JP7759030B2 - Preventive or therapeutic agent for attention deficit hyperactivity disorder - Google Patents

Description

The present invention relates to the prevention or treatment of attention deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental or behavioral disorder characterized by three cardinal features: hyperactivity, impulsivity, and inattention. Its prevalence in Japan is estimated at approximately 3-5% among school-age children and 2-2.5% among adults. Clinically, ADHD is classified into three types based on the individual's characteristics: predominantly inattentive type, predominantly hyperactive-impulsive type, and combined type. There is no cure for ADHD; only symptomatic treatment is available. In drug therapy, the first step involves the prescription of a single central nervous system stimulant (methylphenidate hydrochloride or atomoxetine hydrochloride). If insufficient efficacy is observed even after administration of the maximum recommended optimal dose of each drug, or if serious side effects occur during dose increase, the patient moves on to the second step, in which the other central nervous system stimulant not selected in the first step is selected. If efficacy is still insufficient, the patient moves on to the third step, in which the decision to discontinue drug therapy is considered. If drug therapy is continued, the patient will move to the fourth stage, which involves a drug therapy chosen from three options: a combination of two central nervous system stimulants, a combination of one central nervous system stimulant and a mood regulator, or a combination of one central nervous system stimulant and an antipsychotic. However, caution is required as mood regulators and antipsychotics are prescribed off-label for attention deficit hyperactivity disorder.

While reactive oxygen species are necessary for life maintenance, 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 extremely oxidizing radicals, and when generated in the body, they are known to oxidize nearby substances such as DNA, lipids, and proteins, causing damage to organs. Due to these actions, hydroxyl radicals are believed to cause various diseases such as cancer and lifestyle-related diseases, as well as aging.

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

However, the saturated hydrogen concentration at room temperature is 1.6 ppm, 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 has a small molecular size, 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 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 provide enough hydrogen to react with hydroxyl radicals in the body. Furthermore, even if hydrogen is absorbed and transported to various organs, its concentration returns to the level before ingesting the hydrogen water within about an hour. Inhaling gaseous hydrogen in daily life is also difficult.

Silicon microparticles can generate hydrogen when they come into contact with water. This reaction hardly occurs 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 proceeds more rapidly at a pH of 8 or higher. Surface-treating the silicon microparticles also facilitates this reaction. Furthermore, while in contact with water, silicon microparticles can generate hydrogen continuously for 20 hours or more, and under certain conditions, 1 gram of silicon microparticles can generate more than 400 ml 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.

Patent Document 3 describes a solid preparation that contains silicon microparticles as its main ingredient and has the ability to generate hydrogen. However, it does not state that silicon microparticles can prevent or treat disease.

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 the ability of silicon microparticles to prevent or treat disease.

Patent Document 5 describes the treatment of silicon microparticles with hydrogen peroxide water. However, it does not state that silicon microparticles can prevent or treat diseases.

Patent Document 6 describes formulations containing silicon microparticles, and cites embodiments in which the formulations are contained in "base materials" such as animal medicines, livestock or pet foods, animal feed, plant medicines, plant fertilizers, or plant compost. While 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 could be used as a medicine.

Patent Document 7 primarily describes a silicon oxide film formed on the surface of silicon microparticles. It lists possible uses for the silicon microparticles, such as feed, supplements, food additives, and transdermal and/or transmucosal hydrogen uptake, and also mentions the promotion of animal health and/or disease prevention. However, it does not mention that silicon microparticles can prevent or treat disease to the extent that they could be used as a pharmaceutical.

The inventors have discovered 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 impairment, spinal cord injury, hearing loss, cerebral ischemia-reperfusion injury, diabetes, and hangovers, and have filed patent applications for this finding (Patent Documents 8 to 11).

Japanese Patent Application Laid-Open No. 2016-155118 Japanese Patent Application Laid-Open 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 JP 2019-214556 A JP 2020-007300 A

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

The present invention aims to provide pharmaceuticals, medical devices, foods, beverages, etc. for the prevention or treatment of attention deficit hyperactivity disorder.

The present inventors have discovered that silicon microparticles can prevent and/or treat attention deficit hyperactivity disorder, and have completed the present invention.
1. A preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon microparticles.
2. The prophylactic or therapeutic agent according to the above item 1, wherein the attention deficit hyperactivity disorder is hyperactivity in attention deficit hyperactivity disorder.
3. The preventive or therapeutic agent according to the preceding item 1 or 2, wherein the silicon microparticles are silicon-containing microparticles capable of generating hydrogen upon contact with water.
4. The preventive or therapeutic agent according to any one of the preceding items 1 to 3, wherein the silicon-containing microparticles are microparticles containing elemental silicon.
5. The preventive or therapeutic agent according to any one of items 1 to 4 above, wherein the silicon microparticles are silicon microparticles having a silicon oxide film formed on the surface thereof.
6. The preventive or therapeutic agent according to the preceding item 5, wherein the silicon oxide film is a silicon oxide film having a hydroxyl group added thereto.
7. The preventive or therapeutic agent according to any one of items 1 to 6 above, wherein the silicon microparticles are silicon microparticles and/or aggregates of the silicon microparticles.
8. The preventive or therapeutic agent according to the preceding item 7, wherein the silicon microparticles are microparticles made of simple silicon and have a silicon oxide film formed on the surface thereof.
9. The preventive or therapeutic agent according to any one of the preceding items 1 to 6, wherein the silicon microparticles are porous silicon particles.
10. The preventive or therapeutic agent according to any one of items 1 to 9 above, wherein the silicon microparticles are silicon microparticles that have been hydrophilized.
11. The preventive or therapeutic agent according to any one of the preceding items 1 to 10, which is for oral administration.
12. A pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder, comprising the prophylactic or therapeutic agent according to any one of the preceding items 1 to 11.
13. A medical device for preventing or treating attention deficit hyperactivity disorder, comprising the prophylactic or therapeutic agent according to any one of the preceding items 1 to 11.
14. A food or drink for preventing or treating attention deficit hyperactivity disorder, comprising the prophylactic or therapeutic agent according to any one of the preceding items 1 to 11.
15. A therapeutic agent for attention deficit hyperactivity disorder containing silicon microparticles.
16. A method for preventing or treating attention deficit hyperactivity disorder, comprising administering silicon microparticles.
17. A method for treating attention deficit hyperactivity disorder comprising administering silicon microparticles.
18. An agent for use in the prevention or treatment of attention deficit hyperactivity disorder, comprising silicon microparticles.
19. An agent for use in treating attention deficit hyperactivity disorder, comprising silicon microparticles.
20. Use of silicon microparticles for the preparation of a medicament for the prevention or treatment of attention deficit hyperactivity disorder.
21. Use of silicon microparticles for the preparation of a therapeutic agent for attention deficit hyperactivity disorder.

The preventive or therapeutic agent of the present invention can prevent and/or treat attention deficit hyperactivity disorder.

Prevention and treatment using the preventive or therapeutic agent of the present invention can be one of the causal therapies for attention deficit hyperactivity disorder, and is highly effective and safe. Since there is no fundamental cure for attention deficit hyperactivity disorder and only symptomatic treatments have been available, the discovery of a causal treatment will greatly contribute to future medical care and health promotion.

Furthermore, unlike hydrogen water, the preventive or therapeutic agent of the present invention does not allow hydrogen to diffuse before administration. This property contributes to maintaining the quality of pharmaceuticals and other products, and contributes to convenience for manufacturers, sellers, and users.

FIG. 1 is a photograph of silicon microparticles (a mixture of silicon crystallites and their aggregates) taken with a scanning electron microscope (SEM) (Example 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 2 with water at 36° C. and pH 8.2. FIG. 3 is a photograph of silicon microparticles (aggregates of silicon crystallites) taken with a scanning electron microscope (SEM) (Example 3). 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 is a graph showing that the control group and the silicon microparticle-administered group can be distinguished by 10 types of sulfur-related compounds as a result of multivariate analysis of sulfur-related compounds contained in the large intestine. Con indicates the control group, and Si indicates the silicon microparticle-administered group. Figure 6 is a graph showing the results of a comparative analysis of the amounts of glutathione and glutathione monosulfide in the colons of the silicon microparticle-administered group and the control group (n=6 per group). *p<0.05, t-test FIG. 7 shows the procedure for producing a mouse model of attention deficit hyperactivity disorder and the experimental procedure. Figure 8 is a graph showing the results of a hyperactivity test using an open field. The vertical axis shows the total distance traveled by mice in the open field over 10 minutes. Compared to the group (n=14) given normal diet and saline (far left), the group (n=31) given normal diet and 6-OHDA showed a significant increase in distance traveled and showed hyperactivity (center). In contrast, the group (n=19) given normal diet and 6-OHDA showed an improvement in distance traveled to the same level as the group given normal diet and saline (far right), and hyperactivity was improved. ***p<0.001, **p<0.01, t-test Figure 9 shows immunohistochemical staining images of coronal sections from the forebrain of a mouse model of attention deficit hyperactivity disorder (ADHD), showing the status of dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC). Compared to the group administered saline on a normal diet (far left), the group administered 6-OHDA on a normal diet showed significantly reduced tyrosine hydroxylase (TH) staining in the VTA and SNC, indicating damage to dopaminergic neurons (center). In contrast, the group administered 6-OHDA on a silicon microparticle-containing diet showed improved TH staining to the same level as the group administered saline on a normal diet (far right). Figure 10 shows immunohistochemical staining images of coronal sections from the midbrain of a mouse model of attention deficit hyperactivity disorder (ADHD), showing the state of dopaminergic neurons in the striatum. Compared to the group administered normal diet and saline (far left), the group administered normal diet and 6-OHDA showed significantly reduced tyrosine hydroxylase (TH) staining in the striatum, indicating damage to dopaminergic neurons (center). In contrast, the group administered 6-OHDA and silicon microparticle-containing diet showed improved TH staining to the same level as the group administered normal diet and saline (far right).

The silicon microparticles contained in the preventive or therapeutic agent of the present invention are microparticles containing silicon and can generate hydrogen when in contact with water.

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, this 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.

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 with a purity of 99% or more, preferably 99.9% or more, and more preferably 99.99% or more.

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

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.

When elemental silicon is exposed to the atmosphere, its surface is oxidized, forming a silicon oxide film. The silicon microparticles of the present invention are preferably microparticles having a silicon oxide film formed on their surface. 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 with a silicon oxide film formed on their surface, aggregates of such silicon microparticles, and porous silicon particles made of porous elemental silicon with a silicon oxide film formed on their surface.

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.

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 formed with a silicon oxide film to which hydroxyl groups have been added have improved contact efficiency between the surface and water, promoting the hydrogen generation reaction and enabling the generation of large amounts of hydrogen. The hydrophilization method is not particularly limited, and any known hydrophilization 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 the SiH groups in the silicon oxide film on the particle surface and add hydroxyl groups to the particle surface.

The silicon microparticles having a silicon oxide film with hydroxyl groups added thereto on their surfaces preferably have 5×10 ¹³ /cm ² or more hydroxyl groups on their surfaces. More preferably, they have 1×10 ¹⁴ /cm ² or more hydroxyl groups. Even more preferably, they have 3×10 ¹⁴ /cm ² or more hydroxyl groups. The 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.

Specific methods for hydrogen peroxide treatment include immersing silicon microparticles in hydrogen peroxide and stirring them. The hydrogen peroxide concentration is preferably 1-30%, more preferably 1.5-20%, even more preferably 2-15%, 2.5-10%, and most preferably 3-5%. The immersion and stirring time is preferably 5-90 minutes, more preferably 10-80 minutes, and even more preferably 20-70 minutes. Most preferably 30-60 minutes. Treatment with hydrogen peroxide can improve the hydrophilicity of silicon microparticles, but prolonged treatment time will cause the hydrogen generation reaction from the silicon microparticles to progress, affecting the thickness of the oxide film on the silicon microparticles. The temperature of the hydrogen peroxide during hydrogen peroxide treatment is preferably 20-60°C, more preferably 25-50°C, even more preferably 30-40°C, and most preferably 35°C.

There are no restrictions on the shape of the silicon microparticles. Examples include irregular, polygonal, spherical, elliptical, cylindrical, etc.

The silicon microparticles may be crystalline silicon microparticles, which have crystallinity. They may also be amorphous silicon microparticles, which do not have crystallinity. If they have crystallinity, they may be single crystal or polycrystalline. Crystalline silicon microparticles are preferred, and single crystal silicon microparticles are more preferred.

The amorphous silicon microparticles may be amorphous silicon microparticles formed by a plasma CVD method, a laser ablation method, or the like.

The silicon oxide film formed on the surface of silicon microparticles in the present invention may be a silicon oxide film formed by natural oxidation upon exposure to the atmosphere. It may also be a silicon oxide film formed artificially by known methods such as chemical oxidation using an oxidizing agent such as nitric acid.

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, _SiO3 , and _SiO2 that are formed when silicon on the surface of the particles made of elemental silicon combines with oxygen. _SiO , SiO, _{and SiO3} promote _the hydrogen generation reaction.

The silicon microparticles may be crystalline silicon microparticles, which have crystallinity. They may also be amorphous silicon microparticles, which do not have crystallinity. If 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).

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.

The silicon microparticles in the present invention may be silicon microparticles on which a silicon oxide film has been formed naturally or artificially after the silicon microparticles are produced. More preferred silicon microparticles are those on which a silicon oxide film has been formed on the surface of the silicon crystallites.

The silicon microparticles in the present invention may be particles obtained by crushing lumps of elemental silicon (high-purity silicon) or particles of elemental silicon. When elemental silicon lumps or particles are crushed to produce silicon microparticles, the surfaces of the silicon microparticles naturally oxidize to form a silicon oxide film.

The particle diameter of the silicon microparticles in the present invention (or the crystallite diameter if the microparticles are silicon crystallites) is preferably 0.5 nm or more and 100 μm or less, more preferably 1 nm or more and 50 μm or less, 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. A particle diameter of 500 nm or less provides a suitable rate and amount of hydrogen generation, and a particle diameter of 200 nm or less provides an even more suitable rate and amount of hydrogen generation.

The silicon microparticle aggregates of the present invention are aggregates of the silicon microparticles described above. They may be naturally formed or artificially formed. Preferably, they are aggregates of silicon microparticles on which a silicon oxide film is formed. Naturally formed aggregates are thought to remain aggregated in the digestive tract. Preferred aggregates have internal voids that allow water molecules to penetrate the aggregate and react with the microparticles inside. The hydrogen generation rate of naturally formed aggregates does not depend on the aggregate size, so the aggregates have internal voids that allow water molecules to penetrate the aggregate and react with the microparticles inside.

There are no particular restrictions on the size of the silicon microparticle agglomerates. The particle size of the silicon microparticle agglomerates 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 agglomerates can be formed so as to retain the surface area of the microparticles, and can have a surface area sufficient to achieve high hydrogen generation capacity.

The particle diameter of the silicon microparticles constituting the silicon microparticle agglomerates 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 microparticles constituting the silicon aggregates may be crystalline silicon microparticles or amorphous silicon microparticles. Preferred aggregates are aggregates of silicon crystallites with a crystallite diameter of 1 nm to 10 μm. Preferably, the aggregates are formed by agglomerating silicon crystallites having a silicon oxide film formed on their surfaces.

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 their surface, and/or aggregates thereof. Preferably, the agent contains, as a main component, aggregates of silicon crystallites with a silicon oxide film formed on their surface.

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 crystallites and/or aggregates thereof, on whose surface a silicon oxide film with added hydroxyl groups is formed. Preferably, the agent contains, as a main component, aggregates of silicon crystallites on whose surface a silicon oxide film with added hydroxyl groups is formed.

Porous silicon particles may be a porous body of silicon particles. They may also 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.

The porous silicon particles may be crystalline porous silicon particles. Alternatively, they may be amorphous porous silicon particles that do not have crystallinity. If they have crystallinity, they may be single crystal or polycrystalline.

There is no limit to the size of the voids present in the porous silicon particles, but they are typically between 1 nm and 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, but they are preferably between 200 nm and 400 μm.

Agglomerates of silicon microparticles and porous silicon particles have a large overall particle size and a large surface area, making them ideal for oral administration. Larger 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 superior from a safety perspective.

There are no particular restrictions 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. They may be polydisperse. They may also be formulations containing silicon microparticles with a specific range of particle size or crystallite size. Furthermore, there are no particular restrictions on the size distribution of aggregates of silicon microparticles.

The rate at which hydrogen is generated 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.

While there are no particular limitations on the method for producing silicon microparticles of the present invention, they can be produced by physically pulverizing silicon-containing particles to the 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 combination of two or more of these. Known chemical methods can also be used. From the perspective of production cost and ease of production management, physical pulverization is the preferred pulverization method. When microparticles consisting of fine particles of elemental silicon are exposed to the atmosphere, their surfaces are oxidized, forming 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.

When silicon-containing particles are produced by grinding them to the 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.

There are no restrictions on the silicon-containing particles used as the starting material, 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 used as the starting material can be single-crystalline, polycrystalline, or amorphous.

This application includes inventions relating to a preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon microparticles, an invention relating to a method for preventing or treating attention deficit hyperactivity disorder comprising administering silicon microparticles, an invention relating to an agent for use in the prevention or treatment of attention deficit hyperactivity disorder containing silicon microparticles, and an invention relating to the use of silicon microparticles for the preparation of a preventive or therapeutic agent for attention deficit hyperactivity disorder. The description and embodiments of the invention relating to a preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon microparticles in this specification include description and embodiments of all of these inventions.

The prophylactic or therapeutic agents for attention deficit hyperactivity disorder of the present invention include agents for preventing attention deficit hyperactivity disorder, agents for treating attention deficit hyperactivity disorder, and agents for both preventing and treating attention deficit hyperactivity disorder.

The prophylactic or therapeutic agent of the present invention has the effect of preventing the onset of one or more symptoms of attention deficit hyperactivity disorder, ameliorating symptoms, suppressing the worsening of symptoms, preventing the recurrence of symptoms, and promoting early recovery from symptoms. Symptoms of attention deficit hyperactivity disorder include hyperactivity, impulsivity, and lack of attention.

The prophylactic or therapeutic agent of the present invention may be an agent for the prophylaxis or treatment of hyperactivity in attention deficit hyperactivity disorder. Symptoms of hyperactivity include high activity, being unable to sit still, being unable to stop talking, restlessness, and an inability to control behavior.

The preventive or therapeutic agent of the present invention may be a therapeutic agent for attention deficit hyperactivity disorder. It has effects such as improving one or more symptoms of attention deficit hyperactivity disorder, suppressing the worsening of symptoms, preventing the recurrence of symptoms, and accelerating recovery from symptoms.

The preventive or therapeutic agent of the present invention can be a therapeutic agent for hyperactivity in attention deficit hyperactivity disorder. Symptoms of hyperactivity include high activity, inability to sit still, inability to stop talking, restlessness, and inability to control behavior.

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

When the silicon microparticles of the present invention are orally administered, due to the properties described above, it is thought that little 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. 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 typically 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.

It is also believed that by leaving silicon microparticles on the skin or mucous membranes for a long period of time, hydrogen can be distributed throughout the body transdermally or transmucosally for a long period of time.

In addition, when rats were administered silicon microparticles and their plasma antioxidant power was evaluated (BAP test), it was confirmed that the group administered silicon microparticles had significantly higher antioxidant power.

One mechanism by which attention deficit hyperactivity disorder (ADHD) is prevented and/or treated is thought to be the prolonged generation of hydrogen by the silicon microparticles of the present invention, which is then transported to the blood and various organs, where it selectively reacts with hydroxyl radicals. Furthermore, the increased antioxidant activity in the blood suggests that this is due to antioxidants produced in the blood. Furthermore, in studies using animal models of diseases involving oxidative stress, the silicon microparticles demonstrated significant effects compared to hydrogen water, suggesting that the silicon microparticles may have other effects not found in hydrogen water. When 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 and reacting with hydroxyl radicals to eliminate them.

The prophylactic or therapeutic agent of the present invention can be used in combination with other drugs for treating attention deficit hyperactivity disorder. As described above, the mechanism of action of the prophylactic or therapeutic agent of the present invention differs from the mechanism of action of existing drugs for treating attention deficit hyperactivity disorder, such as methylphenidate hydrochloride and atomoxetine hydrochloride, and therefore, a higher therapeutic effect is expected when used in combination.

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

One or more types of silicon microparticles of the present invention may be administered directly to humans or non-human animals. However, if necessary, they may be mixed with acceptable additives or carriers and formulated into forms known to those skilled in the art. 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), 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.

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

Formulations for oral administration include tablets, capsules, granules, powders, syrups (dry syrups), and oral jellies. Formulations for transdermal or transmucosal administration include patches and ointments.

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

The preventive or therapeutic agent of the present invention can be formulated into the above-mentioned dosage form and then administered to humans or non-human animals.

There are no particular restrictions on the content of silicon microparticles in the preventive or therapeutic agent of the present invention, but examples include 0.1 to 100% by weight, 1 to 99% by weight, and 5 to 95%.

The dosage and frequency of administration of silicon microparticles in the present invention can vary appropriately depending on factors such as the recipient, their age, weight, sex, purpose (e.g., prevention or treatment), severity of symptoms, dosage form, and route of administration. When administered to humans, a 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. Furthermore, 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 per day, one to two times per day, or once per day.

The agent for preventing or treating attention deficit hyperactivity disorder containing the silicon microparticles of the present invention can be used in pharmaceuticals, quasi-drugs, medical devices, foods, and beverages.

The present application also relates to an invention of a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder, which contains silicon microparticles. The present application also relates to an invention of a pharmaceutical composition for preventing or treating attention deficit hyperactivity disorder, which contains an agent for preventing or treating attention deficit hyperactivity disorder, which contains the silicon microparticles. 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 above-mentioned agent for preventing or treating attention deficit hyperactivity disorder.

This application also relates to an invention for a medical device for preventing or treating attention deficit hyperactivity disorder, which contains the aforementioned silicon microparticles and an agent for preventing or treating attention deficit hyperactivity disorder. This application also relates to an invention for a medical device for preventing or treating attention deficit hyperactivity disorder, which contains the aforementioned silicon microparticles. A medical device in this invention is an instrument or device intended for use in the treatment or prevention of disease in humans or non-human animals. An example of a medical device is a mask. By wearing the mask of the present invention, hydrogen can be supplied directly to the trachea or lungs. Another example is a bandage.

This application also relates to an invention for a food or beverage for preventing or treating attention deficit hyperactivity disorder, which contains the aforementioned silicon microparticles as a preventive or therapeutic agent for attention deficit hyperactivity disorder. This application also relates to an invention for a food or beverage for preventing or treating attention deficit hyperactivity disorder, which contains the aforementioned silicon microparticles. 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 the onset of symptoms of attention deficit hyperactivity disorder 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, and the like.

The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples.

Example 1
200 g of high-purity silicon powder (manufactured by Kojundo Chemical Laboratory Co., Ltd., 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)).

The ethanol solution containing the micronized silicon particles was separated from the beads through a separation slit installed inside the grinding chamber of the bead mill, and then heated to 30-35°C using a vacuum evaporator. Micronized silicon particles (crystallites) were obtained by evaporating the ethanol solution.

The micronized silicon particles (crystallites) obtained by the above method primarily had crystallite diameters of 1 nm to 100 nm, with most of the crystallites forming aggregates. The crystallites were also coated with a silicon oxide film, which was approximately 1 nm thick. Measurement of these silicon crystallites using an X-ray diffractometer (Rigaku Electric's Smart Lab) revealed a volumetric 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 coated with a silicon oxide film is one embodiment of the silicon microparticles that are the active ingredient of the present invention.

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.

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 inside 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.

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, 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.

Example 4
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.

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 vacuum evaporator, as in Example 1. The ethanol evaporated, and two-stage crushed silicon crystallites were obtained. These two-stage crushed silicon crystallites with a silicon oxide film formed thereon are also one embodiment of the silicon microparticles that are the active ingredient of the present invention.

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.

<Test Example>
I. 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.

II. Pharmacological effects of silicon microparticles

A. Improvement of antioxidant capacity SD rats (6 weeks old) were obtained. The silicon microparticle administration group was fed the silicon microparticle-containing diet, while the control group was fed regular feed (normal diet) (manufactured by 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 radical analyzer FREE Carrio Duo). The results are shown in Figure 4. It was shown that the antioxidant capacity was significantly higher in the silicon microparticle administration group.

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 received the silicon microparticle-containing diet described above, while the control group received regular feed (Oriental Yeast Co., Ltd., Model AIN93M) for one week. Each group of five mice received a large intestine excision 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 obtain a large intestine 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.). Sample preparation was performed in the same manner at a later date, and frozen colon samples from a total of 10 mice from five mice per group were prepared and similarly used for sulfur index analysis (Euglena Co., Ltd.).

B-2 Analytical Pretreatment Frozen mouse colon samples (5 samples) from the same group obtained in the first sample preparation were combined, a methanol extract containing an internal standard compound was added (1 ml/g (organ)), and the samples were 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 were 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).

B-3 Sulfur Index Analysis (1)
The sulfur compounds 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.

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 8.
Glutathione monosulfide (labeled)
Cysteinylglycine (labeled)
Thiosulfate ion (labeled)
Hypotaurine
5-Glutamylcysteine (labeled)
Cysteine monosulfide (labeled)
S-Sulfocysteine Sulfite Ion (Labeled)
Serine Taurine

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 effects of silicon microparticles. As no such reports have been made about hydrogen, this may be one of the antioxidant effects unique to the preventive or therapeutic agent of the present invention.

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 large intestines of the silicon microparticle-administered group and the control group. The test method was the same as that 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.

C. Pharmacological Tests in an Attention Deficit Hyperactivity Disorder Model C-1. Creation of an Attention Deficit Hyperactivity Disorder Model Five-day-old neonatal male mice (C57BL/6JJmsSlc) were intraventricularly administered with desipramine (20 mg/kg), a selective noradrenaline reuptake inhibitor. Thirty minutes later, an ADHD model was created by intraventricularly administered 6-hydroxydopamine (6-OHDA) (25 μg), a neurotoxin that selectively degenerates dopaminergic and noradrenergic neurons (Figure 7). The ventricle was injected 0.6 mm lateral to the sagittal suture, 2.0 mm rostral to the sagittal suture, and 1.3 mm deep from the skin. The injection was unilateral, not bilateral. Reference: Bouchatta O. et al., Sci Rep, 2018; 8: 15349

C-2. Administration of silicon microparticles Mother mice and newborn mice were given a normal diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) and the silicon microparticle-containing diet obtained in I above in powder form without solidification so that they could eat ad libitum. The normal diet or the silicon microparticle-containing diet was given to mother mice and newborn mice from 3 days after birth until analysis at 24 days after birth.

C-3. Hyperactivity Test Using an Open Field A behavioral test for hyperactivity was performed in an open field (50 cm x 50 cm) at 24 days of age. The results are shown in Figure 8. The vertical axis of Figure 8 indicates the total distance traveled by mice in the open field over 10 minutes. The group administered normal diet and saline showed normal activity levels, but the group administered normal diet and 6-OHDA showed a significant increase in activity levels and hyperactivity. In contrast, the group administered 6-OHDA and silicon microparticle-containing diet showed activity levels similar to those of the group administered normal diet and saline, and hyperactivity was significantly improved.

C-4. Neuroprotective Effect Furthermore, perfusion fixation was performed on the 25th day of life, the day after behavioral analysis, and frozen sections of the brain were prepared and immunostained. In the group administered saline on a normal diet, staining of tyrosine hydroxylase (TH), a marker of dopaminergic neurons, was observed in the ventral tegmental area (VTA), substantia nigra pars compacta (SNC) (Figure 9), and striatum (Figure 10). On the other hand, in the group administered 6-OHDA on a normal diet, TH staining in the VTA, SNC (Figure 9), and striatum (Figure 10) was significantly reduced, suggesting dysfunction of dopaminergic neurons. However, in the group administered 6-OHDA on a silicon microparticle-containing diet, TH staining in the VTA, SNC (Figure 9), and striatum (Figure 10) was observed to the same extent as in the group administered saline on a normal diet, suggesting improvement in dopaminergic neuron dysfunction. These findings demonstrate the effectiveness of diets containing silicon microparticles in treating attention deficit hyperactivity disorder.

From the above results, it is clear that the silicon microparticles of the present invention have high preventive and therapeutic effects against attention deficit hyperactivity disorder.

The present invention may become one of the causal therapies for attention deficit hyperactivity disorder, and will make a great contribution to future medical care and health promotion.

Claims (13)

A preventive or therapeutic agent for attention deficit hyperactivity disorder containing silicon microparticles. The preventive or therapeutic agent according to claim 1, wherein the attention deficit hyperactivity disorder is hyperactivity in attention deficit hyperactivity disorder. The preventive or therapeutic agent according to claim 1 or 2, wherein the silicon microparticles are silicon-containing microparticles capable of generating hydrogen upon contact with water. The preventive or therapeutic agent according to any one of claims 1 to 3, wherein the silicon-containing microparticles are microparticles containing elemental silicon. The preventive or therapeutic agent according to any one of claims 1 to 4, wherein the silicon microparticles are silicon microparticles having a silicon oxide film formed on the surface. The preventive or therapeutic agent according to claim 5, wherein the silicon oxide film is a silicon oxide film to which hydroxyl groups have been added. The preventive or therapeutic agent according to any one of claims 1 to 6, wherein the silicon microparticles are silicon microparticles and/or aggregates of such silicon microparticles. The preventive or therapeutic agent according to claim 7, wherein the silicon microparticles are microparticles made of simple silicon and have a silicon oxide film formed on their surfaces. The preventive or therapeutic agent according to any one of claims 1 to 6, wherein the silicon microparticles are porous silicon particles. The preventive or therapeutic agent according to any one of claims 1 to 9, wherein the silicon microparticles are hydrophilically treated silicon microparticles. The preventive or therapeutic agent according to any one of claims 1 to 10, which is for oral administration. A pharmaceutical composition for the prevention or treatment of attention deficit hyperactivity disorder, comprising the prophylactic or therapeutic agent according to any one of claims 1 to 11. A food or drink for preventing or treating attention deficit hyperactivity disorder, comprising the prophylactic or therapeutic agent according to any one of claims 1 to 11.