Dry mouth remedy

Abstract

To provide an agent for improving dryness in the oral cavity that improves dryness in the oral cavity.SOLUTION: An agent for improving dryness in the oral cavity includes a quercetin glycoside represented by formula (1). [In the formula (1), R1 and R2 each independently represent a structure derived from sugars].SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for relieving dry mouth. [Background technology]

[0002] Dry mouth is caused by stress, an irregular lifestyle, and other factors, and prolonged dryness is known to lead to bad breath, increased plaque, tongue pain, changes in taste, and other problems, reducing quality of life. Furthermore, the feeling of dry mouth increases with age, and an epidemiological study conducted in 2016 targeting people aged 65 and older reported that the prevalence of xerostomia was approximately one in three people, and the prevalence of reduced saliva secretion was approximately one in ten people (Non-Patent Document 1). Therefore, in Japan, which is an ultra-aging society, the proportion of people experiencing dry mouth is expected to increase year by year.

[0003] Aquaporins are membrane proteins that specifically allow water molecules to pass through, and are present in most internal organs. Thirteen aquaporin isoforms, aquaporin 0 to aquaporin 12, have been identified to date. Of these, aquaporin 1 and aquaporin 3 to aquaporin 8 have been identified in the salivary glands and are thought to contribute to saliva secretion (Non-Patent Document 2). Research on aquaporin 3 and aquaporin 5 in dry mouth and Sjögren's syndrome has revealed that, although the function of aquaporin 3 in saliva secretion has not yet been clarified, it has been confirmed that aquaporin 3 mRNA expression levels are low in dry mouth patients, suggesting that aquaporin 3 may be involved in diseases such as saliva secretion, dry mouth, and dry oral cavity in Sjögren's syndrome (Non-Patent Document 3).

[0004] Patent Document 1 discloses a composition containing resveratrol as an active ingredient as a relief agent for dry mouth. In this document, capsules containing resveratrol were produced and used to evaluate the effect on saliva secretion in nine patients with Sjögren's syndrome, and it was reported that the intake of resveratrol tended to increase saliva secretion.

[0005] Patent Document 2 discloses a xerostomia relieving agent containing pineapple ceramide as an active ingredient for promoting aquaporin production. The document reports that 12 subjects evaluated dry mouth symptoms using the VAS method after using a chewable tablet containing pineapple ceramide with a specific structure obtained from pineapple pulp, a residue of pineapple. The document reports that the results showed improvement in the "stickiness in the mouth upon waking up" and "lip moisturization." Furthermore, in an example using normal human neonatal foreskin epidermal keratinocytes, the document reports that the expression levels of AQP3 and AQP5 mRNA were promoted.

[0006] α-Glucosylrutin, a quercetin glycoside, is a compound in which one or more (approximately 2-20) glucose residues are bound to the glucose residue in the rutinose unit of rutin via an α1→4 bond. α-Glucosylrutin is 12,000 times more soluble than the original rutin and has been used in beverages, foods, functional foods, cosmetics, and other fields. However, the effect of α-glucosylrutin on dry mouth was unknown, and the effects of continued use had not been investigated. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2017-57144 [Patent Document 2] Japanese Patent Application Laid-Open No. 2014-169238 [Non-patent literature]

[0008] [Non-Patent Document 1] Ohara Y, Hirano H, Yoshida H, et al. Prevalence and factors associated with xerostomia and hyposalivation among community-dwelling older people in Japan. Gerodontology.2016;33(1):20-7. [Non-patent document 2] Delporte C, Steinfeld S. Distribution and roles of aquaporins in salivary glands. Biochim Biophys Acta-Biomembr. 2006;1758(8):1061-70. [Non-patent document 3] Ichiyama T, Nakatani E, Tatsumi K, et al. Expression of aquaporin 3 and 5 as a potential marker for distinguishing dry mouth from Sjoegren's syndrome. J Oral Sci.2018;60(2):212-20. Summary of the Invention [Problem to be solved by the invention]

[0009] The present inventors believe that improving the dry state of the oral cavity is strategically important for preventing the onset and progression of diseases caused by oral dryness and for treating them, and therefore an object of the present invention is to provide an agent for improving oral dryness that improves oral dryness. [Means for solving the problem]

[0010] The present inventors have conducted extensive research to solve the above problems, and as a result have found that the above problems can be solved by providing the following configuration, which has led to the completion of the present invention. The present invention relates to, for example, the following [1] to [6].

[0011] [1] A dry mouth relieving agent comprising a quercetin glycoside represented by formula (1). [ka] [In formula (1), R1 and R2 each independently represent a structure derived from a saccharide.] [2] The agent for relieving dry mouth according to [1], wherein R1 in the formula (1) is a structure derived from rhamnose. [3] The agent for relieving dry mouth according to [1] or [2], wherein the quercetin glycoside represented by the formula (1) is α-glucosylrutin. [4] The agent for relieving dry mouth according to any one of [1] to [3], wherein the quercetin glycoside represented by the formula (1) is α-monoglucosylrutin. [5] The agent for relieving dry mouth according to any one of [1] to [4], wherein the quercetin glycoside represented by the formula (1) promotes the production of aquaporin. [6] A food or drink, a medicine, or a quasi-drug containing the agent for improving dry mouth according to any one of [1] to [5]. [Effects of the Invention]

[0012] According to the present invention, an agent for relieving dry mouth that relieves dry mouth can be provided. [Brief explanation of the drawings]

[0013] [Figure 1] Figure 1 is a graph showing the actual values ​​measured by the VAS method for dry mouth sensation when healthy humans ingested a dry mouth remedy containing αG-rutin. The horizontal axis represents the intake time (weeks), and the vertical axis represents the position (mm) on the line on the VAS recording sheet showing the degree of sensation. [Figure 2] Figure 2 is a graph showing the change in dry mouth sensation measured by the VAS method when healthy subjects ingested a dry mouth remedy containing αG-rutin. The horizontal axis represents the intake time (weeks), and the vertical axis represents the change in linear position on the VAS recording sheet. [Figure 3]FIG. 3 is a graph showing the relative intensity of aquaporin 3 mRNA expression in Ca9-22 cells cultured in a culture medium containing αG-rutin. DETAILED DESCRIPTION OF THE INVENTION

[0014] Next, the oral cavity dryness relieving agent of the present invention will be specifically described. <Dry mouth remedy> An agent for alleviating dry mouth, which is one embodiment of the present invention, contains a quercetin glycoside represented by formula (1).

[0015] [ka] [In formula (1), R1 and R2 each independently represent a structure derived from a saccharide.]

[0016] [Quercetin glycoside] The quercetin glycoside represented by formula (1) is a compound in which glucose is β-bonded to the hydroxyl group at the 3-position of quercetin, a type of polyphenol, and saccharides are bound to the hydroxyl groups at the 4- and 5-positions of the glucose. As the quercetin glycoside represented by formula (1), only one type of quercetin glycoside may be used, or a mixture of multiple types of quercetin glycosides may be used. Furthermore, the agent for relieving dry mouth may contain components (other components) other than the quercetin glycoside, such as isoquercitrin (isoquercetin), quercetin, rutin, etc., within the scope of not impairing the effects of the present invention.

[0017] R1 and R2 in formula (1) are each independently a structure derived from a sugar. Examples of sugar-derived structures include structures in which one of the multiple OH groups contained in a sugar has been eliminated. Examples of sugars that can be used include monosaccharides such as hexoses (e.g., glucose, rhamnose, fructose, mannose, galactose), pentoses (e.g., xylose, arabinose), polysaccharides (e.g., sucrose, lactose, primeverose, gentiobiose, rutinose, strophantobiose, cellobiose, amylose, amylopectin, cellulose), sugar alcohols (e.g., erythritol, xylitol), and derivatives thereof. From the viewpoints of availability of raw materials, reaction efficiency, stability of quercetin glycoside, and the effect of improving dry mouth, R1 and R2 are preferably monosaccharides or polysaccharides. R1 is preferably a rhamnose-derived structure. Furthermore, R2 is preferably a glucose-derived structure or an amylose-derived structure.

[0018] From the viewpoints of availability of raw materials, reaction efficiency, stability of the quercetin glycoside, and the effect of improving dry mouth, when R1 is a structure derived from rhamnose, the quercetin glycoside is preferably represented by formula (1-1). [ka] [In formula (1-1), R2 is a structure derived from a saccharide.]

[0019] From the viewpoints of availability of raw materials, reaction efficiency, stability of the quercetin glycoside, and the effect of improving dry mouth, when R2 is a glucose-derived structure or an amylose-derived structure, the quercetin glycoside is preferably represented by formula (1-2). Amylose is a polysaccharide in which glucose is bonded via an α1→4 bond. [ka] [In formula (1-2), R1 is a structure derived from a saccharide, and n is an integer of 1 or more.]

[0020] In terms of the availability of raw materials, reaction efficiency, stability of quercetin glycoside, and the effect of improving dry mouth, in formula (1-2), n=1 or n=2 to 20 is preferred, n=1 or n=2 to 10 is more preferred, and n=1 is even more preferred.

[0021] From the viewpoints of availability of raw materials, reaction efficiency, stability of quercetin glycoside, and effect of improving dry mouth, the quercetin glycoside represented by formula (1-3) is particularly preferred. [ka]

[0022] From the viewpoints of availability of raw materials, reaction efficiency, stability of quercetin glycoside, and effect of improving dry mouth, in formula (1-3), n=1 or n=2 to 20 is preferred, n=1 or n=2 to 10 is more preferred, and n=1 is even more preferred.

[0023] Quercetin glycosides of formula (1-3) are also collectively called α-glucosylrutin. Among α-glucosylrutins, quercetin glycosides in which n=1 in formula (1-3) are also called α-monoglucosylrutin.

[0024] The quercetin glycoside represented by formula (1) preferably contains α-monoglucosylrutin as the main component, and the quercetin glycoside represented by formula (1) more preferably contains 50 to 100% by mass of α-monoglucosylrutin, and even more preferably contains 65 to 85% by mass.

[0025] The hydroxyl group contained in the sugar may be modified with another group.

[0026] Among the quercetin glycosides represented by formula (1), those that promote the production of aquaporins (hereinafter also referred to as "AQPs") are preferred in terms of the effect of improving dry mouth. The AQP is not particularly limited, but is preferably at least one selected from AQP1 and AQP3 to AQP8, and more preferably AQP3 or AQP5.

[0027] The effectiveness of promoting aquaporin production can be determined by the expression level of aquaporin or the expression level of aquaporin genes in cells contacted with the quercetin glycoside, for example, by the expression level of aquaporin or the expression level of aquaporin genes in cells cultured in a medium containing the quercetin glycoside.

[0028] The expression level of aquaporin or the expression level of aquaporin gene can be measured by known methods. The expression level of aquaporin can be measured, for example, by spectrophotometry, ELISA, and electrophoresis. The expression level of aquaporin gene can be measured, for example, by known analytical methods such as PCR, microarray, and RNA sequencing.

[0029] If the expression level of aquaporins or the expression level of aquaporin genes in cells exposed to quercetin glycoside shows an increasing trend, for example, an increase of 10% or more, preferably 15% or more, and more preferably 20% or more, compared to the expression level in cells not exposed to quercetin glycoside, it can be determined that aquaporin production is promoted.

[0030] [Method for producing quercetin glycoside] The quercetin glycoside may be derived from a natural product or may be a synthetic product. When natural products are used as raw materials, extracts obtained from the raw materials, such as animals and plants, by known extraction methods may be used as they are, or may be further separated and purified.

[0031] When quercetin glycoside is a synthetic product, the starting compound is not limited and can be produced using known methods, even if it contains unreacted starting materials, by-products, and impurities. From the viewpoints of availability of starting materials, reaction efficiency, stability of quercetin glycoside, and the effect of improving dry mouth, quercetin glycoside is preferably produced by binding a sugar to quercetin, isoquercitrin, or rutin, and more preferably by binding a sugar to rutin. Furthermore, it is more preferable to specifically cleave the sugar bond after binding to the sugar to obtain the desired molecular species of quercetin glycoside. For example, enzymatic methods, organic chemical methods, and bioconversion methods can be used to bind or cleave the sugar. However, it is preferable to subject the starting material quercetin, isoquercitrin, or rutin to the action of one or more enzymes, and the enzymatic treatment described in Japanese Patent Publication No. 2816030 is more preferable.

[0032] The enzymatic treatment described in the above-mentioned Patent Publication No. 2816030 can be summarized as follows: (1) A glycosyltransferase is applied to rutin in the presence of a sugar donor to add glucose to the glucose units of rutin via an α-1,4 bond, thereby producing α-glucosylrutin, and a composition containing unreacted rutin and α-glucosylrutin is obtained. (2) A glucoamylase or the like is applied to the α-glucosylrutin produced by (1) above to cleave all but one glucose molecule from the glucose chain bound to the glucose units of rutin, thereby producing α-monoglucosylrutin, and a composition containing unreacted rutin and α-monoglucosylrutin is obtained. (3) An α-L-rhamnosidase is applied to unreacted rutin to cleave the rhamnose contained in the rutinose units of rutin, thereby producing isoquercitrin, and a composition containing isoquercitrin and α-monoglucosylrutin is obtained.

[0033] The combination, order, etc. of the enzyme treatment can be adjusted as appropriate depending on the desired form of the agent for improving dry mouth. Alternatively, multiple enzymes may be added simultaneously to allow multiple enzymatic reactions to proceed in parallel in one step. After or during such an enzyme treatment step, other treatments may be performed as needed. Examples of such treatments include filtration to remove precipitates, concentration to an extent that precipitates do not form, desalting using ion exchange resins, purification to remove other impurities, and drying or freeze-drying to prepare solids from these liquids.

[0034] The composition obtained by the above-mentioned production method is generally manufactured and sold as "enzyme-treated rutin," and such products can be used in the present invention. For example, "αG Rutin PS," a product manufactured by Toyo Sugar Refining Co., Ltd., is a composition containing 75% by mass of α-monoglucosylrutin and 15% by mass of isoquercitrin. Furthermore, "αG Rutin P," a product also manufactured by Toyo Sugar Refining Co., Ltd., is a composition containing 70% by mass of α-glucosylrutin and 15% by mass of rutin.

[0035] 〔composition〕 The agent for alleviating dry mouth of the present invention may contain the above-mentioned quercetin glycoside, and may consist solely of quercetin glycoside. Alternatively, it may further contain known optional ingredients such as excipients, lubricants, stabilizers, binders, sweeteners, disintegrants, humectants, colorants, coating agents, emulsifiers, etc., as long as they do not interfere with the effect of quercetin glycoside in alleviating dry mouth.

[0036] The content of the quercetin glycoside contained in the agent for relieving dry mouth is not particularly limited. For example, the lower limit of the content of the quercetin glycoside in the agent for relieving dry mouth of the present invention may be, for example, 30% by mass, 40% by mass, 45% by mass, 50% by mass, 60% by mass, or 70% by mass. Furthermore, the upper limit of the content of the quercetin glycoside in the agent for relieving dry mouth of the present invention may be, for example, 100% by mass, 99% by mass, 98% by mass, 95% by mass, 90% by mass, or 85% by mass. The content of the quercetin glycoside in the agent for relieving dry mouth of the present invention may be set to any range that combines the above lower and upper limits, such as 30 to 100% by mass, 60 to 100% by mass, or 60 to 90% by mass.

[0037] Examples of agents for relieving dry mouth containing quercetin glycoside include the following commercially available products. "αG Rutin PS," a product manufactured by Toyo Sugar Refining Co., Ltd., is a composition containing 75% by mass of α-monoglucosylrutin and 15% by mass of isoquercitrin. Also, "αG Rutin P," a product manufactured by Toyo Sugar Refining Co., Ltd., is a composition containing 70% by mass of α-glucosylrutin and 15% by mass of rutin. These products can be used as agents for relieving dry mouth. Alternatively, purified versions of these commercially available products can be used as agents for relieving dry mouth.

[0038] [Application] The agent for relieving dry mouth of the present invention has the effect of relieving dryness in the oral cavity. Therefore, the agent for relieving dry mouth of the present invention is useful for improving symptoms caused by dry mouth, such as stickiness in the oral cavity, dental plaque, tongue coating, bad breath, burning sensation, pain, tongue discomfort, taste abnormality, atrophy of the tongue papillae, inflammation of the oral mucosa, erosion, ulcer formation, cracks in the tongue or corners of the mouth, etc., and is useful for treating diseases including these symptoms, such as xerostomia (dry mouth).

[0039] The dosage of the agent for alleviating dry mouth may be appropriately selected depending on the severity of symptoms caused by dry mouth. For example, from the viewpoint of the effect of alleviating dry mouth, the dosage of the quercetin glycoside per day is usually 65 to 520 mg, preferably 130 to 390 mg, and more preferably 195 to 255 mg. Furthermore, the daily dosage can be divided into 1 to 3 doses per day, preferably 2 or 3 doses per day.

[0040] The administration period of the agent for alleviating dry mouth may be appropriately selected depending on the severity of symptoms caused by dry mouth. For example, it is usually 28 to 168 days, preferably 42 to 112 days, and more preferably 56 to 84 days. The administration method is not particularly limited, but oral administration is preferred.

[0041] 〔evaluation〕 The oral dryness alleviating effect of the agent for alleviating dry mouth of the present invention can be evaluated by, for example, subjective symptoms of oral dryness using the VAS method, as described later in the Examples. The alleviating effect varies depending on the amount of quercetin glycoside and the administration period, but the numerical value indicating oral dryness after ingestion of the agent for alleviating dry mouth preferably decreases by 15% or more, more preferably by 20% or more, and even more preferably by 25% or more.

[0042] <Foods, beverages, quasi-drugs, or pharmaceuticals containing oral dryness relief agents> One embodiment of the present invention is a food, drink, quasi-drug, or pharmaceutical product containing the above-mentioned agent for relieving dry mouth. The agent for relieving dry mouth may be administered to a living body as is, or may be administered as a food, drink, quasi-drug, or pharmaceutical product (hereinafter referred to as "food, drink, etc.") containing an effective amount of the agent for relieving dry mouth and a pharmaceutically acceptable carrier. The method of administration is not particularly limited, but oral administration is preferred.

[0043] Examples of foods and beverages include beverages such as fruit drinks, oolong tea, green tea, black tea, cocoa, vegetable juice, green juice, soy milk, dairy drinks, lactic acid drinks, near water, sports drinks, and nutritional drinks, Western or Japanese sweets such as jelly, pudding, candy, gum, chewing gum, candy tablets (ramune), and yogurt, seasonings, processed fish products, processed livestock products, and health-promoting foods such as foods for specified health uses, foods with nutrient functions, and foods with functional claims, as well as other so-called health foods, supplements, feed, and pet food. Of these, candy, gum, chewing gum, and candy tablets (ramune) are preferred in terms of the length of retention time of the oral cavity improvement promoter in the oral cavity.

[0044] Examples of quasi-drugs or pharmaceuticals include solid preparations and liquid preparations. Specific examples of solid preparations include powders, granules, tablets, capsules, and troches. Liquid preparations include oral liquids, topical liquids, suspensions, emulsions, syrups, drinks, injections, and infusions. These and other dosage forms may be selected appropriately depending on the purpose. Tablets or capsules are preferred because they are easy to administer and easily exert an effect of improving oral dryness.

[0045] In solid preparations, auxiliary agents such as excipients, binders, disintegrants, lubricants, flavoring agents, stabilizers, etc. may be used. Suitable examples of excipients in solid preparations include lactose, D-mannitol, starch, etc. Suitable examples of binders include crystalline cellulose, sucrose, D-mannitol, sugar alcohols, dextrin, hydroxypropyl cellulose, etc. Suitable examples of disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, etc. Suitable examples of lubricants include calcium stearate, etc.

[0046] In the liquid formulation, a solvent that can dissolve the active ingredient, quercetin glycoside, and that is highly biologically safe is selected. Suitable examples of solvents include purified water, ethanol, and propylene glycol. The liquid formulation may also contain auxiliary ingredients such as solubilizers, suspending agents, isotonicity agents, buffers, and antioxidants.

[0047] The food, drink, etc. containing the agent for alleviating dry mouth can be produced by adding the agent for alleviating dry mouth according to a commonly used method. The agent for alleviating dry mouth may be added at the beginning, middle or end of the production process of the food, drink, etc., and the method of addition may be selected from an appropriate method such as mixing, kneading, dissolving, immersing, scattering, spraying, coating, etc. depending on the type of the food, drink, etc.

[0048] The quercetin glycoside contained in the agent for improving dry mouth has good water solubility, and therefore can be uniformly dissolved or dispersed even when added to water or foods and beverages with a high water content.

[0049] The amount of the agent for improving dry mouth to be added to foods, beverages, etc. may be selected appropriately depending on the severity of symptoms caused by dry mouth, etc., but from the standpoint of ease of administration and stability in foods, beverages, etc., the amount of the quercetin glycoside is preferably 0.045 to 25.00 mass%, more preferably 0.225 to 14.15 mass%.

[0050] <Aquaporin production promoter> One embodiment of the present invention is an aquaporin production promoter containing the quercetin glycoside represented by formula (1). The meaning and preferred embodiments of quercetin glycoside are the same as those described in the section "Dry Mouth Relief Agent." The aquaporin production promoter may contain the quercetin glycoside, may consist solely of quercetin glycoside, or may further contain known optional ingredients such as excipients, lubricants, stabilizers, binders, sweeteners, disintegrants, humectants, colorants, coating agents, and emulsifiers, as long as they do not interfere with the aquaporin production-promoting effect of quercetin glycoside.

[0051] The content of the quercetin glycoside contained in the aquaporin production promoter is not particularly limited. For example, the lower limit of the quercetin glycoside content in the agent for relieving dry mouth of the present invention may be, for example, 30% by mass, 40% by mass, 45% by mass, 50% by mass, 60% by mass, or 70% by mass. The upper limit of the quercetin glycoside content in the agent for relieving dry mouth of the present invention may be, for example, 100% by mass, 99% by mass, 98% by mass, 95% by mass, 90% by mass, or 85% by mass. The content of the quercetin glycoside in the agent for relieving dry mouth of the present invention may be set to any range that combines the above lower and upper limits, such as 30 to 100% by mass, 60 to 100% by mass, or 60 to 90% by mass.

[0052] Because aquaporin production promoters promote the production of aquaporins, they are useful for improving symptoms caused by dry oral cavity, such as a sticky feeling in the oral cavity, dental plaque, tongue coating, bad breath, a burning sensation, pain, tongue discomfort, taste abnormalities, atrophy of the lingual papillae, inflammation of the oral mucosa, erosion, ulcer formation, and cracks in the tongue and corners of the mouth, and are useful for treating diseases including these symptoms, such as xerostomia (dry mouth). The aquaporin production promoter may be used by being included in a food, quasi-drug, or pharmaceutical product having the same meaning as described in the section "Food, drink, quasi-drug, or pharmaceutical food, drink, or product containing an agent for improving dry oral cavity," and the amount to be added thereto can be selected appropriately depending on the severity of the symptoms caused by dry oral cavity. [Example]

[0053] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0054] [Example 1] [Production of tablets containing an agent for improving dry mouth] Tablets of the examples and comparative examples containing the agent for alleviating dry mouth of the present invention were produced by weighing raw materials to obtain the compositions shown in Table 1 below, and then performing fluidized bed granulation, sieving, and tableting. In the table, αG Rutin PS (containing 75% by mass of α-monoglucosyl rutin) was purchased from Toyo Sugar Refining Co., Ltd., Compressel S101 from Fushimi Pharmaceutical Co., Ltd., Amalty MR-50 from Mitsubishi Shoji Foodtech Co., Ltd., calcium stearate from Seti Company Limited, and Gardenia 50 from Nihon Noh Chemical Industry Co., Ltd.

[0055] [Table 1]

[0056] [Example 2] [Dry mouth sensation evaluation test] A test for evaluating dry mouth sensation was carried out on healthy human subjects using the tablets of the Examples and Comparative Examples produced in Example 1 above, as follows.

[0057] (Study participants) Fifty-five healthy Japanese adults who experienced dry mouth were selected as study participants and were divided into a test food group (11 men and 16 women, a total of 27 people) who took the tablets of the example as the test food, and a placebo group (12 men and 16 women, a total of 28 people) who took the tablets of the comparative example as a placebo.

[0058] (method) The subjective symptom of dry mouth was assessed using a visual analogue scale (VAS). The VAS method involves assessing subjective symptoms by marking the current level of sensation on a 100mm line, with the best and worst levels of sensation indicated at either end. 0 represents the best imaginable state and 100 represents the worst state.

[0059] The test group was instructed to take the tablets of the Example, and the placebo group was instructed to take the tablets of the Comparative Example, three times a day, one tablet at a time. The test was carried out for 8 weeks, and the sensation of dry mouth was evaluated 4 and 8 weeks after the start of administration.

[0060] (result) The measured values ​​for dry mouth sensation after 8 weeks of intake in the test food group were significantly lower than those in the comparison group (Figure 1). In addition, the change in dry mouth sensation from before intake to 8 weeks after intake was significantly lower in the oral cavity improvement agent group than in the comparison group (Figure 2).

[0061] [Example 3] [Test to evaluate the ability to promote aquaporin production] Using Ca2-99 cells (human gingival squamous cell carcinoma cells), the ability of αG-rutin to promote aquaporin 3 (AQP3) production was evaluated using the following method.

[0062] (method) Confluent Ca2-99 cells were washed with PBS and treated with 0.25% trypsin / 0.02% EDTA to detach the cells from the plate. 5 The solution was diluted with DMEM to a concentration of 100 cells / mL, and 1 mL of the solution was added to a 12-well plate. The mixture was then cultured for 48 hours at 37°C and 5% CO2. After the culture, the medium was removed, and 1 mL of αG-rutin solution adjusted with DMEM to a final concentration of 500 μM was added, followed by culture for 6 hours at 37°C and 5% CO2. The cultured cells were used as test cells. Endotoxin-free water was used as a control for the αG-rutin solution. αG-rutin was prepared by column-purifying αG-Rutin PS (manufactured by Toyo Sugar Refining Co., Ltd.) to remove impurities, and the purity of α-monoglucosylrutin was approximately 100%.

[0063] The test cell culture medium was removed, and 500 μL of ISOGEN II (Nippon Gene Co., Ltd.) was added to each well. The cells were lysed by pipetting, and the cell lysate was collected in an Eppendorf tube. 200 μL of DEPC-treated water (Nippon Gene Co., Ltd.) was added, stirred, and then allowed to stand at room temperature for 15 minutes. The tube was centrifuged at 20°C and 13,500 rpm for 15 minutes, and 500 μL of the supernatant was collected in a new tube. 2.5 μL of p-Bromoanisole was added and stirred for 15 seconds. After centrifugation for 10 minutes, 400 μL of the supernatant was collected in a new tube, and 0.4 volumes of 75% ethanol were added, mixed by inversion, and allowed to stand at room temperature for 10 minutes. After centrifugation of the tube, the supernatant was discarded, and 500 μL of 75% ethanol was added to wash the precipitate. This ethanol washing procedure was repeated, and the supernatant was completely removed and the precipitate was air-dried. When the precipitate began to become transparent, 12 μL of DEPC-treated water was added to dissolve the precipitate (total RNA).

[0064] 2 μL of the obtained total RNA was placed on a μDrop Plate (manufactured by Thermo Fisher Scientific Inc.), and the RNA concentration was adjusted to 250 ng / μL with DEPC-treated water.

[0065] 1 μL of the total RNA whose concentration was adjusted as described above was mixed with 1 μL of 5× Prime Script RT (registered trademark) Master Mix (Perfect Real Time: manufactured by Takara Bio Inc.) and 3 μL of RNase-free dH2O, and the mixture was reacted at 37°C for 15 minutes. After the reaction, the reaction solution was heated to 85°C to inactivate the reverse transcriptase, and cDNA was obtained.

[0066] The resulting cDNA was diluted 10-fold with sterile MilliQ water and used as a template to perform semi-quantitative PCR using the primers shown in Table 2 under the conditions shown in Table 3. The reaction solution was prepared by mixing 0.5 μL each of 10 μM forward and reverse primers, 5 μL of 2× Go-Taq® Green Master Mix (Promega), and 4 μL of the 10-fold diluted cDNA. 18S rRNA was used as an internal standard.

[0067] [Table 2]

[0068] [Table 3]

[0069] 1.0 g of agarose S was dissolved in 50 mL of 1x TAE by heating, and 1.5 μL of ethidium bromide was added. The mixture was then poured onto a gel plate with a comb inserted. After the gel solidified, the comb was removed and the gel was placed in an electrophoresis chamber, which was then filled with 1x TAE. 8 μL of the PCR product was applied to the gel and electrophoresed at 100 V for 15 minutes. After electrophoresis, the gel was placed on a UV transilluminator, and a photograph of the electrophoresis was taken under UV light. The band intensity of each mRNA was determined using ImageJ image processing software. The relative intensity was calculated by dividing the band intensity of AQP3 by the band intensity of 18S rRNA. The relative intensity of each sample, with the relative intensity of the control set at 100, is shown in Figure 3.

[0070] The same experiment as above was conducted, except that a rutin solution or a quercetin solution of the same concentration was used instead of αG-rutin, and DMSO water was used instead of endotoxin-free water as a control. The relative intensities obtained are shown in Figure 3.

[0071] (result) In Ca9-22 cells cultured with αG-rutin, a quercetin glycoside represented by formula (1), the relative intensity of AQP3 mRNA was confirmed to be significantly higher than in the control, indicating that the expression level of AQP3 mRNA was promoted. On the other hand, in Ca9-22 cells cultured with rutin and quercetin, which are not quercetin glycosides represented by formula (1), no significant difference in the relative intensity of AQP3 mRNA was confirmed compared to the control, and no promotion of AQP3 mRNA expression was observed.

[0072] [Example 4] [Drink containing oral dryness relief agent] Component B was added to component A shown in the composition table in Table 4 below and heated to dissolve component B, then component C was added, mixed and stirred, and cooled to produce a drink containing an agent for alleviating dry mouth.

[0073] [Table 4]

[0074] [Example 5] [Lobster containing oral dryness relief agent] Component A shown in the composition table in Table 5 below was heated and dissolved, concentrated, and then component B was added and mixed and stirred, and the mixture was filled into trays to produce candy containing an agent for alleviating dry mouth.

[0075] [Table 5]

[0076] [Example 6] [Gummy containing oral dryness relieving agent] Component A shown in the composition table in Table 6 below was heated and dissolved, concentrated, then component B was added and mixed and stirred, component C was added, and the mixture was filled into trays to produce gummies containing an agent for alleviating dry mouth.

[0077] [Table 6]

Claims

1. A dry mouth alleviating agent comprising a quercetin glycoside represented by formula (1), wherein the quercetin glycoside is α-monoglucosylrutin, and the dry mouth alleviating agent is administered at a frequency of at least once a day for at least 8 weeks. 【Chemical 1】 [In formula (1), R 1 and R 2 are each independently a structure derived from a sugar.

2. 2. The agent for relieving dry mouth according to claim 1, wherein the quercetin glycoside represented by formula (1) promotes the production of aquaporin.

3. A food or drink, medicine, or quasi-drug for alleviating dry mouth, comprising the agent for alleviating dry mouth according to claim 1 or 2.

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