Citrulline-reducing agent

Abstract

To provide a citrulline-reducing agent for intraoral use.SOLUTION: The present invention provides a citrulline-reducing agent for intraoral use that contains vitamin B6. The citrulline-reducing agent for intraoral use inhibits citrulline production and / or secretion by intraoral bacteria such as those belonging to Porphyromonas, Fusobacterium, Prevotella, Veillonella, Treponema, or Streptococcus.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a citrulline reducing agent in the oral cavity.

Background Art

[0002] Free amino acids in saliva have been reported as biomarkers for various diseases. Citrulline, which is one of the free amino acids, has attracted attention as a predictor for various diseases such as rheumatoid arthritis and arteriosclerosis (Non-Patent Document 1). There is also a report that citrulline increases in the saliva of periodontal disease patients (Non-Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] Although the suppression of citrulline is considered important for the prevention of various diseases, no technology for suppressing its production / secretion has been reported. The present invention provides a technology for suppressing citrulline.

Means for Solving the Problems

[0005] The present invention provides the following [1] to [4]. [1] An oral cavity citrulline reducing agent containing vitamin B6. [2] The oral cavity citrulline reducing agent according to claim 1, which suppresses the production and / or secretion of citrulline by oral bacteria. The oral citrulline reducing agent according to [2], wherein the oral bacteria are one or more selected from the group consisting of Porphyromonas bacteria, Fusobacterium bacteria, Prevotella bacteria, Veillonella bacteria, Treponema bacteria, and Streptococcus bacteria. The oral citrulline reducing agent according to any one of [1] to [3], which is a periodontal disease preventive or a periodontal disease risk reducing agent.

Advantages of the Invention

[0006] According to the present invention, it is possible to reduce citrulline in the oral cavity, and it is expected to lead to an improvement in the oral environment such as a reduction in the risk of periodontal disease and prevention of periodontal disease.

Modes for Carrying Out the Invention

[0007] 〔1. Citrulline Reducing Agent〕 〔Vitamin B6〕 The agent of the present invention contains vitamin B6 as an active ingredient. Thereby, citrulline in the oral cavity can be reduced. Vitamin B6 is one of the water-soluble vitamins and is defined, for example, in "About Vitamin B6" JFRL News Vol.6 No.21 Aug.2019 (https: / / www.jfrl.or.jp / storage / file / news_vol6_no21.pdf). Examples of vitamin B6 include pyridoxine, pyridoxal, pyridoxamine, and their esters (for example, hydrochloride ester, phosphate ester). Pyridoxine or its ester is preferred, and pyridoxine hydrochloride is more preferred. Pyridoxine hydrochloride may conform to the specifications of the 18th Revised Japanese Pharmacopoeia, Pharmaceutical Excipient Raw Material Standards 2021, and the 9th Edition of the Official Monographs of Food Additives (preferably, the 18th Revised Japanese Pharmacopoeia, Pharmaceutical Excipient Raw Material Standards 2021), or it may be a general reagent. Among them, those conforming to the 18th Revised Japanese Pharmacopoeia are preferred.

[0008] The content of vitamin B6 is usually 0.03% by mass or more, preferably 0.04% by mass or more, and more preferably 0.05% by mass or more, based on 100% by mass of the agent. Thereby, the amount of citrulline in the oral cavity can be reduced more efficiently. The upper limit is usually 0.2% by mass or less, preferably 0.1% by mass or less. Therefore, the content of vitamin B6 is usually 0.03 to 0.2% by mass, preferably 0.04 to 0.1% by mass, and more preferably 0.05 to 0.1% by mass.

[0009] [1.2 Citrulline reduction effect] Each of the above components has a citrulline reduction effect in the oral cavity. In this specification, the citrulline reduction effect means reducing the amount of citrulline in the oral cavity, and it is preferably reduced to such an extent that there is no adverse effect such as the risk of diseases such as periodontal disease. By exerting the citrulline reduction effect in the oral cavity, the risk of periodontal disease can be reduced and periodontal disease can be prevented.

[0010] A reduction effect of citrulline is regarded as having a reduction effect of 1% or more, preferably 5% or more, and more preferably 15% or more. The citrulline reduction effect can be determined as the percentage of the value obtained by subtracting 1 from the ratio of the amount of citrulline in a sample (for example, saliva, gingival sulcus exudate) collected from the oral cavity of a subject when each agent is applied to the control (the amount of citrulline in the case of no application).

[0011] [Oral bacteria] Citrulline in the oral cavity is derived from oral bacteria or components in food (e.g., single-chain fatty acids contained in fermented foods such as dairy products), but most of it is derived from oral bacteria. Each active ingredient preferably suppresses the production and / or secretion of citrulline by oral bacteria. In this specification, oral bacteria are bacteria present in the oral cavity, regardless of their pathogenicity. Examples of oral bacteria that produce citrulline include bacteria belonging to the genus Porphyromonas, Fusobacterium, Prevotella, Veillonella, Treponema, and Streptococcus.

[0012] - Bacteria belonging to the genus Porphyromonas - Examples of bacteria belonging to the genus Porphyromonas include Porphyromonas gingivalis. The target bacteria belonging to the genus Porphyromonas may be a single species or a combination of two or more species.

[0013] - Bacteria belonging to the genus Fusobacterium - Examples of bacteria belonging to the genus Fusobacterium include Fusobacterium nucleatum and Fusobacterium gonidiaformans. Among these, Fusobacterium nucleatum is preferred. The target bacteria belonging to the genus Fusobacterium may be a single species or a combination of two or more species.

[0014] - Bacteria belonging to the genus Prevotella - Examples of Prevotella bacteria include Prevotella intermedia, Prevotella buccae, Prevotella dentalis, Prevotella heparinolytica, Prevotella oralis, Prevotella oris, Prevotella oulorum, and Prevotella veroralis. The target Prevotella bacteria may be a single species or a combination of two or more species.

[0015] -Veillonella bacteria- Examples of Veillonella bacteria include Veillonella parvula and Veillonella dispar. The target Veillonella bacteria may be a single species or a combination of two or more species.

[0016] -Treponema bacteria- Examples of Treponema bacteria include Treponema denticola and Treponema socranskii. The target Treponema bacteria may be a single species or a combination of two or more species.

[0017] -Streptococcus bacteria- Examples of Streptococcus bacteria include Streptococcus gordonii, Streptococcus oralis, Streptococcus mitis, Streptococcus salivarius, Streptococcus peroris, Streptococcus infantis, and Streptococcus sanguinis. The target Streptococcus bacteria may be a single species or a combination of two or more species.

[0018] [1.3 Optional Components] When the agent of the present invention is in the form of a so-called composition containing other optional components, examples of other components include bactericides, preservatives, medicinal ingredients, surfactants, abrasives, wetting agents, binders, buffers, solubilizing agents, isotonic agents, stabilizers, chelating agents, moisturizing agents, flavoring agents (sweeteners, fragrances, acidulants), oily components, coloring agents, pH adjusters, solvents, excipients, disintegrants, binders, lubricants, color developers, antioxidants, fortifiers, swelling agents, thickeners, cooling agents, astringents, ultraviolet absorbers, aqueous solvents, seasonings, food ingredients (including food additives), etc., which are components other than the active ingredient in the agent of the present invention. The type and content of the optional components may be selected according to the uses of pharmaceuticals, quasi-drugs, food compositions, cosmetics, and / or dosage forms, administration methods, etc., and may be one type or a combination of two or more types.

[0019] -Bactericide- Examples of bactericides include cetylpyridinium chloride, benzalkonium chloride, alkyl diminoethyl glycine hydrochloride, chlorhexidine or its salts, triclosan, isopropyl methylphenol, hinokitiol, chlorhexidine gluconate, decalinium chloride, iodine, potassium iodide, sulfamethoxazole, sodium sulfamethoxazole, sulfisoxazole, sodium sulfisomidine.

[0020] -Preservative- Examples of the preservative include paraoxybenzoic acid esters such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben, benzoic acid or its salts, dehydroacetic acid or its salts, sorbic acid or its salts (such as potassium sorbate), boric acid, borax, alcohols such as phenylethyl alcohol, benzyl alcohol, phenol, and acrinol, and alkyl polyaminoethyl glycine.

[0021] In the present invention, a bactericide and / or a preservative may be contained as long as the effects of the present invention are not impaired. When contained, usually, the total amount of the bactericide and / or the preservative is 0.1% by mass or less, preferably 0.05% by mass or less, more preferably 0.03% by mass or less, still more preferably 0.01% by mass or less, and even more preferably 0.005% by mass or less of the entire agent composition. Thereby, non-selective sterilization against pathogenic bacteria and resident bacteria can be suppressed, and the risk of dysbacteriosis due to the disruption of the bacterial balance in the oral cavity can be reduced.

[0022] -Medicinal ingredient- Examples of the active ingredients include enzymes such as dextranase, mutanase, amylase, protease, lytech enzyme, lysozyme (e.g., lysozyme chloride); fluorides such as sodium fluoride, sodium monofluorophosphate, stannous fluoride; anti-inflammatory agents such as glycyrrhizinate (e.g., dipotassium glycyrrhizinate), azulene, dihydrocholesterol, tranexamic acid, glycyrrhetinic acid (e.g., β-glycyrrhetinic acid), allantoin, allantoin chlorhydroxyaluminum, epsilon-aminocaproic acid; bactericidal or antibacterial agents such as chlorhexidine, triclosan, isopropylmethylphenol, cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, zinc gluconate, zinc citrate; metal salts such as zinc salts, copper salts, tin salts; tartar inhibitors such as condensed phosphates, ethanehydroxydiphosphonate; blood flow promoters such as vitamin E (e.g., tocopherols such as tocopherol acetate); hypersensitivity inhibitors such as strontium chloride; coating agents such as hydroxyethylcellulose dimethyldiallylammonium chloride; astringents such as vitamin C (e.g., ascorbic acid or its salts), sodium chloride; water-soluble copper compounds such as copper chlorophyll, sodium copper chlorophyllin; tartar inhibitors; amino acids such as alanine, glycine, proline; plant extracts such as thyme, saffron, cloves, witch hazel, cinnamon; caropeptide; polyvinylpyrrolidone and the like. Other examples include decongestants, anti-inflammatory agents, astringents, antihistamines, vitamins, amino acids, local anesthetics, components having a citrulline-reducing effect other than the active ingredients in the present invention, 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, naphazoline nitrate. Examples of anti-inflammatory and astringent agents include neostigmine methylsulfate, berberine sulfate, zinc sulfate, zinc lactate, bromelain, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, methyl salicylate, sodium azulenesulfonate, chamomile, sodium cromoglycate.Examples of antihistamines include iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, and chlorpheniramine maleate. Examples of vitamins (other than vitamin B6) include flavin adenine dinucleotide sodium, cyanocobalamin, vitamin A compounds (e.g., retinol acetate, retinol palmitate), and vitamin E compounds (tocopherol succinate (e.g., d-α-tocopherol succinate)). Examples of amino acids include potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, and sodium chondroitin sulfate. Examples of local anesthetics include lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, and chlorobutanol. Each of these medicinal ingredients may be used alone or in combination of two or more. The content of the medicinal ingredient can be appropriately set to an effective amount according to conventional methods.

[0023] -Surfactant- Examples of surfactants include nonionic surfactants, anionic surfactants, and amphoteric surfactants.

[0024] 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, polyglycerin fatty acid esters, sucrose fatty acid esters (e.g., sucrose palmitic acid monoester, maltose fatty acid ester), sugar alcohol fatty acid esters (e.g., maltitol fatty acid ester, lactitol fatty acid ester), fatty acid diethanolamides (e.g., lauric acid mono- or diethanolamide), polyoxyethylene polyoxypropylene copolymers, polyoxyethylene polyoxypropylene fatty acid esters, glycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene glycol fatty acid esters, polyoxyethylene phytosterols and phytostanols, polyoxyethylene lanolin and lanolin alcohol, polyoxyethylene alkylamines and fatty acid amides, polyoxyethylene alkyl phenyl formaldehyde condensates, polyoxyethylene polyoxypropylene alkyl ethers, and polyoxyethylene alkyl phenyl ethers. Among these, polyoxyethylene alkyl ethers and polyoxyethylene hydrogenated castor oil are preferred, and polyoxyethylene hydrogenated castor oil is more preferred.

[0025] - Examples of polyoxyethylene alkyl ethers - The number of carbon atoms in the alkyl chain of polyoxyethylene alkyl ether is usually 12 or more, preferably 14 or more. The upper limit is usually 26 or less, preferably 24 or less, more preferably 22 or less. Therefore, the number of carbon atoms is usually 12 to 26, preferably 14 to 24, more preferably 14 to 22. The alkyl chain may have an unsaturated bond, and the number thereof may be at least one, preferably one. The alkyl chain may be either straight-chain or branched-chain, but a straight-chain is preferred. The average number of moles of ethylene oxide added is usually 5 or more, preferably 10 or more. The upper limit is usually 100 or less, preferably 60 or less. Therefore, the average number of moles of ethylene oxide added is 5 to 100, preferably 10 to 60.

[0026] Examples of polyoxyethylene alkyl ethers include polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene lauryl ether, polyoxyethylene behenyl ether, and polyoxyethylene oleyl ether.

[0027] -Examples of Polyoxyethylene Hydrogenated Castor Oil- The average number of moles of ethylene oxide added to polyoxyethylene hydrogenated castor oil is usually 5 or more, preferably 20 or more, more preferably 40 or more. The upper limit is usually 150 or less, preferably 100 or less. Therefore, it is usually 5 to 150, preferably 5 to 100, more preferably 20 to 100, and even more preferably 40 to 100.

[0028] -Examples of Other Nonionic Surfactants- The number of carbon atoms in the fatty acid of sorbitan fatty acid ester is usually 12 to 18. The number of carbon atoms in the fatty acid of polyoxyethylene sorbitan fatty acid ester is usually 16 to 18, and the average number of moles of ethylene oxide added is usually 10 to 40 moles. The number of carbon atoms in the alkyl chain of alkylolamide is usually 12 to 14.

[0029] The nonionic surfactant may be a single type or a combination of two or more different nonionic surfactants.

[0030] Examples of the anionic surfactant include alkyl sulfates, acyl amino acid salts, acyl taurine salts, α-olefin sulfonates, hydrogenated coconut fatty acid monoglyceride monosulfates, and lauryl sulfacetates. The alkyl group and acyl group may be either straight-chain or branched-chain, and either saturated or unsaturated, and the number of carbon atoms thereof is usually 10 to 20, preferably 12 to 18, and more preferably 12 to 14. The salt may be selected from pharmacologically acceptable salts. Examples of the pharmacologically acceptable salts include basic addition salts and amino acid salts. Specific examples thereof include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt; and basic amino acid salts such as arginine salt. Among them, inorganic base salts are preferred, alkali metal salts (for example, sodium salt, potassium salt) or ammonium salts are more preferred, and sodium salt is even more preferred. Examples of the alkyl sulfate include lauryl sulfate and myristyl sulfate. Examples of the acyl amino acid salt include acyl glutamic acid salts such as lauroyl glutamate, myristoyl glutamate, and palmitoyl glutamate; acyl glycine salts such as N-lauroyl-N-methylglycine salt and cocoyl glycine salt; acyl alanine salts such as N-lauroyl-β-alanine salt, N-myristyl-β-alanine salt, N-cocoyl-β-alanine salt, N-lauroyl-N-methyl-β-alanine salt, N-myristoyl-N-methyl-β-alanine salt, and N-methyl-N-acylalanine salt; and acyl aspartic acid salts such as lauroyl aspartate. Examples of the acyl taurine salt include N-methyl-N-acyl taurine salt and N-cocoyl methyl taurine salt. Other examples of the anionic surfactant include sodium hydrogenated coconut fatty acid monoglyceride monosulfate and sodium lauryl sulfacetate.

[0031] Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaines (e.g., lauryldimethylaminoacetic acid betaine), fatty acid amidopropyldimethylaminoacetic acid betaine; imidazoline-type amphoteric surfactants such as N-fatty acyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine salts, coconut oil fatty acid imidazolinium betaine; and alkyl betaines such as lauryldimethylaminoacetic acid betaine.

[0032] 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 0.2 to 3% by mass of the whole agent.

[0033] - Abrasive As the abrasive, for example, either an inorganic abrasive or an organic abrasive may be used. Examples of inorganic abrasives include abrasive silica such as precipitated silica, aluminosilicate, zirconosilicate, crystalline zirconium silicate, titanium-bonded silica; calcium phosphate-based compounds such as dibasic calcium phosphate dihydrate or anhydrate, monobasic calcium phosphate, tribasic calcium phosphate, calcium pyrophosphate; calcium carbonate-based abrasives such as calcium carbonate; calcium-based abrasives other than carbonates / phosphates such as calcium hydroxide, calcium sulfate; aluminum-based materials such as aluminum oxide, aluminum hydroxide, alumina; silicate-based materials such as anhydrous silicic acid, zeolite, zirconium silicate; magnesium-based materials such as magnesium carbonate, tribasic magnesium phosphate; apatite-based materials such as hydroxyapatite, fluoroapatite, calcium-deficient apatite; titanium-based materials such as titanium dioxide, mica titanium, titanium oxide; and minerals such as bentonite. Examples of organic abrasives include polymethyl methacrylate and synthetic resin-based abrasives. Among these, abrasive silica and calcium phosphate-based compounds are preferred, and anhydrous silicic acid is more preferred. The amount of the abrasive is preferably 50% by mass or less, more preferably 8 to 50% by mass based on the whole agent.

[0034] - Wetting agent Examples of the wetting agent include sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of the sugar alcohol include sorbitol (sorbit), erythritol, maltitol, lactitol, xylitol, etc. Examples of the polyhydric alcohol other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and polyethylene glycol (PEG); and reduced starch saccharides. As the 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 more preferable. The average molecular weight is the average molecular weight described in the 2006 Specification of Quasi-drug Raw Materials. The content of the wetting agent is usually 40% by mass or less, preferably 1 to 30% by mass, based on the whole preparation.

[0035] -Binder- Examples of the binder include any conventionally known and optionally suitable organic binders, such as polysaccharides, cellulose-based binders (e.g., carboxymethyl cellulose (CMC), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, cationized cellulose), 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, polyvinyl pyrrolidone, polyvinyl alcohol, propylene glycol alginate). Further, 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, based on the whole preparation. The content of the inorganic binder is preferably 0 to 10% by mass, more preferably 1 to 8% by mass.

[0036] -Buffer- Examples of buffers 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), tartaric acid or its salts (e.g., sodium tartrate), gluconic acid or its salts (e.g., sodium gluconate), acetic acid or its salts (e.g., sodium acetate), carbonic acid or its salts (e.g., sodium bicarbonate), trometamol, amino acids (e.g., potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), and combinations of two or more of these.

[0037] -Solubilizing agent- Examples of solubilizing agents include propylene glycol, polyethylene glycol, and combinations of two or more of these.

[0038] -Isotonic agent- Examples of isotonic agents include sodium chloride, potassium chloride, glycerin, and combinations of two or more of these.

[0039] -Stabilizer- Examples of stabilizers include sodium edetate, cyclodextrin, sulfite, citric acid or its salts, dibutylhydroxytoluene, ascorbic acid, and combinations of two or more of these.

[0040] -Chelating agent- Examples of chelating agents include sodium edetate, sodium citrate, and combinations of these.

[0041] -Humectant- Examples of humectants include glycerin, concentrated glycerin, sugar alcohols (e.g., sorbitol, xylitol, maltitol, mannitol, reduced maltose, reduced palatinose, erythritol, lactitol, isomalt), and combinations of two or more of these.

[0042] -Flavoring agent- Examples of flavoring agents include, for example, sweeteners (e.g., sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, stevioside, paramethoxysinnamic aldehyde, neohesperidin dihydrochalcone, perillartine, aspartylphenylalanine methyl ester, thaumatin, acesulfame potassium, sucralose, maltitol, sorbitol, mannitol, reduced maltose, reduced palatinose, xylitol, erythritol, lactitol, etc., artificial sweeteners); fragrances (e.g., natural essential oils such as anise oil, cassia oil, wintergreen oil, mastic oil, neroli oil (orange flower oil), lemongrass oil, jasmine oil, rose oil, iris oil, clove oil, sage oil, cardamom oil, rosemary oil, laurel oil, chamomile oil, basil oil, marjoram oil, lemon oil, orange oil, lime oil, yuzu oil, nutmeg oil, lavender oil, paracresol oil, vanilla oil, cinnamon oil, pimento oil, bay leaf oil, perilla oil, wintergreen oil, peppermint oil, lychee oil, etc.); 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., fragrance components contained in the above natural essential oils; ethyl acetate, ethyl butyrate, isoamyl acetate, hexanal, hexanal, methyl anthranilate, ethyl methylphenyl glycidate, benzaldehyde, vanilla, ethyl vanillin, furaneol, N-ethyl-p-menthane-3-carboxamide, menthyl lactate, ethylene glycol-l-menthyl carbonate, etc., fragrance components; and various compounded flavors such as mint, fruit, herb, etc., formed by combining some fragrance components and natural essential oils (e.g., peppermint micron X-8277-T, dry coat matcha #421), acidulants (e.g., citric acid, tartaric acid, malic acid), and green tea powder.

[0043] - Oil-based components - Examples of the oily component include fatty acid esters (e.g., glycerin fatty acid esters), hydrocarbons (e.g., paraffin, liquid paraffin, ceresin, squalane, petrolatum, microcrystalline wax), higher fatty acids (e.g., fatty acids having 8 to 22 carbon atoms such as lauric acid, myristic acid, oleic acid, isostearic acid), higher alcohols (e.g., alcohols having 8 to 22 carbon atoms such as lauryl alcohol, cetyl alcohol, cetostearyl alcohol, oleyl alcohol, isostearyl alcohol), vegetable oils and fats (e.g., vegetable oils such as olive oil, castor oil, coconut oil; fatty acid esters such as isopropyl myristate), beeswax, and combinations of two or more thereof.

[0044] - Humectant - Examples of the humectant include sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of the sugar alcohol include sorbitol (sorbit), erythritol, maltitol, lactitol, xylitol. Examples of the polyhydric alcohol other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, polyethylene glycol (PEG); and reduced starch saccharides. As the 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 Raw Material Specifications for Quasi-Drugs 2006. The amount of the humectant is usually 40% by mass or less, preferably 1 to 30% by mass, based on the whole preparation.

[0045] - Colorant - Examples of colorants include natural colorants such as safflower red pigment, gardenia yellow pigment, gardenia blue pigment, perilla pigment, red yeast rice pigment, red cabbage pigment, carrot pigment, hibiscus pigment, cocoa pigment, spirulina blue pigment, tamarind pigment, etc., legal colorants such as Red No. 2, Red No. 3, Red No. 104, Red No. 105, Red No. 106, Red No. 227, Yellow No. 4, Yellow No. 5, Green No. 3, Blue No. 1, etc., riboflavin, copper chlorophyllin sodium, and titanium dioxide. When a colorant is included, its content is preferably 0.00001 to 3% by mass based on the total amount of the agent.

[0046] -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 (sodium citrate), inorganic acids such as phosphoric acid (orthophosphoric acid) or their salts (e.g., potassium salt, sodium salt, and ammonium salt), hydroxides such as sodium hydroxide and potassium hydroxide. Examples of inorganic acid salts include disodium hydrogen phosphate and sodium dihydrogen phosphate. The content of the pH adjuster can usually be an amount such that the pH of the agent after addition is 5 to 9, preferably 6 to 8.5. In this specification, the pH value usually refers to the value 25°C and 3 minutes after the start of measurement. The pH value can be measured, for example, using a pH meter (model number Hm-30S) manufactured by Toa Denpa Kogyo Co., Ltd.

[0047] -Solvent- Examples of solvents include water (purified water) and ethanol, with water being preferred. The solvent may be used alone or in combination of two or more.

[0048] -Excipient- Examples of excipients include celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, methyl ethylcellulose, and low-substituted hydroxypropylcellulose, and pharmacologically acceptable derivatives thereof; synthetic polymers such as polyvinylpyrrolidone and partially hydrolyzed polyvinyl alcohol; polysaccharides such as gelatin, gum arabic powder, pullulan, agar, alginic acid, sodium alginate, and chitosan gum; starches such as corn starch, potato starch, pregelatinized starch, and hydroxypropyl starch, and pharmacologically acceptable derivatives thereof; lactose, lactose granules, fructose, glucose, sucrose, granulated sugar, hydrous glucose, trehalose, palatinose, mannitol, sorbitol, erythritol, xylitol, maltotetraose, lactitol, isomalt, reduced palatinose, reduced maltose syrup, powdered reduced maltose syrup, and maltitol; inorganic excipients such as magnesium carbonate, calcium carbonate, light anhydrous silicic acid, silicon dioxide (also known as anhydrous silicic acid, fine particle silicon dioxide), titanium oxide, and aluminum hydroxide gel; and combinations of two or more of these.

[0049] - Disintegrant - Examples of disintegrants include crospovidone, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethyl starch, croscarmellose sodium, cross-linked insoluble polyvinylpyrrolidone, hydroxypropyl starch, partially pregelatinized starch, corn starch, and combinations of two or more of these.

[0050] - Binder - Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin (starch degradation product), starch, and pregelatinized starch, and combinations of two or more of these.

[0051] - Lubricant - Examples of the lubricant include calcium stearate, magnesium stearate, sucrose fatty acid ester, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid, and combinations of two or more of these.

[0052] -Other optional components- Examples of the optional components other than those described above include gum base, polyisobutylene, polybutadiene, urethane, silicon, and natural rubber. The content of these other optional components can be appropriately set within a range that does not interfere with the effects of the present invention.

[0053] [1.4 Dosage form] Examples of the dosage form include liquid (solution), syrup-like (syrup), cream-like, paste-like, tablet (tablet, tablet), capsule-like (capsule), powder-like (granule, fine granule), soft capsule-like (soft capsule with gelatin base, etc.), hard capsule-like (hard capsule), and may be appropriately selected according to the administration form.

[0054] [1.5 Use as a preparation] The preparation of the present invention can be used as a medicine, quasi-drug, oral cosmetic, or food. The dosage form is not particularly limited and includes, for example, solution, spray, solid, semi-solid, solution, powder, and granule. In the case of medicine and quasi-drug, the application site includes, for example, the oral cavity. For oral use, examples include dentifrices (e.g., paste dentifrice, gel dentifrice, moistened dentifrice, liquid dentifrice), mouthwashes, tongue cleaners, oral sprays, oral tablets, gums, oral cooling agents, gargle tablets, oral pastes, gel agents, and ointment agents.

[0055] As an oral cosmetic, it can be used in dosage forms such as cream agents, emulsions, pack agents, gel agents, aerosols, and sheet agents.

[0056] Examples of the food (food composition) include food compositions for uses such as health foods, functional foods, dietary supplements, nutritional supplements, foods for specified health uses, foods with nutritional functions, medical foods, foods for patients, foods for infants, foods for nursing care, foods for the elderly, etc. The type of the food composition is not particularly limited. For example, processed foods such as beverages (soft drinks, carbonated drinks, nutritional drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks, etc.), confectioneries (cookies, cakes, gums (chewing gums), candies, soft candies, tablets, gummies, solid confectioneries, steamed buns, yokan, puddings, jellies, ice creams, sherbets, etc.), processed fishery products (kamaboko, chikuwa, hanpen, etc.), processed livestock products (hamburgers, hams, sausages, wieners, cheeses, butters, yogurts, fresh creams, cheeses, margarines, fermented milks, etc.), soups (powdered soups, liquid soups, etc.), staple foods (rices, noodles (dried noodles, fresh noodles), breads, cereals, etc.), seasonings (mayonnaise, shortenings, dressings, sauces, gravies, soy sauces, etc.) can be mentioned. Among these, confectioneries are preferred, and gums, candies, soft candies, gummies, and solid confectioneries are more preferred.

[0057] [1.6 Administration Method and Target] Examples of the administration method of the citrulline reducing agent include oral administration (internal administration; for example, buccal administration, sublingual administration).

[0058] The administration target may be an animal including humans, and usually is a human. The administration target may be a healthy person, but may also be a person infected with a bacterial infection in the oral cavity (for example, periodontal disease, dental caries, bad breath) or a person suspected of being infected. Examples of animals other than humans include mammals such as mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, monkeys, etc.

[0059] [1.7 Manufacturing Method] The manufacturing method of the agent of the present invention may be determined according to the dosage form, use, and application site. For example, when used as a dentifrice, after preparing the components soluble in a solvent, the other insoluble components are mixed, and defoaming (e.g., under reduced pressure, etc.) is performed as necessary. Another example is a method of preparing a composition by dispersing and dissolving the active ingredient and other components used as necessary in an aqueous solvent (e.g., water such as purified water, sterilized water, etc.), and filling it in a suitable container (e.g., made of glass, resin). As a container for an oral agent, for example, a laminated tube can be mentioned, and as the material, resins such as polyethylene, polypropylene, polyethylene terephthalate, nylon, etc. can be used. In the case of a spray agent, a container equipped with a spraying means (e.g., trigger type, pump type, aerosol type container) may be selected. The obtained dentifrice can be filled in a container and made into a product. The container is not particularly limited in shape and material, and a container usually used for an oral composition can be used.

[0060] [1.8 Method of Use] The method of using the citrulline reducing agent of the present invention may be, for example, administering the agent to the application site. The number of administrations per day is not particularly limited, but for example, it may be 1 to 6 times or more. In the case of an oral agent, for example, an appropriate amount of the agent is placed on a toothbrush and the tooth surface is brushed and then rinsed with water after use (dentifrice), an appropriate amount of the agent is held in the mouth and gargled and then spit out (mouthwash), an appropriate amount of the agent is chewed and swallowed (oral tablet), or an appropriate amount of the agent is sprayed into the oral cavity (oral spray).

Examples

[0061] Hereinafter, examples, comparative examples, and formulation examples will be shown to specifically explain the present invention, but the present invention is not limited to the following examples. In the following examples, % indicates mass % unless otherwise specified.

[0062] The substances shown in the table were prepared as evaluation samples, and each evaluation sample was evaluated by the test methods shown below. The evaluation results are also shown in the table.

[0063] <Test 1>Confirmation of Citrulline Production by Periodontal Disease-Related Bacteria 1. Method Cultivation of bacteria Porphyromonas gingivalis (ATCC33277) (hereinafter sometimes abbreviated as P. g bacterium) and Veillonella parvula (ATCC17745) were prepared using Tryptic Soy Broth (Becton Dickinson) + 0.5% Yeast Extract (Becton Dickinson) + 5 μg / mL hemin (Sigma) + 1 μg / ml menadione (Sigma) medium so that the final concentration OD(450nm) = 0.1. For the cultivation of Veillonella parvula (ATCC17745), filter-sterilized lactic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added so that the final concentration was 2%. 0.25 ml per well was seeded into a 96-well plate. After 18 hours, 200 μL of the bacterial solution was collected and used for the analysis of Citrulline concentration in the bacterial culture solution. The evaluation was carried out with n = 3.

[0064] [Measurement of Citrulline Concentration by MSI-CE-MS / MS] The collected bacterial culture solution was diluted 2-fold with methanol, centrifuged at 17750 g, 3 min, 4°C (MDX-310, TOMY SEIKO CO., LTD. Japan), and 50 μL of the supernatant was suspended with 130 μL of MeOH. 200 μL of chloroform and 100 μL of 10 μM Citrulline -13C5 (L-CITRULLINE(1,2,3,4,5-13C5,98%): Cambridge Isotope Laboratories, Inc. MA, USA) were added, and centrifuged at 4600 g, 5 min, 4°C. The liquid phase was transferred to an ultrafiltration column, centrifuged at 9100 g, 3 hr, r.t., and solidified. 50 μL of MQ was added and subjected to MSI-CE-MS / MS. The concentration was calculated by conversion from the peak area of the standard solution.

[0065] 2. Results The results are shown in Table 1. Citrulline production from Porphyromonas gingivalis and Veillonella parvula was confirmed.

[0066]

Table 1

[0067] <Test 2> Evaluation of the inhibitory effect on pathogenic factors in vitro using human saliva 1. Method [Preculture of bacteria] The frozen bacterial solution of the bacteria described below was inoculated onto a blood agar medium *1 with an inoculating loop and anaerobically cultured at 37 °C for 72 hours (80% by volume nitrogen, 10% by volume carbon dioxide, 10% by volume hydrogen) to initiate growth. Subsequently, the grown colonies were suspended in 4 mL of Todd Hewitt Broth (Becton and Dickinson, hereinafter abbreviated as THBHM) containing 5 mg / L of hemin (manufactured by Sigma) and 1 mg / L of vitamin K (manufactured by Fujifilm Wako Pure Chemical Corporation) and anaerobically cultured at 37 °C for 24 hours. Furthermore, 1% of this culture solution was inoculated into 20 mL of THBHM and anaerobically cultured at 37 °C for 24 hours. Note that the evaluation was performed with n = 3. For the evaluation, P.g bacteria were used.

[0068] *1: Composition of blood agar medium THBHM: 30 g / L Agar (manufactured by Becton and Dickinson): 15 g / L Hemin (manufactured by Sigma - Aldrich): 5 mg / L Vitamin K (manufactured by Fujifilm Wako Pure Chemical Corporation): 1 mg / L Distilled water: the remainder (Made up to 1 L in total volume and autoclaved at 121 °C for 20 minutes) Sheep defibrinated blood (manufactured by Nippon Bio - Test Laboratories): 100 mL

[0069] [Inhibitory effect on pathogenic factors in vitro using human saliva] 4 mL of liquid medium *2Into a test tube (manufactured by Kimble Chase Life Science and Research Products LLC) containing , 80 μL of resting saliva and an evaluation sample solution prepared to have P. g bacteria adjusted to OD(550 nm) = 0.01 and each addition concentration shown in Table 2 were added, and anaerobic culture was performed at 37°C for 24 hours. Then, the collected culture solution was measured using gas chromatography tandem mass spectrometry (GC-MS / MS) and multisegment injection capillary electrophoresis triple quadrupole tandem mass spectrometry (MSI-CE-MS / MS), and the Propionate and Citrulline concentrations in the bacterial culture cough were calculated.

[0070] *2: Liquid medium composition Proteose peptone: 10.0 g / L (manufactured by Becton and Dickinson) Tryptone (manufactured by Becton and Dickinson): 5.0 g / L Yeast extract (manufactured by Becton and Dickinson): 5.0 g / L Hemin (manufactured by Sigma): 1.0 mg / L Vitamin K (manufactured by Fujifilm Wako Pure Chemical Corporation): 0.2 mg / L KCl (manufactured by Fujifilm Wako Pure Chemical Corporation): 2.5 g / L Cysteine (manufactured by Fujifilm Wako Pure Chemical Corporation): 0.5 g / L Glucose: 1.0 g / L Distilled water: The remainder (Made up to 1 L in total volume and autoclaved at 121°C for 20 minutes.)

[0071] [Measurement of Citrulline Concentration by MSI-CE-MS / MS] The recovered bacterial culture solution was diluted 2-fold with methanol and centrifuged at 17,750 g for 3 min at 4°C (MDX-310, TOMY SEIKO CO., LTD., Japan). 50 μL of the supernatant was suspended with 130 μL of MeOH. 200 μL of chloroform and 100 μL of 10 μM Citrulline-13C5 (L-CITRULLINE(1,2,3,4,5-13C5, 98%): Cambridge Isotope Laboratories, Inc., MA, USA) were added, and centrifuged at 4,600 g for 5 min at 4°C. The liquid phase was transferred to an ultrafiltration column and centrifuged at 9,100 g for 3 hr at room temperature to solidify. 50 μL of MQ was added and subjected to MSI-CE-MS / MS. The concentration was calculated by conversion from the peak area of the standard solution.

[0072] [Evaluation method] The inhibitory effect by the evaluation sample was calculated by the following formula: [(1 - concentration of the sample treatment group / concentration of the non-additive group) × 100 (%)].

[0073] 2. Results The results are shown in Table 2. It was confirmed that pyridoxine hydrochloride has a citrulline inhibitory effect.

[0074]

Table 2

[0075] The raw materials used in the examples are as follows. Monammonium glycyrrhizinate (Maruzen Pharmaceutical Co., Ltd., Pharmaceutical Excipient Raw Material Standard 2021) Pyridoxine hydrochloride (DSM Co., Ltd., The Eighteenth Revised Japanese Pharmacopoeia)

Claims

1. An oral citrulline reducing agent containing vitamin B6.

2. The oral citrulline reducing agent according to Claim 1, which suppresses the production and / or secretion of citrulline by oral bacteria.

3. The oral citrulline reducing agent according to Claim 2, wherein the oral bacteria are one or more selected from the group consisting of Porphyromonas bacteria, Fusobacterium bacteria, Prevotella bacteria, Veillonella bacteria, Treponema bacteria, and Streptococcus bacteria.

4. The oral citrulline reducing agent according to Claim 1 or 2, which is a periodontal disease preventive or a periodontal disease risk reducing agent.

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