JP2021147318A - Oral composition - Google Patents

Abstract

To provide an oral composition that has a bactericidal effect with 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and has reduced cytotoxicity.SOLUTION: An oral composition contains 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and also contains β-cyclodextrin.SELECTED DRAWING: None

Description

The present disclosure relates to oral compositions and the like. The contents of all documents described herein are incorporated herein by reference.

The oral composition may contain one or more surfactants for the purpose of bactericidal effect, foaming effect and the like.

JP-A-2018-104376

However, depending on the surfactant, when blended in the oral composition in order to obtain a desired effect, an undesired effect may be exhibited in addition to the desired effect.

The present inventors focused on 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine (also referred to as sodium cocoamphoacetate) as a surfactant to be blended in the oral composition, and proceeded with the study. If the surfactant is added to the oral composition in order to obtain the effect of killing periodontal disease bacteria, it may cause cell damage and damage the oral cells to which the oral composition is used. I found it.

Therefore, further studies have been made to provide a method for blending the surfactant into the oral composition so as to obtain a bactericidal effect on periodontal disease bacteria and not cause cytotoxicity.

The present inventors have added β-cyclodextrin in addition to 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine to form 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazole. We have found the possibility of obtaining an oral composition in which the bactericidal effect of linium betaine can be obtained and the cytotoxicity is suppressed, and further improvements have been made.

The present disclosure includes, for example, the subjects described in the following sections.
Item 1.
Oral compositions containing 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and β-cyclodextrin (excluding oral compositions containing tranexamic acid or salts thereof).
Item 2.
Oral composition containing 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and β-cyclodextrin (provided that the oral composition contains a fluorine-containing compound having a fluorine concentration of 1001 to 3000 ppm). Compositions excluded).
Item 3.
The oral composition according to claim 1 or 2, further containing cetylpyridinium chloride.

An oral composition capable of obtaining a bactericidal effect (preferably a periodontal disease bactericidal effect) by 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and suppressing cytotoxicity. Provided.

The results of examining the bactericidal effect of the composition containing each concentration of 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and β-cyclodextrin are shown. The results of examining the cytotoxicity of a composition containing each concentration of 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and β-cyclodextrin are shown.

Hereinafter, each embodiment included in the present disclosure will be described in more detail. The present disclosure preferably includes, but is not limited to, an oral composition, its use, a method for producing the same, and the like, and the present disclosure includes all disclosed in the present specification and recognized by those skilled in the art. ..

The oral compositions included in the present disclosure contain 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and β-cyclodextrin. The oral composition included in the present disclosure may be referred to as "the oral composition of the present disclosure".

In the oral composition of the present disclosure, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine is contained, for example, in an amount of about 0.01 to 0.3% by mass. The upper or lower limit of the range is, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0. It may be .2 or 0.25% by mass. For example, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine may be contained in an amount of 0.01 to 0.1% by mass or 0.02 to 0.1% by mass.

Further, in the oral composition of the present disclosure, β-cyclodextrin is contained, for example, in an amount of about 0.02 to 2% by mass. The upper or lower limit of the range is, for example, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, It may be 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, or 2% by mass. For example, the range may be 0.03 to 1% by mass.

The oral composition of the present disclosure may further contain a known component that can be blended in the oral composition as long as the effect is not impaired. Examples of such components include surfactants, abrasives, binders, flavoring agents, sweetening agents, wetting agents, conditioning agents, preservatives, preservatives, coloring agents, pH adjusters, medicinal ingredients and the like. However, it is not particularly limited. Hereinafter, the known component will be described, but the description is an example and is not limited thereto.

For example, as the surfactant, an amphoteric surfactant other than a nonionic surfactant, an anionic surfactant or 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine can be blended. Specifically, examples of the anionic surfactant include alkyl sulfates, polyoxyethylene alkyl ether sulfates, alkyl phosphates, polyoxyalkyl ether phosphates, fatty acid soaps, and polyoxyethylene alkyl ether carboxylic acids. Salts, polyoxyethylene alkyl ether sulfates, α-olefin sulfonates, alkyl sulfosuccinates, polyoxyalkyl ether sulfosuccinates, acyl amino acid salts, glycerin fatty acid ester sulfates, alkyl ether phosphates, alkyl glutamates, etc. Can be mentioned. Examples of the cationic surfactant include a monoalkyltrimethylammonium salt, a dialkyldimethylammonium salt, an alkylamine salt and the like. Nonionic surfactants include sugar fatty acid ester, fatty acid alkanolamide, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polypropylene alkyl ether, and polyoxy. Examples thereof include ethylene alkyl phenyl ether, polyoxyethylene hydrogenated castor oil, alkyl glucoside, polyoxyethylene polyoxypropylene block copolymer, and lecithin. Examples of the amphoteric tenside include alkyldimethylaminoacetic acid betaine, fatty acid amide propyldimethylaminoacetic acid betaine, alkylsulfobetaine, and alkylbetaine. These surfactants can be used alone or in combination of two or more.

Polishing agents include abrasive silica, calcium hydrogen phosphate, calcium phosphate, calcium phosphate tribasic, magnesium tribasic phosphate, calcium pyrophosphate, hydroxyapatite, insoluble sodium metaphosphate, aluminum silicate, zirconium silicate, calcium silicate, carbonic acid. Calcium, magnesium carbonate, magnesium oxide, alumina, aluminum hydroxide, calcium sulfate, polymethylmethacrylate, pamisu (pallet stone), bentonite, synthetic resin and the like can be mentioned. These abrasives can be used alone or in combination of two or more.

Examples of the binder include sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose salt, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, crystalline cellulose, cellulose derivatives such as crystalline cellulose and carmellose sodium, and high microbial production such as xanthan gum. Molecules, natural polymers or rubbers such as tragant gum, karaya gum, arabiya gum, carrageenan, dextrin, agar, pectin, purulan, gellan gum, locust bean gum, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinylmethyl ether, Examples include synthetic polymers such as sodium polyacrylate, inorganic binders such as thickening silica and beagum, and cationic binders such as O- [2-hydroxy-3- (trimethylammonio) propyl] hydroxyethyl cellulose chloride. Be done. These binders can be used alone or in combination of two or more.

Flavors include menthol, carboxylic, methyl salicylate, vanillin, benzyl succinate, methyl eugenol, anetol, limonene, osimene, n-decyl alcohol, methyl acetate, citronenyl acetate, cineol, ethyl linalol, crocodile, thyme, Natsumeg, Synnamic aldehyde, Benzaldehyde, Timor, Sparemint oil, Peppermint oil, Lemon oil, Orange oil, Sage oil, Rosemary oil, Silica skin oil, Perilla oil, Winter green oil, Chome oil, Eucalyptus oil, Pimento oil, Tea Examples include tree oil, tabana oil, staranis oil, fennel oil, diatomaceous oil and basil oil. These fragrances can be used alone or in combination of two or more.

Sweeteners include saccharin, sodium saccharin, acesulfarm potassium, stevia extract, stebioside, neohesperidyldihydrochalcone, glycyrrhizin, perillartine, soumatin, aspartylphenylalanine methyl ester, methoxycinnamic aldehyde, palatinose, palatinit, erythritol, maltitol. , Xylitol, lactitol and the like. These sweeteners can be used alone or in combination of two or more.

Examples of the wetting agent / hydrotropic agent include ethanol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, isoprene glycol, glycerin, diglycerin, sorbit, polyethylene glycol, tornale, trehalose, hyaluronic acid and the like. These can be used alone or in combination of two or more.

Examples of the conditioning agent include silicone derivatives, cationically modified water-soluble polymers, fatty acid esters, trimethylglycine, protein hydrolysates, amino acids and their derivatives, ureas, phospholipids, glycolipids, ceramides and the like. These can be used alone or in combination of two or more.

As the preservative / preservative, parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride and the like can be blended.

As the colorant, legal pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine blue, enhanced ultramarine blue, and dark blue, titanium oxide, and the like may be blended.

As the pH adjuster, citric acid, phosphoric acid, malic acid, pyrophosphate, lactic acid, tartaric acid, glycerophosphate, acetic acid, nitric acid, chemically possible salts thereof, sodium hydroxide and the like may be blended. These can be blended alone or in combination of two or more so that the pH of the composition is in the range of 4 to 8, preferably 5 to 7. The usual blending amount of the pH adjuster is 0.01 to 2% by mass.

In addition, as other components, animal and plant oils and fats, powders, ultraviolet absorbers, animal and plant extracts and the like can be mentioned.

As medicinal ingredients, for example, as a disinfectant, a cationic disinfectant such as benzethonium chloride, benzalkonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, cetylpyridinium chloride; an anionic disinfectant such as sodium lauroyl sarcosin; alkyldiaminoethylglycine. Amphoteric disinfectants such as hydrochloride, dodecyldiaminoethylglycine; phenolic disinfectants such as triclosan (2', 4,4'-trichloro-2-hydroxy-diphenyl ether) and phenolic disinfectants such as isopropylmethylphenol; hinokithiol; blood circulation Vitamin Es such as dl-α-tocopherol acetate, tocopherol succinate, tocopherol nicotinate as accelerators; enzymes such as dextranase, amylase, protease, mutanase, lysoteam, lytic enzyme (lytecenzyme); epsilon as anti-inflammatory agent Aminocaproic acid, dipotassium glycyrrhizinate, glycyrrhetinic acid, etc .; ascorbic acid, etc. as a bleeding improving agent; allantin, etc. as a tissue repair agent; fluorine compounds such as sodium fluoride as a remineralizing agent; other plant extracts extracted with a water-soluble solvent Examples include compounds, chlorophyridinium, sodium chloride, zinc chloride, potassium nitrate and the like. These medicinal ingredients can be used alone or in combination of two or more. Although not particularly limited, it preferably contains cetylpyridinium chloride, for example, 0.01 to 0.5% by mass. The upper or lower limit of the range is, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0. It may be .2, 0.25, 0.3, 0.35, 0.4, or 0.45% by mass. For example, the range may be 0.02 to 0.3% by mass or 0.05 to 0.1% by mass.

Further, as a base, water, alcohols, silicon, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane and the like can be used.

Although not particularly limited, it is preferable that the oral composition containing tranexamic acid or a salt thereof is excluded from the oral composition of the present disclosure. Further, it is preferable that the oral composition containing a fluorine-containing compound having a fluorine concentration of 1001 to 3000 ppm is excluded from the oral composition of the present disclosure.

Examples of the salt of tranexamic acid include acid addition salts, alkali metal salts, alkaline earth metal salts and amine salts, and salts with amino acids. More specifically, for example, hydrohalogenates such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, phosphate and the like. Inorganic acid salts; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate; aryl sulfonates such as benzene sulfonate, p-toluene sulfonate; acetate, apple Organic acid salts such as acid salts, fumarates, succinates, citrates, ascorbates, tartrates, oxalates and maleates; alkali metal salts such as sodium salts and potassium salts; calcium salts and magnesium salts. Alkaline earth metal salts such as salts; N-methylmorpholin salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidin salt, pyridine salt, 4-pyrrolidinopyridine salt, picolin salt, etc. Organic amine salts; and salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, asparaginate; can be mentioned.

Moreover, as a fluorine-containing compound, for example, a water-soluble fluorine-containing compound can be mentioned. The water-soluble fluorine-containing compound is a fluorine-containing compound that can be dissolved in 100 g of water at 20 ° C. in an amount of 2 g or more. More specifically, the fluorine-containing compound includes sodium fluoride, potassium fluoride, ammonium fluoride, tin fluoride, amine fluoride, sodium monofluorophosphate, potassium monofluorophosphate, sodium silicon fluoride, and fluoride. Calcium silicon and the like are mentioned, and sodium fluoride and sodium monofluorophosphate are preferable.

The form of the oral composition of the present disclosure is also not particularly limited, and for example, as a dentifrice (liquid toothpaste, liquid toothpaste, dentifrice), a mouthwash, a mouth spray, an oral coating agent, an oral gel, and the like. Can be used. Further, for example, it can be used as a drug, a quasi drug, or a cosmetic product.

Since the oral composition of the present disclosure exerts a bactericidal effect (preferably a periodontal disease bactericidal effect), it can be suitably used for anti-periodontal disease bacteria. Although not particularly limited, the bactericidal effect on Porphyromonas gingivalis is particularly preferable among those for periodontal disease bacteria.

The oral composition of the present disclosure can be prepared by a known method or a method that can be easily conceived from a known method. For example, it can be adjusted by appropriately mixing each raw material component.

In addition, in this specification, "including" also includes "consisting essentially" and "consisting of" (The term "comprising" includes "consisting essentially of" and "consisting of."). The present disclosure also includes all combinations of the constituent requirements described herein.

In addition, the various properties (property, structure, function, etc.) described for each embodiment of the present disclosure described above may be combined in any way in specifying the subject matter included in the present disclosure. That is, the present disclosure includes all subjects consisting of any combination of each combinable property described herein.

Hereinafter, embodiments of the present disclosure will be described in more detail with reference to examples, but the embodiments of the present disclosure are not limited to the following examples. Unless otherwise specified,% indicates mass%, except that the CO ₂ concentration, the viable cell rate, and the cell viability rate are shown below.

The bactericidal effect and cytotoxicity of 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine were examined using gingival epithelial cells and periodontal disease bacteria. The bactericidal effect was examined by the viable bacterial rate of periodontal disease bacteria (Porphyromonas gingivalis; hereinafter also referred to as "PG"), and the cytotoxicity was examined by the viable rate of gingival epithelial cells.

Gingival epithelial cells Epi4 (derived from human gingival epithelial cells) were inoculated into 1% Supplement S7 / Epilife medium ^{, adjusted to 1x10 5} cells / ml, and then 0.2 ml of the adjusting solution was transferred to each well of a 96-well plate. The cells were cultured under the conditions of 37 ° C. and 5% CO ₂ for one day, the medium was changed, and the cells were cultured for another day.

β-Cyclodextrin and 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine P.I. Examination of bactericidal effect of g bacteria P. Bacteria g (P. gingivalis OMZ314 was cultured in modified GAM medium and adjusted to absorbance (OD (600)) = 1.0. Β-cyclodextrin (βCD) adjusted to each concentration in modified GAM medium. ) Solution, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine solution, or a mixture of these, or 180 μL of the modified GAM medium itself, add 20 μL of the prepared bacterial solution and leave it for 3 minutes. After leaving, 20 μL of the reaction solution was transferred to 180 μL of a bactericidal inactivating medium (0.07% lecithin + 0.5% Tween 80) to stop the bactericidal effect, and the cells were cultured under anaerobic conditions at 37 ° C. for 24 hours. After culturing, the absorbance (OD (600)) of the medium was measured with an absorption plate reader (xMark microplate reader) to confirm the bactericidal effect. The viable cell ratio was obtained by treating the modified GAM medium itself. It is a value indicating what percentage the absorbance of each sample corresponds to, where the absorbance of the cultured bacterial solution is 100%.

The results are shown in FIG. The “βCD concentration” in FIG. 1 is the concentration of β-cyclodextrin in the reaction solution, and the concentration of 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine is also the concentration in the reaction solution.

It was found that the combination of 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine with β-cyclodextrin had almost no effect on bactericidal activity.

Cytotoxicity reduction evaluation test of β-cyclodextrin and 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine (WST-1 assay)
After culturing gingival epithelial cells in a 96-well plate, the medium in each well was changed. Add 0.2 ml of β-cyclodextrin solution, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine solution, or a mixture thereof adjusted to each concentration in 1% Supplement S7 / Epilife medium to the cells. The cells were cultured for 30 minutes under the conditions of 37 ° C. and 5% CO _2.

Then, after washing each well with PBS (phosphate buffered saline), 0.1 ml of 9% Premix WST-1 (manufactured by Takara) / Epilife medium was added to each well (including the well of the control experiment). The cells were reacted with viable cells in the wells by culturing for 1 hour under the conditions of 37 ° C. and 5% CO _2. Then, using an xMARK microplate reader (manufactured by BioRad), the absorbance at 450 nm was measured (reference 600 nm). The survival rate is a value indicating what percentage the absorbance of each sample corresponds to, where 100% is the absorbance of the 1% Supplement S7 / Epilife medium-treated group.

The results are shown in FIG. The “βCD concentration” in FIG. 2 is the concentration of β-cyclodextrin in the reaction solution, and the concentration of 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine is also the concentration in the reaction solution.

It was found that the addition of β-cyclodextrin to 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine suppressed cytotoxicity.

An example of prescription is shown below.

Claims (3)

Oral compositions containing 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and β-cyclodextrin (excluding oral compositions containing tranexamic acid or salts thereof). Oral composition containing 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine and β-cyclodextrin (provided that the oral composition contains a fluorine-containing compound having a fluorine concentration of 1001 to 3000 ppm). Compositions excluded). The oral composition according to claim 1 or 2, further containing cetylpyridinium chloride.

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