WO2021079921A1

WO2021079921A1 - Growth inhibitor for pathogenic bacteria in oral cavity, oral microflora improver, and composition for oral cavity

Info

Publication number: WO2021079921A1
Application number: PCT/JP2020/039636
Authority: WO
Inventors: 悠菜瀧本; 隆太郎城
Original assignee: ライオン株式会社
Priority date: 2019-10-25
Filing date: 2020-10-22
Publication date: 2021-04-29
Also published as: JP7548240B2; JPWO2021079921A1

Abstract

Provided are: a growth inhibitor against pathogenic bacteria in the oral cavity and to be added to a composition for the oral cavity; an oral microflora improver; and a composition for the oral cavity using the growth inhibitor and the oral flora improver.　This composition for the oral cavity contains (A) a milk oligosaccharide and (B) a sugar alcohol.　According to the present invention, a growth accelerating agent that is for pathogenic bacteria in the oral cavity and that is to be added to a composition for the oral cavity, contains component (A). This oral microflora improver to be added to a composition for the oral cavity contains component (B) and the growth accelerating agent for pathogenic bacteria in the oral cavity. This composition for the oral cavity contains component (A).

Description

Growth inhibitor for pathogenic bacteria in the oral cavity, flora improver in the oral cavity and composition for the oral cavity

The present invention relates to a growth inhibitor for pathogenic bacteria in the oral cavity, a bacterial flora improving agent in the oral cavity, and an oral composition using these.

Various bacteria coexist in the human oral cavity, forming a bacterial population called the bacterial flora. This bacterial flora is a mixture of so-called non-pathogenic indigenous bacteria and pathogenic bacteria, but it is usually a so-called healthy state in which the bacterial flora is balanced and pathogenic. Diseases caused by bacteria are suppressed.

However, if the bacterial flora is out of balance due to eating habits, intake of antibiotics, stress, aging, poor cleaning, etc., pathogenic pathogenic bacteria and opportunistic infectious bacteria will increase and become a 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 indigenous bacteria.

Among the hundreds of bacteria that grow in the oral cavity, the pathogenic bacteria are Streptococcus mutans, which is the causative agent of caries, and Porphyromonas gingivalis, which is the causative agent of periodontal disease and bad odor. There are only a few types of bacteria represented by (Porphyromonas gingivalis), Prevotella intermedia, and Fusobacterium nucleatum. Most of the remaining, normal, Streptococcus show no pathogenicity to humans Gorudoniai (Streptococcus Gordonii), Streptococcus mitis (Streptococcus mitis), Streptococcus oralis (Streptococcus oralis), Streptococcus Perorisu (Streptococcus peroris), Streptococcus Rakutariusu (Streptococcus lactarius) Representatives include Streptococcus bacteria such as the Mitis group, Streptococcus bacteria such as Neisseria subflava, and Actinomyces naeslundii such as Actinomyces naeslundii. It is a non-pathogenic Streptococcus.
Therefore, in order to prevent oral diseases, it is important to maintain and form a well-balanced and healthy bacterial flora composed of these non-pathogenic indigenous bacteria in the oral cavity.

However, while many oral compositions having excellent bactericidal activity against pathogenic bacteria have been reported, focusing on non-pathogenic bacteria as described above, the balance control effect of the oral bacterial flora is excellent. There are few things. Focusing on prebiotics, preventive or therapeutic agents for oral diseases containing specific lactic acid bacteria as an active ingredient (Patent Document 1: Japanese Patent No. 5982376), prebiotic technology using plants including Perilla plants (Patent Document 2: Patent Document 2: Patent No. 6235138), a technique for improving the oral bacterial flora using caffeine (Patent Document 3; Japanese Patent Application Laid-Open No. 2012-77053), etc. have been proposed, but the effect of these techniques is the oral bacterial flora. It was not enough in terms of balance control.
In addition, sugar alcohol, which is a sweetener, is used as a substitute component for sugar because it has the effect of suppressing the growth of caries-causing bacteria and its pH production, but the effect is not sufficient and it is an oral bacterium. The balance control of the flora was not reached.

Japanese Patent No. 5982376 Japanese Patent No. 6235138 Japanese Unexamined Patent Publication No. 2012-77053

The present invention has been made in view of the above circumstances, and provides an agent for suppressing the growth of pathogenic bacteria in the oral cavity, an agent for improving the flora of the oral cavity, and an oral composition using these. The purpose is.

As a result of diligent studies to achieve the above object, the present inventors have found that (A) milk oligosaccharide has a growth-suppressing effect on pathogenic bacteria in the oral cavity, and moreover, non-pathogenic bacteria in the oral cavity. It has the effect of promoting the growth of (resident bacteria in the oral cavity, the same applies hereinafter), and when this (A) milk oligosaccharide and (B) sugar alcohol are used in combination, the growth of non-pathogenic bacteria in the oral cavity is selective. Bacterial flora that promotes the growth of pathogenic bacteria, selectively suppresses the growth of pathogenic bacteria, increases the abundance ratio of non-pathogenic bacteria to pathogenic bacteria, and improves the balance of bacterial composition ratio of the bacterial flora mainly to non-pathogenic bacteria. It was found that the effect of improvement is excellent. Then, it was found that by blending the above-mentioned combination system into the oral composition, the above-mentioned excellent bacterial flora improving effect can be imparted, and it can be applied to the prevention or suppression of oral diseases, particularly caries, and the present invention has been developed. I came to the eggplant.

More specifically, the present inventors attempted to develop an oral composition for improving the bacterial flora in the oral cavity into a bacterial flora mainly composed of non-pathogenic indigenous bacteria. Was found to have the effect of promoting the growth of non-pathogenic bacteria in the oral cavity, and proceeded with studies to apply this to the improvement of the flora.
As a result, (A) milk oligosaccharide does not have a growth-suppressing effect on pathogenic bacteria in the oral cavity, but in the oral cavity in which non-pathogenic indigenous bacteria, particularly Streptococcus perolis or Streptococcus lactalius, are present. It was found that when applied to, the growth-suppressing effect of these bacteria on pathogenic bacteria in the oral cavity is dramatically promoted, and a remarkable growth-suppressing effect on pathogenic bacteria in the oral cavity can be obtained. Furthermore, it was found that the component (A) promotes the growth of Streptococcus perolis or Streptococcus lactalius, and exerts a remarkably excellent growth promoting effect on non-pathogenic bacteria in the oral cavity.
When the component (A) is used in combination with the component (B), surprisingly, the two interact with each other, and at the same time, the above-mentioned action of the component (A) itself, particularly the growth promoting action of non-pathogenic bacteria is further enhanced, and at the same time, ( The action of the component B) on pathogenic bacteria, particularly caries-causing bacteria, was improved, and the action of suppressing its growth was enhanced. As a result, the non-pathogenic bacteria and the pathogenic bacteria in the oral cavity coexist by the combined system of the components (A) and (B), and in the bacterial flora formed by a plurality of bacterial species in this way, the non-pathogenic bacteria Selectively promotes growth, increases the number of bacteria to increase the abundance ratio, and selectively suppresses the growth of pathogenic bacteria that cause caries, and decreases the number of bacteria to increase the abundance ratio. As a result, the growth of non-pathogenic bacteria can be remarkably promoted, and the abundance ratio of non-pathogenic bacteria to pathogenic bacteria can be increased to a high ratio, which gives an excellent flora improving effect. I was able to.
In the present invention, a peculiar and remarkable bacterial flora improving effect was obtained by using the components (A) and (B) in combination, and the bacterial flora improving effect was low with the component (A) alone or the component (B) alone.
As shown in Examples described later, when the oral composition containing the components (A) and (B) of the present invention is treated against a plurality of non-pathogenic bacteria and a mixed bacterial solution of pathogenic bacteria, The number of caries-causing bacteria (iii) after treatment is low and the abundance ratio is low, and the number of non-pathogenic bacteria (i) + (ii) after treatment is high and the abundance ratio of these is high. The abundance ratio of non-pathogenic bacteria to pathogenic bacteria ({(i) + (ii)} / (iii)) was higher than that of the untreated control (sample untreated), and the effect of improving the flora was excellent. .. On the other hand, as shown in the comparative example described later, even if the component (B) is blended, the oral composition in which the component (A) is not blended can be used as an untreated control (sample untreated). In comparison, the number of caries-causing bacteria decreased slightly after the treatment, but the abundance ratio of non-pathogenic bacteria to pathogenic bacteria hardly changed, and the effect of improving the flora was low.

In the present invention, Streptococcus mutans, Streptococcus sobrinus, Porphyromonas streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptococcus streptoccus ) Etc., especially Streptococcus mutans and Streptococcus sobrinus, which are caries-causing bacteria, are selectively suppressed in growth and proliferation, and Streptococcus gordonii, which is a non-pathogenic bacterium resident in the oral cavity, Streptococcus gordonii (Streptococcus gordonii) Streptococcus mitis), Streptococcus oralis (Streptococcus oralis), Streptococcus Perorisu (Streptococcus Peroris), Streptococcus Rakutariusu (Streptococcus Lactarius), etc. Streptococcus (Streptococcus) bacteria, Neisseria Sabufuraba (Neisseria Subflava) Neisseria bacteria such as, Actinomyces Ness The growth of Streptococcus genus bacteria such as Randy (Actinomyces naeslundii) is selectively promoted, and the bacterial flora balance in the oral cavity can be improved mainly by non-pathogenic indigenous bacteria. Therefore, according to the present invention, it is possible to maintain and form a bacterial flora in the oral cavity in a healthy state mainly composed of non-pathogenic indigenous bacteria, which is effective for prevention or suppression of oral diseases, especially caries. Oral composition can be provided.

Therefore, the present invention provides the following oral composition, an agent for suppressing the growth of pathogenic bacteria in the oral cavity for blending the oral composition, and an agent for improving the flora of the oral cavity.
[1]
(A) Milk oligosaccharides and
(B) An oral composition comprising a sugar alcohol.
[2]
(A) The milk oligosaccharide is at least one selected from 2'-fucosyl lactose, 3'-sialyl lactose, 6'-sialyl lactose, lacto-N-tetraose and lacto-N-fucopentaose I [1]. The above-mentioned oral composition.
[3]
(B) The oral composition according to [1] or [2], wherein the sugar alcohol is at least one selected from xylitol, sorbitol, maltitol, erythritol and mannitol.
[4]
The oral composition according to any one of [1] to [3], which contains 0.01 to 50% by mass of the component (A) and 1 to 90% by mass of the component (B).
[5]
The oral composition according to any one of [1] to [4], wherein (A) / (B) indicating the quantitative ratio of the component (A) to the component (B) is 0.0005 to 1 as a mass ratio. Stuff.
[6]
From dentifrices, mouthwashes, coatings, mouth sprays, patches, sheets, oral sustained release agents, chewing agents, oral dissolving agents, oral disintegrants, denture care agents, tongue care agents and mouth refreshers The oral composition according to any one of [1] to [5], which is the oral preparation of choice.
[7]
The oral composition according to any one of [1] to [5], which is a food or drink selected from chewing gum, tablet confectionery, candy, gummies, edible films, troches and beverages.
[8]
(A) A growth inhibitor for pathogenic bacteria in the oral cavity, which contains a milk oligosaccharide and is used for blending an oral composition.
[9]
The pathogenic bacterium in the oral cavity according to [8], which promotes the growth-suppressing effect of Streptococcus perolis or Streptococcus lactalius in the oral cavity against pathogenic bacteria in the oral cavity and suppresses the growth of pathogenic bacteria in the oral cavity. Growth inhibitor against.
[10]
An oral flora improving agent for blending an oral composition, which comprises the growth inhibitor for pathogenic bacteria in the oral cavity according to [8] or [9] and (B) sugar alcohol.
[11]
(A) Tongue polish, mouthwash, coating agent, mouth spray, patch, sheet agent, oral sustained release agent, chewing agent, oral solubilizer, oral disintegrant, denture care containing milk oligosaccharide An oral composition selected from agents, tongue care agents and mouthwashes.

According to the present invention, it is possible to provide a growth inhibitor for pathogenic bacteria in the oral cavity, a bacterial flora improving agent in the oral cavity, and an oral composition to which these are applied. The oral composition containing the components (A) and (B) of the present invention promotes the growth of non-pathogenic bacteria in the oral cavity, suppresses the growth of pathogenic bacteria, and has a bacterial composition ratio of the flora. It has an excellent flora improving effect that improves the balance mainly of non-pathogenic bacteria. This oral composition is particularly effective in promoting the growth of non-pathogenic bacteria and further improving the bacterial flora, and can also be effectively used for preventing or suppressing oral diseases, particularly caries.

Hereinafter, the present invention will be described in more detail.
The oral composition of the present invention contains (A) milk oligosaccharide, or (A) milk oligosaccharide and (B) sugar alcohol.
In the present invention, when the components (A) and (B) are used in combination, non-pathogenic bacteria in the oral cavity (resident bacteria in the oral cavity, hereinafter referred to as "non-pathogenic bacteria") and pathogenic bacteria coexist. In a bacterial flora formed by multiple bacterial species, it selectively promotes the growth of non-pathogenic bacteria and selectively suppresses the growth of pathogenic bacteria, which in particular promotes the growth of non-pathogenic bacteria. Therefore, by increasing the abundance ratio of non-pathogenic bacteria to pathogenic bacteria, it is excellent in improving the flora. Therefore, the components (A) and (B) are active ingredients for the growth of non-pathogenic bacteria in the oral cavity and the improvement of the flora in the oral cavity, and the above-mentioned action and effect can be obtained by blending them. be able to.
Here, the improvement of the flora in the oral cavity means that the treatment increases the number of non-pathogenic bacteria and increases the abundance ratio, and the pathogenic bacteria in the oral cavity decrease and the abundance ratio decreases. The abundance ratio of non-pathogenic bacteria is increasing, and the flora in the oral cavity is improving the balance of healthy conditions mainly composed of non-pathogenic bacteria.

(A) Milk oligosaccharide is a bacterial flora in which a plurality of bacterial species exist as described above, and has an action of promoting the growth of non-pathogenic bacteria and increasing non-pathogenic bacteria, and is also a component of (B). It also has the effect of enhancing the growth inhibitory effect on non-pathogenic bacteria.
As the milk oligosaccharide (A), the milk oligosaccharides shown below can be used, and one or more selected from these can be used.
The milk oligosaccharide has a free lactose unit on the reducing end side, and N-acetylglucosamine (GlcNAc), galactose (Gal), fucose (Fuc), and N-acetylneuraminic acid (Neu5Ac) are added.
Examples of milk oligosaccharides are 2'-fucosyl lactose, 3-fucosyl lactose, 3'-sialyl lactose, 6'-sialyl lactose, lacto-N-tetraose, lacto-N-neotetraose, lacto-N-fucopentaose I. , Lact-N-Fucopentaose II, Lactose-N-Fucopentaose III, Lact-N-Difucohexaose I, Lact-N-Difucohexaose II, Lactose-N-Hexaose, Lact-N-Neohexaose, 6 '-N-Acetylneuraminyl lactose, 3'-N-acetylneuraminyl lactose and the like can be mentioned. Among them, 2'-fucosyl lactose, 3'-sialyl lactose, 6'-sialyl lactose, lacto-N-tetraose, lacto-N-fucopentaose I are preferable, and more preferably 2'-fucosyl lactose, 3'-sialyl lactose, 6'-sialyl lactose, more preferably 3'-sialyl lactose, 6'-sialyl lactose.
Further, lactulose can be used as the milk oligosaccharide. Lactulose is a disaccharide in which galactose and fructose are β-1,4-glycosidic bonded, and is used for improving constipation and the like. (A) Lactulose can also be preferably used as the milk oligosaccharide.
As the milk oligosaccharide (A), a commercially available product can be used, and for example, a product manufactured by Carbosynth can be used.

The amount of the milk oligosaccharide (A) to be blended is preferably 0.01% (mass%, the same applies hereinafter) or more, preferably 0.1% or more, from the viewpoint of promoting the growth of non-pathogenic bacteria and improving the bacterial flora. Is more preferable, and 0.5% or more is further preferable. When the blending amount is 0.01% or more, the growth promoting effect of non-pathogenic bacteria and the bacterial flora improving effect can be sufficiently obtained. The above effect increases as the blending amount increases, and the upper limit thereof is not particularly limited. However, from the viewpoint of the stability of the preparation and the ease of taking, the blending amount of the component (A) is 50% or less of the entire composition. Is preferable, 10% or less is more preferable, and 5% or less is further preferable.

(B) Sugar alcohol is a bacterial flora in which a plurality of bacterial species exist as described above, has an effect of suppressing the growth of pathogenic bacteria and reducing pathogenic bacteria, and is non-pathogenic of the component (A). It also has the effect of enhancing the growth promoting effect on bacteria.
Examples of the sugar alcohol include xylitol, sorbitol, maltitol, erythritol, mannitol, glycerin, lactitol, isomalt and the like, and one or more selected from these can be used. Among them, xylitol, sorbitol, maltitol, erythritol, and mannitol are preferable, and xylitol and sorbitol, particularly xylitol, are preferable from the viewpoint of suppressing the growth of pathogenic bacteria and improving the bacterial strength.
As the sugar alcohol, a commercially available product can be used, and for example, a product manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. can be used.

(B) The blending amount of the sugar alcohol is preferably 1% or more, more preferably 5% or more, still more preferably 10% or more of the entire composition from the viewpoint of suppressing the growth of pathogenic bacteria and improving the bacterial flora. When the blending amount is 1% or more, the effect of suppressing the growth of pathogenic bacteria and the effect of improving the flora can be sufficiently obtained. The larger the blending amount, the higher the effect, and the upper limit thereof is not particularly limited, but it is preferable to adjust the amount according to the mass ratio of (A) / (B) described later. If too much is added, the stability of the preparation may be lowered, and the amount of the component (B) is preferably 1 to 90% of the whole composition, particularly 5 to 50%, particularly 10 to 20%. preferable.

In the present invention, (A) / (B), which indicates the quantitative ratio of the component (A) to the component (B), preferably has a mass ratio of 0.0005 to 1, more preferably 0.005 to 0.5. Particularly preferably, it is 0.025 to 0.10. When the mass ratio of (A) / (B) is within the above range, the effect of promoting the growth of non-pathogenic bacteria and the effect of suppressing the growth of pathogenic bacteria are further enhanced, and a more excellent effect of improving the flora can be obtained. ..

The oral composition of the present invention can be prepared in various shapes such as liquid (liquid, liquid), paste, and solid (solid, solid), and the dosage form is not particularly limited.
In the present invention, the oral composition is mainly intended to be used in the oral cavity, and is not only an oral preparation discharged from the oral cavity after use, but also an ingestible food and drink. Good. For example, toothpaste (toothpaste, liquid toothpaste, liquid toothpaste, powdered toothpaste, etc.), mouthwash, coating agent, mouth spray, patch, sheet agent, oral sustained release agent, chewing agent, oral dissolving agent, oral cavity It can be prepared as a general oral preparation such as an internal disintegrant, a dentifrice care agent, a tongue care agent, and a mouth refreshing agent. It can also be prepared for foods and drinks such as chewing gum, tablet confectionery, candy, gummies, edible films, troches, and powdered beverages that are dissolved in water and used in the oral cavity. As the preparation method, each conventional method can be adopted. The form of the food or drink is preferably chewing gum, tablet confectionery, candy, gummies, or edible film from the viewpoint of convenience and portability that can be used anytime and anywhere.

The oral composition of the present invention may optionally contain other known components in addition to the above components, if necessary. Optional ingredients include, for example, surfactants, abrasives, thickeners, binders, colorants, sweeteners, preservatives, flavors, active ingredients, as well as pH adjusters, brighteners, fluidizers. , Static eliminators, binders, acidulants, lubricants, preservatives, disintegrants, excipients, solvents, etc., and the blending amounts thereof may be appropriately adjusted as long as the effects of the present invention are not impaired. , Ordinary dose may be used.
In oral preparations such as dentifrices and mouthwashes, surfactants, abrasives, thickeners, binders, colorants, sweeteners, preservatives, fragrances, active ingredients, pH adjusters and the like can be blended.
In foods and drinks such as chewing gum, tablets, candies and gummies, gum bases, colorants, sweeteners, flavors, brighteners, fluidizers, binders, acidulants, lubricants, preservatives, disintegrants, excipients Etc. can be blended.

As the surfactant, an anionic surfactant, a nonionic surfactant, a cationic surfactant, and an amphoteric surfactant, which are generally used for oral use, can be blended. The anionic surfactant is an alkyl sulfate such as sodium lauryl sulfate, and the nonionic surfactant is a sugar fatty acid ester, a sugar alcohol fatty acid ester, a sorbitan fatty acid ester, a glycerin fatty acid ester, a polyoxyethylene fatty acid ester or a higher alcohol ester. Can be mentioned. Examples of the cationic surfactant include an alkylammonium salt, and examples of the amphoteric surfactant include a betaine type and an imidazoline type. The blending amount of the surfactant is usually 0 to 10%, particularly 0.01 to 5% of the total composition.

Examples of the abrasive include silica-based abrasives, calcium phosphate-based abrasives, and calcium carbonate-based abrasives, and the blending amount thereof is usually 2 to 50% of the total composition of dentifrices such as dentifrice.

Examples of the thickener include polyhydric alcohols such as propylene glycol and glycerin. Since the component (B) also acts as a thickener, it is not necessary to add any thickener. The blending amount of these arbitrary thickeners is preferably 0 to 89% of the entire composition, and the total blending amount combined with the blending amount of the component (B) is 90% or less, particularly 50% or less, and further 20% or less. It is preferable to have.

Examples of the binder include cellol derivatives such as sodium carboxymethyl cellulose and gums as organic binders, and gelling silica and the like as inorganic binders. The blending amount is usually 0.5 to 10% of the total composition.

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

Fragrances are peppermint oil, sparemint oil, anis oil, eucalyptus oil, winter green oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamon oil, coriander oil, mandarin oil, lime. Oil, lavender oil, rosemary oil, laurel oil, camomill oil, caraway oil, majorum oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, grapefruit oil, sweetie oil , Yuzu oil, iris concrete, absolute peppermint, absolute rose, orange flower and other natural fragrances, and processing of these natural fragrances (pre-reservoir cut, rear-reservoir cut, distilling, liquid extraction, essence, powder fragrance Perfume, menthol, carboxylic, anator, cineole, methyl salicylate, synamic aldehyde, eugenol, 3-l-mentoxypropane-1,2-diol, timole, linalol, linaryl acetate, limonene, menton , Menthylacetate, N-substituted-paramentan-3-carboxamide, pinen, octylaldehyde, citral, pregon, calvier acetate, anisaldehyde, ethylacetate, ethylbutyrate, allylcyclohexanepropionate, methylanthranilate, ethylmethyl Single flavors such as phenylglycidate, vanillin, undecalactone, hexanal, butanol, isoamyl alcohol, hexenol, dimethylsulfide, cycloten, furfural, trimethylpyrazine, ethyllactate, ethylthioacetate, strawberry flavor, apple flavor, banana flavor , Peppermint flavor, Grape flavor, Mango flavor, Butter flavor, Milk flavor, Fruit mix flavor, Tropical fruit flavor and other blended flavors, and known flavoring materials used in oral compositions can be used.
The amount of these flavors to be added to the composition is usually preferably 0.00001 to 1% for oral preparations such as dentifrices and mouthwashes, and 0. 001 to 50% is good. It is preferable to use 0.1 to 10% of the perfume for perfume using the above perfume material in the composition.

As an arbitrary active ingredient, a known one that is usually blended in an oral composition can be blended. For example, nonionic bactericides such as isopropylmethylphenol, cationic bactericides such as cetylpyridinium chloride, anti-inflammatory agents such as tranexamic acid and epsilon aminocaproic acid, enzymes such as dextranase, sodium fluoride and monofluorophosphate. Examples thereof include fluorides such as sodium, water-soluble phosphoric acid compounds, copper compounds, potassium nitrate, aluminum lactate, various vitamins, and plant extracts. The blending amount of the active ingredient can be set within a range that does not interfere with the effects of the present invention.
In the present invention, it is preferable to limit the formulation of a non-selective fungicide that kills not only pathogenic bacteria in the oral cavity but also non-pathogenic bacteria. The non-selective bactericide is often found in bactericides widely used in oral preparations, and examples thereof include cationic bactericides such as cetylpyridinium chloride and nonionic bactericides such as isopropylmethylphenol. .. These non-selective bactericides can be blended within the range in which the effects of the present invention are exhibited, but when blended, 0.1% or less, particularly 0.05% or less of the entire composition is preferable, and it is best not to blend them. preferable. These non-selective bactericidal agents have a non-selective bactericidal action that kills not only pathogenic bacteria but also non-pathogenic indigenous bacteria in the oral cavity. The balance of the bacterial flora inside may be lost and control may be lost. Therefore, in the present invention, it is more preferable that the non-selective bactericidal agent is not blended for selective improvement of the oral flora and balance control.

Further, in the present invention, it is composed of (A) a growth inhibitor for pathogenic bacteria in the oral cavity composed of milk oligosaccharide, and (A) milk oligosaccharide and (B) sugar alcohol, preferably (B) / (A). ) Provided an agent for promoting the growth of non-pathogenic bacteria in the oral cavity having a mass ratio of 0.0005 to 1, and an agent for improving the flora of the oral cavity. In this case, it is sufficient to contain only the component (A) or the components (A) and (B), but if necessary, any component may be added as described above. The details of the types, amounts, ratios, etc. of the components (A), (B), and other components are the same as described above.

The growth inhibitor for pathogenic bacteria in the oral cavity according to the present invention contains the component (A), and in particular, by making an oral composition containing the component (A), the growth inhibitor for the pathogenic bacteria in the oral cavity is suppressed. The effect is obtained. As is clear from the results of the experimental examples described later, Streptococcus perolis or Streptococcus lactalius present in the oral cavity has a growth-suppressing effect on pathogenic bacteria in the oral cavity. On the other hand, although the component (A) itself does not have a growth-suppressing effect on pathogenic bacteria in the oral cavity, by applying these components in the oral cavity, the pathogenicity of Streptococcus perolis or Streptococcus lactalius in the oral cavity It has the effect of dramatically promoting the growth-suppressing effect on bacteria, and a remarkable growth-suppressing effect on pathogenic bacteria in the oral cavity can be obtained. From the above, the component (A) is effective as an accelerator for promoting the growth inhibitory effect of Streptococcus perolis or Streptococcus lactalius on pathogenic bacteria in the oral cavity. In addition, since the component (A) has a growth promoting effect of Streptococcus perolis or Streptococcus lactalius, it is also effective as a promoter for promoting the growth of non-pathogenic bacteria in the oral cavity including these.
Further, the oral bacterial flora improving agent according to the present invention contains a component (A) and a component (B), and in particular, by preparing an oral composition containing these components, as described above, A growth-suppressing effect on pathogenic bacteria in the oral cavity is obtained, and a growth-promoting effect is obtained on non-pathogenic bacteria in the oral cavity, whereby the balance of bacterial composition ratio of the bacterial flora in the oral cavity is non-pathogenic. A remarkable effect of improving the flora can be obtained, which improves mainly on sex bacteria.

Hereinafter, the present invention will be specifically described with reference to Examples, Comparative Examples, Experimental Examples, and Formulation Examples, but the present invention is not limited to the following Examples. In the following examples,% indicates mass% unless otherwise specified.

[Examples, comparative examples]
The oral compositions having the compositions shown in Tables 1 to 3 were evaluated for their influence on the bacterial composition ratio by the method shown below, and the effect of improving the bacterial flora in the oral cavity was evaluated.

The main raw materials used are shown below.
(A) Ingredient 3'-Sialyl lactose: Made by Carbosynth 6'-Sialyl lactose: Made by Carbosynth 2'-Fucosyl lactose: Made by Carbosynth (B) Ingredient Xylitol: Fujifilm Wako Pure Chemical Industries Sorbitol: Fujifilm Made by Kojunyaku Kogyo Co., Ltd.

Evaluation method of effect on bacterial composition ratio:
<Strain used>
Each of the bacteria shown below was purchased from the American Type Culture Collection and used.
Non-pathogenic bacteria (indigenous bacteria in the oral cavity)
(I) Streptococcus Gordonii (Streptococcus)
gordonii: Hereafter, S. Abbreviated as gordonii. ) ATCC
10558
(Ii) Actinomyces na
eslunadi: Hereinafter, A. Abbreviated as naeslundii. ) AT
CC43146
Pathogenic bacteria (caries-causing bacteria)
(Iii) Streptococcus mutans
s mutans: Hereinafter, S. mutant) ATCC25175

<Bacterial preculture>
Frozen bacterial solutions of the above various bacteria were inoculated into Todd Hewitt Broth (manufactured by Becton and Dickinson) agar medium containing horse defibrated blood with a loop loop, and anaerobically cultured at 37 ° C. for 72 hours. Bacteria were germinated with 80% by volume nitrogen, 10% by volume carbon dioxide, and 10% by volume hydrogen). Subsequently, the grown colonies were mixed with 5 mg / L of hemin (manufactured by Sigma) and 1 mg / L of vitamin K (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) by Todd Hewitt Broth, manufactured by Becton and Dickinson. ) [THBHM] was suspended in 4 mL and anaerobically cultured at 37 ° C. for 24 hours. Further, 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 culturing was centrifuged to collect the bacterial cells, and the non-pathogenic bacteria (i) and (ii) were each 2 × 10 ⁸ cfu / mL and caries-causing bacteria using a medium having the following composition. A mixed bacterial solution was prepared so that (iii) was 4 × 10 ^{8 cfu / mL.}
Medium composition Proteopeptone (manufactured by Becton and Dickinson)
10.0 g / L (final concentration 1.0%)
Tryptone (manufactured by Becton and Dickinson)
5.0 g / L (final concentration 0.5%)
Yeast extract (manufactured by Becton and Dickinson)
5.0 g / L (final concentration 0.5%)
Mucin (manufactured by Sigma) 12.5 g / L (final concentration 1.25%)
Hemin (manufactured by Sigma) 1.0 mg / L (final concentration 0.0001%)
Vitamin K (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.)
0.2 mg / L (final concentration 0.00002%)
KCl (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.)
2.5 g / L (final concentration 0.25%)
Cysteine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.)
0.5 g / L (final concentration 0.05%)
Distilled water residue
Total 100.0%

<Preparation of evaluation sample>
Each composition shown in Tables 1 to 3 was prepared by a conventional method and used as an evaluation sample.

<Evaluation of bacterial composition ratio>
2 mL each of the above evaluation samples was added to the test tube. Subsequently, 2 mL of the mixed bacterial solution was inoculated and anaerobically cultured at 37 ° C. for 24 hours. Then, the mixture was stirred with a vortex mixer and further dispersed by ultrasonic treatment (200 μA, 10 seconds) to make it uniform. This dispersion was diluted with Triptic Soy Broth (manufactured by Becton and Dickinson) to prepare a 10-fold dilution series. 10 ^-5 , 10 ^-6 , 10 ^-7 Dilute solution is smeared on Todd Hewitt Broth (manufactured by Becton and Dickinson) agar medium in 50 μL increments, and the number of bacterial colonies that grow after aerobic culture is measured. By doing so, the viable cell count of each bacterium (the number of non-pathogenic bacteria {(i) + (ii)} after treatment, the number of caries-causing bacteria (iii) after treatment, cfu / mL) Bacterial composition ratio (ratio of non-pathogenic bacteria {(i) + (ii)} after treatment, ratio of caries-causing bacteria (iii) after treatment,%) was calculated. The bacterial composition ratio is a ratio to the total viable cell count of the viable cell count of each bacterium after treatment.
(I) S. on agar medium. Gordonii, (ii) A. naeslundii (iii) S.A. Mutants were discriminated by colony morphology.

<Evaluation criteria for improving bacterial flora>
The ratio (%) of non-pathogenic bacteria {(i) + (ii)} to the ratio (%) of caries-causing bacteria (iii) in the mixed bacterial solution treated with the evaluation sample is calculated by the following formula. did.
X = {(i) + (ii)} / (iii)
From the calculated X value, the effect of improving the bacterial flora in the oral cavity was determined according to the following criteria.
Judgment criteria
a: 4 or more b: 2.5 or more and less than 4 c: 1.5 or more and less than 2.5 d: less than 1.5 Calculated from the viable cell count, bacterial composition ratio of each bacterial in the control (sample untreated) {(I) + (ii)} / (iii), the bacterial flora improving effect was as shown in Tables 1 to 3.
Since the number of each bacterium in the mixed bacterial solution varies from the initial number even after preparation, the viable number of each bacterium after culturing the control (sample untreated) was used as a reference.

The effect of improving the bacterial flora of the present invention is evaluated by the ratio of the number of non-pathogenic bacteria to the ratio of the number of pathogenic bacteria (caries-causing bacteria) in the oral cavity, and the higher the ratio, the higher the effect. The higher the effect of improving the bacterial flora.
In the above evaluation method of the present invention, the number of bacteria increases by culturing even in the control (sample untreated). Therefore, if the number of caries-causing bacteria is smaller than the number of control (sample untreated) bacteria, there is an effect of suppressing the growth of caries-causing bacteria, and the number of non-pathogenic bacteria is controlled (sample untreated). If the number of bacteria is larger than the number of bacteria (treated), it can be said that there is an effect of promoting the growth of non-pathogenic bacteria, but what is important in the effect of improving the flora is the ratio of caries-causing bacteria to non-pathogenic bacteria in the oral cavity.
In this case, in the present invention, in the above evaluation method, the abundance ratio of non-pathogenic bacteria to pathogenic bacteria (caries-causing bacteria) {(i) + (ii)} / (iii) is controlled (sample untreated). The abundance ratio in the above is preferably 2 times or more, particularly 4 times or more, particularly 6 times or more, and such an abundance ratio is excellent in the effect of improving the bacterial flora.

As shown in Table 3, if the component (B) is blended and the component (A) is not blended (Comparative Examples 1 and 2), the caries-causing bacteria after the treatment (compared to the control (sample untreated)) Although the number of bacteria in iii) decreases slightly, the abundance ratio of non-pathogenic bacteria to pathogenic bacteria (ratio of {(i) + (ii)} / (iii)) is almost unchanged and is the same, and the flora It was inferior in improvement effect.
On the other hand, as shown in Tables 1 and 2, the oral composition (Example) containing the components (A) and (B) of the present invention was treated as compared with the control (sample untreated). Later, the number and proportion of non-pathogenic bacteria {(i) + (ii)} increased, the number and proportion of caries-causing bacteria (iii) decreased, and the number of non-pathogenic bacteria against pathogenic bacteria decreased. The abundance ratio (ratio of {(i) + (ii)} / (iii)) was high, and the effect of improving the bacterial flora was excellent.

[Experimental example]
The following test was conducted on the component (A).
[I] Antibacterial effect test against pathogenic bacteria The antibacterial effect against pathogenic bacteria was evaluated by the following method.
The main raw materials used are shown below.
(A) Ingredient 3'-Sialyl lactose: Lactulose manufactured by Carbosynth: Fujifilm Wako Pure Chemical Industries, Ltd. Non-pathogenic bacteria (indigenous bacteria in the oral cavity)
Streptococcus peroris: S.I. Abbreviated as peroris. ) ATCC 700780
Streptococcus lactarius: S.I. Abbreviated as lactarius. ) CCUG 66490T
Pathogenic bacterium Porphyromonas gingivalis (hereinafter abbreviated as P. gingivalis) ATCC33277

<Bacterial preculture>
Frozen bacterial solutions of the above various bacteria were inoculated into Todd Hewitt Broth (manufactured by Becton and Dickinson) agar medium containing horse defibrated blood with a loop loop, and anaerobically cultured at 37 ° C. for 72 hours. Bacteria were germinated with 80% by volume nitrogen, 10% by volume carbon dioxide, and 10% by volume hydrogen). Subsequently, the grown colonies were mixed with 5 mg / L of hemin (manufactured by Sigma) and 1 mg / L of vitamin K (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) in Todd Hewitt Broth (manufactured by Becton and Dickinson). It was suspended in 4 mL of [THBHM] and anaerobically cultured at 37 ° C. for 24 hours. Further, 20 mL of THBHM was inoculated with 1% of this culture solution, and anaerobically cultured at 37 ° C. for 24 hours.

The bacterial solution after culturing was centrifuged at 11,000 rpm for 5 minutes, and the precipitate was prepared using Todd Hevitbros medium to obtain the above-mentioned S. cerevisiae. peroris, S.M. The bacterial solution was prepared by resuspending each lactarius so as to have a turbidity (OD550 nm) of 1.0. Then, 1% of the prepared bacterial solution was added to 40 mL of Todd Hevitbros medium to which 1% of the component (A) was added, and the cells were anaerobically cultured at 37 ° C. for 24 hours.
The obtained culture broth was centrifuged at 11,000 rpm for 5 minutes, and the supernatant was collected. After adjusting the pH of the supernatant to pH 7, the cells were removed by filtration through a 0.22 μ filter. The filtered culture solution was dispensed into small test tubes in an amount of 3 mL each (n = 2). The turbidity (OD550 nm) was adjusted to 1.0 in the same manner as above. 30 μL of Gingivalis bacterium solution was added, and the turbidity (OD550 nm) was measured after anaerobic culture at 37 ° C. for 24 hours.

<Relative turbidity value (growth suppression effect on pathogenic bacteria)>
The turbidity of the evaluation sample (component (A) or a combination system of component (A) and S. peroris or S. lactarius) was set to a, and the turbidity was controlled (no non-pathogenic bacteria, distilled water instead of component (A)). In the following formula when the turbidity of (addition) was b, the relative turbidity value X of the evaluation sample with respect to the control was used as an index of the growth suppressing effect. The lower the X, the higher the growth inhibitory effect on pathogenic bacteria. The result is shown by the average value of n = 2.
X = (a / b) x 100

As is clear from the above results, S. peroris or S. Lactarius has a growth-suppressing effect on oral pathogenic bacteria. On the other hand, although the component (A) itself does not have a growth-suppressing effect on oral pathogenic bacteria, S. peroris or S. When used in combination with lactarius, S. peroris or S. It has the effect of dramatically promoting the growth-suppressing effect of lactarius on oral pathogenic bacteria, and a remarkable growth-suppressing effect on oral pathogenic bacteria was obtained.

This will be described more specifically. As the controls in Table 4 and the component (A) in Tables 5 and 6 are clear from the results of distilled water (control), S.A. peroris or S. Lactarius is described in P. et al. It has a growth-suppressing effect on gingivalis.
On the other hand, as is clear from the controls in Table 4 and the results when the component (A) is 3'-sialyl lactose or streptococcus, the component (A) itself suppresses growth against oral pathogenic bacteria. Although it has no effect, on the other hand, as is clear from the results in Tables 5 and 6, the component (A) can be applied to the oral cavity in which Streptococcus perolis or Streptococcus lactalius is present. It was found that Streptococcus perolis or Streptococcus lactose has the effect of dramatically promoting the growth-suppressing effect on oral pathogenic bacteria.

The amount of 3'-sialyl lactose added to Todd Hevitbros medium was changed as shown in Table 7 below for evaluation. The results for the above 1% case are also shown.

[II] S. Growth promotion effect test of peroris By the following method, S. The growth promoting effect of peroris was evaluated.
Turbidity (OD550 nm) as described in [I] above in 200 μL of Todd Hevitbroth medium supplemented with an evaluation sample (component (A); 3'-sialyllactose or lactulose) or distilled water (control). S. resuspended to 1.0. 1% of peroris bacterial solution was added, and the cells were anaerobically cultured at 37 ° C. for 18 hours using a 96-well plate. The amount of bacterial growth was measured by turbidity (OD550 nm), and the degree of bacterial growth was evaluated. The concentrations (%) in Tables 8 and 9 are the concentrations in Todd Hevitbros medium.
When the turbidity of the evaluation sample addition was (Ts) and the turbidity of the control (distilled water addition) was (Tc), the relative turbidity value Y of the evaluation sample with respect to the control was used as an index of the growth promoting effect. .. That is, when Y is larger than 100, the growth is promoted.
Y = Ts / Tc × 100

An example of prescription is shown below. The raw materials used are the same as above. The oral composition of the formulation example can increase the abundance ratio of non-pathogenic bacteria to pathogenic bacteria (ratio of {(i) + (ii)} / (iii)), and is excellent in the effect of improving the flora. It was.

[Prescription Example 1] Chewing Gum (A) 3'-Sialyl Lactose 2
(B) Xylitol 48
(B) Maltitol 20
Gum base 20
Gum arabic 9
Fragrance 1
100% in total
Mass ratio of (A) / (B) = 0.029

[Prescription Example 2] Chewing Gum (A) 6'-Sialyl Lactose 2
(B) Xylitol 48
(B) Maltitol 20
Gum base 20
Gum arabic 9
Fragrance 1
100% in total
Mass ratio of (A) / (B) = 0.029

[Prescription Example 3] Tablet Confectionery (A) 3'-Sialyl Lactose 7
(B) Sorbitol 75
(B) Xylitol 10
Sucrose fatty acid ester 3
Fragrance 4.5
Fine Silicon Dioxide 0.5
Total 100.0%
Mass ratio of (A) / (B) = 0.082

[Prescription Example 4] Tablet Confectionery (A) 6'-Sialyl Lactose 7
(B) Sorbitol 75
(B) Xylitol 10
Sucrose fatty acid ester 3
Fragrance 4.5
Fine Silicon Dioxide 0.5
Total 100.0%
Mass ratio of (A) / (B) = 0.082

[Prescription Example 5] Gummy (A) 3'-Sialyl Lactose 1
(B) Xylitol 10
Sugar 32
Syrup 30
Glucose liquid sugar 10
Glycerin 5
Gelatin 5
Fragrance 0.2
Water balance
Total 100.0%
Mass ratio of (A) / (B) = 0.1

[Prescription Example 6] Gummy (A) 6'-Sialyl Lactose 1
(B) Xylitol 10
Sugar 32
Syrup 30
Glucose liquid sugar 10
Glycerin 5
Gelatin 5
Fragrance 0.2
Water balance
Total 100.0%
Mass ratio of (A) / (B) = 0.1

[Prescription Example 7] Candy (A) 3'-Sialyl Lactose 1
(B) Xylitol 10
Sugar 44
Syrup 33
Citric acid 2.0
Fragrance 0.2
Water balance
Total 100.0%
Mass ratio of (A) / (B) = 0.1

[Prescription Example 8] Candy (A) 6'-Sialyl Lactose 1
(B) Xylitol 10
Sugar 44
Syrup 33
Citric acid 2.0
Fragrance 0.2
Water balance
Total 100.0%
Mass ratio of (A) / (B) = 0.1

[Prescription Example 9] Toothpaste (A) 3'-Sialyl lactose 2
(B) Sorbitol 25
Silicic acid anhydride 10
Sodium lauryl sulfate 1
Sodium Carboxymethyl Cellulose 1.5
Saccharin sodium 0.1
Fragrance 1
Water balance
Total 100.0%
Mass ratio of (A) / (B) = 0.08

[Prescription Example 10] Toothpaste (A) 6'-Sialyl lactose 2
(B) Sorbitol 25
Silicic acid anhydride 10
Sodium lauryl sulfate 1
Sodium Carboxymethyl Cellulose 1.5
Saccharin sodium 0.1
Fragrance 1
Water balance
Total 100.0%
Mass ratio of (A) / (B) = 0.08

[Prescription Example 11] Mouthwash (A) 3'-Sialyl lactose 0.5
(B) Xylitol 5
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) = 0.1

[Prescription Example 12] Mouthwash (A) 6'-Sialyl lactose 0.5
(B) Xylitol 5
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) = 0.1

[Prescription Example 13] Mouthwash (A) 3'-Sialyl lactose 1
(B) Xylitol 1
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) = 1

Claims

(A) Milk oligosaccharides and
(B) An oral composition comprising a sugar alcohol.
(A) The invention according to claim 1, wherein the milk oligosaccharide is at least one selected from 2'-fucosyl lactose, 3'-sialyl lactose, 6'-sialyl lactose, lacto-N-tetraose and lacto-N-fucopentaose I. Oral composition.
(B) The oral composition according to claim 1 or 2, wherein the sugar alcohol is at least one selected from xylitol, sorbitol, maltitol, erythritol and mannitol.
The oral composition according to any one of claims 1 to 3, which contains 0.01 to 50% by mass of the component (A) and 1 to 90% by mass of the component (B).
The oral composition according to any one of claims 1 to 4, wherein (A) / (B) indicating the quantitative ratio of the component (A) to the component (B) is 0.0005 to 1 as a mass ratio. ..
From dentifrices, mouthwashes, coatings, mouth sprays, patches, sheets, oral sustained release agents, chewing agents, oral dissolving agents, oral disintegrants, denture care agents, tongue care agents and mouth refreshers The oral composition according to any one of claims 1 to 5, which is the oral preparation of choice.
The oral composition according to any one of claims 1 to 5, which is a food or drink selected from chewing gum, tablet confectionery, candy, gummies, edible films, troches and beverages.
(A) A growth inhibitor for pathogenic bacteria in the oral cavity, which contains milk oligosaccharides and is used for blending oral compositions.
The treatment against pathogenic bacteria in the oral cavity according to claim 8, which promotes the growth-suppressing effect of Streptococcus perolis or Streptococcus lactalius in the oral cavity against pathogenic bacteria in the oral cavity and suppresses the growth of pathogenic bacteria in the oral cavity. Growth inhibitor.
An oral flora improving agent for blending an oral composition, which comprises the growth inhibitor for pathogenic bacteria in the oral cavity according to claim 8 or 9 and (B) sugar alcohol.
(A) Tongue polish, mouthwash, coating agent, mouth spray, patch, sheet agent, oral sustained release agent, chewing agent, oral solubilizer, oral disintegrant, denture care containing milk oligosaccharide An oral composition selected from agents, tongue care agents and mouthwashes.