Promoter for proliferation of nitrate-reducing bacteria in oral cavity

Abstract

To provide a promoter for proliferation of nitrate-reducing bacteria in the oral cavity, which enables selective proliferation of nitrate-reducing bacteria in the oral cavity.SOLUTION: A promoter for proliferation of nitrate-reducing bacteria in the oral cavity comprises component (A): one or more selected from the group consisting of azulenesulfonic acid and salts thereof. Preferably, the promoter further comprises component (B): a nitrate ion-supplying compound. Component (A) is sodium azulenesulfonate, and component (B) is one or more selected from the group consisting of potassium nitrate, sodium nitrate, and ammonium nitrate.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an agent for promoting the growth of oral nitrate-reducing bacteria.

Background Art

[0002] There are more than 700 species of bacteria in the oral cavity. In recent years, it has been reported that the balance of the oral microbiota is disrupted in patients with dental caries and periodontal disease compared to healthy individuals, and it has come to be considered that controlling the oral microbiota is important for preventing dental caries and periodontal disease. Furthermore, with the progress of analysis techniques using bacteria-derived DNA, understanding has advanced not only about bacteria that cause diseases but also about bacteria related to health. For example, bacteria of the genus Neisseria and Haemophilus are representative bacteria that are abundant in healthy individuals and have the ability to reduce nitrate ions (NO3 - ) to nitrite ions (NO2 - ) or nitric oxide (NO). As mechanisms by which nitrate-reducing bacteria, i.e., nitrate-reducing bacteria, bring benefits to the host human, there are known an action of lowering blood pressure of nitric oxide, an antibacterial action against periodontal pathogenic bacteria, and an action of preventing tooth demineralization by suppressing a decrease in saliva pH. Therefore, selectively growing nitrate-reducing bacteria in the oral cavity and controlling the balance of the oral microbiota are useful in preventing dental caries and periodontal disease.

[0003] Since nitrate-reducing bacteria use nitrate as a major energy source, a high concentration of nitrate must be supplied for nitrate-reducing bacteria to grow in the oral cavity. On the other hand, it has also been pointed out that there is a risk of involvement in the production of carcinogenic N-nitroso compounds due to excessive intake of nitrate. Therefore, even under a situation where the oral nitrate concentration is low, a means for growing nitrate-reducing bacteria is desired. Thus, an attempt was made to search for an agent for promoting the growth of nitrate-reducing bacteria among additives (quasi-drug additives, food additives).

[0004] As a technique for controlling the balance of the microbiota, the following have been proposed. Patent Document 1 describes an oral Neisseria mucosa increasing agent containing a nitrate ion supply compound and a sugar alcohol as active ingredients. Patent Document 2 describes an oral care composition containing a water-soluble nitrate, a basic amino acid, a water-soluble alkali metal polyphosphate, and water. Patent Document 3 describes an intestinal flora composition ratio regulator containing γ-oryzanol and biocompatible particles encapsulating γ-oryzanol, and sterols are exemplified as the biocompatible particles.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0006] However, no component having an effect of selectively growing specific oral bacteria is known.

[0007] An object of the present invention is to provide an oral nitrate-reducing bacteria growth agent that selectively grows nitrate-reducing bacteria in the oral cavity.

Means for Solving the Problems

[0008] The present invention provides the following [1] to

[11] . 〔1〕Agent (A): An oral nitrate-reducing bacteria growth agent containing one or more selected from the group consisting of azulenesulfonic acid and its salts. 〔2〕Agent according to [1], further containing (B) component: a nitrate ion supply compound. 〔3〕Agent according to [1] or [2], wherein the component (A) is sodium azulenesulfonate. The agent according to any one of [1] to [3], wherein the component (B) is at least one selected from the group consisting of potassium nitrate, sodium nitrate, and ammonium nitrate. 〔5〕The agent according to any one of [1] to [4], wherein the nitrate-reducing bacteria contain at least one selected from the group consisting of bacteria of the genus Haemophilus, bacteria of the genus Neisseria, bacteria of the genus Veillonella, bacteria of the genus Granulicatella, bacteria of the genus Lautropia, bacteria of the genus Rothia, bacteria of the genus Actinomyces, bacteria of the genus Leptotrichia, and bacteria of the genus Scardovia. 〔6〕The agent according to [5], satisfying at least any one of the following: the bacteria of the genus Haemophilus contain Haemophilus parainfluenzae; the bacteria of the genus Neisseria contain at least one selected from the group consisting of Neisseria mucosa, Neisseria flavescens, Neisseria subflava, Neisseria perflava, Neisseria sicca, and Neisseria flava; the bacteria of the genus Veillonella contain Veillonella parvula; the bacteria of the genus Granulicatella contain Granulicatella adiacens; the bacteria of the genus Lautropia contain Lautropia mirabilis; the bacteria of the genus Rothia contain at least one selected from the group consisting of Rothia mucilaginosa, Rothia dentocariosa, and Rothia aeria; the bacteria of the genus Actinomyces contain at least one selected from the group consisting of Actinomyces viscosus and Actinomyces naeslundii; the bacteria of the genus Leptotrichia contain Leptotrichia buccalis; and the bacteria of the genus Scardovia contain Scardovia odontolyticus. 〔7〕The agent according to any one of [1] to [6], wherein the effective amount of the component (A) is 1 to 300 ppm. 〔8〕The agent according to any one of [2] to [7], wherein the effective amount ratio of the component (B) to the component (A) is 1.5 to 500. 〔9〕The agent according to any one of [1] to [8], which is an oral flora improver, a caries prevention / improvement agent, and a periodontal disease prevention / improvement agent. 〔10〕An oral composition containing (A) component: at least one selected from the group consisting of azulene sulfonic acid and its salts, and (B) component: a nitrate ion supply compound, and the effective amount ratio of the component (B) to the component (A) is 2 to 500. 〔11〕The oral composition according to 〔10〕, which is a tablet, a drink, or an oral film.

Advantages of the Invention

[0009] According to the present invention, since nitrate-reducing bacteria in the oral cavity can be selectively grown, the nitrate-reducing ability in the oral cavity is enhanced, and caries and periodontal diseases can be prevented or improved by nitrite and nitric oxide.

Modes for Carrying Out the Invention

[0010] [1. Oral nitrate-reducing bacteria growth agent] The oral nitrate-reducing bacteria growth agent contains the following component (A) and preferably further contains component (B).

[0011] [Component (A)] Component (A) contains one or more selected from the group consisting of azulenesulfonic acid and its salts (hereinafter sometimes abbreviated as azulenesulfonic acids). Combinations of two or more of these may be contained. Component (A) can increase the nitrate-reducing bacteria ratio and the amount of bacteria and exhibit a nitrate-reducing bacteria growth effect.

[0012] Examples of azulenesulfonic acid include 1,4-dimethyl-7-isopropylazulene and 4,8-dimethyl-2-isopropylazulene.

[0013] Azulenesulfonic acid exists as an azulenesulfonate. Examples of the salt of azulenesulfonic acid include counterions of nitrate ions such as alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt), and ammonium salts.

[0014] Component (A) is preferably sodium azulenesulfonate. Sodium azulenesulfonate may conform to the specifications of the Pharmaceutical Excipients Raw Material Standards 2021 (New Excipient Standards) and the 9th Edition of the Japanese Pharmacopoeia of Food Additives, or may be a general reagent.

[0015] [Component (B)] (B) component is a nitrate ion supply compound. The (B) component can supply nitrate ions utilized by nitrate-reducing bacteria, and can multiply the ratio of nitrate-reducing bacteria and the amount of bacteria in the bacterial flora synergistically.

[0016] As the nitrate ion supply compound, any compound that can generate and supply nitrate ions (NO3 - ) when contacting with water may be used, for example, nitrate esters and nitrates can be mentioned, and nitrates are preferred. As the salts of nitrates, for example, counter ions of nitrate ions such as alkali metal salts (e.g., sodium salts, potassium salts), alkaline earth metal salts (e.g., calcium salts), ammonium salts, etc. can be mentioned. The nitrates are preferably potassium nitrate, sodium nitrate, calcium nitrate, and ammonium nitrate, more preferably potassium nitrate, sodium nitrate, and ammonium nitrate, and still more preferably potassium nitrate.

[0017] The nitrate ion supply compound may be any of natural raw materials (natural) containing the nitrate ion supply compound itself, extracts or purified products obtained from the above raw materials, and chemically synthesized products (chemically synthesized origin) containing the nitrate ion supply compound, but those of chemically synthesized origin are preferred. Examples of natural raw materials include vegetables or fruits, and more specifically, beets, spinach, green and yellow vegetables (e.g., Chinese cabbage, spinach, broccoli, Komatsuna), light-colored vegetables (e.g., cabbage, lettuce, celery), combinations of two or more of these, and processed products thereof (e.g., powders). (B) component may be a single nitrate ion supply compound or a combination of two or more.

[0018] [Effective amount] -(A) component- In the oral nitrate-reducing bacteria growth agent, the effective amount (mass fraction) of component (A) is preferably 1 ppm or more, more preferably 8 ppm or more, still more preferably 20 ppm or more, and even more preferably 50 ppm or more. Thereby, the effect of growing oral nitrate-reducing bacteria can be exerted. The upper limit is preferably 300 ppm or less, more preferably 270 ppm or less, and still more preferably 250 ppm or less. Thereby, oral nitrate-reducing bacteria can be moderately grown. Therefore, the effective amount of component (A) is preferably 1 to 300 ppm, more preferably 8 to 300 ppm, still more preferably 20 to 270 ppm, and even more preferably 50 to 250 ppm. Note that the above-mentioned "effective amount" indicates the effective amount of component (A) in the saliva secreted into the oral cavity when the saliva secretion rate is assumed to be 1 mL / min. The same applies to the effective amount of component (B) below.

[0019] - Component (B)- When the oral nitrate-reducing bacteria growth agent further contains component (B), the effective amount (mass fraction) of component (B) in the oral nitrate-reducing bacteria growth agent is preferably 100 ppm or more, more preferably 300 ppm or more. Thereby, nitrate ions can be sufficiently provided to nitrate-reducing bacteria. The upper limit is preferably 50000 ppm or less. Thereby, the oral nitrate concentration can be suppressed within an appropriate range. Therefore, the effective amount of component (B) is preferably 100 to 50000 ppm, more preferably 300 to 50000 ppm.

[0020] - Effective amount ratio of component (B) to component (A)- When the oral nitrate-reducing bacteria growth promoter further contains the component (B), the effective amount ratio of the component (B) to the component (A) is preferably 1.5 or more, more preferably 2 or more. The upper limit is preferably 500 or less, more preferably 300 or less. Therefore, the effective amount ratio of the component (B) to the component (A) is preferably 1.5 to 500, more preferably 2 to 300. By the effective amount ratio of the component (B) to the component (A) satisfying the above numerical range, the effects of the present invention can be more preferably exhibited.

[0021] [2. Nitrate-Reducing Bacteria Growth Effect] The oral nitrate-reducing bacteria growth promoter can exhibit an oral nitrate-reducing bacteria growth effect. In this specification, the oral nitrate-reducing bacteria growth effect means increasing or maintaining at an appropriate state the number of nitrate-reducing bacteria in the oral cavity and / or the ratio of the number of nitrate-reducing bacteria to the total number of bacteria in the oral cavity.

[0022] -Oral Nitrate-Reducing Bacteria- The oral nitrate-reducing bacteria may be any microorganisms that are present in the oral cavity and have nitrate-reducing ability. For example, bacteria of the genus Haemophilus, bacteria of the genus Neisseria, bacteria of the genus Veillonella, bacteria of the genus Granulicatella, bacteria of the genus Rothia, bacteria of the genus Rothia, bacteria of the genus Actinomyces, bacteria of the genus Leptotrichia, and bacteria of the genus Sneathia can be mentioned.

[0023] Examples of bacteria of the genus Haemophilus include Haemophilus parainfluenzae. Examples of bacteria of the genus Neisseria include Neisseria mucosa, Neisseria flavescens, Neisseria subflava, Neisseria perflava, Neisseria sicca, and Neisseria flava. Examples of the genus Veillonella bacteria include, for example, Veillonella parvula. Examples of the genus Granullicatella bacteria include, for example, Granullicatella adiacens. Examples of the genus Lautropia bacteria include, for example, Lautropia mirabilis. Examples of the genus Rothia bacteria include, for example, Rothia mucilaginosa, Rothia dentocariosa, and Rothia aeria. Examples of the genus Actinomyces bacteria include, for example, Actinomyces viscosus and Actinomyces naeslundii. Examples of the genus Leptotrichia bacteria include, for example, Leptotrichia buccalis. Examples of the genus Schaalia bacteria include, for example, Schaalia odontolytica.

[0024] Among these, Haemophilus genus bacteria, Neisseria genus bacteria, and Veillonella genus bacteria are preferred, and Neisseria genus bacteria and Haemophilus genus bacteria are more preferred. Also, among these bacterial genera, Haemophilus parainfluenzae, Neisseria mucosa, and Veillonella parvula are more preferred, and Neisseria mucosa, Neisseria flavescens, and Haemophilus parainfluenzae are even more preferred.

[0025] Confirmation of the effect of promoting the growth of nitrate-reducing bacteria in the oral cavity can be achieved, for example, by determining the ratio (nitrate-reducing bacteria ratio) of the total number of bacteria in the oral cavity to the total number of bacteria belonging to the genera Haemophilus, Neisseria, Veillonella, Granulicatella, Rothia, Actinomyces, Leptotrichia, and Scardovia, which is usually 20% or more, preferably 24% or more, more preferably 30% or more. The measurement conditions for the number of each type of bacteria can be carried out according to the conditions described in the examples below.

[0026] -Other effects- The combination of the above components (A) and (B) can exhibit effects associated with the effect of promoting the growth of nitrate-reducing bacteria. For example, improvement of the oral flora, prevention and improvement of dental caries and / or periodontal disease, increase in nitric oxide, improvement and enhancement of motor function, prevention and improvement of hypertension can be mentioned.

[0027] -Administration method and target- Examples of the administration method of the agent include oral administration (for example, intraoral administration, sublingual administration), parenteral administration (for example, transdermal administration, intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, pulmonary administration). Among these, an administration form with less invasiveness is preferred, and oral administration (oral ingestion) is more preferred.

[0028] The administration target may be an animal including humans, usually humans. The administration target may be a healthy person, but since the oral nitrate-reducing bacteria growth agent of the present invention can exhibit good effects even in the oral cavity of periodontal disease patients, it may also be a person infected with or suspected of being infected with a bacterial infection in the oral cavity (for example, periodontal disease, dental caries, halitosis). Examples of animals other than humans include mammals such as mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, and monkeys.

[0029] [3. Use as pharmaceuticals, quasi-drugs, cosmetics, and foods] The oral nitrate-reducing bacteria growth agent can be used as a pharmaceutical, a quasi-drug, a cosmetic, or a food. Examples of the dosage form include liquid agents, spray agents, solid agents, semi-solid agents, liquid agents, powder agents, and granule agents, which can be determined according to various uses.

[0030] [4. Oral composition] The above components (A) and (B) can be used as an oral composition. Thereby, the effect of promoting the growth of nitrate-reducing bacteria in the oral cavity can be efficiently exerted.

[0031] [Effective amounts of components (A) and (B) in the oral composition] -(Component (A)) When the agent of the present invention is an oral composition, the effective amount of component (A) in the composition is preferably 1 ppm or more, more preferably 10 ppm or more. The upper limit is preferably 500 ppm or less, more preferably 200 ppm or less. Therefore, the effective amount of component (A) in the composition is preferably 1 to 500 ppm, more preferably 10 to 200 ppm.

[0032] The daily intake amount of component (A) is not particularly limited, but when targeting humans, it is usually 1 to 10 mg / day, preferably 3 to 7 mg / day.

[0033] -(Component (B)) When the agent of the present invention is an oral composition and the oral composition further contains component (B), the effective amount of component (B) in the composition is usually 50 ppm or more, preferably 100 ppm or more, more preferably 300 ppm or more. The upper limit is usually 70000 ppm or less, preferably 50000 ppm or less. Therefore, the effective amount of component (B) in the composition is usually 50 to 70000 ppm, preferably 100 to 50000 ppm, more preferably 300 to 50000 ppm.

[0034] The daily intake amount of component (B) is not particularly limited, but when targeting humans, it is usually 20 to 500 mg / day, preferably 20 to 300 mg / day, more preferably 30 to 200 mg / day, still more preferably 60 to 200 mg / day.

[0035] [Effective amount ratio of component (B) to component (A) in the oral composition] The agent of the present invention is an oral composition. When the oral composition further contains the component (B), the effective amount ratio of the component (B) to the component (A) is preferably 1.5 or more, more preferably 2 or more. The upper limit is preferably 500 or less, more preferably 300 or less. Therefore, the effective amount ratio of the component (B) to the component (A) is preferably 1.5 to 500, more preferably 2 to 500, and still more preferably 2 to 300.

[0036] As used herein, the oral composition means a composition applied to the oral cavity, regardless of whether it is a medicine, quasi-drug, food, or cosmetic. For example, dentifrices (e.g., toothpaste, gel toothpaste, moisturizing toothpaste, liquid toothpaste), mouthwashes, tongue cleaners, oral sprays, tablets, oral films, gums, oral cooling agents, gargle tablets, oral pastes, gels, ointments can be mentioned. Examples of foods (food compositions) include food compositions for uses such as health foods, functional foods, health 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, and foods for the elderly. The type of food is not particularly limited, but processed products such as beverages, confectionery (e.g., drinks, candies, gummies, chewing gums), and seasonings can be mentioned. Among these, tablets, drinks, or oral films are preferred.

[0037] [Dosage form] Examples of dosage forms include liquid (solution), syrup (syrup), cream, paste, tablets (tablets, tablets), capsules (capsules), powder (granules, fine granules), film, soft capsules (soft capsules based on gelatin, etc.), hard capsules (hard capsules), and can be appropriately selected according to the use.

[0038] [Optional components] The oral composition may contain components other than components (A) and (B). Examples of other components include bactericides, preservatives, medicinal ingredients, surfactants, abrasives, wetting agents, binders, buffers, solubilizing agents, isotonic agents, stabilizers, chelating agents, humectants, 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 above active ingredients. The type and content of 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.

[0039] -Bactericide- Examples of bactericides include cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, alkyl diminoethyl glycine hydrochloride, chlorhexidine or its salts, triclosan, isopropylmethylphenol, hinokitiol, chlorhexidine gluconate, decalinium chloride, iodine, potassium iodide, sulfamethoxazole, sodium sulfamethoxazole, sulfisoxazole, sodium sulfisomidine.

[0040] -Preservative- Examples of preservatives include paraoxybenzoic acid esters such as methylparaben, ethylparaben, propylparaben, butylparaben, benzoic acid or its salts, dehydroacetic acid or its salts, propionic acid or its salts, sorbic acid or its salts (such as potassium sorbate), boric acid, borax, alcohol derivatives such as phenylethyl alcohol, benzyl alcohol, phenol, acrinol, alkyl polyaminoethyl glycine.

[0041] In the present invention, it is more suitable in terms of the growth of nitrate-reducing bacteria not to contain the above-mentioned bactericide and / or preservative (each content is 0%), but the bactericide and / or 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 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 whole 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.

[0042] -Pharmaceutical active ingredient- Examples of the active ingredients include enzymes such as dextranase, mutanase, amylase, protease, and lytic enzyme; fluorides such as sodium fluoride, sodium monofluorophosphate, and stannous fluoride; anti-inflammatory agents such as tranexamic acid, epsilon-aminocaproic acid, allantoin, glycyrrhetinate (e.g., dipotassium glycyrrhizinate), allantoin chlorhydroxyaluminum, azulene, and dihydrocholesterol; metal salts such as zinc salts, copper salts, and tin salts; tartar preventives such as condensed phosphates and ethanehydroxydiphosphonate; blood flow promoters such as vitamin E (e.g., tocopherol acetate); hypersensitivity inhibitors such as aluminum lactate and strontium chloride; coating agents such as hydroxyethylcellulose dimethyldiallylammonium chloride; astringents such as vitamin C (e.g., ascorbic acid or its salts), lysozyme chloride, and sodium chloride; water-soluble copper compounds such as copper chlorophyll; tartar preventives; amino acids such as alanine, glycine, and proline; plant extracts such as thyme, saffron, cloves, and witch hazel; caropeptide; polyvinylpyrrolidone, etc. Other examples include decongestants, anti-inflammatory agents, astringents, antihistamines, vitamins, amino acids, bactericides, local anesthetics, components having an effect of improving the oral flora other than the active ingredients in the present invention, and combinations of two or more selected from these. Examples of the decongestant include naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, and dl-methyl ephedrine hydrochloride. Examples of the anti-inflammatory and astringent include neostigmine methylsulfate, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, lysozyme chloride, bromelain, dipotassium glycyrrhetinate, ammonium glycyrrhetinate, glycyrrhetinic acid, methyl salicylate, chamomile, and sodium cromoglycate. Examples of the antihistamine include iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, and chlorpheniramine maleate.Examples of vitamins include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, vitamin A compounds (e.g., retinol acetate, retinol palmitate), and vitamin E compounds (tocopherol acetate (e.g., d-α-tocopherol acetate)). 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 active ingredient may be used alone or in combination of two or more. The content of the active ingredient can be appropriately set to an effective amount according to conventional methods.

[0043] -Surfactant- Examples of surfactants include nonionic surfactants, anionic surfactants, and amphoteric surfactants.

[0044] 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.

[0045] Examples of anionic surfactants include, for example, 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 linear or branched, either saturated or unsaturated, and usually have 10 to 20 carbon atoms, preferably 12 to 18 carbon atoms, and more preferably 12 to 14 carbon atoms. The salt can be selected from pharmacologically acceptable salts. Examples of pharmacologically 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, ammonium salts, etc.; organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts, diisopropylammonium salts, etc.; and basic amino acid salts such as arginine salts. Among them, inorganic base salts are preferred, alkali metal salts (for example, sodium salts, potassium salts) or ammonium salts are more preferred, and sodium salts are even more preferred. Examples of alkyl sulfates include, for example, myristyl sulfate and lauryl sulfate. Examples of acyl amino acid salts include, for example, acyl glutamic acid salts such as lauroyl glutamate, myristoyl glutamate, palmitoyl glutamate, etc.; acyl sarcosine salts such as lauroyl sarcosine salt (e.g., sodium lauroyl sarcosine); acyl glycine salts such as N-lauroyl-N-methylglycine salt, cocoyl glycine salt, etc.; 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, N-methyl-N-acylalanine salt, etc.; and acyl aspartic acid salts such as lauroyl aspartate. Examples of acyl taurine salts include, for example, N-methyl-N-acyl taurine salts and N-cocoyl methyl taurine salts. Examples of anionic surfactants also include sodium hydrogenated coconut fatty acid monoglyceride monosulfate and sodium lauryl sulfacetate.

[0046] Examples of the amphoteric surfactant include betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaine (e.g., lauryldimethylaminoacetic acid betaine), fatty acid amidopropyldimethylaminoacetic acid betaine; imidazoline-type amphoteric surfactants such as N-fatty acyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine salt, coconut oil fatty acid imidazolinium betaine; and alkyl betaines such as lauryldimethylaminoacetic acid betaine.

[0047] When the 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.

[0048] - Abrasive - As the abrasive, for example, either an inorganic abrasive or an organic abrasive may be used. Examples of the inorganic abrasive 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 anhydride, monobasic calcium phosphate, tribasic calcium phosphate, calcium pyrophosphate; calcium carbonate-based abrasives such as calcium carbonate; calcium-based abrasives other than carbonate / phosphate 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, trimagnesium 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 the organic abrasive 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 composition.

[0049] - Wetting agent - 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, 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 Specifications for Quasi-Drug Ingredients. The content of the humectant is usually 40% by mass or less, preferably 1 to 30% by mass, based on the whole composition.

[0050] -Binder- Examples of the binder include any conventionally known suitable organic binder, such as polysaccharides, cellulose-based binders (e.g., carboxymethyl cellulose (CMC), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, cationized 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, 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 composition. The content of the inorganic binder is preferably 0 to 10% by mass, more preferably 1 to 8% by mass.

[0051] -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), tromethamine, amino acids (e.g., potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), and combinations of two or more of these.

[0052] - Solubilizing agent - Examples of solubilizing agents include propylene glycol, polyethylene glycol, and combinations of two or more of these.

[0053] - Isotonic agent - Examples of isotonic agents include sodium chloride, potassium chloride, glycerin, and combinations of two or more of these.

[0054] - Stabilizing agent - Examples of stabilizing agents include sodium edetate, cyclodextrin, sulfite, citric acid or its salts, dibutylhydroxytoluene, ascorbic acid, and combinations of two or more of these.

[0055] - Chelating agent - Examples of chelating agents include sodium edetate, sodium citrate, and combinations of these.

[0056] - 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.

[0057] - 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, and other 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); 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, and other 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, and other fragrance components; and various compounded flavors such as mint-based, fruit-based, herb-based, etc. formed by combining several 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.

[0058] - 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 of these.

[0059] - 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, etc. 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, 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 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 composition.

[0060] - Colorant - Examples of the colorant 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 the colorant is included, its content is preferably 0.00001 to 3% by mass based on the whole composition.

[0061] -pH adjuster- Examples of the pH adjuster 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), hydrochloric acid or their salts (for example, potassium salt, sodium salt, and ammonium salt), hydroxides such as sodium hydroxide and potassium hydroxide. Examples of the inorganic acid salt 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 3 minutes after starting the measurement at 25°C. The pH value can be measured, for example, using a pH meter (model number Hm-30S) manufactured by Toa Denpa Kogyo Co., Ltd.

[0062] -Solvent- Examples of the solvent include water (purified water) and ethanol, and water is preferred. The solvent may be used alone or in combination of two or more.

[0063] -Excipient- Examples of excipients include celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, crystalline cellulose, ethylcellulose, methyl ethylcellulose, 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, hydroxypropyl starch, and pharmacologically acceptable derivatives thereof; lactose, lactose granules, fructose, glucose (e.g., dextrose), 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 particulate silicon dioxide), titanium oxide, and aluminum hydroxide gel; and combinations of two or more of these.

[0064] - Disintegrants - Examples of disintegrants include crospovidone, calcium carboxymethylcellulose, sodium croscarmellose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium croscarmellose, cross-linked insoluble polyvinylpyrrolidone, hydroxypropyl starch, pregelatinized starch, corn starch, and combinations of two or more of these.

[0065] - Binders - Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, dextrin (starch degradation product), starch, pregelatinized starch, and combinations of two or more of these.

[0066] - Lubricant - Examples of the lubricant include, for example, 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.

[0067] - Other Optional Components - Examples of the optional components other than those described above include gum base, polyisobutylene, polybutadiene, urethane, silicone, 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.

[0068] [5. Manufacturing Method] The method for manufacturing an oral nitrate-reducing bacterium growth agent and an oral composition containing the same may be determined according to the dosage form, use, and application site. For example, when used as a dentifrice, after preparing the components dissolved 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 the 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), and filling it into an appropriate container (e.g., made of glass or 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, and nylon 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 contained in a container and used as a product. The container is not particularly limited in shape and material, and a container commonly used for oral compositions can be used.

[0069] [6. Method of Use] The method of using the oral nitrate-reducing bacteria growth agent may be, for example, to administer the agent to the application site. The number of administrations per day is not particularly limited, but may be, for example, 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 (toothpaste), 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

[0070] Hereinafter, the present invention will be described by way of examples. The following examples do not limit the present invention.

[0071] (1) Preparation of multi-species biofilm using human saliva A medium was prepared by adding 4 mL of inactivated FBS (manufactured by Sigma) and 0.4 mL of HM solution (Table 2) to 18 mL of a liquid medium (Table 1) (TP medium). 0.8 mL of resting saliva was added to the prepared TP medium, and 0.825 mL was added to each well of a 24-well plate (manufactured by FALCON). In the nitrate-added group, 0.675 mL of an 11 mM potassium nitrate aqueous solution was added and adjusted to a final concentration of 5 mM (500 ppm) (Table 9, Comparative Example 2, Examples 5 to 8). In the nitrate non-added group, 0.675 mL of dH2O was added (Table 9, Comparative Examples 1 and 2, Examples 1 to 4). Each active ingredient (sodium azulene sulfonate) was added to a final concentration of 5, 10, 100, or 200 ppm (Table 9, Examples 1 to 8). A test plate equipped with a HAP plate was inserted into a 24-well plate and anaerobically cultured at 37°C. After 8 hours, the HAP plate was washed with a washing medium (Table 3), and TP medium, nitrate, and seeds (sodium azulene sulfonate) were added as described above, and anaerobic culture was performed at 37°C. After 16 hours, the HAP plate was washed again with the washing medium. Porphyromonas gingivalis ATCC 33277 was 1×10 8It was prepared using TP medium to obtain CFU / mL, nitrate and seeds were added as described above, and anaerobic culture was performed at 37°C. Thereafter, the HAP plates were washed and the medium was changed (without adding P. gingivalis) for 1 week (excluding Saturdays and Sundays) to form a biofilm on the HAP plates. After culturing, the HAP plates were removed with tweezers, transferred to a test tube containing 2 mL of PBS (manufactured by Gibco), and ultrasonic treatment was performed 10 times for 1 second. The PBS was transferred to a tube, centrifuged at 16400×g for 5 minutes, the supernatant was removed, and the pellet was recovered.

[0072] [Raw materials used in the examples] Potassium nitrate (manufactured by FUJIFILM Wako Pure Chemical Corporation) Sodium azulen sulfonate (Tokyo Chemical Industry Co., Ltd., Pharmaceutical Excipient Raw Material Standard 2021 (New Gaihara Standard))

[0073]

Table 1

[0074] [Annotations for Table 1] ※: After adding 200 mL of 0.1 M phosphate buffer (pH 8.0), it was adjusted to pH 8.0 with 1 N NaOH and made up to 450 mL with distilled water. After filtering with a filter (45 μm), it was autoclaved (121°C for 40 minutes).

[0075]

Table 2

[0076] [Annotations for Table 2] ※1: Adjusted to pH 7.0 with 1 N Hco and autoclaved (121°C for 25 minutes). ※2: Filtered.

[0077]

Table 3

[0078] [Annotations for Table 3] ※: Adjusted to pH 7.3 with 1N NaOH, made up to volume with distilled water, and autoclaved (121 °C for 25 minutes).

[0079] (2) DNA extraction DNA extraction was performed on the pellet recovered in (1) using the Nexttec 1-Step DNA Isolation Kit (manufactured by nexttec Biotechnologie GmbH).

[0080] (3) Bacterial flora analysis The bacterial flora was analyzed as follows using the next-generation sequencer MiSeq (manufactured by illumina). Using the amplification primers for the V1-V2 region of the 16S rRNA gene shown in Table 4 (forward primer: 27Fmod consisting of the nucleotide sequence represented by SEQ ID NO: 1, reverse primer: 338R consisting of the nucleotide sequence represented by SEQ ID NO: 2), the 16S rRNA gene was amplified by performing PCR using Ex Taq polymerase (manufactured by Takara Bio Inc.) under the composition shown in Table 5 and the conditions shown in Table 6. The obtained PCR product was subjected to electrophoresis to confirm the amplification of the sequence length of the target region. DNA purification was performed using AM Pure XP (manufactured by Beckman Coulter) according to a predetermined procedure. The concentration of the purified sample was measured using the Quant-iT PicoGreen dsDNA Assay Kit (manufactured by Thermo Fisher Scientific), and libraries were prepared by mixing the samples to have the same DNA amount. Library purification was performed using the MinElute PCR Purification Kit (manufactured by QIAGEN) according to a predetermined procedure. The concentration of the library was measured by real-time PCR using the KAPA Library Quant Kit (manufactured by Kapa Biosystems). The sequence length of the library was confirmed using a Bioanalyzer (manufactured by Agilent). Acquisition of sequence information was performed using MiSeq Reagent Kits v3 (illumina) and the next-generation sequencer MeSeq (illumina) according to a predetermined procedure.

[0081]

Table 4

[0082]

Table 5

[0083]

Table 6

[0084] The obtained sequences were compared with the sequences containing both the Forward primer and the Reverse primer, the sequences with a Quality value indicating the reliability of the sequences of 25 or more, and the gene sequences in the database, and filtering was performed on the condition that the alignment length was 90% or more. For subsequent analysis, only the sequences that passed the filtering were used. For each sample, 10,000 sequences were randomly extracted to unify the number of data. Sequences with a homology of 97% or more were grouped into one group as an Operational Taxonomic Unit (OTU). The representative sequences of each OTU were compared with four public databases (RDP, CORE, NCBI, HOMD) to identify bacterial species. For the analysis at the genus level and the species level, only bacterial species with a homology of 94% and 97% or more were adopted, respectively, and the rest were regarded as Undefined.

[0085] (4) Total bacterial count measurement (2) Using the extracted DNA obtained in (2) as a template, quantitative PCR was performed using SsoAdvanced Universal SYBR® Green Supermix (BIO - RAD) (Table 7). The primers shown in Table 4 were used. Also, the reaction conditions were carried out as shown in Table 8, and for the calibration curve, a plasmid with a known concentration (7.99 × 10 8 copies / μL) (a plasmid incorporating Staphylococcus aureus 16S rDNA) was used, 10 5Those diluted stepwise up to [multiple] times were used. A calibration curve was created from the DNA concentration of the calibration curve and the number of cycles (Ct value) in the linear part of the curve, and the total bacterial count (copies / μL) of each sample was calculated.

[0086]

Table 7

[0087]

Table 8

[0088] (6) Data analysis In each evaluation sample, assuming that the ratio of nitrate-reducing bacteria in the bacterial flora identified by the bacterial flora analysis in (3) is a (%) and the total bacterial count (copies / μL) is b, the number of nitrate-reducing bacteria (copies / μL) was calculated using the following calculation formula. From the ratio and number of nitrate-reducing bacteria, the relative value with respect to the non-additive group was calculated, and the growth effect on nitrate-reducing bacteria was evaluated. The results are shown in Table 9.

[0089] The number of nitrate-reducing bacteria (copies / μL) was calculated as b × a / 100. The growth rate by the evaluation sample was calculated as (the ratio of nitrate-reducing bacteria in the sample treatment group / the ratio of nitrate-reducing bacteria in the non-additive group) × 100 - 100 (%).

[0090]

Table 9

[0091] (7) Results It was shown that sodium azulene sulfonate has the ability to promote the growth of nitrate-reducing bacteria. More specifically, in Examples 1 to 8 containing the component (A), the ratio of nitrate-reducing bacteria was large and the growth of nitrate-reducing bacteria was confirmed as compared with Comparative Example 1 in which the components (A) and (B) were not added. In addition, as compared with Comparative Example 2 in which only the component (B) was added, Examples 5 to 7 in which the components (A) and (B) were added showed higher nitrate-reducing bacteria ratios and nitrate-reducing bacteria growth rates. The nitrate-reducing bacteria growth rates in Examples 5 to 7 exceeded the numerical values obtained by adding the nitrate-reducing bacteria growth rates exhibited by the component (A) or (B) alone in Comparative Example 2 and Examples 1 to 4, and a synergistic effect of the nitrate-reducing bacteria growth effect by the components (A) and (B) was confirmed. This indicates that the agent of the present invention containing azulenesulfonic acids not only exhibits a nitrate-reducing bacteria growth effect alone, but can further enhance the nitrate-reducing bacteria growth effect by a nitrate ion supply compound, and shows an unexpected nitrate-reducing bacteria growth effect by the combination of azulenesulfonic acids and a nitrate ion supply compound.

[0092] As described above, this example was conducted in the presence of P. gingivalis, and the nitrate-reducing bacteria growth effect was confirmed in all cases. P. gingivalis is one of the most important periodontal pathogenic bacteria. That is, these results indicate that the nitrate-reducing bacteria growth agent of the present invention can exhibit a nitrate-reducing bacteria growth effect even in the presence of periodontal disease-causing bacteria, such as in the oral cavity of periodontal disease patients.

Claims

1. Component (A): One or more selected from the group consisting of azulenesulfonic acid and its salts An oral nitrate-reducing bacteria growth agent containing the same.

2. Component (B): The agent according to Claim 1, further containing a nitrate ion supply compound.

3. The agent according to Claim 1 or 2, wherein component (A) is sodium azulenesulfonate.

4. The agent according to Claim 1 or 2, wherein component (B) is one or more selected from the group consisting of potassium nitrate, sodium nitrate, and ammonium nitrate.

5. The agent according to Claim 1 or 2, wherein the nitrate-reducing bacteria include one or more selected from the group consisting of bacteria of the genus Haemophilus, bacteria of the genus Neisseria, bacteria of the genus Veillonella, bacteria of the genus Granulicatella, bacteria of the genus Rothia, bacteria of the genus Rothia, bacteria of the genus Actinomyces, bacteria of the genus Leptotrichia, and bacteria of the genus Sneathia.

6. The bacteria of the genus Haemophilus includes Haemophilus parainfluenzae, The bacteria of the genus Neisseria includes one or more selected from the group consisting of Neisseria mucosa, Neisseria flavescens, Neisseria subflava, Neisseria perflava, Neisseria sicca, and Neisseria flava, The bacteria of the genus Veillonella includes Veillonella parvula, The bacteria of the genus Granulicatella includes Granulicatella adiacens, The bacteria of the genus Rothia includes Rothia dentocariosa, The bacteria of the genus Rothia includes one or more selected from the group consisting of Rothia mucilaginosa, Rothia dentocariosus, and Rothia aeria, The bacteria of the genus Actinomyces includes one or more selected from the group consisting of Actinomyces viscosus and Actinomyces naeslundii, The agent according to claim 5, satisfying at least one of the following: the bacterium of the genus Leptotrichia includes Leptotrichia buccalis, and the bacterium of the genus Scardovia includes Scardovia odontolyticus.

7. The agent according to claim 1 or 2, wherein the effective amount of component (A) is 1 to 300 ppm.

8. The agent according to claim 2, wherein the effective amount ratio of component (B) to component (A) is 1.5 to 500.

9. The agent according to claim 1 or 2, which is an oral flora improving agent, a dental caries prevention / improving agent, or a periodontal disease prevention / improving agent.

10. Component (A): one or more selected from the group consisting of azulenesulfonic acid and its salts, and Component (B): containing a nitrate ion supply compound, wherein the effective amount ratio of component (B) to component (A) is 2 to 500, and an oral composition containing the same.

11. The oral composition according to claim 10, which is a tablet, a drink, or an oral film.

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