JP2023097067A - Oral flora-improving agent - Google Patents

Abstract

To provide an ingredient that can improve oral flora and contribute to oral health.SOLUTION: The present invention provides an oral flora-improving agent containing (A) berberine or a salt thereof. Preferably, the ingredient (A) is Phellodendron amurense or Phellodendron amurense extract containing berberine or a salt thereof. The oral flora-improving agent may further contain (B) a nonionic surfactant. Preferably, the ingredient (B) contains a polyoxyethylene hydrogenated castor oil and at least one selected from polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, and polyoxyethylene alkyl ether such as polyoxyethylene oleyl ether.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to an oral flora improving agent.

Periodontal disease is one of the most prevalent diseases in Japan, and approximately 70% of Japanese adults have some findings (periodontal disease) in the gums. Prevention of periodontal disease is important for prolonging the life span of teeth and extending the healthy life span. Periodontal disease is an infectious disease caused by oral bacteria, and with the recent development of analysis technology using DNA derived from bacteria, it has been reported that the balance of oral bacteria in patients with periodontal disease differs from that in healthy subjects. It is said that it is important to adjust the balance of the oral flora to a suitable state for the prevention of periodontal disease. This oral flora contains a mixture of so-called non-pathogenic indigenous bacteria and pathogenic bacteria including opportunistic bacteria. and diseases caused by pathogenic bacteria are suppressed. In addition, although the composition of bacteria differs depending on the part of the body, the balance of the composition of bacteria is disturbed by internal or external factors, and the homeostasis is disrupted.

Periodontal disease develops when pathogenic bacteria become dominant due to disruption of homeostasis of the oral flora that coexists in the oral cavity. Pathogenic bacteria can be reduced by using disinfectants, but they also reduce resident bacteria, leaving the balance of the oral flora unchanged. On the other hand, it not only sterilizes pathogenic bacteria, but also maintains or increases the ratio of non-pathogenic indigenous bacteria other than pathogenic bacteria to make the indigenous bacteria more dominant. Maintaining or improving the homeostasis of the bacterial flora is also effective in preventing the onset of oral diseases, and is considered important for suppressing the onset or progression of oral diseases.

However, bactericidal agents generally used in oral compositions have a certain therapeutic and preventive effect on oral diseases by eliminating pathogenic bacteria due to their bactericidal action, but their action causes pathogenicity. Since it kills not only bacteria but also other non-pathogenic indigenous bacteria, there is a risk of superinfection. Furthermore, the bacteria in the oral cavity may increase again in several hours, and it cannot be said that the effect of the disinfectant is sufficiently sustained.

Therefore, in order not only to maintain the homeostasis of the bacterial composition, but also to suppress only pathogenic bacteria, non-pathogenic indigenous bacteria become more dominant, and the oral flora is less likely to break homeostasis, for example, , Oral bacterial flora improving agent using dry powder or extract of mushroom such as Lion's Mane mushroom (Patent Document 1: International Publication No. 2016/043103), specific lysophosphatidic acid and its derivatives and phosphatidic acid and its A growth promoter for oral indigenous bacteria combined with a derivative or the like (Patent Document 2: JP 2019-001720 A), an oral biofilm remover and an oral composition containing the same (Patent Document 3: JP 2019-001720 A) 2019-48802) has been proposed.

WO2016/043103 JP 2019-001720 A JP 2019-48802 A

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a component that can improve oral flora and contribute to oral health.

The present invention provides the following.
[1] (A) an oral flora-improving agent containing berberine or a salt thereof;
[2] The oral flora-improving agent according to [1], wherein the component (A) is Phellodendron bark or Phellodendron bark extract containing berberine or a salt thereof.
[3] (B) The oral flora improving agent according to [1] or [2], further comprising a nonionic surfactant.
[4] The oral flora improving agent according to [1] or [2], wherein the component (B) contains one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether.
[5] The oral flora improving agent according to [3] or [4], wherein the component (B) contains at least polyoxyethylene hydrogenated castor oil having an average number of added moles of ethylene oxide of 5 to 100.
[6] Component (B) contains at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, and polyoxyethylene oleyl ether [3] or [ 4], the oral flora improving agent.
[7] The oral flora improving agent according to any one of [3] to [6], wherein the mass ratio of component (B) to component (A) is 0.2-100.
[8] Any one of [1] to [7], which reduces the ratio of the number of pathogenic bacteria to the total number of at least one pathogenic bacteria and at least one indigenous bacteria oral flora improving agent.
[9] The oral flora-improving agent of [8], wherein the pathogenic bacteria include periodontal pathogenic bacteria.
[10] The oral flora-improving agent of [8] or [9], wherein the pathogenic bacteria include black pigment-producing bacteria.
[11] The oral flora-improving agent according to any one of [8] to [10], wherein the indigenous bacteria include Streptococcus bacteria.

ADVANTAGE OF THE INVENTION According to this invention, the agent which can improve a bacterial flora efficiently is provided. According to the oral flora-improving agent of the present invention, the oral cavity can be maintained in a healthy state by selectively antibacterially controlling pathogenic bacteria in the oral cavity.

The present invention will be described in detail below.

[1. Active ingredient]
[(A) component: berberine or its salt]
The oral flora improving agent of the present invention contains berberine or a salt thereof (component (A)). Thereby, a bacterial flora improvement effect can be exhibited. Berberine is a substance contained in plants such as Phellodendron bark (yellow oak), Japanese coptis, Oregon grape, hydrastis, and holly. Examples of berberine salts include berberine chloride, berberine sulfate, and berberine tannate. Berberine or a salt thereof is preferably derived from the above plant or plant extract, and more preferably derived from Phellodendron bark or Phellodendron bark extract. The component (A) may be a plant or plant extract containing berberine or a salt thereof, preferably Phellodendron bark or Phellodendron bark extract.

Berberine or a salt thereof is an active ingredient for periodontal disease prevention, etc., having anti-inflammatory action, antibacterial action, and the like. Phellodendron bark extract containing berberine or a salt thereof is a solvent extract of a plant containing Phellodendron bark (Pelargonium pavilion), and one obtained by a known method can be used. Phellodendron bark extract may be in a liquid form, but may also be in a dried solid form, or a powdered extract may be used. Specifically, as a raw material, the bark of Rutaceae plants such as yellowfin tuna can be used. A hydrophilic solvent can be used as an extraction solvent, and hydrophilic solvents such as water, lower monohydric alcohols such as ethanol and propanol, and polyhydric alcohols such as 1,3-butylene glycol and propylene glycol can be used. A single solvent or a mixed solvent of two or more species can be used. Water, ethanol are preferred, and water, especially hot water, is preferred. Usual methods can be adopted for extraction conditions and post-treatment.
In addition, the Phellodendron bark extract preferably has a berberine content of 1% by mass or more, more preferably 2 to 80% by mass.

Phellodendron bark powder listed in the 18th revision of the Japanese Pharmacopoeia, Phellodendron bark extract listed in Quasi-drug Ingredients Standards 2021, and commercially available products can be used as the Phellodendron bark extract. As a commercially available product, a powdery extract obtained by extracting the bark of yellowfin husk with hot water and spray-drying it, such as Phellodendron bark extract S manufactured by Ogi Pharmaceutical Co., Ltd., can be mentioned. Further, as a liquid extract containing ethanol, Phellodendron bark extract-J manufactured by Maruzen Pharmaceutical Co., Ltd. may be mentioned.
Phellodendron amurense Ruprecht or Phellodendron chinense Schneider (Rutaceae) of yellowfin husk, bark removed from the perimeter, and powder thereof, respectively, are quantified. In this case, it is described as containing 1.2% or more of berberine [as berberine chloride (C ₂₀ H ₁₈ ClNO ₄ : 371.81)] based on the converted dry crude drug.
In addition, the Phellodendron bark extract in the Quasi-drug Ingredients Standards 2021 is yellowfin Phellodendron amurense Rupr. (Rutaceae) or other plants of the same genus from which the pericardium has been removed.

- Content of component (A) -
The content of component (A) is preferably 0.0005% by mass or more, more preferably 0.00125% by mass or more, and still more preferably 0% by mass, as the amount of berberine and a salt thereof, relative to the entire agent (100% by mass). 0025% by mass or more. The upper limit is usually 0.025% by mass or less, preferably 0.005% by mass or less. Therefore, it is preferably 0.0005 to 0.025% by mass, more preferably 0.00125 to 0.005% by mass, still more preferably 0.0025 to 0.005% by mass. Thereby, the intraoral bacterial flora improvement effect and the bacterial flora improvement effect can be heightened more.
For example, the amount of Phellodendron bark extract as component (A) is preferably 0.01% by mass or more, more preferably 0.025% by mass or more, and still more preferably 0.05% by mass, relative to the entire agent (100% by mass). % or more. The upper limit is usually 0.5% by mass or less, preferably 0.1% by mass or less. Therefore, it is preferably 0.01 to 0.5% by mass, more preferably 0.025 to 0.1% by mass, still more preferably 0.05 to 0.1% by mass. Thereby, the intraoral bacterial flora improvement effect and the bacterial flora improvement effect can be heightened more.

[(B) Component]
The oral flora improving agent of the present invention may be a composition that further contains a nonionic surfactant (component (B)). As a result, the effect of component (A) on improving the bacterial flora can be enhanced, and above all, the balance of the bacterial flora can be made more appropriate (for example, the ratio of indigenous bacteria can be increased).

- Examples of nonionic surfactants -
Examples of nonionic surfactants include polyoxyethylene alkyl ethers, polyoxyethylene hydrogenated castor oils, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monostearate), alkylolamides, Polyoxyethylene fatty acid ester, polyglycerol fatty acid ester, sucrose fatty acid ester (e.g., maltose fatty acid ester), sugar alcohol fatty acid ester (e.g., maltitol fatty acid ester, lactitol fatty acid ester), fatty acid diethanolamide (e.g., lauric acid mono- or diethanolamide), polyoxyethylene polyoxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene glycol fatty acid ester, polyoxyethylene phytosterol and phytostanol, poly Oxyethylene lanolin and lanolin alcohols, polyoxyethylene alkylamines and fatty acid amides, polyoxyethylene alkylphenyl formaldehyde condensates, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene alkylphenyl ethers. Among these, polyoxyethylene alkyl ether and polyoxyethylene hydrogenated castor oil are preferred, and polyoxyethylene hydrogenated castor oil is more preferred.

-Example of polyoxyethylene alkyl ether-
The number of carbon atoms in the alkyl chain of the 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 generally 12-26, preferably 14-24, more preferably 14-22. The alkyl chain may have an unsaturated bond, the number of which is at least one, preferably one. The alkyl chain may be straight or branched, but is preferably straight. The average number of added moles of ethylene oxide is usually 5 or more, preferably 10 or more. The upper limit is usually 100 or less, preferably 60 or less. Therefore, the average added mole number of ethylene oxide is 5-100, preferably 10-60.

Polyoxyethylene alkyl ethers include, for example, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, and polyoxyethylene oleyl ether.

-Example of polyoxyethylene hydrogenated castor oil-
The average number of moles of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is usually 5 or more, preferably 20 or more, and more preferably 40 or more. The upper limit is usually 150 or less, preferably 100 or less. Therefore, it is usually 5-150, preferably 5-100, more preferably 20-100, still more preferably 40-100.

- Examples of other nonionic surfactants -
The number of carbon atoms in the fatty acid of the sorbitan fatty acid ester is usually 12-18. The number of carbon atoms in the fatty acid of the polyoxyethylene sorbitan fatty acid ester is generally 16-18, and the average number of moles of ethylene oxide added is generally 10-40 mol. The alkyl chain of the alkylolamide usually has 12-14 carbon atoms.

Component (B) may be one nonionic surfactant or a combination of two or more different nonionic surfactants.

- Content of component (B) -
The content of component (B) is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, relative to the entire agent (100% by mass). The upper limit is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 3% by mass or less. Therefore, it is preferably 0.01 to 10% by mass, more preferably 0.01 to 5% by mass, still more preferably 0.1 to 3% by mass. Thereby, the effect by blending the component (B) is exhibited more efficiently.

-B/A mass ratio-
In the oral flora improving agent of the present invention, the mass ratio of component (B) to component (A) ((B)/(A) (berberine and salt equivalent)) is usually 2 or more, preferably 4 or more, and more It is preferably 20 or more, more preferably 40 or more. The upper limit is usually 4,000 or less, preferably 3,000 or less, more preferably 2,000 or less, and even more preferably 1,200 or less. Therefore, (B)/(A) is usually 2 to 4,000, preferably 4 to 3,000, more preferably 20 to 2,000, still more preferably 40 to 1,200.
(B)/(A) (mass of Phellodendron bark extract) when component (A) is Phellodendron bark extract is usually 0.1 or more, preferably 0.2 or more, more preferably 1 or more, and still more preferably 2 or more is. The upper limit is usually 200 or less, preferably 150 or less, more preferably 100 or less, still more preferably 60 or less. Therefore, (B)/(A) is generally 0.1-200, preferably 0.2-150, more preferably 1-100, and still more preferably 2-60. When the mass ratio of (B)/(A) is within the above range, the effect of improving bacterial flora can be enhanced, and the balance between pathogenic bacteria and indigenous bacteria can be well adjusted.

[2. Bacterial flora improving effect]
The oral flora-improving agent of the present invention has a flora-improving action. As used herein, improving the bacterial flora means improving or maintaining an appropriate bacterial composition ratio in the oral cavity. Methods for improving bacterial flora include, for example, decreasing the abundance of pathogenic bacteria (one or more species), increasing the abundance of indigenous bacteria (one or more species), and both. Among them, it is preferable to reduce the abundance ratio of pathogenic bacteria (one or more), and the ratio of the number of pathogenic bacteria to the total number of at least one pathogenic bacteria and at least one indigenous bacteria is reduced. Lowering is more preferable.

The pathogenic bacterium may be any bacterium that exists in vivo (for example, in the oral cavity) and has pathogenicity. Causative bacteria of periodontal disease such as bacteria of the genus Eubacterium can be mentioned. Examples of black pigment-producing bacteria include Porphyromonas genus bacteria such as Porphyromonas gingivalis, Prevotella bacteria such as Prevotella intermedia, Nishikawa et al. Identification of black chromogenic Bacteroides isolated from cereals and research on drug susceptibility," Dental Medicine, 1990, Vol.53, No.3, p. 299-312.

The indigenous bacteria may be bacteria that are always present in the body (e.g., the oral cavity) and are other than the pathogenic bacteria described above. Examples include Actinomyces bacteria, and Streptococcus bacteria are preferred. Examples of Streptococcus bacteria include Streptococcus gordonii, Streptococcus oralis, Streptococcus mitis, and Streptococcus saliva. rius), Streptococcus peroris, Streptococcus infantis ), Streptococcus sanguinis, Actinomyces viscosus, Actinomyces naeslundii, Neisseria subflaba, Lochia dentcariosa ( Rothia dentocariosa) and the like.

In the present invention, the growth of periodontal disease-causing bacteria (e.g., black pigment-producing bacteria, especially Porphyromonas gingivalis) is suppressed, and the growth of oral bacteria (e.g., Streptococcus bacteria, especially Streptococcus gordonii) is suppressed. It is preferable to improve the flora in the oral cavity by maintenance or both. When evaluated in Test 1 or 2 described later, the reduction rate of the percentage of pathogenic bacteria is preferably 20% or more and 30% or more, more preferably 40% or more, 50% or more or 60% or more, It is more preferably 70% or more or 80% or more. On the other hand, the ratio of Porphyromonas gingivalis to the sum of the oral cavity indigenous bacteria and the bacteria in Test 1 is preferably 30% or less, more preferably 25% or less. In Test 2, the ratio of black pigment-producing bacteria to the total number of bacteria is preferably 10% or less, more preferably 8% or less.

[3. dosage form]
Dosage forms include, for example, liquid (solution), syrup (syrup), cream, paste, tablets (tablets, tablets), capsules (capsules), powder (granules, fine granules), and soft capsules. (soft capsules such as gelatin bases) and hard capsules (hard capsules), which may be appropriately selected according to the dosage form.

[4. Administration method/target]
Methods for administering oral flora-improving agents include, for example, oral administration (e.g., oral administration, sublingual administration), parenteral administration (e.g., transdermal administration, intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, transpulmonary administration), and among these, less invasive administration forms are preferred, transdermal administration (external use) and oral administration (internal use) are more preferred, and mucosal administration (extramucosal use) is even more preferred.

The subject of administration may be any animal including humans, and is usually a human. The subject of administration may be a healthy subject, but may also be a subject infected or suspected of having an intraoral bacterial infection (eg, periodontal disease, caries, halitosis). Examples of animals other than humans include mammals such as mice, rats, hamsters, dogs, cats, sheep, goats, cows, pigs, and monkeys.

[5. Optional component]
When the oral flora-improving agent of the present invention is in the form of a so-called composition containing other optional ingredients, the other ingredients include, for example, bactericides, antiseptics, medicinal ingredients, surfactants, abrasives, and wetting agents. agents, binders, buffers, solubilizers, tonicity agents, stabilizers, chelating agents, humectants, corrigents (sweeteners, flavors, acidulants), oily ingredients, coloring agents, pH adjusters, Solvents, excipients, disintegrants, binders, lubricants, color formers, antioxidants, reinforcing agents, swelling agents, thickeners, cooling agents, astringents, UV absorbers, aqueous solvents, seasonings, foods Ingredients other than the above active ingredients, such as raw materials (including food additives), are included. The type and content of optional ingredients may be selected according to the application of pharmaceuticals, quasi-drugs, food compositions, cosmetics, dosage forms, administration methods, etc., and may be one or two. A combination of the above may also be used.

-Fungicide-
Bactericides include, for example, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, alkyldiaminoethylglycine hydrochloride, chlorhexidine or its salts, triclosan, isopropylmethylphenol, hinokitiol, chlorhexidine gluconate, dequalinium chloride, iodine, potassium iodide. , sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium.

-Preservative-
Examples of antiseptics 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 (potassium sorbate etc.), boric acid, borax, phenylethyl alcohol, benzyl alcohol, phenol, alcohol derivatives such as acrinol, and alkylpolyaminoethylglycine.

In the present invention, it is preferable not to contain the above-mentioned bactericide and / or antiseptic (each content is 0%) in terms of oral flora improvement, as long as it does not interfere with the effects of the present invention. Bactericides and/or preservatives may be included. When contained, the total amount of bactericides and/or preservatives is usually 0.1% by mass or less, preferably 0.05% by mass or less, more preferably 0.03% by mass or less, and further It is preferably 0.01% by mass or less, and still more preferably 0.005% by mass or less. As a result, non-selective sterilization of pathogenic bacteria and indigenous bacteria can be suppressed, and the risk of superinfection due to disruption of the balance of bacteria in the oral cavity can be reduced.

- Medicinal Ingredients -
Examples of medicinal ingredients include enzymes such as dextranase, mutanase, amylase, protease, and litek enzyme; fluorides such as sodium fluoride, sodium monofluorophosphate, and tin fluoride; tranexamic acid, epsilon aminocaproic acid, allantoin, Anti-inflammatory agents such as glycyrrhizinate (e.g., dipotassium glycyrrhizinate), allantoin chlorohydroxyaluminum, azulene, dihydrocholesterol; metal salts such as zinc salts, copper salts, tin salts; condensed phosphates, ethane hydroxydiphos anticalculus agents such as phonates; blood flow promoters such as vitamin E (e.g., tocopherol acetate); hypersensitivity inhibitors such as strontium chloride; coating agents such as hydroxyethyl cellulose dimethyldiallylammonium chloride; or its salt), lysozyme chloride, astringents such as sodium chloride; water-soluble copper compounds such as copper chlorophyll; anticalculus agents; amino acids such as alanine, glycine, proline; caropeptide; polyvinylpyrrolidone and the like. Other examples include decongestants, antiphlogistic agents, astringents, antihistamines, vitamins, amino acids, bactericidal agents, local anesthetics, and components other than the active ingredients of the present invention that have an action to improve bacterial flora. Combinations of two or more are also included. Examples of decongestants include naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, and naphazoline nitrate. Examples of anti-inflammatory and astringent agents include neostigmine methyl sulfate, allantoin, zinc sulfate, zinc lactate, lysozyme chloride, bromelain, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, sodium azulene sulfonate, chamomile, cromoglycic acid. sodium. Antihistamines include, for example, iproheptine hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, and chlorpheniramine maleate. Examples of vitamins include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, vitamins A (e.g. retinol acetate, retinol palmitate), vitamins E (tocopherol acetate (e.g. d-α-tocopherol acetate)). be done. Amino acids include, for example, potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, and sodium chondroitin sulfate. Local anesthetics include, for example, lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, chlorobutanol. Each medicinal ingredient may be used singly or in combination of two or more. The content of the medicinal ingredient can be appropriately set to an effective amount according to a conventional method.

-Surfactant-
The surfactant may be any surfactant other than (B), and examples thereof include anionic surfactants and amphoteric surfactants.

Anionic surfactants include, for example, alkyl sulfates, acyl amino acid salts, acyl taurine salts, α-olefin sulfonates, hydrogenated coconut fatty acid monoglyceride monosulfate, and lauryl sulfoacetate. Alkyl groups and acyl groups may be linear or branched, saturated or unsaturated, and usually have 10 to 20 carbon atoms, preferably 12 to 18 carbon atoms, more preferably 12 to 14. Salts may be selected from pharmacologically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and amino acid salts. Specific examples thereof include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts; organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts and diisopropylammonium salts; arginine salts and the like. and basic amino acid salts of Among them, inorganic base salts are preferred, alkali metal salts (such as sodium salts and potassium salts) or ammonium salts are more preferred, and sodium salts are even more preferred. Alkyl sulfates include, for example, myristyl sulfate. Examples of acyl amino acid salts include acyl glutamates such as lauroyl glutamate, myristoyl glutamate and palmitoyl glutamate; acylglycinates such as N-lauroyl-N-methylglycinate and cocoylglycinate; N-lauroyl-β- Alanine salt, N-myristoyl-β-alanine salt, N-cocoyl-β-alanine salt, N-lauroyl-N-methyl-β-alanine salt, N-myristoyl-N-methyl-β-alanine salt, N-methyl - acyl alanine salts such as N-acyl alanine salts; and acyl aspartates such as lauroyl aspartate. Acyl taurine salts include, for example, N-methyl-N-acyl taurine salts and N-cocoyl methyl taurine salts. Examples of anionic surfactants also include hydrogenated coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate.

Examples of amphoteric surfactants include betaine-type amphoteric surfactants such as alkyldimethylaminoacetic acid betaine (eg, lauryldimethylaminoacetic acid betaine), fatty acid amidopropyldimethylaminoacetic acid betaine; N-fatty acid acyl-N-carboxymethyl- imidazoline-type amphoteric surfactants such as N-hydroxyethylethylenediamine salts and coconut oil fatty acid imidazolinium betaine; and alkylbetaines such as lauryldimethylaminoacetate betaine.

When a surfactant is included, the content of each anionic and amphoteric surfactant is usually 0.01 to 10% by mass, preferably 0.1 to 5% by mass, more preferably 0.2 to It is 3% by mass.

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

-wetting agent-
Wetting agents include, for example, sugar alcohols and polyhydric alcohols other than sugar alcohols. Examples of sugar alcohols include sorbitol (sorbitol), erythritol, maltitol, lactitol, and xylitol. Examples of polyhydric alcohols other than sugar alcohols include glycerin; glycols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol and polyethylene glycol (PEG); and reduced starch saccharification products. As polyethylene glycol, for example, polyethylene glycol having an average molecular weight of 150 to 6000 is preferable, and polyethylene glycol having an average molecular weight of 190 to 630 (PEG200, PEG300, PEG400, PEG600) is preferable. The average molecular weight is the average molecular weight described in the Standards for Quasi-drug Ingredients 2006. The content of the wetting agent is usually 40% by mass or less, preferably 1 to 30% by mass, based on the entire agent.

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

- Buffer -
Examples of buffering agents include citric acid or salts thereof (e.g., sodium citrate), phosphoric acid or salts thereof (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen 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 (eg, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate), and combinations of two or more thereof.

－Solubilizer－
Solubility aids include, for example, propylene glycol, polyethylene glycol, and combinations of two or more thereof.

- Tonicity agent -
Tonicity agents include, for example, sodium chloride, potassium chloride, glycerin, and combinations of two or more thereof.

-Stabilizer-
Stabilizers include, for example, sodium edetate, cyclodextrins, sulfites, citric acid or salts thereof, dibutylhydroxytoluene, ascorbic acid, combinations of two or more thereof.

- Chelating agent -
Chelating agents include, for example, sodium edetate, sodium citrate, and combinations thereof.

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

-Flavoring agent-
Flavoring agents include, for example, sweeteners (e.g., sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, stevioside, paramethoxycinnamic aldehyde, neohesperidin dihydrochalcone, perillartine, asparatylphenylalanine methyl ester, thaumatin, acesulfame potassium, sucralose , maltitol, sorbitol, mannitol, reduced starch syrup, reduced palatinose, xylitol, erythritol, artificial sweeteners such as lactitol, etc.); flavors (e.g. 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, paracress oil, vanilla oil, cinnamon oil, pimento oil, cinnamon 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. Perfume ingredients contained in essential oils: ethyl acetate, ethyl butyrate, isoamyl acetate, hexanal, hexenal, methyl anthranilate, ethyl methyl phenylglycidate, benzaldehyde, vanillin, ethyl vanillin, furaneol, N-ethyl-p-menthane Fragrant ingredients such as 3-carboxamide, menthyl lactate, ethylene glycol-l-menthyl carbonate; and various compounded flavors such as mint, fruit, herb, etc., which are obtained by combining several perfume ingredients and natural essential oils (for example, peppermint micron X-8277-T, dry coat matcha #421), acidulants (eg, citric acid, tartaric acid, malic acid), green tea powder.

- Oily component -
Oily components include, for example, fatty acid esters (e.g. glycerin fatty acid esters), hydrocarbons (e.g. paraffin, liquid paraffin, ceresin, squalane, vaseline, microcrystalline wax), higher fatty acids (e.g. lauric acid, myristic acid, olein acids, fatty acids with 8 to 22 carbon atoms such as isostearic acid), higher alcohols (for example, alcohols with 8 to 22 carbon atoms such as lauryl alcohol, cetyl alcohol, cetostearyl alcohol, oleyl alcohol, and isostearyl alcohol), plants Oils and fats (eg, vegetable oils such as olive oil, castor oil, and coconut oil; fatty acid esters such as isopropyl myristate), beeswax, and combinations of two or more thereof.

-coloring agent-
Examples of coloring agents include natural pigments such as safflower red pigment, gardenia yellow pigment, gardenia blue pigment, perilla pigment, monascus pigment, red cabbage pigment, carrot pigment, hibiscus pigment, cacao pigment, spirulina blue pigment, tamarind pigment, Legal pigments such as Red No. 2, Red No. 3, Red No. 104, Red No. 105, Red No. 106, Red No. 227, Yellow No. 4, Yellow No. 5, Green No. 3, Blue No. 1, riboflavin, sodium copper chlorophyllin, Titanium dioxide may be mentioned. When a coloring agent is included, its content is preferably 0.00001 to 3% by mass with respect to the entire agent.

-pH adjuster-
Examples of pH adjusters include organic acids such as phthalic acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid, and lactic acid, salts thereof (sodium citrate), and inorganic acids such as phosphoric acid (orthophosphoric acid). Acids or salts thereof (eg, potassium salts, sodium salts, and ammonium salts), and 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 be adjusted so that the pH of the agent after addition is usually 5 to 9, preferably 6 to 8.5. In this specification, the pH value usually refers to the value after 3 minutes at 25°C from the start of measurement. The pH value can be measured, for example, using a pH meter (model number Hm-30S) manufactured by Toa Denpa Kogyo Co., Ltd.

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

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

-Disintegrant-
Examples of disintegrants include crospovidone, carmellose calcium, carmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose (CMC) or salts thereof (e.g., sodium salts), sodium carboxymethylstarch, croscarmellose sodium, Crosslinked insoluble polyvinylpyrrolidone, hydroxypropyl starch, partially pregelatinized starch, corn starch, combinations of two or more thereof.

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

-lubricant-
Lubricants include, for example, calcium stearate, magnesium stearate, sucrose fatty acid esters, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid, and combinations of two or more of these.

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

[6. dosage form, application site]
The agent of the present invention can be used as pharmaceuticals, quasi-drugs, cosmetics, and foods. The dosage form is not particularly limited and includes, for example, liquids, sprays, solids, semi-solids, liquids, powders, and granules. Examples of application sites for pharmaceuticals and quasi-drugs include the oral cavity, nasal cavity, and eyes. For the oral cavity, for example, dentifrice (e.g., toothpaste, gel toothpaste, wet toothpaste, liquid toothpaste), mouthwash, tongue polish, oral spray, oral tablet, gum, mouth freshener, gargle tablets, buccal pastes, gels, and ointments. For the nasal cavity, for example, nasal drops and nasal washes can be mentioned. For the eyes, for example, eye drops (e.g., general eye drops, eye drops for contact lens users), eye washes (general eye wash, eye wash for contact lens users), contact lens agents (e.g., contact lens preservatives, contact lens cleaning agents).

As cosmetics, for example, it can be used in dosage forms such as creams, milky lotions, packs, gels, aerosols, and sheets. Specifically, for example, skin cosmetics such as lotion, serum, whitening agent, moisturizer, face mask, milky lotion, foundation, eye shadow, mascara, eyebrow, eyeliner, cheek powder, lipstick, lip balm; hair rinse , hair conditioners, hair treatments, hair lotions, hair tonics, hair packs, hair creams, conditioning mousses, hair mousses, hair sprays, shampoos, leave-on treatments, hair dyes, and hair cosmetics.

Foods (food compositions) include, for example, health foods, functional foods, health supplements (supplements), dietary supplements, foods for specified health uses, functional nutritional foods, medical foods, foods for the sick, foods for infants, Food compositions with uses such as food for nursing care and food for the elderly can be mentioned.

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

[8. how to use]
The oral flora improving agent of the present invention may be used, for example, by administering the oral flora improving 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 oral preparations, for example, put an appropriate amount of the agent on a toothbrush, brush the surface of the teeth, and then rinse with water after use (dentifrice), or spit out after gargling with an appropriate amount of the agent in the mouth (mouthwash). , a method of chewing and swallowing an appropriate amount of the agent (intraoral tablet), and a method of spraying an appropriate amount of the agent into the oral cavity (intraoral spray).

Examples, Comparative Examples, and Formulation Examples are shown below to specifically describe the present invention, but the present invention is not limited to the following Examples. In the following examples, % indicates % by mass unless otherwise specified.

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.

<Test 1> Evaluation of selective antibacterial effect against two types of mixed bacteria (Examples 1 to 18, Comparative Examples 1 to 3)
[Pre-culture of bacteria]
Frozen bacterial solutions of various bacteria (indigenous bacteria in the oral cavity, periodontal pathogens) described later were inoculated on a blood plate medium ^{* 1} with a platinum loop, and anaerobically cultured at 37 ° C. for 72 hours (80 vol% nitrogen, 10 vol. % carbon dioxide, 10% by volume hydrogen) was performed to initiate bacteria. Subsequently, the grown colonies were treated with Todd Hewitt Broth (manufactured by Becton and Dickinson) containing 5 mg/L hemin (manufactured by Sigma) and 1 mg/L vitamin K (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). , hereinafter abbreviated as THBHM) was suspended in 4 mL, and anaerobically cultured at 37°C for 24 hours. Further, 1% of this culture solution was inoculated into 20 mL of THBHM, and anaerobically cultured at 37° C. for 24 hours.

For the evaluation, the following bacterial strains purchased from the American Type Culture Collection (hereinafter abbreviated as ATCC) were used.
Indigenous bacteria in the oral cavity:
Streptococcus gordonii (S.gordonii) ATCC10558 (hereinafter abbreviated as S.g fungus)
Periodontal pathogens:
Porphyromonas gingivalis ATCC33277 (hereinafter abbreviated as P.g bacteria)

*1: Composition of blood plate 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 Industries, Ltd.): 1 mg / L
Distilled water: Remainder (filled up to 1 L and autoclaved at 121°C for 20 minutes)
Defibrinated sheep blood (manufactured by Nihon Biotest Laboratories): 100 mL

[Selective antibacterial effect against two kinds of mixed bacteria]
The bacterial solution after the culture is centrifuged at 11,000 rpm for 5 minutes, and the precipitate is resuspended using THBHM so that each of the above bacteria has a turbidity (OD 550 nm) of 1.0. A liquid was prepared. After that, various bacteria adjusted to a turbidity of 1.0 were added to 4 mL of THBHM containing 5 mg/L hemin (manufactured by Sigma) and 1 mg/L vitamin K (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). The final concentration of S.g bacteria was 5%. 200 μL and 20 μL of g bacteria were added to a final concentration of 0.5%, respectively, and then 40 μL of the evaluation sample solution or distilled water (control) prepared as shown in Tables 1 to 4 was added and incubated at 37 ° C. for 8 hours. Anaerobically cultured. After culturing, a 10-fold dilution series was prepared using Tryptic Soy Broth (manufactured by Becton and Dickinson). 50 μL of the 10 ⁻³ , 10 ⁻⁴ , 10 ⁻⁵ and 10 ⁻⁶ dilutions were smeared on the selective medium shown below and cultured. After culturing, the number of viable bacteria was calculated by counting the number of bacterial colonies that grew. That is, S. cerevisiae grown by anaerobic culture at 37° C. for 2 days on a tryptic soy agar agar medium (Tryptic Soy Agar, manufactured by Becton and Dickinson). The number of P. g bacteria and P. spp. grown by anaerobically culturing at 37° C. for 7 days on a blood plate medium ^* 1 supplemented with 200 μg/mL of kanamycin. g Bacterial count was measured.

Percentage of periodontal disease bacteria in total bacteria in each evaluation sample (percentage of Pg bacteria count to total bacteria count (Sg bacteria count + Pg bacteria count); Pg bacteria ratio in the table ) is a (%), the ratio of periodontal disease bacteria in the culture solution of the control (Comparative Example 1) not treated with the evaluation sample (the ratio of the number of P.g bacteria to the total number of bacteria) is b (%), The ratio reduction rate of periodontal pathogens (P.g bacteria ratio reduction rate: %) was calculated using the formula shown below. From this reduction rate, the selective antibacterial effect against periodontal pathogens was evaluated based on the evaluation criteria shown below.
Reduction rate of periodontal pathogens (%) = {1-(a/b)} x 100
The proportion of periodontopathogenic bacteria (b in the formula) in the culture solution of the control (Comparative Example 1) was 50.9%.

Details of the components (A) and (B) contained in the sample solution are as follows. The number in parentheses after polyoxyethylene is the degree of polymerization of ethylene oxide.
(A) Component Manufactured by Ogi Pharmaceutical Co., Ltd., trade name: Phellodendron bark extract S, 5% berberine content
(B) Component Polyoxyethylene (60) hydrogenated castor oil: NIKKOL HCO-60 (manufactured by NIKKO CHEMICALS Co., Ltd.)
Polyoxyethylene (5) hydrogenated castor oil: NIKKOL HCO-5 (manufactured by NIKKO CHEMICALS Co., Ltd.)
Polyoxyethylene (100) hydrogenated castor oil: NIKKOL HCO-100 (manufactured by NIKKO CHEMICALS Co., Ltd.)
Polyoxyethylene (40) cetyl ether: NIKKOL BC-40 (manufactured by NIKKO CHEMICALS Co., Ltd.)
Polyoxyethylene (20) stearyl ether: NIKKOL BS-20 (manufactured by NIKKO CHEMICALS Co., Ltd.)
Polyoxyethylene (30) behenyl ether: NIKKOL BB-30 (manufactured by NIKKO CHEMICALS Co., Ltd.)
Polyoxyethylene (50) oleyl ether: NIKKOL BO-50V (manufactured by NIKKO CHEMICALS Co., Ltd.)

Examples 1 to 18 containing component (A) are compared with Comparative Example 1 containing neither component (A) nor component (B), and Comparative Examples 2 and 3 containing no component (A). and high P.I. g bacteria ratio reduction rate is shown. Among them, Examples 5 to 18 containing components (A) and (B) are compared with each example in which the content of component (A) is the same, and component (B) is the same as component (A). S. g bacteria, P. By adjusting the antibacterial effect on P.g bacteria, more P.g. By enhancing the selective inhibitory effect on P.g bacteria, higher P.g. g bacteria ratio reduction rate is shown (Tables 1 to 4).

<Test 2> Evaluation of in vitro bacterial flora improvement effect using human saliva (Examples 19 to 30, Comparative Examples 4 to 6)
Test tube containing 4 mL of liquid medium ^{* 2} (manufactured by Kimble Chase Life Science and Research Products LLC), 80 μL of resting saliva and 40 μL of evaluation sample prepared to have each addition concentration shown in Tables 5 to 7. A solution or distilled water (control) was added, and anaerobic culture was performed at 37° C. for 8 hours. Thereafter, the recovered culture medium was serially diluted 10-fold using Tryptic Soy Broth (manufactured by Becton and Dickinson). 50 μL of each of the 10 ⁻³ , 10 ⁻⁴ , 10 ⁻⁵ and 10 ⁻⁶ diluted solutions was smeared on the selective medium shown below and cultured. After culturing, the number of viable bacterial colonies and bacterial composition ratio were calculated by counting the number of bacterial colonies that grew. That is, the total number of bacteria grown by anaerobically culturing on a blood plate medium ^*1 at 37°C for 7 days, and the total number of bacteria grown on a blood plate medium ^*1 supplemented with 200 µg/mL of kanamycin are anaerobicly cultured at 37°C for 7 days. The number of periodontal pathogens (black-pigment-producing bacteria) that grew by this was measured.

*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 Industries, Ltd.): 0.2 mg/L
KCl (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.): 2.5 g / L
Cysteine (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.): 0.5 g/L
Glucose: 1.0g/L
Distilled water: Remainder (filled up to 1 L and autoclaved at 121°C for 20 minutes)

In each evaluation sample, the ratio of black pigment-producing bacteria in the total number of bacteria (the ratio of the number of black pigment-producing bacteria to the total number of bacteria; black pigment-producing bacteria ratio in the table) is a (%), and the evaluation sample is treated. The ratio of black pigment-producing bacteria in the total bacteria in the culture solution of the control (Comparative Example 4) without black pigment-producing bacteria (the ratio of the number of black pigment-producing bacteria to the total number of bacteria) is defined as b (%), and the black color is expressed by the formula shown below. The rate of decrease in the percentage of pigment-producing bacteria (ratio of decrease in ratio of black pigment-producing bacteria: %) was calculated. Based on this reduction rate, the oral flora against black pigment-producing bacteria was evaluated based on the evaluation criteria shown below.
Decrease rate of black pigment-producing bacteria (%) = {1-(a/b)} × 100
The ratio (b) of black pigment-producing bacteria in the control (Comparative Example 4) was 16.1%.

Details of the components (A) and (B) contained in the sample solution are as follows. The number in parentheses after polyoxyethylene is the degree of polymerization of ethylene oxide.
(A) Component Manufactured by Ogi Pharmaceutical Co., Ltd., trade name: Phellodendron bark extract S, 5% berberine content
(B) Component Polyoxyethylene (60) hydrogenated castor oil: NIKKOL HCO-60 (manufactured by NIKKO CHEMICALS Co., Ltd.)

Examples 19 to 30 containing component (A) are compared with Comparative Example 4 containing neither component (A) nor component (B), and Comparative Examples 5 and 6 containing no component (A). As a result, the rate of decrease in the proportion of black pigment-producing bacteria was high at 30% or more. Among them, Examples 23 to 30 containing components (A) and (B) significantly reduced the ratio of black pigment-producing bacteria compared to each example in which the content of component (A) was the same. was observed, showing a higher reduction rate (60% or more) (Tables 5-7).
The results of these Examples demonstrate that the agent of the present invention can favorably improve the bacterial flora in the oral cavity.

The formulation examples of the oral flora-improving agent are shown below.

[Prescription Example 1-1] Gel-like dentifrice (A) Phellodendron bark extract 0.5
Silicic anhydride 15.0
Carboxymethylcellulose sodium 1.5
Saccharin sodium 0.1
Polyethylene glycol 3.0
Glycerin 15.0
Perfume 1.0
water
Total 100.0%

[Prescription Example 1-2] Gel-type dentifrice (A) Phellodendron bark extract 0.5
(B) Polyoxyethylene (60) hydrogenated castor oil 1.0
Silicic anhydride 15.0
Carboxymethylcellulose sodium 1.5
Saccharin sodium 0.1
Polyethylene glycol 3.0
Glycerin 15.0
Perfume 1.0
water
Total 100.0%

[Prescription Example 2-1] Mouthwash (A) Phellodendron bark extract 0.5
Propylene glycol 3.0
Saccharin sodium 0.2
Sodium citrate 0.3
Citric acid 0.1
Perfume 0.5
water
Total 100.0%

[Prescription Example 2-2] Mouthwash (A) Phellodendron bark extract 0.5
(B) Polyoxyethylene (60) hydrogenated castor oil 1.0
Propylene glycol 3.0
Saccharin sodium 0.2
Sodium citrate 0.3
Citric acid 0.1
Perfume 0.5
water
Total 100.0%

[Prescription Example 3-1] Mouth freshener (A) Phellodendron bark extract 0.5
Ethanol 10.0
Glycerin 5.0
Perfume 1.0
water
Total 100.0%

[Prescription Example 3-2] Mouth freshener (A) Phellodendron bark extract 0.5
(B) Polyoxyethylene (60) hydrogenated castor oil 1.0
Ethanol 10.0
Glycerin 5.0
Perfume 1.0
water
Total 100.0%

Claims (11)

(A) An oral flora-improving agent containing berberine or a salt thereof. 2. The oral flora-improving agent according to claim 1, wherein the component (A) is Phellodendron bark or Phellodendron bark extract containing berberine or a salt thereof. (B) The oral flora-improving agent according to claim 1 or 2, further comprising a nonionic surfactant. The oral flora improving agent according to claim 3, wherein the component (B) comprises one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether. 5. The oral flora improving agent according to claim 3, wherein component (B) contains at least polyoxyethylene hydrogenated castor oil having an average added mole number of ethylene oxide of 5 to 100. 5. The product according to claim 3, wherein component (B) contains at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, and polyoxyethylene oleyl ether. Oral flora improving agent. The oral flora improving agent according to any one of claims 3 to 6, wherein the mass ratio of component (B) to component (A) is 0.1-200. The oral flora improvement according to any one of claims 1 to 7, which reduces the ratio of the number of pathogenic bacteria to the total number of at least one pathogenic bacteria and at least one indigenous bacteria. agent. The oral flora-improving agent according to claim 8, wherein the pathogenic bacteria include pathogenic bacteria for periodontal disease. The oral flora-improving agent according to claim 8 or 9, wherein the pathogenic bacteria include black pigment-producing bacteria. The oral flora-improving agent according to any one of claims 8 to 10, wherein the indigenous bacteria include Streptococcus bacteria.