WO2021215364A1 - Agent for preventing or treating intrauterine infection - Google Patents

Abstract

[Problem] To provide a medicament, etc., capable of preventing or treating intrauterine infection. [Solution] Intrauterine infection 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 intrauterine infection, and which contain the silicon fine particles. Preferably, the silicon fine particles are: silicon fine particles each having a silicon oxide film to which a hydroxy group is added; and/or an aggregate of said silicon fine particles.

Description

Preventive or therapeutic agents for intrauterine infections

The present invention relates to the prevention or treatment of endometrial infections.

Humans prevent illness by working their immunity normally, but pregnancy is in a special condition that lowers this immunity. This is because the foetation having the antigen derived from the father is recognized as a foreign substance in the mother and suppresses the attack by the mother's immune system. Therefore, in the pregnant mother's body, inhibitory T cells that specifically recognize the father-derived antigen expressed by the foetation proliferate and suppress the immune response of the mother to the foetation (Rowe et al, 2012, Nature 490). (7418): 102-106).

In mother-to-child transmission, a pathogen that infects the mother with reduced immunity infects the baby, or cytokines produced by the immune reaction of the infected mother are transmitted to the baby through the mother (body fluid, placenta, birth canal, breast milk, etc.). It is classified into intrauterine infection during pregnancy, birth canal infection at birth, and breast milk infection after birth, depending on the time of infection.

The routes of intrauterine infection include the placental route and the ascending route, but most of them are the placental route. Typical pathogens of intrauterine infections include toxoplasma, ruin virus, measles virus, cytomegalovirus, herpes simplex virus, varicella, syphilis, influenza virus, human immunodeficiency virus (HIV), porbovirus, hepatitis B virus, C. Hepatitis virus, human T lymphocyte tropic virus type 1, mumps virus, tuberculosis, listeria, group B streptococcus and the like can be mentioned. Since coping with intrauterine infections is the most important in clinical practice, it can be diagnosed as an endometrial infection without distinction by transmission route. Drug treatment is limited, and in reality, even if an intrauterine infection is suspected, fetal treatment is rare due to problems such as drug exposure to the foetation, and most of the treatment is postnatal treatment. If the child cannot be treated during pregnancy and suffers from various diseases such as microcephaly, hydrocephalus, eye lesions, hemorrhagic spots, hepatic splenoma, intrauterine growth retardation, visual impairment, epilepsy, as well as serious cases Will be stillborn, miscarriage, or premature birth. Thus, the health of the mother, fetal, and newborn during pregnancy is one of the serious social problems not only in the medical field but also in the age of declining birthrate and super-aging.

While active oxygen is necessary for life support, it is known to oxidize and damage the cells that make up the living body. Reactive oxygen species include superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and singlet oxygen. Hydroxyl radicals are radicals with extremely high oxidizing power, and substances that are close to each other when generated in vivo, such as DNA and lipids, It is known to oxidize proteins and the like and damage radicals. Hydroxyl radicals are said to cause various diseases such as cancer and lifestyle-related diseases, and aging due to such actions.

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

However, the saturated hydrogen concentration is 1.6 ppm at room temperature, and the amount of hydrogen contained in 1 liter of hydrogen water is only 18 ml (milliliter) in terms of gas even in the saturated state. Further, hydrogen has a small molecular size, hydrogen in hydrogen water passes through a container and diffuses into air, and it is difficult to maintain the amount of dissolved hydrogen in hydrogen water. In addition, even if high-concentration hydrogen water is ingested, most of the hydrogen in the hydrogen water is gasified in the upper digestive tract such as the stomach, which may cause a belching symptom (so-called "belching"). Therefore, it is not easy to take in a sufficient amount of hydrogen into the body to react with hydroxyl radicals in the body by the method of ingesting hydrogen water. Furthermore, even if hydrogen is absorbed and transported to each organ, its concentration returns to the concentration before ingestion of hydrogen water in about 1 hour. In addition, it is difficult to aspirate gaseous hydrogen in daily life.

Silicon fine particles can generate hydrogen in contact with water. This reaction hardly proceeds when it comes into contact with water having a pH of less than 5, and when it comes into contact with water having a pH of 7 or more, the reaction proceeds, and when it comes into contact with water having a pH of 8 or more, the reaction proceeds faster. Further, by surface-treating the silicon fine particles, the above reaction proceeds favorably. Further, the silicon fine particles continuously generate hydrogen for 20 hours or more while in contact with water, and depending on the conditions, 1 g of the silicon fine particles generate 400 ml or more of hydrogen (Patent Document 1, Patent Document 2, Non-Patent Document 2). Patent Document 1). 400 ml of hydrogen corresponds to hydrogen contained in 22 liters of saturated hydrogen water.

Patent Document 3 describes a solid preparation having a hydrogen generating ability containing silicon fine particles as a main component. However, it is not described that the silicon fine particles can prevent or treat the disease.

Patent Document 4 describes a hydrogen supply material including a medium containing silicon fine particles and water. It is described that the hydrogen supply material is used to supply hydrogen to the skin or mucous membranes. However, it is not described that the silicon fine particles can prevent or treat the disease.

Patent Document 5 describes the hydrogen peroxide solution treatment of silicon fine particles. However, it is not described that the silicon fine particles can prevent or treat the disease.

Patent Document 6 describes a formulation containing silicon fine particles, and is used in a "base material" such as an animal drug, a livestock or pet food, an animal feed, a plant drug, a plant fertilizer, or a plant compost. The embodiments included in the above are listed. Although it is described as promoting animal health and / or preventing diseases, it is not described that silicon fine particles can prevent or treat diseases to the extent that they can be used as medicines.

Patent Document 7 mainly describes a silicon oxide film formed on the surface of silicon fine particles. As usage patterns, feeds, supplements, food additives, transdermal and / or transmucosal hydrogen uptake are described, and animal health promotion and / or disease prevention are also described. However, there is no description that silicon fine particles can prevent or treat diseases to the extent that they can be used as pharmaceuticals.

Kidney disease, inflammatory disease (inflammatory bowel disease, arthritis, hepatitis, dermatitis), visceral discomfort, depression or depression, Parkinson's disease, autism spectrum disorder, memory loss, spinal cord injury, hearing loss, cerebral ischemia The present inventors have found that silicon fine particles can prevent or treat these diseases for perfusion disorder, diabetes, and depression (Patent Documents 8 to 11).

Japanese Unexamined Patent Publication No. 2016-155118 Japanese Unexamined Patent Publication No. 2017-104848 International Publication No. 2017/130709 International Publication No. 2018/037752 International Publication No. 2018/037818 International Publication No. 2018/037819 International Publication No. 2019/21960 International Publication No. 2019/021769 International Publication No. 2019/235577 JP-A-2019-214556 Japanese Unexamined Patent Publication No. 2020-007300

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

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

The present inventors have found that silicon fine particles can prevent and / or treat endometrial infections, and have completed the present invention.
1. 1. A preventive or therapeutic agent for intrauterine infections containing silicon fine particles.
2. The preventive or therapeutic agent according to item 1 above, wherein the silicon fine particles are fine particles containing silicon that can generate hydrogen in contact with water.
3. 3. The preventive or therapeutic agent according to item 2 above, wherein the silicon-containing fine particles are fine particles containing a simple substance of silicon.
4. The preventive or therapeutic agent according to any one of items 1 to 3 above, wherein the silicon fine particles are silicon fine particles having a silicon oxide film formed on the surface.
5. The preventive or therapeutic agent according to item 4, wherein the silicon oxide film is a silicon oxide film to which a hydroxyl group is added.
6. The prophylactic or therapeutic agent according to any one of the above items 1 to 5, wherein the silicon fine particles are silicon fine particles and / or an aggregate of the silicon fine particles.
7. The preventive or therapeutic agent according to item 6, wherein the silicon fine particles are fine particles made of elemental silicon and have a silicon oxide film formed on the surface thereof.
8. The preventive or therapeutic agent according to any one of items 1 to 5 above, wherein the silicon fine particles are porous silicon particles.
9. The preventive or therapeutic agent according to any one of items 1 to 8 above, wherein the silicon fine particles are hydrophilized silicon fine particles.
10. The preventive or therapeutic agent according to item 9, wherein the hydrophilization treatment is hydrogen peroxide solution treatment.
11. The prophylactic 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 an endometrial infection containing the prophylactic or therapeutic agent according to any one of the preceding items 1 to 11.
13. A medical device for preventing or treating an endometrial infection containing the prophylactic or therapeutic agent according to any one of the preceding items 1 to 11.
14. A food or beverage for preventing or treating an endometrial infection containing the prophylactic or therapeutic agent according to any one of the preceding paragraphs 1 to 11.
15. A therapeutic agent for endometrial infections containing silicon fine particles.
16. A method for preventing or treating an endometrial infection, which comprises administering silicon fine particles.
17. A method for treating an endometrial infection, which comprises administering silicon microparticles.
18. An agent containing silicon fine particles for use in the prevention or treatment of endometrial infections.
19. An agent containing silicon fine particles for use in the treatment of intrauterine infections.
20. Use of silicone microparticles for the prevention or preparation of therapeutic agents for endometrial infections.
21. Use of silicone microparticles for the preparation of therapeutic agents for endometrial infections.

The prophylactic or therapeutic agent of the present invention can prevent and / or treat endometrial infections.

The prevention or treatment with the prophylactic or therapeutic agent of the present invention can be one of the causative therapies for intrauterine infectious diseases, and is excellent in effectiveness and safety. Although endometrial infections have serious effects on the fetus, fetal treatment is rare even if endometrial infection is suspected, and most of them are postnatal treatment. Prevention and early treatment of endometrial infections are desired by many patients, their families, and medical professionals, and will greatly contribute to future medical care.

FIG. 1 is a photograph of silicon fine particles (mixture of silicon crystallites and aggregates thereof) taken with a scanning electron microscope (SEM) (Example 3). FIG. 2 is a graph showing the amount of hydrogen (cumulative amount) per 1 g of silicon fine particles generated by contacting the silicon fine particles obtained in Example 3 with water at 36 ° C. and pH 8.2. FIG. 3 is a photograph of silicon fine particles (aggregates of silicon crystallites) taken with a scanning electron microscope (SEM) (Example 4). FIG. 4 is a graph showing the results of plasma antioxidant power (BAP test) of normal SD rats to which silicon fine particles were administered for 8 weeks. Con indicates a control group, and Si indicates a silicon fine particle administration group. FIG. 5 is a graph showing that, as a result of multivariate analysis of sulfur-related compounds contained in the large intestine, the control group and the silicon fine particle administration group can be distinguished by 10 types of sulfur-related compounds. Con indicates a control group, and Si indicates a silicon fine particle administration group. FIG. 6 is a graph showing the results of comparative analysis of the amounts of glutathione (A) and glutathione monosulfide (B) using the large intestines of the silicon fine particle administration group and the control group (n = 6 in each group). * p <0.05, t test FIG. 7 is a diagram showing a procedure for producing and experimenting with an endometrial infection model mouse. FIG. 8 is a graph showing the rate of miscarriage in pregnant mother mice. The vertical axis shows the ratio of the number of miscarried (dead) fetuses to the number of pregnant fetuses for each mother mouse. The rate of miscarriage was significantly increased in the LPS-administered group of the normal diet (center) as compared with the control of the normal diet (saline administration) (leftmost). On the other hand, the rate of miscarriage recovered in the LPS-administered group fed the diet containing silicon fine particles (far right). *** p <0.001, * p <0.06, t-test FIG. 9 is a diagram showing the degree of inflammation of the placenta in an endometrial infection. The vertical axis shows the fluorescence intensity (A) in immunostaining of IL-6, which is an inflammation marker, and the number of positive cells (B) in Ly-6G staining, which is a marker of neutrophils. Inflammation markers and neutrophil markers were significantly increased in the LPS-administered group of the normal diet (center) as compared with the control of the normal diet (saline administration) (leftmost). In contrast, inflammation and neutrophil markers were significantly recovered in the LPS-administered group fed a diet containing silicon fine particles (far right). *** p <0.001, ** p <0.01, t-test FIG. 10 is a graph showing the fetal survival rate of endometrial infection model mice. The vertical axis shows the survival rate of the fetal, and the horizontal axis shows the time (h) after LPS administration. The survival rate of 16 hours after the first LPS administration and the survival rate of 4 hours after the second LPL administration are shown. Four hours after the second LPS administration (20 hours after the first LPS administration), all fetuses were alive under normal diet control (saline administration) (black line), which is normal. The fetal survival rate decreased to 6.7% in the dietary LPS-administered group (dotted line). On the other hand, in the LPS-administered group fed with the silicon fine particle-containing diet, the fetal survival rate recovered to 62.5% (thick black line).

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

The above-mentioned "silicon-containing fine particles capable of generating hydrogen in contact with water" (silicon fine particles capable of generating hydrogen) continuously generate hydrogen when in contact with water at 36 ° C. and pH 8.2. However, it means silicon fine particles capable of generating 10 ml or more of hydrogen per gram of silicon fine particles in 24 hours. Preferably, it is 20 ml or more, 40 ml or more, 80 ml or more, 150 ml or more, 200 ml or more, and 300 ml or more.

The silicon-containing fine particles are preferably fine particles containing a simple substance of silicon. The silicon simple substance is high-purity silicon. In the present specification, the high-purity silicon is silicon having a purity of 99% or more, preferably 99.9% or more, more preferably 99.99% or more, still more preferably 99.999% or more.

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

The active ingredient of the prophylactic or therapeutic agent of the present invention is preferably at least one kind of particles selected from the group consisting of silicon fine particles, aggregates of the silicon fine particles, and porous silicon particles. That is, the preferable active ingredient may be silicon fine particles alone, agglomerates of silicon fine particles alone, or porous silicon particles alone. Further, two or more kinds of silicon fine particles may be contained as an active ingredient. The prophylactic or therapeutic agent of the present invention preferably contains silicon fine particles and / or agglomerates of the silicon fine particles. More preferably, the main component is an aggregate of silicon fine particles.

When exposed to the atmosphere, the surface of silicon alone is oxidized to form a silicon oxide film. The silicon fine particles in the present invention are preferably fine particles having a silicon oxide film formed on the surface. The preferable silicon fine particles in the present invention are fine particles made of silicon alone, and are silicon fine particles having a silicon oxide film formed on the surface thereof, aggregates of the silicon fine particles, and particles made of porous silicon alone. It is at least one kind of particles selected from the group consisting of porous silicon particles having a silicon oxide film formed on the surface thereof.

The content of silicon in the silicon fine particles is preferably 10% by weight or more, more preferably 20% by weight or more, further preferably 50% by weight or more, and most preferably 70% by weight or more.

The silicon oxide film is preferably a silicon oxide film to which a hydroxyl group (-OH group) is added. The silicon oxide film to which a hydroxyl group is 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, a hydroxyl group can be added to the silicon oxide film by a hydrophilic treatment. Silicon fine particles on which a silicon oxide film to which a hydroxyl group is added have improved contact efficiency between the surface and water, promote a hydrogen generation reaction, and can generate a large amount of hydrogen. The method of hydrophilic treatment is not particularly limited, and a known hydrophilic treatment method may be used. For example, hydrogen peroxide solution treatment and nitric acid treatment can be mentioned. Hydrogen peroxide solution treatment is preferable. By the hydrogen peroxide solution treatment, hydrogen of the SiH group of the silicon oxide film on the particle surface can be removed and a hydroxyl group can be added to the particle surface.

The silicon fine particles to which the silicon oxide film to which the hydroxyl group is added are formed on the surface preferably have ^{a hydroxyl group of 5 × 10 13} / cm ² or more on the surface. More preferably, it has a hydroxyl group ^{of 1 × 10 14} / cm ^{2 or more.} More preferably, it has a hydroxyl group ^{of 3 × 10 14} / cm ^{2 or more.} The particle surface is a surface of silicon fine particles, a surface of porous silicon particles, a surface of aggregates of silicon fine particles, and a surface of silicon fine particles forming the aggregates.

The specific method of hydrogen peroxide solution treatment is, for example, immersing silicon fine particles in hydrogen peroxide solution and stirring. The concentration of hydrogen peroxide is preferably 1 to 30%, more preferably 1.5 to 20%, still more preferably 2 to 15%, 2.5 to 10%, and most preferably 3 to 5%. The time for immersing and stirring 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. The hydrophilicity of the silicon fine particles can be improved by treating with hydrogen peroxide solution, but if the treatment time is long, the hydrogen generation reaction from the silicon fine particles proceeds and affects the thickness of the oxide film of the silicon fine particles. The temperature of the hydrogen peroxide solution during the hydrogen peroxide solution treatment is preferably 20 to 60 ° C., more preferably 25 to 50 ° C., more preferably 30 to 40 ° C., and most preferably 35 ° C.

There are no restrictions on the shape of silicon fine particles. Examples include amorphous, polygonal, spherical, elliptical, and columnar.

The silicon fine particles may be crystalline silicon fine particles having crystallinity. Further, it may be amorphous silicon fine particles having no crystallinity. As long as it has crystallinity, it may be single crystal or polycrystal. It is preferably crystalline silicon fine particles, and more preferably single crystal silicon fine particles.

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

The silicon oxide film formed on the surface of the silicon fine particles in the present invention may be a silicon oxide film formed by being naturally oxidized by being exposed to the atmosphere. Further, it may be a silicon oxide film artificially formed by a known method such as chemical oxidation with an oxidizing agent such as nitric acid.

The thickness of the silicon oxide film may be any thickness as long as the fine particles made of simple silicon are stable and enable efficient hydrogen generation. For example, it is 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, and 1.0 nm to 1.7 nm. The silicon oxide film may be a film containing oxides such as _{Si 2} O, SiO, Si ₂ O ₃ , and SiO ₂ formed by combining silicon on the surface of fine particles made of silicon alone with oxygen. Oxides in which silicon is incompletely oxidized, such as Si ₂ O, SiO, and Si ₂ O _{3, promote the hydrogen generation reaction.}

The silicon fine particles may be crystalline silicon fine particles having crystallinity. Further, it may be amorphous silicon fine particles having no crystallinity. As long as it has crystallinity, it may be single crystal or polycrystal. Preferred silicon fine particles are crystalline silicon fine particles, and more preferably single crystal silicon fine particles (hereinafter, also referred to as silicon crystallites).

The silicon fine particles may be fine particles in which at least two selected from the group consisting of single crystal silicon fine particles, polycrystalline silicon fine particles and amorphous silicon fine particles are mixed.

The silicon fine particles in the present invention can be silicon fine particles in which a silicon oxide film is naturally or artificially formed after the silicon fine particles are produced. More preferable silicon fine particles are fine particles in which a silicon oxide film is formed on the surface of silicon crystallites.

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

The particle size of the silicon fine particles in the present invention (the crystallite size when the fine particles are silicon crystallites) is preferably 0.5 nm or more and 100 μm or less, more preferably 1 nm or more and 50 μm or less, and more preferably 1. .5 nm or more and 10 μm or less, more preferably 2 nm or more and 5 μm or less, more preferably 2.5 nm or more and 1 μm or less, 5 nm or more and 500 nm or less, 7.5 nm or more and 200 nm or less, 10 nm or more and 100 nm or less. When the particle size is 500 nm or less, a suitable hydrogen generation rate and hydrogen generation amount can be obtained, and when the particle size is 200 nm or less, a more suitable hydrogen generation rate and hydrogen generation amount can be obtained.

The aggregate of silicon fine particles in the present invention is the aggregate of the silicon fine particles. It may be naturally formed or artificially formed. Preferably, it is an agglomerate in which silicon fine particles on which a silicon oxide film is formed are aggregated. Naturally formed aggregates are believed to remain aggregated in the gastrointestinal tract. The preferred aggregate has a structure having voids inside and allowing water molecules to infiltrate the aggregate and react with the fine particles inside. Since the hydrogen generation rate of naturally formed aggregates does not depend on the size of the aggregates, the aggregates have voids inside and water molecules can infiltrate the aggregates and react with the fine particles inside. Has.

There is no particular limitation on the size of the aggregate of silicon fine particles. The particle size of the agglomerates of preferable silicon fine particles is 10 nm or more and 500 μm or less. More preferably, it is 50 nm or more and 100 μm or less, and further preferably 100 nm or more and 50 μm or less. The agglomerates can be formed to retain the surface area of the fine particles and can have sufficient surface area to achieve high hydrogen generation potential.

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

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

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

Porous silicon particles (porous silicon particles) can be a porous body of silicon particles. Further, it may be a porous body in which silicon fine particles are aggregated and processed. The porous silicon particles are preferably particles made of a simple substance of porous silicon, and have a silicon oxide film formed on the surface thereof. More preferably, the silicon oxide film is a silicon oxide film to which a hydroxyl group is added.

The porous silicon particles can be porous silicon particles having crystallinity. Further, it may be amorphous porous silicon particles having no crystallinity. As long as it has crystallinity, it may be single crystal or polycrystal.

The size of the voids existing in the porous silicon particles is not limited, but usually can be 1 nm to 1 μm, and the porous silicon particles have a sufficient surface area to realize high hydrogen generating ability. The size of the porous silicon particles is not particularly limited. It can be preferably 200 nm to 400 μm.

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

There are no particular restrictions on the particle size distribution of silicon fine particles contained in the preventive or therapeutic agent of the present invention, the particle size distribution of fine particles composed of simple substances of silicon, or the crystallite size distribution. It may be polydisperse. It may be a preparation containing silicon fine particles having a specific range of particle size or crystallite size. Further, the size distribution of the aggregates of silicon fine particles is not particularly limited.

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

The method for producing the silicon fine particles of the present invention is not particularly limited, but the silicon-containing particles can be produced by physically pulverizing the silicon-containing particles to the desired particle size. Preferable examples of the physical crushing method are a bead mill crushing method, a planetary ball mill crushing method, a shock wave crushing method, a high pressure collision method, a jet mill crushing method, or a crushing method in which two or more kinds thereof are combined. It is also possible to employ known chemical methods. From the viewpoint of manufacturing cost or ease of manufacturing control, a suitable crushing method is a physical crushing method. When the fine particles composed of fine particles of silicon alone are exposed to the atmosphere, the surface is oxidized to form a silicon oxide film. Further, after pulverization, a silicon oxide film may be artificially formed by a known method such as chemical oxidation with an oxidizing agent such as hydrogen peroxide solution or nitric acid.

When silicon-containing particles are pulverized to a target particle size using a bead mill device for production, the target particle size or particle size distribution can be obtained by appropriately changing the bead size and / or type. be able to.

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

The present application relates to an invention relating to a preventive or therapeutic agent for an intrauterine infection containing silicon fine particles, an invention relating to a method for preventing or treating an intrauterine infection including administration of silicon fine particles, and an intrauterine infection containing silicon fine particles. Includes inventions relating to agents used for the prevention or treatment of diseases, and inventions relating to the use of silicon fine particles for the prevention or preparation of therapeutic agents for intrauterine infections. The description and embodiments of the invention relating to the preventive or therapeutic agent for endometrial infectious diseases containing silicon fine particles in the present specification are the description and embodiments of all these inventions.

The preventive or therapeutic agent for intrauterine infections of the present invention includes an agent for preventing intrauterine infections, an agent for treating intrauterine infections, and an agent for preventing and treating intrauterine infections.

The endometrial infection in the present invention is any symptom or disorder exhibited by the foetation caused by maternal infection. Intrauterine infection in the present invention includes fetal symptoms or disorders caused by infection of the fetus by a pathogen that infects the mother, and fetal symptoms or disorders caused by transmission of cytokines produced by the immune response of the infected mother to the fetal. , And fetal symptoms or disorders due to the maternal immune system, which is in a special immune response state so as not to recognize the fetus as a foreign body, disrupted by infection and adversely affect the fetus.

Typical pathogens of intrauterine infections include toxoplasma, ruin virus, measles virus, cytomegalovirus, herpes simplex virus, varicella, syphilis, influenza virus, human immunodeficiency virus (HIV), porbovirus, hepatitis B virus, type C Hepatitis virus, human T lymphocyte tropic virus type 1, mumps virus, tuberculosis, listeria, group B streptococcus, etc. can be mentioned.

Intrauterine infections include the effects of maternal influenza virus infection, congenital toxoplasma infection, congenital eczema syndrome, congenital cytomegalovirus infection, congenital syphilis, human immunodeficiency virus (HIV) infection, and the like. .. Specific diseases include various diseases such as microcephaly, hydrocephalus, eye lesions, hemorrhagic spots, hepatosplenomegaly, intrauterine growth retardation, visual impairment, and epilepsy.

During pregnancy, when an endometrial infection occurs, the foetation forms tissues and organs, so unlike the adult stage, it is greatly affected by pathogens, etc., and the development and developmental abnormalities of organs and foets are likely to occur. In addition, the placental barrier becomes dysfunctional due to inflammation of the mother and the like, which greatly damages the health of the foetation. Serious disorders and sequelae may remain in vital organs such as the liver, lungs, kidneys, and central nerves, and / or sensory organs such as the eyes and ears. Mental developmental delay can also occur.

The prophylactic or therapeutic agent of the present invention has effects such as prevention of onset, improvement of symptom, suppression of exacerbation of symptom, and early recovery of symptom for one or more symptom related to intrauterine infection.

The prophylactic or therapeutic agent of the present invention can suppress the barrier dysfunction of the placenta and prevent the transfer (infection) of the pathogen from the mother infected with the pathogen to the foetation and the transfer of other harmful substances.

Intrauterine infections cause fetal development and developmental abnormalities, malformations, stunted growth, serious disability, and even threaten the life of the fetal. The prophylactic therapeutic agent of the present invention can also be a preventive agent for miscarriage, premature birth or stillbirth.

The prophylactic or therapeutic agent of the present invention can suppress the barrier dysfunction of the placenta and prevent the transfer (infection) of the pathogen from the mother infected with the pathogen to the fetus and the transfer of other harmful substances. It can be a prophylactic or therapeutic agent for the disease.

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

When the silicon fine particles in the present invention are orally administered, it is considered that hydrogen is hardly generated in the stomach due to the above-mentioned properties, but hydrogen is generated in the intestine. When the silicon fine particles of the present invention were administered to normal mice, hydrogen generation was confirmed in the cecum, which is a part of the large intestine, and even if normal mice were fed a normal diet under the same conditions, hydrogen was below the detection limit. Since the residence time of food in the intestine is usually 20 hours or more in humans, the prophylactic or therapeutic agent of the present invention continuously generates hydrogen in the intestine for a long time when orally administered, and hydrogen in the body. It is thought that can be distributed.

It is also considered that hydrogen can be distributed into the body for a long time by percutaneous or transmucosal by indwelling silicon fine particles on the skin or mucous membrane for a long time.

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

After administering the silicon fine particles according to the present invention to rats, the antioxidant power of plasma was evaluated (BAP test), and it was confirmed that the antioxidant power was significantly higher in the silicon fine particle administration group.

One of the mechanisms of action in which intrauterine infections are prevented and / or treated is that the silicon fine particles in the present invention continue to generate hydrogen for a long period of time, and the generated hydrogen is transported to blood and various organs to generate hydrogen. Is thought to be due to the selective reaction of hydroxyl radicals. In addition, since the antioxidant power in blood is improved, it is considered that it is due to the antioxidant substance produced in blood. Furthermore, since it shows a remarkable effect compared with hydrogen water in studies using disease model animals in which oxidative stress is involved, it is considered that there is another action that hydrogen water does not have. Comparing the large intestine tissues of the silicon fine particle-administered mice and the non-administered mice, the large intestine of the silicon fine particle-administered mice contained a large amount of glutathione monosulfide and cysteine monosulfide, which are involved in antioxidant action in vivo. This may be a peculiar action of silicon fine particles. As another mechanism, for example, a protein containing a metal element such as cobalt that captures hydrogen in the initial state of development generated in the intestine by the reaction between silicon fine particles and water, or a hydrogen atom donates an electron, resulting in reducing power. It is considered that the protein that has become stronger is transported to each organ, reacts with the hydroxy radical, and eliminates it.

The prophylactic or therapeutic agent of the present invention can be used in combination with other therapeutic agents for endometrial infections. A high therapeutic effect is expected by using the prophylactic or therapeutic agent of the present invention in combination with a drug having a different mechanism of action.

The prophylactic or therapeutic target of the prophylactic or therapeutic agent of the present invention is humans and non-human animals. Preferred non-human animals include pets, livestock and the like.

One or more of the silicon fine particles in the present invention may be directly administered to humans or non-human animals, but if necessary, they are mixed with an acceptable additive or carrier and are well known to those skilled in the art. It can be formulated into a form and administered. Such additives or carriers include, for example, pH adjusters (eg, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, citric acid, etc.), excipients (eg, sugar derivatives such as mannitol, sorbitol; corn starch, etc. Steel derivatives such as potato starch; or cellulose derivatives such as crystalline cellulose; or lubricants (eg, metal stearate salts such as magnesium stearate; or talc, etc.), binders (eg, hydroxypropyl cellulose, hydroxypropyl). Methyl cellulose or polyvinylpyrrolidone, etc.), disintegrants (eg, cellulose derivatives such as carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), preservatives (eg, paraoxybenzoic acid esters such as methylparaben, propylparaben; or chlorobutanol, benzyl alcohol Alcohols, etc.). These additives and carriers may be blended into silicon fine particles alone or in admixture of two or more. Preferred additives include pH adjusters that can adjust the pH to 8 or higher. Preferred pH adjusters include sodium hydrogen carbonate.

The administration route of the prophylactic or therapeutic agent of the present invention is not particularly limited, but preferred administration routes include oral, transdermal, and transmucosa (oral, rectum, vagina, etc.).

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

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

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

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

The dose and frequency of administration of the silicon fine particles in the present invention are appropriately determined according to conditions such as the subject to be administered, the age, body weight, sex, purpose (preventive or therapeutic, etc.), severity of symptoms, dosage form, administration route, and the like. Can change. When administered to humans, the preferred dose of silicon microparticles is, for example, about 0.1 mg to 10 g, preferably about 1 mg to 5 g, more preferably about 1 mg to 2 g per day. In addition, the number of administrations may be once or a plurality of times per day, or once every few days. For example, it may be 1 to 3 times, 1 to 2 times, or 1 time per day.

The preventive or therapeutic agent for intrauterine infectious diseases containing silicon fine particles of the present invention can be used for pharmaceuticals, quasi-drugs, medical devices, foods, and beverages.

The present application also relates to the invention of a pharmaceutical composition for preventing or treating an endometrial infection containing silicon fine particles. The present application also relates to the invention of a pharmaceutical composition for the prevention or treatment of an endometrial infection containing the silicon fine particles or a therapeutic agent for the prevention or treatment of an endometrial infection. The pharmaceutical composition in the present invention also includes a composition having a mild action that corresponds to a quasi-drug. Examples of the embodiment of the pharmaceutical composition of the present invention include embodiments of the invention relating to the above-mentioned preventive or therapeutic agent.

The present application also relates to the invention of a medical device for the prevention or treatment of an intrauterine infection containing the silicon fine particles or a therapeutic agent for the prevention or treatment of the intrauterine infection. It also relates to an invention of a medical device for preventing or treating an endometrial infection containing the silicon fine particles. The medical device in the present invention is a tool or device intended to be used for treating or preventing a disease of a human or non-human animal. Examples of medical devices include masks. By wearing the mask of the present invention, hydrogen can be directly supplied to the trachea or lungs. Another example is adhesive plasters.

The present application also relates to the invention of a food or beverage for the prevention or treatment of an intrauterine infection containing the silicon fine particles or a therapeutic agent for the prevention or treatment of an intrauterine infection. It also relates to an invention of a food or beverage for preventing or treating an endometrial infection containing the silicon fine particles. Preferred examples of the food or beverage of the present invention include health foods, foods with functional claims, foods for specified health use and the like. The health food, the functional food, and the food for specified health use are foods or beverages capable of preventing intrauterine infection and / or preventing the onset of symptoms. There are no restrictions on the form of food or beverage. For example, the form of a mixture mixed with existing foods and beverages and the form of a formulation can be mentioned. For example, tablets, capsules, powders, granules, jellies and the like can be mentioned.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

<Example 1>
200 g of high-purity silicon powder (manufactured by High-Purity Chemical Laboratory Co., Ltd., particle size distribution <φ5 μm (however, silicon particles having a crystal particle size of more than 1 μm), purity 99.9%), 4 L (liter) of 99.5 wt% ethanol solution ), Add zirconia beads (capacity: 750 ml) of φ0.5 μm, and rotate for 4 hours using a bead mill device (IMEX Co., Ltd., horizontal continuous ready mill (model, RHM-08)). The particles were pulverized by pulverizing (one-step pulverization) at several 2500 rpm.

The ethanol solution containing the finely divided silicon particles was separated from the beads by a separation slit provided in the crushing chamber of the bead mill device, and then heated to 30 ° C. to 35 ° C. using a vacuum evaporator. By evaporating the ethanol solution, finely divided silicon particles (crystallites) were obtained.

The finely divided silicon particles (crystallites) obtained by the above method mainly had a crystallite diameter of 1 nm or more and 100 nm or less, and most of the crystallites formed aggregates. The crystallites were coated with a silicon oxide film, and the thickness of the silicon oxide film was about 1 nm. As a result of measuring this silicon crystallite by an X-ray diffractometer (Smart Lab manufactured by Rigaku Electric Co., Ltd.), the mode diameter was 6.6 nm, the median diameter was 14.0 nm, and the average crystallite diameter was 20.3 nm in the volume distribution. .. The mixture of the obtained silicon crystallites on which the silicon oxide film is formed and the aggregates thereof is an embodiment of silicon fine particles which are the active ingredients of the present invention.

<Example 2>
High-purity silicon powder (manufactured by Osaka Titanium Technologies Co., Ltd., particle size distribution <φ300 μm (however, silicon particles having a crystal particle size of more than 1 μm), purity 99.9%) was sieved to remove particles having a particle size of 45 μm or more. 200 g of the obtained silicon particles are dispersed in 4 L (liter) of a 99.5 wt% ethanol solution, and zirconia beads (capacity: 750 ml) having a diameter of 0.5 μm are added to a bead mill device (made by IMEX Co., Ltd., horizontal continuous type). Using a ready mill (model, RHM-08), pulverization (one-step pulverization) was carried out at a rotation speed of 2500 rpm for 4 hours to make fine particles.

The ethanol solution containing the finely divided silicon particles was separated from the beads by a separation slit provided in the crushing chamber of the bead mill device, and then heated to 30 ° C. to 35 ° C. using a vacuum evaporator. By evaporating the ethanol solution, finely divided silicon particles (crystallites) were obtained.

The average crystallite diameter of the finely divided silicon particles (crystallites) obtained by the above method was 20 to 30 nm, and most of the crystallites formed aggregates. The crystallites were coated with a silicon oxide film, and the thickness of the silicon oxide film was about 1 nm. The mixture of the obtained silicon crystallites on which the silicon oxide film is formed and the aggregates thereof is an embodiment of silicon fine particles which are the active ingredients of the present invention.

<Example 3>
The silicon crystallites and aggregates thereof obtained in Example 1 were mixed with hydrogen peroxide solution (3 wt%) in a glass container and stirred at 35 ° C. for 30 minutes. Silicon crystals and aggregates thereof treated with hydrogen peroxide solution were removed by solid-liquid separation treatment using a known centrifugation device. After that, the obtained silicon crystallites and aggregates thereof were mixed with an ethanol solution (99.5 wt%), and the mixture was sufficiently stirred. Silicon crystals and aggregates thereof mixed with an ethanol solution were sufficiently dried after removing the highly volatile ethanol solution by a solid-liquid separation treatment using a known centrifugation device. The obtained mixture of silicon crystals and aggregates thereof, which have been treated with hydrogen peroxide solution and have a silicon oxide film formed, is an embodiment of silicon fine particles which are the active ingredients of the present invention. An electron scanning microscope (SEM) photograph of the obtained silicon fine particles is shown in FIG. The hydrogen generation rate of the obtained aggregates of silicon crystals did not depend on the size of the aggregates.

The amount of hydrogen generated by the silicon fine particles (silicon crystallites and their aggregates) obtained in Example 3 was measured. 10 mg of silicon fine particles were placed in a glass bottle having a capacity of 100 ml (glass borosilicate glass with a thickness of about 1 mm, a Labran screw tube bottle manufactured by AS ONE). Water adjusted to pH 8.2 with sodium hydrogen carbonate was placed in this glass bottle, the liquid temperature was sealed under a temperature condition of 36 ° C., and the hydrogen concentration in the liquid in the glass bottle was measured. A portable dissolved hydrogen meter (manufactured by Toa DKK Corporation, model DH-35A) was used for measuring the hydrogen concentration. The amount of hydrogen generated per 1 g of silicon fine particles is shown in FIG.

<Example 4>
The silicon fine particles (silicon crystals and aggregates thereof) obtained in Example 1 were treated with hydrogen peroxide solution, mixed with an ethanol solution, and stirred in the same manner as in Example 3. The silicon fine particles mixed with the ethanol solution were dried using a spray dryer (ADL311SA, manufactured by Yamato Scientific Co., Ltd.). The obtained aggregate of silicon crystallites is an embodiment of silicon fine particles which are the active ingredients of the present invention. An electron scanning microscope (SEM) photograph of the obtained silicon fine particles (aggregates of silicon crystals) is shown in FIG.

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

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

<Example 6>
A mixture of silicon crystals and aggregates thereof on which a hydrogen peroxide solution-treated silicon oxide film obtained in Example 3 was formed was filled in a commercially available capsule No. 3 to obtain a capsule preparation. This capsule product contains agglomerates of silicon crystallites on which a hydrogen peroxide solution-treated silicon oxide film is formed as a main component, and further contains silicon crystallites on which a hydrogen peroxide solution-treated silicon oxide film is formed. contains.

<Test example>
I. Preparation of Silicon Fine Particle-Containing Food The silicon fine particles (silicon crystallites and aggregates thereof) produced in Example 3 were mixed with a normal feed (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) so as to be 2.5 wt%. .. Further, an aqueous citric acid solution (pH 4) was added in an amount of about 0.5 wt% with respect to the total amount of the silicon fine particles and the feed, and kneaded using a known kneading device to obtain a silicon fine particle-containing food. ..

II. Pharmacological action of silicon fine particles

A. Improvement of antioxidant power SD rats (6 weeks old) were obtained. The silicon fine particle-administered group was given the above-mentioned silicon fine particle-containing diet, and the control group was given a normal feed (normal diet) (manufactured by Oriental Yeast Co., Ltd., model number AIN93M). Blood was collected after 8 weeks of administration, and plasma antioxidant power was evaluated (BAP test) (free radical analyzer FREE Carrio Duo). The results are shown in FIG. It was shown that the antioxidant power was significantly increased in the silicon fine particle administration group.

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

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

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

B-4 Multivariate analysis As a result of multivariate analysis of each sample based on the 35 types of sulfur-related compounds detected in B-3 above, the silicon fine particle administration group and the control group should be distinguished by the following 10 compounds. Was done. FIG. 5 shows the results of multivariate analysis (the average value of the analysis results of each of the two samples) using the following 10 compounds in the silicon fine particle administration group and the control group.
Glutathione monosulfide (labeled)
Systenylglycine (labeled)
Thiosulfate ion (labeled)
Hypotaurine 5-glutamylcysteine (labeled)
Cysteine monosulfide (labeled)
S-sulfocysteine sulfite ion (labeled)
Serine taurine

The above compounds contain glutathione monosulfide, cysteine monosulfide, etc., which are involved in the antioxidant action in the living body, and are considered to play a part in the antioxidant action of the silicon fine particles. Since such a report has not been made for hydrogen, it may be one of the antioxidant effects peculiar to the preventive or therapeutic agent of the present invention.

B-5 Sulfur Index Analysis (2)
A comparative analysis (n = 6 / group) was performed on the amounts of glutathione and glutathione monosulfide (Glutathione-S) in the large intestine using the large intestines of the silicon fine particle administration group and the control group. The test method was the same as for B-1 to B-3. The results are shown in FIG. There was no difference in the amount of glutathione between the silicon fine particle administration group and the control group, but the amount of glutathione monosulfide was significantly increased in the silicon fine particle administration group. Glutathione monosulfide has a strong antioxidant power and is considered to play a part in the mechanism of action of silicon fine particles.

C. Pharmacological test in an endometrial infection model C-1. Preparation of an intrauterine infection model In the production of an intrauterine infection model mouse, lipopolysaccharide (LPS) was used to mimic the infection of pathogenic bacteria. An intrauterine infection model by intraperitoneally administering LPS (Sigma-Aldrich) (1 mg / kg) to a 15-day-old mother mouse (C57BL / 6JJmsSlc) and intraperitoneally administering the same amount of LPS 16 hours later. Was produced (Fig. 7). Similarly, the control group intraperitoneally administered saline instead of LPS (Fig. 7). See also: Hudalla et al, 2018, Pediatric Research 84 (5): 757-764.

C-2. Silicon fine particle administration The normal diet (manufactured by Oriental Yeast Co., Ltd., model number AIN93M) or the silicon fine particle-containing diet obtained in I above was given to mother mice from 13 days gestation to 16 days gestation.

C-3. Degree of endometrial infection and rate of miscarriage To analyze the effects of intrauterine infection, from mother mice 20 hours after LPS administration at 15 days of gestation (4 hours after the second LPS administration) The fetus and placenta were removed and the degree of endometrial infection and the rate of miscarriage were analyzed. Control group (normal diet saline administration group, CTL-Saline) (mother individual n = 3, total number of fetuses n = 42), normal diet LPS administration group (CTL-LPS) (mother individual n = 4, total) The analysis was performed using an LPS-administered group (Si-LPS) (mother individual n = 5, total number of fetuses n = 40) fed with a diet containing silicon fine particles and the number of fetuses n = 30). The gestation period of mice is 19 to 20 days, and usually 5 to 14 fetuses can be obtained per individual.

C-3-1. Miscarriage rate To analyze the effects of endometrial infections on the foetation, the rate of miscarriage in each mother was quantified. The number of fetal abortions 16 hours and 20 hours after the administration of LPS at the age of 15 days of gestation (4 hours after the second administration of LPS) was counted. After 20 hours of observation, each mother was dissected to accurately calculate the rate of miscarriage, and the ratio of the number of dead fetuses to the number of pregnant fetuses of the mother was defined as the ratio of miscarriage. The results are shown in FIG. The rate of miscarriage in the control group was 0%, but the rate of miscarriage in the LPS-administered group of the normal diet increased to 87.5% (Fig. 8). However, the rate of miscarriage recovered to 40% in the LPS-administered group fed the diet containing silicon fine particles (Fig. 8). Therefore, it was clarified that the risk of miscarriage was reduced by administering a diet containing silicon fine particles.

C-3-2. Degree of placental inflammation in endometrial infections In order to analyze the effects of maternal infection on the foetation, we analyzed the function of the placenta that connects the mother and the foetation. After fixing the removed placenta, paraffin sections were prepared and immunostained with IL-6 (inflammation marker) and Ly-6G (neutrophil marker) antibodies. The results are shown in FIG. Inflammation and neutrophil infiltration in the placenta connecting the mother and the fetus were significantly increased in the LPS-administered group of the normal diet as compared with the control group (Fig. 9). This result suggests that the maternal immune response due to infection is mediated by maternal blood and impairs placental function. On the other hand, in the LPS-administered group fed with the silicon fine particle-containing diet, the degree of inflammation of the placenta and the infiltration of neutrophils were significantly reduced as compared with the LPS-administered group of the normal diet (Fig. 9). Therefore, it was clarified that the administration of a diet containing silicon fine particles suppressed the inflammation of the placenta and the infiltration of neutrophils and alleviated the impaired placental function, thus showing an effect on endometrial infections (Fig. 9). )

C-3-3. Fetal survival rate in endometrial infections To analyze the effects of endometrial infections on the fetus, the fetal survival rate was quantified. The fetal survival rate (ratio of surviving fetal to total fetal number) in each group was observed 16 hours after the first LPS administration and 4 hours after the second LPL administration. The results are shown in FIG. The fetal survival rate 20 hours after the first LPS administration (4 hours after the second LPS administration) was 100% in the control group. In the normal diet LPS-administered group, the fetal survival rate decreased to 6.7% (Fig. 10). However, the fetal survival rate recovered to 62.5% in the LPS-administered group fed the silicon fine particle-containing diet (Fig. 10). From the above, the effectiveness of the silicon fine particle-containing diet for intrauterine infection was proved.

From the above results, it was clarified that the silicon fine particles in the present invention exert a high preventive effect and a high therapeutic effect on endometrial infections.

The present invention can be one of the causative therapies for endometrial infections and will greatly contribute to future medical treatment and health promotion.

Claims (15)

A preventive or therapeutic agent for intrauterine infections containing silicon fine particles. The preventive or therapeutic agent according to claim 1, wherein the silicon fine particles are fine particles containing silicon that can generate hydrogen in contact with water. The preventive or therapeutic agent according to claim 2, wherein the silicon-containing fine particles are fine particles containing a simple substance of silicon. The preventive or therapeutic agent according to any one of claims 1 to 3, wherein the silicon fine particles are silicon fine particles having a silicon oxide film formed on the surface thereof. The preventive or therapeutic agent according to claim 4, wherein the silicon oxide film is a silicon oxide film to which a hydroxyl group is added. The preventive or therapeutic agent according to any one of claims 1 to 5, wherein the silicon fine particles are silicon fine particles and / or an aggregate of the silicon fine particles. The preventive or therapeutic agent according to claim 6, wherein the silicon fine particles are fine particles made of elemental silicon and have a silicon oxide film formed on the surface thereof. The preventive or therapeutic agent according to any one of claims 1 to 5, wherein the silicon fine particles are porous silicon particles. The preventive or therapeutic agent according to any one of claims 1 to 8, wherein the silicon fine particles are hydrophilized silicon fine particles. The preventive or therapeutic agent according to claim 9, wherein the hydrophilization treatment is a hydrogen peroxide solution treatment. The prophylactic or therapeutic agent according to any one of claims 1 to 10, which is for oral administration. A pharmaceutical composition for preventing or treating an endometrial infection, which comprises the prophylactic or therapeutic agent according to any one of claims 1 to 11. A medical device for preventing or treating an endometrial infection containing the prophylactic or therapeutic agent according to any one of claims 1 to 11. A food or beverage for preventing or treating an endometrial infection containing the prophylactic or therapeutic agent according to any one of claims 1 to 11. A therapeutic agent for endometrial infections containing silicon fine particles.

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