JP7143198B2 - oral composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an oral composition and the like.

Porphyromonas gingivalis (P. g bacterium) is a periodontal pathogen considered most important in the onset and progression of periodontitis.

P. Gingipain is known as a representative virulence factor produced by G. g. Gingipain is a type of protease, and there are Lys-gingipain (Kgp) and Arg-gingipain (Rgp) having different peptide cleavage site specificities. While interacting with each other, they cause destruction of the junction between gingival epithelial cells, injury to the epithelial cells themselves and/or inhibition of proliferation, and eventually destruction and inhibition of repair of the epithelial barrier. Gingipain is also said to have the effect of suppressing phagocytosis by phagocytic cells and intracellular digestion, as well as the effect of assisting destruction of the complement system and entry into epithelial cells. It is also involved in the evasion of g bacteria from the immune system. Furthermore, recently, it has been reported that the suppressive effect of gingipain on the immune system leads to dysbiosis of the oral flora, and these actions of gingipain lead to the progression and intractability of periodontal disease.

WO2016/104524

Due to the circumstances as described above, it is important to suppress gingipain activity for the prevention and/or treatment of periodontal disease (especially inhibition of progression of periodontal disease).

Therefore, when research was conducted for the purpose of finding a method for suppressing gingipain activity, it was found that copper chlorophyllin sodium efficiently suppresses gingipain activity.

Therefore, we next inhibited gingipain activity and P. In order to prepare an oral composition having a bactericidal effect against g bacteria, the use of a combination of cetylpyridinium chloride and sodium copper chlorophyllin, which are components exhibiting a bactericidal effect, was investigated. However, as a result of further studies, it was found that the combination of sodium copper chlorophyllin and cetylpyridinium chloride sometimes fails to achieve the expected effect of inhibiting gingipain activity.

Therefore, in the case of using sodium copper chlorophyllin and cetylpyridinium chloride in combination, further studies were conducted with the aim of discovering a technique capable of efficiently suppressing the gingipain activity.

As a result, the present inventors found that by using a combination of sodium copper chlorophyllin and cetylpyridinium chloride in a specific ratio, gingipain activity can be efficiently suppressed and sterilization can be achieved as compared with the case of using sodium copper chlorophyllin alone. The inventors have discovered the possibility of preparing an oral composition with improved effects, and have made further improvements to complete the present invention.

The invention includes, for example, the subject matter described in the following sections.
Section 1.
An oral composition containing sodium copper chlorophyllin and cetylpyridinium chloride in a weight ratio of 1:1.2 to 100 or 1.2 to 20:1.
Section 2.
Item 2. The composition according to Item 1, which is an oral composition for anti-periodontal disease.
Item 3.
Item 3. The composition according to Item 2, wherein the anti-periodontal disease suppresses progression of periodontal disease.
Section 4.
Item 4. The composition according to any one of items 1 to 3, containing 0.001 to 0.1% by mass of sodium copper chlorophyllin.
Item 5.
Item 5. The composition according to any one of Items 1 to 4, containing 0.005 to 0.1% by mass of cetylpyridinium chloride.

Provided is an oral composition that can efficiently suppress the activity of gingipain and has an improved bactericidal effect as compared with the case where sodium copper chlorophyllin is used alone. The oral cavity composition is particularly useful for anti-periodontal disease (especially inhibition of progression of periodontal disease).

Fig. 2 shows the results of examining the inhibitory effect of sodium copper chlorophyllin on the activity of gingipain (Kgp and Rgp).

Each embodiment included in the present invention will be described in further detail below. The present invention preferably includes, but is not limited to, oral compositions and uses thereof, etc. The present invention includes everything disclosed herein and recognized by those skilled in the art.

The oral compositions encompassed by the present invention contain sodium copper chlorophyllin and cetylpyridinium chloride. Hereinafter, the oral composition included in the present invention may be referred to as "the oral composition of the present invention". In the present specification, sodium copper chlorophyllin may be abbreviated as SCC, and cetylpyridinium chloride may be abbreviated as CPC. Both copper chlorophyllin sodium and cetylpyridinium chloride are known ingredients used in the oral composition field. These components can also be used by purchasing commercially available products.

The oral composition of the present invention contains SCC and CPC in a mass ratio (SCC:CPC) of 1:1.2-100 or 1.2-20:1.

It was also found in this study that the bactericidal effect of CPC may be weakened by SCC. Compared with the case of using SCC alone, the combination of SCC and CPC has a higher bactericidal effect, but the original bactericidal effect of CPC is difficult to achieve. From the viewpoint that the bactericidal effect is exhibited more efficiently, the CPC content is preferably equal to or greater than the SCC content. Therefore, in the composition for oral cavity of the present invention, the content ratio of SCC and CPC (SCC:CPC) is 1:1.2 from the viewpoint that the bactericidal effect of CPC is more efficiently exhibited. ~100 is more preferred.

Among the SCC and CPC content mass ratios (ie, 1:1.2 to 100 or 1.2 to 20:1) in the oral composition of the present invention, the SCC content ratio is low (ie, 1: 1.2 to 100) is sometimes referred to as mass ratio (i). Further, among the mass ratios, the ratio in which the SCC content ratio is high (that is, 1.2 to 20:1) is sometimes referred to as mass ratio (ii).

The lower limit of the CPC content ratio range (that is, 1.2 to 100) in the mass ratio (i) is, for example, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.8. 9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3. Further, the upper limit of the CPC content ratio range in the mass ratio (i) is, for example, 95, 90, 85, 80, 75, 70, 65, 60, 50, 45, 40, 35, 30, 29, 28, 27, 26 , 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 There may be.

The lower limit of the SCC content ratio range (that is, 1.2 to 20) in the mass ratio (ii) is, for example, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.8 9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3. Further, the upper limit of the SCC content ratio range in the mass ratio (ii) is, for example, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 , or two.

The oral composition of the present invention is a composition containing SCC and CPC in a weight ratio (SCC:CPC) of 1:100 to 20:1, provided that the ratio is 1:1.2 to 1.2:1. It can also be referred to as an oral composition, excluding compositions containing (but not excluding compositions containing preferably 1:1.2 and 1.2:1). Surprisingly, as the content mass of SCC and CPC approached 1:1, the gingipain activity-inhibiting effect obtained by combining SCC and CPC sharply decreased compared to the gingipain activity-inhibiting effect exhibited by SCC alone. Therefore, an oral composition containing SCC and CPC in the above mass ratio range (1:1.2 to 1.2:1) is excluded from the oral composition of the present invention (however, preferably Compositions containing 1:1.2 and 1.2:1 are not excluded).

In addition, according to this "exclude" description method, for example, the oral composition of the present invention more preferably contains SCC and CPC at a mass ratio (SCC:CPC) of 1:100 to 20:1. with the exception of compositions containing 1:1.3 to 1.3:1 (but preferably excluding compositions containing 1:1.3 and 1.3:1) No) Oral compositions, compositions containing SCC and CPC in a mass ratio (SCC:CPC) of 1:100 to 20:1, provided that the composition contains 1:1.4 to 1.4:1 Oral compositions, excluding (but not excluding compositions containing preferably 1:1.4 and 1.4:1) compositions, SCC and CPC in a weight ratio (SCC:CPC) of 1:100 -20:1, except for compositions containing 1:1.5 to 1.5:1, but preferably containing 1:1.5 and 1.5:1 compositions containing SCC and CPC in a weight ratio (SCC:CPC) of 1:100-20:1, provided that the ratio is 1:1.6-1. Oral compositions, excluding compositions containing 6:1 (but preferably excluding compositions containing 1:1.6 and 1.6:1), SCC and CPC in a weight ratio (SCC :CPC) from 1:100 to 20:1, except for compositions containing from 1:1.7 to 1.7:1 (but preferably 1:1.7 and 1:1.7:1). Compositions containing SCC and CPC in a mass ratio (SCC:CPC) of 1:100 to 20:1, with the proviso that 1: Oral compositions, SCC and CPC, excluding compositions containing 1.8 to 1.8:1 (but preferably excluding compositions containing 1:1.8 and 1.8:1) and in a mass ratio (SCC:CPC) of 1:100 to 20:1, excluding compositions containing 1:1.9 to 1.9:1 (preferably 1 : Compositions containing 1.9 and 1.9:1 are not excluded) Oral compositions, or compositions containing SCC and CPC at a mass ratio (SCC:CPC) of 1:100 to 20:1 oral compositions, except compositions containing 1:2 to 2:1 (but preferably excluding compositions containing 1:2 and 2:1) can be done. In addition, the mass ratio (1:100 to 20:1) of SCC and CPC of "1:100" and "20:1" also applies to the "upper limit of the CPC content ratio range in the mass ratio (i)" described above. and "the upper limit of the SCC content ratio range in the mass ratio (ii)" apply as they are.

The content of SCC in the oral composition of the present invention is preferably about 0.001 to 0.1% by mass. The lower limit of the range is 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.011, 0.012, It may be about 0.013, 0.014, or 0.015% by mass. Moreover, the upper limit of the said range may be about 0.09, 0.08, 0.07, 0.06, or 0.05 mass %.

Moreover, the content of CPC in the oral composition of the present invention is preferably about 0.005 to 0.1% by mass. The lower limit of the range may be about 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, or 0.05% by mass. . Moreover, the upper limit of the said range may be about 0.09, 0.08, 0.07, 0.06, or 0.05 mass %.

When the CPC content is 0.025% by mass or more, even if the CPC content is equal to or less than the SCC content, the bactericidal effect of CPC is efficiently exhibited. Therefore, from the viewpoint that the bactericidal effect of CPC is more efficiently exhibited, the CPC content is more preferably 0.025% by mass or more.

In addition, when the oral composition of the present invention is particularly a liquid oral composition (including liquid oral compositions as well as compositions such as gel-like and cream-like compositions whose concentration can be considered), The concentration of SCC in the oral composition is preferably 10-1000 μg/ml. The lower end of the range may be 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 μg/ml. Alternatively, the upper limit of the range may be 900, 800, 700, 600, or 500 μg/ml.

Furthermore, when the oral composition of the present invention is particularly a liquid oral composition (including liquid oral compositions as well as gel-like, cream-like compositions with possible concentrations), the present invention The concentration of CPC in the oral composition is preferably 50-1000 μg/ml. The lower end of the range may be 100, 150, 200, 250, 300, 350, 400, 450, or 500 μg/ml. Alternatively, the upper limit of the range may be 900, 800, 700, 600, or 500 μg/ml.

When the concentration of CPC is 250 μg/ml or more, even if the CPC content is not equal to or higher than the SCC content, the bactericidal effect of CPC is efficiently exhibited. Therefore, from the viewpoint that the bactericidal effect of CPC is exhibited more efficiently, the CPC concentration is more preferably 250 μg/ml or more.

Although not particularly limited, from the viewpoint of particularly efficiently suppressing the gingipain activity and particularly efficiently obtaining the bactericidal effect of CPC, the content of CPC in the composition for oral cavity of the present invention is 0.025. ~0.1% by mass, SCC content is 0.012 to 0.1% by mass, and the content mass ratio (SCC:CPC) is 1:2.5 to 8 or 1.2 to 4:1 It is particularly preferred that the degree is In particular, when the oral composition of the present invention is a liquid composition, from this point of view, the concentration of CPC is about 250 to 1000 μg/ml, and the concentration of SCC is about 120 to 1000 μg/ml, It is particularly preferred that the content mass ratio (SCC:CPC) is about 1:2.5 to 8 or 1.2 to 4:1.

The anti-periodontal oral composition of the present invention can be a solid composition or a liquid composition. The anti-periodontal disease composition for oral cavity can be used, for example, as a pharmaceutical product or a quasi-drug. In addition, the form of the anti-periodontal disease oral composition of the present invention is not particularly limited. It can be in the form (dosage form) of liquid dentifrice, toothpaste, gum, and the like. Among them, mouthwashes, liquid dentifrices, toothpastes, ointments, pastes, liquids and gels are preferred.

The anti-periodontal disease oral composition of the present invention may further contain one or two or more optional components that can be blended in the oral composition within a range that does not impair the effects of the present invention.

For example, nonionic surfactants, anionic surfactants or amphoteric surfactants can be blended as surfactants. Specifically, for example, 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; sorbitan fatty acid esters; fatty acid monoglycerides; ~10, polyoxyethylene alkyl ethers in which the number of carbon atoms in the alkyl group is 13 to 15; polyoxyethylene alkylphenyl ethers in which the polyoxyethylene addition coefficient is 10 to 18, and the number of carbon atoms in the alkyl group is 9; diethyl sebacate; polyoxyethylene hydrogenated castor oil; fatty acid polyoxyethylene sorbitan; and the like. Examples of anionic surfactants include sulfuric acid 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; sodium cocoyl sarcosinate and lauroyl methylalanine. acyl amino acid salts such as sodium; cocoyl methyl taurate sodium; Zwitterionic surfactants include betaine acetate type surfactants such as betaine lauryldimethylaminoacetate and betaine coconut oil fatty acid amidopropyldimethylaminoacetate; imidazoline type surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium. Active agent: amino acid-type active agent such as N-lauryldiaminoethylglycine, and the like. These surfactants can be blended singly or in combination of two or more. The blending amount thereof is usually 0.1 to 5% by mass based on the total amount of the composition.

Flavoring agents such as menthol, carboxylic acid, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronol, 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, Perfumes such as d-borneol, fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil and vanillin can be used. These may be blended singly or in combination of two or more in an amount of, for example, 0.001 to 1.5% by mass based on the total amount of the composition.

Sweeteners that can be used include, for example, saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartylphenylalanylmethyl ester, p-methoxycinnamic aldehyde, and the like. These can be blended, for example, in an amount of 0.01 to 1% by mass relative to the total amount of the composition.

Furthermore, as wetting agents, sorbit, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylit, maltit, lactit, polyoxyethylene glycol, etc. may be blended alone or in combination of two or more. can.

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

As a coloring agent, legal dyes such as Blue No. 1, Yellow No. 4, Red No. 202 and Green No. 3, mineral dyes such as ultramarine blue, enhanced ultramarine blue and Prussian blue, titanium oxide, and the like may be blended.

As a pH adjuster, citric acid, phosphoric acid, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically possible salts thereof, sodium hydroxide, or the like may be added. These may be blended singly or in combination of two or more so that the pH of the composition is in the range of 4-8, preferably 5-7. The blending amount of the pH adjuster may be, for example, 0.01 to 2% by weight.

The oral cavity composition of the present invention further contains, as active ingredients, vitamin E compounds such as dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate, amphoteric fungicides such as dodecyldiaminoethylglycine, triclosan, Nonionic fungicides such as isopropylmethylphenol, enzymes such as dextranase, amylase, protease, mutanase, lysozyme, lytic enzyme (retech enzyme), alkali metal monofluorophosphates such as sodium monofluorophosphate and potassium monofluorophosphate Phosphate, fluorides such as sodium fluoride and stannous fluoride, tranexamic acid and epsilon aminocaproic acid, aluminum chlorohydroxyallantoin, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizic acid, glycerophosphate, chlorophyll, sodium chloride, calopeptide, allantoin , carbazochrome, hinokitiol, potassium nitrate, palatinit and the like can be blended alone or in combination of two or more.

As a base, alcohols, silicon, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, etc. can be added.

In addition, the oral composition of the present invention can be prepared by a known method or a method easily conceived from known methods. For example, it can be prepared by appropriately mixing SCC and CPC and, if necessary, other ingredients.

In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present invention encompasses all arbitrary combinations of the constituent elements described herein.

Also, the various characteristics (property, structure, function, etc.) described for each of the embodiments of the invention described above may be combined in any way to identify subject matter encompassed by the invention. That is, the invention encompasses all subject matter consisting of any and all possible combinations of the features described herein.

The present invention will be described in more detail below, but the present invention is not limited to the following examples. The amounts of chemicals (sodium copper chlorophyllin (SCC), cetylpyridinium chloride (CPC), and mixtures thereof) are shown below in terms of concentration (μg/mL), but the mass per 1 ml of the liquid used is slightly greater than 1 g. However, it can also be considered that approximately 1 ml ≈ 1 g.

Investigation of the inhibitory effect of SCC on gingipain activityP . P. gingivalis W83 was cultured in GAM medium and adjusted to absorbance (OD (600)) = 1.0. The bacterial solution was centrifuged at 10,000 rpm to collect the supernatant. Gingipain is contained in the recovered supernatant. Sodium copper chlorophyllin (SCC) adjusted to each concentration was mixed with the recovered supernatant and allowed to stand for 3 minutes. After 3 minutes, the mixture was mixed with a gingipain substrate (Z-His-Glu-Lys-MCA or Z-Phe-Arg-MCA; Peptide Institute, Inc.) diluted 100-fold with PBS, and allowed to stand at 37°C for 1 hour in the dark. placed. In addition, Z-His-Glu-Lys-MCA is Benzyloxycarbonyl-L-Histidyl-L-Glutamyl-L-Lysine 4-methylcoumaryl-7-amide (Hydrochloride Form), cleaved by Lys-gingipain (Kgp) activity It is a fluorescent reagent. In addition, 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 and emits fluorescence. . After 1 hour, fluorescence intensity (excitation light: 380 nm, emission light: 440 nm) was measured with a fluorescence plate reader (Gemini XPS). The fluorescence intensity at a drug concentration of 0 μg/mL was converted to 100%, and the gingipain activity when SCC of each concentration was treated was calculated. Note that each concentration was examined with n=2, and the calculated value was the average value. A smaller calculated value indicates that the gingipain activity was suppressed. The results are shown in FIG.

P.S.C. by SCC and CPC. Investigation of inhibitory effect on gingipain activity of bacterium g . The inhibitory effect on the gingipain activity of bacterium g was examined. That is, the study was conducted as follows. P. P. gingivalis W83 was cultured in GAM medium and adjusted to absorbance (OD (600)) = 1.0. The bacterial solution was centrifuged at 10,000 rpm to collect the supernatant. Gingipain is contained in the recovered supernatant. Drugs (sodium copper chlorophyllin (SCC), cetylpyridinium chloride (CPC), and mixtures thereof) adjusted to each concentration were mixed with the recovered supernatant and allowed to stand for 3 minutes. After 3 minutes, the mixture was mixed with a Lys-gingipain (Kgp) substrate (Z-Phe-Arg-MCA; Peptide Research Institute, Inc.) diluted 100-fold with PBS, and allowed to stand at 37° C. for 1 hour, shielded from light. After 1 hour, fluorescence intensity (excitation light: 380 nm, emission light: 440 nm) was measured with a fluorescence plate reader (Gemini XPS). The fluorescence intensity at a drug concentration of 0 μg/mL was converted to 100%, and the gingipain activity upon treatment with each concentration of drug was calculated. Note that each concentration was examined with n=2, and the calculated value was the average value. A smaller calculated value indicates that the gingipain activity was suppressed. The results are summarized in Table 1.

P.S.C. by SCC and CPC. g Investigation of bactericidal effectP . P. gingivalis W83 was cultured in GAM medium and adjusted to absorbance (OD (600)) = 1.0. The drug (sodium copper chlorophyllin (SCC), cetylpyridinium chloride (CPC), and a mixture thereof) adjusted to twice the concentration of each treatment was mixed with the adjusted bacterial solution in equal amounts and allowed to stand for 3 minutes. After 3 minutes, 1/10 amount of sterilant-inactivated PBS (0.07% lecithin + 0.5% Tween 80) was added to the mixture of the drug and bacterial solution to stop the bactericidal effect. Thereafter, 10 times the amount of the mixture was added to the GAM medium, and the cells were cultured at 37°C under anaerobic conditions for 16 hours. After culturing, the absorbance (OD (600)) of the medium was measured using an absorption plate reader (xMark microplate reader), and the turbidity was measured to confirm the bactericidal effect. Since the smaller the absorbance, the less the bacteria grow, it can be said that the smaller the absorbance, the higher the bactericidal effect. Table 2 summarizes the results.

Claims (4)

An oral composition containing sodium copper chlorophyllin and cetylpyridinium chloride at a weight ratio of 1:1.2 to 100 or 1.2 to 20:1 and containing 0.005 to 0.09% by weight of cetylpyridinium chloride . The composition according to claim 1, which is an oral composition for anti-periodontal disease. 3. The composition according to claim 2, wherein the anti-periodontal disease is inhibition of progression of periodontal disease. The composition according to any one of claims 1 to 3, containing 0.001 to 0.1% by mass of sodium copper chlorophyllin.

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