JP7351296B2 - Oral flora improving agent and oral composition - Google Patents

Description

The present invention relates to an oral flora improving agent that suppresses the growth of pathogenic bacteria in the oral cavity, promotes the growth of non-pathogenic bacteria, and improves the bacterial flora balance, and an oral composition containing the same.

Various bacteria coexist in the human oral cavity, forming a bacterial population called the bacterial flora. This bacterial flora contains a mixture of so-called non-pathogenic resident bacteria and pathogenic bacteria, but normally the flora is in a balanced state, a so-called healthy state, and pathogenic bacteria. Diseases caused by bacteria are under control.

However, when the balance of the bacterial flora is disrupted due to factors such as diet, antibiotic intake, stress, aging, or poor cleaning, pathogenic bacteria and opportunistic bacteria increase, resulting in disease. Therefore, in order to control the disease, it is important not only to suppress pathogenic bacteria but also to maintain a healthy bacterial flora balance with non-pathogenic resident bacteria.

Among the hundreds of types of bacteria that grow in the oral cavity, pathogenic bacteria include Porphyromonas gingivalis, which causes periodontal disease and bad breath, Prevotella intermedia, and Fusobacterium nucleatum. (Fusobacterium nucleatum) and Streptococcus mutans, which is a caries-causing bacterium, are just a few types of bacteria. Most of the rest are Streptococcus gordonii, Streptococcus mitis, and Streptococcus oralis, which are not normally pathogenic to humans. Streptococcus (streptococcus), such as the tis group ), bacteria of the genus Neisseria such as Neisseria subflaba, and bacteria of the genus Actinomyces such as Actinomyces viscosus.
Therefore, in order to prevent oral diseases, it is important to maintain and form a well-balanced and healthy bacterial flora consisting of these non-pathogenic resident bacteria in the oral cavity.

However, while many oral compositions have been reported to have excellent bactericidal activity against pathogenic bacteria, as mentioned above, we have focused on non-pathogenic bacteria and developed oral compositions that have excellent effects on controlling the balance of oral flora. There are few things. Focusing on prebiotics, there are preventive or therapeutic agents for oral diseases containing specific lactic acid bacteria as active ingredients (Patent Document 1: Japanese Patent No. 5982376), and prebiotic technology using plants including Perilla plants (Patent Document 2: Japanese Patent No. 6235138), technology to improve oral bacterial flora using caffeine (Patent Document 3; Japanese Unexamined Patent Publication No. 2012-77053), etc. have been proposed, but the effects of these techniques are limited to improving oral bacterial flora. balance control was not sufficient.
In addition, as a technology for maintaining the balance of oral flora, oral antibacterial agents using plant extracts such as pterostilbene and Cistanche annuus (Patent Documents 4 and 5: JP 2017-81831A, JP 2017-81831A, JP 2016-113460) and an oral bacterial flora improving agent using dried powder of mushrooms such as Yamabushitake or an extract thereof (Patent Document 6: International Publication No. 2016/043103).

Patent No. 5982376 Patent No. 6235138 Japanese Patent Application Publication No. 2012-77053 Japanese Patent Application Publication No. 2017-81831 Japanese Patent Application Publication No. 2016-113460 International Publication No. 2016/043103

The present invention was made in view of the above circumstances, and suppresses the growth of pathogenic bacteria in the oral cavity, particularly pathogenic bacteria that cause periodontal disease and bad breath, and promotes the growth of non-pathogenic bacteria. An object of the present invention is to provide an oral flora improving agent that improves the bacterial flora balance and an oral composition containing the same.

As a result of intensive studies to achieve the above object, the present inventors have found that when spermine, spermidine, sialic acid, or lactoferrin is used in combination with a specific saccharide, the growth of pathogenic bacteria in the oral cavity is selectively suppressed. and selectively promotes the growth of non-pathogenic bacteria, and exhibits an excellent bacterial flora-improving effect that improves the bacterial flora balance in the oral cavity to be dominated by non-pathogenic resident bacteria; The present inventors have discovered that an excellent effect of improving bacterial flora can be imparted by incorporating it into an oral composition as an active ingredient for improving oral bacterial flora, and the present invention has been completed.

In the present invention, when (A) one or more selected from spermine, spermidine, sialic acid, and lactoferrin are used in combination with (B) one or more saccharides selected from lactulose, oligosaccharides, and sialic acid-containing disaccharides, ( A) The component selectively suppresses the growth of pathogenic bacteria without inhibiting the growth of non-pathogenic bacteria in the oral cavity, and at the same time, the component (B) selectively suppresses the growth of pathogenic bacteria without inhibiting the growth of non-pathogenic bacteria in the oral cavity. It had the unique effect of selectively promoting the growth of indigenous bacteria. In this case, the combined system of components (A) and (B) is used to kill pathogenic bacteria such as Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis. selective growth of It suppresses and selectively promotes the growth of non-pathogenic bacteria resident in the oral cavity, especially Streptococcus bacteria such as Streptococcus gordonii, and Actinomyces viscosus, thereby making it non-pathogenic. By increasing the proportion of bacteria present, we were able to improve the balance of the bacterial composition to be dominated by non-pathogenic bacteria. Therefore, according to the present invention, periodontal disease and bad breath can be prevented by improving the bacterial flora in the oral cavity to mainly include non-pathogenic resident bacteria.
As shown in the comparative example below, component (A) had almost no bacterial flora improving effect, and component (B) had almost no bacterial flora improving effect, but in the present invention, (A) When used in combination with component (B), the proportion of non-pathogenic bacteria increased, resulting in an excellent bacterial flora improvement effect that improved the bacterial composition ratio, and was able to specifically impart particularly remarkable effects ( (See Examples below).

Therefore, the present invention provides the following oral flora improving agent and oral composition.
[1]
(A) one or more selected from spermine, spermidine, sialic acid, and lactoferrin;
(B) An oral flora improving agent containing one or more selected from lactulose, oligosaccharides, and sialic acid-containing disaccharides.
[2]
The oral flora improving agent according to [1], wherein the oligosaccharide is selected from milk oligosaccharides and raffinose.
[3]
The oral flora improving agent according to [2], wherein the milk oligosaccharide is selected from 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose, and lacto-N-fucopentaose I .
[4]
The oral flora improving agent according to any one of [1] to [3], wherein the sialic acid of the component (A) is N-acetylneuraminic acid.
[5]
When component (A) contains one or more selected from (A-1) spermine and spermidine, the mass ratio of (A-1)/(B) is 0.0005 to 2, and (A-2 ) When containing sialic acid, (A-2)/(B) is 0.005 to 1 as a mass ratio, and when containing (A-3) lactoferrin, (A-3)/(B) is The oral flora improving agent according to any one of [1] to [4], which has a mass ratio of 0.005 to 6.
[6]
The oral flora improving agent according to any one of [1] to [5], wherein the component (A) is selected from spermine, spermidine, and sialic acid.
[7]
Selectively suppresses the growth of pathogenic bacteria in the oral cavity, selectively promotes the growth of non-pathogenic bacteria, increases the proportion of non-pathogenic bacteria, and improves the bacterial composition [1] - [ 6]. The oral flora improving agent according to any one of [6].
[8]
The oral flora improving agent according to [7], wherein the pathogenic bacteria in the oral cavity are one or more selected from Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis.
[9]
The oral flora improving agent according to [7] or [8], wherein the non-pathogenic bacteria are one or more types selected from Streptococcus bacteria and Actinomyces viscosus.
[10]
An oral composition containing the oral flora improving agent according to any one of [1] to [9] as an active ingredient.
[11]
(A) one or more components selected from spermine, spermidine and sialic acid;
(B) An oral composition containing one or more selected from lactulose, oligosaccharides, and sialic acid-containing disaccharides.
[12]
The oral composition according to [11], wherein the oligosaccharide is selected from milk oligosaccharides and raffinose.
[13]
The oral composition according to [12], wherein the milk oligosaccharide is selected from 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose, and lacto-N-fucopentaose I.
[14]
The oral composition according to any one of [11] to [13], wherein the sialic acid of component (A) is N-acetylneuraminic acid.
[15]
When component (A) contains one or more selected from (A-1) spermine and spermidine, the mass ratio of (A-1)/(B) is 0.0005 to 2, and (A-2 ) The oral composition according to any one of [11] to [14], wherein (A-2)/(B) is 0.005 to 1 as a mass ratio when containing sialic acid.
[16]
(A) When containing one or more selected from spermine and spermidine as component (A-1), the content is 0.001 to 1% by mass; (A-2) When containing sialic acid, the content is 0.001 to 1% by mass; The oral composition according to any one of [11] to [15], wherein the content is 0.01 to 1% by mass, and the content of component (B) is 0.1 to 10% by mass.
[17]
(A) as an ingredient (A-3) lactoferrin;
An oral composition containing (B-3) a sialic acid-containing disaccharide as the component (B).
[18]
(A-3) The oral cavity according to [17], wherein the content of lactoferrin is 0.01 to 10% by mass, and (B-3) the content of the sialic acid-containing disaccharide is 0.1 to 10% by mass. Composition for use.
[19]
(A) as an ingredient (A-3) lactoferrin;
(B) contains one or more selected from (B-1) lactulose and (B-2) oligosaccharides as the component, and the content of (A-3) lactoferrin is 0.01 to 10% by mass. Composition for use.
[20]
The oral composition according to [19], wherein the content of the component selected from (B-1) lactulose and (B-2) oligosaccharides is 0.1 to 10% by mass.
[21]
The oral composition according to [19] or [20], wherein the oligosaccharide is a milk oligosaccharide.
[22]
The oral composition according to [21], wherein the milk oligosaccharide is selected from 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose and lacto-N-fucopentaose I.
[23]
The oral composition according to any one of [17] to [22], wherein (A-3)/(B) is 0.005 to 6 as a mass ratio.
[24]
Oral preparations selected from dentifrices, mouth washes, liniments, mouth sprays, patches, chewing agents, oral dissolving agents, oral disintegrating agents, denture care agents, tongue care agents, and mouth fresheners [11 ] to [23].
[25]
The oral composition according to any one of [11] to [23], which is a food or drink preparation selected from chewing gum, tablet confectionery, candy, gummy, edible film, troche, and drink.
[26]
A bacterial flora improvement product that selectively suppresses the growth of pathogenic bacteria in the oral cavity and selectively promotes the growth of non-pathogenic bacteria, increasing the proportion of non-pathogenic bacteria and improving the bacterial composition ratio. The oral composition according to any one of [11] to [25].

According to the present invention, the growth of pathogenic bacteria in the oral cavity, particularly bacteria that cause periodontal disease and bad breath, is selectively suppressed, and the growth of non-pathogenic bacteria is selectively promoted, thereby improving the bacterial flora balance. It is possible to provide an oral flora improving agent and an oral composition containing the same. This oral composition can be suitably used for preventing or suppressing periodontal disease and bad breath.

The present invention will be explained in more detail below. The oral flora improving agent of the present invention comprises (A) one or more selected from spermine, spermidine, sialic acid, and lactoferrin, and (B) one or more selected from lactulose, oligosaccharides, and sialic acid-containing disaccharides. Components (A) and (B) are the active ingredients for improving oral flora. In this case, component (A) selectively suppresses the growth of pathogenic bacteria in the oral cavity, especially pathogenic bacteria that cause periodontal disease and bad breath, and component (B) selectively inhibits the growth of non-pathogenic bacteria. By promoting this method, it has the effect of increasing the proportion of non-pathogenic bacteria and improving the bacterial composition ratio.
Here, improvement of oral flora means that the proportion of non-pathogenic bacteria (resident bacteria) in the oral cavity after treatment has increased compared to before treatment, and the balance is maintained in a healthy state dominated by resident bacteria. This is an improvement.

<(A) component>
Component (A) is one or more selected from spermine, spermidine, sialic acid, and lactoferrin. As component (A), sialic acid and lactoferrin are preferable, particularly from the viewpoint of improving the oral flora, and sialic acid is particularly preferable.
Component (A) exhibits a selective growth-inhibiting effect that inhibits the growth of pathogenic bacteria without inhibiting the growth of non-pathogenic bacteria (resident bacteria) in the oral cavity. Examples of pathogenic bacteria include bacteria that cause periodontal disease and bad breath, such as Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis, and these may be used alone or in combination of two or more.

(A-1) Spermine and/or Spermidine Spermine and spermidine are low molecular organic compounds classified as polyamines. These may be used alone or in combination of two types. Commercially available products can be used for these.

(A-2) Sialic acid Sialic acid is a family name that collectively refers to substances obtained by substituting the amino group or hydroxyl group of neuraminic acid, which has an amino group or carboxyl group.
Examples of sialic acid include N-acetylneuraminic acid, N-glycolylneuraminic acid, and the like, with N-acetylneuraminic acid being particularly preferred. Commercially available products can be used for these.

(A-3) Lactoferrin Lactoferrin is an iron-binding glycoprotein with a molecular weight of approximately 80,000 that is widely distributed in animal bodies. The origin and manufacturing method of lactoferrin are not limited. For example, the conventional method ( For example, lactoferrin separated by ion exchange chromatography, etc.) and lactoferrin produced from plants (eg, tomatoes, rice, tobacco, etc.) can be used. As lactoferrin, a commercially available product may be used, or one prepared by a known method may be used.
As lactoferrin, those derived from bovine are preferably used. Two or more types of lactoferrin having different origins or separation conditions may be used in combination.

<(B) component>
Component (B) is one or more selected from lactulose, oligosaccharides, and sialic acid-containing disaccharides. As component (B), lactulose and oligosaccharides are preferred, particularly from the viewpoint of improving oral flora.
Component (B) exhibits a selective growth-promoting effect that promotes the growth of non-pathogenic bacteria (common bacteria) without promoting the growth of pathogenic bacteria in the oral cavity. Typical examples of non-pathogenic bacteria (common bacteria) include Streptococcus bacteria such as Streptococcus gordonii, Streptococcus mitis, Streptococcus oralis, and Streptococcus perolis, Neisseria subflava, and Actinomyces viscosus. One type may be used alone or two or more types may be used.

(B-1) Lactulose Lactulose is a disaccharide in which galactose and fructose are linked to β-1,4-glycoside.

(B-2) Oligosaccharides Oligosaccharides are saccharides consisting of 3 to 10 sugars, including glucose, fructose, galactose, mannose, idose, altose, gulose, talose, allose, xylose, arabinose, lyxose, ribose, Threose, erythrose, erythrulose, xylulose, ribulose, psicose, sorbose, tagatose, D-2-deoxyribose, L-rhamnose, L-fucose, N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid, glucuronic acid , mannuronic acid, galacturonic acid, iduronic acid, D-glucitol, D-mannitol, ribitol, galactitol, and other monosaccharides.
Examples of oligosaccharides include raffinose, fructooligosaccharide, maltooligosaccharide, isomaltooligosaccharide, galactooligosaccharide, glucosaminooligosaccharide, mannan oligosaccharide, xylooligosaccharide, agarooligosaccharide, milk oligosaccharide, and the like. Particularly preferred are milk oligosaccharides, raffinose, and especially milk oligosaccharides.

Milk oligosaccharide has a free lactose unit on the reducing end side and has N-acetylglucosamine (GlcNAc), galactose (Gal), fucose (Fuc), and N-acetylneuraminic acid (Neu5Ac) added thereto. Examples of milk oligosaccharides include 2'-fucosyllactose, 3-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose, lacto-N-neotetraose, lacto-N-fucopentaose I , lacto-N-fucopentaose II, lacto-N-fucopentaose III, lacto-N-difucohexaose I, lacto-N-difucohexaose II, lacto-N-hexaose, lacto-N-neohexaose, 6 '-N-acetylneuraminyllactose, 3'-N-acetylneuraminyllactose, and the like. Particularly preferred are 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose, and lacto-N-fucopentaose I.

(B-3) Sialic acid-containing disaccharide Examples of the sialic acid-containing disaccharide include sialylgalactose, sialylglucose, sialylmannose, and sialylgalactose is particularly preferred.
As component (B), commercially available products may be used.

The oral flora improving agent of the present invention can be obtained by using components (A) and (B) in combination as active ingredients and blending these components. In addition, it can be used as an oral flora improving agent consisting only of the above-mentioned active ingredients, but if necessary, it may further contain other optional ingredients known for use in the oral cavity. In this case, the optional ingredients are those of the present invention. It can be blended within a range that does not impede the effect.
In this case, components (A) and (B), which are active ingredients for improving oral flora, are particularly effective when applied to oral compositions. The blending amounts of the components are preferably within the ranges described below, and it is preferable to use both components at concentrations that satisfy these ranges.

The blending amount of component (A) is preferably in the following range.
(A-1) When blending spermine and/or spermidine, the blending amount is preferably 0.001 to 1% (mass%, hereinafter the same) of the entire composition from the viewpoint of improving bacterial flora in the oral cavity. More preferably 0.002 to 0.5%, particularly preferably 0.005 to 0.25%. When the blending amount is 0.001% or more, pathogenic bacteria can be sufficiently suppressed and bacterial flora can be improved. When the amount is 1% or less, the bacterial flora improvement effect can be sufficiently maintained. If it exceeds 1%, the growth of non-pathogenic resident bacteria may be inhibited.
(A-2) When blending sialic acid, the blending amount is preferably 0.01 to 1%, more preferably 0.02 to 0.3% of the total composition, from the viewpoint of improving bacterial flora in the oral cavity. %, particularly preferably 0.05 to 0.2%. When the blending amount is 0.01% or more, pathogenic bacteria can be sufficiently suppressed and bacterial flora can be improved. When the amount is 1% or less, the bacterial flora improvement effect can be sufficiently maintained. If it exceeds 1%, the growth of non-pathogenic resident bacteria may be inhibited.
(A-3) When blending lactoferrin, the blending amount is preferably 0.01 to 10% of the entire composition, more preferably 0.03 to 3%, especially Preferably it is 0.05 to 1%. When the blending amount is 0.01% or more, pathogenic bacteria can be sufficiently suppressed and bacterial flora can be improved. When the amount is 10% or less, the bacterial flora improvement effect can be sufficiently maintained. If it exceeds 10%, the growth of non-pathogenic resident bacteria may be inhibited.

The blending amount of component (B) is preferably 0.1% or more of the entire composition, more preferably 0.5% or more, particularly preferably 1% or more, from the viewpoint of improving bacterial flora in the oral cavity. When the blending amount is 0.1% or more, the growth of non-pathogenic resident bacteria can be sufficiently promoted and the bacterial flora can be improved. The upper limit of the blending amount is not particularly limited, but it is preferably 10% or less of the total composition.
In addition, within the range of the blending amount of component (B) above, when blending (B-1) lactulose, (B-2) oligosaccharide, or (B-3) sialic acid-containing disaccharide as component (B), From the viewpoint of improving the bacterial flora in the oral cavity, the amount of each compounding amount is preferably 0.1% or more of the entire composition, more preferably 0.5% or more, and particularly preferably 1% or more. When the blending amount is 0.1% or more, the growth of non-pathogenic resident bacteria can be sufficiently promoted and the bacterial flora can be improved. The upper limit of the blending amount is not particularly limited, but it is preferably 10% or less of the total composition.

In addition, the blending ratio of component (A) and component (B) should be within the range that can be calculated from the blending amount of each component above, but if it is within the following range, the effect of improving the bacterial flora in the oral cavity will be further improved, and preferable.
(A-1) When blending spermine and/or spermidine, (A-1)/(B), which indicates the blending ratio of component (A-1) and component (B), is from 0.0005 to 0.0005 as a mass ratio. 2, particularly preferably from 0.0001 to 0.4, especially from 0.0025 to 0.2.
(A-2) When blending sialic acid, (A-2)/(B), which indicates the blending ratio of component (A-2) and component (B), is 0.005 to 1 as a mass ratio, especially 0.01-0.2, especially 0.025-0.1 is preferred.
(A-3) When blending lactoferrin, (A-3)/(B), which indicates the blending ratio of component (A-3) and component (B), is 0.005 to 6 as a mass ratio, especially 0. 0.015 to 1.5, especially 0.025 to 0.6 are preferred. In addition, when blending (B-1) and/or (B-2) as component (B), the blending ratio of component (A-3) and (B-1) and/or (B-2) (A-3)/{(B-1) and/or (B-2)} is preferably within the above range, and when component (B-3) is blended as component (B). (A-3)/(B-3), which indicates the blending ratio of components (A-3) and (B-3), is preferably within the above range.

The oral composition of the present invention can be prepared in various forms such as liquid (liquid, liquid), paste, solid (solid, solid), and the dosage form is not particularly limited. For example, dentifrices (toothpaste, liquid toothpaste, liquid toothpaste, powdered toothpaste, etc.), mouth rinses, liniments, mouth sprays, patches, chewing agents, oral dissolving agents, oral disintegrating agents, tongue care agents, oral General oral preparations such as refreshing agents and denture care agents, as well as chewing gum, tablets, candies, gummies, edible films, pastilles, and powdered drinks that can be dissolved in water. They are suitable as foods and drinks, and can be prepared by conventional methods. In addition, the form of the food/drink is preferably chewing gum, tablet, candy, gummy, or edible film from the viewpoint of convenience and portability so that it can be used anytime and anywhere.
In the present invention, the oral composition is intended primarily for use in the oral cavity, and may be not only an oral preparation that is discharged from the oral cavity after use, but also an ingestible food or drink. As shown above, in addition to oral preparations such as dentifrices and mouthwashes, food and drink products such as chewing gum, tablets, and candies are also included.

The oral composition of the present invention may optionally contain other known ingredients as necessary. Optional components include, for example, surfactants, abrasives, thickeners, binders, colorants, sweeteners, preservatives, fragrances, active ingredients, as well as pH adjusters, brighteners, and fluidizing agents. , a static eliminator, a binder, an acidulant, a lubricant, a preservative, a disintegrant, an excipient, a solvent, etc., and the amounts of these may be adjusted as appropriate within a range that does not impair the effects of the present invention. , a regular dose may be used.
Oral preparations, such as dentifrices and mouthwashes, can contain surfactants, abrasives, thickeners, binders, colorants, sweeteners, preservatives, fragrances, active ingredients, pH adjusters, and the like.
Food and beverages, such as chewing gum, tablets, candies, and gummies, include gum bases, colorants, sweeteners, flavors, brighteners, fluidizers, binders, acidulants, lubricants, preservatives, disintegrants, and excipients. etc. can be combined.

As the surfactant, general anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants for oral cavity use can be blended. Anionic surfactants include alkyl sulfates such as sodium lauryl sulfate, and nonionic surfactants include sugar fatty acid esters, sugar alcohol fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene fatty acid esters, and higher alcohol esters. Can be mentioned. Cationic surfactants include alkyl ammonium salts, and amphoteric surfactants include betaine and imidazoline surfactants. The amount of surfactant added is usually 0 to 10%, particularly 0.01 to 5%.

Examples of abrasives include silica-based abrasives, calcium phosphate-based abrasives, and calcium carbonate-based abrasives, and the amount thereof is usually 2 to 50% in dentifrices such as toothpaste.

Examples of thickeners include sugar alcohols such as sorbitol and xylitol, and polyhydric alcohols such as propylene glycol and glycerin, and the amount thereof is usually 5 to 50%.
Examples of the binder include organic binders such as cellulose derivatives such as sodium carboxymethylcellulose and gums, and inorganic binders such as gelatinous silica. Its blending amount is usually 0.5 to 10%.

Coloring agents include Red No. 2 and Blue No. 1, sweeteners include saccharin sodium, and preservatives include paraoxybenzoic acid ester.

Fragrances include peppermint oil, spearmint oil, anise oil, eucalyptus oil, wintergreen oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander oil, mandarin oil, lime. Oil, lavender oil, rosemary oil, laurel oil, chamomile oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, grapefruit oil, sweetie oil Natural fragrances such as , yuzu oil, iris concrete, absolute peppermint, absolute rose, orange flower, etc., and processing of these natural fragrances (front distillation cut, rear distillation cut, fractional distillation, liquid-liquid extraction, essence formation, powder fragrance) menthol, carvone, anethole, cineole, methyl salicylate, cinnamic aldehyde, eugenol, 3-l-menthoxypropane-1,2-diol, thymol, linalool, linaryl acetate, limonene, menthone , menthyl acetate, N-substituted-paramenthane-3-carboxamide, pinene, octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allylcyclohexane propionate, methyl anthranilate, ethyl methyl Individual fragrances such as phenylglycidate, vanillin, undecalactone, hexanal, butanol, isoamyl alcohol, hexenol, dimethyl sulfide, cyclotene, furfural, trimethylpyrazine, ethyl lactate, ethylthioacetate, as well as strawberry flavor, apple flavor, and banana flavor. , pineapple flavor, grape flavor, mango flavor, butter flavor, milk flavor, mixed fruit flavor, tropical fruit flavor, etc., and known flavor materials used in oral compositions can be used.
The amount of these fragrances is usually 0.00001 to 1% in toothpastes and mouthwashes, and 0.001 to 50% in tablets, gummies, and chewing gum. It is preferable to use 0.1 to 10% of the fragrance in the composition.

As the active ingredient, known ingredients that are commonly included in oral compositions can be included. For example, nonionic disinfectants such as isopropylmethylphenol, cationic disinfectants such as cetylpyridinium chloride, anti-inflammatory agents such as tranexamic acid and epsilon aminocaproic acid, enzymes such as dextranase, sodium fluoride, and monofluorophosphate. Examples include fluorides such as sodium, water-soluble phosphoric acid compounds, copper compounds, potassium nitrate, aluminum lactate, various vitamins, and plant extracts. The amount of the above-mentioned active ingredient can be set within a range that does not impede the effects of the present invention.
In the present invention, it is preferable to limit the amount of non-selective disinfectants that kill non-pathogenic bacteria as well as pathogenic bacteria in the oral cavity. The non-selective disinfectants are commonly found in disinfectants that have been widely used in oral preparations, such as cationic disinfectants such as cetylpyridinium chloride and nonionic disinfectants such as isopropylmethylphenol. . These non-selective fungicides can be blended within the range where the effects of the present invention are exhibited, but when blended, it is preferably 0.1% or less, particularly 0.05% or less of the entire composition, and it is best not to blend them. preferable. These non-selective bactericidal agents have a non-selective bactericidal effect that kills both pathogenic bacteria and non-pathogenic oral bacteria. The bacterial flora within the body may become unbalanced and uncontrollable. Therefore, in the present invention, it is more suitable for selectively improving the oral flora and controlling the balance if the non-selective bactericidal agent is not blended.

EXAMPLES Hereinafter, the present invention will be specifically explained by showing Examples, Comparative Examples, and Prescription Examples, but the present invention is not limited to the following Examples. In addition, all % in the following example shows mass percentage.

[Example, Comparative Example]
<Evaluation of oral flora improvement effect>
The compositions shown in Tables 1 to 9 were evaluated by the following method. The results are also listed in the table.

The main raw materials used are shown below.
(A) Ingredients Spermine: Manufactured by Wako Pure Chemical Industries, Ltd. Spermidine: Manufactured by Wako Pure Chemical Industries, Ltd. N-acetylneuraminic acid (sialic acid): Manufactured by Wako Pure Chemical Industries, Ltd. Lactoferrin: Manufactured by Morinaga Milk Industries, Ltd. Component (B) Lactulose: Wako Pure Chemical Industries, Ltd. Sialylgalactose (sialic acid-containing disaccharide): Nagara Science Co., Ltd.
Raffinose (oligosaccharide): manufactured by Wako Pure Chemical Industries, Ltd. 3'-sialyllactose (oligosaccharide): manufactured by Carbosynth 6'-sialyllactose (oligosaccharide): 2'-fucosyllactose (oligosaccharide) manufactured by Carbosynth : Manufactured by Carbosynth Lacto-N-tetraose (oligosaccharide) : Manufactured by Carbosynth Lacto-N-fucopentaose I (oligosaccharide): Carbosynt
Manufactured by h company

Bacterial Strains Used The following bacteria were purchased from American Type Culture Collection and used.
Non-pathogenic bacteria (common bacteria in the oral cavity)
<P> Streptococcus gordonii
gordonii: hereinafter referred to as S. gordonii. Abbreviated as gordonii. )
ATCC10558
<Q> Actinomyces vis
cosus: hereinafter referred to as A. Abbreviated as viscosus. )
ATCC43146
Pathogenic bacteria (bacteria that cause periodontal disease and bad breath)
<R> Fusobacterium nucleatum (Fusobacterium n
ucleatum: hereinafter referred to as F. Abbreviated as nucleatum. )
ATCC23726
<S> Prevotella intermedia
media: Hereinafter, P. Abbreviated as intermedia. )
ATCC49046
<T> Porphyromonas gingivalis (Porphyromonas g.
ingivalis: hereinafter referred to as P. Abbreviated as gingivalis. )
ATCC33277

Bacterial preculture The frozen bacterial solutions of the various bacteria mentioned above were inoculated onto a Todd Hewitt Broth (manufactured by Becton and Dickinson) agar medium containing defibrinated horse blood using a platinum loop, and incubated at 37°C for 72 hours. Bacteria were incubated in anaerobic culture (80% by volume nitrogen, 10% by volume carbon dioxide, 10% by volume hydrogen). Subsequently, the grown colonies were placed in Todd Hewitt Broth (manufactured by Becton and Dickinson) containing 5 mg/L hemin (manufactured by Sigma) and 1 mg/L vitamin K (manufactured by Wako Pure Chemical Industries, Ltd.). ) [THBHM] was suspended in 4 mL and cultured anaerobically at 37°C for 24 hours. Furthermore, 20 mL of THBHM was inoculated with 1% of this culture solution, and anaerobically cultured at 37° C. for 24 hours.

Preparation of mixed bacterial solution The bacterial solution after the above cultivation was collected by centrifugation, and mixed bacteria was prepared using a medium with the following composition so that each of the bacteria from <P> to <T> was 2 x 10 ⁸ cfu/mL. A liquid was prepared.
Medium composition Proteose peptone (manufactured by Becton and Dickinson)
10.0g/L (final concentration 1.0%)
Tryptone (manufactured by Becton and Dickinson)
5.0g/L (final concentration 0.5%)
Yeast extract (manufactured by Becton and Dickinson)
5.0g/L (final concentration 0.5%)
Mucin (manufactured by Sigma) 12.5g/L (final concentration 1.25%)
Hemin (manufactured by Sigma) 1.0mg/L (final concentration 0.0001%)
Vitamin K (manufactured by Wako Pure Chemical Industries, Ltd.)
0.2mg/L (final concentration 0.00002%)
KCl (manufactured by Wako Pure Chemical Industries, Ltd.)
2.5g/L (final concentration 0.25%)
Cysteine (manufactured by Wako Pure Chemical Industries, Ltd.)
0.5g/L (final concentration 0.05%)
Glucose 1.0g/L (final concentration 0.1%)
distilled water residue
Total 100.0%

Preparation of Evaluation Samples Each composition shown in Tables 1 to 9 was prepared by a conventional method and used as evaluation samples.

Evaluation of bacterial composition ratio of biofilm 0.5 mL of each of the above evaluation samples was added to a 24-well multi-plate (manufactured by Sumitomo Bakelite Co., Ltd.). For control, 0.5 mL of purified water was added instead of the evaluation sample. Subsequently, 0.5 mL of the above mixed bacterial solution was inoculated and cultured anaerobically at 37° C. for 24 hours to form a biofilm on the bottom of the plate. Thereafter, after washing four times with 1 mL of phosphate buffered saline PBS, 1 mL of PBS was added again, and the biofilm was scraped off with the tip of the tip. The biofilm was dispersed by sonication (200 μA, 10 seconds), and a 10-fold dilution series was prepared using Tryptic Soy Broth (Becton and Dickinson). 10 ^-3 , 10 ^-4 , 10 ^-5 dilutions were smeared onto a selective medium that selectively grows each bacteria, and after culturing, the number of bacterial colonies that grew was counted to determine the growth of each bacteria. The number of bacteria and bacterial composition ratio were calculated.
Incidentally, <P>S. gordonii and <Q>A. viscosus is grown anaerobically on the CVE agar medium described below. nucleatum is grown anaerobically on a tryptic soy agar medium containing kanamycin (Todd Hewitt Broth, manufactured by Becton and Dickinson) containing horse defibrinated blood. intermedia, <T>P. P. gingivalis was distinguished by colony morphology.

CVE agar medium (composition in 1 liter)
Trypticase Peptone (manufactured by Nippon Becton Dickinson Co., Ltd.)
10g
Yeast extract (manufactured by Nippon Becton Dickinson Co., Ltd.) 5g
Sodium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) 5g
Glucose (manufactured by Wako Pure Chemical Industries, Ltd.) 2g
L-tryptophan (manufactured by Wako Pure Chemical Industries, Ltd.) 0.2g
Agar (manufactured by Wako Pure Chemical Industries, Ltd.) 15g
Horse defibrated blood 50mL
Erythromycin (manufactured by Sigma, 4mg/mL) 1mL
Crystal violet (manufactured by Wako Pure Chemical Industries, Ltd., 5mg/mL)
1mL

Evaluation criteria for improving bacterial flora of biofilms <R>F of pathogenic bacteria in biofilms treated with evaluation samples. nucleatum, <S>P. intermedia and <T>P. a (%) of total <R>F. nucleatum, <S>P. intermedia and <T>P. gingivalis total percentage is b (%), <R>F. nucleatum, <S>P. intermedia and <T>P. The rate of decrease in the proportion of S. gingivalis in the biofilm was calculated using the following formula. b of the control was 60%.
In addition, for each evaluation sample, <P> + <Q> (%) and <R> + <S> + <T> (%) in the biofilm are also written. The control was <P>+<Q>=40%, <R>+<S>+<T>=60%.
The total number of bacteria in the control biofilm was approximately 1×10 ⁸ , and there was almost no difference in the biofilm treated with the evaluation samples shown in Examples.

The reduction rate X (%) of the proportion of pathogenic bacteria when compared to the control was calculated using the following formula, and the oral flora improvement effect was evaluated according to the following criteria.
X (%) = 100 - {(a/b) x 100}
Evaluation criteria A: X is 70% or more B: X is 50% or more and less than 70% C: X is 20% or more and less than 50% D: X is less than 20%

Prescription examples are shown below. The raw materials used are the same as above, and the sialic acid is N-acetylneuraminic acid.

[Formulation example 1] Chewing gum (A) sialic acid 0.1
(B) Lactulose 4
Xylitol 45.9
Maltitol 20
gum base 20
gum arabic 9
Fragrance 1
Total 100%
Mass ratio of (A)/(B) = 0.025

[Formulation example 2] Chewing gum (A) sialic acid 0.1
(B) 3'-sialyllactose 4
Xylitol 45.9
maltitol 20
gum base 20
gum arabic 9
Fragrance 1
Total 100%
Mass ratio of (A)/(B) = 0.025

[Formulation example 3] Chewing gum (A) Lactoferrin 0.1
(B) Lactulose 4
Xylitol 45.9
Maltitol 20
gum base 20
gum arabic 9
Fragrance 1
Total 100%
Mass ratio of (A)/(B) = 0.025

[Formulation example 4] Chewing gum (A) Lactoferrin 0.1
(B) 3'-sialyllactose 4
Xylitol 45.9
Maltitol 20
gum base 20
gum arabic 9
Fragrance 1
Total 100%
Mass ratio of (A)/(B) = 0.025

[Formulation Example 5] Tablet confectionery (A) Sialic acid 0.1
(B) Lactulose 4
Sorbitol 77.9
xylitol 10
Sucrose fatty acid ester 3
Fragrance 4.5
Fine silicon dioxide 0.5
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation example 6] Tablet confectionery (A) Sialic acid 0.1
(B) 3'-sialyllactose 4
Sorbitol 77.9
xylitol 10
Sucrose fatty acid ester 3
Fragrance 4.5
Fine silicon dioxide 0.5
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Prescription Example 7] Tablet confectionery (A) Lactoferrin 0.1
(B) Lactulose 4
Sorbitol 77.9
xylitol 10
Sucrose fatty acid ester 3
Fragrance 4.5
Fine silicon dioxide 0.5
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation example 8] Tablet confectionery (A) Lactoferrin 0.1
(B) 3'-sialyllactose 4
Sorbitol 77.9
xylitol 10
Sucrose fatty acid ester 3
Fragrance 4.5
Fine silicon dioxide 0.5
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation example 9] Gummy (A) sialic acid 0.1
(B) Lactulose 4
sugar 40
Starch syrup 30
Glucose liquid sugar 10
glycerin 5
Gelatin 5
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation example 10] Gummy (A) sialic acid 0.1
(B) 3'-sialyllactose 4
sugar 40
Starch syrup 30
Glucose liquid sugar 10
glycerin 5
gelatin 5
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Prescription Example 11] Gummy (A) Lactoferrin 0.1
(B) Lactulose 4
sugar 40
Starch syrup 30
Glucose liquid sugar 10
glycerin 5
Gelatin 5
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Prescription Example 12] Gummy (A) Lactoferrin 0.1
(B) 3'-sialyllactose 4
sugar 40
Starch syrup 30
Glucose liquid sugar 10
glycerin 5
Gelatin 5
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation example 13] Candy (A) sialic acid 0.1
(B) Lactulose 4
sugar 50
Starch syrup 33
Citric acid 2.0
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation example 14] Candy (A) sialic acid 0.1
(B) 3'-sialyllactose 4
sugar 50
Starch syrup 33
Citric acid 2
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Prescription Example 15] Candy (A) Lactoferrin 0.1
(B) Lactulose 4
sugar 50
Starch syrup 33
Citric acid 2
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation Example 16] Candy (A) Lactoferrin 0.1
(B) 3'-sialyllactose 4
sugar 50
Starch syrup 33
Citric acid 2
Fragrance 0.2
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation Example 17] Dentifrice (A) Sialic acid 0.1
(B) Lactulose 4
Silicic anhydride 10
Sodium lauryl sulfate 1
Carboxymethyl cellulose sodium 1.5
Saccharin sodium 0.1
Sorbitol 25
Fragrance 1
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation Example 18] Dentifrice (A) Sialic acid 0.1
(B) 3'-sialyllactose 4
Silicic anhydride 10
Sodium lauryl sulfate 1
Carboxymethyl cellulose sodium 1.5
Saccharin sodium 0.1
Sorbitol 25
Fragrance 1
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Prescription Example 19] Toothpaste (A) Spermine 0.02
(B) Lactulose 4
Silicic anhydride 10
Sodium lauryl sulfate 1
Carboxymethyl cellulose sodium 1.5
Saccharin sodium 0.1
Sorbitol 25
Fragrance 1
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.005

[Prescription Example 20] Toothpaste (A) Spermine 0.02
(B) 3'-sialyllactose 4
Silicic anhydride 10
Sodium lauryl sulfate 1
Carboxymethyl cellulose sodium 1.5
Saccharin sodium 0.1
Sorbitol 25
Fragrance 1
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.005

[Formulation Example 21] Mouthwash (A) Sialic acid 0.1
(B) Lactulose 4
Propylene glycol 5
glycerin 5
Citric acid 0.03
Sodium citrate 0.25
Fragrance 0.8
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Formulation Example 22] Mouthwash (A) Sialic acid 0.1
(B) 3'-sialyllactose 4
Propylene glycol 5
glycerin 5
Citric acid 0.03
Sodium citrate 0.25
Fragrance 0.8
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.025

[Prescription Example 23] Mouthwash (A) Spermine 0.02
(B) Lactulose 4
Propylene glycol 5
glycerin 5
Citric acid 0.03
Sodium citrate 0.25
Fragrance 0.8
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.005

[Prescription Example 24] Mouthwash (A) Spermine 0.02
(B) 3'-sialyllactose 4
Propylene glycol 5.0
glycerin 5
Citric acid 0.03
Sodium citrate 0.25
Fragrance 0.8
water balance
Total 100.0%
Mass ratio of (A)/(B) = 0.005

Claims (24)

(A) one or more selected from spermine, spermidine, sialic acid, and lactoferrin;
(B) An oral flora improving agent containing one or more selected from milk oligosaccharides, raffinose, and sialic acid-containing disaccharides (however,
(i) soluble ICAM-1 or ICAM-1 inhibitor;
(ii) sialic acid (which may be in the form of sialyllactose),
Excludes pharmaceutical compositions comprising (iii) lysozyme, and (iv) lactoferrin and a pharmaceutically acceptable carrier. ). The oral flora improving agent according to claim 1, wherein the milk oligosaccharide is selected from 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose and lacto-N-fucopentaose I. The oral flora improving agent according to claim 1 or 2, wherein the sialic acid of component (A) is N-acetylneuraminic acid. When component (A) contains one or more selected from (A-1) spermine and spermidine, the mass ratio of (A-1)/(B) is 0.0005 to 2, and (A-2 ) When containing sialic acid, (A-2)/(B) is 0.005 to 1 as a mass ratio, and when containing (A-3) lactoferrin, (A-3)/(B) is The oral flora improving agent according to any one of claims 1 to 3, which has a mass ratio of 0.005 to 6. (A) one or more selected from spermine, spermidine and sialic acid;
(B) one or more selected from lactulose, milk oligosaccharides, raffinose, and sialic acid-containing disaccharides;
An oral flora improving agent containing (however,
(i) soluble ICAM-1 or ICAM-1 inhibitor;
(ii) sialic acid (which may be in the form of sialyllactose),
(iii) lysozyme, and
(iv) lactoferrin, and
Excludes pharmaceutical compositions containing pharmaceutically acceptable carriers. ). Claims 1 to 5 which selectively suppress the growth of pathogenic bacteria in the oral cavity, selectively promote the growth of non-pathogenic bacteria, increase the proportion of non-pathogenic bacteria, and improve the bacterial composition ratio. The oral flora improving agent according to any one of the above. The oral flora improving agent according to claim 6, wherein the pathogenic bacteria in the oral cavity are one or more selected from Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis. The oral flora improving agent according to any one of claims 1 to 7, which is used for preventing periodontal disease or bad breath. An oral composition containing the oral flora improving agent according to any one of claims 1 to 8 as an active ingredient. (A) one or more selected from spermine, spermidine and sialic acid;
(B) An oral composition containing milk oligosaccharides, raffinose, and one or more selected from sialic acid-containing disaccharides (however,
(i) soluble ICAM-1 or ICAM-1 inhibitor;
(ii) sialic acid (which may be in the form of sialyllactose),
Excludes pharmaceutical compositions comprising (iii) lysozyme, and (iv) lactoferrin and a pharmaceutically acceptable carrier. ). The oral composition according to claim 10, wherein the milk oligosaccharide is selected from 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose and lacto-N-fucopentaose I. The oral composition according to claim 10 or 11 , wherein the sialic acid of component (A) is N-acetylneuraminic acid. When component (A) contains one or more selected from (A-1) spermine and spermidine, the mass ratio of (A-1)/(B) is 0.0005 to 2, and (A-2 ) The oral composition according to any one of claims 10 to 12 , wherein (A-2)/(B) is 0.005 to 1 as a mass ratio when containing sialic acid. (A) When containing one or more selected from spermine and spermidine as component (A-1), the content is 0.001 to 1% by mass; (A-2) When containing sialic acid, the content is 0.001 to 1% by mass; The oral composition according to any one of claims 10 to 13 , wherein the content is 0.01 to 1% by mass, and the content of component (B) is 0.1 to 10% by mass. (A-3) Lactoferrin,
(B-3) An oral composition containing a sialic acid-containing disaccharide. 16. For the oral cavity according to claim 15 , wherein the content of (A-3) lactoferrin is 0.01 to 10% by mass, and the content of (B-3) the sialic acid-containing disaccharide is 0.1 to 10% by mass. Composition. ( A-3) Lactoferrin and
( B-2) An oral composition containing one or more selected from milk oligosaccharides and raffinose, and (A-3) having a lactoferrin content of 0.01 to 10% by mass (however,
(i) soluble ICAM-1 or ICAM-1 inhibitor;
(ii) sialic acid (which may be in the form of sialyllactose),
Excludes pharmaceutical compositions comprising (iii) lysozyme, and (iv) lactoferrin and a pharmaceutically acceptable carrier. ). ( B-2) The oral composition according to claim 17 , wherein the content of the component selected from milk oligosaccharides and raffinose is 0.1 to 10% by mass. The oral composition according to claim 17 or 18 , wherein the milk oligosaccharide is selected from 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-tetraose and lacto-N-fucopentaose I. The oral composition according to any one of claims 17 to 19, wherein (A-3)/(B -2 ) is 0.005 to 6 as a mass ratio. The oral cavity composition according to any one of claims 9 to 20 , which is used for preventing periodontal disease or bad breath. The claim is an oral preparation selected from dentifrices, mouthwashes, liniments, mouth sprays, patches, chewing agents, orally dissolving agents, orally disintegrating agents, denture care agents, tongue care agents, and mouth fresheners. The oral composition according to any one of items 9 to 21 . The oral composition according to any one of claims 9 to 21 , which is a food or drink preparation selected from chewing gum, tablet confectionery, candy, gummy, edible film, troche, and drink. A bacterial flora improvement product that selectively suppresses the growth of pathogenic bacteria in the oral cavity and selectively promotes the growth of non-pathogenic bacteria, increasing the proportion of non-pathogenic bacteria and improving the bacterial composition ratio. The oral composition according to any one of claims 9 to 23 .