Composition for preventing or relieving urinary urge stress, and composition for improving sleep

Abstract

To provide a novel composition capable of preventing or relieving urinary urge stress.SOLUTION: A composition for preventing or relieving urinary urge stress and a composition for improving sleep, comprises at least one selected from the group consisting of the following components (1)-(3) as an active ingredient: (1) at least one selected from the group consisting of ellagic acid, analogs thereof, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, salts thereof, and hydrates thereof; and (3) processed plants of the genus Punica, etc.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for preventing or alleviating urinary stress and a method for preventing or alleviating urinary stress.The present invention also relates to a composition for improving sleep and a method for improving sleep. [Background technology]

[0002] Today, many people experience anxiety about going out due to a decline in urinary function. For example, they may refrain from going out or traveling by car or train because they are not in an environment where they can urinate quickly when they feel the urge to urinate. Furthermore, many people have to go out despite this anxiety, and the increased frequency of urination at night disrupts sleep. Therefore, the psychological stress caused by the urge to urinate is a major source of distress in daily life.

[0003] Ellagic acid is a type of polyphenol known to date and is known to be produced by hydrolyzing punicalagin. Ellagic acid has been known to have antioxidant and anticancer effects. It has also been reported to have skin-whitening effects and promote vitamin C absorption in the body (Patent Documents 1 and 2).

[0004] However, it is not known that ellagic acid or punicalagin can prevent or alleviate stress caused by the urge to urinate. Furthermore, although plants belonging to the genus Pomegranate are known, it is not known that plants belonging to the genus Pomegranate can prevent or alleviate stress caused by the urge to urinate. Furthermore, it is not known that ellagic acid, punicalagin, or plants belonging to the genus Pomegranate can improve sleep. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 2019-14672 [Patent Document 2] Japanese Patent Application Publication No. 2018-138525 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a novel composition that can prevent or relieve urinary stress, a composition that can improve sleep, etc. [Means for solving the problem]

[0007] The present inventors have conducted extensive research in light of the above-mentioned problems and have found that ellagic acid, punicalagin, and processed products of pomegranate plants can prevent and alleviate urinary stress. The present inventors have also found that ellagic acid, punicalagin, and processed products of pomegranate plants can improve sleep. The present invention was completed as a result of further research based on these findings, and is as follows: Item 1. A composition for preventing or alleviating urinary stress, comprising at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. Item 2. The composition according to Item 1, wherein the urinary stress is caused by a decrease in urinary tract function. Item 3. The composition according to Item 1 or 2, wherein the urinary urge stress is psychological stress caused by the urge to urinate. Item 4. The composition according to any one of Items 1 to 3, wherein the stress is at least one type of stress selected from the group consisting of worry, annoyance, tension, pain, fatigue, lethargy, irritability, and depression due to the need to urinate. Item 5. The composition according to any one of Items 1 to 4, wherein the composition is for women. Item 6. A composition used for preventing or alleviating urinary stress, comprising at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. Item 7. The composition according to Item 6, wherein the urinary stress is caused by a decrease in urinary tract function. Item 8. The composition according to Item 6 or 7, wherein the urinary urge stress is psychological stress caused by the urge to urinate. Item 9. The composition according to any one of Items 6 to 8, wherein the stress is at least one type of stress selected from the group consisting of worry, annoyance, tension, pain, fatigue, lethargy, irritability, and depression due to the need to urinate. Item 10. The composition according to any one of Items 6 to 9, wherein the composition is for women. Item 11. A method for preventing or alleviating urinary stress, comprising applying, preferably orally administering to a subject, a composition containing at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. Item 12. Use of at least one selected from the group consisting of the following ingredients (1) to (3) for producing a composition for preventing or alleviating urinary stress: (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. Item 13. A sleep-improving composition containing at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. Item 14. The composition according to Item 13, which improves sleep quality. Item 15. A composition according to Item 13 or 14, which improves sleep impaired due to urination stress, preferably improves the quality of sleep impaired due to urination stress. Item 16. The composition according to any one of Items 13 to 15, wherein the composition is for women. Item 17. A composition used for improving sleep, comprising at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. Item 18. The composition according to Item 17, wherein the sleep improvement is an improvement in sleep quality. Item 19. The composition according to Item 17 or 18, wherein the sleep improvement is an improvement in the quality of sleep that has deteriorated due to urinary stress. Item 20. The composition according to any one of Items 17 to 19, which is used to improve sleep in women. Item 21. A method for improving sleep, comprising applying, preferably orally administering to a subject, a composition containing at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. Item 22. Use of at least one selected from the group consisting of the following components (1) to (3) for producing a composition for improving sleep: (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants. [Effects of the Invention]

[0008] The composition of the present invention can prevent or relieve urinary stress, and furthermore, can improve sleep. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the results based on the urination diary in Test Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to a composition for preventing or alleviating urinary stress, which contains, as an active ingredient, at least one selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants.

[0011] The present invention also relates to a composition for improving sleep, which contains at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, a salt thereof, and a hydrate thereof; (3) Processed products from pomegranate plants.

[0012] These will be explained in more detail below. In the present disclosure, "contain" also encompasses "contain," "consist essentially of," and "consist only of."

[0013] Ingredients (1) Regarding component (1), ellagic acid is a conventionally known substance represented by CAS number 476-66-4 (molecular formula C 14 H6O8, molecular weight 302.19). In the present invention, commercially available ellagic acid may be used. Although not limiting the present invention, ellagic acid is commercially available from, for example, Fujifilm Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co., Ltd., etc.

[0014] Examples of the ellagic acid analogs include, but are not limited to, 3-O-methylellagic acid, flabellagic acid, 3,3'-di-O-methylellagic acid, 3,4,3'-trimethylellagic acid, carboxylellagic acid, ellagic acid 4-xyloside, 3'-O-methylellagic acid 4-xyloside, 3-O-methylellagic acid 3'-rhamnoside, ellagic acid 3-glucoside, ellagic acid 4-acetylxyloside, 3'-O-methylellagic acid 4-O-β-D-glucose, etc. These analogs may be used alone or in combination of two or more.

[0015] Examples of the salts of ellagic acid and the salts of the analogues include salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and magnesium, ammonium salts, amine salts, etc. These may be used alone or in combination of two or more.

[0016] Examples of the hydrates of ellagic acid, its analogs, and its salts include conventionally known hydrates of these compounds. These may be used alone or in combination of two or more.

[0017] Although not limiting the present invention, component (1) is preferably at least one selected from the group consisting of ellagic acid, its salts, and hydrates thereof, and more preferably ellagic acid.

[0018] Furthermore, component (1) used in producing the composition for preventing or alleviating urinary stress and the composition for improving sleep may be a purified product (pure product), but is not limited thereto as long as the effects of the present invention are achieved, and may be, for example, a crude product of component (1). Although the crude product does not limit the present invention, preferred examples include crude products of at least one selected from the group consisting of ellagic acid, its salts, and hydrates thereof, and more preferably crude products of ellagic acid.

[0019] These may be used alone or in combination of two or more.

[0020] As an example of the crude product, a crude product of ellagic acid will be described below, but the same explanation applies to crude products of the component (1) other than ellagic acid.

[0021] An example of a crude product of ellagic acid is an ellagic acid fraction prepared from a plant containing ellagic acid. Although not limiting the present invention, examples of crude products of ellagic acid include crude products from plants such as strawberries (plants belonging to the genus Fragaria), cranberries (plants belonging to the genus Vaccinium), raspberries (plants belonging to the genus Rubus), grapes (plants belonging to the genus Vitis), walnuts (plants belonging to the genus Juglans), chestnuts (plants belonging to the genus Castanea), pecans (plants belonging to the genus Carya), geranium (plants belonging to the genus Geranium), wolfberries (plants belonging to the genus Lycium), and pomegranates (plants belonging to the genus Punica). Although not limiting the present invention, for example, to explain plants belonging to the genus Punica, the genus Punica belongs to the Lythraceae family, and although not limiting the present invention, examples of plants belonging to this genus include pomegranate (Punica granatum).

[0022] As long as the plant contains ellagic acid, the part to be used is not particularly limited, and examples thereof include leaves, stems, fruits, pericarp, flowers, buds, branches, trunks, bark, roots, seeds, and seed coats, and may be appropriately selected depending on the plant. For example, in the case of a plant belonging to the genus Pomegranate, preferred parts to be used include fruits, pericarp, seeds, and seed coats, although this does not limit the present invention. The parts to be used may be used alone or in combination of two or more.

[0023] It is also known that ellagitannins such as punicalagin, punicalin, and gallic acid produce ellagic acid by hydrolysis or the like. Therefore, an example of a crude product of ellagic acid is an ellagic acid fraction prepared by decomposition treatment such as hydrolysis from a plant containing ellagitannin. It is also known that ellagic acid can be produced by chemical synthesis using gallic acid. Therefore, an example of a crude product of ellagic acid is an ellagic acid fraction prepared by chemical synthesis from a plant containing gallic acid.

[0024] The ellagic acid fraction is not prepared by a single extraction from an ellagic acid-containing plant (any part) with a single solvent (e.g., water; alcohols such as methanol and ethanol; or aqueous alcohols), followed by filtration and concentration. Rather, it refers to a fraction obtained by, for example, repeating solvent extraction multiple times to obtain a fraction with a high degree of ellagic acid purification (purity) or obtaining a concentrated fraction containing ellagic acid at a high concentration, or by any combination of purification procedures such as molecular weight filtration, size exclusion chromatography, and ion exchange chromatography. More specifically, an example of the ellagic acid fraction is a fraction obtained by removing components other than ellagic acid from an ellagic acid-containing fraction to increase the ellagic acid content to 50% by mass or more. The ellagic acid content of the ellagic acid fraction is preferably 60 to 100% by mass, more preferably 70 to 100% by mass, even more preferably 80 to 100% by mass, and particularly preferably 90 to 100% by mass.

[0025] From this viewpoint, when the component (3) described below is such a crude product, the component (3) described below may be used as the crude product when producing the composition for preventing or alleviating urinary stress and the composition for improving sleep.

[0026] These may be used alone or in combination of two or more.

[0027] Ingredients (2) Regarding component (2), punicalagin is a conventionally known substance, and commercially available punicalagin may be used in the present invention. While not limiting the present invention, it is commercially available from, for example, Cayman Chemical, Sigma-Aldrich, etc. Examples of the salt of punicalagin include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, and amine salts. Examples of hydrates of punicalagin and its salts include conventionally known hydrates of these. Although not limiting the present invention, a preferred example of component (2) is punicalagin. These may be used alone or in combination of two or more.

[0028] Furthermore, component (2) used in producing the composition for preventing or alleviating urinary stress and the composition for improving sleep may be a purified product (pure product), and is not limited thereto as long as the effects of the present invention are achieved. For example, it may be a crude product of component (2). Although the present invention is not limited to such a crude product, a preferred example of such a crude product is a crude product of punicalagin. These may be used alone or in combination of two or more.

[0029] As an example of the crude product, a crude product of punicalagin will be described below, but the same explanation can be given for crude products of the component (2) other than punicalagin.

[0030] An example of a crude product of punicalagin is a punicalagin fraction prepared from a plant containing punicalagin. Examples of crude products of punicalagin include, but are not limited to, crude products of plants such as myrobalan (a plant belonging to the genus Terminalia) and pomegranate (a plant belonging to the genus Punica). Although not limited to, for example, plants belonging to the genus Punica are described above.

[0031] As long as the plant contains punicalagin, the part to be used is not particularly limited, and examples thereof include leaves, stems, fruits, pericarp, flowers, buds, branches, trunks, bark, roots, seeds, and seed coats, and may be appropriately selected depending on the plant. For example, in the case of a plant belonging to the genus Pomegranate, preferred parts to be used include fruits, pericarp, seeds, and seed coats, although this does not limit the present invention. One part may be used alone, or two or more parts may be used in combination.

[0032] The punicalagin fraction can be explained in the same way as the ellagic acid fraction, that is, it is not prepared by a single extraction using a single solvent (e.g., water; alcohols such as methanol and ethanol; aqueous alcohols) from a plant (any part) containing punicalagin, followed by filtration and concentration, but rather refers to a fraction obtained by repeating solvent extraction multiple times, or by any combination of purification procedures such as molecular weight filtration, size exclusion chromatography, and ion exchange chromatography, in order to obtain a fraction with a high degree of purification (purity) of punicalagin or a concentrated fraction containing punicalagin at a high concentration, or a fraction obtained by squeezing a plant (any part) containing punicalagin and repeatedly concentrating it by column filtration, etc. More specifically, examples of such fractions include those in which components other than punicalagin have been removed from a fraction containing punicalagin, thereby increasing the punicalagin content to 25% by mass or more, preferably 30% by mass or more. In other words, examples of the punicalagin content in such fractions include 25 to 100% by mass or 30 to 100% by mass, and examples of the punicalagin content in such punicalagin fractions include preferably 50 to 100% by mass, more preferably 70 to 100% by mass, even more preferably 80 to 100% by mass, and particularly preferably 90 to 100% by mass.

[0033] From this viewpoint, when the component (3) described below is such a crude product, the component (3) described below may be used as the crude product when producing the composition for preventing or alleviating urinary stress and the composition for improving sleep.

[0034] These may be used alone or in combination of two or more.

[0035] Ingredients (3) The processed pomegranate plant product is a processed product of a plant belonging to the genus Punica, i.e., the raw material of the processed product is a plant belonging to the genus Punica. The genus Punica belongs to the family Lythraceae, and although the present invention is not limited thereto, examples of plants belonging to the genus include pomegranate (Punica granatum).

[0036] As long as it is a plant belonging to the genus, the part to be used is not particularly limited, and examples thereof include leaves, stems, fruits, pericarp, flowers, buds, branches, trunks, bark, roots, seeds, and seed coats, with fruits, pericarp, seeds, and seed coats being preferred. The parts to be used may be used alone or in combination of two or more.

[0037] In the present invention, examples of processed plant products include pulverized products, dried products, extracts, etc. of the plant (any part) used as the raw material.

[0038] Although the pulverized material is not limited to the present invention, examples thereof include the above-mentioned plants pulverized by a pulverizer known in the art, such as a jet mill.

[0039] The dried product is not particularly limited as long as it is obtained by drying the plant, and examples include products dried according to conventionally known drying methods such as sun drying, far-infrared irradiation, and dryers (hot air drying, cold air drying, vacuum freeze drying, etc.). Furthermore, the moisture content of the dried product is not a limitation of the present invention, but is preferably 10% by mass or less, more preferably 8% by mass or less. In the present invention, the dried product may be in any form, such as a dried product of the plant (any part) itself, or a pulverized product of the dried product (dried pulverized product). The dried pulverized product can be obtained by pulverizing the dried product according to the same method as for the pulverized product. Furthermore, in the present invention, the dried product may be obtained by subjecting the plant material to fermentation or enzymatic treatment followed by drying.

[0040] The method for producing the extract (extraction method) and the extraction conditions are not particularly limited, and may be any conventionally known method. For example, the plant may be cut, crushed, or dried as needed, and then squeezed or solvent extracted to obtain an extract. As the solvent extraction method, any method known in the art may be used, and conventionally known extraction methods such as water (including warm water and hot water) extraction, alcohol extraction, and supercritical extraction may be used.

[0041] When solvent extraction is performed, examples of the solvent include water; alcohols (whether anhydrous or hydrous) such as lower alcohols such as methanol, ethanol, and isopropanol, and polyhydric alcohols such as propylene glycol and 1,3-butylene glycol; ketones such as acetone; esters such as diethyl ether, dioxane, acetonitrile, and ethyl acetate; xylene, benzene, and chloroform. Preferred solvents are water, lower alcohols, and 1,3-butylene glycol, more preferably water, methanol, ethanol, and 1,3-butylene glycol, and even more preferably water, methanol, and hydrous ethanol. These solvents may be used alone or in combination of two or more.

[0042] In the present invention, the extract obtained through solvent extraction in this manner can be particularly referred to as a “solvent extract.” Furthermore, without limiting the present invention, as described above, for example, when water is used as the solvent, it can be called a water extract, when a lower alcohol is used, it can be called a lower alcohol extract, when ethanol is used, it can be called an ethanol extract, etc.

[0043] The obtained extract may be used as is, or may be dried and used in a solid form such as powder or granules. If necessary, the obtained extract may be purified, concentrated, or subjected to a separation process for a highly active fraction. While not limiting the present invention, examples of the purification process include filtration, adsorption using an ion exchange resin or an activated carbon column, and decolorization. Conventional methods such as an evaporator can be used for concentration. For separation of a highly active fraction, known separation processes such as gel filtration, adsorption, silica gel column chromatography, and HPLC (High Performance Liquid Chromatography) can be used.

[0044] Alternatively, the extract obtained as described above (and further its dried product, purified product, concentrated product, or highly active fraction) may be powdered by a conventional method, such as freeze-drying, or spray-drying with the addition of excipients such as dextrin, corn starch, or gum arabic, as needed, to provide the extract used in the present invention. Alternatively, the extract may be dissolved in water, ethanol, or the like as needed.

[0045] Preferred examples of the extract include extracts obtained by drying, crushing, and / or cutting the raw plant material (any part), extracting using a suitable solvent, and filtering, as well as extracts obtained by further drying the extract thus obtained.

[0046] The present invention is not limited to this, and extraction can be performed by a person skilled in the art depending on the part of the plant to be used. The extract can be obtained by immersing 100 g of the plant material, more preferably 100 g of dried, crushed, and / or cut pieces of the plant, in 1 to 50 L of extraction solvent, extracting at a desired temperature (e.g., 15 to 90°C) for a desired time (e.g., 10 minutes to 24 hours) with stirring as needed, and then filtering. Furthermore, as mentioned above, the obtained extract may be subjected to purification, concentration, various separation processes for highly active fractions, etc., as needed.

[0047] The processed product of a plant of the genus pomegranate may be a commercially available product, or may be a commercially available product that has been further subjected to appropriate treatment such as drying.

[0048] In the present invention, the processed product from a plant of the genus pomegranate is preferably an extract from a plant of the genus pomegranate (including a dried product thereof).

[0049] The processed pomegranate plant product may be used alone or in combination of two or more.

[0050] In each of the compositions for preventing or alleviating urinary stress and the sleep-improving compositions, the content of at least one selected from the group consisting of components (1) to (3) can be appropriately determined depending on the symptoms, application form, etc., and is not limited. While not limiting the present invention, the total amount of at least one selected from the group consisting of components (1) (solid concentration), (2) (solid concentration), and (3) (dry mass equivalent) in each composition may be greater than 0% by mass and less than 100% by mass, preferably 1 to 70% by mass, more preferably 3 to 40% by mass, and even more preferably 5 to 30% by mass. Here, the dried processed product of a pomegranate plant can be obtained by freeze-drying the processed product. The freeze-drying process is performed by vacuum concentration using a conventional evaporator and freeze-drying in a vacuum.

[0051] As described above, in each composition, the content of at least one selected from the group consisting of components (1) to (3) is not limited, but the following contents can be exemplified.

[0052] The content of the component (1) in each composition is not limited and may be determined appropriately depending on the symptoms, application form, etc., but the total amount (solid content concentration) in each composition is preferably 3 to 70 mass %, or 15 to 30 mass %, for example.

[0053] The content of the component (2) in each composition is not limited and may be determined appropriately depending on the symptoms, application form, etc., but the total amount (solid content concentration) in each composition is preferably 1 to 25 mass %, or 5 to 10 mass %, for example.

[0054] The content of the component (3) in each composition is not limited and may be determined appropriately depending on the symptoms, application form, etc., but the total amount (converted to dry mass) in each composition is preferably 3 to 70 mass%, or 15 to 30 mass%, for example.

[0055] In each composition, the dosage (intake) of at least one component selected from the group consisting of components (1) to (3) is not particularly limited as long as the effects of the present invention are achieved, and may be appropriately determined depending on the symptoms, application form, physique, age, and expected level of effect of the target (subject or target animal). While not limiting the present invention, an example of a daily dosage (intake) for humans is preferably 0.5 to 70 mg / kg body weight, more preferably 1 to 5 mg / kg body weight, in total of at least one component selected from the group consisting of component (1) (solid concentration), component (2) (solid concentration), and component (3) (dry mass equivalent). The composition of the present invention may be administered (ingested) once or multiple times per day, and may be administered (ingested) at any period and interval.

[0056] Each composition is preferably administered orally (ingested), regardless of whether it is orally or parenterally. The form of the composition of the present invention is also not limited and may be appropriately selected depending on the purpose. Examples of the form of the composition of the present invention include liquid forms such as solutions, emulsions, suspensions, syrups, extracts, spirits, and elixirs, powders, granules, fine granules, tablets (including coated tablets such as sugar-coated tablets), pills, capsules (including hard capsules and soft capsules), troches, chewable tablets, gels, creams, pastes, mousses, sheets, and liquid freeze-dried products, as well as various other forms such as aerosols, patches, poultices, and transdermal absorption preparations.

[0057] The use mode of each composition is not limited, and may be appropriately determined depending on the purpose. The use mode of the composition of the present invention includes food compositions (including beverages, health functional foods (including specified health foods, nutrient functional foods, functional food products, supplements, etc.), and foods for patients), pharmaceutical compositions, quasi-drug compositions, feed compositions, and additives for food compositions, pharmaceutical compositions, quasi-drug compositions, feed, etc.

[0058] Each composition may be produced according to conventional procedures known in the art for the various forms, modes of use, etc. described above, and may be produced by mixing, as necessary, with optional ingredients such as pharmaceutically acceptable ingredients, cosmetically acceptable ingredients, edible ingredients, etc. Examples of optional ingredients include solvents (alcohols (whether anhydrous or hydrous), such as water, lower alcohols such as methanol, ethanol, and isopropanol, and polyhydric alcohols such as propylene glycol and 1,3-butylene glycol), excipients, disintegrants, diluents, lubricants, flavorings, colorants, sweeteners, flavoring agents, suspending agents, humectants, emulsifiers, solubilizers, dispersants, buffers, binders, penetration enhancers, stabilizers, bulking agents, preservatives, thickeners, pH adjusters, surfactants, coating agents, absorption enhancers, adsorbents, fillers, antioxidants, anti-inflammatory agents, cooling agents, film-forming agents, gelling agents, amino acids, vitamins, enzymes, and various nutritional ingredients. These may be used alone or in combination of two or more.

[0059] In the present invention, the subject (subject, target animal) to which the composition is applied is not limited, and examples thereof include humans and non-human mammals. In addition, in the present invention, the subject (target animal) to which the composition is applied is preferably a woman (female).

[0060] According to this composition for preventing or alleviating urinary stress, at least one selected from the group consisting of components (1) to (3) can be used as an active ingredient to prevent or alleviate urinary stress. Therefore, the present invention can also be said to provide a method for preventing or alleviating urinary stress, characterized by using at least one selected from the group consisting of components (1) to (3). Furthermore, the present invention can also be said to provide a method for producing a composition for preventing or alleviating urinary stress. In these methods, the various descriptions of components (1) to (3), etc., are all the same as those given above.

[0061] Furthermore, this sleep-improving composition can improve sleep by using at least one active ingredient selected from the group consisting of components (1) to (3). Therefore, the present invention can also be said to provide a sleep-improving method characterized by using at least one active ingredient selected from the group consisting of components (1) to (3). Therefore, the present invention can also be said to provide a method for producing a sleep-improving composition. In these methods, the various descriptions of components (1) to (3), etc., are all the same as those given above.

[0062] Thus, the composition and method for preventing or alleviating urinary urge stress of the present invention can prevent or alleviate urinary urge stress. In particular, the composition has the effect of reducing the frequency of urination and allowing urine to be properly stored in the bladder and then properly voided. Therefore, the composition and method can prevent or alleviate urinary urge stress caused by impaired urinary tract function. Therefore, the present invention can prevent or alleviate stress caused by the urge to urinate, such as worry (anxiety), bother, tension, pain, fatigue, lethargy, irritability (irritability), and depression (depression).

[0063] For this reason, the composition for preventing or alleviating urinary stress is not a limitation of the present invention, but can be preferably applied to subjects (subject animals) who are concerned about urinary problems such as frequent urination or urgency, subjects (subject animals) who are concerned about urinary problems and feel anxious about going out, subjects (subject animals) who are concerned about urinary problems due to aging, and subjects (subject animals) who are concerned about urinary problems associated with aging (e.g., those in their 40s or older). For this reason, the composition of the present invention can also be preferably applied to subjects (subject animals) who are concerned about urinary problems, particularly the urge to urinate at night (nocturia), subjects (subject animals) who feel that they are not getting enough sleep because they are concerned about the urge to urinate while asleep, and subjects (subject animals) who feel a sense of sleep deprivation. The composition of the present invention can also be preferably applied to healthy individuals (healthy animals) who are stressed by the worry (anxiety) and annoyance caused by the urge to urinate, but who do not require medical treatment at a hospital, etc. Furthermore, the gender of these subjects (subject animals) does not matter, and they may be either male or female, with females being preferred. The present invention is useful for preventing or alleviating psychological stress felt in daily life due to urinary problems.

[0064] Furthermore, the sleep-improving composition and method of the present invention can improve sleep. These compositions and methods can particularly improve sleep quality, and can particularly improve sleep quality impaired by urinary stress. Furthermore, these compositions and methods have the effect of reducing the frequency of urination, allowing urine to be properly stored in the bladder and then properly urinated. Therefore, these compositions and methods can improve sleep quality impaired by impaired urinary tract function and sleep quality impaired by urinary stress due to impaired urinary tract function. Therefore, these compositions and methods can be said to be useful in terms of achieving sound (deep) sleep.

[0065] For this reason, the composition and method can be preferably applied to subjects (subject animals) who feel sleep deprived, subjects (subject animals) who feel they are not able to sleep soundly (deeply), subjects (subject animals) who are not satisfied with their current sleep, subjects (subject animals) who feel that they have trouble waking up, etc. Furthermore, the gender of these subjects (subject animals) does not matter and they may be either males (males) or females (females), with females being preferred. [Example]

[0066] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0067] Test Example 1 Test Procedure The subjects were women aged 20 to 70 years who experienced frequent urination. They were asked to take the test substance twice daily (once in the morning and once in the evening) with approximately one glass of water for eight consecutive weeks. The subjects were also asked to report their subjective symptoms before and during the test substance intake. The survey was conducted using the Quality of Life (QOL) questionnaire of the Japanese version of the Overactive Bladder Questionnaire (OAB-q) (from the Japanese Journal of Urinary Function (2006), Vol. 17, No. 2), which has been internationally recognized for its reliability and validity. The subjects themselves completed the questionnaire. The effect of the test substance on urinary stress was evaluated based on the assessment criteria of the questionnaire. The survey was scored in four areas: "coping," "worry," "sleep," and "social activity," and a "total score" was also evaluated.

[0068] In this example, capsules containing commercially available pomegranate extract (product name: Pomegranate Ellagic Acid (manufactured by Sabinsa Japan Corporation), an ethanol extract of Punica granatum peel containing 80% ellagic acid), starch, calcium stearate, fine silicon dioxide, gelatin, and coloring were prepared according to standard procedures and used as test substances. The subjects were divided into three groups: Group H, which received a high dose of pomegranate extract (250 mg / person / day), Group L, which received a low dose (125 mg / person / day), and Group P, which received capsules prepared in the same manner but without the pomegranate extract. Each subject received two capsules per day, with the contents of the capsules administered at 190 mg / capsule for the low-dose group, 170 mg / capsule for the high-dose group, and 190 mg / capsule for the placebo group.

[0069] result The results are shown in Table 1. Table 1 is an excerpt of the evaluation results of the effect on urinary stress. In this test example, in Groups H and L that ingested the test substance, a tendency for improvement was observed in "coping," "worry," and "sleep" compared to before ingestion, and a tendency for improvement was also observed in the "total score" of the above evaluation. In particular, significant improvements were observed in the "total score" of Groups H and L, and in "worry" and "sleep" of Group L. Furthermore, compared to Group P, significant improvements were observed in Group L, particularly in "coping," "sleep," and "total score." This demonstrates that pomegranate extract can alleviate urinary stress. It also demonstrates that pomegranate extract can improve sleep.

[0070] [Table 1]

[0071] Although not shown in the results, the subjects' urination frequency and urination volume were also measured from before intake of the test substance until 8 weeks after intake. In Group H and Group L, the total urination frequency improved, especially the daytime urination frequency. In addition, the subjects' nighttime urination frequency was less than once per night before intake, but after intake, there was also a tendency for the nighttime urination frequency to improve. Furthermore, the subjects' daily urine volume did not decrease significantly even after intake, that is, the urination frequency could be reduced despite the urination volume not decreasing.

[0072] These findings suggest that pomegranate extract can alleviate urinary stress.

[0073] Test Example 2 Test Procedure A placebo-controlled, randomized, double-blind, parallel-group comparative study was conducted on 42 women aged 20 to 70 who suffered from frequent urination. They took three tablets of the test substance daily with a glass of water for eight consecutive weeks. The subjects experienced psychological stress due to the urge to urinate, such as feeling anxious when there was no toilet nearby in their daily lives. Subjects were surveyed about their subjective symptoms before and during the administration of the test substance, and the effect of the test substance on urinary stress was evaluated based on the assessment criteria of the questionnaire.

[0074] Specifically, tablets (301.5 mg per tablet) containing commercially available pomegranate extract (trade name Pomanox P30 (manufactured by NC Corporation, an extract obtained by squeezing and concentrating the whole fruit, including the skin, of Punica granatum; 250 mg of extract contains 69 mg of punicalagin)), starch, calcium stearate, fine silicon dioxide, gelatin, maltose, crystalline cellulose, and shellac were manufactured according to a standard method and used as the test substance (PE tablet). In addition, a placebo containing starch, powdered reduced maltose syrup, crystalline cellulose, fine silicon dioxide, calcium stearate, shellac, and coloring was used. Tablets containing punicalagin (301.5 mg per tablet) were manufactured according to standard methods and used as P tablets. The subjects were divided into two groups (21 subjects per group), with the PE group taking three PE tablets per day (pomegranate extract intake of 250 mg per person per day), and the P group taking three P tablets per day. These tablets were prepared so that the difference in appearance and flavor was indistinguishable, and the PE tablets and P tablets are essentially the same, except that only the PE tablets contain pomegranate extract containing punicalagin.

[0075] The evaluation used sleep-related items from the Overactive Bladder Questionnaire (OAB-q), six items from the SF-8 (trademark), a comprehensive health-related quality of life questionnaire, and a urination diary to evaluate urination-related and urinary urge functions.

[0076] result The results are shown in Tables 2 to 4.

[0077] Table 2 shows the results regarding sleep.

[0078] [Table 2]

[0079] As shown in Table 2, only in the PE group was there a significant improvement (P<0.01) after ingestion compared to before ingestion, and the amount of change was higher than in the P group. This confirmed that sleep disturbance caused by the urge to urinate was significantly reduced in the PE group.

[0080] Table 3 shows the results of the SF-8 (6 items). Each item is based on the explanation of the health-related QOL questionnaire SF-8, and the mental summary score is also based on this (https: / / www.sf-36.jp / qol / sf8.html (Source: Shunichi Fukuhara, Yoshimi Suzukamo, SF-8 TM Japanese manual, iHope International Co., Ltd., Kyoto, 2004, 2019, etc.

[0081] [Table 3]

[0082] As shown in Table 3, after 8 weeks of intake, improvements were observed in all items in the PE group, and the rate of change exceeded that of the P group. In particular, social life function and mental summary scores improved significantly in the PE group compared to the P group (P<0.05 for each). This confirmed that psychological urinary stress was significantly improved in the PE group.

[0083] Table 4 shows the results of the urination diary (number of nighttime urinations and number of times of urgency due to the need to urinate).

[0084] [Table 4]

[0085] As shown in Table 4, the number of nighttime urinations was significantly reduced from before to after intake only in the PE group (P<0.01). This confirmed that the number of nighttime urinations was significantly reduced (improved) in the PE group compared to the P group. Furthermore, the number of times the urge to urinate was felt to be urgent was also significantly improved from before to after intake only in the PE group at 8 weeks of intake (P<0.05). This confirmed that the urge to urinate was also significantly improved in the PE group compared to the P group.

[0086] This also shows that pomegranate extract can alleviate urinary stress. It was also found that pomegranate extract can improve sleep. As described above, the present inventors have discovered that pomegranate extract can alleviate urinary stress and improve sleep, and as shown in the following Test Example 3, they have found that both pomegranate extract containing punicalagin and punicalagin can similarly improve urinary function. Based on these findings, it can be said that pomegranate extract containing punicalagin and punicalagin can achieve similar effects, and that the urinary stress alleviating effect and sleep improving effect of pomegranate extract containing punicalagin found in Test Example 2 can be similarly achieved even when punicalagin is used instead of the pomegranate extract, or that the alleviating effect and the improving effect are mainly due to punicalagin.

[0087] Test Example 3 Evaluation Procedure Urinary function was evaluated as follows. Rats (female SD rats (Sprague-Dawley rats), 8-9 weeks old at the start of the experiment (body weight 190-220 g / rat)) underwent laparotomy under isoflurane anesthesia, and both common iliac veins and both uterine veins were ligated to create a pelvic congestion model. After suturing the laparotomy, the pelvic congestion rat models were housed in cages for 16 days. During this time, the rats were allowed to freely consume standard commercially available feed and water. Next, tadalafil, pomegranate extract (pomegranate extract containing punicalagin), or punicalagin was mixed with the feed to prepare a powdered mixed feed. After 16 days of housing, the rat models were divided into three groups (n=6) and were allowed to freely consume the mixed sample for 14 consecutive days. During this time, water was also allowed to be consumed ad libitum.

[0088] The dosages are as shown in Table 5. For example, in Table 5, "5 mg / 2 mL / kg" in the tadalafil group means that 2 mL of the mixed solution was administered per kg of body weight per day to the rat model, and that 2 mL of the mixed solution contained 5 mg of tadalafil. Furthermore, in the mixed feed, the amount of pomegranate extract is calculated as the dry mass, and the amount of punicalagin is calculated as the solid concentration.

[0089] The tadalafil used was the trade name Tadalafil (manufactured by Combi-Blocks), the pomegranate extract was the same as in Test Example 2, and the punicalagin used was purified punicalagin from the pomegranate extract (containing 96.7% by mass of punicalagin). In the table, the dosage of tadalafil indicates the dosage of the commercially available product, and the dosage of punicalagin indicates the dosage of the purified product.

[0090] On the final day of the study (day 14 of mixed feed intake), rats were restrained under light urethane anesthesia. One hour after the effects of anesthesia appeared, a catheter was inserted into the urethra of each rat. Normal saline was continuously infused into the bladder at a rate of 3 mL / h, and intravesical pressure was continuously measured. Measurements were performed using a Delfusion Syringe Pump TE-331 (Terumo Corporation), a disposable pressure transducer DX-100 (Nihon Kohden Corporation), a linear coder WR3320A-8H (Graphtec Corporation), an analog input / output USB I / O unit 8ch AIO-160802AY-USB (Contec Co., Ltd.) as an amplifier data acquisition device, and LaBDAQ5-CT ver. 1.06 (Matsuyama Advance Co., Ltd.) as data acquisition software.

[0091] The group in which the test was conducted in the same manner as above except that the pelvic congestion was not performed and water was given instead of the mixed solution was designated as the reference group (n=6).Furthermore, the group in which the test was conducted in the same manner as above except that the pelvic congestion was performed and water was given instead of the mixed solution was designated as the comparison group (n=6).

[0092] [Table 5]

[0093] result The results are shown in Tables 6 to 8.

[0094] [Table 6]

[0095] Table 6 shows the results of bladder contraction intervals (mean values ​​in minutes). As shown in Table 6, the bladder contraction interval in the reference group was 18.9 minutes, while the bladder contraction interval in the comparison group was 11.0 minutes, indicating that the comparison group had a shorter bladder contraction interval. This indicates that the comparison group had a higher urination frequency than the reference group. In contrast, the pomegranate extract group and the punicalagin group both had bladder contraction intervals similar to those of the reference group, and these bladder contraction intervals were similar to those of the positive control group, tadalafil. This indicates that processed pomegranate products, such as punicalagin and pomegranate extract containing punicalagin, are useful for prolonging the bladder contraction interval.

[0096] [Table 7]

[0097] [Table 8]

[0098] Table 7 shows the results of urination volume. Table 8 shows the results of bladder capacity. As shown in Table 7, the urination volume of the reference group was 0.9 mL, while the urination volume of the comparison group was 0.6 mL. As shown in Table 8, the bladder capacity of the reference group was 1.0 mL, while the bladder capacity of the comparison group was 0.6 mL. This shows that both the urination volume and bladder capacity of the comparison group were reduced compared to the reference group.

[0099] In the reference group, the urination volume was 0.9 mL and the bladder capacity was 1.0 mL, indicating that most of the urine accumulated in the bladder was voided. Furthermore, these findings indicate that the reference group had a larger bladder capacity than the comparison group, and therefore was able to store a larger amount of urine in its bladder than the comparison group, and that despite being able to store such a large amount of urine, it was still able to urinate the large amount of urine that had accumulated.

[0100] Both the pomegranate extract group and the punicalagin group showed similar urine output and bladder capacity to the reference group, which was also similar to the positive control group (tadalafil). These results suggest that punicalagin and pomegranate extract containing punicalagin enable subjects to store larger volumes of urine in the bladder than the control group, and that despite storing larger volumes of urine, the stored urine can still be voided adequately. The dosage for humans can generally be calculated using a human equivalent dose (HED) of 6.2 based on rat body surface area (see "Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers").

[0101] Test Example 4 Test Procedure A stratified analysis was performed on the results of Test Example 2. Specifically, based on a questionnaire survey conducted on the subjects of Test Example 2 eight weeks after the start of the study, subjects who perceived that going to the toilet had become easier due to changes in their living environment (2 subjects in the PE group, 2 subjects in the P group) were excluded. Also, subjects whose urination diaries in Test Example 2 showed a nocturnal urination frequency of 2 or more times before intake or an average of 2 or more times during the intake period (1 subject in the PE group, 1 subject in the P group) were excluded. After excluding these 6 subjects, the results of the remaining subjects are shown in Table 9 below and Figure 1. Table 9 relates to the evaluation according to the SF-8, and Figure 1 relates to the evaluation based on the urination diary.

[0102] result [Table 9]

[0103] As shown in Table 9, in the PE group, significant improvements were observed in physical function (P<0.05), daily role function (physical) (PE group: P<0.01), and daily role function (mental) (P<0.05) at 8 weeks of intake compared to before intake. Furthermore, particularly in social function, mental summary score, and daily role function (mental), the PE group showed significant improvements compared to the P group. Furthermore, as shown in Figure 1, the PE group also showed significant improvements in the number of urinary urgency episodes compared to the P group. This also demonstrates that pomegranate extract can alleviate urinary stress.

[0104] In addition, in Test Example 4, subjects who met the diagnostic criteria for urinary urgency in the Overactive Bladder Symptom Score (OABSS) according to the Overactive Bladder Guidelines, with a score of 2 or more and a total score of 3 or more, were excluded from the test. In particular, as mentioned above, Test Example 4 also excluded subjects whose nocturnal urination frequency was 2 or more times before intake or an average of 2 or more times during intake in the urination diary. Thus, the subjects in Test Example 4 were healthy individuals who felt stress due to the hassle of going to the toilet due to the urge to urinate, but whose symptoms were not severe enough to require medical treatment at a hospital or the like. As can be seen from these test examples, it was confirmed that processed products from pomegranate plants, especially punicalagin and processed products from pomegranate plants containing punicalagin, can significantly alleviate stress, such as worry (anxiety) and hassle, caused by the urge to urinate, even in healthy individuals.

Claims

[Claim 1] A composition for preventing or alleviating urinary stress, comprising at least one active ingredient selected from the group consisting of the following ingredients (1) to (3): (1) at least one selected from the group consisting of ellagic acid, its analogs, salts thereof, and hydrates thereof; (2) at least one selected from the group consisting of punicalagin, its salts, and hydrates thereof; (3) Processed products of pomegranate plants.

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