Oral composition

Abstract

The present invention aims to effectively utilize the effects of ellagic acid. [Solution] An oral composition characterized by containing ellagic acid and gallic acid.

Description

Technical Field

[0001] The present invention relates to an oral composition containing ellagic acid and gallic acid.

Background Art

[0002] In recent years, in health foods, there has been an increasing demand for improving physical conditions and functions with natural material components. For example, as a protein that enhances the biosynthesis of neutral fat and cholesterol in the liver and the like, Sterol Regulatory Element Binding Transcription Factor 1 (hereinafter referred to as "SREBF1") is known (Non-Patent Document 1). Further, as a protein that promotes the reduction of cholesterol and neutral fat in the blood and the like, Peroxisome Proliferator-Activated Receptor α (hereinafter also referred to as "PPARα") is known (Item 2.2 of Non-Patent Document 1 and Non-Patent Document 2). Therefore, if there is a composition that suppresses the expression of SREBF1 or enhances the expression of PPARα, it is considered useful for suppressing the increase or promoting the decrease of cholesterol and neutral fat in the blood and the like.

[0003] In addition, oxidative stress and mitochondrial disorders are considered to be partly responsible for the decline in brain function (Non-Patent Document 3), and it is considered that mitochondrial disorders are caused by various stresses and induce nerve cell disorders, which is one of the causes of depression, and it is known that oxidative stress accumulates in depression (Non-Patent Document 4). Heme Oxygenase 1 (hereinafter also referred to as "HO-1") is known to have a mitochondrial protective effect under oxidative stress (Non-Patent Document 5). From this, a composition that enhances the gene expression of HO-1 is considered useful for improving brain function and enhancing resistance to various stresses.

[0004] Furthermore, Nitric Oxide Synthase 3 (hereinafter also referred to as "NOS3") is known to improve blood flow (Non-Patent Literature 6), and by improving blood flow, it is known to promote nutrient supply to muscles and reduce physical fatigue. Moreover, decreased NOS3 activity is also known to be related to ED (erectile dysfunction) (Non-Patent Literature 7).

[0005] On the other hand, in the field of health foods, ingredients that provide multiple effects with a single component, such as indigestible dextrin, are attracting attention, and the demand for health foods containing such ingredients is increasing (Non-Patent Document 8). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Chemistry and Biology, Vol. 42, No. 5, 2004, pp. 300-308 [Non-Patent Document 2] Atherosclerosis, 205, (2005) p1-8 [Non-Patent Document 3] Biomed.Pharmacother.,74(2015),p101-110 [Non-Patent Document 4] Curr.Neuropharmacol.2016,14(6),p610-618 [Non-Patent Document 5] Mol.Pharmacol.2015,Sep.,88(3),p437-449 [Non-Patent Document 6] Proceedings of the 120th Japan Medical Association Symposium, pp. 68-73, http: / / jams.med.or.jp / symposium / full / 120068.pdf, accessed March 31, 2021. [Non-Patent Document 7] Int.J.Impot.Res.,2007,19(2),p129-138 [Non-Patent Document 8] Asahi Soft Drinks Co., Ltd. News Release: "New Proposal! A Double-Rated Food for Specified Health Uses with Two Health Claims: 'Asahi Jurokucha W (Double)' to be Released on April 15th (Tue)" Homepage (URL: https: / / www.asahiinryo.co.jp / company / newsrelease / 2014 / pick_0205-2.html) [Disclosure of the Invention] [Problems that the invention aims to solve]

[0007] In this invention, we focused on ellagic acid as an ingredient that provides multiple effects with a single component. However, there has been insufficient research on the multiple functions of ellagic acid, such as its effectiveness in preventing lifestyle-related diseases. This invention aims to effectively utilize the effects of ellagic acid. [Means for solving the problem]

[0008] In light of the above issues, we conducted thorough research and found that by including ellagic acid and gallic acid, we can achieve excellent effects in various aspects, such as suppressing and / or reducing cholesterol levels, suppressing and / or reducing triglyceride levels, improving brain function, reducing and / or alleviating stress-induced depressive states, or improving stress tolerance. This led to the present invention.

[0009] The outline of this invention is as follows: <1> An oral composition characterized by containing ellagic acid and gallic acid. <2> The oral composition is characterized in that the ellagic acid and gallic acid are in a mass ratio of 0.5 or less gallic acid to 100 ellagic acid. <1> The oral composition described above. <3> Furthermore, it is characterized by containing excipients and / or lubricants. <1> or <2> An oral composition as described in any of the following. <4> The excipient is characterized by being at least one selected from starch or its derivatives, cellulose or its derivatives, sugar alcohols, and disaccharides. <3> The oral composition described above. <5> Furthermore, it is characterized by containing amino acids and / or nucleotides. <1> ~ <4> An oral composition as described in any of the following. <6> Characterized for suppressing and / or reducing cholesterol levels. <1> ~ <5> An oral composition as described in any of the following. <7> It is characterized by being for suppressing and / or reducing the rise in triglycerides. <1> ~ <5> An oral composition as described in any of the following. <8> Characterized for improving brain function <1> ~ <5> An oral composition as described in any of the following. <9> It is characterized by being for reducing and / or alleviating depressive states caused by stress, or for improving stress tolerance. <1> ~ <5> An oral composition as described in any of the following. <10> Characterized by being a tablet. <1> ~ <9> An oral composition as described in any of the following. [Effects of the Invention]

[0010] According to the present invention, by containing ellagic acid and gallic acid, it is possible to provide an oral composition that has excellent effects in suppressing and / or reducing the rise in blood cholesterol, suppressing and / or reducing the rise in blood triglycerides, improving brain function, reducing and / or alleviating depressive states caused by stress, or improving stress tolerance. In particular, according to the present invention, by suppressing the expression of SREBF1 or promoting the expression of PPARα, HO-1, or NOS3, it is possible to provide an oral composition that can contribute to suppressing or promoting the reduction of the rise in triglycerides or cholesterol, improving brain function, reducing and / or alleviating depressive states such as mood swings caused by stress, improving stress tolerance, improving blood flow, improving physical fatigue, or improving erectile dysfunction. [Best Mode for Carrying Out the Invention]

[0011] The oral compositions of the present invention will be described below. However, the present invention is not limited to the embodiments described below.

[0012] [Ellagic acid] The present invention includes ellagic acid as an essential component. Ellagic acid is a kind of natural phenolic compound and exists in a free state, but in many cases, it exists as one of the components of tannins called ellagitannins. The content of ellagic acid in the oral composition of the present invention is not particularly limited, but preferably, it is 0.05% by mass or more in the solid content, more preferably, it is 0.1% by mass or more in the solid content. From the viewpoint of exhibiting excellent cholesterol elevation suppression and / or reduction effects, neutral fat elevation suppression and / or reduction effects, brain function improvement effects, stress-induced depression state alleviation and / or relaxation effects, or stress tolerance improvement effects, particularly preferably, it is 0.5% by mass or more in the solid content. In this specification, when the composition is in a solid state, the solid content refers to the content in the composition, and when the composition is in a liquid or fluid state, the solid content refers to the total amount of all components excluding water in the composition.

[0013] The ellagic acid of the present invention is not particularly limited as long as it can be used as a food, and plant-derived ellagic acid as it is, or those obtained by extracting and purifying this, or those obtained by synthesis can be used. When using plant-derived ellagic acid, examples of the plants from which it is derived include strawberries, raspberries, pomegranates, etc. Further, the ellagic acid used in the present invention may be an anhydride or a hydrate such as a monohydrate. In the present invention, when ellagic acid is a hydrate, the amount of ellagic acid referred to in this specification is converted to anhydride. The content of ellagic acid in the composition of the present invention can be measured, for example, by high performance liquid chromatography. As a measurement method, for example, high performance liquid chromatography equipped with an ultraviolet absorption detector can be used, and it can be measured using a 1% by volume aqueous formic acid solution and a 1% by volume formic acid acetonitrile solution as the liquid medium of the mobile phase. In addition, when measuring, appropriate treatment may be carried out as necessary, such as removing impurities in the sample to conform to the separation ability of the apparatus.

[0014] [Gallic acid] The present invention uses gallic acid as an essential component. Gallic acid is a type of polyphenol. The content of gallic acid in the oral composition of the present invention is not particularly limited, but preferably, it is 0.00001% by mass or more and 30% by mass or less in the solid content, more preferably, it is 0.00005% by mass or more and 25% by mass or less in the solid content, and from the viewpoint of exhibiting excellent cholesterol increase inhibitory and / or reduction effects, triglyceride increase inhibitory and / or reduction effects, brain function improvement effects, stress-induced depression state alleviation and / or relaxation effects, or stress tolerance improvement effects, particularly preferably, it is 0.0001% by mass or more and 20% by mass or less in the solid content.

[0015] The gallic acid of the present invention is not particularly limited as long as it can be used as a food, and plant-derived gallic acid, those obtained by extracting and purifying it, and those obtained by synthesis can be used. When using plant-derived gallic acid, examples of the plant from which it is derived include green tea, coconut, persimmon, and the like. Further, the gallic acid used in the present invention may be an anhydride or a hydrate such as a monohydrate. In the present invention, when gallic acid is a hydrate, the amount of gallic acid referred to in this specification is converted to the anhydride. The content of gallic acid in the composition of the present invention can be measured, for example, by high performance liquid chromatography. As the measurement method, for example, it can be measured in the same manner as ellagic acid, using high performance liquid chromatography equipped with an ultraviolet absorption detector, and measuring using 1% by volume aqueous formic acid solution and 1% by volume formic acid acetonitrile solution as the liquid medium of the mobile phase. In addition, when measuring, appropriate treatment may be performed as necessary, such as removing impurities in the sample to conform to the separation ability of the apparatus.

[0016] In the present invention, it is preferable that ellagic acid is present in greater mass than gallic acid, and more preferably, the mass ratio of ellagic acid to gallic acid is 1 or less per 100 ellagic acid, and particularly preferable to 0.5 or less. Furthermore, it is preferable that the amount of gallic acid per 100 ellagic acid be 0.00001 or more, and more preferably 0.0005 or more, and particularly preferable to 0.001 or more from the viewpoint of exhibiting excellent cholesterol elevation suppression and / or reduction effects, triglyceride elevation suppression and / or reduction effects, brain function improvement effects, stress-induced depressive state reduction and / or mitigation effects, or stress tolerance improvement effects.

[0017] In the present invention, the total amount of ellagic acid and gallic acid in the oral composition is preferably 5% to 95% by mass, more preferably 10% to 90% by mass, and particularly preferably 15% to 85% by mass, from the viewpoint of exhibiting excellent cholesterol elevation suppression and / or reduction effects, triglyceride elevation suppression and / or reduction effects, brain function improvement effects, stress-induced depressive state reduction and / or alleviation effects, or stress tolerance improvement effects.

[0018] [Excipients] The oral composition of the present invention preferably contains an excipient in addition to ellagic acid and gallic acid. Excipients are added to improve the handling or molding of the composition or to make it easier to take. There are no particular limitations on the excipients that can be used in the present invention, and examples include starch or its derivatives such as starch, pregelatinized starch, partially pregelatinized starch, and starch hydrolysates; sugar alcohols such as dextrin, reduced palatinose, and reduced maltose; disaccharides such as lactose and maltose; brewer's yeast; cellulose or its derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; refined sucrose; light anhydrous silicic acid; calcium silicate; titanium dioxide; precipitated calcium carbonate, etc. These may be used individually or in combination of two or more. Commercially available excipients can be used. In the present invention, from the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect, starch or derivatives thereof, sugars such as sugar alcohols and disaccharides are preferred, and pregelatinized starch, crystalline cellulose, hydroxypropyl cellulose, dextrin, reduced palatinose, reduced maltose, lactose, and maltose are more preferred.

[0019] When excipients are included in the oral composition of the present invention, their content is not particularly limited, but preferably 1% to 90% by mass, preferably 5% to 85% by mass, in the solid content. From the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect, 10% to 80% by mass in the solid content is particularly preferred. If multiple excipients are included, the total amount refers to the total amount.

[0020] [lubricant] The oral composition of the present invention preferably contains a lubricant in addition to ellagic acid and gallic acid. A lubricant is used to reduce friction between the tablet press die and the tablet when compressing powder for tablets, thereby preventing tableting defects such as sticking. The lubricant that can be used in the present invention is not particularly limited as long as it is an ingredient that can achieve the above objective. Examples include stearic acid, calcium stearate, magnesium stearate, or other stearic acid or its salts, sodium stearyl fumarate, polyethylene glycol, fatty acid esters such as sucrose fatty acid esters, silicon dioxide, calcium phosphate, vegetable oils and fats, hydrogenated oils, and talc. These may be used individually or in combination of two or more. Commercially available lubricants can be used. In the present invention, stearic acid or its salts, fatty acid esters, and hydrogenated rapeseed oil are preferred from the viewpoint of the excellent cholesterol-lowering and / or reducing effect, triglyceride-lowering and / or reducing effect, brain function-improving effect, stress-induced depressive state-reducing and / or alleviating effect, or stress tolerance-improving effect of the resulting composition, and calcium stearate, sucrose fatty acid esters, and hydrogenated rapeseed oil are more preferred.

[0021] The content of the lubricant in the oral composition of the present invention is not particularly limited, but it is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, and particularly preferably 0.5% by mass or more, from the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect. Furthermore, it is preferably 20% by mass or less, more preferably 15% by mass or less, and particularly preferably 10% by mass or less, from the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect. Note that if multiple lubricants are contained, the total amount is used.

[0022] In the present invention, the content of excipients and / or lubricants may be 5% by mass or more, preferably 10% by mass or more, relative to the total amount of ellagic acid, gallic acid, excipients and / or lubricants. Furthermore, it is preferably 95% by mass or less, and more preferably 90% by mass or less. By using the above blending ratio, it is possible to enhance the excellent effect of suppressing and / or reducing cholesterol increase, suppressing and / or reducing triglyceride increase, improving brain function, reducing and / or alleviating depressive states caused by stress, or improving stress tolerance. If multiple excipients and / or lubricants are included, the total amount refers to the sum of their amounts.

[0023] [amino acid] The oral composition of the present invention preferably contains an amino acid in addition to ellagic acid and gallic acid. Neutral amino acids are preferred as the amino acids used in the present invention, and leucine, phenylalanine, and tyrosine are particularly preferred. In the present invention, "amino acid" refers to a free amino acid. The amino acids used in the present invention may be synthesized or obtained from plants or animals.

[0024] The amino acid content in the oral composition of the present invention is not particularly limited, but it is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and particularly preferably 0.1% by mass or more, from the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect. Furthermore, it is preferably 10% by mass or less, more preferably 8% by mass or less, and particularly preferably 5% by mass or less, from the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect.

[0025] [nucleotide] The oral composition of the present invention preferably contains nucleotides in addition to ellagic acid and gallic acid. In the present invention, nucleotides are a concept that encompasses nucleotides, which are phosphate esters of nucleosides, and polynucleotides (nucleic acids), which are conjugates of nucleotides. As phosphate esters of nucleosides, for example, taste-enhancing nucleotides such as inosinic acid (IMP) and guanylic acid (GMP), ribonucleotides such as adenylic acid (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP), and deoxynucleotides such as dAMP, dADP, and dATP can be used. As nucleic acids, deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) can be used. From the viewpoint of improving taste, stability, and anti-obesity effects, taste-enhancing nucleotides and nucleic acids are preferred as nucleotides used in the present invention, inosinic acid, guanylic acid, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA) are more preferred, and inosinic acid, DNA, and RNA are particularly preferred. The nucleotides used in the present invention may be synthesized or obtained from plants or animals.

[0026] The nucleotide content in the oral composition of the present invention is not particularly limited, but it is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and particularly preferably 0.1% by mass or more, from the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect. Furthermore, it is preferably 10% by mass or less, more preferably 8% by mass or less, and particularly preferably 5% by mass or less, from the viewpoint of excellent cholesterol elevation suppression and / or reduction effect, triglyceride elevation suppression and / or reduction effect, brain function improvement effect, stress-induced depressive state reduction and / or alleviation effect, or stress tolerance improvement effect.

[0027] In the present invention, the content of amino acids and / or nucleotides may be 0.0001% by mass or more, preferably 0.0005% by mass or more, relative to the total amount of ellagic acid, gallic acid, amino acids and / or nucleotides. Furthermore, it is preferably 30% by mass or less, and more preferably 20% by mass or less. By using the above blending ratio, it is possible to enhance the excellent effect of suppressing and / or reducing cholesterol increase, suppressing and / or reducing triglyceride increase, improving brain function, reducing and / or alleviating depressive states caused by stress, or improving stress tolerance. Note that if multiple amino acids and / or nucleotides are included, the total amount refers to the sum of those amounts.

[0028] In addition to ellagic acid, gallic acid, and the above components, the oral composition of the present invention may use any other components suitable for oral composition. For example, other animal and plant-derived components besides ellagic acid and gallic acid, fluidizers, binders, disintegrants, colorants, coating agents, various carriers, stabilizers, surfactants, plasticizers, solubilizers, reducing agents, buffers, sweeteners, bases, adsorbents, flavoring agents, antioxidants, glossing agents, coatings, wetting agents, wetting modifiers, fillers, cooling agents, flavoring agents, fragrances, isotonic agents, softeners, emulsifiers, viscosity enhancers, foaming agents, pH adjusters, diluents, dispersants, disintegration aids, disintegration extenders, fragrances, moisture-proofing agents, preservatives, solvents, solubilizers, solvents, antistatic agents, humectants, and moisturizing agents can be used.

[0029] [Oral composition of the present invention] The oral composition of the present invention can be used, for example, as a pharmaceutical product (including quasi-drugs), a functional food such as a food for specified health uses, a food with nutritional function claims, or a food with functional claims whose efficacy has been approved by a designated institution, as well as a general food product, a food additive, etc.

[0030] As shown in the examples described later, the oral composition of the present invention can effectively suppress the expression of SREBF1 and effectively promote the expression of PPARα, HO-1, and NOS3.

[0031] As described in Non-Patent Literature 1, SREBF1 is a transcription factor that regulates intracellular cholesterol biosynthesis and uptake in the liver and other cells. Increased expression of SREBF1 in the liver leads to increased expression of ATP citrate lyase. ATP citrate lyase is an enzyme that synthesizes acetyl-CoA from citrate, and cholesterol is formed from acetyl-CoA through the action of several enzymes, thus increasing cholesterol levels in the liver. Furthermore, SREBF1 is a fatty acid synthesis-related gene that enhances the expression of various enzymes involved in fatty acid and triglyceride synthesis (called ribogenic enzymes), playing a role in actively storing energy obtained through diet by converting it into fatty acids and triglycerides. Therefore, suppressing SREBF1 expression in liver cells can help suppress increases in cholesterol and triglycerides in the blood and liver.

[0032] As described in Non-Patent Literature 1, PPARα enhances the expression of genes involved in β-oxidation of fatty acids in the liver, thereby regulating fatty acid breakdown. Fatty acids taken up from the bloodstream by adipocytes undergo β-oxidation in liver cells and are used for energy production. The gene expression of the enzymes responsible for this β-oxidation is regulated by PPARα, and it is known that increased PPARα expression promotes β-oxidation of fatty acids. Furthermore, as described in Non-Patent Literature 2, it is known that increased PPARα expression in the liver promotes an increase in HDL in blood vessels by regulating the expression of apolipoprotein in the liver. HDL is said to play a role in collecting excess cholesterol in the blood and transporting it to the liver for processing. Therefore, by promoting PPARα expression in liver cells, it is possible to suppress or reduce the increase in cholesterol and triglycerides in the blood and liver.

[0033] Furthermore, Heme Oxygenase 1 (HO-1, sometimes called "HMOX1") is an enzyme that breaks down heme into biliverdin, carbon monoxide (CO), and free iron (Fe). HO cleaves the porphyrin ring of heme and adds oxygen molecules (oxygenase). Increased expression of HO-1 is considered one of the main mechanisms protecting cells from oxidative stress. Also, as described in Non-Patent Literature 3, oxidative stress such as reactive oxygen species and mitochondrial damage are considered to be contributing factors to decreased brain function. As described in Non-Patent Literature 4, it is known that various physical, psychological, and physiological stresses applied to an individual can cause mitochondrial damage in nerve cells, inducing nerve cell damage, which is one of the causes of depression, and that oxidative stress in the brain progresses under depression (Non-Patent Literature 4). Oxidative stress causes damage to mitochondrial DNA in nerve cells and nerve-like cells, and the expression of proteins that play an important role in ATP production decreases, thus reducing the production of ATP, which is important for brain function. As described in Non-Patent Literature 5, HO-1 is known to have a mitochondrial protective effect under oxidative stress in nerve-like cells. Therefore, by promoting the expression of HO-1 in nerve cells and nerve-like cells, it is possible to prevent mitochondrial damage in nerve cells and nerve-like cells in the brain and other areas, thereby improving brain function. In addition, it is possible to improve stress tolerance by reducing or alleviating depressive states in response to various physical, psychological (sociopsychological), and physiological stresses.

[0034] In this specification, brain function improvement includes the mitigation or reduction of neurological disorders, depressive states such as depression, neuropathic pain, eye damage, cognitive decline, memory impairment, and impaired judgment by protecting nerve cells or nerve-like cells of the brain from oxidative stress. Furthermore, in this specification, improving stress tolerance includes not only the suppression or mitigation of the above-mentioned depressive states caused by physical, physiological, and psychosocial stress, but also the prevention of neurological disorders, neuropathic pain, eye damage, cognitive decline, memory impairment, and impaired judgment by protecting nerve cells or nerve-like cells.

[0035] Nitric oxide synthase 3 (NOS3), also known as endothelial nitric oxide synthase (eNOS), is primarily responsible for NO production in the vascular endothelium. The vascular endothelium consists of a single layer of squamous cells lining the inner surface of blood vessels, forming the interface between the blood circulating in the lumen and the rest of the vessel wall. NO produced by NOS3 in the vascular endothelium plays a crucial role in regulating vascular tone, cell proliferation, leukocyte adhesion, and platelet aggregation. Activating NOS3 is known to dilate capillaries and improve blood flow (Non-Patent Literature 6), and improved blood flow is known to promote nutrient supply to muscles and reduce physical fatigue. Therefore, it is thought that increasing NOS3 expression improves blood flow and thus alleviates physical fatigue. Furthermore, it has been suggested that decreased NOS3 activity inhibits smooth muscle relaxation and may cause ED (erectile dysfunction) (Non-Patent Literature 7), and it is thought that increasing NOS3 expression improves erectile dysfunction. In this specification, physical fatigue includes lethargy, malaise, fatigue, physical exhaustion, and decreased physical function due to poor blood circulation. Erectile dysfunction, also known as erectile failure, includes a decrease in erectile function.

[0036] The oral composition of the present invention can be used, for example, as a composition for inhibiting cholesterol increase or a composition for reducing cholesterol. Such a composition for inhibiting cholesterol increase or a composition for reducing cholesterol is not particularly limited as long as it contains ellagic acid and gallic acid and can be distinguished from other products in that it is used to inhibit cholesterol increase or reduce cholesterol. For example, any product that displays on the product itself, packaging, instructions, or promotional materials that it has the function of inhibiting cholesterol increase or reducing cholesterol is included in the scope of the present invention. It should be noted that the composition for inhibiting cholesterol increase or a composition for reducing cholesterol of the present invention is not limited to those in which ellagic acid or gallic acid is indicated as the active ingredient for inhibiting cholesterol increase or reducing cholesterol on the product packaging, etc., and may not specify an active ingredient.

[0037] Specifically, the cholesterol-raising inhibitory composition and cholesterol-reducing composition of the present invention include so-called health foods such as pharmaceuticals (including quasi-drugs), functional foods whose efficacy has been approved by designated institutions, such as Foods for Specified Health Uses, Foods with Nutrient Function Claims, and Foods with Function Claims. Examples of so-called health foods include those that display phrases such as "For those concerned about cholesterol," "Lower cholesterol," and "For those concerned about LDL cholesterol."

[0038] Furthermore, the oral composition of the present invention can be used, for example, as a composition for inhibiting the rise in triglycerides or a composition for reducing triglycerides. Such compositions for inhibiting the rise in triglycerides or reducing triglycerides are not particularly limited as long as they contain ellagic acid and gallic acid and can be distinguished from other products in that they are used to inhibit the rise in triglycerides or reduce triglycerides. For example, any product in which the body, packaging, instructions, or promotional materials of the present invention indicate that it has the function of inhibiting the rise in triglycerides or reducing triglycerides is included within the scope of the present invention. It should be noted that the compositions for inhibiting the rise in triglycerides or reducing triglycerides of the present invention are not limited to those in which ellagic acid or gallic acid is indicated as the active ingredient for inhibiting the rise in triglycerides or reducing triglycerides on the product packaging, etc., and may not specify an active ingredient.

[0039] Specifically, examples of the present invention's composition for suppressing triglyceride elevation and composition for reducing triglycerides include so-called health foods such as pharmaceuticals (including quasi-drugs), functional foods whose efficacy has been approved by designated institutions, such as Foods for Specified Health Uses, Foods with Nutrient Function Claims, and Foods with Function Claims. Examples of so-called health foods include those that display claims such as "suppresses the rise in triglycerides," "for those concerned about triglycerides," and "for those with elevated triglycerides."

[0040] Furthermore, the oral composition of the present invention can be used, for example, as a composition for improving brain function or a composition for enhancing brain function. Such a composition for improving brain function or a composition for enhancing brain function is not particularly limited as long as it contains ellagic acid and gallic acid and can be distinguished from other products in that it is used to improve and enhance brain function. For example, any product that displays on the product itself, packaging, instructions, or promotional materials that it has a function of improving brain function or enhancing brain function is included in the scope of the present invention. It should be noted that the composition for improving brain function or a composition for enhancing brain function of the present invention is not limited to those in which ellagic acid or gallic acid is indicated as an active ingredient for improving or enhancing brain function on the product packaging, etc., and may not specify an active ingredient.

[0041] Specifically, the brain function improving composition, brain function enhancement composition, cognitive function improving composition, and cognitive function enhancement composition of the present invention include so-called health foods such as pharmaceuticals (including quasi-drugs), functional foods whose efficacy has been approved by designated institutions, such as foods for specified health uses, nutritional function foods, and foods with functional claims. Examples of so-called health foods include those that claim to "improve brain activity" or "maintain memory."

[0042] Furthermore, the oral composition of the present invention can be used, for example, as a stress-reducing composition, a stress-mitigating composition, or a composition for alleviating depressive states such as low mood caused by stress. Such stress-reducing compositions, stress-mitigating compositions, and compositions for alleviating depressive states such as low mood caused by stress are not particularly limited as long as they contain ellagic acid and gallic acid and can be distinguished from other products in that they are used for stress reduction, stress mitigation, and alleviation of depressive states such as low mood caused by stress. For example, any product according to the present invention that displays on the product body, packaging, instructions, or promotional materials that it has the function of reducing stress, reducing stress, or alleviating depressive states such as low mood caused by stress is included in the scope of the present invention. It should be noted that the stress-reducing compositions, stress-mitigating compositions, and compositions for alleviating depressive states such as low mood caused by stress of the present invention are not limited to those in which ellagic acid or gallic acid is indicated on the product packaging, etc., as the active ingredient for stress reduction, stress mitigation, or alleviation of depressive states such as low mood caused by stress, and the active ingredient may not be specified.

[0043] Specifically, the stress-reducing composition, stress-alleviating composition, and composition for alleviating depressive states such as mood swings caused by stress according to the present invention include so-called health foods such as pharmaceuticals (including quasi-drugs), functional foods such as Foods for Specified Health Uses, Foods with Nutrient Function Claims, and Foods with Function Claims whose efficacy has been approved by designated institutions. Examples of so-called health foods include those that display phrases such as "relieves stress," "alleviates stress," "for those concerned about stress and fatigue," "relieves work-related stress," "relieves mental stress," "reduces temporary psychological stress," "alleviates mood swings," "alleviates mood swings," "alleviates depressive states," and "alleviates depressive states."

[0044] Examples of the oral composition of the present invention include tablets, granules, fine granules, powders, capsules such as soft capsules and hard capsules, chewable tablets, granular tablets, rod-shaped tablets, plate-shaped tablets, block-shaped tablets, solid tablets, round tablets, caplets, and stick-shaped tablets. Among these, tablets, granules, powders, capsules, and chewable tablets are preferred, granules, tablets, and hard capsules are particularly preferred, and tablets are especially preferred.

[0045] The packaging form of the oral composition of the present invention is not particularly limited and can be appropriately selected depending on the dosage form, etc., but examples include blister packs such as PTP; strip packaging; heat seal; aluminum pouch; film packaging using plastic or synthetic resin; glass containers such as vials; plastic containers such as ampoules. [Examples]

[0046] The present invention will be described in detail below with reference to examples. However, the present invention is not limited to these examples.

[0047] In each of the following examples, comparative examples, and manufacturing examples, the following components were used as listed in the tables below. • Ellagic acid: Ellagic acid reagent (Fujifilm Wako Pure Chemical Industries) (anhydrous, powder, purity approximately 100% by mass) was used. • Gallic acid: Gallic acid reagent (SIGMA) (anhydrous, powder, purity approximately 100% by mass) was used. • Calcium stearate: A commercially available product was used. • Leucine: Leucine reagent (Nacalai Tesque) (anhydrous, powder, purity approximately 100% by mass) was used. • Phenylalanine: Phenylalanine reagent (Nacalai Tesque) (anhydrous, powder, purity approximately 100% by mass) was used. • Tyrosine: Tyrosine reagent (Nacalai Tesque) (anhydrous, powder, purity approximately 100% by mass) was used. • Inosine 5'-monophosphate disodium hydrate (inosinic acid): Inosinic acid reagent (Tokyo Chemical Industries) (hydrate, powder, purity approximately 100% by mass) was used. • Dextrin: Commercially available product was used.

[0048] [Examples 1-1 to 1-10, Comparative Examples 1-1 to 1-14] (Test 1: Triglycerides, Cholesterol (1)) (1) Human liver cancer-derived cells (HepG2, RIKEN) were cultured in 10% FBS-DMEM by volume, and the cells were placed in 2 × 10⁶ wells of a collagen-coated 96-well plate. 4 100 μL / well was seeded to achieve a cell / well ratio, and pre-cultured for 24 hours in a 37°C, 5V %CO2 incubator. (2) After removing the culture medium from each well, 100 μL / well of culture medium containing the test substance and 1.5 mM sodium oleate (Nacalai Tesque) as a fatty acid load was added. The culture medium used was 0.5 vol. %DMSO2 vol. %BSA-DMEM. The proportions (mass %) of each component in the test substance are shown in Tables 1 and 2. The concentration of the test substance in the culture medium was 10 μg / mL. The culture was performed for 24 hours at 37°C in a 5 vol. %CO2 incubator. (3) After removing the culture medium from each well, wash once with PBS, recover RNA using the RNeasy Mini Kit (QIAGEN), and synthesize cDNA using ReverTra Ace(R) qPCR RT Master Mix (TOYOBO). (4) Using the obtained cDNA as a template, quantitative real-time PCR was performed using a Rotor-Gene SYBR Green PCR Kit (QIAGEN) with a PPARα primer (QIAGEN, trade name: Hs_PPARA_1_SG QuantiTect Primer Assay (QT00017451)) to measure the gene expression level of PPARα. As an endogenous control, the gene expression level of ACTB was measured using an ACTB primer (QIAGEN, trade name: Hs_ACTB_1_SG QuantiTect primer assay (QT00095431)). The relative value of PPARα gene expression level / ACTB gene expression level was calculated with Comparative Example 1-1 set to 1. The results are shown in Tables 1 and 2.

[0049] [Table 1]

[0050] [Table 2]

[0051] HepG2 is a cell commonly used as a model cell for the liver. As shown in Tables 1 and 2, the oral composition of the present invention, by containing ellagic acid and gallic acid, can effectively promote the expression of PPARα and be effective in suppressing and / or reducing cholesterol increases and triglyceride increases. In particular, it can be seen that when ellagic acid and gallic acid are combined in a mass ratio of 0.5 or less of gallic acid to 100 ellagic acid, the composition can effectively promote the expression of PPARα and be effective in suppressing and / or reducing cholesterol increases and triglyceride increases. Furthermore, it can be seen that by containing ellagic acid and gallic acid, and also containing any of dextrin, calcium stearate, inosinic acid, leucine, phenylalanine, and tyrosine, the composition can effectively promote the expression of PPARα and be effective in suppressing and / or reducing cholesterol increases and triglyceride increases.

[0052] [Examples 2-1 to 2-9, Comparative Examples 2-1 to 2-12] (Test 2: Triglycerides, Cholesterol (2)) (1) Human liver cancer-derived cells (HepG2, RIKEN) were cultured in 10% FBS-DMEM by volume, and the cells were placed in 2 × 10⁶ wells of a collagen-coated 96-well plate. 4 100 μL / well was seeded to achieve a cell / well ratio, and pre-cultured for 24 hours in a 37°C, 5V %CO2 incubator. (2) After removing the culture medium from each well, 100 μL / well of culture medium containing the test substance and 1.5 mM sodium oleate (Nacalai Tesque) as a fatty acid load was added. The culture medium used was 0.5 vol. %DMSO2 vol. %BSA-DMEM. The proportions (mass %) of each component in the test substance are shown in Tables 3 and 4. The concentration of the test substance in the culture medium was 10 μg / mL. The culture was performed for 24 hours at 37°C in a 5 vol. %CO2 incubator. (3) After removing the culture medium from each well, wash once with PBS, recover RNA using the RNeasy Mini Kit (QIAGEN), and synthesize cDNA using ReverTra Ace(R) qPCR RT Master Mix (TOYOBO). (4) Using the obtained cDNA as a template, quantitative real-time PCR was performed using a Rotor-Gene SYBR Green PCR Kit (QIAGEN) with a primer for SREBF1 (QIAGEN, trade name: Hs_SREBF1_1_SG QuantiTect Primer Assay (QT00036897)) to measure the gene expression level of SREBF1. As an endogenous control, the gene expression level of ACTB was measured using a primer for ACTB (QIAGEN, trade name: Hs_ACTB_1_SG QuantiTect primer assay (QT00095431)). The relative value of the SREBF1 gene expression level / ACTB gene expression level was calculated with Comparative Example 2-1 set to 1. The results are shown in Tables 3 and 4.

[0053] [Table 3]

[0054] [Table 4]

[0055] HepG2 is a cell commonly used as a model cell for the liver. As shown in Tables 3 and 4, the oral composition of the present invention, by containing ellagic acid and gallic acid, can effectively suppress the expression of SREBF1 and have an effect on suppressing cholesterol and triglyceride increases. In particular, it can be seen that when the mass ratio of ellagic acid to gallic acid is 0.5 or less per 100 units of ellagic acid, it can effectively suppress the expression of SREBF1 and have an effect on suppressing cholesterol and triglyceride increases. Furthermore, it can be seen that by containing ellagic acid and gallic acid, and also containing any of dextrin, calcium stearate, inosinic acid, leucine, and phenylalanine, the expression of SREBF1 can be effectively suppressed and have an effect on suppressing cholesterol and triglyceride increases.

[0056] From the results of Tests 1 and 2, it can be seen that the oral composition of the present invention, by containing ellagic acid and gallic acid, can exhibit excellent effects in suppressing and / or reducing cholesterol increases and triglyceride increases. Furthermore, it can be seen that by including one of the following in addition to ellagic acid and gallic acid, an excipient, a lubricant, an amino acid, and a nucleotide, it can exhibit excellent effects in suppressing and / or reducing cholesterol increases and triglyceride increases.

[0057] [Examples 3-1 to 3-8, Comparative Examples 3-1 to 3-10] (Test 3: Brain Function) (1) Rat adrenal pheochromocytoma cells (PC12, JCRB cell bank) were cultured in 10 volume %FBS-RPMI 1640 medium and placed in 4 × 10⁶ well plates coated with collagen in a 96-well plate. 4 100 μL / well was seeded to achieve a cell / well ratio, and pre-cultured for 24 hours in a 37°C, 5V %CO2 incubator. (2) After pre-culturing as described above, 100 μL / well of the culture medium containing the test substance was added on top of the culture medium already in the wells, and the culture was incubated at 37°C in a 5V %CO2 incubator for 24 hours. The culture medium used was 0.5V %DMSO-10V %FBS-RPMI 1640 medium. The proportions (mass%) of each component in the test substance are shown in Tables 5 and 6. The concentration of the test substance in the culture medium was 0.5 μg / mL. (3) After 24 hours of incubation, hydrogen peroxide was diluted to 2.2 mM with 10 vol. %FBS-RPMI 1640 and added at a rate of 20 μL / well to the culture medium already in the wells (final concentration 200 μM). The cultures were incubated at 37°C in a 5 vol. %CO2 incubator for 2 hours. (4) After removing the culture medium from each well, RNA was recovered using the RNeasy Mini Kit (QIAGEN), and cDNA was synthesized using the ReverTra Ace(R) qPCR RT Master Mix (TOYOBO). (5) Using the obtained cDNA as a template, quantitative real-time PCR was performed using a Rotor-Gene SYBR Green PCR Kit (QIAGEN) with a primer for the HO-1 gene (Hmox1) (QIAGEN, trade name: Rn_Hmox1_1_SG QuantiTect Primer Assay (QT00175994)) to measure the expression level of the HO-1 gene (Hmox1). As an endogenous control, the gene expression level of GAPDH was measured using a primer for GAPDH (QIAGEN, trade name: Rn_Gapd_1_SG QuantiTect Primer Assay (QT00199633)). Relative values ​​were calculated with Comparative Example 3-1 set to 1. The results are shown in Tables 5 and 6 below.

[0058] [Table 5]

[0059] [Table 6]

[0060] As shown in Tables 5 and 6, the oral composition of the present invention, by containing ellagic acid and gallic acid, can effectively promote the expression of HO-1 (HMOX1) in neuronal-like cells, and can be effective in improving brain function, reducing and / or alleviating depressive states such as mood swings caused by stress, and improving stress tolerance. In particular, it can be seen that when the mass ratio of ellagic acid to gallic acid is 0.5 or less per 100 units of ellagic acid, it can effectively promote the expression of HO-1 (HMOX1) in neuronal-like cells, and can be effective in improving brain function, reducing and / or alleviating depressive states such as mood swings caused by stress, and improving stress tolerance. Furthermore, by containing ellagic acid and gallic acid, and one of dextrin, calcium stearate, inosinic acid, and leucine, the expression of HO-1 (HMOX1) can be effectively promoted in neuronal cells. Therefore, it can be seen that the oral composition of the present invention, by containing ellagic acid and gallic acid along with one of excipients, lubricants, amino acids, and nucleotides, can exhibit excellent effects for improving brain function, reducing and / or alleviating depressive states such as mood swings caused by stress, and improving stress tolerance.

[0061] [Examples 4-1 to 4-10, Comparative Examples 4-1 to 4-14] (Test 4: Blood flow) (1) Human umbilical vein endothelial cells (HUVEC, Lonza) were cultured in EGM-2 medium (Lonza). The cells were placed in a collagen-coated 96-well plate in a 1 × 10⁶ well. 4 Seeds were seeded at a rate of 100 μL / well to achieve a cell / well ratio, and pre-cultured for 24 hours in a 37°C, 5V %CO2 incubator. (2) After removing the culture medium from each well, 100 μL / well of culture medium containing the test substance was added. 0.5 vol. %DMSO-EGM-2 medium was used. The proportions (mass %) of each component in the test substance are shown in Tables 7 and 8. The concentration of the test substance in the culture medium was 2.5 μg / mL. (3) After removing the culture medium from each well, wash once with PBS, recover RNA using the RNeasy Mini Kit (QIAGEN), and synthesize cDNA using ReverTra Ace(R) qPCR RT Master Mix (TOYOBO). (4) Using the obtained cDNA as a template, quantitative real-time PCR was performed using the Rotor-Gene SYBR Green PCR Kit (QIAGEN) with NOS3 (eNOS) primers (Takara, trade name: sense (5'-CCAGCTAGCCAAAGTCACCAT-3') (JP33538048), anti-sense (5'-GTCTCGGAGCCATACAGGATT-3') (JP33538049)) to measure the gene expression level of NOS3 (eNOS). As an endogenous control, the gene expression level of ACTB was measured using ACTB primers (QIAGEN, trade name: Hs_ACTB_1_SG QuantiTect primer assay (QT00095431)). Relative values ​​were calculated with Comparative Example 3-1 set to 1. The results are shown in Tables 7 and 8 below.

[0062] [Table 7]

[0063] [Table 8]

[0064] As shown in Tables 7 and 8, the oral composition of the present invention, by containing ellagic acid and gallic acid, can effectively promote the expression of NOS3 in vascular endothelial cells and can be effective for improving blood flow, reducing physical fatigue, or improving erectile dysfunction. In particular, it can be seen that when the mass ratio of ellagic acid to gallic acid is 0.5 or less per 100 parts ellagic acid, it can effectively promote the expression of NOS3 in vascular endothelial cells and can be effective for improving blood flow, reducing physical fatigue, or improving erectile dysfunction. Furthermore, since the oral composition of the present invention can effectively promote the expression of NOS3 in vascular endothelial cells by containing ellagic acid and gallic acid, along with any of dextrin, calcium stearate, inosinic acid, leucine, phenylalanine, and tyrosine, it can be seen that the oral composition of the present invention can be excellent for improving blood flow, reducing physical fatigue, or improving erectile dysfunction by containing ellagic acid and gallic acid along with any one of excipients, lubricants, amino acids, and nucleotides.

[0065] The following shows an example of the preparation of the oral composition of the present invention.

[0066] Manufacturing Examples 1-17 Tablets (250 mg per tablet) were manufactured according to Tables 9 and 10 below. The values ​​listed in Tables 9 and 10 represent mass percentages. Taking 1 to 3 tablets 1 to 3 times a day yields excellent effects such as suppressing or promoting the reduction of triglycerides or cholesterol, improving brain function, reducing and / or alleviating depressive states such as mood swings caused by stress, improving stress tolerance, improving blood flow, improving physical fatigue, or improving erectile dysfunction.

[0067] [Table 9]

[0068] [Table 10]

[0069] Manufacturing examples 18-25 The ingredients listed in Tables 11 and 12 below were mixed, and the resulting powder was filled into hard capsule shells to produce capsules (300 mg per capsule). The values ​​in Table 11 represent mass percentages. Taking 1 to 3 capsules once a day provides excellent suppression or promotion of the rise in triglycerides or cholesterol, improvement of brain function, reduction and / or alleviation of depressive states such as mood swings caused by stress, improved stress tolerance, improved blood flow, improved physical fatigue, or improved erectile dysfunction.

[0070] [Table 11]

[0071] [Table 12] [Industrial applicability]

[0072] According to the present invention, by containing ellagic acid and gallic acid, it is possible to provide an oral composition that has excellent effects in suppressing or promoting the reduction of triglycerides or cholesterol, improving brain function, reducing and / or alleviating depressive states such as mood swings caused by stress, improving stress tolerance, improving blood flow, improving physical fatigue, or improving erectile dysfunction.

Claims

1. An oral composition containing ellagic acid and gallic acid, further characterized by containing amino acids and / or nucleotides.

2. The oral composition according to claim 1, characterized in that it is for suppressing and / or reducing cholesterol levels.

3. The oral composition according to claim 1, characterized in that it is for suppressing and / or reducing the rise in triglycerides.

4. The oral composition according to claim 1, characterized in that it is for improving brain function, for reducing and / or alleviating depressive states such as mood swings caused by stress, or for improving stress tolerance.

5. The oral composition according to claim 1, characterized in that it is for improving blood flow, reducing physical fatigue, or improving erectile dysfunction.

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