JP2020117485A - Prophylactic or therapeutic agents for diabetes - Google Patents

Abstract

To provide pharmaceuticals and the like for preventing or treating diabetes.SOLUTION: The invention provides prophylactic or therapeutic agents, pharmaceutical composition, medical instruments, food or drink for diabetes containing silicon fine particles. Diabetes can be prevented or treated by orally administering or indwelling on the skin or mucous membrane the silicon fine particles with excellent prophylactic or therapeutic effects. The silicon fine particles are fine particles containing silicon which generates hydrogen in contact with water, and preferably silicon microparticles and/or aggregates of silicon microparticles.SELECTED DRAWING: Figure 5

Description

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

Diabetes is a disease in which hyperglycemia continues chronically due to decreased or insufficient action of insulin. It is roughly classified into two types depending on the presence or absence of insulin dependence. Risk factors for onset include aging, family history, obesity, lack of exercise, and impaired glucose tolerance. It is a very dangerous disease which may be accompanied by serious complications of retinopathy, nephropathy and neuropathy without subjective symptoms, and early treatment and prevention of onset are very important. Glycemic control is important for the treatment of diabetes, and diet and exercise are the first steps. Oral hypoglycemic agent (insulin resistance improving system (biguanide drug, thiazolidine drug); insulin secretagogue system (SU drug, glinide drug, DPP-4 inhibitor); glucose absorption if no effect after 2 to 3 months -Perform drug therapy using an excretion control system (α-Gl inhibitor, SLGT2 inhibitor, etc.).

While active oxygen is necessary for life support, it is known to oxidize and damage the cells that compose the living body. Active oxygen includes superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and singlet oxygen, but hydroxyl radicals are radicals with extremely high oxidative power, and when they are generated in the living body, substances that are close to them, such as DNA, lipids, It is known to oxidize proteins etc. and damage organs. Hydroxyl radicals are said to cause various diseases such as cancer and lifestyle-related diseases and aging due to such an action.

Hydrogen is known as a substance that extinguishes hydroxyl radicals generated in the body. It is water that produces hydrogen when it reacts with hydroxyl radicals, and does not produce substances that are harmful to living organisms. Therefore, there are many reports on hydrogen water containing hydrogen that extinguishes hydroxyl radicals in the body.

However, 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 a saturated state. Further, 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. Further, even if a high concentration of hydrogen water is ingested, a large amount of hydrogen in the hydrogen water is gasified in the upper digestive tract such as the stomach, which may cause a nausea symptom (so-called “belching”). Therefore, it is not easy to take in a sufficient amount of hydrogen in the body to react with hydroxyl radicals in the body by the method of ingesting hydrogen water. Furthermore, even if hydrogen is absorbed and transported to each organ, its concentration returns to that before hydrogen water intake in about 1 hour. Also, it is difficult to suck gaseous hydrogen in daily life.

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

The present inventors have found that silicon particles can generate hydrogen by contacting with water. The reaction is represented by the following formula.
Si+2H ₂ O→SiO ₂ +2H ₂
It was also found that this reaction hardly progressed when contacted with water having a pH of less than 5, and that when contacted with water having a pH of 7 or higher, the reaction proceeded, and at pH 8 or higher, the reaction proceeded faster. It was also found that the above reaction is favorably promoted by surface-treating the silicon fine particles. Further, it has been found that silicon fine particles continuously generate hydrogen for 20 hours or longer while being in contact with water, and depending on conditions, 1 g of silicon fine particles generate 400 ml or more of hydrogen (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 2017/130709 International Publication No. 2018/037752 International publication 2018/037818 International Publication 2018/037819

Shinsuke Matsuda et al., Water Decomposition and Hydrogen Concentration by Silicon Nanoparticles, Proc. of the 62nd JSAP Spring Meeting, 2015, 11a-A27-6

An object of the present invention is to provide a medicine, medical device, food, beverage or the like for prevention or treatment of diabetes.

The present inventors have found that silicon microparticles can prevent and/or treat diabetes, and have completed the present invention.
1. A preventive or therapeutic agent for diabetes containing silicon fine particles.
2. The preventive or therapeutic agent according to item 1, wherein the silicon fine particles are fine particles containing silicon capable of generating hydrogen when contacted with water.
3. 3. The preventive or therapeutic agent according to item 1 or 2, wherein the silicon fine particles are silicon fine particles and/or an aggregate of the silicon fine particles.
4. 4. The preventive or therapeutic agent according to the above 3, wherein the silicon fine particles are fine particles composed of simple substance of silicon 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 of silicon simple substance or particles.
6. The preventive or therapeutic agent according to any one of items 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.
7. The preventive or therapeutic agent according to any one of 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. The preventive or therapeutic agent according to any one of items 1 to 8 above, wherein the silicon fine particles are hydrophilized silicon fine particles.
10. The preventive or therapeutic agent according to item 9, wherein the hydrophilic treatment is a hydrogen peroxide solution treatment.
11. The preventive or therapeutic agent according to any one of items 1 to 10 above, which is for oral administration.
12. A pharmaceutical composition for preventing or treating diabetes, which comprises silicon fine particles.
13. A medical device containing the prophylactic or therapeutic agent according to any one of the above 1 to 11.
14. A food or beverage containing the prophylactic or therapeutic agent according to any one of the above 1 to 11.

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

The silicon fine particles contained in the preventive or therapeutic agent of the present invention are fine particles capable of generating hydrogen. Since OH ⁻ ions act catalytically in the hydrogen generation reaction, hydrogen is efficiently generated under alkaline conditions for more than 20 hours. On the other hand, the retention time of food in the human intestine is usually 20 hours or more.

The orally administered preventive or therapeutic agent of the present invention can continue to generate hydrogen in the intestine for a long time and continue to deliver hydrogen to the body. Further, it is considered that when the preventive or therapeutic agent of the present invention is left on the skin or mucous membrane for a long time, hydrogen can be continuously distributed into the body for a long time. It is considered that, by continuously delivering hydrogen in this manner, the antioxidant power in the body is improved and the improved antioxidant power is maintained.

Hydrogen water or gaseous hydrogen could not continuously deliver hydrogen to the body for a long time, but the preventive or therapeutic agent of the present invention should continuously deliver hydrogen to the body for a long time. You can Further, since the preventive or therapeutic agent of the present invention has a remarkable effect, it is considered that hydrogen water has an action not present.

Prevention and treatment with the prophylactic or therapeutic agent of the present invention can be one of the causative therapies for diabetes. Causal therapy is highly effective and safe. Further, the preventive or therapeutic agent of the present invention is excellent in safety because the product formed by reacting with the hydroxyl radical is water. The number of diabetic patients has been increasing in recent years with the aging of the population and the increase of obesity, and finding a causative therapy for diabetes will greatly contribute to future medical care and health promotion.

Further, the preventive or therapeutic agent of the present invention does not diffuse 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 photograph of silicon fine particles (a mixture of silicon crystallites and aggregates thereof) taken by 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 by a scanning electron microscope (SEM) (Example 3). FIG. 4 is a graph showing the results of antioxidative activity (BAP test) of plasma of normal SD rats to which silicon microparticles were administered for 8 weeks. Con represents a control group, and Si represents a silicon fine particle administration group. FIG. 5 is a graph showing measured body weights (g) of a normal diet group and a silicon fine particle-containing diet group in diabetic model mice. The vertical axis represents weight (g) and the horizontal axis represents time (week). The time on the horizontal axis starts from the start of administration of the normal diet or the silicon fine particle-containing diet. ○: Normal diet group, ●: Silicon fine particle-containing diet group FIG. 6 is a graph showing blood test results and urine test results of diabetic model mice fed a normal diet and diabetic model mice fed a silicon microparticle-containing diet. From the left, the blood glucose level (mg/dL), the amount of neutral fat (mg/dL), the total amount of ketone bodies (μmol/L), and the urine sugar level (mg/dL) are shown. ○: Normal diet diabetes model mouse ●: Silicon fine particle-containing diet diabetes model mouse FIG. 7 is a graph showing that a control group and a silicon fine particle administration group can be distinguished by 10 kinds of sulfur-related compounds as a result of multivariate analysis based on sulfur-related compounds. Con represents a control group, and Si represents a silicon fine particle administration group.

The fine silicon particles contained in the preventive or therapeutic agent of the present invention may be fine particles containing silicon and fine particles containing silicon 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) means that hydrogen is continuously generated when contacted with water at 36° C. and pH 8.2. However, it means 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, 300 ml or more.

The fine silicon particles contained in the preventive or therapeutic agent of the present invention are preferably fine silicon particles, an aggregate of the fine silicon 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, an aggregate 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 an aggregate 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 made of simple substance of silicon, but when exposed to the atmosphere, the surface of silicon simple substance is 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 made of simple silicon, silicon fine particles having a silicon oxide film formed on the surface thereof, aggregates of the fine silicon particles, and particles made of porous simple silicon. And 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 simple substance of silicon is high-purity silicon. In the present specification, high-purity silicon is silicon having a purity of 99% or higher, preferably 99.9% or higher, more preferably 99.99% or higher.

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

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 single crystal or polycrystal. Crystalline silicon fine particles are preferable, and single crystal silicon fine particles are more preferable.

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 according to the present invention may be a silicon oxide film formed by being naturally oxidized by being exposed to the air. 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 silicon oxide film may have any thickness as long as the fine particles made of silicon are stable and can efficiently generate hydrogen. For example, 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 containing silicon oxide such as Si ₂ O, SiO, Si ₂ O ₃ , and SiO ₂ in which silicon on the surface of fine particles is bonded to oxygen. Si ₂ O, SiO, Si ₂ O _{3 and the} like accelerate 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 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 a mixture of at least two selected from the group consisting of single crystal silicon fine particles, polycrystalline silicon fine particles and amorphous silicon fine particles.

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 preferable 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 crushing a lump of silicon simple substance (high-purity silicon) or particles obtained by crushing silicon simple substance particles. When silicon lumps or 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 size of the silicon fine particles in the present invention (the crystallite size when the fine particles are silicon crystallites) is preferably 0.5 nm or more and 100 μm or less, more preferably 1 nm or more and 50 μm or less, and more preferably 1 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, and 10 nm or more and 100 nm or less. When 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 an aggregate of the above silicon fine particles. It may be naturally formed or artificially formed. Preferably, it is an agglomerate of silicon fine particles having a silicon oxide film formed thereon. The naturally formed aggregates are believed to remain aggregated within the digestive tract. A preferred aggregate has a structure having voids inside so that water molecules can penetrate into the aggregate and react with the fine particles inside. The hydrogen generation rate of the naturally formed agglomerates does not depend on the agglomerate size, and thus the agglomerates have a structure in which water molecules can penetrate into the agglomerates and react with fine particles inside. Have.

The size of the aggregate of silicon fine particles is not particularly limited. The particle size of the aggregate of preferable silicon fine particles is 10 nm or more and 500 μm or less. The thickness is more preferably 50 nm or more and 100 μm or less, still more preferably 100 nm or more and 50 μm or less. Aggregates can be formed to retain the surface area of the fine particles and have sufficient surface area to achieve high hydrogen generating capacity.

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 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, and even 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 forming 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. It is preferably 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 size of 1 nm to 1 μm, more preferably a crystallite size 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 an aggregate thereof. Preferably, the main component is an aggregate of silicon crystallites having a silicon oxide film formed on the surface.

The porous silicon particles (porous silicon particles) can be a porous body of silicon particles. Further, it may be a porous body in which fine silicon particles are aggregated and processed. The porous silicon particles are preferably particles made of a simple substance of porous silicon, and particles having a silicon oxide film formed on the surface thereof.

The porous silicon particles may be crystalline porous 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.

There is no limitation on the size of the voids present in the porous silicon particles, but it can usually be 1 nm to 1 μm, and the porous silicon particles have a sufficient surface area to realize a high hydrogen generating ability. There is no particular limitation on the size of the porous silicon particles. It may preferably be 200 nm to 400 μm.

Aggregates 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, particularly the intestinal tract, and 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 hydrophilized silicon fine particles. The hydrophilized silicon fine particles improve the contact efficiency of water with the surface, promote the hydrogen generation reaction, and generate a large amount of hydrogen. The hydrophilic treatment method is not particularly limited, and a known hydrophilic treatment method may be used. For example, hydrogen peroxide solution treatment and nitric acid treatment may be mentioned. Peroxide water treatment is preferred. The hydrophilic treatment is preferably a treatment of removing the SiH group of the silicon oxide film on the particle surface and adding a hydroxyl group to the particle surface. The particle surfaces are 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 hydrogen peroxide solution and stirred. The concentration of hydrogen peroxide is preferably 1 to 30%, more preferably 1.5 to 20%, further preferably 2 to 15%, 2.5 to 10%, and most preferably 3 to 5%. The immersion and stirring time is preferably 5 to 90 minutes, more preferably 10 to 80 minutes, and further preferably 20 to 70 minutes. Most preferably, the hydrophilicity of the silicon fine particles can be improved by treating with hydrogen peroxide solution for 30 to 60 minutes. However, when the treatment time becomes long, the hydrogen generation reaction from the silicon fine particles proceeds to oxidize the silicon fine particles. Affects film thickness. The temperature of the hydrogen peroxide solution during the treatment with the hydrogen peroxide solution is preferably 20 to 60°C, more preferably 25 to 50°C, more preferably 30 to 40°C, and most preferably 35°C.

There is no particular limitation on the particle size distribution of the silicon fine particles contained in the preventive or therapeutic agent of the present invention, the particle size distribution of the 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 particle size or crystallite size in a specific range. The size distribution of the aggregate of silicon fine particles is not particularly limited.

The method for producing silicon fine particles of the present invention is not particularly limited, but the silicon fine particles can be produced by physically pulverizing the silicon-containing particles to a target particle size. Preferable examples of 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. It is also possible to adopt a known chemical method. From the viewpoint of manufacturing cost or easiness of manufacturing control, a suitable grinding method is a physical grinding method. When exposed to the air, fine particles made of fine particles of silicon are oxidized on the surface to form a silicon oxide film. Further, after crushing, the 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.

When the silicon-containing particles are pulverized to a target particle size using a bead mill, the size and/or type of the beads are appropriately changed to obtain the target particle size or particle size distribution. be able to.

The silicon-containing particles as 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, polycrystal, or amorphous.

The present invention is a preventive or therapeutic agent for diabetes. The preventive or therapeutic agent for diabetes includes an agent for preventing diabetes, an agent for treating diabetes, and an agent for preventing and treating diabetes.

The preventive or therapeutic agent of the present invention prevents an increase in blood sugar level, improves the blood sugar level, and suppresses the increase in blood sugar level. Further, with respect to one or more symptoms related to diabetes, the effects of prevention of onset, improvement of symptoms, suppression of exacerbation of symptoms, prevention of recurrence of symptoms, early recovery of symptoms and the like are exhibited. Symptoms of diabetes include thirst due to hyperglycemia, polydipsia, nocturia, rapid weight loss due to dehydration, and obesity due to polyphagia.

Diabetes as used herein includes all types of diabetes, including Type 1 diabetes, Type 2 diabetes and gestational diabetes. The preventive or therapeutic agent of the present invention may be preferably a preventive or therapeutic agent for type 2 diabetes.

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 formulation of one embodiment of the present invention, hydrogen is generated when the silicon fine particles come into contact with water having a pH of 7 or higher, and more hydrogen is generated at a pH of 8 or higher. 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 hydrogen is hardly generated in the stomach due to the above 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, and hydrogen was below the detection limit even when normal mice were fed under the same conditions. The retention time of food in the intestine is usually 20 hours or more in humans. Therefore, the prophylactic or therapeutic agent of the present invention, when orally administered, continues to generate hydrogen in the intestine for a long time and Could be distributed.

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

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

One of the mechanism of action for preventing and/or treating diabetes is that the silicon fine particles in the present invention continue to generate hydrogen for a long time, the generated hydrogen is transported to the blood or each organ, and the hydrogen is a hydroxyl radical. It is thought to be due to selective reaction with. Further, since the antioxidant power in blood is improved, it is considered that the antioxidant substances are generated in blood. Furthermore, in studies using disease model animals in which oxidative stress is involved, it shows a remarkable effect as compared with hydrogen water, so it is considered that there is another action that hydrogen water does not have. For example, a protein containing a metal element such as cobalt captures hydrogen in the initial state of generation in the intestine caused by the reaction between silicon fine particles and water, or a hydrogen atom donates an electron. A possible mechanism is that it is transported to organs, reacts with hydroxyl radicals, and disappears.

Targets for prevention or treatment of the preventive or therapeutic agent of the present invention are humans and non-human animals. Examples of preferable non-human animals include pets and livestock.

One kind or two or more kinds of the silicon fine particles in the present invention may be directly administered to humans or non-human animals, but if necessary, they may be mixed with an acceptable additive or carrier and well known to those skilled in the art. It can be formulated into a form and administered. Examples of such additives or carriers include pH adjusters (eg, sodium hydrogen carbonate, 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; lubricants (eg, stearic acid metal salts such as magnesium stearate; or talc); binders (eg hydroxypropyl cellulose, hydroxypropyl) Methylcellulose, polyvinylpyrrolidone, etc.), disintegrants (eg, cellulose derivatives such as carboxymethylcellulose, carboxymethylcellulose calcium, etc.), preservatives (eg, paraoxybenzoic acid esters such as methylparaben, propylparaben; or chlorobutanol, benzyl alcohol Such as alcohols). These additives and carriers may be blended in the silicon microparticles alone or in admixture of two or more. As a preferable additive, a pH adjuster capable of adjusting pH to 8 or more can be mentioned. Examples of preferable 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, 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 the preparation 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 enteric coated. As the enteric coating agent, an enteric coating agent which is poorly soluble in the stomach can be used. The capsule can be made enteric by filling the enteric-coated capsule with the silicon fine particles of the present invention. Further, the generation rate of hydrogen can be adjusted by adjusting the particle size and particle size distribution of the silicon particles.

The prophylactic or therapeutic agent of the present invention can be administered to a human or non-human animal after being formulated into the above dosage form.

The content of the silicon fine particles in the preventive or therapeutic agent of the present invention is not particularly limited, but 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 depending on conditions such as administration subject, age, weight, sex, purpose (whether for prophylactic treatment or therapeutic treatment), severity of symptoms, dosage form, administration route, etc. It can change. When administered to humans, a preferable 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 administration frequency may be once or multiple times per day, or once every several 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 diabetes containing the silicon microparticles of the present invention can be used for pharmaceuticals, quasi drugs, medical devices, hygiene products, foods and beverages.

The present application also relates to the invention of a pharmaceutical composition for preventing or treating diabetes, which comprises fine silicon particles. The present application also relates to the invention of a pharmaceutical composition containing a prophylactic or therapeutic agent for diabetes containing the above-mentioned silicon fine particles. The pharmaceutical composition of the present invention also includes a composition having a gradual action corresponding to a quasi drug. Examples of the embodiment of the pharmaceutical composition of the present invention include the 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 containing a preventive or therapeutic agent for diabetes containing the above-mentioned silicon fine particles. The present invention also relates to an invention of a medical device for preventing or treating diabetes, which contains the above silicon fine particles. The medical device in the present invention is a tool or device intended to be used for treatment or prevention of human or non-human animal disease. Examples of the medical device include a mask. By wearing the mask of the present invention, hydrogen can be directly supplied to the trachea or lungs. Another example is a bandage.

The present application also relates to the invention of a food or drink containing the preventive or therapeutic agent for diabetes containing the above silicon fine particles. The present invention also relates to an invention of a food or beverage for preventing or treating diabetes, which contains the above silicon fine particles. Preferable 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. There is no limitation on the form of food or beverage. For example, it may be in the form of a mixture mixed with existing foods or beverages or in the form of a formulation. Examples thereof include tablets, capsules, powders, granules, jellies and the like.

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., particle size distribution <φ5 μm (however, silicon particles having a crystal particle size of more than 1 μm), purity 99.9%), 200 g of 99.5 wt% ethanol solution 4 L (liter ), Φ0.5 μm zirconia beads (capacity 750 ml) were added, and the mixture was rotated for 4 hours using a bead mill device (IMEX Co., Ltd., horizontal continuous ready mill (model, RHM-08)). Pulverization (single-stage pulverization) was performed at several 2500 rpm to make it fine.

The ethanol solution containing finely divided silicon particles was separated from the beads by a separation slit provided inside the grinding chamber of the bead mill, 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 refined silicon particles (crystallites) obtained by the above method had a crystallite diameter of mainly 1 nm or more and 100 nm or less, and most of the crystallites formed aggregates. The crystallite was covered with a silicon oxide film, and the thickness of the silicon oxide film was about 1 nm. As a result of measuring this silicon crystallite by an X-ray diffractometer (Smart Lab manufactured by Rigaku Denki Co., Ltd.), in the 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 obtained mixture of silicon crystallites on which the silicon oxide film is formed and aggregates thereof is one embodiment of silicon fine particles which is an active ingredient 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. The silicon crystallites and aggregates thereof treated with the hydrogen peroxide solution were subjected to solid-liquid separation treatment to remove the hydrogen peroxide solution using a known centrifugal separator. After that, the obtained silicon crystallites and their aggregates were mixed with an ethanol solution (99.5 wt %), and they were 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 process using a known centrifugal separation device. The obtained mixture of silicon crystallites having a silicon oxide film formed thereon and aggregates thereof treated with hydrogen peroxide solution is one embodiment of silicon fine particles which is an active ingredient 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 silicon crystallite aggregates did not depend on the aggregate size.

The hydrogen generation amount of the silicon fine particles (silicon crystallites and aggregates thereof) obtained in Example 2 was measured. 10 mg of silicon fine particles were placed in a glass bottle having a capacity of 100 ml (borosilicate glass thickness of about 1 mm, Laborone screw tube bottle manufactured by ASONE). Water adjusted to pH 8.2 with sodium hydrogen carbonate was placed in this glass bottle, and the liquid temperature was sealed under the 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 Ltd., 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>
In the same manner as in Example 2, the silicon fine particles (silicon crystallites and aggregates thereof) obtained in Example 1 were treated with hydrogen peroxide solution, mixed with an ethanol solution, and stirred. The silicon fine particles mixed with the ethanol solution were dried using a spray dryer (ADL311S-A, manufactured by Yamato Scientific Co., Ltd.). The obtained aggregate of silicon crystallites is an embodiment of silicon fine particles which is an active ingredient of the present invention. An electron scanning microscope (SEM) photograph of the obtained silicon fine particles (aggregates of silicon crystallites) is shown in FIG.

<Example 4>
One-step pulverization was performed in the same manner as in Example 1. The φ0.5 μm zirconia beads (volume: 750 ml) used for the one-step pulverization were automatically separated from the solution containing silicon crystallites inside the bead mill pulverization chamber. 0.3 μm beads made of zirconia (capacity: 750 ml) were added to the obtained solution containing silicon crystallites, and the silicon crystallites were further pulverized (two-stage pulverization) at a rotation speed of 2500 rpm for 4 hours to be miniaturized.

The beads were separated from the solution containing silicon crystallites as described above, and the obtained ethanol solution containing silicon crystallites was heated to 40° C. using a vacuum evaporator as in Example 1. The ethanol was evaporated and a two-step crushed silicon crystallite was obtained. The silicon crystallite on which the silicon oxide film obtained by the two-step pulverization is formed is also an embodiment of the silicon fine particles which are the active ingredient of the present invention.

<Example 5>
A commercially available capsule No. 3 was filled with the mixture of the silicon crystallite having the hydrogen peroxide solution-treated silicon oxide film formed in Example 2 and its aggregate, to obtain a capsule preparation. This capsule formulation is mainly composed of an aggregate of silicon crystallites on which a hydrogen peroxide solution-treated silicon oxide film is formed, and further a silicon crystallite on which a hydrogen peroxide solution-treated silicon oxide film is formed. contains.

<Test example>
I. Preparation of Food Containing Silicon Microparticles Normal feed (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) was mixed with the silicon microparticles (silicon crystallites and aggregates thereof) produced in Example 2 to 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 the mixture was kneaded using a known kneading device to obtain a silicon fine particle-containing food. ..

II. Pharmacological action of silicon particles

A. Improvement of antioxidant capacity SD rats (6 weeks old) were obtained. 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 administration for 8 weeks, and the antioxidative activity of plasma was evaluated (BAP test) (free radical analyzer FREE Carrio Duo). The results are shown in Fig. 4. It was shown that the antioxidative power was significantly increased in the silicon fine particle administration group.

B. Pharmacological test in diabetic model mice db/db mice (male, 5 weeks old) were obtained from Charles River Japan. The db/db mouse is a type 2 diabetic model showing a tendency toward hyperphagia because the leptin receptor involved in appetite control is deficient. This mouse was fed with a normal diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) and the diet containing silicon fine particles from 5 weeks to 2 months (up to 13 weeks). The weight measurement result is shown in FIG. As shown in FIG. 5, the mice fed with normal diet showed a significant weight increase due to the influence of overeating, whereas those fed with the diet containing silicon microparticles suppressed the increase significantly. In addition, blood test results and urine test results at 13 weeks of age (blood sugar level: left end of FIG. 6, neutral fat: left center of FIG. 6, total ketone body amount: right center of FIG. 6, urine sugar value: right end of FIG. 6) In comparison with mice on a normal diet, mice fed a diet containing silicon microparticles tended to suppress the increases in blood glucose, triglyceride, total ketone bodies and urinary glucose observed in diabetic patients. Was observed. In the above-mentioned test, diabetic model mice of 5 in the normal diet group and 5 in the diet group containing silicon particles were used.

C. Multivariate analysis C-1 sample preparation based on sulfur related compounds
C57BL/6J mice (male, 7 weeks old) were obtained from Japan SLC. The silicon microparticle-administered group was fed with the above-mentioned silicon microparticle-containing diet, and the control group was fed with a normal feed (normal diet) (manufactured by Oriental Yeast Co., Ltd., model number AIN93M), 5 animals per group for 1 week. For each mouse, the large intestine was removed under deep anesthesia and divided into three parts, the cecum, colon and rectum. Part of each site (about 2 cm) from which the intestinal tract inclusion was taken out was put together and weighed. After the measurement, the sample is rapidly frozen with powdered dry ice to obtain a large intestine sample of one mouse. A total of 10 frozen large intestine samples of 5 animals per group were used for the sulfur index analysis (Euglena Co., Ltd.). Samples were prepared in the same manner as the following day, and a total of 10 frozen large intestine samples of 5 animals per group were prepared and similarly used for sulfur index analysis (Euglena Co., Ltd.).

C-2 Pretreatment for analysis The frozen mouse large intestine samples of the same group (5) obtained in the first sample preparation were combined, and a methanol extract containing an internal standard compound was added (1 ml/g (organ)), Mashed with pestle. Then, centrifugation was performed, and 100 μl of the supernatant was used as a sample. Sulfur compound labeling reagents and the like were added to 100 μl of the sample supernatant after centrifugation (total 130 μl) and suspended. The centrifuged supernatant (87 μl) was dried on a centrifugal evaporator. 5 μl of the supernatant resuspended in 60 μl of water and centrifuged was used as a sample for sulfur index analysis. The sample obtained in the second sample preparation was processed in the same manner to obtain a sample for sulfur index analysis. The samples used for the sulfur index analysis were 2 samples (2 mixed samples from 5 animals) in the silicon fine particle administration group and 2 samples (2 mixed samples from 5 animals) in the control group.

C-3 Sulfur Index Analysis Sulfur compounds contained in the prepared samples were analyzed by LC MSMS 8040 (manufactured by Shimadzu Corporation) using a sulfur index method. Specifically, among the measurement target compound types in Tables 1 and 2, all 61 types of sulfur-related compound types, excluding the internal standard compound (No. 53; Camphorsulfonate) and the thiol group modifier (No. 40; Monobromobimane) Relative quantification was performed at. The peak area of the obtained mass chromatogram (standardized with the internal standard compound) was used for the relative quantification. A total of 35 compounds were detected in the colon sample. Mapping analysis of similarity between samples (using R software vegan package) was performed based on multivariate analysis based on the detected sulfur-related compound data.

C-4 Multivariate analysis As a result of performing a multivariate analysis on each sample based on the 35 kinds of sulfur-related compounds detected in C-3 above, the silicon fine particle administration group and the control group should be distinguished by the following 10 compounds. I was able to. FIG. 7 shows the multivariate analysis results (average values of the analysis results of each two samples) of the following 10 compounds in the silicon fine particle administration group and the control group.
Glutathione monosulfide (labeled)
Cysteinylglycine (labeled)
Thiosulfate ion (labeled)
Hipotaurine
5-glutamylcysteine (labeled)
Cysteine monosulfide (labeled)
S-sulfocysteine sulfite ion (labeled)
Serine taurine

The above compounds include glutathione monosulfide, cysteine monosulfide, etc., which are involved in antioxidative action in vivo, and are considered to play a part in the antioxidative action of silicon preparations. Since no such report has been made for hydrogen, it may be one of the antioxidant effects peculiar to the preventive or therapeutic agent of the present invention.

From the above results, it became clear that the silicon microparticles of the present invention exert a high preventive effect and a high therapeutic effect against diabetes.

INDUSTRIAL APPLICABILITY The present invention can be one of the causal treatments for diabetes and will greatly contribute to future medical treatment and health promotion.

Claims (14)

A preventive or therapeutic agent for diabetes containing silicon fine particles. The preventive or therapeutic agent according to claim 1, wherein the silicon fine particles are fine particles containing silicon capable of generating hydrogen in contact with water. The preventive or therapeutic agent according to claim 1 or 2, wherein the fine silicon particles are fine silicon particles and/or aggregates of the fine silicon particles. The preventive or therapeutic agent according to claim 3, wherein the silicon fine particles are fine particles made of simple substance of silicon and having a silicon oxide film formed on the surface thereof. The preventive or therapeutic agent according to claim 3 or 4, wherein the silicon fine particles are lumps of silicon simple substance or fine particles obtained by crushing particles. 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 preventive or therapeutic agent according to any one of claims 3 to 6, wherein the silicon fine particles are silicon crystallites. The preventive or therapeutic agent according to claim 1 or 2, 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 hydrophilized silicon fine particles. The preventive or therapeutic agent according to claim 9, wherein the hydrophilic treatment is a hydrogen peroxide solution treatment. The preventive or therapeutic agent according to any one of claims 1 to 10, which is for oral administration. A pharmaceutical composition for preventing or treating diabetes, which comprises fine silicon particles. A medical device containing the prophylactic or therapeutic agent according to any one of claims 1 to 11. A food or beverage containing the prophylactic or therapeutic agent according to any one of claims 1 to 11.