles. The medical device in the present invention is a tool or a device intended to be used for treating or preventing a disease of a human or non-human animal. Examples of the medical device include a mask. By wearing the mask of the present invention, hydrogen can be supplied directly to the trachea or lung. Another example is a bandage.

  The present invention also relates to an invention of a food or beverage containing a prophylactic or therapeutic agent for depression or depressive state containing the silicon microparticles. The present invention also relates to a food or beverage for prevention or treatment of depression or depression containing the silicon microparticles. Preferred examples of the food or beverage of the present invention include health foods, functionally labeled foods, foods for specified health use, and the like. There are no restrictions on the form of the food or beverage. For example, it may be in the form of a mixture mixed with existing foods and beverages or in the form of a formulation. For example, tablets, capsules, powders, granules, jellies and the like can be mentioned.

  Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

<Example 1>
200 g of high-purity silicon powder (manufactured by Kojundo Chemical Laboratory Co., Ltd., particle size distribution <φ5 μm (however, silicon particles having a crystal particle diameter of more than 1 μm), purity 99.9%) are mixed with 4 L (liter) of a 99.5 wt% ethanol solution. ), Zirconia beads (capacity: 750 ml) having a diameter of 0.5 μm were added, and the mixture was rotated for 4 hours using a bead mill (manufactured by IMEX Co., Ltd., horizontal continuous ready mill (model: RHM-08)). Pulverization (single-step pulverization) was performed at several 2,500 rpm to make finer.

  The ethanol solution containing the finely divided silicon particles was separated from the beads by a separation slit provided inside the pulverizing chamber of the bead mill, and then heated to 30 ° C. to 35 ° C. using a reduced-pressure evaporator. By evaporating the ethanol solution, fine 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 crystallite was covered with the silicon oxide film, and the thickness of the silicon oxide film was about 1 nm. As a result of measuring this silicon crystallite with an X-ray diffractometer (Smart Lab made by Rigaku Denki), in volume distribution, the mode diameter was 6.6 nm, the median diameter was 14.0 nm, and the average crystallite diameter was 20.3 nm. . The resulting mixture of the silicon crystallites on which the silicon oxide film is formed and the aggregates thereof is one embodiment of the silicon fine particles that are the effective components of the present invention.

<Example 2>
The silicon crystallites and their aggregates obtained in Example 1 were mixed with a hydrogen peroxide solution (3 wt%) in a glass container and stirred at 35 ° C. for 30 minutes. The silicon crystallites and the aggregates thereof treated with the aqueous hydrogen peroxide solution were subjected to solid-liquid separation treatment using a known centrifugal separator to remove the aqueous hydrogen peroxide solution. Thereafter, the obtained silicon crystallites and their aggregates were mixed with an ethanol solution (99.5 wt%), and sufficiently stirred. The silicon crystallites and the aggregates thereof mixed with the ethanol solution were sufficiently dried after removing the highly volatile ethanol solution by a solid-liquid separation treatment using a known centrifugal separator. The resulting mixture of silicon crystallites on which a silicon oxide film is formed and the aggregates thereof, which has been treated with a hydrogen peroxide solution, is one embodiment of the silicon fine particles that are the effective components of the present invention. The hydrogen generation rate of the obtained silicon crystallite aggregate did not depend on the size of the aggregate.

  The amount of hydrogen generated in the silicon fine particles (silicon crystallites and aggregates thereof) obtained in Example 2 was measured. 10 mg of silicon microparticles were placed in a glass bottle having a capacity of 100 ml (a borosilicate glass having a thickness of about 1 mm and a Labolan screw tube manufactured by ASONE). Water adjusted to pH 8.2 with sodium bicarbonate was put into this glass bottle, the solution was sealed at a temperature of 36 ° C., and the hydrogen concentration in the solution in the glass bottle was measured. For the measurement of the hydrogen concentration, a portable dissolved hydrogen meter (model DH-35A, manufactured by Toa DKK Co., Ltd.) was used. FIG. 1 shows the amount of hydrogen generated per gram of silicon fine particles.

<Example 3>
Aggregates were separated from the mixture of silicon crystallites and the aggregates obtained in Example 2. The obtained aggregate of silicon crystallites is an embodiment of the silicon fine particles which are the active ingredients of the present invention. An electron scanning microscope (SEM) photograph of the obtained aggregate of silicon crystallites is shown in FIG.

<Example 4>
One-stage pulverization was performed in the same manner as in Example 1. The zirconia beads having a diameter of 0.5 μm (capacity: 750 ml) used in the one-stage pulverization were automatically separated from the solution containing silicon crystallites inside the bead mill pulverization chamber. To the obtained solution containing silicon crystallites, 0.3 μm zirconia beads (capacity: 750 ml) was added, and the silicon crystallites were further pulverized (two-step pulverization) at 2500 rpm for 4 hours to be refined.

  The beads were separated from the solution containing silicon crystallites as described above, and the resulting ethanol solution containing silicon crystallites was heated to 40 ° C. using a reduced pressure evaporator as in Example 1. The ethanol was evaporated, yielding a two-stage milled silicon crystallite. The silicon crystallite on which the silicon oxide film pulverized in two stages as described above is also one embodiment of the silicon fine particles which are the effective components of the present invention.

<Example 5>
The mixture of the silicon crystallites formed with the silicon oxide film treated with the hydrogen peroxide solution obtained in Example 2 and the aggregates thereof was filled in a commercially available Capsule 3 to obtain a capsule preparation. This capsule formulation is mainly composed of an aggregate of silicon crystallites having a silicon oxide film treated with a hydrogen peroxide solution, and further has a silicon crystallite having a silicon oxide film treated with a hydrogen peroxide solution. contains.

<Test example>
I. Preparation of Silicon Fine Particle-Containing Food A normal feed (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) was mixed with the silicon fine particles (silicon crystallites and aggregates thereof) produced in Example 2 so as to have a concentration of 2.5 wt%. . Further, an aqueous citric acid solution (pH 4) was added in an amount of about 0.5 wt% based on the total amount of the silicon fine particles and the feed, and the mixture was kneaded using a known kneading apparatus to obtain a food containing silicon fine particles. .

II. Pharmacological action of silicon microparticles

A. Improvement of antioxidant power SD rats (6 weeks old) were obtained. The group containing silicon microparticles was given the diet containing silicon microparticles, and the control group was given a normal feed (normal diet) (Model No. AIN93M, manufactured by Oriental Yeast Co., Ltd.). Blood was collected after administration for 8 weeks, and the antioxidant power of the plasma 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 microparticle administration group.

B. Pharmacological test in depression model mouse B-1. Preparation of Depression Model Mice ICR mice (male, 7 weeks old, weight: 30 to 35 g) were obtained from Japan SLC (Day 1). The silicon microparticle-containing group was fed the silicon microparticle-containing food for 7 days (Day1 to Day7), and the control group was fed a normal diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) (Day1 to Day7). A depression model was prepared by intraperitoneally administering 1 mg / kg of lipopolysaccharide (LPS) on day 6 (Day 6). For the control (normal group), physiological saline (Sal) was intraperitoneally administered.

B-2. Behavioral Test for Depression A behavioral test (tail suspension test, forced swimming test, and measurement of spontaneous activity) was performed 24 hours after LPS or saline administration (Day 7). The tail suspension test and the forced swimming test are behavioral tests for depression. In each test, 8 mice were used in each group.
B-2-1 Tail suspension test The mouse was hung upside down from the tail for 6 minutes, and the time of immobility was measured. FIG. 4 shows the results. The suspended mouse moves about to escape. A longer immobility time indicates an increase in depression, and a shorter one indicates a decrease.

B-2-2 Forced swimming test The mouse was put in a cylindrical container containing water for 4 minutes, and the time of immobility was measured. FIG. 5 shows the results. The forced swimming test is a test that utilizes the fact that mice forced to swim in an unavoidable environment do not swim. The longer the immobility time, the higher the depression behavior, and the shorter the immobility time, the lower the depression behavior.

B-2-3 Results As shown in FIGS. 4 and 5, in the depression model mouse (LPS), the control group (□) showed a depressed state, but the depressed state was suppressed in the silicon microparticle administration group (■). I was In addition, even when the normal group (Sal) was fed a diet containing silicon microparticles, no change in behavior related to depression occurred. This result indicates that the hydrogen generated by the silicon microparticles suppresses the depression state but does not act in the normal state. This is thought to be the result of hydrogen acting upstream of the path of depression (close to the cause of the pathogenesis). The prophylactic or therapeutic agent of the present invention is considered to be a safe drug which eliminates the causes of depression and depression and has few side effects.

B-3 Spontaneous Activity Measurement At the same time as the above-mentioned action test for depression, the spontaneous activity was measured using a Supermex (Muromachi Kikai Co., Ltd.) device for 10 minutes. FIG. 6 shows the results. There were no differences in spontaneous activity in any group. Therefore, it was confirmed that the depression model mouse (LPS) and the normal mouse (Sal) subjected to the tail suspension test and the forced swimming test have no difference in the amount of spontaneous activity. It was also confirmed that administration of silicon microparticles did not affect spontaneous activity.

B-4 Inflammatory cytokine Blood was collected 24 hours after LPS or physiological saline administration, and the concentration of inflammatory cytokines (IL-6 and TNF-α) in the serum was measured by ELISA (R & D systems). FIG. 7 shows the results. It was shown that the increase in the amount of inflammatory cytokine production was suppressed by silicon microparticles.

  From the above results, it has been clarified that the silicon microparticles according to the present invention exert a high preventive effect and a high therapeutic effect on depression or depression.

INDUSTRIAL APPLICABILITY The present invention can be one of the causative therapies for depression or depression, and greatly contributes to future medical treatment and health promotion.

Claims (14)

A prophylactic or therapeutic agent for depression or depressive state containing silicon microparticles. 2. The preventive or therapeutic agent according to claim 1, wherein the silicon fine particles are silicon-containing fine particles capable of generating hydrogen upon contact with water. 3. The preventive or therapeutic agent according to claim 1, wherein the silicon fine particles are silicon fine particles and / or aggregates of the silicon fine particles. 4. The preventive or therapeutic agent according to claim 3, wherein the silicon fine particles are fine particles composed of silicon alone and have a silicon oxide film formed on a surface thereof. The preventive or therapeutic agent according to claim 3, wherein the silicon fine particles are fine particles obtained by crushing a lump or particles of silicon alone. The preventive or therapeutic agent according to any one of claims 3 to 5, wherein the particle size of the aggregate of the silicon fine particles is 10 nm or more and 500 µm or less. The prophylactic or therapeutic agent according to any one of claims 3 to 6, wherein the silicon fine particles are silicon crystallites. 3. The preventive or therapeutic agent according to claim 1, wherein the silicon fine particles are porous silicon particles. The preventive or therapeutic agent according to any one of claims 1 to 8, wherein the silicon fine particles are silicon fine particles that have been subjected to a hydrophilic treatment. The preventive or therapeutic agent according to claim 9, wherein the hydrophilization treatment is a hydrogen peroxide solution treatment. The prophylactic or therapeutic agent according to any one of claims 1 to 10, which is for oral administration. A pharmaceutical composition for preventing or treating depression or depressive state, comprising silicon microparticles. A medical device comprising the prophylactic or therapeutic agent according to claim 1. A food or beverage containing the prophylactic or therapeutic agent according to claim 1.