Fine silicon particle-containing preventive or therapeutic agent for diseases

Abstract

[Problem] To provide a medicine capable of preventing or treating non-alcoholic fatty liver disease, pain associated with inactivity or acute pancreatitis, etc. [Solution] Non-alcoholic fatty liver disease, pain associated with inactivity and acute pancreatitis can be prevented or treated by orally administering fine silicon particles or placing the same on the skin or a mucosa. The fine silicon particles are particles that generate hydrogen when coming into contact with an aqueous solution of pH 7 or higher. Provided are a preventive or therapeutic agent for non-alcoholic fatty liver disease, pain associated with inactivity or acute pancreatitis, a medicinal composition, a medical instrument, a food or a beverage, each containing the fine silicon particles. Preferably, the fine silicon particles are ultrafine silicon particles and / or an aggregate of the ultrafine silicon particles.

Description

Preventive or therapeutic agent for diseases containing silicon microparticles

[0001] The present invention relates to the prevention or treatment of non-alcoholic fatty liver disease, inactivity-associated pain and acute pancreatitis.

[0002] Non-alcoholic steatohepatitis (NASH) is a type of hepatitis caused by the accumulation of fat in the liver due to factors other than alcohol. It is often asymptomatic and can be caused by overeating or lack of exercise. Fatty liver, a precursor to NASH, increases the risk of arteriosclerosis, myocardial infarction, and stroke, and prolonged NASH increases the risk of developing cirrhosis and liver cancer, so early treatment is important. The main treatments are dietary restrictions and exercise therapy, but the development of a therapeutic drug is urgently needed.

[0003] Excessive bed rest, being bedridden, and prolonged immobilization such as plaster casts as conservative treatments for fractures can lead to complications such as disuse muscle atrophy, pain, nerve paralysis, and circulatory disorders. Prolonged joint immobility is considered a risk factor for the development of intractable chronic pain such as complex regional pain syndrome (CRPS). Pain treatments primarily involve nonsteroidal anti-inflammatory drugs and acetaminophen, but chronic pain such as CRPS can sometimes be resistant to drug treatment, and therapeutic agents with new mechanisms of action are needed.

[0004] Acute pancreatitis is an acute inflammatory disease in which activated pancreatic enzymes autodigest the pancreas and surrounding organs. It is primarily caused by alcohol or gallstones, and symptoms include severe upper abdominal pain, vomiting, and fever. In severe cases, the patient may lose consciousness or go into shock. Severe acute pancreatitis is a highly fatal disease in which inflammatory substances such as cytokines produced by autodigestion spread throughout the body via the bloodstream, causing shock, respiratory failure, acute nephritis, and other organ damage. The primary treatment for acute pancreatitis is nutritional management, including fasting and intravenous fluid administration. While there are therapeutic drugs, such as protease inhibitors (gabexate mesilate) that suppress the activity of pancreatic enzymes and prevent the progression of pancreatitis, the development of a cure for acute pancreatitis is urgently needed.

[0005] While reactive oxygen species are necessary for life maintenance, they are known to oxidize and damage cells that constitute living organisms. Reactive oxygen species include superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and singlet oxygen. Hydroxyl radicals are radicals with extremely high oxidizing power, and when generated in living organisms, they are known to oxidize nearby substances such as DNA, lipids, and proteins, thereby damaging organs. Due to these actions, hydroxyl radicals are believed to cause various diseases such as cancer and lifestyle-related diseases, as well as aging.

[0006] Hydrogen is known as a substance that can eliminate hydroxyl radicals generated in the body. When hydrogen reacts with hydroxyl radicals, it produces water, which does not produce substances harmful to the body. Therefore, there have been many reports on hydrogen water, which contains hydrogen that can eliminate hydroxyl radicals in the body.

[0007] However, the saturated hydrogen concentration is 1.6 ppm at room temperature, and the amount of hydrogen contained in 1 liter of hydrogen water, even at saturated state, is only 18 ml (milliliters) of gaseous hydrogen. Furthermore, hydrogen's small molecular size means that hydrogen in hydrogen water passes through the container and diffuses into the air, making it difficult to maintain the amount of dissolved hydrogen in hydrogen water. Even if high-concentration hydrogen water is ingested, much of the hydrogen in the hydrogen water will gasify in the upper digestive tract, such as the stomach, which can cause aerophagia (commonly known as "burping"). Therefore, ingesting hydrogen water does not easily deliver sufficient hydrogen to the body to react with hydroxyl radicals in the body. Furthermore, even if hydrogen is absorbed and transported to various organs, its concentration returns to its pre-intake concentration within about an hour. Inhaling gaseous hydrogen in daily life is also difficult.

[0008] Silicon microparticles can generate hydrogen when they come into contact with water. This reaction hardly progresses when they come into contact with an acidic aqueous solution with a pH of less than 5, but the reaction progresses when they come into contact with an aqueous solution with a pH of 7 or higher, and the reaction progresses more rapidly at a pH of 8 or higher. Furthermore, the reaction proceeds favorably by surface-treating the silicon microparticles. Furthermore, while the silicon microparticles are in contact with the aqueous solution, they continue to generate hydrogen for 20 hours or more, and under certain conditions, 1 g of silicon microparticles can generate 400 ml or more of hydrogen (Patent Document 1, Patent Document 2, Non-Patent Document 1). 400 ml of hydrogen is equivalent to the hydrogen contained in 22 liters of saturated hydrogen water.

[0009] Patent Document 3 describes a solid preparation that contains silicon microparticles as a main component and has hydrogen generating ability, but does not describe that silicon microparticles can prevent or treat diseases.

[0010] Patent Document 4 describes a hydrogen supplying material comprising a medium containing silicon microparticles and water. It also describes the use of this hydrogen supplying material to supply hydrogen to the skin or mucous membranes. However, it does not describe that silicon microparticles can prevent or treat diseases.

[0011] Patent Document 5 describes the treatment of silicon microparticles with hydrogen peroxide water, but does not describe that silicon microparticles can prevent or treat diseases.

[0012] Patent Document 6 describes a formulation containing silicon microparticles, and cites embodiments in which the silicon microparticles are contained in a "matrix" such as animal medicines, livestock or pet foods, animal feed, plant medicines, plant fertilizers, or plant compost. Although it describes the promotion of animal health and / or disease prevention, it does not state that the silicon microparticles can prevent or treat disease to the extent that they can be used as a medicine.

[0013] Patent Document 7 mainly describes a silicon oxide film formed on the surface of silicon microparticles. It describes possible uses for the silicon microparticles, such as feed, supplements, food additives, and transdermal and / or transmucosal hydrogen uptake, and describes the improvement of animal health and / or disease prevention. However, it does not describe the ability of silicon microparticles to prevent or treat disease to the extent that they could be used as a pharmaceutical.

[0014] The present inventors have found that silicon microparticles can prevent and treat kidney disease, inflammatory bowel disease, arthritis, hepatitis, dermatitis, visceral discomfort, depression or depressive states, Parkinson's disease, autism spectrum disorder, memory disorders, spinal cord injury, hearing loss, cerebral ischemia-reperfusion injury, diabetes, and hangovers, and have filed patent applications for these diseases (Patent Documents 8 to 22).

[0015] Japanese Patent Application Publication No. 2016-155118 Japanese Patent Application Publication No. 2017-104848 International Publication No. 2017 / 130709 International Publication No. 2018 / 037752 International Publication No. 2018 / 037818 International Publication No. 2018 / 037819 International Publication No. 2019 / 211960 International Publication No. 2019 / 021769 International Publication No. 2019 / 235577 Japanese Patent Application Publication No. 2019-214556 Japanese Patent Application Publication No. 2020-007 No. 300, Japanese Patent Application Laid-Open No. 2020-079228, Japanese Patent Application Laid-Open No. 2020-079240, Japanese Patent Application Laid-Open No. 2020-117480, Japanese Patent Application Laid-Open No. 2020-117481, Japanese Patent Application Laid-Open No. 2020-117482, Japanese Patent Application Laid-Open No. 2020-117483, Japanese Patent Application Laid-Open No. 2020-117484, Japanese Patent Application Laid-Open No. 2020-117485, Japanese Patent Application Laid-Open No. 2020-117486, Japanese Patent Application Laid-Open No. 2020-200302, International Publication No. 2020 / 152985

[0016] Matsuda Shinsuke et al., Water decomposition and hydrogen concentration by silicon nanoparticles, Proceedings of the 62nd Spring Meeting of the Japan Society of Applied Physics, 2015, 11a-A27-6

[0017] An objective of the present invention is to provide a medicine, medical device, food, beverage, or the like for preventing or treating non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.

[0018] The present inventors have discovered that silicon microparticles can prevent and / or treat non-alcoholic fatty liver disease, pain associated with disuse, and acute pancreatitis, and have completed the present invention. 1. A preventive or therapeutic agent for a disease, containing silicon microparticles, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with disuse, and acute pancreatitis. 2. The preventive or therapeutic agent according to the preceding paragraph 1, wherein the disease is non-alcoholic fatty liver disease. 3. The preventive or therapeutic agent according to the preceding paragraph 2, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis. 4. The preventive or therapeutic agent according to the preceding paragraph 1, wherein the disease is pain associated with disuse. 5. The preventive or therapeutic agent according to the preceding paragraph 4, wherein the pain associated with disuse is pain associated with musculoskeletal disuse syndrome. 6. The preventive or therapeutic agent according to the preceding paragraph 5, wherein the pain associated with musculoskeletal disuse syndrome is pain associated with muscle atrophy or joint contracture. 7. The preventive or therapeutic agent according to the preceding paragraph 1, wherein the disease is acute pancreatitis. 8. The preventive or therapeutic agent according to item 7 above, wherein the acute pancreatitis is severe acute pancreatitis. 9. The preventive or therapeutic agent according to any one of items 1 to 8 above, wherein the silicon microparticles are microparticles containing elemental silicon capable of generating hydrogen on contact with water. 10. The preventive or therapeutic agent according to any one of items 1 to 9 above, wherein the silicon microparticles are silicon microparticles and / or aggregates of said silicon microparticles. 11. The preventive or therapeutic agent according to any one of items 1 to 9 above, wherein the silicon microparticles are porous silicon particles. 12. A pharmaceutical composition containing silicon microparticles for preventing or treating a disease, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with sedentary lifestyle, and acute pancreatitis. 13. A medical device containing silicon microparticles for preventing or treating a disease, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with sedentary lifestyle, and acute pancreatitis. 14. A food or beverage containing silicon microparticles for the prevention or treatment of a disease, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.15. A therapeutic agent for a disease, containing silicon microparticles, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis. 16. A method for preventing or treating at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis, comprising administering silicon microparticles. 17. A method for treating at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis, comprising administering silicon microparticles. 18. An agent for use in preventing or treating at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis, containing silicon microparticles. 19. An agent for use in treating at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis, containing silicon microparticles. 20. 20. Use of silicon microparticles for the preparation of a medicament for the prevention or treatment of at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis. 21. Use of silicon microparticles for the preparation of a medicament for the treatment of at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.

[0019] The preventive or therapeutic agent of the present invention can prevent and treat non-alcoholic fatty liver disease. The preventive or therapeutic agent of the present invention can prevent and treat liver dysfunction associated with non-alcoholic fatty liver disease. Furthermore, the preventive or therapeutic agent of the present invention can suppress fat accumulation in the liver. Furthermore, the preventive or therapeutic agent of the present invention can suppress liver fibrosis. The therapeutic agent of the present invention can suppress the exacerbation of non-alcoholic fatty liver and prevent non-alcoholic steatohepatitis.

[0020] The preventive or therapeutic agent of the present invention can prevent and treat pain associated with sedentary behavior, as well as pain associated with joint contracture and muscle atrophy.

[0021] The preventive or therapeutic agent of the present invention can prevent and treat acute pancreatitis, and can also inhibit the shedding of pancreatic acinar cells associated with acute pancreatitis and reduce the infiltration of immune cells into pancreatic tissue.

[0022] Prevention and treatment using the preventive or therapeutic agent of the present invention can be one of the causal therapies for non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis, and is highly effective and safe. Because of its excellent safety, it can also be administered long-term. Therefore, it will make a significant contribution to future medical care.

[0023] Figure 1 is a photograph of silicon microparticles (a mixture of silicon crystallites and their aggregates) taken with a scanning electron microscope (SEM) (Example 2). Figure 2 is a graph showing the amount of hydrogen (cumulative amount) generated per gram of silicon microparticles by contacting the silicon microparticles obtained in Example 2 with water at 36°C and pH 8.2. Figure 3 is a photograph of silicon microparticles (aggregates of silicon crystallites) taken with a scanning electron microscope (SEM) (Example 3). Figure 4 shows the total bilirubin concentration in the blood of non-alcoholic steatohepatitis model mice. It shows that administration of silicon microparticles significantly suppressed the total bilirubin concentration in the blood and alleviated liver dysfunction. Con: control group, Si: silicon microparticle-administered group, each group n = 13, *p < 0.05, **p < 0.01, t-test (vs. Con). Figure 5 shows the total bile acid concentration in the blood of non-alcoholic steatohepatitis model mice. This shows that administration of silicon microparticles significantly suppressed blood total bile acid concentration and alleviated liver dysfunction. Con: control group, Si: silicon microparticle-administered group, n=13 for each group, **p<0.01, t-test (vs. Con). Figure 6 shows (a) an image of the liver of a non-alcoholic steatohepatitis model mouse stained with Sudan III and (b) a graph showing the ratio of the stained area to the total tissue area. Neutral fat is stained orange-red. Administration of silicon microparticles significantly suppressed fat accumulation in the liver. Con: control group, Si: silicon microparticle-administered group, n=13 for each group, **p<0.01, t-test (vs. Con). Figure 7 shows (a) an image of the liver of a non-alcoholic steatohepatitis model mouse stained with oil red and (b) a graph showing the ratio of the stained area to the total tissue area. With oil red staining, only neutral fat droplets are stained red. Administration of silicon microparticles significantly suppressed fat droplet accumulation in the liver. Con: control group, Si: silicon microparticle-administered group, n=13 for each group, **p<0.01, t-test (vs. Con). Figure 8 shows (a) an HE-stained image of the liver of a nonalcoholic steatohepatitis model mouse and (b) a graph showing the degree of fat deposition (ratio of vacuolar area to total tissue area). In image (a), lipid droplets are observed as vacuoles. The flat white areas are not vacuoles but vascular lumens. In the livers of control mice, balloon-like swelling and fibrosis of hepatocytes were observed.On the other hand, these were not observed in the livers of mice administered silicon microparticles. Administration of silicon microparticles significantly suppressed fat deposition. Con: control group; Si: silicon microparticle-administered group; n=13 for each group, **p<0.01, t-test (vs. Con). Figure 9 is a graph showing the results of pain threshold measurements in a von Frey test on a mouse model of disuse muscle atrophy caused by wearing a cast (mice fed a normal diet). It was confirmed that wearing a cast lowered the pain threshold. n=8-9, **p<0.01, t-test. Figure 10 shows the results of pain threshold measurements in a von Frey test on a mouse model wearing a cast, showing the ratio of the pain threshold on the side with the cast to the pain threshold on the untreated side. This shows that the decrease in pain threshold caused by wearing a cast was suppressed by administration of silicon microparticles. Con: control group n=8-9, Si: silicon microparticle-administered group n=10, #p<0.1, *p<0.05, t-test (vs. Con). Figure 11 shows HE-stained images of the pancreas of a severe acute pancreatitis model, indicating the degree of inflammation in the pancreas. Low magnification is shown on the left, and high magnification is shown on the right. The infiltration of blood cells and the loss of acinar cells, which are responsible for exocrine secretion, observed in the pancreas of control mice were hardly observed in the pancreas of mice administered with silicon microparticles, indicating that the administration of silicon microparticles suppresses inflammation and the loss of pancreatic acinar cells. Con: control mouse, Si: silicon microparticle-administered mouse. Figure 12 shows fluorescent immunostained images of the pancreas of a severe acute pancreatitis model, indicating the degree of infiltration of neutrophils (marker: Gr-1) and macrophages (marker: F4 / 80). Low magnification is shown on the left, and high magnification is shown on the right. While there was significant infiltration of neutrophils and macrophages in the pancreas of control mice, no neutrophil infiltration was observed in the pancreas of mice administered with silicon microparticles, and only a small number of macrophages infiltrated outside the cells, indicating that immune cell infiltration was suppressed by the administration of silicon microparticles. Con: control mouse, Si: mouse administered with silicon microparticles.

[0024] The silicon microparticles contained in the preventive or therapeutic agent of the present invention are microparticles containing elemental silicon, and are capable of generating hydrogen when in contact with water.

[0025] The above-mentioned "microparticles containing silicon element capable of generating hydrogen upon contact with water" (silicon microparticles having hydrogen generating ability) means silicon microparticles that, when contacted with an aqueous solution at 36°C and pH 8.2, continuously generate hydrogen, and are capable of generating 10 ml or more of hydrogen per gram of silicon microparticles in 24 hours. Preferably, the amount is 20 ml or more, 40 ml or more, 80 ml or more, 150 ml or more, 200 ml or more, or 300 ml or more.

[0026] The silicon element is high-purity silicon. In this specification, high-purity silicon means silicon having a purity of 98% or more, preferably 99% or more, more preferably 99.5% or more, more preferably 99.9% or more, more preferably 99.99% or more, and even more preferably 99.999% or more.

[0027] The silicon microparticles contained in the preventive or therapeutic agent of the present invention are preferably silicon microparticles, aggregates of the silicon microparticles, and / or porous silicon particles.

[0028] The active ingredient of the preventive or therapeutic agent of the present invention is preferably at least one type of particle selected from the group consisting of silicon microparticles, agglomerates of said silicon microparticles, and porous silicon particles. That is, the preferred active ingredient may be silicon microparticles alone, agglomerates of silicon microparticles alone, or porous silicon particles alone. The active ingredient may also contain two or more types of silicon microparticles. The preventive or therapeutic agent of the present invention preferably contains silicon microparticles and / or agglomerates of said silicon microparticles. More preferably, the main ingredient is agglomerates of silicon microparticles.

[0029] When elemental silicon is exposed to the atmosphere, its surface is oxidized to form a silicon oxide film. The silicon microparticles of the present invention are preferably microparticles having a silicon oxide film formed on their surfaces. The preferred silicon microparticles of the present invention are at least one type of particle selected from the group consisting of fine particles made of elemental silicon and having a silicon oxide film formed on their surfaces, aggregates of such silicon microparticles, and porous silicon particles made of porous elemental silicon and having a silicon oxide film formed on their surfaces.

[0030] The silicon content in the silicon microparticles is preferably 10% by weight or more, more preferably 20% by weight or more, even more preferably 50% by weight or more, and most preferably 70% by weight or more.

[0031] The silicon oxide film is preferably a silicon oxide film to which hydroxyl groups (—OH groups) have been added. A silicon oxide film to which hydroxyl groups have been added is a silicon oxide film that has been treated to increase the number of hydroxyl groups contained in the silicon oxide film. For example, hydroxyl groups can be added to the silicon oxide film by hydrophilization treatment. Silicon microparticles having a silicon oxide film to which hydroxyl groups have been added have improved contact efficiency between the surface and water, which promotes the hydrogen generation reaction and allows a large amount of hydrogen to be generated. The hydrophilization treatment method is not particularly limited, and any known hydrophilization treatment method may be used. Examples include hydrogen peroxide treatment and nitric acid treatment. Hydrogen peroxide treatment is preferred. Hydrogen peroxide treatment can remove hydrogen from SiH groups in the silicon oxide film on the particle surface and add hydroxyl groups to the particle surface.

[0032] The silicon fine particles having a silicon oxide film with hydroxyl groups added thereto on the surface thereof preferably have a surface area of ​​5×10 １３ / cm ２ More preferably, it has 1×10 １４ / cm ２ More preferably, the number of hydroxyl groups is 3×10 １４ / cm ２The particle surfaces include the surfaces of silicon microparticles, the surfaces of porous silicon particles, the surfaces of aggregates of silicon microparticles, and the surfaces of silicon microparticles that form aggregates.

[0033] A specific method for hydrogen peroxide treatment involves, for example, immersing silicon microparticles in hydrogen peroxide and stirring them. The hydrogen peroxide concentration is preferably 1 to 30%, more preferably 1.5 to 20%, even more 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 even more preferably 20 to 70 minutes. Most preferably 30 to 60 minutes. Treatment with hydrogen peroxide can improve the hydrophilicity of silicon microparticles, but longer treatment times can promote the hydrogen generation reaction from the silicon microparticles, increasing the thickness of the oxide film on the silicon microparticles. The temperature of the hydrogen peroxide during hydrogen peroxide treatment is preferably 20 to 60°C, more preferably 25 to 50°C, more preferably 30 to 40°C, and most preferably 35°C.

[0034] There is no limitation on the shape of the silicon particles, and examples thereof include amorphous, polygonal, spherical, elliptical, and cylindrical shapes.

[0035] The silicon microparticles may be crystalline silicon microparticles having crystallinity. Alternatively, they may be amorphous silicon microparticles having no crystallinity. When they have crystallinity, they may be single crystal or polycrystalline. Crystalline silicon microparticles are preferred, and single crystal silicon microparticles are more preferred.

[0036] The amorphous silicon particles may be amorphous silicon particles formed by a plasma CVD method, a laser ablation method, or the like.

[0037] The silicon oxide film formed on the surface of the silicon microparticles in the present invention may be a silicon oxide film formed by natural oxidation upon exposure to the atmosphere, or may be a silicon oxide film formed artificially by a known method such as chemical oxidation using an oxidizing agent such as nitric acid.

[0038] The thickness of the silicon oxide film may be any thickness that stabilizes the particles made of simple silicon and enables efficient hydrogen generation, for example, 0.3 nm to 5 nm, 0.3 nm to 3 nm, 0.5 nm to 2.5 nm, 0.7 nm to 2 nm, 0.8 nm to 1.8 nm, 1.0 nm to 1.7 nm. The silicon oxide film is formed by bonding silicon on the surface of the particles made of simple silicon with oxygen. ２ O, SiO, Si ２ O ３ , SiO ２ The film may contain oxides such as Si. ２ O, SiO, Si ２ O ３ Oxides in which silicon is incompletely oxidized, such as those mentioned above, promote the hydrogen generation reaction.

[0039] The silicon microparticles may be crystalline silicon microparticles having crystallinity. Alternatively, they may be amorphous silicon microparticles having no crystallinity. When the silicon microparticles have crystallinity, they may be single crystal or polycrystalline. Preferred silicon microparticles are crystalline silicon microparticles, and more preferably single crystal silicon microparticles (hereinafter also referred to as silicon crystallites).

[0040] The silicon microparticles in the present invention may be silicon microparticles on which a silicon oxide film is formed naturally or artificially after production of the silicon microparticles, and more preferably, silicon microparticles on which a silicon oxide film is formed on the surface of silicon crystallites.

[0041] The silicon microparticles in the present invention may be particles obtained by pulverizing a mass of silicon element (high-purity silicon) or particles obtained by pulverizing particles of silicon element. When silicon element lumps or particles are pulverized to produce silicon microparticles, the surfaces of the silicon microparticles are naturally oxidized to form a silicon oxide film.

[0042] The particle diameter of the silicon fine particles in the present invention (crystallite diameter when the fine particles are silicon crystallites) is preferably 0.5 nm to 100 μm, more preferably 1 nm to 50 μm, more preferably 1.5 nm to 10 μm, more preferably 2 nm to 5 μm, more preferably 2.5 nm to 1 μm, 5 nm to 500 nm, 7.5 nm to 200 nm, or 10 nm to 100 nm. If the particle diameter is 500 nm or less, a suitable hydrogen generation rate and amount can be obtained, and if it is 200 nm or less, an even more suitable hydrogen generation rate and amount can be obtained.

[0043] The agglomerates of silicon microparticles in the present invention are agglomerates of the above-mentioned silicon microparticles. They may be naturally formed or artificially formed. Preferably, they are agglomerates formed by agglomeration of silicon microparticles on which a silicon oxide film is formed. It is believed that naturally formed agglomerates remain agglomerated in the digestive tract. Preferred agglomerates have a structure with internal voids that allow water molecules to penetrate the agglomerates and react with the internal microparticles. Since the hydrogen generation rate of naturally formed agglomerates does not depend on the agglomerate size, the agglomerates have a structure with internal voids that allow water molecules to penetrate the agglomerates and react with the internal microparticles.

[0044] There is no particular limitation on the size of the aggregates of silicon fine particles, but the particle diameter of the aggregates of silicon fine particles is preferably 50 nm or more and 500 μm or less.

[0045] The particle diameter of the silicon fine particles constituting the silicon fine particle aggregate 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, 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, or 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 with a crystallite diameter of 1 nm or more and 10 μm or less. Preferably, the aggregate is an aggregate of silicon crystallites having a silicon oxide film formed on the surface.

[0046] The preventive or therapeutic agent of the present invention preferably contains silicon crystallites having a crystallite diameter of 1 nm to 1 μm, more preferably 1 nm to 100 nm, with a silicon oxide film formed on the surface thereof, and / or aggregates thereof. Preferably, the agent contains, as a main component, aggregates of silicon crystallites having a silicon oxide film formed on the surface thereof.

[0047] The preventive or therapeutic agent of the present invention preferably contains silicon crystallites with a crystallite diameter of 1 nm to 1 μm, more preferably 1 nm to 100 nm, and contains, as a main component, silicon crystallites having a silicon oxide film with hydroxyl groups added to their surface, and / or aggregates thereof. Preferably, the preventive or therapeutic agent of the present invention contains, as a main component, silicon crystallites having a silicon oxide film with hydroxyl groups added to their surface, and / or aggregates thereof.

[0048] The porous silicon particles may be a porous body of silicon particles. Alternatively, they may be a porous body formed by agglomerating and processing fine silicon particles. The porous silicon particles are preferably particles made of porous silicon alone, with a silicon oxide film formed on the surface. More preferably, the silicon oxide film is a silicon oxide film with hydroxyl groups added thereto.

[0049] The porous silicon particles may be crystalline or amorphous. If the porous silicon particles are crystalline, they may be single crystal or polycrystalline.

[0050] There is no particular limitation on the size of the voids present in the porous silicon particles, but it may usually be 0.3 nm to 1 μm, and preferably 0.5 nm to 0.1 μm. The porous silicon particles have a sufficient surface area to achieve high hydrogen generation capacity. The porous silicon particles may be aggregated to form aggregates. There is no particular limitation on the size of the porous silicon particles and the aggregates of the porous silicon particles. The size may preferably be 200 nm to 400 μm.

[0051] Agglomerates of silicon microparticles and porous silicon particles have a large overall particle size and a large surface area, making them suitable for oral administration. Large particles do not pass through the cell membranes and spaces between cells in the digestive tract, particularly the intestinal tract, and the silicon microparticles are not absorbed into the body, making them excellent from the standpoint of safety.

[0052] There are no particular limitations on the particle size distribution of the silicon microparticles contained in the preventive or therapeutic agent of the present invention, or on the particle size distribution or crystallite size distribution of the microparticles consisting of simple silicon. Polydispersion is also possible. A formulation containing silicon microparticles having a specific range of particle size or crystallite size is also possible. Furthermore, there are no particular limitations on the size distribution of aggregates of silicon microparticles.

[0053] The rate of hydrogen generation can be adjusted by the particle size and particle size distribution of the silicon particles and / or the film thickness of the silicon oxide film.

[0054] The method for producing silicon microparticles of the present invention is not particularly limited, but can be produced by physically pulverizing silicon-containing particles to a desired particle size. Suitable examples of physical pulverization methods include bead mill pulverization, planetary ball mill pulverization, shock wave pulverization, high-pressure collision pulverization, jet mill pulverization, or a pulverization method combining two or more of these. It is also possible to employ known chemical methods. From the viewpoint of production cost or ease of production management, a preferred pulverization method is physical pulverization. When microparticles consisting of fine particles of simple silicon are exposed to the atmosphere, their surfaces are oxidized to form a silicon oxide film. Alternatively, after pulverization, a silicon oxide film may be artificially formed by known methods such as chemical oxidation using an oxidizing agent such as hydrogen peroxide or nitric acid.

[0055] When silicon-containing particles are produced by pulverizing them to a desired particle size using a bead mill, the desired particle size or particle size distribution can be obtained by appropriately changing the size and / or type of beads.

[0056] 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 powders can be used. The silicon-containing particles as the starting material can be single crystal, polycrystalline, or amorphous.

[0057] This application includes inventions relating to a disease preventive or therapeutic agent containing silicon microparticles, inventions relating to a disease preventive or therapeutic method comprising administering silicon microparticles, inventions relating to an agent containing silicon microparticles for use in the preventive or therapeutic treatment of disease, and inventions relating to the use of silicon microparticles for the preparation of a disease preventive or therapeutic agent, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, inactivity-associated pain, and acute pancreatitis. The description and embodiments of the invention relating to a disease preventive or therapeutic agent containing silicon microparticles in this specification include description and embodiments of all of these inventions.

[0058] The agent for preventing or treating at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis of the present invention includes an agent for preventing a disease, an agent for treating a disease, and an agent for both preventing and treating a disease.

[0059] Prevention or treatment in the present invention includes prevention of onset, delay of onset, amelioration of symptoms, suppression of worsening of symptoms, prevention of recurrence of symptoms, early recovery of symptoms, and the like of one or more symptoms associated with the disease.

[0060] The prophylactic or therapeutic agent of the present invention can prevent and treat non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease in the present invention includes non-alcoholic fatty liver and non-alcoholic steatohepatitis.

[0061] The preventive or therapeutic agent of the present invention can prevent and treat liver dysfunction associated with non-alcoholic fatty liver disease. Furthermore, the preventive or therapeutic agent of the present invention can suppress fat accumulation in the liver. Furthermore, the preventive or therapeutic agent of the present invention can suppress liver fibrosis. The therapeutic agent of the present invention can suppress the exacerbation of non-alcoholic fatty liver and prevent non-alcoholic steatohepatitis. The present invention can also be referred to as an agent for suppressing fat accumulation in the liver containing silicon microparticles. The present invention can also be referred to as an agent for suppressing the exacerbation of non-alcoholic fatty liver containing silicon microparticles.

[0062] The preventive or therapeutic agent of the present invention can prevent and treat pain associated with inactivity. In the present invention, pain associated with inactivity includes pain caused by inactivity itself and pain caused by the effects of inactivity on the living body. When inactivity is combined with tissue damage due to trauma or degenerative changes due to aging, pain occurs and often develops into chronic pain. In the present invention, pain associated with inactivity includes systemic pain and local pain.

[0063] In the present invention, inactivity refers to excessive rest, immobilization of the affected area, no weight-bearing, immobility, limited exercise, prolonged bed rest, etc. Inactivity itself causes pain, and inactivity is a risk factor for the development of chronic pain. Inactivity in the present invention includes partial body inactivity (such as immobilization of the limbs) and whole-body inactivity (such as rest). In addition, inactivity in the present invention is not limited by time, and includes short-term inactivity such as short-term rest or immobilization of the affected area due to acute illness, and long-term inactivity such as limited exercise or prolonged bed rest due to old age.

[0064] Pain associated with inactivity in the present invention includes pain after immobilization with a plaster cast, muscle pain associated with inactivity, such as lower back pain and stiff shoulders associated with inactivity, and joint pain associated with inactivity.

[0065] Disuse syndrome refers to various conditions resulting from inactivity. In the present invention, disuse syndrome of the musculoskeletal system includes muscle atrophy, muscle weakness, joint contracture, bone atrophy, etc. The preventive or therapeutic agent of the present invention can preferably prevent and treat pain associated with joint contracture, muscle atrophy, and muscle weakness, more preferably prevent and treat pain associated with joint contracture and muscle atrophy, and even more preferably prevent and treat pain associated with joint contracture.

[0066] The preventive or therapeutic agent of the present invention can prevent and treat acute pancreatitis, particularly severe acute pancreatitis.

[0067] Acute pancreatitis is an acute inflammation of the pancreas, and is characterized by symptoms such as severe upper abdominal pain, back pain, vomiting, fever, etc. Severe acute pancreatitis can cause multiple organ disorders such as impaired consciousness, shock, respiratory failure, and acute nephritis. The preventive or therapeutic agent of the present invention can prevent the onset of these symptoms, ameliorate the symptoms, and suppress the exacerbation of the symptoms.

[0068] The preventive or therapeutic agent of the present invention can suppress the loss of pancreatic acinar cells associated with acute pancreatitis and can suppress the infiltration of immune cells. The present invention can also be said to be an agent for suppressing the loss of pancreatic acinar cells associated with acute pancreatitis.

[0069] The silicon microparticles of the present invention have the property of continuing to generate hydrogen for a long period of time (20 hours or more) in vitro. The silicon microparticles of the present invention generate hydrogen when they come into contact with an aqueous solution of pH 7 or higher, and generate even more hydrogen at pH 8 or higher. On the other hand, they have the property of generating almost no hydrogen at pH 5 or lower.

[0070] When the silicon microparticles of the present invention are orally administered, due to the above-mentioned properties, it is thought that almost no hydrogen is generated in the stomach, but hydrogen is generated in the intestines. When the silicon microparticles of the present invention were administered to normal mice, hydrogen generation was confirmed in the cecum, which is part of the large intestine, and 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 intestines is usually 20 hours or more in humans, it is thought that the preventive or therapeutic agent of the present invention, when administered orally, continues to generate hydrogen in the intestines for a long period of time, allowing hydrogen to be distributed throughout the body.

[0071] It is also believed that by leaving silicon microparticles on the skin or mucous membrane for a long period of time, hydrogen can be delivered transdermally or transmucosally into the body for a long period of time.

[0072] Unlike hydrogen water, the preventive or therapeutic agent of the present invention does not lose its hydrogen before administration. This property contributes to maintaining the quality of pharmaceutical products and contributes to convenience for manufacturers, sellers, and users.

[0073] The inventors' research has confirmed that when rats were administered the silicon microparticles of the present invention and then their plasma antioxidant capacity was evaluated (BAP test), the antioxidant capacity was significantly higher in the group administered the silicon microparticles (WO2019 / 235577).

[0074] One of the mechanisms underlying the prevention and treatment of nonalcoholic fatty liver disease, inactivity-related pain, and acute pancreatitis is believed to be the prolonged hydrogen generation of the silicon microparticles used in the present invention, which is then transported to the blood and various organs, where it selectively reacts with hydroxyl radicals. Furthermore, the improved antioxidant activity in the blood suggests that this is due to antioxidants produced in the blood. Furthermore, the inventors' research has confirmed that silicon microparticles exhibit significant effects compared to hydrogen water in studies using animal models of diseases involving oxidative stress (WO 2019 / 235577). Therefore, it is likely that silicon microparticles have other effects not found in hydrogen water. Comparing the colonic tissues of mice treated with silicon microparticles and those not treated with silicon microparticles, the colons of mice treated with silicon microparticles contained higher amounts of glutathione monosulfide and cysteine ​​monosulfide, which are involved in antioxidant activity in vivo. This may be a unique effect of silicon microparticles (Patent Publication No. 2020-117481, PCT / JP2021 / 016176). Another possible mechanism is that proteins containing metal elements such as cobalt capture hydrogen in the early stages of generation that occurs in the intestines as a result of the reaction between silicon microparticles and water, or proteins whose reducing power has increased as a result of hydrogen atoms donating electrons, are transported to various organs, where they react with hydroxyl radicals and eliminate them.

[0075] The preventive or therapeutic agent of the present invention can be used in combination with other therapeutic agents. Higher therapeutic effects are expected when the preventive or therapeutic agent of the present invention is used in combination with a drug having a different mechanism of action.

[0076] The subjects for prevention or treatment by the prophylactic or therapeutic agent of the present invention are humans and non-human animals. Preferred non-human animals include pets and livestock.

[0077] The silicon microparticles of the present invention may be administered to humans or non-human animals as one or more of them, or, if necessary, may be mixed with an acceptable additive or carrier and formulated into a form well known to those skilled in the art and administered. Examples of such additives or carriers include pH adjusters (e.g., sodium bicarbonate, sodium carbonate, potassium carbonate, citric acid, etc.), excipients (e.g., sugar derivatives such as mannitol and sorbitol; starch derivatives such as corn starch and potato starch; or cellulose derivatives such as crystalline cellulose), lubricants (e.g., metal stearates such as magnesium stearate; or talc), binders (e.g., hydroxypropyl cellulose, hydroxypropylmethylcellulose, or polyvinylpyrrolidone), disintegrants (e.g., cellulose derivatives such as carboxymethylcellulose and calcium carboxymethylcellulose), preservatives (e.g., parahydroxybenzoates such as methylparaben and propylparaben; or alcohols such as chlorobutanol and benzyl alcohol). These additives and carriers can be blended into the silicon microparticles either alone or in combination of two or more. Preferred additives include pH adjusters capable of adjusting the pH to 8 or higher. Preferred pH adjusters include sodium bicarbonate.

[0078] The route of administration of the preventive or therapeutic agent of the present invention is not particularly limited, but preferred routes of administration include oral, transdermal, and transmucosal (oral, rectal, vaginal, etc.) routes.

[0079] Examples of preparations for oral administration include tablets, capsules, granules, powders, syrups (dry syrups), oral jellies, etc. Examples of preparations for transdermal or transmucosal administration include patches, ointments, etc.

[0080] Tablets, capsules, granules, powders, and the like can be made into enteric preparations. For example, tablets, granules, and powders can be provided with an enteric coating. As the enteric coating agent, a gastric insoluble enteric coating agent can be used. Capsules can be made enteric by filling enteric capsules with the silicon microparticles of the present invention.

[0081] The prophylactic or therapeutic agent of the present invention can be formulated into the above-mentioned dosage forms and then administered to humans or non-human animals.

[0082] The content of silicon microparticles 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%.

[0083] The dosage and frequency of administration of silicon microparticles in the present invention can be varied as appropriate depending on the recipient, their age, weight, sex, purpose (e.g., prevention or treatment), severity of symptoms, dosage form, route of administration, and other conditions. When administered to humans, a preferred dosage of silicon microparticles is, for example, about 10 mg to 10 g per day, preferably about 100 mg to 5 g, and more preferably about 500 mg to 2 g. The frequency of administration may be one or more times per day, or once every few days. For example, it may be one to three times, one to two times, or once per day.

[0084] The agent for preventing or treating at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis, containing the silicon microparticles of the present invention, can be used in pharmaceuticals, quasi-drugs, medical devices, foods, and beverages.

[0085] The present application also relates to a pharmaceutical composition containing silicon microparticles for preventing or treating a disease, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis. The pharmaceutical composition of the present invention also includes compositions with mild effects that fall under the category of quasi-drugs. Embodiments of the pharmaceutical composition of the present invention include embodiments of the invention relating to the preventive or therapeutic agent described above.

[0086] This application also relates to an invention of a medical device containing silicon microparticles for the prevention or treatment of a disease, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis. The medical device of this invention refers to tools, instruments, etc. intended for use in the treatment or prevention of disease in humans or non-human animals. Examples of medical devices include masks. By wearing the mask of this invention, hydrogen can be supplied directly to the trachea or lungs. Another example is a bandage.

[0087] The present application also relates to an invention of a food or beverage containing silicon microparticles for the prevention or treatment of a disease, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis. Preferred examples of the food or beverage of the present invention include health foods, functional foods, and foods for specified health uses. These health foods, functional foods, and foods for specified health uses are foods or beverages that can prevent, delay the onset of, and / or prevent recurrence of the diseases. There are no limitations on the form of the food or beverage. Examples include mixtures in which the food or beverage is mixed with existing foods or beverages, and formulated forms. Examples include tablets, capsules, powders, granules, jellies, and the like.

[0088] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0089] Example 1 High-purity silicon powder (manufactured by Osaka Titanium Technologies Co., Ltd., particle size distribution <φ300 μm (however, silicon particles with a crystal particle diameter of more than 1 μm), purity 99.9%) was sieved to remove particles of 45 μm or larger. 200 g of the obtained silicon particles were dispersed in 4 L (liters) of a 99.5 wt % ethanol solution, and φ0.5 μm zirconia beads (volume 750 ml) were added. The mixture was then pulverized (single-stage pulverization) for 4 hours at a rotation speed of 2500 rpm using a bead mill (manufactured by Imex Co., Ltd., horizontal continuous ready mill (model RHM-08)).

[0090] The ethanol solution containing the micronized silicon particles was separated from the beads by a separation slit provided inside the grinding chamber of the bead mill device, and then heated to 30°C to 35°C using a reduced pressure evaporator. Micronized silicon particles (crystallites) were obtained by evaporating the ethanol solution.

[0091] The average crystallite diameter of the fine silicon particles (crystallites) obtained by the above method was 20 to 30 nm, and most of the crystallites formed aggregates. The crystallites were also coated with a silicon oxide film, and the thickness of the silicon oxide film was approximately 1 nm. The resulting mixture of silicon crystallites and their aggregates on which the silicon oxide film was formed is one embodiment of the silicon microparticles that are the active ingredient of the present invention.

[0092] Example 2 The silicon crystallites and their aggregates obtained in Example 1 were mixed with hydrogen peroxide (3 wt%) in a glass container and stirred at 35°C for 30 minutes. The silicon crystallites and their aggregates treated with hydrogen peroxide were subjected to solid-liquid separation using a known centrifugal separator to remove the hydrogen peroxide. The obtained silicon crystallites and their aggregates were then mixed with an ethanol solution (99.5 wt%) and thoroughly stirred. The silicon crystallites and their aggregates mixed with the ethanol solution were subjected to solid-liquid separation using a known centrifugal separator to remove the highly volatile ethanol solution, and then thoroughly dried. The obtained mixture of silicon crystallites and their aggregates treated with hydrogen peroxide and having a silicon oxide film formed thereon is one embodiment of the silicon microparticles that are the active ingredient of the present invention. A scanning electron microscope (SEM) photograph of the obtained silicon microparticles is shown in Figure 1. The hydrogen generation rate of the obtained silicon crystallite aggregates did not depend on the aggregate size.

[0093] The amount of hydrogen generated from the silicon microparticles (silicon crystallites and their aggregates) obtained in Example 2 was measured. 10 mg of silicon microparticles were placed in a 100 ml glass bottle (borosilicate glass, approximately 1 mm thick, ASONE's Labolan screw cap bottle). Water adjusted to pH 8.2 with sodium bicarbonate was placed in the glass bottle, which was then sealed at a temperature of 36°C, and the hydrogen concentration in the liquid in the glass bottle was measured. A portable dissolved hydrogen meter (Toa DKK Corporation, Model DH-35A) was used to measure the hydrogen concentration. The amount of hydrogen generated per 1 g of silicon microparticles is shown in Figure 2.

[0094] <Example 3> In the same manner as in Example 2, the silicon microparticles (silicon crystallites and their aggregates) obtained in Example 1 were treated with hydrogen peroxide water, mixed with an ethanol solution, and stirred. The silicon microparticles mixed with the ethanol solution were dried using a spray dryer (ADL311S-A, manufactured by Yamato Scientific). The obtained silicon crystallite aggregates are one embodiment of the silicon microparticles that are the active ingredient of the present invention. A scanning electron microscope (SEM) photograph of the obtained silicon microparticles (silicon crystallite aggregates) is shown in Figure 3.

[0095] Example 4: Single-stage pulverization was carried out in the same manner as in Example 1. The 0.5 μm zirconia beads (volume 750 ml) used in the single-stage pulverization were automatically separated from the solution containing silicon crystallites in the bead mill pulverization chamber. 0.3 μm zirconia beads (volume 750 ml) were added to the resulting 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 refine them.

[0096] 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 evaporated, and two-stage crushed silicon crystallites were obtained. The silicon crystallites thus crushed in two stages and having a silicon oxide film formed thereon are also one embodiment of the silicon microparticles that are the active ingredient of the present invention.

[0097] Example 5 The mixture of silicon crystallites and their aggregates formed with a silicon oxide film treated with hydrogen peroxide obtained in Example 2 was filled into commercially available capsules No. 3 to obtain a capsule preparation. This capsule preparation contains, as its main component, aggregates of silicon crystallites formed with a silicon oxide film treated with hydrogen peroxide, and further contains silicon crystallites formed with a silicon oxide film treated with hydrogen peroxide.

[0098] <Test Example>

[0099] A. Pharmacological study of silicon microparticles (non-alcoholic fatty liver disease)

[0100] A1. Preparation of Non-alcoholic Steatohepatitis Model Mice were prepared using a CDAHFD60 (choline-deficient, methionine-reduced, 60 kcal% fat diet (Oriental Yeast Co., Ltd.)) diet to prepare non-alcoholic steatohepatitis model mice (Matsumoto, M. et al. Int. J. Exp. Path. (2013), 94, 93-103).

[0101] A2. Preparation of silicon microparticle-containing diet The silicon microparticles (silicon crystallites and their aggregates) produced in Example 2 were mixed into CDAHFD60 to a concentration of 2.5 wt %. An aqueous citric acid solution (pH 4) was then added in an amount of approximately 0.5 wt % based on the total amount of the silicon microparticles and the feed, and the mixture was kneaded using a known kneading device to obtain a silicon microparticle-containing high-fat diet.

[0102] A3. Silicon Microparticle Administration C57BL6 / J mice (male, 5 weeks old, Charles River Japan) were obtained. After acquisition, they were fed a normal diet (Oriental Yeast Co., Ltd., model number AIN93M) for two weeks as an acclimation period. They were then fed the silicon microparticle-containing high-fat diet obtained in A2 above or a control diet (CDAHFD60) for three months. Each group consisted of 13 mice (n = 13). Blood tests were performed the day after the start of silicon microparticle administration (week 0), 6 weeks later, and 12 weeks later. In both groups, AST and ALT levels were significantly elevated at week 6, indicating the development of fatty liver or hepatitis.

[0103] A4. Blood tests Total bilirubin concentration in the blood is shown in Figure 4, and total bile acid concentration is shown in Figure 5. It was revealed that administration of silicon microparticles significantly suppressed liver dysfunction associated with non-alcoholic fatty liver disease.

[0104] A5. Morphological Analysis A5-1. Fat Accumulation Liver tissue was collected after 12 weeks of blood testing and tissue sections were prepared. The degree of fat accumulation in the liver was evaluated using two types of fat staining methods: Sudan III staining and Oil Red staining (both staining solutions are from Muto Chemical Co., Ltd.). Image acquisition and analysis were performed using a Keyence microscope. Sudan III staining is a staining method that stains neutral fat orange-red, while Oil Red staining is a staining method that stains neutral fat droplets red. Stained images and graphs showing the percentage (%) of the stained area relative to the total tissue area are shown in Figures 6 and 7. It was revealed that administration of silicon microparticles suppresses fat accumulation in the liver.

[0105] A5-2. Fat Deposition and Fibrosis Liver tissue sections prepared in A5-1 above were HE stained to observe vacuoles, fibrosis, etc. Lipid droplets in hepatocytes are seen as vacuoles in paraffin-embedded specimens. Figure 8 shows the stained image and the percentage (%) of vacuolar area relative to the total tissue area. Note that the flat white areas are not vacuoles but vascular lumens. Balloon-like swelling and fibrosis of hepatocytes were observed in the livers of control mice. However, these were not observed in the livers of mice administered with silicon microparticles. It was revealed that administration of silicon microparticles suppressed macrovesicular fat deposition and fibrosis.

[0106] B. Pharmacological Study of Silicon Microparticles (Pain Associated with Inactivity)

[0107] B1. Preparation of silicon microparticle-containing diet The silicon microparticles (silicon crystallites and their aggregates) produced in Example 2 were mixed with normal feed (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) to a concentration of 2.5 wt%. Furthermore, a citric acid solution (pH 4) was added in an amount of about 0.5 wt% relative to the total amount of the silicon microparticles and the feed, and the mixture was kneaded using a known kneading device to obtain a silicon microparticle-containing diet.

[0108] B2. Preparation of a disuse muscle atrophy model with casts C57BL6 / J mice (male, 7 weeks old, Japan SLC) were obtained. One hind limb of the mouse was fixed in an extended position with casting tape (Alcare Co., Ltd.) that hardens when immersed in water to prepare a cast-wearing mouse model.

[0109] The plaster cast model is widely used in research on disuse muscle atrophy and joint contracture. In this model, the joints are constantly in extension due to the application of the cast, reflecting the state of joint contracture in humans. Furthermore, joint immobilization due to the application of a plaster cast induces significant skeletal muscle atrophy simply by restricting skeletal muscle contractile activity through joint immobilization, even though gravity and nerve innervation are maintained under normal circumstances. Therefore, the plaster cast model accurately reflects the state of skeletal muscle atrophy observed during inactivity in daily human life (Yuki Toga et al., Fukuoka University Sports Science Research 45(2), 53-58 (2015)).

[0110] B3. Administration of Silicon Microparticles Starting one week before the application of a cast (one leg immobilization treatment), the mice administered with silicon microparticles were fed the silicon microparticle-containing diet prepared in B1 above, while the control mice were fed the normal diet in B1 above.

[0111] B4. Evaluation of pain threshold One, two, and three weeks after the single-leg immobilization treatment, a mechanical pain test (von Frey test, Dynamic Plantar Aesthesiometer (Catalog No. 37450; UGO BASILE, Varese, Italy)) was performed to evaluate the pain threshold of each mouse.

[0112] First, we compared the pain thresholds of the cast-wearing hind limbs of control mice with those of the untreated hind limbs and confirmed the decrease in pain threshold associated with cast wear (Figure 9). Next, we calculated the ratio of the pain thresholds of the cast-wearing hind limbs to the untreated hind limbs in mice treated with silicone microparticles and control mice. The results are shown in Figure 10. Pain associated with long-term joint contracture due to cast wear increases somewhat in proportion to the duration (load). After one week of cast wear (acute phase), the untreated group (control group) experienced a decrease in pain threshold, while the silicone microparticle-treated group experienced a significant reduction in this threshold. However, after two weeks of cast wear, the load due to long-term contracture increased, and a decrease in the threshold was observed in the silicone microparticle-treated group. After three weeks of cast wear, the untreated group experienced a further increase in pain and a decrease in the threshold, while the silicone microparticle-treated group showed a tendency to alleviate the exacerbation of pain associated with long-term joint contracture. Silicon microparticles are thought to be effective in alleviating the sudden increase in pain during the acute phase after cast wear and the increase in pain due to prolonged immobility. It has been shown that pain associated with joint contracture and disuse muscle atrophy can be alleviated by administering silicon microparticles.

[0113] C. Pharmacological study of silicon microparticles (acute pancreatitis)

[0114] C1. Generation of a mouse model of severe acute pancreatitis. C57BL6 / J mice (male, 7 weeks old, Japan SLC) were intraperitoneally administered L-arginine at 1.5 mg / g body weight three times every hour to generate a mouse model of severe acute pancreatitis (Kui B. et al. PLOS ONE. 2015 Feb 17;10(2):e0117588).

[0115] C2. Administration of Silicon Microparticles Starting one week before the severe acute pancreatitis model was produced, the silicon microparticle-administered mice were fed the silicon microparticle-containing diet prepared in B1 above, and the control mice were fed the normal diet in B1 above.

[0116] C3. Morphological Analysis Three days after model creation, the pancreas was perfused with 4% paraformaldehyde fixative, and tissue sections were prepared. The degree of inflammation, blood cell infiltration, and changes in tissue structure were evaluated by HE staining (Figure 11). At the onset of acute pancreatitis, blood cell infiltration and acinar cell loss, which were observed in the control mice, were hardly observed in the silicon microparticle-treated mice. The degree of immune cell infiltration was evaluated by immunostaining using an antibody against the neutrophil marker Gr-1 (Thermo Fisher Scientific) and an antibody against the macrophage marker F4 / 80 (Abcam) (Figure 12). As shown in Figures 11 and 12, pancreatic inflammation and immune cell infiltration were significantly suppressed in the silicon microparticle-treated mice compared to the control mice.

[0117] From the above results, it is clear that the silicon microparticles of the present invention have a high preventive effect and a high therapeutic effect against non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.

[0118] The present invention can be one of the causal therapies for non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis, and will make a great contribution to future medical care and health promotion.

Claims

1. A preventive or therapeutic agent for a disease, comprising silicon microparticles, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.

2. The method according to claim 1, wherein the disease is non-alcoholic fatty liver disease.

3. The method according to claim 2, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

4. The preventive or therapeutic agent according to claim 1 , wherein the disease is pain associated with inactivity.

5. The preventive or therapeutic agent according to claim 4, wherein the pain associated with disuse is pain associated with musculoskeletal disuse syndrome.

6. The preventive or therapeutic agent according to claim 5 , wherein the pain associated with musculoskeletal disuse syndrome is pain associated with muscle atrophy or joint contracture.

7. The preventive or therapeutic agent according to claim 1 , wherein the disease is acute pancreatitis.

8. The preventive or therapeutic agent according to claim 7, wherein the acute pancreatitis is severe acute pancreatitis.

9. 9. The preventive or therapeutic agent according to claim 1, wherein the silicon microparticles are microparticles containing simple silicon capable of generating hydrogen upon contact with water.

10. The preventive or therapeutic agent according to any one of claims 1 to 8, wherein the silicon microparticles are silicon fine particles consisting of simple silicon with a silicon oxide film formed on the surface thereof and / or aggregates of the silicon fine particles.

11. The preventive or therapeutic agent according to any one of claims 1 to 8, wherein the silicon microparticles are porous silicon particles.

12. A pharmaceutical composition for preventing or treating a disease, comprising silicon microparticles, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.

13. A medical device for preventing or treating a disease, comprising silicon microparticles, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.

14. A food or beverage containing silicon microparticles for the prevention or treatment of a disease, wherein the disease is at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.

15. A therapeutic agent for treating a disease, comprising silicon microparticles, the disease being at least one disease selected from the group consisting of non-alcoholic fatty liver disease, pain associated with inactivity, and acute pancreatitis.