JP7835541B2 - Oral composition - Google Patents

Description

This invention relates to an oral composition.

Generally, oral diseases such as periodontal disease, gingivitis, dental caries, and bad breath are caused by oral bacteria. Many bacteria in the oral cavity exist as bacterial aggregates called biofilms. Biofilms are composed of bacteria or their remains, polysaccharides secreted by bacteria, proteins, and other high-molecular-weight substances, and have a film-like structure. Therefore, it has been difficult for disinfectants used in general oral care compositions to penetrate biofilms. To remove bacteria within biofilms, it is necessary to improve the penetration of disinfectants, or, more effectively, to disperse and remove the biofilm by physical or chemical means.

For example, Patent Document 1 discloses a biofilm dispersion solution comprising nattokinase and carrageenan.
Patent Document 2 discloses an oral composition containing a betaine-based amphoteric surfactant, glycerin, and β-cyclodextrin.

Japanese Patent Publication No. 2016-204262 Japanese Patent Publication No. 2020-83787

Furthermore, in addition to the biofilm dispersion solutions and oral compositions mentioned above, there is a need for oral compositions that can suitably disperse and remove biofilms in the oral cavity.

The oral composition for solving the above problems contains at least one selected from the following phenol derivatives and aromatic alcohols.
Phenol derivatives: Phenols having a straight-chain hydrocarbon group with 1 to 3 carbon atoms, but without a branched hydrocarbon group.

Aromatic alcohols: Compounds in which a primary alcohol having between 1 and 3 carbon atoms is added to a benzene ring.
In the above oral composition, it is preferable that the phenol derivative is a phenol having a linear hydrocarbon group with 2 carbon atoms.

In the above oral composition, it is preferable that the aromatic alcohol is a compound obtained by adding a primary alcohol having 2 carbon atoms to a benzene ring.
The above oral composition is preferably used for the dispersion and removal of biofilms.

The oral composition of the present invention can suitably disperse and remove biofilms in the oral cavity.

A graph showing the absorbance ratio of oral compositions using alcohol as a solvent. A graph showing the absorbance ratio of another oral composition using alcohol as the solvent. A graph showing the absorbance ratio of oral compositions using water as the solvent.

An embodiment of the oral composition of the present invention will be described.
The oral composition contains at least one selected from the following phenol derivatives and aromatic alcohols.

Phenol derivatives: Phenols having a straight-chain hydrocarbon group with 1 to 3 carbon atoms, but without a branched hydrocarbon group.
Aromatic alcohols: Compounds in which a primary alcohol having between 1 and 3 carbon atoms is added to a benzene ring.

By containing the above-mentioned phenol derivatives and aromatic alcohols, the oral composition can effectively disperse and remove biofilms in the oral cavity.
The following describes each component that makes up the oral composition.

<Phenol derivatives>
The linear hydrocarbon group having 1 to 3 carbon atoms in the above-mentioned phenol derivative is not particularly limited and may be either a saturated hydrocarbon group or an unsaturated hydrocarbon group.

Specific examples of saturated hydrocarbon groups include, for example, methyl, ethyl, and propyl groups.
The unsaturated hydrocarbon group may be an alkenyl group having one double bond as an unsaturated carbon bond, or an alkynyl group having one triple bond as an unsaturated carbon bond.

The number of carbon atoms in the linear hydrocarbon group is preferably two.
The bonding position of the linear hydrocarbon group is not particularly limited and may be at the ortho, meta, or para position.

The number of linear hydrocarbon groups is not particularly limited; there may be one or two or more.
The above phenol derivatives do not have branched hydrocarbon groups. Here, a branched hydrocarbon group refers to a hydrocarbon group having a branched chain. Examples of hydrocarbon groups having a branched chain include isopropyl groups, isobutyl groups, and isopentyl groups.

Specific examples of the above-mentioned phenol derivatives include, for example, 2-methylphenol (also called o-cresol), 3-methylphenol (also called m-cresol), 4-methylphenol (also called p-cresol), 2-ethylphenol, 3-ethylphenol, 4-ethylphenol, 2-propylphenol, 3-propylphenol, and 4-propylphenol.

The above phenol derivatives may be used individually or in combination of two or more.
<Aromatic alcohols>
The primary alcohol having 1 to 3 carbon atoms added to the benzene ring is not particularly limited and may be a saturated alcohol or an unsaturated alcohol.

Examples of saturated alcohols include methanol, ethanol, and propanol.
The primary alcohol preferably has two carbon atoms.

There is no particular limit to the number of primary alcohols; it can be one or two or more.
Specific examples of the above aromatic alcohols include, for example, phenylmethanol, 2-phenylethanol, and 3-phenyl-1-propanol.

The above aromatic alcohols may be used individually or in combination of two or more.
The oral composition of this embodiment may contain only one of the above-mentioned phenol derivative and/or aromatic alcohol, or it may contain both. Furthermore, the oral composition of this embodiment can be manufactured by mixing and stirring the above-mentioned components by conventional methods.

The following describes the intended use, application methods, and other components of the oral composition.
<Application purpose, application form>
The purpose of application of the oral composition is not particularly limited, and examples include compositions for exerting the efficacy of phenol derivatives and aromatic alcohols, such as bactericidal compositions that improve the penetration of bactericides into biofilms, and biofilm dispersion and removal compositions for dispersing and removing biofilms. Among these, it is preferable to apply it as a biofilm dispersion and removal composition.

The application forms of oral compositions are not particularly limited and can be used, for example, as pharmaceuticals or quasi-drugs. Known uses of oral compositions can be appropriately adopted, including, for example, toothpaste, mouthwash, rinsing agents, liquid toothpaste, biofilm dispersants, bad breath preventatives, gum massage agents, oral moisturizing agents, tongue coating removers, intraoral application agents, oral disinfectants, throat disinfectants, oral and throat agents, periodontal disease treatment agents, denture attachment agents, denture coating agents, denture stabilizers, denture preservatives, denture cleaners, implant care agents, etc.

Furthermore, while the dosage form is not particularly limited, by including a base such as water or alcohol, it can be applied to ointments, pastes, pastes, sprays, gels, liquids, suspensions/emulsifiers, gums, etc.

The alcohol mentioned above is not particularly limited; for example, ethanol can be cited. The alcohol concentration is not particularly limited, but is preferably 1% by mass or more and 40% by mass or less, and more preferably 5% by mass or more and 30% by mass or less.

Furthermore, in the embodiment containing the above-mentioned base materials such as water and alcohol, the content of the oral composition is not particularly limited. The content of the oral composition is preferably 0.05% by mass or more and 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less.

<Other ingredients>
Oral compositions may contain other components besides those mentioned above, depending on the intended use, form, and application. Examples of other components include antibacterial agents, anti-inflammatory agents, fragrances, humectants, surfactants, abrasives, alcohols, thickeners, sweeteners, medicinal components, stabilizers, and pH adjusters. Known components commonly used in oral compositions may be used for each of these. These components may be used individually or in combination of two or more.

Specific examples of antibacterial agents include cetylpyridinium chloride, parabens, sodium benzoate, triclosan, chlorhexidine hydrochloride, isopropylmethylphenol, benzalkonium chloride, and benzethonium chloride.

Specific examples of anti-inflammatory agents include glycyrrhizinate, tranexamic acid, ε-aminocaproic acid, and Phellodendron amurense extract.
Specific examples of fragrances include anethole, eugenol, linalool, menthol, carvone, limonene, wintergreen, methyl salicylate, cineole, thymol, clove oil, eucalyptus oil, rosemary oil, sage oil, lemon oil, orange oil, ocimene oil, citronellol, and various water-soluble fragrances.

Specific examples of wetting agents include polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, 1,3-brylene glycol, and polyethylene glycol.

Specific examples of surfactants include nonionic surfactants, anionic surfactants, and amphoteric surfactants. Specific examples of nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters and maltose fatty acid esters, sugar alcohol fatty acid esters such as maltitol fatty acid esters, sorbitan fatty acid esters such as sorbitan monolaurate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monostearate, fatty acid alkanolamides such as lauric acid diethanolamide, polyoxyethylene alkyl ethers such as polyoxyethylene stearyl ether and polyoxyethylene oleyl ether, polyethylene glycol fatty acid esters such as polyethylene glycol monooleate and polyethylene glycol monolaurate, alkyl glucosides such as lauryl glucoside and decyl glucoside, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene fatty acid esters, alkyl glucosides, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, and polyoxyethylene propylene block copolymers.

Furthermore, specific examples of anionic surfactants include sulfate ester salts such as sodium lauryl sulfate and sodium polyoxyethylene lauryl ether sulfate, sulfosuccinates such as sodium lauryl sulfosuccinate and sodium polyoxyethylene lauryl ether sulfosuccinate, acyl amino acid salts such as sodium cocoyl sarcosinate and sodium lauroyl methylalanine, and sodium cocoyl methyl taurate.

Furthermore, specific examples of amphoteric surfactants include amino acid-type amphoteric surfactants such as N-lauryldiaminoethylglycine and N-myristyldiethylglycine.
Examples of abrasives include calcium carbonate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium phosphate, silica, zeolite, sodium metaphosphate, aluminum hydroxide, magnesium hydroxide, calcium pyrophosphate, red iron oxide, calcium sulfate, and anhydrous silicic acid.

Specific examples of alcohols include, for instance, lauryl alcohol and myristyl alcohol.
Specific examples of thickening agents include sodium polyacrylate, carrageenan, sodium carboxymethylcellulose, sodium alginate, xanthan gum, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, and propylene glycol alginate.

Examples of sweetening agents include saccharin, sodium saccharin, sucralose, stevioside, acesulfame cam, aspartame, xylitol, maltitol, and erythritol.

Specific examples of medicinal ingredients include fluorides such as sodium monofluorophosphate, sodium fluoride, stannous fluoride, and strontium fluoride; condensed phosphates such as sodium pyrophosphate and sodium polyphosphate; phosphates such as sodium monohydrogen phosphate and trisodium phosphate; vitamins such as ascorbic acid, sodium ascorbate, pyridoxine hydrochloride, and tocopherol acetate; glucanase enzymes such as dextranase and mutanase; degrading enzymes such as proteases and lysozyme; inorganic salts such as zinc chloride, zinc citrate, strontium chloride, and potassium nitrate; chelating compounds such as chlorophyll and glycerophosphate; lipid-dissolving polyethylene glycol; sodium chloride, aluminum lactate, and strontium chloride.

Specific examples of stabilizers include legally approved dyes such as Green No. 1, Blue No. 1, and Yellow No. 4, as well as titanium dioxide.
Specific examples of pH adjusting agents include, for example, citric acid, malic acid, lactic acid, tartaric acid, acetic acid, phosphoric acid, pyrophosphate, glycerophosphate, and various salts thereof such as potassium salts, sodium salts, and ammonium salts, as well as sodium hydroxide. It is preferable that the oral composition is adjusted to have a pH of 5 to 9, and particularly 6 to 8, by incorporating a pH adjusting agent.

The operation of this embodiment will now be described.
The oral composition of this embodiment contains a phenol derivative or aromatic alcohol having a predetermined structure, which allows for a balanced expression of the hydrophilic effect of the hydroxyl groups and the lipophilic effect of the hydrocarbon groups of the phenol derivative or aromatic alcohol. Therefore, it becomes possible to suitably improve the penetration of the oral composition into biofilms that are complexly composed of bacterial remains, proteins, and other materials.

The effects of this embodiment will now be explained.
(1) The oral composition contains at least one selected from the following phenol derivatives and aromatic alcohols.

Phenol derivatives: Phenols having a straight-chain hydrocarbon group with 1 to 3 carbon atoms, but without a branched hydrocarbon group.
Aromatic alcohols: Compounds in which a primary alcohol having between 1 and 3 carbon atoms is added to a benzene ring.

Therefore, it can be effectively penetrated into the biofilm in the oral cavity and effectively dispersed and removed.
(2) The phenol derivative is a phenol having a linear hydrocarbon group with two carbon atoms. Even if the oral composition contains water or alcohol as a solvent, it can be suitably penetrated into the biofilm in the oral cavity and suitably dispersed and removed.

(3) The aromatic alcohol is a compound in which a primary alcohol with two carbon atoms is added to a benzene ring. Even if the oral composition contains water or alcohol as a solvent, it can effectively penetrate and disperse biofilms in the oral cavity.

The present invention will be described in more detail below with reference to test examples, but the present invention is not limited to these.
The oral compositions of Examples 1 to 24 and Comparative Examples 1 to 4 shown in Table 1 were prepared by mixing and stirring each component according to a conventional method and dissolving them in a solvent as a base. In Table 1, the numerical values to the right of each component represent the content (mass%).

The details of the phenol derivative (A), aromatic alcohol (B), and solvent (C) in Table 1 are as follows.

(Phenol derivative (A))
A-1: o-cresol A-2: m-cresol A-3: p-cresol A-4: 2-ethylphenol A-5: 3-ethylphenol A-6: 4-ethylphenol A-7: 2-propylphenol A-8: 3-propylphenol A-9: 4-propylphenol rA-1: isopropylmethylphenol rA-2: 4-isopropylphenol (aromatic alcohol (B))
B-1: Phenylmethanol B-2: 2-phenyl-1-ethanol B-3: 3-phenyl-1-propanol rB-1: 4-phenyl-1-butanol rB-2: 5-phenyl-1-hexanol (solvent (C))
C-1: 30% ethanol C-2: water Note that A-1 to A-3, B-1 to B-3, and rB-1 were manufactured by Tokyo Chemical Industry Co., Ltd. rA-1 was manufactured by Osaka Chemical Co., Ltd. rA-2 and rB-2 were manufactured by Sigma-Aldrich.

(Evaluation test)
The biofilm dispersion and removal effects of the oral compositions of Examples 1 to 24 and Comparative Examples 1 to 4 were evaluated.

The method for evaluating the effectiveness of biofilm dispersion and removal is shown below.
<Preparation of hydroxyapatite discs>
A hydroxyapatite disc (hereinafter also referred to as HA disc) manufactured by Asahi Optical Co., Ltd. was placed in a 14 mL polypropylene round-bottom tube.

Furthermore, 1 mL of 1 mol/L hydrochloric acid was added and the samples were immersed for 3 hours. Afterward, they were washed with purified water and heated in an autoclave at 121°C for 20 minutes to prepare the HA disks for testing.

<Preparation of Brain Heart Infusion Medium>
37 g of Brainheart Infusion (hereinafter also referred to as BHI) agar medium manufactured by Becton Dickinson, Inc. was added to 1 L of purified water and mixed. The mixture was then heated in an autoclave at 121°C for 20 minutes to prepare the BHI medium.

<Methods for collecting saliva>
Saliva samples from three volunteers were collected in 50 mL conical tubes placed on ice. After collection, the tubes were centrifuged with a 3000 g centrifugal force for 10 minutes. Subsequently, the samples were irradiated with 254 nm wavelength ultraviolet light at a pressure of 2000 × 100 μJ/ ^cm² for 30 minutes using a UV irradiator (UVP Crosslinker, manufactured by Funakoshi Co., Ltd.). The saliva samples were then diluted to one-tenth using deionized water to prepare the test saliva.

<Culturing of Streptococcus mutans solution>
First, as a pre-culture, several colonies were collected from plates inoculated with Streptococcus mutans (hereinafter also referred to as S.m.). The collected colonies were suspended in a test tube containing 10 mL of BHI medium. They were cultured under anaerobic conditions at 37°C for 2-3 days.

Next, for the main culture, 100 μL of the pre-cultured S. m bacterial suspension was taken and suspended in a test tube containing 10 mL of a different BHI medium than the one used for the pre-culture. The culture was incubated at 37°C under anaerobic conditions for 24 hours to prepare the main culture medium.

<Biofilm Dispersion and Removal Test>
The above-mentioned test HA disc was attached to a commercially available 12-well plate using double-sided tape. Two mL of the above-mentioned test saliva, collected within the same day to two weeks prior, was added to the disc and allowed to stand at 37°C for one hour. Subsequently, it was washed once with phosphate-buffered saline (hereinafter also referred to as PBS). Next, a 1% sucrose solution of the culture medium was added and suspended. Furthermore, S. m bacteria were cultured at 37°C under anaerobic conditions for 18 hours to form a biofilm (hereinafter also referred to as BF) on the test HA disc.

Afterward, the culture medium was removed, and the HA disc with BF attached was carefully attached to a new 12-well plate using double-sided tape and tweezers. Then, it was washed once with PBS.
After washing, 3 mL of each oral composition from the examples and comparative examples was individually added to a 12-well plate and shaken at 500 rpm for 10 minutes. Then, the oral compositions were removed, and another 3 mL of PBS was added and shaken at 500 rpm for 10 minutes. Finally, one wash was performed with PBS. The HA disk was carefully peeled from the double-sided tape and placed in a 14 mL polypropylene round-bottom tube containing 1 mL of sodium hydroxide. The mixture was stirred for 60 seconds using a vortex mixer. After standing for 60 minutes, the mixture was stirred again for 60 seconds using a vortex mixer. Then, 200 μL of the suspension in the polypropylene round-bottom tube was placed in a 96-well plate, and the absorbance was measured at 540 nm using a UV-Vis spectrophotometer (Shimadzu Corporation, UV-2600).

The absorbance measurement results are shown in Figures 1 to 3. In Figures 1 and 2, a 30% ethanol solution was used as the control. In Figure 3, water was used as the control. The absorbance of each example and comparative example is expressed as an absorbance ratio, with the absorbance of the control set to 100.

The dispersion removal effect was evaluated according to the following criteria. The results are shown in Table 1.
- Evaluation criteria for dispersion removal effect ◎ (Good): Absorbance ratio is less than 90 ○ (Acceptable): Absorbance ratio is 90 or more and less than 95 × (Unacceptable): Absorbance ratio is 95 or more Note that in the suspension in the polypropylene round bottom tube described above, a larger amount of BF results in a larger absorbance due to BF. Also, with Control, dispersion removal of BF is less likely to occur, so the amount of BF tends to be large, and the absorbance due to BF tends to be large. Therefore, in the suspension in the polypropylene round bottom tube, a larger amount of BF results in a relatively smaller difference in absorbance between Control and BF, and the absorbance ratio becomes close to 100.

In contrast, if BF is suitably dispersed and removed, the absorbance due to BF decreases. Because the difference in absorbance between BF and Control becomes relatively larger, the absorbance ratio becomes smaller. Therefore, a smaller absorbance ratio indicates that BF has been dispersed and removed.

As shown in Figures 1-3 and Table 1, Comparative Examples 1-4 all had absorbance ratios of 95 or higher. In contrast, Examples 1-24 all had absorbance ratios of less than 95, confirming a suitable dispersion and removal effect. Furthermore, Examples 7, 8, and 10-21 had absorbance ratios of less than 90, confirming an even more suitable dispersion and removal effect.

Furthermore, in embodiments where the phenol derivative is a phenol having a linear hydrocarbon group with two carbon atoms, the absorbance ratio was less than 90 in all Examples 16-18, where the solvent was water. Also, in Examples 4-5, where the solvent contained alcohol, the absorbance ratio was 91.8 or less in all cases. It was confirmed that the solvent exhibits excellent dispersion and removal effects regardless of the type of solvent.

Furthermore, in the embodiment where the aromatic alcohol is a compound obtained by adding a primary alcohol with two carbon atoms to a benzene ring, the absorbance ratio was less than 95 in Example 23, where the solvent was water. In Example 11, where the solvent contained alcohol, the absorbance ratio was 81.2. It was confirmed that the solvent exhibits excellent dispersion and removal effects regardless of the type of solvent.

Claims (2)

An oral composition for use in the dispersion and removal of biofilms, comprising the following phenol derivatives and water or ethanol with a concentration of 5% by mass or more and 30% by mass or less as a solvent, characterized in that the content of the phenol derivative is 0.1% by mass or more and 5% by mass or less.
Phenol derivatives: Phenols having a straight-chain hydrocarbon group with 1 to 3 carbon atoms, but without a branched hydrocarbon group . The oral composition according to claim 1, wherein the phenol derivative is a phenol having a linear hydrocarbon group with two carbon atoms.