Glycation inhibitors

Abstract

To provide a novel active ingredient that can suppress saccharification reaction.SOLUTION: Provided are asaccharification inhibitor, a discoloration inhibitor, an embrittlement inhibitor, a whitening agent, and an aging inhibitor of teeth which contain one or more kinds selected from the group consisting of cysteine, hinokitiols, citric acids such as isopropyl citrate, and gluconic acids such as calcium gluconate. Each agent can be used as an oral agent or a composition for food.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a glycation inhibitor. [Background technology]

[0002] Glycation in living organisms is a process in which advanced glycation end products (AGEs) are produced through the Maillard reaction, which occurs at a temperature-dependent rate in the presence of carbohydrates and amino acids that constitute the body. AGEs are well known to cause browning and cross-linking between proteins, leading to discoloration and embrittlement of various tissues and cells. The various effects of AGEs, including physiological and physical damage caused by the AGE production process, are collectively referred to as glycative stress. Glycative stress is one of the risk factors for aging, and its effects are most pronounced in diabetes. Large amounts of AGEs accumulate in tissues in the three major diabetic complications of neuropathy, retinopathy, and nephropathy. The production and accumulation of AGEs through glycation is involved not only in diabetic complications but also in the progression of skin aging, dementia, hypertension, arteriosclerosis, osteoporosis, and other conditions (Non-Patent Document 1).

[0003] Glycation reactions in the body involve complex, multi-pathways. For this reason, focusing on a single pathway may not be effective in inhibiting the production of AGEs. Therefore, combining materials that inhibit multiple reaction pathways has been proposed (Non-Patent Document 1). Research into glycation reaction inhibitors aimed at treating diabetic complications has revealed that aminoguanidine and OPB-9195 (2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide) have the ability to capture carbonyl compounds, which are intermediates in glycation reactions, and inhibit the production of AGEs. However, continued intake of these compounds poses safety concerns, including side effects such as vitamin B deficiency, and they have not yet been approved as pharmaceuticals. Meanwhile, the glycation inhibitory effects of natural compounds, such as food and cosmetic ingredients and plant extracts derived from these, have also been reported (Non-Patent Document 1).

[0004] Furthermore, Non-Patent Document 2 describes that some antioxidants have an effect of inhibiting the production of AGEs. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Masayuki Yagi et al., "Evaluation of Glycative Stress and Anti-Glycative Effects," Oleoscience, Vol. 18, No. 2 (2018) [Non-patent document 2] Q.Song.et al,(2021)Biomedicine & Pharmacotherapy 140 111750(https: / / doi.org / 10.1016 / j.biopha.2021.111750) Summary of the Invention [Problem to be solved by the invention]

[0006] Previous reports on glycation-inhibiting ingredients are based on the confirmation of their glycation-inhibiting effects in diabetic complications, skin aging, dementia, high blood pressure, arteriosclerosis, and osteoporosis. Because glycation reaction pathways in the body are diverse and varied, their glycation-inhibiting activity in diseases and tissues (e.g., teeth) other than those mentioned above is unconfirmed and unpredictable.

[0007] The present invention has been made in view of the above, and an object of the present invention is to provide a novel active ingredient capable of inhibiting glycation reactions. [Means for solving the problem]

[0008] The present invention provides the following [1] to [9]. [1] A dental glycation inhibitor containing one or more members selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids. [2] A tooth discoloration inhibitor containing one or more members selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids. [3] A tooth embrittlement inhibitor containing one or more members selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids. [4] A tooth whitening agent containing one or more members selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids. [5] A tooth aging inhibitor containing one or more members selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids. [6] The agent according to any one of [1] to [5], wherein the citric acid is isopropyl citrate. [7] The agent according to any one of [1] to [6], wherein the gluconic acid is calcium gluconate. [8] An oral preparation comprising the agent according to any one of [1] to [7]. [9] A food composition comprising the agent according to any one of [1] to [7]. [Effects of the Invention]

[0009] According to the present invention, there is provided a glycation reaction inhibitor that can effectively inhibit glycation reactions (Maillard reaction), such as inhibiting the production of AGEs. The glycation reaction inhibitor can exhibit various effects, such as inhibiting discoloration, embrittlement, and aging, and can be used as an oral agent, a food composition, etc. DETAILED DESCRIPTION OF THE INVENTION

[0010] [1. Agent] [1.1 Active ingredient] The agent of the present invention contains, as an active ingredient, one or more selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids, and may contain a combination of two or more active ingredients.

[0011] <Cysteine> Cysteine ​​may be L-cysteine, D-cysteine, DL-cysteine, or a cysteine ​​salt (e.g., cysteine ​​hydrochloride, cysteine ​​hydrochloride hydrate). Cysteine ​​may be derived from natural products such as animals and plants, may be chemically synthesized, or may be a commercially available product. Among these cysteines, one type may be used alone, or two or more types may be used in combination. However, from the viewpoint of more efficiently exhibiting the desired effects of the present invention, L-cysteine ​​is preferred.

[0012] <Hinokitiols> In this specification, hinokitiols refer to hinokitiol, its derivatives, and salts thereof (such as sodium salts). Methods for producing hinokitiol include, but are not limited to, obtaining it from oil obtained by distilling the wood or roots of Taiwan cypress or Aomori cypress. Examples of hinokitiols include hinokitiol, its salts, metal complexes, and combinations of two or more selected from these. These hinokitiols may be used alone or in combination, but hinokitiol is preferred from the viewpoint of achieving the desired effects of the present invention.

[0013] <Citric acids> In this specification, citric acids refer to citric acid, its salts, and esters. Citric acid and its salts may be anhydrous or hydrated. Methods for producing citric acid include, but are not limited to, obtaining it from oil obtained by distilling the wood or roots of Taiwan cypress or Aomori cypress. Examples of citric acids include citric acid (either crystalline (citric acid monohydrate) or anhydrous); citrates (e.g., sodium citrate (e.g., sodium citrate, trisodium citrate, trisodium citrate monohydrate, trisodium citrate dihydrate), potassium citrate (e.g., monopotassium citrate, tripotassium citrate, tripotassium citrate monohydrate), calcium citrate, ammonium citrate (e.g., diammonium citrate, diammonium hydrogen citrate), copper citrate, zinc citrate, iron citrate, sodium iron citrate, ammonium iron citrate, gallium citrate), isopropyl citrate, and the like. Examples of the citric acid compound include trialkyl citrate (e.g., triethyl citrate, triisoalkyl citrate (e.g., triisocetyl citrate, triisooctyl citrate, triesters of citric acid and alcohols having a branched alkyl group having 12 and 13 carbon atoms), triethylhexyl citrate (e.g., tri-2-ethylhexyl citrate), trioctyldodecyl citrate (e.g., tri-2-octyldodecyl citrate), triesters of citric acid and alcohols having an alkyl group having 14 and 15 carbon atoms), octyldodecyl citrate (e.g., 2-octyldodecyl citrate), acetyltributyl citrate, and isocitric acid. Among these citric acids, one type may be used alone, or two or more types may be combined. From the viewpoint of more efficiently exhibiting the desired effects of the present invention, isopropyl citrate and citric acid are preferred, and isopropyl citrate is more preferred.

[0014] <Gluconic acids> In this specification, gluconic acids refer to gluconic acid, its salts, esters, and gluconolactone (which hydrolyzes to produce gluconic acid). Examples of gluconates include zinc gluconate, potassium gluconate, calcium gluconate, iron gluconate, copper gluconate, sodium gluconate, and chlorhexidine gluconate. Gluconates may be hydrates. These gluconic acids may be used alone or in combination of two or more. However, from the viewpoint of more efficiently achieving the desired effects of the present invention, calcium gluconate and gluconic acid are preferred, and calcium gluconate is more preferred.

[0015] [1.2 Effective dose] The effective amount of each active ingredient to exert its activity on the target subject can be determined appropriately depending on the target subject. The amount used per administration for humans is usually 0.00001 mg or more, preferably 0.001 mg or more, and more preferably 0.01 mg or more. This allows the glycation inhibitory effect to be fully exerted. The upper limit is usually 1 g or less, and preferably 0.1 g or less. This allows the glycation inhibitory effect to be efficiently exerted. The lower limit, therefore, the effective amount of each active ingredient is usually 0.00001 mg to 1 g, preferably 0.001 mg to 0.1 g, and more preferably 0.01 mg to 0.1 g.

[0016] [1.3 Glycation reaction inhibitory effect] The active ingredient can inhibit glycation reactions (for example, glycation reactions in the oral cavity, preferably in teeth). In this specification, glycation reactions include all of the reactions that occur from the binding of sugar and protein (glycation reaction; Maillard reaction) to the production of AGEs (AGE production reaction), through the act of AGEs in the body to cause symptoms such as discoloration, embrittlement, and aging of tissues (for example, teeth). The active ingredient can act on, for example, the oral cavity or epithelium, preferably the oral cavity, and more preferably teeth (especially dentin). Each active ingredient can be used for the purpose of suppressing (including alleviating, preventing, or treating) symptoms caused by glycation or permeation reactions. Examples of uses include glycation reaction inhibitors, discoloration inhibitors, embrittlement inhibitors, whitening agents, and anti-aging agents, with tooth glycation reaction inhibitors, tooth discoloration inhibitors, tooth embrittlement inhibitors, tooth whitening agents, and tooth anti-aging agents being preferred.

[0017] [2.Application] Agents containing the above-mentioned active ingredients can be used as quasi-drugs, medicines, cosmetics, and foods.

[0018] [2.1 Target and application area] The target of application may be any animal, including humans, and is usually mammals, birds, or fish, preferably mammals, and more preferably humans. The target of application may be either healthy individuals or patients with diseases caused by AGEs, and may be either young or elderly. Examples of non-human animals include mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, and monkeys.

[0019] The application site may be local (oral, ophthalmic mucosa, skin, hair) or systemic, but oral application is preferred, and teeth are more preferred.

[0020] 2.2 Dosage Form Examples of administration modes include oral administration (e.g., oral administration, sublingual administration) and parenteral administration (e.g., transdermal transmucosal administration, intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, and pulmonary administration). Among these, less invasive administration modes are preferred, with transdermal transmucosal administration (external application) and oral administration being more preferred.

[0021] 2.3 Dosage Form The agent containing the active ingredient can be used as a medicine, a quasi-drug, a cosmetic, a functional food, etc. The dosage form is not particularly limited, and examples thereof include a liquid agent, a spray agent, a solid agent, a semi-solid agent, a powder agent, a granule agent, and a sheet agent.

[0022] 2.4 Use in Pharmaceutical Formulations The agent containing the above-mentioned active ingredient can be prepared in various forms such as an external preparation or an internal preparation.

[0023] Examples of external preparations include preparations for mucous membranes, preparations for skin, and preparations for hair, with preparations for mucous membranes being preferred and preparations for oral cavity being more preferred.

[0024] Oral preparations may be added to dentifrices (e.g., toothpaste, gel toothpaste, moistened toothpaste, liquid toothpaste), mouthwashes, tongue rubs, oral sprays, oral tablets, gums, mouth fresheners, gargle tablets, oral pastes, oral gels, oral ointments, and dental sheets.

[0025] Examples of skin preparations (external skin preparations) include gels, ointments, creams, external liquids, lotions, sprays, and packs.

[0026] Examples of oral dosage forms (pharmaceuticals, functional foods) include oral liquids, syrups, creams, jellies, pastes, tablets, granules, fine granules, and capsules (soft capsules, hard capsules).

[0027] Cosmetics can be used in the form of, for example, creams, emulsions, packs, gels, aerosols, sheets, etc. Specific examples include skin cosmetics such as lotions, beauty serums, whitening agents, moisturizers, face masks, emulsions, foundations, eye shadows, mascaras, eyebrow pencils, eyeliners, blush powders, lipsticks, lip balms, packs, and soaps; and hair cosmetics such as hair rinses, hair conditioners, hair treatments, hair lotions, hair tonics, hair packs, hair creams, conditioning mousses, hair mousses, hair sprays, shampoos, leave-on treatments, hair dyes, and hair styling products.

[0028] Examples of foods (food compositions) include health foods, functional foods, health supplements (supplements), nutritional supplements, foods for specified health uses, foods with nutrient functions, medical foods, foods for the sick, foods for infants, foods for caregivers, and foods for the elderly, and include food compositions with uses (for example, for inhibiting glycation reactions, inhibiting discoloration, inhibiting embrittlement, whitening, and inhibiting aging) such as health foods. Examples of foods include beverages (e.g., soft drinks, carbonated drinks, energy drinks, powdered drinks, fruit drinks, dairy drinks, jelly drinks), sweets (cookies, cakes, gum, candy, tablets, gummy candies, buns, yokan, puddings, jellies, ice cream, sherbet, etc.), processed seafood products (kamaboko, chikuwa, hanpen, etc.), processed livestock products (hamburger steaks, ham, sausages, wieners, cheese, butter, yogurt, fresh cream, margarine, fermented milk, etc.), soups (powdered soups, liquid soups, etc.), staple foods (rice, noodles (dried noodles, fresh noodles), bread, cereal, etc.), and seasonings (mayonnaise, shortening, dressings, sauces, soy sauce, etc.).

[0029] [2.5 Content of agent] The content of the active ingredients (the respective contents of cysteine, hinokitiols, citric acids, and gluconic acids) in each of the above uses is not particularly limited. For example, it is preferably 10% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less, relative to the total mass of the agent. By setting the upper limit to 10% by mass or less, the desired effects of the present invention can be efficiently achieved. The lower limit is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more. By setting the lower limit to 0.0001% by mass or more, the desired effects of the present invention can be efficiently achieved. Therefore, the content of the active ingredients of the present invention is preferably 0.0001 to 10% by mass, more preferably 0.0001 to 2% by mass, and even more preferably 0.001 to 1% by mass, relative to the total mass of the agent.

[0030] [2.6 Optional components] When the agent containing the active ingredient is in the form of a so-called composition containing other optional ingredients, the other ingredients may include, for example, ingredients other than the active ingredient, such as medicinal ingredients, buffers, solubilizers, isotonicity agents, stabilizers, chelating agents, pH adjusters, preservatives, oily ingredients, excipients, disintegrants, binders, lubricants, coating agents, colorants, color formers, flavoring agents (acidulants, fragrances, sweeteners), antioxidants, strengthening agents, leavening agents, thickeners, surfactants, abrasives, humectants, moisturizers, cooling agents, abrasives, binders, astringents, plant extracts, UV absorbers, aqueous solvents, preservatives, seasonings, food ingredients (including food additives), etc. The type and content of the optional ingredients may be selected depending on the intended use of the pharmaceutical, quasi-drug, food composition, or cosmetic product, and / or the dosage form and administration method, and may be one or a combination of two or more.

[0031] <Medicinal ingredients> Examples of active ingredients include enzymes such as dextranase, mutanase, amylase, and protease; fluorides such as sodium fluoride, sodium monofluorophosphate, and stannous fluoride; anti-inflammatory agents such as allantoin, glycyrrhizinic acid, glycyrrhizinate salts (e.g., dipotassium glycyrrhizinate), glycyrrhetinic acid, glycyrrhetinic acid derivatives (e.g., stearyl glycyrrhetinate), allantoin chlorohydroxyaluminum, azulene, tranexamic acid, and dihydrocholesterol; metal salts such as zinc salts, copper salts, and tin salts; anti-tartar agents such as condensed phosphates and ethanehydroxydiphosphonate; vitamin E ( Examples of the active ingredient include blood flow promoters such as tocopherol acetate; anti-dentin hypersensitivity agents such as potassium nitrate, aluminum lactate, and strontium chloride; coating agents such as hydroxyethyl cellulose dimethyldiallylammonium chloride; astringents such as vitamin C (e.g., ascorbic acid or its salts) and sodium chloride; anti-tartar agents; amino acids other than cysteine ​​such as alanine, glycine, proline, potassium L-aspartate, magnesium L-aspartate, and aminoethylsulfonic acid; plant extracts such as thyme, Scutellaria Root, clove, and witch hazel; callopeptides; and polyvinylpyrrolidone. Other examples include decongestants, anti-inflammatory agents, astringents, antihistamines, vitamins, disinfectants, local anesthetics, ingredients with glycation inhibitory activity other than the active ingredient of the present invention, and combinations of two or more thereof. Decongestants include, for example, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, and naphazoline nitrate. Anti-inflammatory and astringent agents include, for example, neostigmine methylsulfate, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, bromelain, chamomile, sodium cromoglycate, and lysozyme chloride. Antihistamines include, for example, iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, and chlorpheniramine maleate.Examples of vitamins include flavin adenine dinucleotide sodium, cyanocobalamin, vitamin A (e.g., retinol acetate, retinol palmitate), and vitamin E (tocopherol acetate (e.g., d-α-tocopherol acetate)). Examples of disinfectants include cetylpyridinium chloride, dequalinium chloride, benzalkonium chloride, benzetrium chloride, iodine, potassium iodide, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, and isopropylmethylphenol. Examples of local anesthetics include lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, and chlorobutanol. Each of the active ingredients may be used alone or in combination of two or more. The content of the active ingredient can be appropriately determined as an effective amount according to conventional methods.

[0032] <Surfactant> The surfactant may be an anionic surfactant, a nonionic surfactant, or an amphoteric surfactant.

[0033] Examples of anionic surfactants include alkyl sulfates, acylamino acid salts, acyltaurine salts, α-olefin sulfonates, hydrogenated coconut fatty acid monoglyceride monosulfates, and lauryl sulfoacetates. The alkyl and acyl groups may be linear or branched, saturated or unsaturated, and typically contain 10 to 20 carbon atoms, preferably 12 to 18, and more preferably 12 to 14 carbon atoms. The salts may be selected from pharmacologically acceptable salts. Examples of pharmacologically acceptable salts include base addition salts and amino acid salts. Specific examples include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts; organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts, and diisopropylammonium salts; and basic amino acid salts such as arginine salts. Among these, inorganic base salts are preferred, with alkali metal salts (e.g., sodium salts and potassium salts) and ammonium salts being more preferred, and sodium salts being even more preferred.

[0034] Examples of alkyl sulfates include lauryl sulfate (sodium lauryl sulfate) and myristyl sulfate. Examples of acylamino acid salts include acyl glutamates such as lauroyl glutamate, myristoyl glutamate, palmitoyl glutamate, etc.; acyl glycine salts such as N-lauroyl-N-methyl glycine salt and cocoyl glycine salt; acyl alanine salts such as N-lauroyl-β-alanine salt, N-myristyl-β-alanine salt, N-cocoyl-β-alanine salt, N-lauroyl-N-methyl-β-alanine salt, N-myristoyl-N-methyl-β-alanine salt, and N-methyl-N-acylalanine salt; and acyl aspartates such as lauroyl aspartate. Examples of acyltaurine salts include lauroyl methyl taurine salt, N-methyl-N-acyltaurine salt, and N-cocoyl methyl taurine salt. Examples of α-olefin sulfonates include α-olefin sulfonates having 12 to 18 carbon atoms, such as tetradecene sulfonate. Other examples of anionic surfactants include hydrogenated coconut fatty acid monoglyceride sodium monosulfate and sodium lauryl sulfoacetate.

[0035] Examples of nonionic surfactants include polyoxyethylene alkyl ethers, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monostearate), alkylolamides, polyoxyethylene fatty acid esters, polyoxyethylene alkenyl ethers, polyglycerin fatty acid esters, sucrose fatty acid esters (e.g., maltose fatty acid esters), sugar alcohol fatty acid esters (e.g., maltitol fatty acid esters, lactitol fatty acid esters), fatty acid diethanolamides (e.g., lauric acid mono- or diethanolamide), polyoxyethylene polyoxypropylene copolymers, and polyoxyethylene polyoxypropylene fatty acid esters. The number of carbon atoms in the alkyl chain of the polyoxyethylene alkyl ether is typically 14 to 18, and the average number of moles of ethylene oxide added is typically 5 to 30. The average number of moles of ethylene oxide added in polyoxyethylene hydrogenated castor oil is typically 20 to 100 moles, preferably 20 to 60 moles. The number of carbon atoms in the fatty acid of the sorbitan fatty acid ester is usually 12 to 18. The number of carbon atoms in the fatty acid of the polyoxyethylene sorbitan fatty acid ester is usually 16 to 18, and the average number of moles of ethylene oxide added is usually 10 to 40. The number of carbon atoms in the alkyl chain of the alkylolamide is usually 12 to 14.

[0036] Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyl dimethylamino acetic acid betaine (e.g., lauryl dimethylamino acetic acid betaine) and fatty acid amidopropyl dimethylamino acetic acid betaine (e.g., cocamidopropyl betaine); imidazoline-type amphoteric surfactants such as N-fatty acid acyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine salts (e.g., N-coconut oil fatty acid acyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine), coconut oil fatty acid imidazolinium betaine, and 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine; and alkyl betaines such as lauryl dimethylamino acetic acid betaine.

[0037] When a surfactant is contained, the content of each of the anionic, nonionic and amphoteric surfactants is usually 0.01 to 10% by mass, preferably 0.1 to 5% by mass, more preferably 0.2 to 3% by mass of the total agent.

[0038] <Abrasives> The abrasive may be either inorganic or organic. Examples of inorganic abrasives include abrasive silicas such as precipitated silica, aluminosilicate, zirconosilicate, crystalline zirconium silicate, and titanium-bonded silica; calcium phosphate compounds such as dibasic calcium phosphate dihydrate or anhydrate, monobasic calcium phosphate, tribasic calcium phosphate, and calcium pyrophosphate; calcium carbonate abrasives such as calcium carbonate; calcium abrasives other than carbonates or phosphates such as calcium hydroxide and calcium sulfate; aluminum-based materials such as aluminum oxide, aluminum hydroxide, and alumina; silicate-based materials such as anhydrous silicic acid, zeolite, and zirconium silicate; magnesium-based materials such as magnesium carbonate and tribasic magnesium phosphate; apatite-based materials such as hydroxyapatite, fluoroapatite, and calcium-deficient apatite; titanium-based materials such as titanium dioxide, titanium mica, and titanium oxide; and minerals such as bentonite. Examples of organic abrasives include polymethyl methacrylate and synthetic resin-based abrasives. Among these, abrasive silica and calcium phosphate compounds are preferred, and silicic anhydride is more preferred. The amount of the abrasive is preferably 50% by mass or less, more preferably 8 to 50% by mass, based on the total mass of the agent.

[0039] <Wetting agent> Examples of humectants include sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include sorbitol (sorbitol), erythritol, maltitol, lactitol, and xylitol. Examples of polyhydric alcohols other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and polyethylene glycol (PEG); and reduced starch saccharification products. Examples of polyethylene glycols are, for example, polyethylene glycols with an average molecular weight of 150 to 6,000, and polyethylene glycols with an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600). The average molecular weight is the average molecular weight specified in the Quasi-drug Raw Materials Standards 2006. The content of the humectant is usually 40% by mass or less, preferably 1 to 30% by mass, of the total agent.

[0040] <Binding agent> Examples of binders include any suitable organic binders known in the art, such as polysaccharides, cellulose-based binders (e.g., carboxymethyl cellulose (CMC), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and cationized cellulose), other polysaccharide thickeners (e.g., xanthan gum, guar gum, gellan gum, tragacanth gum, karaya gum, gum arabic, locust bean gum, carrageenan, and sodium alginate), and synthetic water-soluble polymers (e.g., sodium polyacrylate, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, and propylene glycol alginate). Furthermore, inorganic binders such as thickening silica and aluminum silicate may also be added. The content of the organic binder is preferably 0 to 3% by mass, and more preferably 0.1 to 2% by mass, based on the total mass of the agent. The content of the inorganic binder is preferably 0 to 10% by mass, and more preferably 1 to 8% by mass.

[0041] <Buffering agent> Examples of buffering agents include phosphoric acid or a salt thereof (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate), tartaric acid or a salt thereof (e.g., sodium tartrate), acetic acid or a salt thereof (e.g., sodium acetate), carbonic acid or a salt thereof (e.g., sodium bicarbonate), trometamol, amino acids (e.g., potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), and combinations of two or more thereof. Examples of solubilizing agents include polyoxyethylene higher fatty acid esters such as polyoxyethylene (e.g., p=60) hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters such as polyoxyethylene (e.g., p=20) sorbitan monooleate, propylene glycol, polyethylene glycol, and combinations of two or more thereof. Examples of isotonic agents include sodium chloride, potassium chloride, glycerin, and combinations of two or more thereof. Examples of stabilizers include sodium edetate, cyclodextrin, sulfites, dibutylhydroxytoluene, ascorbic acid, and combinations of two or more thereof. Examples of chelating agents include sodium edetate and combinations of two or more thereof. Examples of pH adjusters include sodium hydroxide, potassium hydroxide, hydrochloric acid, and combinations of two or more thereof. Examples of preservatives include parahydroxybenzoic acid esters such as methylparaben, ethylparaben, propylparaben, and butylparaben, alcohol derivatives such as phenylethyl alcohol, benzyl alcohol, phenol, and acrinol, sorbic acid and its salts (potassium sorbate, etc.), benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkylpolyaminoethylglycine, and combinations of two or more thereof.

[0042] <Moisturizer> Examples of moisturizing agents include glycerin, concentrated glycerin, sugar alcohols (for example, sorbitol, xylitol, maltitol, mannitol, reduced starch syrup, reduced palatinose, erythritol, lactitol, and isomalt), and combinations of two or more of these.

[0043] <Flavoring agent> Examples of flavoring agents include sweeteners (e.g., saccharin sodium, aspartame, stevia, stevioside, para-methoxycinnamic aldehyde, neohesperidin dihydrochalcone, perillartine, glycyrrhizin, aspartyl phenylalanine methyl ester, thaumatin, acesulfame potassium, sucralose, maltitol, sorbitol, mannitol, reduced starch syrup, reduced palatinose, xylitol, erythritol, lactitol, and other artificial sweeteners), flavorings (e.g., Natural essential oils such as anise oil, cassia oil, wintergreen oil, mastic oil, neroli oil (orange flower oil), lemongrass oil, jasmine oil, rose oil, iris oil, clove oil, sage oil, cardamom oil, rosemary oil, laurel oil, chamomile oil, basil oil, marjoram oil, lemon oil, orange oil, lime oil, yuzu oil, nutmeg oil, lavender oil, paracles oil, vanilla oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, peppermint oil, lychee oil, etc.); menthol, carvone, cinnamic aldehyde Fragrance components contained in the above natural essential oils, such as hydrazine, anethole, methyl salicylate, eugenol, linalool, limonene, menthone, menthyl acetate, citral, decanal, camphor, borneol, pinene, spilanthol, n-decyl alcohol, citronellol, α-terpineol, citronellyl acetate, ethyl linalool, and vanillin; ethyl acetate, ethyl butyrate, isoamyl acetate, hexanal, hexenal, methyl anthranilate, and ethyl These include flavoring ingredients such as methyl phenyl glycidate, benzaldehyde, vanillin, ethyl vanillin, furaneol, N-ethyl-p-menthane-3-carboxamide, menthyl lactate, and ethylene glycol-l-menthyl carbonate; and various blended flavors such as mint, fruit, and herb flavors that combine several flavoring ingredients and natural essential oils (e.g., Peppermint Micron X-8277-T, Dry Coat Matcha #421), acidulants (e.g., tartaric acid, malic acid), and green tea powder.

[0044] <Oily ingredients> Examples of oily components include fatty acid esters (e.g., glycerin fatty acid esters), hydrocarbons (e.g., paraffin, liquid paraffin, ceresin, squalane, petrolatum, microcrystalline wax), higher fatty acids (e.g., fatty acids having 8 to 22 carbon atoms such as lauric acid, myristic acid, oleic acid, and isostearic acid), higher alcohols (e.g., alcohols having 8 to 22 carbon atoms such as lauryl alcohol, cetyl alcohol, cetostearyl alcohol, oleyl alcohol, and isostearyl alcohol), vegetable oils (e.g., vegetable oils such as olive oil, castor oil, and coconut oil; fatty acid esters such as isopropyl myristate), beeswax, and combinations of two or more of these.

[0045] <Preservatives> Examples of preservatives include parahydroxybenzoic acid esters (eg, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate), sodium benzoate, and combinations of two or more thereof.

[0046] <Wetting agent> Examples of humectants include sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include sorbitol (sorbitol), erythritol, maltitol, lactitol, and xylitol. Examples of polyhydric alcohols other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and polyethylene glycol (PEG); and reduced starch saccharification products. Examples of polyethylene glycols are, for example, polyethylene glycols with an average molecular weight of 150 to 6,000, and polyethylene glycols with an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600). The average molecular weight is the average molecular weight specified in the Quasi-drug Raw Materials Standards 2006. The amount of humectant is usually 40% by mass or less, preferably 1 to 30% by mass, of the total agent.

[0047] <Coloring agent> Examples of colorants include natural colorants such as safflower red pigment, gardenia yellow pigment, gardenia blue pigment, perilla pigment, red kojic pigment, red cabbage pigment, carrot pigment, hibiscus pigment, cocoa pigment, spirulina blue pigment, tamarind pigment, etc., legal colorants such as Red No. 2, Red No. 3, Red No. 104, Red No. 105, Red No. 106, Red No. 227, Yellow No. 4, Yellow No. 5, Green No. 3, Blue No. 1, etc., riboflavin, copper chlorophyll sodium, titanium dioxide, etc. When a colorant is included, its content is preferably 0.00001 to 3% by mass based on the whole agent.

[0048] <pH adjuster> Examples of pH adjusters include organic acids such as phthalic acid, succinic acid, acetic acid, fumaric acid, malic acid, and lactic acid or their salts, inorganic acids such as phosphoric acid (orthophosphoric acid) or their salts (e.g., potassium salt, sodium salt, and ammonium salt), hydroxides such as sodium hydroxide and potassium hydroxide. Examples of inorganic acid salts include disodium hydrogen phosphate and sodium dihydrogen phosphate. The content of the pH adjuster can usually be an amount such that the pH of the agent after addition is 5 to 9, preferably 6 to 8.5. In this specification, the pH value usually refers to the value 25°C and 3 minutes after the start of measurement. The pH value can be measured, for example, using a pH meter (model number Hm-30S) manufactured by Toa Denpa Kogyo Co., Ltd.

[0049] <Solvent> Examples of solvents include water (purified water) and ethanol, with water being preferred. The solvent may be used alone or in combination of two or more. <清

[0050] <Excipient>[[ID=十七]] Examples of excipients include celluloses such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, methylethyl cellulose, and low-substituted hydroxypropyl cellulose, and pharmacologically acceptable derivatives thereof; synthetic polymers such as polyvinylpyrrolidone and partially saponified polyvinyl alcohol; polysaccharides such as gelatin, powdered gum arabic, pullulan, agar, alginic acid, sodium alginate, and xanthan gum; corn starch, potato starch, pregelatinized starch, and hydroxypropyl starch. starches and pharmacologically acceptable derivatives thereof; lactose, lactose granules, fructose, glucose, sucrose, granulated sugar, hydrous glucose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, maltotetraose, lactitol, isomalt, reduced palatinose, reduced starch syrup, powdered reduced maltose starch syrup, maltitol; inorganic excipients such as magnesium carbonate, calcium carbonate, light anhydrous silicic acid, silicon dioxide (also known as anhydrous silicic acid, fine silicon dioxide), titanium oxide, aluminum hydroxide gel, etc.; and combinations of two or more of these.

[0051] <Disintegrant> Examples of disintegrants include crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, croscarmellose sodium, cross-linked insoluble polyvinylpyrrolidone, hydroxypropyl starch, partially pregelatinized starch, corn starch, and combinations of two or more thereof.

[0052] <Binder> Examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch, pregelatinized starch, and combinations of two or more thereof.

[0053] <Lubricant> Examples of lubricants include calcium stearate, magnesium stearate, sucrose fatty acid esters, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid, and combinations of two or more thereof.

[0054] <Other optional ingredients> Examples of optional components other than those mentioned above include polyisobutylene, polybutadiene, urethane, silicone, and natural rubber. The content of these optional components can be appropriately set within a range that does not impair the effects of the present invention.

[0055] [3. Manufacturing method] The manufacturing method of the agent containing the active ingredient may be determined depending on the dosage form, intended use, and application site. For example, when used as a toothpaste, a method is exemplified in which the components soluble in a solvent are prepared, followed by mixing with other insoluble components, and degassing (e.g., by reducing pressure, etc.) as needed. Another example is a method in which the active ingredient and other components used as needed are dispersed and dissolved in an aqueous solvent (e.g., purified water, sterilized water, etc.) to prepare a composition, which is then filled into an appropriate container (e.g., glass, resin). Examples of containers for oral preparations include laminated tubes, and materials that can be used include resins such as polyethylene, polypropylene, polyethylene terephthalate, and nylon. In the case of a spray, a container equipped with a spraying means (e.g., a trigger-type, pump-type, or aerosol-type container) can be selected. The resulting toothpaste can be filled into a container to produce a finished product. The shape and material of the container are not particularly limited, and containers used for ordinary oral compositions can be used.

[0056] [4. How to use] The method of using the agent containing the active ingredient may be, for example, to administer the agent to the application site. In the case of an oral agent, a suitable amount of the agent may be applied to a toothbrush, brushed over the teeth, and then rinsed with water (dentifrice), or an appropriate amount of the agent may be placed in the mouth, gargled, and then spat out (mouthwash). In the case of an external agent, the number of times of administration per day is not particularly limited, but may be, for example, 1 to 6 times or more. [Example]

[0057] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0058] [Components used in Examples and Comparative Examples] PBS pH 7.4 (10X) (Thermo Fisher Scientific, PBS (10X) pH 7.4 (product code: 70011-044)) D(-)-ribose (Tokyo Chemical Industry Co., Ltd., D-(-)-Ribose (product code: R0025)) L-cysteine ​​(Tokyo Chemical Industry Co., Ltd., L-Cysteine ​​(product code: C0515)) Hinokitiol (Tokyo Chemical Industry Co., Ltd., Hinokitiol (product code: H0142)) Isopropyl citrate (Tokyo Chemical Industry Co., Ltd., Isopropyl Citrate (product code: C1030)) Calcium Gluconate Monohydrate (Tokyo Chemical Industry Co., Ltd., Calcium Gluconate Monohydrate (Product Code: G0037)) Citric acid (Fujifilm Wako Pure Chemical Industries, Ltd., Citric Acid (product code: 036-05522)) Gluconic acid (Tokyo Chemical Industry Co., Ltd., Gluconic Acid product code: G0036) Thymol (Tokyo Chemical Industry Co., Ltd., Thymol (product code: M0410))

[0059] Examples 1 to 6 and Comparative Example 1 [Test 1: AGEs production inhibition test] <Preparation of tooth slices> Human teeth extracted at a dental clinic were used with the patient's consent. Sections of specific thickness were prepared using a microcutter.

[0060] <Preparation of sample solution> 200 mM ribose was dissolved in PBS (×1) at pH 7.4 to prepare a tooth saccharification solution. The evaluation compound was dissolved in this solution to a final concentration of 100 mM to obtain a sample solution.

[0061] <Measurement of AGEs activity> Tooth sections obtained from the same specimen were immersed in 1 mL each of a PBS solution (without ribose and evaluation compound), a 200 mM ribose solution (saccharification solution), and the sample solution, and reacted at 60 °C for 3 days. A 1 N HCl solution was added to the saccharified tooth sections at a ratio of 500 μL per 30 mg, and hydrolyzed at 110 °C for 16 hours to obtain a lysate. The lysate was measured using a microplate reader (Flex Station 3, manufactured by Molecular Devices). Fluorescence at 385 nm generated by irradiating excitation light at 335 nm was measured (measurement index: pentosidine).

[0062] <Calculation of AGEs production inhibition rate> From the measured fluorescence intensity, the AGEs production inhibition rate was calculated using the following formula. AGEs production inhibition rate (%) = (measured value B - measured value C) / (measured value B - measured value A) × 100 In the formula, measured values A, B, and C are the measured values in the PBS solution, the measured values in the 200 mM ribose solution, and the measured values in the sample solutions of each example and comparative example, respectively. Each value is the average value of N = 3. The results are shown in Table 1. ​​​​​​​​​​​​​​​​​​A human tooth similar to that used in <Test 1> was equally split in half to prepare a test specimen.

[0066] <Preparation of sample solution> 100 mM ribose was dissolved in PBS to prepare a solution for glycation of teeth. The test compound was dissolved in this solution to a final concentration of 100 mM to prepare a sample solution.

[0067] <Analysis of yellowing of teeth> Test pieces were immersed in 5 mL of 100 mM ribose solution (saccharification solution) and sample solution, and saccharification was carried out at 60°C for 4 days. Images of the test pieces before and after the saccharification reaction were taken with a microscope (Keyence, VHX-2000), and tooth discoloration (yellowing) was analyzed by image analysis. MATLAB (registered trademark, MathWorks) was used as the analysis software. After converting the image color display from the RGB color system to the L*a*b* color system, the color difference ΔE value was calculated, and the amount of color change was compared between the 100 mM ribose solution and each sample solution.

[0068] <Calculation of color inhibition rate> The color difference ΔE value before and after the saccharification reaction in the 100 mM ribose solution was calculated from the L* value, a* value, and b* value according to the following formula to calculate the coloration inhibition rate. ΔE = {(L* value after saccharification - L* value before saccharification) 2 + (a* value after glycation - a* value before glycation) 2 + (b* value after glycation - b* value before glycation) 2} 1 / 2 Color suppression rate (%) = {1 - (ΔE value of sample solution / ΔE value of saccharification solution)} x 100 Each coloration inhibition rate is the average value of N = 4. The results are shown in Table 2.

[0069] [Table 2]

[0070] All of the examples showed good coloring inhibition rates, confirming the effect of inhibiting yellowing. Among them, Examples 8 and 9 showed high coloring inhibition rates of 35% or more (Table 2).

[0071] Examples 11 to 14 and Comparative Example 2 [Test 3: Test for inhibiting embrittlement of human teeth] <Preparation of test specimen> A human tooth similar to that used in <Test 1> was equally split in half to prepare a test specimen.

[0072] <Preparation of sample solution> 200 mM ribose was dissolved in PBS to prepare a solution for tooth saccharification. The test compound was dissolved in this solution to a final concentration of 100 mM to prepare a sample solution.

[0073] <Analysis of tooth embrittlement> The test pieces were immersed in 5 mL of PBS solution (no ribose or evaluation compound added), 200 mM ribose solution (glycation solution), or sample solution, and the glycation reaction was carried out at 60°C for 3 days. After the reaction, Young's modulus was measured (test force: 10 mN) using a nanoindenter (Shimadzu Corporation, DUH-211S), and the 200 mM ribose solution and each sample solution were compared.

[0074] <Calculation of tooth embrittlement prevention rate> The difference F in Young's modulus between the PBS solution and the saccharification solution, and the difference E in Young's modulus between the saccharification solution and the sample solution were calculated, and the embrittlement inhibition rate was calculated using the following formula. Brittleness suppression rate (%) = (difference E / difference F) × 100 Each embrittlement inhibition rate is an average value of N=3. The results are shown in Table 3.

[0075] [Table 3]

[0076] All of the Examples showed a good embrittlement prevention rate, confirming the effect of preventing tooth embrittlement. Among them, Examples 11 and 12 showed a high embrittlement prevention rate of 60% or more (Table 3).

[0077] The above examples demonstrate that the agent of the present invention can inhibit glycation reactions that occur in vivo, and can inhibit tooth discoloration and embrittlement.

Claims

1. A dental glycation inhibitor containing one or more members selected from the group consisting of isopropyl citrate, gluconic acid, and calcium gluconate.

2. The tooth discoloration inhibitor contains one or more members selected from the group consisting of cysteine, hinokitiol, salts of hinokitiol, isopropyl citrate, gluconic acid, and calcium gluconate.

3. The tooth embrittlement inhibitor contains one or more members selected from the group consisting of cysteine, hinokitiol, salts of hinokitiol, isopropyl citrate, gluconic acid, and calcium gluconate.

4. A tooth aging inhibitor containing at least one member selected from the group consisting of isopropyl citrate, gluconic acid, and calcium gluconate.

5. The tooth whitening agent comprises a tooth discoloration inhibitor containing one or more selected from the group consisting of cysteine, hinokitiol, a salt of hinokitiol, isopropyl citrate, gluconic acid, and calcium gluconate.

6. The tooth aging inhibitor comprises a tooth embrittlement inhibitor containing one or more members selected from the group consisting of cysteine, hinokitiol, a salt of hinokitiol, isopropyl citrate, gluconic acid, and calcium gluconate.

7. An oral preparation comprising the agent according to any one of claims 1 to 6.

8. A food composition comprising the agent according to any one of claims 1 to 6.

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