Anti-mental fatigue agent

Abstract

To provide a novel anti-mental fatigue agent.SOLUTION: An anti-mental fatigue agent contains at least one component selected from the group consisting of the following components (A) and (B): (A) at least one kind selected from the group consisting of tranexamic acid and a salt thereof; and (B) one or more kinds selected from the group consisting of carbazochrome, a derivative thereof and a salt thereof, and a hydrate thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an anti-mental fatigue agent. [Background technology]

[0002] A technology for alleviating mental fatigue is described in Patent Document 1 (JP 2010-248147 A), which describes an anti-mental fatigue agent containing iron-binding lactoferrin as an active ingredient (claim 1).

[0003] Furthermore, although it is not a technology related to mental fatigue, Patent Document 2 (JP Patent Publication No. 2002-234836) describes a stress-fighting agent consisting of tranexamic acid and / or its derivatives (Claim 1) as a technology for providing an external skin preparation that protects the skin from the effects of stress (paragraph 0017). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2010-248147 [Patent Document 2] Japanese Patent Application Laid-Open No. 2002-234836 Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides a novel anti-mental fatigue agent. [Means for solving the problem]

[0006] According to the present invention, the following anti-mental fatigue agent is provided. [1] An anti-mental fatigue agent containing at least one component selected from the group consisting of the following components (A) and (B): (A) at least one member selected from the group consisting of tranexamic acid and salts thereof (B) one or more selected from the group consisting of carbazochrome, its derivatives, salts thereof, and hydrates thereof [2] The anti-mental fatigue agent described in [1], which is for preventing or improving mental fatigue induced by exposure to blue light. [3] The anti-mental fatigue agent according to [1] or [2], which is an expression regulator of at least one substance selected from the group consisting of neurotransmitters and neurotransmitter receptors. [4] The anti-mental fatigue agent according to [3], wherein the neurotransmitter is noradrenaline. [5] An anti-mental fatigue agent according to any one of [1] to [4], which is a clock gene expression regulator. [6] An anti-mental fatigue agent according to any one of [1] to [5], which is an oral composition.

[0007] Furthermore, the present invention can also provide a clock gene expression regulator, which contains, for example, at least one component selected from the group consisting of the following components (A) and (B): (A) at least one member selected from the group consisting of tranexamic acid and salts thereof (B) one or more selected from the group consisting of carbazochrome, its derivatives, salts thereof, and hydrates thereof [Effects of the Invention]

[0008] According to the present invention, a new anti-mental fatigue agent can be provided. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the results of measuring the expression level of noradrenaline in an example. [Figure 2] FIG. 1 shows the results of measuring the expression level of adrenaline receptor β2 in an example. [Figure 3] FIG. 1 shows the results of measuring the expression level of Bmal1 in an example. [Figure 4] FIG. 1 shows the results of measuring the expression level of CCL2 in an example. [Figure 5] FIG. 1 shows the results of measuring the expression level of ICAM1 in an example. [Figure 6] FIG. 10 is a diagram showing the measurement results of skin thickness in an example. [Figure 7] FIG. 1 shows the results of measuring the expression level of Cyclin D1 in an example. DETAILED DESCRIPTION OF THE INVENTION

[0010] Hereinafter, an embodiment of the present invention will be described. In this embodiment, the composition may contain each component either alone or in combination of two or more. In this specification, the symbol "to" indicating a numerical range means "greater than or equal to" or "less than or equal to," and both of the numerical values at both ends are included.

[0011] (Anti-mental fatigue agent) In this embodiment, the anti-mental fatigue agent contains at least one component selected from the group consisting of the following components (A) and (B): (A) at least one member selected from the group consisting of tranexamic acid and salts thereof (B) one or more selected from the group consisting of carbazochrome, its derivatives, salts thereof, and hydrates thereof Specifically, the anti-mental fatigue agent is a composition containing at least one selected from the group consisting of tranexamic acids, i.e., component (A), and carbazochromes, i.e., component (B).

[0012] In this embodiment, the anti-mental fatigue agent contains at least one of the components (A) and (B), and is therefore effective against mental fatigue, for example, having the effect of preventing or improving mental fatigue.

[0013] Here, fatigue is defined as a state of reduced physical activity capacity accompanied by a particular sense of discomfort and a desire for rest caused by excessive physical and mental activity or illness (Japan Society for Fatigue Studies, 2010). In this embodiment, the anti-mental fatigue agent specifically has an effect on at least mental fatigue among the above-mentioned fatigues, and includes both those effective against mental fatigue and those effective against fatigue sensations.

[0014] Specifically, blue light is blue light with a wavelength in the 400-495 nm range. Blue light is the light with the highest energy in the shortest wavelength range of visible light, and in recent years, there have been concerns about its adverse effects on living organisms. However, there are still many unknowns about the relationship between blue light and mental fatigue. In this regard, the anti-mental fatigue agent of this embodiment contains at least one component selected from the group consisting of components (A) and (B), and is therefore suitable for preventing or ameliorating blue light-induced mental fatigue, which can suppress mental fatigue even in lifestyles involving long periods of blue light exposure.

[0015] More specifically, it has been newly discovered that both components (A) and (B) have the effect of regulating the expression of neurotransmitters and neurotransmitter receptors upon exposure to blue light. That is, the anti-mental fatigue agent is preferably at least one expression regulator selected from the group consisting of neurotransmitters and neurotransmitter receptors, and more preferably at least one expression regulator selected from the group consisting of neurotransmitters and neurotransmitter receptors upon exposure to blue light. By adjusting the expression of neurotransmitters and neurotransmitter receptors, it is possible to suppress their overexpression, which can bring about a relaxing effect on the mind and lead to mental stability.

[0016] Specifically, the neurotransmitter is one or more substances selected from the group consisting of noradrenaline, adrenaline, dopamine, acetylcholine, and serotonin. Furthermore, the neurotransmitter is preferably one or more substances selected from the group consisting of neurotransmitters of the sympathetic nervous system (noradrenaline, adrenaline, dopamine, etc.) that cause anxiety and tension, and more preferably noradrenaline. This allows for a more stable effect against blue light-induced mental fatigue. For example, it can reduce tension and anxiety caused by blue light exposure.

[0017] The neurotransmitter receptor is specifically one or more receptors selected from the group consisting of an adrenaline receptor, a dopamine receptor, and an acetylcholine receptor, preferably one or more receptors selected from the group consisting of an adrenaline receptor and a dopamine receptor, more preferably an adrenaline receptor, and even more preferably an adrenaline receptor β2. This allows for a more stable effect against blue light exposure-induced mental fatigue.

[0018] By adjusting the expression of neurotransmitters and neurotransmitter receptors, it becomes possible to improve, for example, immune abnormalities, thereby making it possible to prevent autoimmune diseases. The immune abnormality may be, for example, hyperimmunity. The anti-mental fatigue agent is preferably an agent for suppressing hyperimmunity, more preferably an agent for suppressing hyperimmunity during exposure to blue light. By using the anti-mental fatigue agent of this embodiment, it is possible to suppress excessive secretion of cytokines such as CCL2, CCL7, CCL8, CCL13, and CCL16; and intercellular adhesion molecules such as ICAM1, VCAM1, LFA-1, and VLA-4.

[0019] By regulating the expression of neurotransmitters and neurotransmitter receptors, for example, it is possible to suppress skin thickening. That is, the anti-mental fatigue agent is preferably an agent for suppressing skin thickening, and more preferably an agent for suppressing skin thickening due to exposure to blue light.

[0020] Furthermore, by regulating the expression of neurotransmitters and neurotransmitter receptors, it is possible to suppress, for example, the secretion of tumor markers. That is, the anti-mental fatigue agent is preferably an agent for suppressing the secretion of tumor markers, more preferably an agent for suppressing the secretion of tumor markers during exposure to blue light. Tumor markers include Cyclin D1 (CCND1), CCND2, and CCND3.

[0021] Furthermore, the anti-mental fatigue agent is preferably a clock gene expression regulator, which can improve daily rhythms and thereby provide a more stable anti-mental fatigue effect. The clock gene expression regulator will be explained in more detail below.

[0022] (regulator of clock gene expression) In this embodiment, the clock gene expression regulator contains at least one component selected from the group consisting of the aforementioned components (A) and (B). Specifically, the clock gene expression regulator is a composition containing at least one selected from the group consisting of tranexamic acids, i.e., component (A), and carbazochromes, i.e., component (B), and is preferably an oral composition.

[0023] In this embodiment, the clock gene expression regulator contains at least one component selected from the group consisting of components (A) and (B), which allows for favorable effects of regulating clock gene expression upon blue light exposure. Furthermore, the clock gene expression regulator is preferably used to suppress changes in clock gene expression levels induced by blue light exposure.

[0024] An example of a change in clock gene expression level induced by blue light exposure is a decrease in Bmal gene expression caused by blue light exposure. The decrease in Bmal gene expression can be suitably suppressed by using a clock gene expression regulator. Furthermore, the clock gene expression regulator is preferably an inhibitor of the decrease in Bmal gene expression, more preferably an inhibitor of the decrease in Bmal gene expression induced by blue light exposure.

[0025] Here, the clock gene specifically refers to a gene that controls the biological clock, and is preferably at least one selected from the group consisting of Bmal (Brain and Muscle Arnt-like) genes such as Bmal1 and Bmal2; Per (Period) genes such as Per1 and Per2; Cry (Cryptochrome) genes such as Cry1 and Cry2; and Clock genes, and more preferably at least one Bmal gene. This allows for a more stable regulation of clock gene expression by blue light exposure. Furthermore, the expression of clock genes specifically refers to the expression of clock genes or proteins encoded by clock genes.

[0026] Next, the components of the anti-mental fatigue agent and clock gene expression regulator (hereinafter, these will also be collectively referred to as the "composition") in this embodiment will be described.

[0027] (Ingredient (A): Tranexamic acids) Component (A) is at least one member selected from the group consisting of tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) and salts thereof. Component (A) can be produced by known methods, or commercially available products can be used. For example, tranexamic acid is listed in the 18th edition of the Japanese Pharmacopoeia.

[0028] Specific examples of salts of tranexamic acid salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; Alkanesulfonates having from 1 to 4 carbon atoms, such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Organic amine salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, and picoline salts; and Examples thereof include one or more salts selected from the group consisting of salts with amino acids such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, and aspartic acid salts.

[0029] Component (A) preferably contains tranexamic acid, more preferably tranexamic acid, which allows for more stable anti-mental fatigue effects and clock gene expression regulating effects.

[0030] The amount of component (A) per daily dose is preferably 50 mg or more, more preferably 400 mg or more, and even more preferably 750 mg or more, which can further enhance the anti-mental fatigue effect and clock gene expression regulating effect. The amount of component (A) per daily application is preferably 3000 mg or less, more preferably 2000 mg or less, and even more preferably 1500 mg or less, which allows for safer application to the body.

[0031] Here, the amount of the composition to be applied can be determined appropriately taking into consideration, for example, the user's sex, age, symptoms, application (e.g., administration) method, number of applications, application timing, dosage form, etc., and it is preferable to use it within a range that does not cause side effects. The composition may be applied, for example, 1 to 6 times per day, and preferably 1 to 3 times per day.

[0032] (Component (B): Carbazochromes) Component (B) is one or more selected from the group consisting of carbazochrome (3-hydroxy-1-methyl-5,6-indolindione-5-semicarbazone, also known as adrenochrome semicarbazone), its derivatives, salts thereof, and hydrates thereof.

[0033] Specific examples of carbazochrome derivatives include esterified products, etherified products, amidated products, sulfonated products, nitrated products, nitrosated products, and halides. Salts of carbazochrome and its derivatives include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium salts and calcium salts, and may be, for example, pharmaceutically, pharmacologically, or physiologically acceptable salts. Carbazochrome, its derivatives and salts thereof may also be hydrates.

[0034] Component (B) is preferably one or more components selected from the group consisting of carbazochrome, carbazochrome sodium sulfonate, and carbazochrome sodium sulfonate hydrate, and more preferably carbazochrome, which allows for more stable anti-mental fatigue effects and clock gene expression regulating effects.

[0035] The amount of component (B) per daily dose is preferably 1 mg or more, more preferably 2 mg or more, and even more preferably 5 mg or more, which can further enhance the anti-mental fatigue effect and clock gene expression regulating effect. The amount of component (B) per daily dose is preferably 3000 mg or less, more preferably 1000 mg or less, even more preferably 600 mg or less, and even more preferably 90 mg or less, which allows for safer application to the body. Even when the composition contains component (B), the composition may be applied, for example, 1 to 6 times per day, preferably 1 to 3 times per day.

[0036] (Other ingredients) The composition may contain ingredients other than the active ingredients described above. The other ingredients can be selected from ingredients used in pharmaceuticals or foods, for example. The other ingredients can also be selected depending on the dosage form of the composition, for example. Examples of other ingredients include known excipients, disintegrants, binders, lubricants, stabilizers, preservatives, colorants, surfactants, pH adjusters, flavoring agents, flavorings, sweeteners, preservatives, fragrances, aqueous components, alcohols, sugars, and water. In addition, ingredients such as anti-aging agents, antioxidants, whitening agents, and various herbal medicines can also be added within a range that does not weaken the effects of the composition.

[0037] (Dosage form, etc.) The composition may be, for example, a pharmaceutical composition, a quasi-drug composition or a food composition, and is preferably a pharmaceutical composition. The composition is preferably an oral composition, which allows for excellent ease of ingestion.

[0038] The composition may be solid or non-solid, such as a liquid, and is preferably solid, such as a solid preparation. This can improve the storage stability of the composition and also make it easier to ingest. The dosage form of the solid preparation may be, for example, a tablet, granule, pill, powder, gummies, or jelly, and preferably a tablet. Examples of tablets include plain tablets, plain tablets, sugar-coated tablets, orally disintegrating tablets, film-coated tablets, and chewable tablets. The tablet may be a multi-layer tablet formed by compressing two or more layers of powders or granules with different compositions. The film may be imparted with properties such as immediate solubility, delayed solubility, gastric solubility, or enteric solubility depending on the desired composition.

[0039] (Manufacturing method) In this embodiment, the method for producing the composition includes, for example, a step of blending at least one component selected from the group consisting of component (A) and component (B) and, if necessary, other components. The composition can be produced, for example, according to its dosage form, and made into a formulation.

[0040] (packaging) The packaged product is a product in which the composition is contained in a packaging container. By forming the packaged product, for example, convenience during use of the composition can be improved. The packaging container can be selected, for example, depending on the dosage form of the composition. Specific examples of packaging forms include bottle packaging, jar packaging, PTP packaging (Press Through Package), pouch packaging, stick packaging, and SP packaging (Strip Package). The composition may be temporarily packaged in these packages and then stored airtight. That is, the composition may be contained in an airtight package. Furthermore, they may be pillow-packaged, or they may be stored in a box or the like. Furthermore, for example, in order to suppress moisture absorption, a desiccant or the like may be contained in the packaging container together with the composition.

[0041] Examples of materials for the packaging container include one or more materials selected from the group consisting of resin materials, metal materials, and inorganic materials such as glass. Furthermore, if necessary, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used for part or all of the packaging material, and environmentally friendly containers and packaging may be used.

[0042] Specific examples of film materials that can be used to form packaging containers include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films to which metal foil such as aluminum foil is attached by vapor deposition, etc. Either a single-layer film or a multi-layer film (for example, a laminate film) may be used.

[0043] The packaging container may be selected depending on the shape of the composition. For example, when the composition is a tablet, the packaging container is, for example, a pouch bag, preferably an aluminum pouch bag. The pouch bag may have a fastener function.

[0044] (Methods for preventing or improving mental fatigue) In this embodiment, the method for preventing or improving mental fatigue (excluding medical procedures for humans) includes, for example, applying the anti-mental fatigue agent of this embodiment to a subject, and preferably includes administering the anti-mental fatigue agent of this embodiment to a subject. A specific example of the form of administration is oral administration. In this embodiment, the anti-mental fatigue agent has the excellent effects described above, and by administering it to a subject, it is possible to obtain an effect of preventing or improving mental fatigue in the subject.

[0045] Although the embodiments of the present invention have been described above, these are merely examples of the present invention, and various other configurations can also be adopted. [Example]

[0046] The present embodiment will be specifically described below with reference to examples, but the present embodiment is not limited to these examples.

[0047] (Test Example 1) In this example, the effect of the composition on blue light exposure when administered orally to mice was confirmed.

[0048] (1) Test substance The test substance for each case was as follows, and the following doses were orally administered three times a week for 15 weeks. Example 1: Blue light irradiation, administration of 12 mg / kg tranexamic acid Example 2: Blue light irradiation, carbazochrome 167 mg / kg administration Comparative Example 1: Blue light irradiation, purified water administration Control example 1: No blue light exposure, purified water administration

[0049] (2) Animals used SPF hairless mice (Japan SLC)

[0050] (3) Test method 100 mg of 7,12-dimethylbenz[a]anthracene (DMBA) was applied to the back of the mice, and two weeks after application, blue light was applied at 40 kJ / m 2 The backs of the mice were irradiated with blue light using a blue light source (ISLM-150X150-BB, manufactured by CCS Inc.) three times a week for 15 weeks under the irradiation conditions of (1). However, in Control Example 1, blue light was not irradiated. In the following tests, these mice were used to evaluate each index.

[0051] (4) Evaluation For each case, the expression levels of noradrenaline and adrenaline receptor β2, the expression level of the clock gene Bmal1, the expression levels of CCL2 and ICAM1, skin thickness, and the expression level of Cyclin D1 were evaluated using the following methods.

[0052] (Expression levels of noradrenaline and cyclin D1) Test 1: Mouse dorsal skin was removed, and 10 mg of the dorsal skin sample was washed with PBS and centrifuged at 1500 × g and 4°C for 15 minutes. After centrifugation, the supernatant was collected and the amounts of norepinephrine and cyclin D1 were measured using a Norepinephrine ELISA Kit (Abcam) or a Mouse Cyclin D1 ELISA Kit (Novus Biological). The results for noradrenaline and Cyclin D1 are shown in Figures 1 and 7, respectively. In Fig. 1, Fig. 7 and Fig. 2 to Fig. 6 described later, "*" indicates a significant difference from Comparative Example 1 (p<0.05, t-test).

[0053] (Adrenergic receptor β2 and expression levels of Bmal1, CCL2, and ICAM1) Experiment 2: Mouse dorsal skin samples were fixed in 4% phosphate-buffered paraformaldehyde, embedded in Tissue-Tek OCT compound (Sakura Finetech), and 5 μm frozen sections were prepared. The sections were washed with phosphate-buffered saline (PBS) and then immersed in the following primary antibody solutions for each assay parameter and incubated overnight at 4°C: Bmal1: 1 / 100 BMAL1 Rabbit mAb (Cell Signaling Technology), β2: 1 / 100 Anti-beta 2 Adrenergic Receptor antibody (Abcam), CCL2: 1 / 100 Anti-MCP1 antibody (Abcam), and ICAM1: 1 / 100 Anti-ICAM1 antibody (Abcam). The sections were then washed with PBS and immersed in the following secondary antibody solution (1 / 30 FITC-conjugated anti-rabbit or anti-mouse (DakoCytomation)) for 1 hour. After washing with PBS, each factor was photographed under a fluorescence microscope, and the luminescence intensity (au) was measured using ImageJ v.1.53 image analysis software. The results are shown in Figures 2 to 5.

[0054] (skin thickness) Test 3: The frozen section samples prepared in Test 2 were stained with hematoxylin and eosin (HE) and photographed under a microscope. The photographed images were analyzed using ImageJ v.1.53 image analysis software to measure the skin thickness (μm). The results are shown in Figure 6.

[0055] (5) Results 1 and 2, in Examples 1 and 2, in which tranexamic acid or carbazochrome was administered, the increase in the expression of the neurotransmitter noradrenaline, a brain hormone that causes tension and anxiety, during blue light exposure was suppressed, as was the increase in the expression of the adrenergic receptor β2. Therefore, the administration of tranexamic acid or carbazochrome can prevent or reduce mental fatigue induced by blue light exposure.

[0056] As shown in Figure 3, the administration of tranexamic acid or carbazochrome in Examples 1 and 2 suppressed the decrease in expression of the clock gene Bmal1 during blue light exposure. Therefore, administration of tranexamic acid or carbazochrome may also suppress the aggravation of autoimmune diseases caused by blue light-induced abnormalities in Bmal1 expression.

[0057] 4 and 5 show that in Examples 1 and 2, in which tranexamic acid or carbazochrome was administered, the increase in expression of CCL2 and ICAM1 during blue light irradiation was suppressed. As can be seen from FIG. 6, in Examples 1 and 2 in which tranexamic acid or carbazochrome was administered, skin thickening during blue light irradiation was suppressed. Furthermore, as can be seen from FIG. 7, in Examples 1 and 2 in which tranexamic acid or carbazochrome was administered, the increase in tumor marker expression during blue light irradiation was suppressed. These findings suggest that administration of tranexamic acid or carbazochrome can suppress, for example, hyperimmunity induced by blue light exposure.

Claims

1. An anti-mental fatigue agent comprising at least one component selected from the group consisting of the following components (A) and (B): (A) at least one selected from the group consisting of tranexamic acid and salts thereof (B) one or more selected from the group consisting of carbazochrome, its derivatives, salts thereof, and hydrates thereof;

2. The anti-mental fatigue agent according to claim 1, which is for preventing or improving mental fatigue induced by exposure to blue light.

3. 3. The anti-mental fatigue agent according to claim 1, which is an expression regulator of at least one substance selected from the group consisting of neurotransmitters and neurotransmitter receptors.

4. 4. The anti-mental fatigue agent according to claim 3, wherein the neurotransmitter is noradrenaline.

5. The anti-mental fatigue agent according to claim 1 or 2, which is a clock gene expression regulator.

6. The anti-mental fatigue agent according to claim 1 or 2, which is an oral composition.

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