JP2023042000A - Saccharification inhibitor - Google Patents

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 The present invention relates to a saccharification inhibitor.

Glycation in a living body is a reaction in which advanced glycation end products (AGEs) are produced by the Maillard reaction formed at a temperature-dependent reaction rate in the presence of sugars and amino acids that constitute the living body. . AGEs are well known to cause browning and cross-linking between proteins, and these characteristics lead to discoloration and embrittlement of various tissues and cells. Such various effects such as AGEs or physiological and physical disorders that occur in the process of producing AGEs are collectively referred to as glycative stress. Glycative stress is one of the risk factors for aging, and diabetes is the pathological condition in which its influence is most pronounced. In neuropathy, retinopathy, and nephropathy, which are the three major complications of diabetes, AGEs are accumulated in large amounts in tissues. The production and accumulation of AGEs due to glycation is involved not only in diabetic complications but also in the development of skin aging, dementia, hypertension, arteriosclerosis, osteoporosis and the like (Non-Patent Document 1).

The saccharification reaction in the body is a complex multi-pathway, and for this reason, it may not be possible to expect the effect of suppressing the production of AGEs by focusing on a single pathway, and it is proposed to combine materials that suppress multiple reaction pathways ( Non-Patent Document 1). Among the research on glycation reaction inhibitors for the treatment of diabetic complications, aminoguanidine, OPB-9195 (2-isopropylidenehydrazono-4-oxo-thiazolidine-5-ylacetanilide), is a glycation reaction intermediate. It has the effect of capturing carbonyl compounds and inhibiting the production of AGEs, but it has safety issues such as side effects such as vitamin B group deficiency when taken continuously, and has not been approved as a drug. On the other hand, it has also been reported that natural compounds such as food/cosmetics materials and plant extracts derived from these have a saccharification reaction inhibitory effect (Non-Patent Document 1).

In addition, Non-Patent Document 2 describes that some antioxidants have an AGE production inhibitory effect.

Masayuki Yagi et al., "Evaluation of glycative stress and anti-glycation effect," Oleoscience Vol. 18, No. 2 (2018) Q. Song. et al, (2021) Biomedicine & Pharmacotherapy 140 111750 (https://doi.org/10.1016/j.biopha.2021.111750)

Conventional reports on glycation-inhibiting ingredients are based on confirmation of glycation-inhibiting effects on diabetic complications, skin aging, dementia, hypertension, arteriosclerosis, and osteoporosis. Since glycation reaction pathways in vivo are various and diversified, glycation-inhibiting activity in diseases and tissues (eg, teeth) other than those described above is unconfirmed and cannot be predicted.

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 suppressing the saccharification reaction.

The present invention provides the following [1] to [9].
[1] A tooth glycation inhibitor containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids.
[2] A tooth discoloration inhibitor containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids.
[3] A tooth embrittlement inhibitor containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids.
[4] A tooth whitening agent containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids, and gluconic acids.
[5] A tooth aging inhibitor containing one or more 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 containing the agent according to any one of [1] to [7].
[9] A food composition containing the agent according to any one of [1] to [7].

ADVANTAGE OF THE INVENTION According to this invention, the saccharification reaction inhibitor which can suppress saccharification reaction (Maillard reaction) satisfactorily, such as suppressing the production|generation of AGEs, is provided. A saccharification reaction inhibitor can exhibit various effects such as discoloration, embrittlement, aging inhibition, etc., and can be used as an oral preparation, a food composition, and the like.

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

<cysteine>
Cysteine may be L-cysteine, D-cysteine, DL-cysteine, or a salt of cysteine (eg, cysteine hydrochloride, cysteine hydrochloride hydrate). Cysteine may be derived from natural products such as animals and plants, may be chemically synthesized, or may be commercially available. Among these cysteines, one type may be used alone, or two or more types may be combined. L-cysteine is preferable from the viewpoint of more efficiently expressing the desired effects of the present invention.

<Hinokitiols>
As used herein, hinokitiols refer to hinokitiol, derivatives thereof, and salts thereof (sodium salt, etc.). Examples of the method for producing hinokitiol include, but are not limited to, a method of obtaining hinokitiol from oil obtained by distilling the wood or root of Taiwan cypress or Aomori hiba. Examples of hinokitiols include hinokitiol, salts thereof, metal complexes, and combinations of two or more selected from these. Among these hinokitiols, one type may be used alone, or two or more types may be combined, but hinokitiol is preferable from the viewpoint of expressing the desired effects of the present invention.

<Citric acids>
As used herein, citric acids refer to citric acid, its salts and esters. Citric acid and its salts may be either anhydrous or hydrated. Methods for producing citric acid include, but are not limited to, a method of obtaining citric acid from oil obtained by distilling the wood or roots of Taiwan cypress or Aomori hiba. As citric acids, for example, citric acid (either crystalline (citric acid monohydrate) or anhydrous); trisodium citrate monohydrate, trisodium citrate dihydrate), potassium citrate (e.g. monopotassium citrate, tripotassium citrate, tripotassium citrate monohydrate), calcium citrate, citric acid ammonium (e.g., diammonium citrate, diammonium hydrogen citrate), copper citrate, zinc citrate, iron citrate, sodium iron citrate, ammonium iron citrate, gallium citrate), isopropyl citrate, tricitrate Alkyl (e.g., triethyl citrate, triisoalkyl citrate (e.g., triisocetyl citrate, triisooctyl citrate, triester of citric acid and an alcohol having a branched alkyl group having 12 and 13 carbon atoms), citric acid triethylhexyl (e.g., tri-2-ethylhexyl citrate), trioctyldodecyl citrate (e.g., tri-2-octyldodecyl citrate), triesters of citric acid and alcohols having alkyl groups of 14 and 15 carbon atoms), octyldodecyl citrate (eg, 2-octyldodecyl citrate), acetyltributyl citrate, isocitric acid and the like. Among these citric acids, one type may be used alone, or two or more types may be combined. Isopropyl is more preferred.

<Gluconic acids>
As used herein, gluconic acids mean gluconic acid, its salts, esters, and gluconolactone (hydrolyzed to produce gluconic acid). Examples of gluconates include zinc gluconate, potassium gluconate, calcium gluconate, iron gluconate, copper gluconate, sodium gluconate, and chlorhexidine gluconate. Gluconate may be a hydrate. Among these gluconic acids, one type may be used alone, or two or more types may be combined. From the viewpoint of more efficiently expressing the desired effects of the present invention, calcium gluconate and gluconic acid are preferable, Calcium is more preferred.

[1.2 Effective amount]
An effective amount for each active ingredient to exert its activity on the target can be appropriately determined according to the target. The dosage for humans is usually 0.00001 mg or more, preferably 0.001 mg or more, more preferably 0.01 mg or more. Thereby, the effect of suppressing saccharification can be sufficiently exhibited. The upper limit is usually 1 g or less, preferably 0.1 g or less. Thereby, the effect of suppressing saccharification can be efficiently exhibited. The lower limit, therefore, the effective amount of each active ingredient is generally 0.00001 mg to 1 g, preferably 0.001 mg to 0.1 g, more preferably 0.01 mg to 0.1 g.

[1.3 Saccharification Reaction Inhibitory Action]
The above active ingredient can suppress glycation reaction (for example, glycation reaction in oral cavity, preferably in teeth). As used herein, the term saccharification reaction refers to the formation of AGEs (AGE-generating reaction) by binding sugar and protein (glycation reaction; Maillard reaction), and then the AGEs act in vivo to discolor tissues (e.g., teeth). , embrittlement, aging, and other symptoms.
The site of action of the above-mentioned active ingredient includes, for example, the oral cavity and the epithelium, preferably the oral cavity, and more preferably the tooth (among them, the dentin). Each active ingredient can be used for the purpose of suppressing (including relieving, preventing or treating) symptoms caused by glycation reaction or permeation reaction. Applications include, for example, glycation reaction inhibitors, discoloration inhibitors, embrittlement inhibitors, whitening agents, and aging inhibitors, including tooth glycation reaction inhibitors, tooth discoloration inhibitors, tooth embrittlement inhibitors, Tooth whitening agents and tooth aging inhibitors are preferred.

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

[2.1 Application target, application part]
The subject of application may be any animal including humans, usually mammals, birds and fish, preferably mammals, and more preferably humans. Applicable subjects may be healthy subjects or patients with diseases caused by AGEs, and may be either young or old. Non-human animals include, for example, mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, and monkeys.

The site of application may be local (for oral cavity, ophthalmic mucosa, skin, or hair) or systemic, preferably oral cavity, more preferably teeth.

[2.2 Dosage form]
Modes of administration include, for example, oral administration (e.g., buccal administration, sublingual administration), parenteral administration (e.g., transdermal and transmucosal administration, intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, pulmonary administration, administration), and among these, less invasive administration forms are preferred, and transdermal transmucosal administration (external use) and oral administration are more preferred.

[2.3 Dosage form]
Agents containing the above active ingredients can be used as pharmaceuticals, quasi-drugs, cosmetics, functional foods, and the like. The dosage form is not particularly limited and includes, for example, liquids, sprays, solids, semi-solids, powders, granules, and sheets.

[2.4 Use in formulations]
The agent containing the above active ingredient can be made into various formulations such as an external agent and an internal agent.

Examples of external preparations include mucosal preparations, skin preparations, and hair preparations, with mucosal preparations being preferred, and oral cavity preparations being more preferred.

Oral preparations include dentifrices (e.g., toothpaste, gel-like toothpaste, wet toothpaste, liquid toothpaste), mouth washes, tongue polishes, oral sprays, oral tablets, gums, mouth fresheners, and gargles. It may be added to tablets, oral pastes, oral gels, oral ointments, and dental sheets.

Skin formulations (external preparations for skin) include, for example, gels, ointments, creams, liquids for external use, lotions, sprays, and packs.

Internal dosage forms (drugs, functional foods) include, for example, internal liquids, syrups, creams, jellies, pastes, tablets, granules, fine granules, capsules (soft capsules, hard capsules) and the like.

As cosmetics, for example, it can be used in dosage forms such as creams, milky lotions, packs, gels, aerosols, and sheets. Specifically, for example, lotions, serums, whitening agents, moisturizers, face masks, milky lotions, foundations, eye shadows, mascara, eyebrows, eyeliners, cheek powders, lipsticks, lip balms, packs, soaps, and other skin products Cosmetics; 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, hair styling agents, etc. be done.

Foods (food compositions) include, for example, health foods, functional foods, health supplements (supplements), dietary supplements, foods for specified health uses, functional nutritional foods, medical foods, foods for the sick, foods for infants, Food compositions with uses such as foods for nursing care and foods for the elderly (for example, for suppressing saccharification reaction, suppressing discoloration, suppressing embrittlement, whitening, and suppressing aging).
Foods include, for example, beverages (e.g., soft drinks, carbonated drinks, nutritional drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks), confectionery (cookies, cakes, gums, candies, tablets, gummies, buns, yokan , pudding, jelly, ice cream, sherbet, etc.), processed marine products (kamaboko, chikuwa, hanpen, etc.), processed livestock products (hamburgers, hams, sausages, wieners, cheese, butter, yogurt, fresh cream, margarine, fermented milk, etc.) ), soups (powdered soups, liquid soups, etc.), staple foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise, shortening, dressings, sauces, sauces, soy sauces, etc.) mentioned.

[2.5 Agent content]
The content of the active ingredient (the content of each of cysteine, hinokitiols, citric acids, and gluconic acids) in each of the above applications 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 exhibited. 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 exhibited. Therefore, the active ingredient of the present invention is preferably 0.0001 to 10% by mass, more preferably 0.0001 to 2% by mass, still more preferably 0.001 to 1% by mass, relative to the total mass of the agent.

[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 include, for example, a medicinal ingredient, a buffer, a solubilizer, a tonicity agent, a stabilizer, a chelate agents, pH adjusters, preservatives, oily ingredients, excipients, disintegrants, binders, lubricants, coating agents, coloring agents, coloring agents, flavoring agents (acidifiers, flavors, sweeteners), antioxidants , Strengthening agent, swelling agent, thickener, surfactant, abrasive, humectant, moisturizer, cooling agent, abrasive, binder, astringent, plant extract, UV absorber, aqueous solvent, preservative , seasonings, food ingredients (including food additives), and other ingredients other than the above active ingredients. The type and content of optional ingredients may be selected according to the application of pharmaceuticals, quasi-drugs, food compositions, cosmetics, dosage forms, administration methods, etc., and may be one or two. A combination of the above may also be used.

<Medicinal Ingredients>
Examples of medicinal ingredients include enzymes such as dextranase, mutanase, amylase, and protease; fluorides such as sodium fluoride, sodium monofluorophosphate, and tin fluoride; allantoin, glycyrrhizic acid, and glycyrrhizinate (eg, glycyrrhizin dipotassium salt), glycyrrhetinic acid, glycyrrhetinic acid derivatives (e.g., stearyl glycyrrhetinate), anti-inflammatory agents such as allantoin chlorohydroxyaluminum, azulene, tranexamic acid, dihydrocholesterol; metal salts such as zinc salts, copper salts, tin salts; anticalculus agents such as condensed phosphates and ethane hydroxydiphosphonate; blood flow promoters such as vitamin E (e.g., tocopherol acetate); hypersensitivity inhibitors such as potassium nitrate, aluminum lactate, and strontium chloride; hydroxyethyl cellulose dimethyl diallyl coating agents such as ammonium chloride; astringents such as vitamin C (eg, ascorbic acid or its salts) and sodium chloride; anticalculus agents; alanine, glycine, proline, potassium L-aspartate, magnesium L-aspartate, aminoethyl Amino acids other than cysteine, such as sulfonic acid; plant extracts such as thyme, Scutellaria root, clove, and hamamelis; calopeptide; polyvinylpyrrolidone, and the like. Other examples include decongestants, antiphlogistic agents, astringents, antihistamines, vitamins, bactericides, local anesthetics, ingredients other than the active ingredients of the present invention that have glycation-inhibiting action, and two or more selected from these. Combinations are also included. Examples of decongestants include naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, and naphazoline nitrate. Examples of anti-inflammatory and astringent agents include neostigmine methyl sulfate, 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, vitamins A (eg, retinol acetate, retinol palmitate), and vitamins E (tocopherol acetate (eg, d-α-tocopherol acetate)). Bactericides include, for example, cetylpyridinium chloride, decalinium chloride, benzalkonium chloride, benzetrium chloride, iodine, potassium iodide, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulphate Examples include isomidin sodium and isopropylmethylphenol. Local anesthetics include, for example, lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, chlorobutanol. Each medicinal ingredient may be used singly or in combination of two or more. The content of the medicinal ingredient can be appropriately set to an effective amount according to a conventional method.

<Surfactant>
Surfactants can be blended with anionic surfactants, nonionic surfactants, and amphoteric surfactants.

Anionic surfactants include, for example, alkyl sulfates, acyl amino acid salts, acyl taurine salts, α-olefin sulfonates, hydrogenated coconut fatty acid monoglyceride monosulfate, and lauryl sulfoacetate. Alkyl groups and acyl groups may be linear or branched, saturated or unsaturated, and usually have 10 to 20 carbon atoms, preferably 12 to 18 carbon atoms, more preferably 12 to 14. Salts may be selected from pharmacologically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and amino acid salts. Specific examples thereof 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; arginine salts and the like. and basic amino acid salts of Among them, inorganic base salts are preferred, alkali metal salts (eg, sodium salts, potassium salts) or ammonium salts are more preferred, and sodium salts are even more preferred.

Examples of alkyl sulfates include lauryl sulfate (sodium lauryl sulfate) and myristyl sulfate. Acyl amino acid salts include acyl glutamates such as lauroyl glutamate, myristoyl glutamate and palmitoyl glutamate; acylglycinates such as N-lauroyl-N-methylglycinate and cocoylglycinate; 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, N-methyl - acyl alanine salts such as N-acyl alanine salts; and acyl aspartates such as lauroyl aspartate. Acyl taurine salts include, for example, lauroyl methyl taurine salts, N-methyl-N-acyl taurine salts, and N-cocoyl methyl taurine salts. 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, for example, hydrogenated coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate.

Nonionic surfactants include, for example, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester (eg, polyoxyethylene sorbitan monostearate), alkylolamide , polyoxyethylene fatty acid ester, polyoxyethylene alkenyl ether, polyglycerin fatty acid ester, sucrose fatty acid ester (eg, maltose fatty acid ester), sugar alcohol fatty acid ester (eg, maltitol fatty acid ester, lactitol fatty acid ester), fatty acid diethanolamide (eg, 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 generally 14-18, and the average number of moles of ethylene oxide added is generally 5-30 mol. The average mole number of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is generally 20 to 100 mol, preferably 20 to 60 mol. The number of carbon atoms in the fatty acid of the sorbitan fatty acid ester is usually 12-18. The number of carbon atoms in the fatty acid of the polyoxyethylene sorbitan fatty acid ester is generally 16-18, and the average number of moles of ethylene oxide added is generally 10-40 mol. The alkyl chain of the alkylolamide usually has 12-14 carbon atoms.

Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaine (eg, lauryldimethylaminoacetic acid betaine), fatty acid amidopropyldimethylaminoacetic acid betaine (eg, cocamidopropyl betaine); Fatty acid acyl-N-carboxymethyl-N-hydroxyethylethylenediamine salts (e.g., N-cocoate acyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine), cocoate imidazolinium betaine, 2-alkyl imidazoline type amphoteric surfactants such as -N-carboxymethyl-N-hydroxyethylimidazolinium betaine; and alkylbetaines such as lauryldimethylaminoacetate betaine.

When a surfactant is included, 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% of the total agent. .2 to 3% by mass.

<Abrasive>
The abrasive may be, for example, either an inorganic abrasive or an organic abrasive. Examples of inorganic abrasives include abrasive silica such as precipitated silica, aluminosilicate, zirconosilicate, crystalline zirconium silicate, and titanium-bonded silica; Calcium phosphate compounds such as tribasic calcium phosphate and calcium pyrophosphate; calcium carbonate abrasives such as calcium carbonate; calcium hydroxide, calcium sulfate and other calcium-based abrasives other than carbonate/phosphate; aluminum oxide, aluminum hydroxide, Aluminum-based materials such as alumina; Silicic acid-based materials such as silicic anhydride, zeolite, and zirconium silicate; Magnesium-based materials, such as magnesium carbonate and magnesium triphosphate; Apatite-based materials, such as hydroxyapatite, fluoroapatite, and calcium-deficient apatite Materials; 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 abrasives. Among these, abrasive silica and calcium phosphate compounds are preferred, and silicic anhydride is more preferred. The amount of abrasive is preferably 50% by mass or less, more preferably 8 to 50% by mass, based on the total amount of the agent.

<Wetting agent>
Wetting agents include, for example, 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. As polyethylene glycol, for example, polyethylene glycol having an average molecular weight of 150 to 6000 is preferable, and polyethylene glycol having an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferable. The average molecular weight is the average molecular weight described in the Standards for Quasi-drug Ingredients 2006. The content of the wetting agent is usually 40% by mass or less, preferably 1 to 30% by mass, based on the entire agent.

<Binder>
As the binding agent, any suitable conventionally known organic binding agent such as polysaccharides, cellulose-based binding agents (e.g., carboxymethylcellulose (CMC), hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, cationic cellulose, etc.), other polysaccharide thickeners (e.g., xanthan gum, guar gum, gellan gum, tragacanth gum, karaya gum, gum arabic, locust bean gum, carrageenan, sodium alginate), synthetic water-soluble polymers (e.g., sodium polyacrylate, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, propylene glycol alginate). Furthermore, inorganic binders such as thickening silica and aluminum silicate can also be contained. The content of the organic binder is preferably 0 to 3% by mass, more preferably 0.1 to 2% by mass, relative to the total agent. The content of the inorganic binder is preferably 0 to 10% by mass, more preferably 1 to 8% by mass.

<Buffer>
Examples of buffering agents include phosphoric acid or salts thereof (e.g. sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate), tartaric acid or salts thereof (e.g. sodium tartrate), acetic acid or salts thereof (e.g. sodium acetate), carbonic acid or salts thereof (e.g. sodium bicarbonate), trometamol, amino acids (e.g. potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), combinations of two or more thereof is mentioned. Examples of solubilizers include polyoxyethylene (e.g., p=60) polyoxyethylene higher fatty acid esters such as hydrogenated castor oil, polyoxyethylene (e.g., p=20) polyoxyethylene sorbitan such as sorbitan monooleate. higher fatty acid esters, propylene glycol, polyethylene glycol, and combinations of two or more of these. Tonicity agents include, for example, sodium chloride, potassium chloride, glycerin, combinations of two or more thereof. Stabilizers include, for example, sodium edetate, cyclodextrins, sulfites, dibutylhydroxytoluene, ascorbic acid, combinations of two or more thereof. Chelating agents include, for example, sodium edetate, combinations thereof. Examples of pH adjusters include sodium hydroxide, potassium hydroxide, hydrochloric acid, and combinations of two or more of these. Examples of antiseptics include paraoxybenzoic acid esters such as methylparaben, ethylparaben, propylparaben, and butylparaben; alcohol derivatives such as phenylethyl alcohol, benzyl alcohol, phenol, and acrinol; sorbic acid and salts thereof (potassium sorbate, etc.); ), benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkylpolyaminoethylglycine, combinations of two or more thereof.

<Moisturizer>
Humectants include, for example, glycerin, concentrated glycerin, sugar alcohols (eg, sorbitol, xylitol, maltitol, mannitol, reduced starch syrup, reduced palatinose, erythritol, lactitol, isomalt), and combinations of two or more thereof.

<Flavoring agent>
Examples of flavoring agents include sweeteners (e.g., sodium saccharin, aspartame, stevia, stevioside, paramethoxycinnamic aldehyde, neohesperidin dihydrochalcone, perillartine, glycyrrhizin, asparatylphenylalanine methyl ester, thaumatin, acesulfame potassium, sucralose, maltitol, , sorbitol, mannitol, reduced starch syrup, reduced palatinose, xylitol, erythritol, artificial sweeteners such as lactitol, etc.), fragrances (e.g. anise oil, cassia oil, wintergreen oil, mastic oil, neroli oil (orange flower oil), lemon Grass 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, paracress oil, vanilla oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, peppermint oil, lychee oil); menthol, carvone, cinnamic aldehyde, anethole, methyl salicylate, eugenol, linalool , limonene, menthone, menthyl acetate, citral, decanal, camphor, borneol, pinene, spiranthol, n-decyl alcohol, citronellol, α-terpineol, citronellyl acetate, ethyl linalool, vanillin, etc. ethyl acetate, ethyl butyrate, isoamyl acetate, hexanal, hexenal, methyl anthranilate, ethyl methyl phenyl glycidate, benzaldehyde, vanillin, ethyl vanillin, furaneol, N-ethyl-p-menthane-3-carboxamide, menthyl lactate, Fragrance ingredients such as ethylene glycol-l-menthyl carbonate; and various prepared flavors such as mint, fruit, herb, etc., which are obtained by combining several fragrance ingredients and natural essential oils (for example, peppermint micron X-8277-T, dry Coated Matcha #421), acidulants (eg, tartaric acid, malic acid), green tea powder.

<Oil component>
Oily components include, for example, fatty acid esters (e.g. glycerin fatty acid esters), hydrocarbons (e.g. paraffin, liquid paraffin, ceresin, squalane, vaseline, microcrystalline wax), higher fatty acids (e.g. lauric acid, myristic acid, olein acids, fatty acids with 8 to 22 carbon atoms such as isostearic acid), higher alcohols (for example, alcohols with 8 to 22 carbon atoms such as lauryl alcohol, cetyl alcohol, cetostearyl alcohol, oleyl alcohol, and isostearyl alcohol), plants Oils and fats (eg, 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 thereof.

<Preservative>
Preservatives include, for example, parahydroxybenzoic acid esters (eg, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate), sodium benzoate, and combinations of two or more thereof.

<Wetting agent>
Wetting agents include, for example, 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. As polyethylene glycol, for example, polyethylene glycol having an average molecular weight of 150 to 6000 is preferable, and polyethylene glycol having an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferable. The average molecular weight is the average molecular weight described in the Standards for Quasi-drug Ingredients 2006. The amount of the wetting agent is generally 40% by mass or less, preferably 1 to 30% by mass, based on the total agent.

<Colorant>
Examples of coloring agents include natural pigments such as safflower red pigment, gardenia yellow pigment, gardenia blue pigment, perilla pigment, monascus pigment, red cabbage pigment, carrot pigment, hibiscus pigment, cacao pigment, spirulina blue pigment, tamarind pigment, Legal pigments 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, riboflavin, sodium copper chlorophyllin, Titanium dioxide etc. are mentioned. When a coloring agent is included, its content is preferably 0.00001 to 3% by mass with respect to the entire agent.

<pH adjuster>
Examples of pH adjusters include organic acids such as phthalic acid, succinic acid, acetic acid, fumaric acid, malic acid, and lactic acid, salts thereof, inorganic acids such as phosphoric acid (orthophosphoric acid), and salts thereof (e.g., potassium salts, sodium salts and ammonium salts), sodium hydroxide, potassium hydroxide and the like. Examples of inorganic acid salts include disodium hydrogen phosphate and sodium dihydrogen phosphate. The content of the pH adjuster can be adjusted so that the pH of the agent after addition is usually 5 to 9, preferably 6 to 8.5. In this specification, the pH value usually refers to the value after 3 minutes at 25°C from 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.

<Solvent>
Examples of the solvent include water (purified water) and ethanol, with water being preferred. A solvent may be used individually by 1 type, or may be used in combination of 2 or more type.

<Excipient>
Excipients include, for example, cellulose such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, crystalline cellulose, ethyl cellulose, methyl ethyl cellulose, low-substituted hydroxypropyl cellulose, and pharmacologically acceptable derivatives thereof; Synthetic polymers such as saponified polyvinyl alcohol; Polysaccharides such as gelatin, gum arabic powder, pullulan, agar, alginic acid, sodium alginate, and xanthan gum; Starches such as corn starch, potato starch, pregelatinized starch, and hydroxypropyl starch, and their pharmacology lactose, lactose granules, fructose, glucose, white sugar, granulated sugar, hydrated glucose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, maltotetraose, lactitol, isomalt, reduced palatinose, reduced starch syrup, powdered reduced maltose syrup, maltitol; magnesium carbonate, calcium carbonate, light anhydrous silicic acid, silicon dioxide (a.k.a. anhydrous silicic acid, fine silicon dioxide), titanium oxide, inorganic excipients such as aluminum hydroxide gel; A combination of two or more of

<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, and hydroxypropyl starch. , partially pregelatinized starch, corn starch, combinations of two or more thereof.

<Binder>
Binders include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, dextrin, starch, pregelatinized starch, combinations of two or more thereof.

<Lubricant>
Lubricants include, for example, 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 of these.

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

[3. Production method〕
The manufacturing method of the agent containing the active ingredient may be determined according to the dosage form, application, and application site. For example, when it is used as a toothpaste, after preparing a component that dissolves in a solvent, other insoluble components are mixed, and defoaming (e.g., reduced pressure, etc.) as necessary. Examples include dispersing and dissolving the active ingredient and optionally other ingredients in an aqueous solvent (e.g. water such as purified water and sterilized water) to prepare a composition and dissolving it in an appropriate container (e.g. , glass, or resin). As for the container, for example, a container for an oral agent includes a laminated tube, and resin such as polyethylene, polypropylene, polyethylene terephthalate, and nylon can be used as the material. In the case of a spray, a container equipped with an atomizing means (for example, a trigger-type, pump-type, or aerosol-type container) may be selected. The obtained toothpaste can be put into a container to be used as a product. The shape and material of the container are not particularly limited, and containers commonly used for oral compositions can be used.

[4. how to use〕
The method of using the agent containing the active ingredient may be, for example, administering the agent to the application site. In the case of oral preparations, put an appropriate amount of the agent on the toothbrush and brush the surface of the teeth, then rinse with water after use (dentifrice), or spit out after gargling with an appropriate amount of the agent in the mouth (mouthwash). According to In the case of external preparations, the number of administrations per day is not particularly limited, but may be, for example, 1 to 6 times or more.

The present invention will be described in detail below by way of examples. However, the following examples do not limit the present invention.

[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 Co., 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))

Examples 1 to 6 and Comparative Example 1 [Test 1: AGEs production suppression test]
<Preparation of tooth section>
Human teeth extracted at a dental clinic were used with patient consent. Sections of specific thickness were made using a microcutter.

<Preparation of sample solution>
200 mM ribose was dissolved in PBS (x1) pH 7.4 to prepare a tooth saccharification solution. An evaluation compound was dissolved in this solution to a final concentration of 100 mM to prepare a sample solution.

<AGEs activity measurement>
Tooth sections obtained from the same specimen were immersed in 1 mL each of PBS solution (no ribose and evaluation compound added), 200 mM ribose solution (solution for saccharification), and sample solution, and reacted at 60° C. for 3 days. A 1N HCl solution was added to the sliced tooth after saccharification at a ratio of 500 μL per 30 mg, and hydrolyzed at 110° C. for 16 hours to obtain a solution. The lysate was measured with a microplate reader (Flex Station 3, manufactured by Molecular Devices). Fluorescence at 385 nm generated by irradiation with excitation light at 335 nm was measured (measurement index: pentosidine).

<Calculation of AGEs production suppression rate>
From the measured fluorescence intensity, the AGEs production suppression rate was calculated according to the following formula.
AGEs production suppression rate (%) = (measured value B - measured value C) / (measured value B - measured value A) x 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 Examples and Comparative Examples, respectively.
Each value is an average of N=3. Table 1 shows the results.

Compared to Comparative Example 1, which is an antioxidant, the AGEs production inhibition rate is high in Examples 1 to 6, and among them, Examples 1 and 2 show a high production inhibition rate of 90% or more (Table 1). .

Examples 7 to 10 [Test 2: Human tooth yellowing suppression test]
<Preparation of test piece>
A test piece was prepared by equally halving a human tooth similar to <Test 1>.

<Preparation of sample solution>
A tooth saccharification solution was prepared by dissolving 100 mM ribose in PBS. An evaluation compound was dissolved in this solution to a final concentration of 100 mM to prepare a sample solution.

<Analysis of yellowing of teeth>
The test pieces were immersed in 5 mL each of a 100 mM ribose solution (solution for saccharification) and a sample solution, and subjected to a saccharification reaction at 60° C. for 4 days. The test pieces before and after the saccharification reaction were photographed with a microscope (manufactured by KEYENCE, VHX-2000), and the coloration (yellowing) of the teeth was analyzed by image analysis. Analysis software is MATLAB (registered trademark) (manufactured by MathWorks). After converting the color display of the image from the RGB color system to the L*a*b* color system, the color difference ΔE value is calculated and the amount of change in color tone. was compared between the 100 mM ribose solution and each sample solution.

<Calculation of coloring suppression rate>
The color difference ΔE value before and after the saccharification reaction in a 100 mM ribose solution was calculated from the following formula using the L* value, a* value and b* value, and the coloring inhibition rate was calculated.
ΔE = {(L* value after saccharification - L* value before saccharification) ² + (a* value after saccharification - a* value before saccharification) ² + (b* value after saccharification - b* value before saccharification) ² } ^{1/ 2}
Coloring inhibition rate (%) = {1-(sample solution ΔE value/saccharification solution ΔE value)} × 100
Each coloring suppression rate is an average value of N=4. The results are shown in Table 2.

All of the examples showed a good coloration suppression rate, and an effect of suppressing yellowing was confirmed. Among them, Examples 8 and 9 had a high coloring suppression rate of 35% or more (Table 2).

Examples 11 to 14 and Comparative Example 2 [Test 3: Human tooth embrittlement suppression test]
<Preparation of test piece>
A test piece was prepared by equally halving a human tooth similar to <Test 1>.

<Preparation of sample solution>
A tooth saccharification solution was prepared by dissolving 200 mM ribose in PBS. An evaluation compound was dissolved in this solution to a final concentration of 100 mM to prepare a sample solution.

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

<Calculation of tooth embrittlement suppression rate>
A difference F in Young's modulus between the PBS solution and the solution for saccharification and a difference E in Young's modulus between the solution for saccharification and the sample solution were calculated, and the embrittlement inhibition rate was calculated by the following formula.
Embrittlement suppression rate (%) = (difference E/difference F) x 100
Each embrittlement suppression rate is an average value of N=3. The results are shown in Table 3.

All of the examples exhibited a good embrittlement inhibition rate, confirming the effect of inhibiting tooth embrittlement. Among them, Examples 11 and 12 had embrittlement suppression rates as high as 60% or more (Table 3).

The above examples demonstrate that the agent of the present invention can suppress the saccharification reaction that occurs in vivo, and can suppress the coloring and embrittlement of teeth.

Claims (9)

A tooth saccharification inhibitor containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids and gluconic acids. A tooth discoloration inhibitor containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids and gluconic acids. A tooth embrittlement inhibitor containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids and gluconic acids. A tooth whitening agent containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids and gluconic acids. A tooth aging inhibitor containing one or more selected from the group consisting of cysteine, hinokitiols, citric acids and gluconic acids. The agent according to any one of claims 1 to 5, wherein the citric acid is isopropyl citrate. The agent according to any one of claims 1 to 6, wherein the gluconic acid is calcium gluconate. An oral preparation containing the agent according to any one of claims 1 to 7. A food composition comprising the agent according to any one of claims 1 to 7.