Oral components

Abstract

To provide an oral composition that exhibits a strong gingipain activity inhibitory effect and a strong P.g bacteria killing effect.SOLUTION: An oral composition contains copper chlorophyllin salt and ethyl cocoyl arginate, with a content of ethyl cocoyl arginate of 0.02 mass% or more, and a content of ethyl cocoyl arginate being 1.5 pts.mass or more relative to the copper chlorophyllin salt 1 pt.mass.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to oral compositions, etc. The contents of all documents described in this specification are incorporated herein by reference. [Background technology]

[0002] Porphyromonas gingivalis (Pg) is a periodontal pathogen that is considered to be of paramount importance in the onset and progression of periodontitis.

[0003] Gingipains are known to be a representative pathogenic factor produced by Pg bacteria. Gingipains are a type of protease that disrupts the bonds between gingival epithelial cells, damages and / or inhibits the proliferation of epithelial cells themselves, and ultimately destroys the epithelial barrier and inhibits its repair. Gingipains are also known to inhibit phagocytosis by phagocytes and intracellular digestion, as well as disrupt the complement system and aid in invasion into epithelial cells, thereby contributing to Pg evasion from the immune system. Furthermore, recent reports have shown that the immune system suppression effect of gingipains leads to dysbiosis of the oral microflora, and these actions of gingipains contribute to the progression and intractability of periodontal disease. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2016 / 104524 [Patent Document 2] Japanese Patent Application Publication No. 2020-090440 Summary of the Invention [Problem to be solved by the invention]

[0005] For the reasons described above, it is important to inhibit gingipain activity for the prevention and / or treatment of periodontal disease (particularly for the inhibition of the progression of periodontal disease). [Means for solving the problem]

[0006] Therefore, we conducted research with the aim of finding a method to inhibit gingipain activity, and found that copper chlorophyllin salts (e.g., sodium salts) efficiently inhibit gingipain activity.

[0007] Next, we investigated the development of a method for more potently suppressing gingipain activity by combining copper chlorophyllin salt with a known antibacterial component. However, unexpectedly, even when we investigated the combination of various antibacterial components with copper chlorophyllin salt, the gingipain activity inhibitory effect was not enhanced, but rather weakened in many cases, and we encountered difficulties in finding a component that could be preferably used in combination with copper chlorophyllin salt to suppress gingipain activity.

[0008] However, after examining many antiseptic ingredients, we found that the inhibitory effect on gingipain activity can be enhanced when cocoyl arginine ethyl salt (especially cocoyl arginine ethyl pyrrolidone carboxylic acid) is combined with copper chlorophyllin salt.

[0009] Furthermore, when the combination ratio of copper chlorophyllin salt and cocoyl arginine ethyl salt was examined, it was surprisingly found that when these components were combined in approximately equal amounts, the gingipain activity inhibitory effect was weakened, and when one component was contained in a higher ratio than the other, the gingipain activity inhibitory effect tended to be stronger.

[0010] The present disclosure includes, for example, the subject matter described in the following sections: Section 1. Contains copper chlorophyllin salt and cocoyl arginine ethyl salt, Contains 0.02% by mass or more of ethyl cocoyl arginine, and Contains 1.5 parts by mass or more of cocoyl arginine ethyl salt per 1 part by mass of copper chlorophyllin salt, Oral composition. Section 2. Item 1. The oral composition according to Item 1, containing 0.005% by mass or more of copper chlorophyllin salt. Section 3. Item 3. The oral composition according to Item 1 or 2, containing 0.05% by mass or more of ethyl cocoyl arginine salt. Section 4. Item 4. The composition according to any one of Items 1 to 3, wherein the copper chlorophyllin salt is sodium copper chlorophyllin. Section 5. Item 5. The composition according to any one of Items 1 to 4, wherein the cocoyl arginine ethyl salt is cocoyl arginine ethyl pyrrolidone carboxylic acid. Section 6. Item 6. The composition according to any one of Items 1 to 5, which is used to combat periodontal disease. [Effects of the Invention]

[0011] By incorporating a specific ratio of ethyl cocoyl arginine salt into copper chlorophyllin salt, an oral composition is provided that exhibits a strong effect of inhibiting gingipain activity and a bactericidal effect against Pg bacteria. This oral composition is particularly suitable for use in preventing periodontal disease.

[0012] Compositions containing copper chlorophyllin salts exhibit a green color. However, this green color often fades over time. However, the inclusion of ethyl cocoyl arginine salts has the effect of suppressing this fading. [Brief explanation of the drawings]

[0013] [Figure 1] This shows the inhibitory effect of gingipain activity when copper chlorophyllin sodium is used in combination with various cationic fungicides. [Figure 2] The gingipain activity inhibitory effect when various concentrations of copper chlorophyllin sodium are used in combination with various concentrations of cocoyl arginine ethylpyrrolidone carboxylic acid is shown. [Figure 3] The degree of fading of the green color over time is shown for aqueous solutions containing copper chlorophyllin sodium and cocoyl arginine ethylpyrrolidone carboxylic acid at various concentrations. DETAILED DESCRIPTION OF THE INVENTION

[0014] Each embodiment of the present disclosure will be described in more detail below. The present disclosure preferably includes oral compositions and uses thereof, but is not limited thereto, and includes all that is disclosed herein and that can be recognized by a person skilled in the art.

[0015] The oral composition included in the present disclosure contains a copper chlorophyllin metal salt and an ethyl cocoyl arginate salt. The oral composition may be referred to as the "oral composition of the present disclosure."

[0016] The copper chlorophyllin salt is preferably a metal salt, more preferably an alkali metal salt, and specifically, for example, copper chlorophyllin sodium, copper chlorophyllin potassium, etc. are preferably mentioned.

[0017] A preferred example of the cocoyl arginine ethyl salt is cocoyl arginine ethyl pyrrolidone carboxylic acid.

[0018] The content of copper chlorophyllin salt in the oral composition of the present disclosure is not particularly limited as long as it remains within a range that exhibits its effects, and is preferably, for example, 0.001% by mass or more. The upper limit is also not particularly limited, and can be, for example, 0.5% by mass or less. The upper or lower limit of this range (0.001 to 0.5% by mass) may be, for example, 0.002, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, or 0.45% by mass. For example, the range may be 0.002 to 0.4% by mass.

[0019] The content of cocoyl arginine ethyl salt in the oral composition of the present disclosure is 0.02% by mass or more, preferably 0.025% by mass or more, or 0.05% by mass or more. The upper limit of the content is not particularly limited, but may be, for example, 5% by mass. The upper or lower limit of this range (0.02 to 5% by mass) may be, for example, 0.025, 0.05, 0.075, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, or 4.5% by mass. For example, the range may be 0.025 to 4% by mass.

[0021] The oral composition of the present disclosure can be, for example, a solid composition or a liquid composition. The oral composition can be used, for example, as a pharmaceutical or quasi-drug. The form is not particularly limited, and can be made into forms (dosage forms) such as ointments, pastes, pastes, gels, liquids, sprays, mouthwashes, liquid dentifrices, toothpastes, and gums according to conventional methods. Among these, mouthwashes, liquid dentifrices, toothpastes, ointments, pastes, liquids, and gels are preferred.

[0022] The oral composition of the present disclosure may further contain one or more optional components that can be blended into the oral composition, as long as the effects are not impaired.

[0023] For example, nonionic surfactants, anionic surfactants, or amphoteric surfactants can be blended as surfactants. Specific examples of nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters; fatty acid alkanolamides; glycerin fatty acid esters; sorbitan fatty acid esters; fatty acid monoglycerides; polyoxyethylene alkyl ethers having a polyoxyethylene addition coefficient of 8 to 10 and an alkyl group having 13 to 15 carbon atoms; polyoxyethylene alkylphenyl ethers having a polyoxyethylene addition coefficient of 10 to 18 and an alkyl group having 9 carbon atoms; diethyl sebacate; polyoxyethylene hydrogenated castor oil; and fatty acid polyoxyethylene sorbitan. Examples of anionic surfactants include sulfate ester salts such as sodium lauryl sulfate and polyoxyethylene lauryl ether sodium sulfate; sulfosuccinates such as sodium lauryl sulfosuccinate and polyoxyethylene lauryl ether sodium sulfosuccinate; acylamino acid salts such as sodium cocoyl sarcosinate and sodium lauroyl methyl alanine; and sodium cocoyl methyl taurate. Examples of zwitterionic surfactants include acetate betaine surfactants such as lauryl dimethylaminoacetate betaine and coconut oil fatty acid amidopropyl dimethylaminoacetate betaine; imidazoline surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium; and amino acid surfactants such as N-lauryldiaminoethylglycine. These surfactants can be used alone or in combination of two or more. The amount of surfactant used is usually 0.1 to 5% by mass based on the total amount of the composition.

[0024] Flavoring agents that can be used include, for example, menthol, carboxylic acid, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronenyl acetate, methyl eugenol, cineole, linalool, ethyl linalool, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, d-borneol, fennel oil, cinnamon oil, cinnamon aldehyde, peppermint oil, vanillin, etc. These can be blended alone or in combination of two or more types, in an amount of, for example, 0.001 to 1.5% by mass based on the total amount of the composition.

[0025] In addition, sweeteners that can be used include, for example, saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartyl phenylalanyl methyl ester, p-methoxycinnamic aldehyde, etc. These can be blended in an amount of, for example, 0.01 to 1% by mass based on the total amount of the composition.

[0026] Furthermore, as a humectant, for example, sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactite, polyoxyethylene glycol, etc. can be blended alone or in combination of two or more kinds.

[0027] As preservatives, for example, parabens such as methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride, etc. may be added.

[0028] As colorants, for example, legal pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine, enhanced ultramarine, and Prussian blue, titanium oxide, and the like may be blended.

[0029] Examples of pH adjusters that may be added include citric acid, phosphoric acid, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically acceptable salts thereof, sodium hydroxide, etc. These may be added alone or in combination of two or more so that the pH of the composition falls within the range of 4 to 8, preferably 5 to 7. The amount of pH adjuster added may be, for example, 0.01 to 2% by weight.

[0030] Furthermore, within the scope that does not impair the effect, the oral composition may further contain, as an active ingredient, vitamin E such as dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate; cationic bactericides such as cetylpyridinium chloride, benzalkonium chloride, and chlorhexidine hydrochloride; anionic bactericides such as sodium lauroyl sarcosinate; amphoteric bactericides such as dodecyldiaminoethylglycine; nonionic bactericides such as triclosan and isopropylmethylphenol; dextranase, amylase, protease, mutanase, lysozyme, bacteriolytic enzyme (retic enzyme), etc. The active ingredient may be an enzyme, alkali metal monofluorophosphates such as sodium monofluorophosphate and potassium monofluorophosphate, fluorides such as sodium fluoride and stannous fluoride, tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizinic acid and its salts, pyridoxine and its salts, ascorbic acid and its salts, glycerophosphate, chlorophyll, sodium chloride, callopeptide, allantoin, carbazochrome, hinokitiol, potassium nitrate, palatinit, salt, etc. The active ingredient may be formulated alone or in combination of two or more. From the viewpoint of adding additional active ingredients within a range that does not impair the effect, it is not preferable to incorporate many ingredients that may impair the effect, and although there is no limitation, it is preferable that cetylpyridinium chloride and chlorhexidine hydrochloride are not incorporated in an amount of more than 0.1%.

[0031] Furthermore, it is also possible to add, as a base, for example, alcohols, silicone, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, etc.

[0032] The oral composition can be prepared by a known method or a method easily derived from a known method, for example, by appropriately mixing a copper chlorophyllin salt, a cocoyl arginine ethyl salt, and other ingredients as needed.

[0033] It should be noted that in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." Furthermore, the present disclosure encompasses all arbitrary combinations of the constituent elements described in this specification.

[0034] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter encompassed by the present disclosure, i.e., the present disclosure encompasses all subject matter consisting of any combination of the combinable characteristics described herein. [Example]

[0035] The following examples are provided to explain the embodiments of the present disclosure in more detail, but the embodiments of the present disclosure are not limited to these examples. The amounts of sodium copper chlorophyllin and various antiseptic components are shown below in terms of concentration (w / v%). However, although the mass per ml of the solution used is slightly greater than 1 g, it can be considered that 1 ml is approximately 1 g, so the concentrations can be considered to be mass % (w / w%).

[0036] Sodium copper chlorophyllin is sometimes abbreviated as SCC. Various fungicides used in combination with SCC are sometimes abbreviated as follows: Cocoyl arginine ethyl pyrrolidone carboxylic acid: CAE Benzalkonium chloride: BKC Chlorhexidine hydrochloride: CHX Cetylpyridinium chloride: CPC

[0037] The inhibitory effect of copper chlorophyllin sodium on gingipain activity in Pg bacteria when used in combination with various fungicides was investigated. Specifically, the study was carried out as follows. Pg bacteria (Porphyromonas gingivalis W83) were cultured in modified GAM medium and adjusted to an absorbance (OD(600)) of 1.0. The cultured fungus solution contained gingipain. SCC and various fungicide aqueous solutions adjusted to various concentrations were added to the fungus solution in a 1 / 4 volume ratio and allowed to stand for 3 minutes. This resulted in a 4-fold dilution of the various fungicide aqueous solutions.

[0038] After 3 minutes of incubation, the mixture was mixed with Arg-gingipain (Rgp) substrate (Z-Phe-Arg-MCA; Peptide Institute, Inc.) diluted 100-fold with PBS and incubated at 37°C for 1 hour in the dark. Z-Phe-Arg-MCA is benzyloxycarbonyl-L-phenylalanyl-L-arginine 4-methylcoumaryl-7-amide (hydrochloride form), a reagent that is cleaved by Arg-gingipain (Rgp) activity to emit fluorescence. After 1 hour, fluorescence intensity (excitation: 380 nm, emission: 440 nm) was measured using a fluorescence plate reader (Gemini XPS). The fluorescence intensity at 0 μg / mL of sodium copper chlorophyllin and various fungicides was converted to 100%, and the gingipain activity at each concentration of fungicide was calculated. Each concentration was tested in duplicate, and the calculated values ​​were averaged. A smaller calculated value indicates a greater inhibition of gingipain activity.

[0039] The results are shown in Figure 1. The concentration % of each component shown in Figure 1 indicates the aqueous solution concentration of each component. As mentioned above, the aqueous solution was diluted four times for the study, so the concentration of each component in the solution actually studied was four times lower than the concentration shown in Figure 1. This is because when toothpaste or the like is used, it is diluted by saliva, etc., so the evaluation was carried out assuming the condition in which it is actually used in the oral cavity.

[0040] As shown in FIG. 1, it was found that the inhibitory effect on gingipain activity was favorably enhanced only when copper chlorophyllin sodium was combined with cocoyl arginine ethylpyrrolidone carboxylic acid.

[0041] Next, in order to investigate the preferred concentrations of copper chlorophyllin sodium and cocoyl arginine ethylpyrrolidone carboxylic acid used to inhibit gingipain activity, the concentrations of these two components were varied and combined, and the investigation was carried out in the same manner as above.

[0042] The results are shown in Table 1. As above, Table 1 shows the calculated values ​​of gingipain activity when treated with each concentration of agent, with the fluorescence intensity at 0 μg / mL of copper chlorophyllin sodium and cocoyl arginine ethylpyrrolidone carboxylic acid converted to 100%. Also, as above, the concentrations of each component in the solutions actually examined were four times lower than the concentrations shown in Table 1.

[0043] The values ​​in Table 1 are graphed and shown in Figure 2.

[0044] [Table 1]

[0045] From Table 1 and Figure 2, it was found that, unexpectedly, when copper chlorophyllin sodium and cocoyl arginine ethylpyrrolidone carboxylic acid are combined in approximately equal amounts (i.e., the closer the mass ratio of the combination is to 1:1), the gingipain activity inhibitory effect is weakened, and when either component is contained in a higher ratio than the other, the gingipain activity inhibitory effect tends to be stronger.

[0046] In addition, a study was conducted to investigate the bactericidal effect of a combination of copper chlorophyllin sodium and cocoyl arginine ethylpyrrolidone carboxylic acid on Pg bacteria. Specifically, in the above study, an aqueous solution of copper chlorophyllin sodium and cocoyl arginine ethylpyrrolidone carboxylic acid was added in a volume ratio of 1 / 4 to the bacterial solution (Pg bacteria (Porphyromonas gingivalis W83) cultured in modified GAM medium and adjusted to an absorbance (OD(600)) = 1.0) to obtain a mixed solution. The same procedure was followed until the mixed solution was obtained. After leaving the mixed solution for 3 minutes, 1 / 10 of the mixed solution was added to a bactericide inactivation medium (modified GAM medium supplemented with 0.07% lecithin and 0.5% Tween 80) to stop the bactericidal effect. Then, 1 / 10 of the mixed solution with the bactericidal effect stopped was added to the modified GAM medium, and the mixture was cultured at 37 ° C under anaerobic conditions for 2 days, and the occurrence of turbidity was visually determined. If turbidity occurs, bacteria are multiplying and it is judged that there is no bactericidal effect. Table 2 shows the results, with + indicating that turbidity occurs (i.e., no bactericidal effect) and - indicating that no turbidity occurs (i.e., there is a bactericidal effect). As above, the concentration of each component in the solution actually examined was four times lower than the concentrations shown in Table 2.

[0047] [Table 2]

[0048] Aqueous solutions containing various concentrations of sodium copper chlorophyllin and ethyl cocoyl arginine pyrrolidone carboxylic acid were placed in each well of a 96-well plate and left to stand at 5°C and 37°C for two days. When the solution contained no or only a small amount of CAE, the green color of the composition derived from sodium copper chlorophyllin faded due to heating, while when CAE was present, the fading of the green color was suppressed. The results are shown in Figure 3.

Claims

1. Contains copper chlorophyllin salt and cocoyl arginine ethyl salt, Contains 0.02 to 0.15% by mass of cocoyl arginine ethyl salt and 0.03 to 0.25% by mass of copper chlorophyllin salt, and Contains more copper chlorophyllin salt than cocoyl arginine ethyl salt. Oral composition.

2. The oral composition according to claim 1, which contains 0.05 to 0.2% by mass of copper chlorophyllin salt.

3. 3. The oral composition according to claim 1, which contains 0.025 to 0.1% by mass of ethyl cocoyl arginine salt.

4. 4. The composition according to claim 1, wherein the copper chlorophyllin salt is sodium copper chlorophyllin.

5. 5. The composition according to claim 1, wherein the cocoyl arginine ethyl salt is cocoyl arginine ethyl pyrrolidone carboxylic acid.

6. The composition according to any one of claims 1 to 5, which is for use in preventing periodontal disease.

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