Advanced glycation end product (ART) degrading agent

Abstract

The present invention aims to provide an advanced glycation end product (AGE) degrading agent that has good AGEs degradation activity and can function well in the oral cavity. [Solution] The present invention provides a final glycation end product (FRI) degrading agent containing one or more selected from nicotinic acid, pyridoxine, aspartic acid, malic acid, pyrrolidone carboxylic acid, methionine, cysteine, tartaric acid, gluconic acid, propionic acid, tryptophan, and salts thereof.

Description

Technical Field

[0001] The present invention relates to a final glycation product degrading agent.

Background Art

[0002] The final glycation products (hereinafter sometimes referred to as AGEs) generated by the glycation reaction have been reported to be related to various diseases such as aging of the body, arteriosclerosis, dementia, and inflammation.

[0003] In the gums as well, AGEs generated by the reaction between proteins and sugars induce gum inflammation and are a cause of oral diseases such as periodontal disease. In particular, since oxidative stress promotes the glycation reaction, diabetic patients and the elderly with high levels of sugar and oxidative stress in the body are at a high risk of developing periodontal disease in which AGEs tend to accumulate. Once formed, AGEs continue to induce inflammation, so decomposing the formed AGEs and eliminating the cause of inflammation is important for maintaining healthy gums.

[0004] Patent Document 1 describes that aminoguanidine, pyridoxamine, N-phenacylthiazolium bromide, alagebrium, and flavonoids act as breakers of arterial AGEs.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] The agent of Patent Document 1 is targeted at emphysema or chronic obstructive pulmonary disease (COPD), and no final glycation product degrading agent that acts in the oral cavity has been known. An object of the present invention is to provide a final glycation product degrading agent that has a good AGEs degrading action and can function well in the oral cavity. [Means for solving the problem]

[0007] The present invention provides the following: [1] A final glycation end product degrading agent containing one or more selected from nicotinic acid, pyridoxine, aspartic acid, malic acid, pyrrolidone carboxylic acid, methionine, cysteine, tartaric acid, gluconic acid, propionic acid, tryptophan, and salts thereof. [2] The final glycation product degrading agent according to [1], comprising one or more selected from nicotinic acid, aspartic acid, pyridoxine, malic acid, pyrrolidone carboxylic acid, and salts thereof. [3] The final glycation product degrading agent according to [1], comprising one or more selected from nicotinic acid, malic acid, propionic acid, pyrrolidone carboxylic acid and salts thereof. [4] A final glycation end product degrading agent contained in an oral preparation as a final glycation end product degrading component, as described in any one of items [1] to [3]. [5] The advanced glycation end product degrading agent described in [4], wherein the oral preparation is selected from toothpaste, mouthwash, mouth spray, topical application, patch, oral dissolving agent, oral disintegrating agent, and masticatory agent. [6] An anti-glycation oral composition containing one or more selected from nicotinic acid, pyridoxine, aspartic acid, malic acid, pyrrolidone carboxylic acid, methionine, cysteine, tartaric acid, gluconic acid, propionic acid, tryptophan, and salts thereof as components for decomposing advanced glycation end products. [7] The oral composition for anti-glycation according to [6], further containing one or more selected from the group consisting of azulene, hinokitiol, copper chlorophyll, lysozyme chloride, epsilon-aminocaproic acid, glycyrrhizic acid, allantoin, and citric acid. [8] An anti-glycation agent containing one or more selected from nicotinic acid, malic acid, propionic acid, pyrrolidone carboxylic acid and salts thereof. [Effects of the Invention]

[0008] The present invention provides an advanced glycation end product (AGE) degrading agent that exhibits good degradation activity against AGEs, particularly in the oral cavity. The agent of the present invention can be used as various pharmaceuticals, quasi-drugs, cosmetics, and foods, such as oral preparations and oral compositions. [Modes for carrying out the invention]

[0009] [1. Advanced Glycation End Product Degrading Agent] [1.1 Active Ingredients] The active ingredient of the advanced glycation end product (AGE) degrading agent is at least one of the following: nicotinic acid, pyridoxine, aspartic acid, malic acid, pyrrolidone carboxylic acid, methionine, cysteine, tartaric acid, gluconic acid, propionic acid, and tryptophan. Of these, if optical isomers exist, they may be in L-form, D-form, or racemic form.

[0010] Each compound may also be in the form of a salt. The salt can 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 salt, potassium salt, calcium salt, magnesium salt, ammonium salt, zinc salt, copper salt, and iron salt; inorganic acid salts such as hydrochloride, nitrate, phosphate, sulfate, and borate; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt; and basic amino acid salts such as arginine salt. Among these, inorganic base salts and inorganic acid salts are preferred, and alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (calcium salt, magnesium salt), zinc salt, copper salt, iron salt, and hydrochloride salt are more preferred.

[0011] As salts of aspartic acid, alkali metal salts of aspartic acid are preferred, sodium aspartate and potassium aspartate are more preferred, and sodium aspartate is even more preferred. As salts of tartaric acid, alkali metal salts of tartaric acid are preferred, potassium bitartrate, sodium bitartrate, potassium tartrate, sodium tartrate, sodium potassium tartrate, and potassium bitartrate are even more preferred. As salts of gluconic acid, zinc salts, copper salts, iron salts, and alkali metal salts of gluconic acid are preferred, and zinc gluconate, copper gluconate, iron gluconate, sodium gluconate, and potassium gluconate are even more preferred. As salts of pyrrolidone carboxylic acid, alkali metal salts of pyrrolidone carboxylic acid are preferred, and sodium pyrrolidone carboxylic acid and potassium pyrrolidone carboxylic acid are even more preferred. As salts of malic acid, alkali metal salts of malic acid are preferred, sodium malate, disodium malate, and potassium malate are even more preferred, and disodium malate is even more preferred. As the salt of nicotinic acid, alkali metal salts and hydrochloride salts of nicotinic acid are preferred. As the salt of pyridoxine, pyridoxine hydrochloride salt is preferred. As the salt of cysteine, hydrochloride salt is preferred. As the salt of methionine, alkali metal salts of methionine are preferred, and sodium methionine is more preferred.

[0012] The active ingredient may be one or a combination of two or more. Preferably, the active ingredient contains at least one selected from nicotinic acid, aspartic acid, pyridoxine, malic acid, pyrrolidone carboxylic acid, and salts thereof. Alternatively, it is preferable to contain at least one selected from nicotinic acid, malic acid, propionic acid, pyrrolidone carboxylic acid, and salts thereof.

[0013] [1.2 Effect] Each of the above components can be used as a degrading agent for advanced glycation end products (AGEs). In this specification, advanced glycation end products (AGEs) are substances with complex structures that are produced by the non-enzymatic binding of sugars to proteins, nucleic acids, and lipids (glycation reactions; e.g., Maillard reaction). Examples of AGEs include carboxymethyllysine, carboxyethyllysine, carboxymethylarginine, argupyrimidine, imidazolons (e.g., hydroimidazolon), pentosidine, crosulin, pyropyridine, pyrarine, glucospan, glyoxal-lysine dimer, methylglyoxal-lysine dimer, and 3-deoxyglucosone-lysine dimer. In this specification, degradation of AGEs means that a part of the structure of the AGEs is broken down and converted into a substance other than the AGEs, and the site of degradation and the degree of degradation are not particularly limited.

[0014] Of the above components, propionic acid, nicotinic acid, malic acid, and their salts have glycation-degrading properties and can therefore be used as anti-glycation agents.

[0015] The agent of the present invention is preferably used for the purpose of gum care, suppression of aging such as periodontal disease and skin aging, prevention of dry eye, cataracts, retinopathy, presbyopia, diabetes, bone diseases, and other diseases.

[0016] [1.3 Effective dose] The effective amount of each component can be appropriately determined depending on the target of application, but the amount used per dose in humans is usually 0.00001 mg or more, preferably 0.001 mg or more, and more preferably 0.01 mg or more. The upper limit is usually 1 g or less, preferably 0.1 g or less. In particular, when the means of administration is local administration (external application), the effective concentration in the administered preparation is preferably 0.0001% by mass or more at the lower limit, and more preferably 0.001% by mass. The upper limit is preferably 10% by mass or less, and more preferably 1% by mass or less.

[0017] [1.4 Combinations with other ingredients] Each of the above components may be used in combination with other components. Examples of other components include azulene, hinokitiol, copper chlorophyll, lysozyme chloride, epsilon-aminocaproic acid, glycyrrhizic acid, allantoin, and citric acid, and combinations of two or more selected from these. These components have an AGEs production inhibitory effect.

[0018] [2. Uses] The agent of the present invention can be used as quasi-drugs, pharmaceuticals, cosmetics, and foods, either alone or together with other components as necessary.

[0019] [2.1 Application Targets, Application Sites] The application targets of the agent of the present invention may be animals including humans, usually mammals, birds, fish, preferably mammals, more preferably humans. The application targets may be healthy individuals, the elderly, infected individuals or those suspected of being infected. Examples of animals other than humans include mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, monkeys, etc. Among them, patients with diseases prone to AGEs accumulation (for example, diabetic patients), and the elderly can be mentioned.

[0020] The application site of the agent of the present invention may be either local (mucous membranes for oral use, ophthalmic use, etc., skin use, hair use) or systemic (oral administration), but oral use is preferred. The agent of the present invention can be used as an oral composition or an oral preparation.

[0021] [2.2 Dosage Forms] Examples of dosage forms when using the agent of the present invention include liquid, gel, cream (paste), powder (powder), granule, tablet, film, sheet, and are not particularly limited. Also, depending on the choice of container, it can be made into a spray agent or the like.

[0022] [2.3 Administration Forms] Examples of administration methods include oral administration (by hand), parenteral administration (e.g., transdermal / transmucosal administration, intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, transpulmonary administration), and among these, less invasive administration methods are preferred, with transdermal / transmucosal administration (topical application) and oral administration being more preferred.

[0023] [2.4 Usage] The agent of the present invention can be incorporated into oral preparations and oral compositions as a component for degrading advanced glycation end products (AGEs) and an anti-glycation component. These can be used as quasi-drugs, pharmaceuticals, cosmetics, and foods, and can be used as products for AGEs degrading and anti-glycation. Among these, oral preparations and oral compositions are preferred, and oral preparations and oral compositions for AGEs degrading and anti-glycation are more preferred.

[0024] The formulation may be for topical use or as an oral preparation. Examples of topical preparations include those for mucous membranes, skin, and hair, but mucous membrane preparations are preferred, oral preparations are more preferred, and it is particularly preferred that they be for gum care, periodontal disease, and the treatment and prevention of oral diseases.

[0025] Oral preparations include toothpastes (e.g., toothpaste, toothpaste gel, moistened toothpaste, liquid toothpaste), mouthwashes, mouth sprays, topical agents, adhesive patches, oral dissolving agents, chewing agents, oral disintegrating agents (tablets), gum care agents, tongue polishing agents, oral tablets, gums, oral films, mouth fresheners, gargle tablets, oral pastes, oral gels, and oral ointments.

[0026] Examples of skin-based formulations (topical skin preparations) include gels, ointments, creams, topical solutions, lotions, sprays, and packs.

[0027] Examples of oral dosage forms (pharmaceuticals, functional foods) include oral solutions, syrups, creams, jellies, pastes, tablets, granules, fine granules, and capsules (soft capsules, hard capsules).

[0028] As cosmetics, it can be used in dosage forms such as creams, lotions, packs, gels, aerosols, and sheets. Specifically, examples include skin cosmetics such as lotions, serums, whitening agents, moisturizers, face masks, emulsions, foundations, eyeshadows, mascaras, eyebrow pencils, eyeliners, cheek 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-in treatments, hair dyes, and hair styling products.

[0029] Examples of food products (food compositions) include food compositions with specific uses such as health foods, functional foods, health supplements, nutritional supplements, foods for specified health uses, foods with nutritional function, medical foods, foods for the sick, infant foods, foods for elderly care, and foods for the elderly.

[0030] [2.5 Content of the agent] The content of the final saccharification product decomposition agent (in terms of active ingredient) of the present invention in each of the above applications may be determined based on the effective amount described above and is not particularly limited. For example, it is preferably 0.0001% by mass or more, and more preferably 0.001% by mass or more, based on the total mass of the agent.

[0031] [2.6 Optional components] When the agent of the present invention is in the form of a so-called composition (formulation) containing other optional components, examples of other components include, but are not limited to, pharmaceutically active ingredients, buffers, solubilizers, isotonic agents, stabilizers, chelating agents, pH adjusters, preservatives, oily components, excipients, disintegrants, binders, lubricants, coating agents, colorants, color fixatives, flavoring agents (acidulants, fragrances, sweeteners), antioxidants, strengtheners, leavening agents, thickeners, surfactants, abrasives, humectants, moisturizers, cooling agents, abrasives, binders, astringents, plant extracts, UV absorbers, aqueous solvents, preservatives, seasonings, and food ingredients (including food additives). The type and content of optional components may be selected according to the intended use of the pharmaceutical, quasi-drug, food composition, and cosmetic, and / or the dosage form, administration method, etc., and may be one type or a combination of two or more types.

[0032] <Medicinal ingredients> Examples of medicinal ingredients include enzymes such as dextranase, mutanase, amylase, protease, and lithocene enzyme; fluorides such as sodium fluoride, sodium monofluorophosphate, and tin fluoride; anti-inflammatory agents such as tranexamic acid and dihydrocholesterol; metal salts such as zinc salts, copper salts, and tin salts; tartar preventatives 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; coating agents such as hydroxyethylcellulose dimethyldiallylammonium chloride; astringents such as vitamin C (e.g., ascorbic acid or its salts) and sodium chloride; water-soluble copper compounds such as copper citrate; tartar preventatives; amino acids such as alanine, glycine, and proline; plant extracts such as thyme, scutellaria baicalensis, clove, and witch hazel; caropeptides; and polyvinylpyrrolidone. Other examples include decongestants, anti-inflammatory agents, astringents, antihistamines, vitamins, amino acids, disinfectants, local anesthetics, components other than the active ingredients in the present invention that have an inhibitory effect on the formation of AGEs or an anti-inflammatory effect, and combinations of two or more selected from these. 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, and sodium cromoglycate. Examples of antihistamines include iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isotipendyl hydrochloride, and chlorpheniramine maleate. Examples of vitamins include flavin adenine dinucleotide sodium, cyanocobalamin, vitamin A compounds (e.g., retinol acetate, retinyl palmitate), and vitamin E compounds (tocopherol acetate (e.g., d-α-tocopherol acetate)). Examples of amino acids include aminoethylsulfonic acid and chondroitin sulfate sodium.Examples of disinfectants include cetylpyridinium chloride, decalinium chloride, benzalkonium chloride, benzethorium 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 active ingredient may be used individually or in combination of two or more. The effective amount of each active ingredient can be appropriately determined according to conventional methods.

[0033] <Surfactants> The surfactant may be anionic, nonionic, or amphoteric.

[0034] Examples of anionic surfactants include alkyl sulfates, acyl amino acid salts, acyl taurine salts, α-olefin sulfonates, hydrogenated coconut fatty acid monoglyceride monosulfates, and lauryl sulfoacetate. The alkyl and acyl groups may be linear or branched, saturated or unsaturated, and typically have 10 to 20 carbon atoms, preferably 12 to 18, and more preferably 12 to 14. The salt can be selected from pharmacokinetically acceptable salts. Examples of pharmacokinetically 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, alkali metal salts (e.g., sodium salts, potassium salts) or ammonium salts are more preferred, and sodium salts are even more preferred.

[0035] Examples of alkyl sulfates include lauryl sulfate (sodium lauryl sulfate) and myristyl sulfate. Examples of acyl amino acid salts include acyl glutamates such as lauroyl glutamate, myristoyl glutamate, and palmitoyl glutamate; acyl glycines such as N-lauroyl-N-methylglycine and cocoyl glycine; acyl alanines such as N-lauroyl-β-alanine, N-myristyl-β-alanine, N-cocoyl-β-alanine, N-lauroyl-N-methyl-β-alanine, N-myristoyl-N-methyl-β-alanine, and N-methyl-N-acyl alanine; and acyl aspartates such as lauroyl aspartate. Examples of acyl taurine salts include lauroyl methyl taurine, N-methyl-N-acyl taurine, and N-cocoyl methyl taurine. Examples of α-olefin sulfonates include α-olefin sulfonates with 12 to 18 carbon atoms, such as tetradecene sulfonate. Other examples of anionic surfactants include hydrogenated coconut fatty acid monoglyceride monosulfate sodium and lauryl sulfoacetate sodium.

[0036] 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 polyoxyethylene alkyl ethers is usually 14 to 18, and the average number of moles of ethylene oxide added is usually 5 to 30 moles. The average number of moles of ethylene oxide added to polyoxyethylene hydrogenated castor oil is usually 20 to 100 moles, preferably 20 to 60 moles. The number of carbon atoms in the fatty acids of sorbitan fatty acid esters is typically 12 to 18. The number of carbon atoms in the fatty acids of polyoxyethylene sorbitan fatty acid esters is typically 16 to 18, and the average number of moles of ethylene oxide added is typically 10 to 40 moles. The number of carbon atoms in the alkyl chain of alkylolamides is typically 12 to 14.

[0037] Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaine (e.g., lauryldimethylaminoacetic acid betaine) and fatty acid amidopropyldimethylaminoacetic acid betaine (e.g., cocamidopropyl betaine); imidazoline-type amphoteric surfactants such as N-fatty acid acyl-N-carboxymethyl-N-hydroxyethylethylenediamine salts (e.g., N-coconut oil fatty acid acyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine), coconut oil fatty acid imidazolinium betaine, and 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine; and alkylbetaines such as lauryldimethylaminoacetic acid betaine.

[0038] When surfactants are included, the content of anionic, nonionic, and amphoteric surfactants is usually 0.01 to 10% by mass of the total agent, preferably 0.1 to 5% by mass, and more preferably 0.2 to 3% by mass.

[0039] <Abrasive> The abrasive can be either an inorganic or 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 dicalcium phosphate dihydrate or anhydrous, monocalcium phosphate, tricalcium phosphate, and calcium pyrophosphate; calcium carbonate abrasives such as calcium carbonate; calcium abrasives other than carbonate / phosphate, 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 trimagnesium 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. Of these, abrasive silica and calcium phosphate compounds are preferred, and anhydrous silicic acid is more preferred. The amount of abrasive is preferably 50% by mass or less of the total amount of the agent, and more preferably 8 to 50% by mass.

[0040] <Humectant> Examples of humectants include sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include 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 saccharifies. As for polyethylene glycol, polyethylene glycol with an average molecular weight of 150 to 6000 is preferred, and polyethylene glycol with an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferred. The average molecular weight is the average molecular weight described in the 2006 Standards for Raw Materials of Quasi-Drugs. The content of the humectant is usually 40% by mass or less of the total amount of the agent, and preferably 1 to 38% by mass.

[0041] <Binding agent> Examples of binders include conventionally known and suitable organic binders, such as polysaccharides, cellulosic binders (e.g., carboxymethylcellulose (CMC, sodium salt), hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, cationized cellulose, etc.), other polysaccharide thickeners (e.g., xanthan gum, guar gum, gellan gum, tragacanth gum, karaya gum, arabic gum, locust bean gum, carrageenan, sodium alginate), and 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 included. The content of organic binders is preferably 0 to 3% by mass, more preferably 0.1 to 2% by mass, relative to the total amount of the agent. The content of inorganic binders is preferably 0 to 10% by mass, more preferably 1 to 8% by mass.

[0042] <buffering agent> Examples of buffering agents include citric acid or its salts (e.g., sodium citrate), phosphoric acid or its salts (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate), acetic acid or its salts (e.g., sodium acetate), carbonic acid or its salts (e.g., sodium bicarbonate), trometamol, amino acids (e.g., aminoethylsulfonic acid, glutamic acid, sodium glutamate), and combinations of two or more of these. Examples of solubilizers include polyoxyethylene (e.g., p=60) hydrogenated castor oil and other polyoxyethylene higher fatty acid esters, polyoxyethylene (e.g., p=20) sorbitan monooleate and other polyoxyethylene sorbitan higher fatty acid esters, propylene glycol, polyethylene glycol, and combinations of two or more of these. Examples of isotonic agents include sodium chloride, potassium chloride, glycerin, and combinations of two or more of these. Examples of stabilizers include sodium edetate, cyclodextrin, sulfites, citric acid or its salts, dibutylhydroxytoluene, ascorbic acid, and combinations of two or more of these. Examples of chelating agents include sodium edetate, sodium citrate, and combinations of these. Examples of pH adjusters include sodium hydroxide, potassium hydroxide, hydrochloric acid, and combinations of two or more of these. Examples of preservatives include para-hydroxybenzoic 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, chlorhexidine gluconate, cetylpyridinium chloride, alkylpolyaminoethylglycine, and combinations of two or more of these.

[0043] <Moisturizer> Examples of humectants include glycerin, concentrated glycerin, sugar alcohols (e.g., sorbitol, xylitol, maltitol, mannitol, reduced starch syrup, reduced palatinose, erythritol, lactitol, isomalt), and combinations of two or more of these.

[0044] <Flavoring agent> Examples of flavoring agents include sweeteners (e.g., sodium saccharin, aspartame, stevia, stevioside, paramethoxycinnamaldehyde, neohesperidin dihydrochalcone, perillartin, aspartylphenylalanine methyl ester, thaumatin, acesulfame potassium, sucralose, maltitol, sorbitol, mannitol, reduced starch syrup, reduced palatinose, xylitol, erythritol, lactitol and other artificial sweeteners), and flavorings (e.g., anise oil, cassia). Natural essential oils such as oil, wintergreen oil, mastic oil, neroli oil (orange blossom 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, paraclete oil, vanilla oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, peppermint oil, lychee oil, etc.); menthol, carvone, cinnamaldehyde, ane Fragrance components contained in the above natural essential oils, such as chol, 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 ethyl acetate Fragrance components such as ylglycidate, 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 (e.g., Peppermint Micron X-8277-T, Drycoat Matcha #421) formed by combining several fragrance components and natural essential oils, as well as acidulants (e.g., citric acid, tartaric acid, malic acid) and green tea powder.

[0045] <Oily components> 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 with 8 to 22 carbon atoms such as lauric acid, myristic acid, oleic acid, and isostearic acid), higher alcohols (e.g., alcohols with 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.

[0046] <Preservatives> Examples of preservatives include parahydroxybenzoic acid esters (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate), sodium benzoate, and combinations of two or more of these.

[0047] <Humectant> Examples of wetting agents include sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include 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 saccharifies. As for polyethylene glycol, polyethylene glycol with an average molecular weight of 150 to 6000 is preferred, and polyethylene glycol with an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferred. The average molecular weight is the average molecular weight described in the 2006 Standards for Raw Materials of Quasi-Drugs. The amount of wetting agent is usually 40% by mass or less of the total amount of the agent, and preferably 1 to 30% by mass.

[0048] <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, titanium dioxide, etc. When a colorant is included, its content is preferably 0.00001 to 3% by mass based on the whole agent.

[0049] <pH adjuster> Examples of pH adjusters include organic acids such as phthalic acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid, and lactic acid or their salts (such as sodium citrate), inorganic acids such as phosphoric acid (orthophosphoric acid) or their salts (such as potassium salts, sodium salts, and ammonium salts), 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.

[0050] <Solvent> Examples of solvents include water (purified water), lower monohydric alcohols such as ethanol, etc., and water is preferred. The solvent may be used alone or in combination of two or more.

[0051] <Excipient> Excipients include, for example, cellulose and its pharmacologically acceptable derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, methylethylcellulose, and low-substituted hydroxypropylcellulose; synthetic polymers such as polyvinylpyrrolidone and partially saponified polyvinyl alcohol; polysaccharides such as gelatin, acacia powder, pullulan, agar, alginic acid, sodium alginate, and xanthan gum; corn starch, potato starch, pregelatinized starch, and hydroxypropyl starch. Starches such as those listed above and their pharmacologically acceptable derivatives; lactose, lactose granules, fructose, glucose, sucrose, granulated sugar, hydrated glucose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, maltotetraose, lactitol, isomalt, reduced palatinose, reduced starch syrup, powdered reduced maltose syrup, maltitol; inorganic excipients such as magnesium carbonate, calcium carbonate, light anhydrous silicic acid, silicon dioxide (also known as anhydrous silicic acid, fine-grained silicon dioxide), titanium dioxide, and aluminum hydroxide gel; and combinations of two or more of these.

[0052] <Disintegrant> Examples of disintegrants include povidone, crospovidone, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethyl starch sodium, croscarmellose sodium, cross-linked insoluble polyvinylpyrrolidone, hydroxypropyl starch, partially pregelatinized starch, corn starch, and combinations of two or more of these.

[0053] <Binder> Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin, starch, pregelatinized starch, and combinations of two or more of these.

[0054] <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 of these.

[0055] <Other optional components> Examples of optional components other than those mentioned above include polyisobutylene, polybutadiene, urethane, silicone, and natural rubber. The content of these other optional components can be appropriately set within a range that does not hinder the effects of the present invention.

[0056] [3. Manufacturing method] The manufacturing method for pharmaceutical formulations and oral compositions may be determined according to the respective dosage form, use, and application site. For example, when used as a toothpaste, one method involves preparing the components that dissolve in a solvent, then mixing in other insoluble components, and performing degassing (e.g., under reduced pressure) as needed. Another example is to prepare a composition by dispersing the active ingredient and other components used as needed in an aqueous solvent (e.g., purified water, sterile water, etc.), dissolving them, and filling it into a suitable container (e.g., glass, resin). For oral preparations, a laminate tube is an example of a container, and the material may be, for example, a resin such as polyethylene, polypropylene, polyethylene terephthalate, or nylon. For liquid formulations such as mouthwashes, a resin bottle such as polyethylene terephthalate is an example. For spray formulations, a container equipped with a spraying mechanism (e.g., trigger type, pump type, aerosol type container) should be selected. The resulting toothpaste can be contained in a container to make a product. The shape and material of the container are not particularly limited, and containers normally used for oral compositions can be used.

[0057] [4. How to use] The method of use for each agent is not particularly limited, as long as it involves administering the agent to the application site. The number of administrations per day is also not particularly limited, but may be, for example, 1 to 6 times, or more. In the case of oral preparations and oral compositions, the method may be to place an appropriate amount of the agent on a toothbrush, brush the surface of the teeth, and rinse with water after use (toothpaste); to take an appropriate amount of the agent into the mouth, gargle, and then spit it out (mouthwash); to spray it into the oral cavity (spray); to apply it to the gums using a finger or tool (topical agent); or to lick or chew it in the oral cavity until it disintegrates or dissolves (tablet), etc. [Examples]

[0058] The present invention will be described in detail below with reference to examples. However, the following examples are not intended to limit the present invention.

[0059] (Experimental Example 1) Evaluation of AGEs (glycated BSA) resolution by fluorescence attenuation Two volumes of 30% ribose solution and one volume of 24% bovine serum albumin (BSA) solution were mixed to prepare a solution containing these, which was cultured at 37°C for 6 days, and then dialyzed to obtain glycated BSA (AGEs).

[0060] Equal volumes of 20 mg protein / ml glycated BSA solution and 100 mM solutions of each seed (Tables 1 and 2) were mixed. Fluorescence at 440 nm at an excitation wavelength (Ex.) of 370 nm was measured (initial fluorescence), and the mixture was incubated at 37°C for 6 days. Fluorescence at 440 nm at an excitation wavelength (Ex.) of 370 nm was then measured again (post-reaction fluorescence).

[0061] The fluorescence retention rate (fluorescence after reaction / initial fluorescence) (%) was calculated from the measurement results. As a control, the relative value was calculated when the fluorescence retention rate when PBS was added instead of the seed was set to 100%. Compounds that showed a lower fluorescence retention rate than the control (relative value less than 100%) were judged to have a saccharification effect.

[0062] (Experimental Example 2) Evaluation of glycation reaction rate by quantitative determination of carboxymethyllysine Two volumes of 30% ribose solution and one volume of 24% BSA solution were mixed to prepare a solution containing these, which was cultured at 37°C for 6 days, and then dialyzed to obtain glycated BSA (AGEs).

[0063] Equal volumes of 20 mg protein / ml glycated BSA solution and 100 mM solutions of each seed (Tables 1 and 2) were mixed and incubated at 37°C for 6 days. The amount of the inflammatory substance carboxymethyllysine (CML) in the solution was then measured using an ELISA kit (MBL).

[0064] As a control, the amount of CML obtained when PBS was added instead of the seed was used and evaluated as follows.

[0065] CML level less than 70% of control: ◎ CML level less than 90% of control but 70% or more: ○ CML levels less than 99% of the control but 90% or more: △ CML level is 99% or more of the control: ×

[0066] (Experimental Example 3) Evaluation of glycation degradation ability by reducing inflammation-inducing capacity Two volumes of 30% ribose solution and one volume of 24% BSA solution were mixed to prepare a solution containing these, which was cultured at 37°C for 6 days, and then dialysis was performed to obtain glycated BSA (AGEs).

[0067] Equal volumes of 20 mg protein / ml glycated BSA solution and 100 mM solutions of each seed (Tables 1 and 2) were mixed and cultured at 37°C for 8 days. After dialysis, the solution was sterilized by filtration, and after degradation testing, samples were obtained.

[0068] The obtained degradation test samples were cultured as gingival fibroblasts in a medium prepared by adding 1 mg protein / ml of Dulbecco's modified Eagle agar (DMEM:gibco).

[0069] Interleukin-6 (IL-6) production after 24 hours was analyzed using ELISA (R&D).

[0070] As a control, the amount of IL6 produced when AGEs degradation products obtained by adding phosphate-buffered saline (PBS) instead of the seed was added was used for evaluation as follows. IL-6 levels less than 70% of control: ◎ IL-6 levels less than 95% of control but 70% or more: ○ IL-6 levels are 95% or higher than the control: ×

[0071] (Experimental Example 4) Fluorescence reduction (glyceraldehyde-saccharified BSA) Two volumes of 5M glyceraldehyde solution and one volume of 20% BSA solution were mixed to prepare a solution containing these, which was incubated at 37°C for 6 days, and then dialyzed to obtain glyceraldehyde-glycated BSA (AGEs).

[0072] Equal volumes of glyceraldehyde-saccharified BSA solution containing 20 mg protein / ml and 100 mM solutions of each seed (Tables 1 and 2) were mixed. Fluorescence at 440 nm at Ex. 370 nm was measured (initial fluorescence), and the mixture was incubated at 37°C for 1 day. Fluorescence at 440 nm at Ex. 370 nm was then measured again (post-reaction fluorescence).

[0073] The fluorescence retention rate (fluorescence after reaction / initial fluorescence) (%) was calculated from the measurement results. As a control, the relative value was calculated when the fluorescence retention rate when PBS was added instead of the seed was set to 100%.

[0074] (Experimental Example 5) Fluorescence reduction (methylglyoxal-glycated BSA) A solution containing equal volumes of 200 mM methylglyoxal solution and 50 mg / ml BSA solution was cultured at 37°C for 6 days, and then dialysis was performed to obtain methylglyoxal-glycated BSA (AGEs).

[0075] Equal volumes of methylglyoxal-saccharified BSA solution (10 mg protein / ml) and 100 mM solutions of each seed were mixed. Fluorescence at 440 nm at Ex.370 nm was measured (initial fluorescence), and the mixture was incubated at 37°C for 4 days. Fluorescence at 440 nm at Ex.370 nm was then measured again (post-reaction fluorescence).

[0076] The fluorescence retention rate (fluorescence after reaction / initial fluorescence) (%) was calculated from the measurement results. As a control, the relative value was calculated when the fluorescence retention rate when PBS was added instead of the seed was set to 100%.

[0077] (Experimental Example 6) Evaluation of concentration dependence In Experimental Example 1, the procedure was carried out similarly except that the amount of seed added was as shown in Table 3.

[0078] [Table 1]

[0079] [Table 2]

[0080] [Table 3]

[0081] [Footnotes for the table] The amino acids used in each experimental example and the formulation examples below are all DL-forms (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.).

[0082] Each seed shown in Table 1 showed good results in all of Experimental Examples 1-5, demonstrating that it possesses advanced glycation end product (TPM) degradation activity (Tables 1 and 2). Furthermore, Experimental Example 6 (Table 3) revealed that each seed can exhibit TMD degradation activity in a concentration-dependent manner, and that it possesses good TMD degradation activity even at low concentrations.

[0083] Examples of formulations are shown below. Each formulation in the examples contained one of the seeds shown in Table 1 and exhibited good advanced glycation end product (TPD) degradation activity.

[0084] [Table 4]

[0085] [Table 5]

[0086] [Table 6]

[0087] [Table 7]

Claims

1. A final glycation end product (FRI) degrading agent containing one or more selected from nicotinic acid, pyridoxine, aspartic acid, malic acid, pyrrolidone carboxylic acid, methionine, cysteine, tartaric acid, gluconic acid, propionic acid, tryptophan, and salts thereof.

2. The advanced glycation end product (AGE) degrading agent according to claim 1, comprising one or more selected from nicotinic acid, aspartic acid, pyridoxine, malic acid, pyrrolidone carboxylic acid, and salts thereof.

3. The advanced glycation end product degrading agent according to claim 1, comprising one or more selected from nicotinic acid, malic acid, propionic acid, pyrrolidone carboxylic acid, and salts thereof.

4. A final glycation end product (FGT) degrading agent according to any one of claims 1 to 3, which is contained in an oral preparation as a FGT degrading component.

5. The advanced glycation end product (AGE) degrading agent according to claim 4, wherein the oral preparation is selected from toothpaste, mouthwash, mouth spray, topical application, patch, oral dissolving agent, oral disintegrating agent, and chewing agent.

6. An anti-glycation oral composition containing one or more selected from nicotinic acid, pyridoxine, aspartic acid, malic acid, pyrrolidone carboxylic acid, methionine, cysteine, tartaric acid, gluconic acid, propionic acid, tryptophan, and salts thereof as components for decomposing advanced glycation end products.

7. The oral composition for anti-glycation according to claim 6, further comprising one or more selected from the group consisting of azulene, hinokitiol, copper chlorophyll, lysozyme chloride, epsilonaminocaproic acid, glycyrrhizic acid, allantoin, and citric acid.

8. An anti-glycation agent containing one or more selected from nicotinic acid, malic acid, propionic acid, pyrrolidone carboxylic acid, and salts thereof.

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