Preventive or therapeutic agent for frailty

Abstract

[Problem] To provide a medicament, etc., capable of preventing or treating frailty. [Solution] Frailty can be prevented or treated by orally administering silicon fine particles or placing the silicon fine particles on skin or mucosa. The silicon fine particles generate hydrogen when coming into contact with water having a pH of 7 or higher. Provided are an agent, a pharmaceutical composition, a medical device, and food or beverage which are for preventing or treating frailty, and which contain the silicon fine particles. For example, it is possible to prevent or treat attenuation of a physical ability, disability in activities of daily living, a decline in motor coordination, a decline in static sense, a decline in activity amount, and weight loss, in the frailty.

Description

[Technical Field]

[0001] The present invention relates to the prevention or treatment of frailty. [Background technology]

[0002] Frailty is defined in a report by a research group from the Ministry of Health, Labor and Welfare as "a state in which physical and mental vitality (motor function, cognitive function, etc.) declines with age, and, due to the coexistence of multiple chronic diseases, daily living functions are impaired and physical and mental frailty appears, but at the same time, with appropriate intervention and support, daily living functions can be maintained and improved." It refers to a state between a healthy state and a state requiring nursing care, and it is thought that many people will progress through frailty to a state requiring nursing care, with elderly people being particularly susceptible to developing frailty.

[0003] The evaluation criteria of Fried et al. are commonly used to diagnose frailty, with a person being considered frail if three or more of the five items - weight loss, subjective fatigue, decreased daily activity, decreased physical ability (walking speed), and decreased muscle strength (grip strength) - are met, and a person being considered pre-frail if one or two of these items are met.

[0004] Healthy life expectancy is a new health indicator proposed by the World Health Organization (WHO) and is defined as the "average period of time during which one can live without restrictions on daily life." This refers to the period during which one can remain healthy and independent in the activities of daily living. Causes of the need for nursing care include cerebrovascular disease, dementia, frailty due to aging, fractures and falls, joint disease, and heart disease.

[0005] While reactive oxygen species are necessary for life, they are known to oxidize and damage the cells that make up living organisms. Reactive oxygen species include superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and singlet oxygen. Hydroxyl radicals are highly oxidizing radicals, and when generated in living organisms, they oxidize nearby substances such as DNA, lipids, and proteins, causing damage to organs. This action of hydroxyl radicals is believed to cause various diseases, including 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 gas. Furthermore, hydrogen molecules are small, so 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 highly concentrated 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 water with a pH of less than 5, but the reaction progresses when they come into contact with water 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 when the silicon microparticles are surface-treated. Furthermore, while the silicon microparticles are in contact with water, 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. However, it does not state that silicon microparticles can prevent or treat diseases.

[0010] Patent Document 4 describes a hydrogen supply material comprising a medium containing silicon microparticles and water. It also describes the use of this hydrogen supply 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. It also describes the silicon microparticles as capable of exerting an anti-aging function. However, it does not describe the silicon microparticles' ability to prevent or treat disease to the extent that they could be used as a pharmaceutical.

[0014] The inventors have found that silicon microparticles can prevent or treat kidney disease, inflammatory diseases (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 (Patent Documents 8 to 11). [Prior art documents] [Patent documents]

[0015] [Patent Document 1] Japanese Patent Application Laid-Open No. 2016-155118 [Patent Document 2] Japanese Patent Application Laid-Open No. 2017-104848 [Patent Document 3] International Publication No. 2017 / 130709 [Patent Document 4] International Publication No. 2018 / 037752 [Patent Document 5] International Publication No. 2018 / 037818 [Patent Document 6] International Publication No. 2018 / 037819 [Patent Document 7] International Publication No. 2019 / 211960 [Patent Document 8] International Publication No. 2019 / 021769 [Patent Document 9] International Publication No. 2019 / 235577 [Patent Document 10] Japanese Patent Application Laid-Open No. 2019-214556 [Patent Document 11] JP 2020-007300 A [Non-patent literature]

[0016] [Non-Patent Document 1] 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 Summary of the Invention [Problem to be solved by the invention]

[0017] An objective of the present invention is to provide a medicine, medical device, food, beverage, etc. for preventing or treating frailty. [Means for solving the problem]

[0018] The present inventors discovered that silicon microparticles can prevent and / or treat frailty, and completed the present invention. 1. A preventive or therapeutic agent for frailty containing silicon microparticles. 2. The preventive or therapeutic agent according to the preceding item 1, wherein the frailty is a decline in physical ability due to frailty. 3. The preventive or therapeutic agent according to the preceding item 1 or 2, wherein the frailty is a disorder in activities of daily living caused by a decline in physical ability. 4. The preventive or therapeutic agent according to the preceding item 3, wherein the activity of daily living is walking. 5. The preventive or therapeutic agent according to any one of the preceding items 2 to 4, wherein the decline in physical ability is a decline in motor coordination and / or a decline in balance. 6. The preventive or therapeutic agent according to the preceding item 1, wherein the frailty is a decrease in activity level associated with frailty. 7. The preventive or therapeutic agent according to the preceding item 1, wherein the frailty is weight loss associated with frailty. 8. The preventive or therapeutic agent according to any one of the preceding items 1 to 7, wherein the frailty is frailty associated with a chronic disease. 9. The preventive or therapeutic agent according to the preceding item 8, wherein the chronic disease is at least one disease selected from the group consisting of chronic obstructive pulmonary disease, diabetes, dementia, cerebrovascular disease, psychiatric disease, and progeria. 10. The preventive or therapeutic agent according to any one of items 1 to 9 above, wherein the silicon microparticles are silicon-containing microparticles capable of generating hydrogen upon contact with water. 11. The preventive or therapeutic agent according to the preceding item 10, wherein the silicon-containing microparticles are microparticles containing elemental silicon. 12. The preventive or therapeutic agent according to any one of items 1 to 11 above, wherein the silicon microparticles are silicon microparticles and / or aggregates of the silicon microparticles. 13. A pharmaceutical composition for preventing or treating frailty, comprising the preventive or therapeutic agent according to any one of the preceding items 1 to 12. 14. A medical device for preventing or treating frailty, comprising the preventive or therapeutic agent according to any one of the preceding paragraphs 1 to 12. 15. A food or beverage for preventing or treating frailty, comprising the preventive or therapeutic agent according to any one of the preceding paragraphs 1 to 12. 16. A treatment for frailty containing silicon microparticles. 17. A method for preventing or treating frailty, comprising administering silicon microparticles. 18. A method for treating frailty, comprising administering silicon microparticles. 19. An agent containing silicon microparticles for use in the prevention or treatment of frailty. 20. An agent for use in treating frailty, containing silicon microparticles. 21. Use of silicon microparticles for preparing an agent for preventing or treating frailty. 22. Use of silicon microparticles for the preparation of a treatment for frailty. [Effects of the Invention]

[0019] The preventive or therapeutic agent of the present invention can prevent and treat frailty. Preferably, it can suppress or prevent, and improve or treat, the decreased activity level, weight loss, and decline in physical ability that are associated with frailty. It can also prevent and treat impairments in activities of daily living caused by decline in physical ability. With regard to decline in physical ability, it can particularly prevent and treat decline in motor coordination, decline in balance, and gait disorders. Patients with chronic diseases often develop frailty, and prevention and treatment are important, and the preventive or therapeutic agent of the present invention makes this prevention and treatment possible. The preventive or therapeutic agent of the present invention makes it possible to maintain and improve daily living functions and contribute to extending healthy life expectancy. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 is a photograph of silicon microparticles (a mixture of silicon crystallites and their aggregates) taken with a scanning electron microscope (SEM) (Example 3). [Figure 2] FIG. 2 is a graph showing the amount of hydrogen (cumulative amount) generated per 1 g of silicon microparticles by contacting the silicon microparticles obtained in Example 3 with water at 36° C. and pH 8.2. [Figure 3] FIG. 3 is a photograph of silicon microparticles (aggregates of silicon crystallites) taken with a scanning electron microscope (SEM) (Example 4). [Figure 4] 4 is a graph showing the results of the antioxidant capacity (BAP test) of plasma from normal SD rats administered silicon microparticles for 8 weeks, where Con represents the control group and Si represents the group administered silicon microparticles. [Figure 5] Figure 5 shows the results of multivariate analysis of sulfur-related compounds in the large intestine, showing that the control group and the silicon microparticle-administered group can be distinguished by 10 sulfur-related compounds. Con indicates the control group, and Si indicates the silicon microparticle-administered group. [Figure 6] Figure 6 shows the results of a comparative analysis of the amounts of glutathione (A) and glutathione monosulfide (B) in the colons of the silicon microparticle-administered group and the control group (n=6 per group). *p<0.05, t-test [Figure 7] Figure 7 shows the results of the open field test on black mice, and is a graph showing the distance traveled in a novel environment. The vertical axis shows the distance traveled by the mice in the open field over a 10-minute period. The distance traveled by the normal diet group (control) was set at 1.0. Compared to the normal diet group, the silicon microparticle-administered group (Si) showed a significant improvement in the decrease in distance traveled due to frailty. *p<0.05, t-test [Figure 8] Figure 8 shows the results of the open field test on black mice, and is a graph showing the speed of movement in a novel environment. The vertical axis represents speed of movement, with the speed of the normal diet group (control) set at 1.0. Compared to the normal diet group, the silicon microparticle-administered group (Si) showed a significant improvement in the decrease in speed of movement due to frailty. *p<0.05, t-test [Figure 9] Figure 9 shows the results of an open field test on black mice, and is a graph showing the activity time and immobility time in a novel environment. The vertical axis represents time, with the activity time of the normal diet group (control) set at 1.0. The group administered silicon microparticles showed an improvement in the decreased activity time (increased immobility time) associated with frailty. [Figure 10]Figure 10 shows the body length and total length of three groups of black mice (C / K: normal diet, S1 / K: diet containing 1% silicon microparticles, S2 / K: diet containing 2.5% silicon microparticles) and three groups of wild-type mice (C / W: normal diet, S1 / W: diet containing 1% silicon microparticles, S2 / W: diet containing 2.5% silicon microparticles). A is a photograph of a representative mouse from each group, B is a graph showing body length excluding the tail, and C is a graph showing total length including the tail. Compared to the normal diet group (C / K), the body length and total length of the silicon microparticle-administered groups (S1 / K and S2 / K) were significantly larger, demonstrating growth. C / K (n=16), S1 / K (n=15), S2 / K (n=15), C / W (n=20), S1 / W (n=20), S2 / W (n=20); *p<0.05 vs C / K, **p<0.01 vs C / K. There were significant differences between each group of black mice and each wild-type mouse group in terms of body length and total length (p<0.01), t-test. [Figure 11] Figure 11 shows the results of a test measuring total locomotor activity using SuperMex in three groups of Cloth mice (C / K: normal diet, S1 / K: diet containing 1% silicon microparticles, S2 / K: diet containing 2.5% silicon microparticles) and three groups of wild-type mice (C / W: normal diet, S1 / W: diet containing 1% silicon microparticles, S2 / W: diet containing 2.5% silicon microparticles). Compared to the normal diet group (C / K), the silicon microparticle-administered groups (S1 / K and S2 / K) significantly suppressed the age-related decline in total locomotor activity. n = 14-20 per group; **p < 0.01 vs C / K. There was a significant difference between each Cloth mouse group and each wild-type mouse group (p < 0.01), t-test. [Figure 12] Figure 12 shows the results of an open field test for three groups of Cloth mice (C / K: normal diet, S1 / K: diet containing 1% silicon microparticles, S2 / K: diet containing 2.5% silicon microparticles) and three groups of wild-type mice (C / W: normal diet, S1 / W: diet containing 1% silicon microparticles, S2 / W: diet containing 2.5% silicon microparticles), showing the distance traveled in a novel environment. Compared to the normal diet group (C / K), the silicon microparticle-administered groups (S1 / K and S2 / K) showed a significant improvement in the decrease in distance traveled in frailty. n = 14-20 per group; **p < 0.01 vs C / K, S1 / K vs C / W, and each Cloth mouse group was significantly different from each wild-type mouse group (p < 0.01), t-test. [Figure 13] Figure 13 shows the results of an open field test for three groups of Cloth mice (C / K: normal diet, S1 / K: diet containing 1% silicon microparticles, S2 / K: diet containing 2.5% silicon microparticles) and three groups of wild-type mice (C / W: normal diet, S1 / W: diet containing 1% silicon microparticles, S2 / W: diet containing 2.5% silicon microparticles), showing the average movement speed in a novel environment. Compared to the normal diet group (C / K), the silicon microparticle-administered groups (S1 / K and S2 / K) showed a significant improvement in the decreased movement speed due to frailty. n = 14-20 per group; **p < 0.01 vs C / K, S1 / K vs C / W, and each Cloth mouse group was significantly different from each wild-type mouse group (p < 0.01), t-test. [Figure 14] Figure 14 shows the results of an open field test in three groups of Cloth mice (C / K: normal diet, S1 / K: diet containing 1% silicon microparticles, S2 / K: diet containing 2.5% silicon microparticles) and three groups of wild-type mice (C / W: normal diet, S1 / W: diet containing 1% silicon microparticles, S2 / W: diet containing 2.5% silicon microparticles), showing activity time and immobility time. Compared to the normal diet group (C / K), the groups administered silicon microparticles (S1 / K and S2 / K) showed significant improvements in the decreased activity time and increased immobility time associated with frailty. n = 14-20 per group; A: activity time, I: immobility time; **p<0.01 vs. C / K. There were significant differences in activity time and immobility time between each Cloth mouse group and each wild-type mouse group, except for S1 / K vs. C / W (p<0.01), t-test. [Figure 15] Figure 15 is a graph showing the cumulative survival rate of elderly mice. In the group administered with silicon microparticles, the number of deaths due to senility was significantly lower than in the group fed a normal diet. ● indicates the group administered with silicon microparticles, and ○ indicates the group fed a normal diet (control). n=12 for each group [Figure 16] Figure 16 is a graph showing the rate of weight change in older mice. Weight loss was significantly suppressed in the group administered with silicon microparticles compared to the normal diet group. ● indicates the group administered with silicon microparticles, and ○ indicates the normal diet group (control). n=12 per group; *p<0.05, **p<0.01, t-test [Figure 17]Figure 17 shows the results of the balance beam test for older mice, showing the reaching time. The test was conducted twice using two types of wooden beams (rods) with an average diameter of 20 mm and 10 mm. A and B show the results of the test using the beam with an average diameter of 20 mm, where A is the average time for the two tests and B shows the time for each test. C and D show the results of the test using the beam with an average diameter of 10 mm, where C is the average time for the two tests and D shows the time for each test. The group administered with silicon microparticles showed a tendency for the reaching time to be shorter than the normal diet group. ● indicates the group administered with silicon microparticles (n=10), ○ indicates the normal diet group (control) (n=7). *p<0.05, t-test [Figure 18] Figure 18 shows the results of the balance beam test for older mice, showing the number of slips (number of falls). The test was conducted twice using two types of wooden beams (rods) with an average diameter of 20 mm and 10 mm. A and B show the results of the test using the beam with an average diameter of 20 mm; A shows the average number of slips in the two tests, and B shows the average number of slips in each test. C and D show the results of the test using the beam with an average diameter of 10 mm; C shows the average number of slips in the two tests, and D shows the average number of slips in each test. The number of slips in the group administered with silicon microparticles was significantly reduced compared to the normal diet group. ● indicates the group administered with silicon microparticles (n=10), ○ indicates the normal diet group (control) (n=7). *p<0.05, #p<0.06, t-test [Figure 19] Figure 19 shows the results of the balance beam test for older mice, showing the achievement rate. The test was conducted twice using two types of wooden beams (rods) with average diameters of 20 mm and 10 mm. The figures show the percentage of mice that reached the goal in both tests and the percentage of mice that reached the goal at least once. The group administered with silicon microparticles had a significantly higher achievement rate than the normal diet group. Silicon microparticles group (n=10), normal diet group (control) (n=7) DETAILED DESCRIPTION OF THE INVENTION

[0021] The silicon microparticles contained in the preventive or therapeutic agent of the present invention are silicon-containing microparticles that can generate hydrogen when in contact with water.

[0022] The above-mentioned "microparticles containing silicon capable of generating hydrogen upon contact with water" (silicon microparticles capable of generating hydrogen) refers to silicon microparticles that, when contacted with water at 36°C and pH 8.2, continuously generate hydrogen, 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.

[0023] The silicon-containing microparticles are preferably microparticles containing elemental silicon. The elemental silicon is high-purity silicon. In this specification, high-purity silicon refers to silicon having a purity of 99% or more, preferably 99.9% or more, more preferably 99.99% or more, and even more preferably 99.999% or more.

[0024] 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.

[0025] 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, aggregates of silicon microparticles, and porous silicon particles. That is, the preferred active ingredient may be silicon microparticles alone, aggregates 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 aggregates of silicon microparticles. More preferably, the main ingredient is aggregates of silicon microparticles.

[0026] 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.

[0027] 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.

[0028] 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 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 with water on the surface, 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.

[0029] 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, 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.

[0030] A specific method for hydrogen peroxide treatment involves 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 prolonged treatment time can promote the hydrogen generation reaction from the silicon microparticles, affecting 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.

[0031] There is no limitation on the shape of the silicon particles, and examples thereof include amorphous, polygonal, spherical, elliptical, and cylindrical shapes.

[0032] 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.

[0033] The amorphous silicon particles may be amorphous silicon particles formed by a plasma CVD method, a laser ablation method, or the like.

[0034] 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.

[0035] The thickness of the silicon oxide film may be any thickness that stabilizes the particles made of elemental silicon and enables efficient hydrogen generation. For example, the thickness may be 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, or 1.0 nm to 1.7 nm. The silicon oxide film may be a film containing oxides such as SiO, SiO, SiO, and SiO, which are formed when silicon on the surface of the particles made of elemental silicon combines with oxygen. Oxides formed by incomplete oxidation of silicon, such as SiO, SiO, and SiO, promote the hydrogen generation reaction.

[0036] 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. Preferred silicon microparticles are crystalline silicon microparticles, and more preferably single crystal silicon microparticles (hereinafter also referred to as silicon crystallites).

[0037] The silicon microparticles may be a mixture of at least two selected from the group consisting of single crystal silicon microparticles, polycrystalline silicon microparticles, and amorphous silicon microparticles.

[0038] The silicon microparticles in the present invention may be silicon microparticles on which a silicon oxide film is formed naturally or artificially after production, and more preferably, silicon microparticles on which a silicon oxide film is formed on the surface of silicon crystallites.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] There are no particular limitations on the size of the silicon microparticle aggregates. The particle size of the silicon microparticle aggregates is preferably 10 nm or more and 500 μm or less. More preferably, it is 50 nm or more and 100 μm or less, and even more preferably, it is 100 nm or more and 50 μm or less. The aggregates can be formed so as to maintain the surface area of ​​the microparticles, and can have a surface area sufficient to achieve high hydrogen generation capacity.

[0043] The particle diameter of the silicon fine particles constituting the silicon fine particle aggregate in the present invention 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. 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 to 10 μm. Preferably, the aggregate is an aggregate of silicon crystallites having a silicon oxide film formed on the surface.

[0044] 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, 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 with a silicon oxide film formed on the surface thereof.

[0045] 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.

[0046] 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.

[0047] The porous silicon particles may be crystalline or amorphous. If the porous silicon particles are crystalline, they may be single crystal or polycrystalline.

[0048] There is no limit to the size of the voids present in the porous silicon particles, but it is usually 1 nm to 1 μm, and the porous silicon particles have a sufficient surface area to achieve high hydrogen generation capacity. There is no particular limit to the size of the porous silicon particles, and it is preferably 200 nm to 400 μm.

[0049] 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.

[0050] 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.

[0051] The rate of hydrogen generation can be adjusted by the particle size and particle size distribution of the silicon microparticles and / or the film thickness of the silicon oxide film.

[0052] 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. Known chemical methods can also be used. From the viewpoint of production cost or ease of production management, physical pulverization is a preferred pulverization method. 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 a known method, such as chemical oxidation using an oxidizing agent such as hydrogen peroxide or nitric acid.

[0053] 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.

[0054] 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.

[0055] This application includes an invention relating to an agent for preventing or treating frailty containing silicon microparticles, an invention relating to a method for preventing or treating frailty comprising administering silicon microparticles, an invention relating to an agent for use in preventing or treating frailty containing silicon microparticles, and an invention relating to the use of silicon microparticles for preparing an agent for preventing or treating frailty, etc. The description and embodiments of the invention relating to an agent for preventing or treating frailty containing silicon microparticles in this specification are description and embodiments of all of these inventions.

[0056] The agent for preventing or treating frailty of the present invention includes an agent for preventing frailty, an agent for treating frailty, and an agent for preventing and treating frailty. In the present invention, frailty includes pre-frailty.

[0057] In this specification, frailty refers to a state in which physical and mental vitality (motor function, cognitive function, etc.) declines with age, daily living functions become impaired, and physical and mental frailty emerges, and refers to a state intermediate between a healthy state and a state in which support in daily life is required and care is required. There are various criteria for frailty, and the present invention is not particularly limited to these, but the criteria proposed by Fried include five items (weight loss, easy fatigue, slow walking speed, slow grip strength, and slow physical activity), and if three or more items are met, it is considered to be frail, while if only one or two items are met, it is considered to be pre-frailty, which is the stage before frailty.

[0058] The prophylactic or therapeutic agent of the present invention has the effect of preventing the onset of one or more symptoms of frailty, delaying the onset of the symptoms, ameliorating the symptoms, suppressing the worsening of the symptoms, preventing the recurrence of the symptoms, and achieving early recovery from the symptoms. Symptoms of frailty include weight loss, subjective fatigue, decreased activity, weakened physical ability, decreased muscle strength, etc.

[0059] The preventive or therapeutic agent of the present invention can be an agent for preventing or treating decline in physical ability due to frailty. Decrease in physical ability is one of the symptoms of frailty. Decrease in physical ability includes declines in motor coordination, balance, standing and walking function, balance function, dexterity, motor speed, reaction time, etc. Decrease in physical ability leads to impairments in activities of daily living, such as inability to move freely, inability to maintain balance, falls, inability to lift heavy objects, slow walking speed, inability to walk, and inability to stand. The preventive or therapeutic agent of the present invention can preferably suppress or prevent, and / or ameliorate or treat impairment in walking in daily life, more preferably a decrease in walking speed. Sarcopenia is one of the causes of decline in physical ability, and the preventive or therapeutic agent of the present invention can be an agent for preventing or treating sarcopenia. Sarcopenia is a syndrome characterized by a progressive and systemic loss of muscle mass and strength. The preventive or therapeutic agent of the present invention can be an agent for preventing or treating a loss of muscle mass or strength. Preferably, the prophylactic or therapeutic agent of the present invention can suppress or prevent, and / or improve or treat, a decrease in motor coordination. Preferably, the prophylactic or therapeutic agent of the present invention can suppress or prevent, and / or improve or treat, a decrease in balance.

[0060] The preventive or therapeutic agent of the present invention can be an agent for preventing or treating a decrease in activity level due to frailty. A decrease in activity level is one of the symptoms of frailty. In the present invention, activity refers to any movement that consumes more energy than a state of rest, such as work including housework, commuting to work or school, going outside, walking, and exercise. The preventive or therapeutic agent of the present invention can suppress or prevent, and / or ameliorate or treat, a decrease in activity level.

[0061] The preventive or therapeutic agent of the present invention may be an agent for preventing or treating weight loss in frailty.

[0062] The preventive or therapeutic agent of the present invention can be an agent for preventing or treating frailty associated with a chronic disease. Chronic diseases are diseases that develop gradually and require long-term treatment and progression. Patients with chronic diseases often develop frailty due to a decrease in physical activity, making prevention and treatment important. The preventive or therapeutic agent of the present invention can be suitably used for frailty associated with chronic obstructive pulmonary disease, diabetes, dementia, cerebrovascular disease, mental disease (particularly depression or depressive state), and progeria.

[0063] Progeria is a general term for diseases in which signs of aging appear prematurely throughout the body, and includes Werner syndrome, Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Bloom syndrome, and Down syndrome.

[0064] 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 water 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.

[0065] 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, a part of the large intestine, and even when normal mice were fed a normal diet under the same conditions, hydrogen was below the detection limit. Since the retention time of food in the 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.

[0066] 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.

[0067] Furthermore, unlike hydrogen water, the preventive or therapeutic agent of the present invention does not allow hydrogen to diffuse before administration, which contributes to maintaining the quality of pharmaceutical products and contributing to convenience for manufacturers, sellers, and users.

[0068] After administering the silicon microparticles of the present invention to rats, the antioxidant power of the plasma was evaluated (BAP test), and it was confirmed that the antioxidant power was significantly higher in the group administered with silicon microparticles.

[0069] One mechanism by which frailty is prevented and / or treated is thought to be the prolonged generation of hydrogen by the silicon microparticles of the present invention, which are then transported to the blood and various organs, where they selectively react with hydroxyl radicals. Furthermore, the increased antioxidant activity in the blood suggests that this is due to antioxidants produced in the blood. Furthermore, studies using animal models of diseases involving oxidative stress have shown significant effects compared to hydrogen water, suggesting that silicon microparticles may have other effects not found in hydrogen water. Comparing the colonic tissues of mice treated with silicon microparticles with those of untreated mice, 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. Other possible mechanisms include proteins containing metal elements such as cobalt capturing nascent hydrogen generated in the intestine by the reaction of silicon microparticles with water, or proteins with increased reducing power as a result of hydrogen atoms donating electrons, being transported to various organs, where they react with hydroxyl radicals and eliminate them.

[0070] 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.

[0071] 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 carboxymethylcellulose calcium), and 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.

[0072] There are no particular limitations on the route of administration of the prophylactic or therapeutic agent of the present invention, but preferred routes of administration include oral, transdermal, and transmucosal (oral, rectal, vaginal, etc.) administration.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] The content of silicon microparticles in the preventive or therapeutic agent of the present invention is not particularly limited, and examples include 0.1 to 100% by weight, 1 to 99% by weight, and 5 to 95%.

[0077] 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, the preferred dosage of silicon microparticles is, for example, about 0.1 mg to 10 g per day, preferably about 1 mg to 5 g, and more preferably about 1 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.

[0078] The agent for preventing or treating frailty containing silicon microparticles of the present invention can be used in medicines, quasi-drugs, medical devices, foods, and beverages.

[0079] The present application also relates to an invention of a pharmaceutical composition for preventing or treating frailty, which contains the silicon microparticles. The present application also relates to an invention of a pharmaceutical composition for preventing or treating frailty, which contains an agent for preventing or treating frailty, which contains the silicon microparticles. The pharmaceutical composition of the present invention also includes compositions with mild effects, such as 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.

[0080] This application also relates to an invention of a medical device for preventing or treating frailty, which contains the agent for preventing or treating frailty containing the silicon microparticles. This application also relates to an invention of a medical device for preventing or treating frailty, which contains the silicon microparticles. The medical device of this invention refers to tools, instruments, etc. intended to be used for the treatment or prevention of diseases 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.

[0081] The present application also relates to an invention of a food or beverage for preventing or treating frailty, which contains the agent for preventing or treating frailty containing the silicon microparticles. The present application also relates to an invention of a food or beverage for preventing or treating frailty, which contains the silicon microparticles. Preferred examples of the food or beverage of the present invention include health foods, functional foods, and foods for specified health uses. The health foods, functional foods, and foods for specified health uses are foods or beverages that can prevent the onset of frailty symptoms, delay the onset, and / or prevent the recurrence of symptoms. 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, etc.

[0082] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples. [Example]

[0083] Example 1 200 g of high-purity silicon powder (manufactured by Kojundo Chemical Laboratory, particle size distribution <φ5 μm (however, silicon particles with a crystal particle diameter of more than 1 μm), purity 99.9%) was dispersed in 4 L (liter) of 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)).

[0084] 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.

[0085] The fine silicon particles (crystallites) obtained by the above method mainly had a crystallite diameter of 1 nm or more and 100 nm or less, and most of the crystallites formed aggregates. Furthermore, the crystallites were covered with a silicon oxide film, and the thickness of the silicon oxide film was approximately 1 nm. Measurement of these silicon crystallites using an X-ray diffractometer (Rigaku Electric Smart Lab) revealed that the volume distribution showed a mode diameter of 6.6 nm, a median diameter of 14.0 nm, and an average crystallite diameter of 20.3 nm. The resulting mixture of silicon crystallites and their aggregates on which a silicon oxide film was formed is one embodiment of the silicon microparticles that are the active ingredient of the present invention.

[0086] <Example 2> High-purity silicon powder (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 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 2500 rpm using a bead mill (Imex Co., Ltd., horizontal continuous ready mill (model RHM-08)).

[0087] 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.

[0088] 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 covered with a silicon oxide film, and the thickness of the silicon oxide film was about 1 nm. The obtained mixture of silicon crystallites with a silicon oxide film and their aggregates is one embodiment of the silicon microparticles that are the active ingredient of the present invention.

[0089] Example 3 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 silicon microparticles, which 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.

[0090] The amount of hydrogen generated from the silicon microparticles (silicon crystallites and their aggregates) obtained in Example 3 was measured. 10 mg of silicon microparticles were placed in a 100 ml glass bottle (borosilicate glass approximately 1 mm thick, ASONE Corporation'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.

[0091] Example 4 Using the same method as in Example 3, the silicon microparticles (silicon crystallites and their aggregates) obtained in Example 1 were treated with hydrogen peroxide, 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 resulting 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.

[0092] <Example 5> Single-stage pulverization was carried out in the same manner as in Example 1. The φ0.5 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.

[0093] 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.

[0094] Example 6 The mixture of silicon crystallites and their aggregates formed with a silicon oxide film treated with hydrogen peroxide obtained in Example 3 was filled into commercially available capsule No. 3 to obtain a capsule formulation. This capsule formulation 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.

[0095] <Test example> I. Preparation of silicon microparticle-containing food The silicon microparticles (silicon crystallites and their aggregates) produced in Example 3 were mixed with normal feed (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) to a concentration of 2.5 wt%. Furthermore, an aqueous citric acid solution (pH 4) was added in an amount of about 0.5 wt% based on the total amount of the silicon microparticles and the feed, and the mixture was kneaded using a known kneading device to obtain a silicon microparticle-containing diet.

[0096] II. Pharmacological effects of silicon microparticles

[0097] A.Improvement of antioxidant capacity SD rats (6 weeks old) were obtained. The group administered silicon microparticles was fed the silicon microparticle-containing diet, while the control group was fed regular feed (normal diet) (Oriental Yeast Co., Ltd., model number AIN93M). After 8 weeks of administration, blood was collected and the antioxidant capacity of the plasma was evaluated (BAP test) (FREE Carrio Duo free radical analyzer). The results are shown in Figure 4. It was shown that the group administered silicon microparticles had significantly higher antioxidant capacity.

[0098] B. Analysis of sulfur-related compounds in the large intestine B-1 Sample preparation C57BL / 6J mice (male, 7 weeks old) were obtained from Japan SLC. The silicon microparticle-treated group was fed the silicon microparticle-containing diet described above, while the control group was fed a regular diet (Oriental Yeast Co., Ltd., model number AIN93M) for one week, with five mice in each group. The large intestine of each mouse was removed under deep anesthesia and divided into three sections: the cecum, colon, and rectum. A portion (approximately 2 cm) from each section, from which the intestinal contents were extracted, was collected and weighed. After weighing, the samples were quickly frozen in powdered dry ice to prepare a colon sample for one mouse. A total of 10 frozen colon samples from five mice per group were used for sulfur index analysis (Euglena Co., Ltd.). Samples were prepared in the same manner at a later date, and a total of 10 frozen colon samples from five mice per group were prepared and used for sulfur index analysis (Euglena Co., Ltd.).

[0099] B-2 Pre-analysis The frozen mouse colon samples (five samples) from the same group obtained in the first sample preparation were combined, and a methanol extract containing an internal standard compound was added (1 ml / g (organ)). The samples were then mashed with a pestle. Then, the samples were centrifuged, and 100 μl of the supernatant was used as the sample. Sulfur compound labeling reagents and other reagents were added to 100 μl of the centrifuged sample supernatant (130 μl in total) and suspended. The centrifuged supernatant (87 μl) was dried in a centrifugal evaporator. After resuspension in 60 μl of water, 5 μl of the supernatant was centrifuged and used as the sample for sulfur index analysis. The samples obtained in the second sample preparation were treated in the same way to obtain samples for sulfur index analysis. The samples used for sulfur index analysis included two samples from the silicon microparticle-administered group (two mixed samples from five mice) and two samples from the control group (two mixed samples from five mice).

[0100] B-3 Sulfur Index Analysis (1) The sulfur compounds contained in the prepared samples were analyzed using the sulfur index method on an LC MSMS 8040 (Shimadzu Corporation). Specifically, relative quantification was performed on all 61 sulfur-related compounds listed in Tables 1 and 2, excluding the internal standard compound (No. 53; camphorsulfonate) and the thiol group modifier (No. 40; monobromobimane). Relative quantification was performed using the peak area of ​​the resulting mass chromatogram (normalized to the internal standard compound). A total of 35 compounds were detected in the colon sample. Based on the detected sulfur-related compound data, a mapping analysis of the similarity between samples (using the R software vegan package) was performed.

[0101] [Table 1]

[0102] [Table 2]

[0103] B-4 Multivariate analysis Multivariate analysis was performed on each sample based on the 35 sulfur-related compounds detected in B-3 above, and the results showed that the silicon microparticle-administered group and the control group could be distinguished by the following 10 compounds. The results of the multivariate analysis of the silicon microparticle-administered group and the control group using the following 10 compounds (average values ​​of the analysis results for each of the two samples) are shown in Figure 5. Glutathione monosulfide (labeled) Cysteinylglycine (labeled) Thiosulfate ion (labeled) Hypotaurine 5-Glutamylcysteine ​​(labeled) Cysteine ​​monosulfide (labeled) S-sulfocysteine Sulfite ion (labeled) Serine Taurine

[0104] The above compounds include glutathione monosulfide and cysteine ​​monosulfide, which are involved in antioxidant effects in the body, and are thought to play a part in the antioxidant effect of silicon microparticles. Since no such report has been made about hydrogen, this may be one of the antioxidant effects unique to the preventive or therapeutic agent of the present invention.

[0105] B-5 Sulfur Index Analysis (2) A comparative analysis (n=6 / group) of the amounts of glutathione and glutathione monosulfide (Glutathione-S) in the large intestine was conducted using the colons of the silicon microparticle-administered group and the control group. The test methods were the same as those described above for B-1 to B-3. The results are shown in Figure 6. There was no difference in the amount of glutathione between the silicon microparticle-administered group and the control group, but the amount of glutathione monosulfide was significantly increased in the silicon microparticle-administered group. Glutathione monosulfide has strong antioxidant properties and is thought to play a part in the mechanism of action of silicon microparticles.

[0106] C. Pharmacological studies in black mice (1) We obtained klotho / Jcl mice (male, 4 weeks old) that develop progeria from CLEA Japan. Klotho mice grow normally until 3-4 weeks of age, then show growth retardation after weaning and die at 8-9 weeks of age. Klotho mice exhibit multiple phenotypes similar to those seen in human aging and are used as a mouse model of aging. Klotho mice exhibit frailty symptoms, such as hypokinesia and gait disturbance. The obtained klotho mice were housed three per cage, and three wild-type mice of the same age were housed in the same cage. Food was provided by scattering, and water was provided by transport agar jelly.

[0107] Two days after being introduced into the experimental facility, the mice were fed either the silicon microparticle-containing diet prepared in I above or a normal diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M). Mice in each group were evaluated by macroscopic observation and behavioral testing at 7 weeks of age.

[0108] When comparing the average lifespan of mice in each group, no significant differences were observed. When comparing the coat condition of each group, one mouse in the normal diet group (n=7) had good coat condition, while five mice in the silicon microparticle administration group (n=8) had good coat condition.

[0109] Spontaneous activity in a novel environment was measured using an open field test to evaluate motor function. A square open field with sides of 50 cm was used, and the experiment lasted 10 minutes. The results are shown in Figures 7 to 9. Figure 7 shows the total distance traveled, Figure 8 shows the movement speed, and Figure 9 shows the active and immobile time. Control indicates the normal diet group (n=7), and Si indicates the silicon microparticle-administered group (n=8). Compared to the normal diet group, the silicon microparticle-administered group showed a significant suppression of the age-related decline in movement distance and movement speed, and also showed a tendency for improvement in the decline in active time. These results demonstrate the effectiveness of a diet containing silicon microparticles in treating the age-related decline in motor function.

[0110] D. Pharmacological study in black mice (2) We obtained male Klotho / Jcl mice (4-week-old) that develop progeria from CLEA Japan. Two Klotho mice were housed per cage with a wild-type mouse of the same age (Klotho mice and their littermates). + / + or Klotho + / - The two animals were kept together. They were fed by scattering food and provided with water by transport agar jelly.

[0111] Two types of silicon microparticle-containing diet were prepared: a diet containing 2.5 wt% silicon microparticles as prepared in I above, and a diet containing 1% silicon microparticles prepared in a similar manner. Two days after introduction to the experimental facility, mice in each group were given either a diet containing 1% silicon microparticles, a diet containing 2.5% silicon microparticles, or a standard diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M). Three weeks later, at 7 weeks of age, the following six groups of mice were evaluated by macroscopic observation of body weight, body length, etc., and behavioral testing. C / K: Kurotomouse normal diet S1 / K: Clotomouse diet containing 1% silicon microparticles S2 / K: Clotomouse diet containing 2.5% silicon microparticles C / W: Wild-type mice fed a normal diet S1 / W: Wild-type mice fed a diet containing 1% silicon microparticles S2 / W: Wild-type mice fed a diet containing 2.5% silicon microparticles

[0112] D-1. Macroscopic observation Table 3 shows the results of observations of Kuroto mice regarding coat condition, hunched back, age-related thymus involution, cryptorchidism (a condition in which the testes are not retracted into the scrotum), which indicates underdeveloped reproductive organs, and pituitary atrophy. Poor coat condition, such as hunched back and broken coat, was observed in most of the normal diet group, but this was observed in approximately 30% of the silicone microparticle-administered group. Furthermore, thymus involution, cryptorchidism, and pituitary atrophy were observed in almost all mice in the normal diet group, but this was observed in approximately 40% of the silicone microparticle-administered group. Furthermore, body length excluding the tail and total length including the tail were significantly greater in the silicone microparticle-administered group compared to the normal diet, indicating growth (Figure 10). There was no significant difference in survival time up to 7 weeks of age between the silicone microparticle-administered group and the normal diet group.

[0113] [Table 3]

[0114] D-2. Behavioral testing To measure spontaneous activity, a multi-channel spontaneous activity measurement system, SuperMex (Muromachi Kikai), was used, and an infrared sensor was used to measure the spontaneous movement of the mice in their cages for 20 minutes. Compared to the normal diet group, the decline in total spontaneous movement due to aging was significantly suppressed in the group administered silicon microparticles (Figure 11).

[0115] A rectangular open field (Muromachi Kikai) (500 x 500 mm, wall height 400 mm) was used to measure behavior in a novel environment. Distance traveled, movement speed, active time, and immobility time over a 10-minute period were analyzed using ANY-mase video tracking software. The results are shown in Figures 12-14. Similar to spontaneous activity, the age-related decline in behavior in a novel environment was significantly suppressed in the silicon microparticle-administered group compared to the normal diet group.

[0116] When two types of silicon microparticle-containing diets, 1% and 2.5%, were tested, macroscopic observation, physical measurements, and spontaneous activity analysis showed that the 1% was more effective, while the 2.5% tended to be more effective in terms of behavioral ability in a novel environment, but there was no significant difference between the two groups. From the above, it was clear that silicon microparticles are effective at a concentration of 1%.

[0117] E. Pharmacological studies in older mice C57Bl6J mice (male, 105 weeks old) were obtained from Charles River Japan and housed four per cage. Food was provided by ground feed, and water was provided by transport agar jelly.

[0118] From the day after their introduction into the experimental facility, the mice were fed either the silicon microparticle-containing diet (containing 2.5% silicon microparticles) prepared in I above or a regular diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M). Mice from each group were evaluated based on survival rate, body weight, and behavioral tests.

[0119] E-1.Survival rate There were 12 mice in each group, and survival was checked daily. The cumulative survival rate is shown in Figure 15. The number of animals that died from old age in the group administered with silicon microparticles was significantly lower than in the group fed the normal diet.

[0120] E-2. Weight The weight of all surviving E-1 mice was measured weekly. The results are shown in Figure 16. Weight loss was significantly suppressed in the group administered silicon microparticles compared to the normal diet group.

[0121] E-3. Behavioral testing To assess motor coordination and balance, a balance beam test (Carter RJ et al. Curr Protoc Neurosci. Chapter 8: Unit 8.12 (2001); Romand R et al. J Neurosci 33:5856-5866 (2013)) was performed. Two wooden beams (rods) with average diameters of 20 mm and 10 mm were prepared. They were 75 cm long and 50 cm high. Before the test, mice were placed in a box at the goal point for 30 seconds to instruct them that it was a safe area. They then trained by walking on the beam near the goal point twice. The test was conducted twice, with each session lasting 3 minutes and requiring three slips before retirement, as adapted for aged mice. The evaluation items were the time to reach the goal, the number of slips, and the rate of reaching the goal. A slip refers to a fall from the beam. The achievement rate is the percentage of mice that reached the goal compared to the test mice, and is shown as the percentage of mice that reached the goal in both of the two tests and the percentage of mice that reached the goal at least once. The results are shown in Figures 17-19. The group administered silicon microparticles showed a tendency for the time to reach the goal to be shorter than the group on the normal diet, the number of slips was significantly reduced, and the achievement rate was significantly higher.

[0122] E-4. Silicon microparticles have been shown to alleviate the decline in motor coordination and balance associated with aging in older mice. Silicon microparticles also suppressed weight loss and reduced the number of deaths associated with aging in older mice.

[0123] From the above results, it became clear that the silicon microparticles of the present invention have a high preventive effect and a high therapeutic effect against frailty. [Industrial Applicability]

[0124] This invention could be one of the therapies for treating the cause of frailty and will make a significant contribution to future medical care and health promotion.

Claims

1. A preventive or therapeutic agent for frailty associated with aging, containing silicon microparticles, wherein the frailty includes at least one symptom selected from the group consisting of weakened physical ability, decreased activity, weight loss, fatigue, and decreased muscle strength.

2. The preventive or therapeutic agent according to claim 1 , wherein the frailty includes symptoms of decreased physical ability.

3. The preventive or therapeutic agent according to claim 2 , wherein the decline in physical ability includes impairment of activities of daily living.

4. The preventive or therapeutic agent according to claim 3, wherein the activity of daily living is walking.

5. The preventive or therapeutic agent according to claim 2, wherein the decline in physical ability includes a decline in motor coordination and / or a decline in balance.

6. The preventive or therapeutic agent according to claim 1 , wherein the frailty includes a symptom of decreased activity.

7. The preventive or therapeutic agent according to claim 1 , wherein the frailty includes a symptom of weight loss.

8. The preventive or therapeutic agent according to claim 1, wherein the frailty associated with aging is frailty associated with progeria.

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

10. The preventive or therapeutic agent according to claim 9 , wherein the silicon-containing microparticles are microparticles containing elemental silicon.

11. The preventive or therapeutic agent according to any one of claims 1 to 10, wherein the silicon microparticles are silicon microparticles and / or aggregates of the silicon microparticles.

12. The preventive or therapeutic agent according to claim 11, wherein the silicon microparticles are microparticles made of simple silicon and have a silicon oxide film formed on the surface thereof.

13. A pharmaceutical composition for preventing or treating frailty associated with aging, comprising the preventive or therapeutic agent according to any one of claims 1 to 12, wherein the frailty comprises at least one symptom selected from the group consisting of weakened physical ability, decreased activity, weight loss, fatigue, and decreased muscle strength.

14. A medical device for preventing or treating frailty associated with aging, comprising the preventive or therapeutic agent according to any one of claims 1 to 12, wherein the frailty includes at least one symptom selected from the group consisting of weakened physical ability, decreased activity, weight loss, fatigue, and decreased muscle strength.

15. A food or beverage for preventing or treating frailty associated with aging, comprising the preventive or therapeutic agent according to any one of claims 1 to 12, wherein the frailty includes at least one symptom selected from the group consisting of weakened physical ability, decreased activity, weight loss, fatigue, and decreased muscle strength.

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