WO2022172807A1 - 口腔ケア用組成物 - Google Patents
口腔ケア用組成物 Download PDFInfo
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- WO2022172807A1 WO2022172807A1 PCT/JP2022/003836 JP2022003836W WO2022172807A1 WO 2022172807 A1 WO2022172807 A1 WO 2022172807A1 JP 2022003836 W JP2022003836 W JP 2022003836W WO 2022172807 A1 WO2022172807 A1 WO 2022172807A1
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- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
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Definitions
- the present invention relates to an oral care composition containing, as an active ingredient, a protein fraction having a specific molecular weight obtained from an algae extract of the Myrraceae family.
- Periodontal disease is an inflammatory disease that begins when periodontal disease-causing bacteria, a type of pathogenic bacteria in the oral cavity, settle in the oral cavity. If oral cleaning is insufficient, dental plaque (oral bacteria and its metabolites) adheres to the boundary between the gums and teeth, then settles and proliferates. In response to this foreign substance, neutrophils and macrophages infiltrate, causing inflammation. If the oral cavity can be cleaned by brushing or the like at an early stage, this inflammation can be improved. However, if the plaque is left unattended, the inflammation will spread, and if a periodontal pocket is formed, the plaque accumulated there will be difficult to remove by brushing or the like. Therefore, it is said that suppression of dental plaque, that is, sterilization and bacteriostasis of pathogenic bacteria in the oral cavity is useful as an effective means for preventing and improving periodontal disease.
- dental plaque has been regarded as a biofilm
- bacteria in oral biofilm differ greatly in bacterial protein expression patterns and drug resistance compared to planktonic bacteria. has been shown to be ineffective against biofilm-forming bacteria.
- antibacterial agents such as cationic antibacterial agents such as cetylpyridinium chloride, benzethonium chloride, and chlorhexidine, and nonionic antibacterial agents such as triclosan, have been found to be effective when incorporated into oral compositions as a means of sterilization.
- these antibacterial agents alone cannot provide a sufficient biofilm inhibitory effect due to the drug resistance mechanism of biofilm bacteria.
- improvement techniques have been proposed by using them in combination with other ingredients, but none of them have achieved remarkable effects due to low drug penetration into biofilms.
- Patent Document 1 mushroom-derived lectins such as ABA, which recognize sugar chains having terminal structures of Gal ⁇ 1-3GalNAc and GlcNAc, are used to attach and proliferate oral bacteria to plaque or biofilm in the oral cavity. It is disclosed that there is an effect of suppressing.
- lectins that are contained in alga body extracts of Myrraceae algae and bind to sugar chains that compete with GalNAc are found to be able to inhibit the adhesion and growth of oral bacteria, particularly Streptococcus mutans, and prevent tooth decay. have been reported (see, for example, Patent Document 2).
- oral care products such as mouthwash contain antibacterial ingredients
- side effects such as diarrhea may occur, and these side effects usually disappear when the antibiotic is stopped. It is.
- antimicrobial components may reduce the naturally occurring non-pathogenic bacteria that colonize the body, providing an opportunity for other pathogens to become infected.
- oral care products that are alternatives to using antibacterial ingredients (including lower content of antibacterial ingredients) and such There is a strong desire to provide materials that can be incorporated into a variety of products.
- the problem to be solved by the present invention is an oral care product and oral care that can suppress the adhesion of bacteria floating in the oral cavity to teeth without using an antibacterial component or by reducing the concentration of the antibacterial component. For example, creating materials that are contained in products for use.
- the present invention has been made to solve the above problems, for example, an oral care product containing a protein fraction having a specific molecular weight contained in an extract of Myrraceae algae, and a material to be contained in the product. (materials for oral care), and so on.
- an oral care composition containing an extract of Myrraceae algae as an active ingredient.
- An oral care composition containing, as an active ingredient, a protein fraction having a molecular weight of 5,000 or more contained in an extract of Myrraceae algae.
- the protein fraction preferably has a molecular weight of 5,000 or more and less than 50,000, more preferably 5,000 or more and less than 30,000. Alternatively, it may be a protein present in a high molecular weight fraction with a molecular weight of 50,000 or more.
- the composition for oral care according to [1] further comprising an antibacterial component.
- the antibacterial component includes cetylpyridinium chloride (CPC), chlorhexidine, benzalkonium chloride, benzethonium chloride, depotassium chloride, chlorhexidine gluconate, protamine, dodecyldiaminoethylglycine, triclosan, 3-methyl-4-isopropylmethylphenol (IPMP), thymol, carvacrol, farnesol, bisabolol, cineol, hinokitiol, sodium lauroyl sarcosinate, l-menthol, one or more selected from the group consisting of l-menthol, oral care according to [1] or [2] composition.
- CPC cetylpyridinium chloride
- IPMP 3-methyl-4-isopropylmethylphenol
- IPMP 3-methyl-4-isopropylmethylphenol
- thymol carvacrol
- farnesol bisabolol
- cineol cineol
- hinokitiol
- the oral care composition of the present invention it is possible to suppress adhesion of bacteria floating in the oral cavity to teeth without using an antibacterial component or at a low concentration.
- FIG. 1 shows the results of bacterial adsorption tests for mill extract (ML), cetylpyridinium chloride (CPC) and their mixture (CPC+ML).
- FIG. 2 shows the results of the fungal adsorption test for mill extract (ML), benzalkonium chloride and their mixture (benzalkonium chloride+ML).
- FIG. 3 shows the results of the fungal adsorption test for mill extract (ML), chlorhexidine and their mixture (chlorhexidine+ML).
- FIG. 4 shows the results of bacterial adsorption test for mill extract (ML), IPMP and their mixture (IPMP+ML).
- FIG. 5 shows the results of a bacterial adsorption test for four fractions molecular weight-fractionated in Example 2 (molecular weights of 50,000 or more, 30,000 or more and less than 50,000, 5,000 or more and less than 30,000, and less than 5,000).
- FIG. 6 shows the results of a bacterial adsorption test for three fractions molecular weight-fractionated in Example 2 (molecular weight less than 5000, 5000 or more and less than 30000, and 30000 or more and less than 50000).
- FIG. 7 shows the results of a bacterial adsorption test when CPC was added as an antibacterial agent to four fractions (molecular weights of 50000 or more, 30000 or more and less than 50000, 5000 or more and less than 30000 and less than 5000) obtained by molecular weight fractionation in Example 2.
- FIG. 8 shows the results of investigating the combined effect of the mill extract and the mouthrinse, etc., by a bacteria adsorption test using the mill extract and the commercially available mouthrinse.
- oral care compositions are, for example: To contact substantially all tooth surfaces and/or oral tissues for the purpose of oral activity, rather than intentionally swallowing for the purpose of systemic administration of a particular therapeutic agent in its normal method of use Products that are retained in the mouth for a sufficient period of time (oral care products). ⁇ Materials contained in the product. The material contains an extract of Myrraceae algae.
- the oral care product may be in the form of mouthwash, mouthwash, dentifrice, toothpaste, gel, solution, or the like. Oral care products may also be incorporated into flosses, strips, or films for direct application or adherence to oral surfaces, or into devices or applicators such as toothbrushes or rolling applicators. Such applicators may be disposable or multi-use.
- An oral care composition in one embodiment of the present invention contains an extract of Myrrhidae algae or a protein fraction with a molecular weight of 5000 or more contained therein as an active ingredient. The details will be described below.
- the extract of Myrrhaceae algae used in one embodiment of the present invention includes Chlorophyceae, Codiales, and Bryopsidales in recent classification.
- Any method for collecting the extract of the present embodiment may be used on the condition that the activity of suppressing or inhibiting the binding of oral bacteria to salivary biopolymers is not substantially impaired.
- the extract of this embodiment may be collected from any tissue of algal bodies. After washing, the algal body is crushed by a homogenizer or the like, powdered by freeze-drying, or powdered by a grinder and then subjected to an extraction treatment in some cases.
- the aqueous solution used for extraction includes an aqueous solution containing NaCl and other salts such as physiological saline, a mixture of acetone and other water-soluble organic solvents and/or alcohol and water, and purified water or deionized water. Other aqueous solvents known to those skilled in the art, including but not limited to, can be used.
- Alcohols herein include, but are not limited to, ethanol, ethylene glycol, butylene glycol, glycerin.
- Aqueous solvents may have an acidic or alkaline pH.
- Tris-HCl buffer, Hepes buffer, phosphate buffer, acetate buffer, citrate buffer, glycine-HCl buffer are included, but not limited to these.
- the extraction method can be appropriately selected from immersion extraction method, pressure extraction method, supercritical or sub-supercritical extraction method, etc., or can be used in combination.
- the extraction conditions may be any conditions provided that the activity of suppressing or inhibiting the binding of oral bacteria to salivary biopolymers is not substantially impaired, and the extraction time is from 10 minutes to 24 hours. and the extraction temperature may be 4° C. or higher, preferably room temperature or higher, and more preferably 15° C. or higher.
- the extract of the present embodiment can be obtained as it is, or by purifying or concentrating it, to obtain an active ingredient as an oral care composition.
- the active ingredient is present in the protein fraction with a molecular weight of 5000 or greater. A fraction with a molecular weight of 5,000 or more and less than 50,000 is more preferable, and a fraction with a molecular weight of 5,000 or more and less than 30,000 is more preferable.
- Purification and concentration of Myrraceae algae extracts include, but are not limited to, techniques such as centrifugation, salting out, dialysis, vacuum concentration, ultrafiltration, gel filtration, ion exchange chromatography, affinity chromatography, etc. It can be carried out alone or in combination of any two or more. After purification or concentration, the algae extract may be dried under reduced pressure or diluted with a solvent if necessary.
- One of the candidates for the active ingredient of the present invention is considered to be, for example, a lectin that binds to a sugar chain that competes with GalNAc (see Patent Document 2).
- this active ingredient does not necessarily bind to all sugar chains having GalNAc at their ends.
- the 2nd to 3rd sugar residues from the terminal bind only to sugar chains with a specific structure, the binding may be inhibited in the presence of GalNAc.
- lectin refers to proteins other than antibodies, T-cell receptors, Toll-like receptors, and other immune proteins involved in the immune system of animals, and having the ability to specifically bind to sugar chains. .
- Lectins are usually capable of agglutinating red blood cells and other animal cells. According to Kanji Hori (Chemistry and Biology, 32:586-594, (1994)), lectins derived from Myrrhaceae algae have in common that they bind to sugar chains that compete with GalNac.
- the active ingredient of the present invention binds to GalNAc present on the surface of the membrane formed by polysaccharides contained in salivary biopolymers and inhibits adhesion of oral bacteria to it. be done.
- the active ingredient of the present invention may have any concentration on the condition that it does not substantially impair the activity of suppressing or inhibiting the binding of oral bacteria and salivary biopolymers, but preferably Myrraceae algae It is preferably 0.001% by mass or more, more preferably 0.01% by mass or more, and even more preferably 0.1% by mass or more, relative to the total amount of the oral care composition in terms of extract.
- the upper limit is 5% by mass or less, preferably 4% by mass or less, more preferably 3% by mass or less, and even more preferably 2% by mass or less.
- the concentration of the protein contained in the active ingredient of the present invention may be any concentration provided that it does not substantially impair the activity of inhibiting or inhibiting the binding of oral bacteria to salivary biopolymers. 0.5 ⁇ g/mL or more is preferable, and 5 ⁇ g/mL or more is more preferable.
- the oral care composition of the present embodiment preferably contains an amount of antimicrobial component.
- An antibacterial ingredient is an ingredient having an antibacterial action.
- Antibacterial action includes, for example, sterilizing action, bactericidal action, disinfecting action, bacteriostatic action, bacteriostatic action, bactericidal action, antiseptic action, antibacterial action, and antifungal action.
- An antimicrobial agent is an agent containing an antimicrobial component.
- Antibacterial agents include, for example, bactericidal agents, antibacterial agents, antifungal agents, antifungal agents, antiseptic agents, deodorants, and insecticides. microbial control agents and deodorants can be suitably used.
- a known compound having the above action may be appropriately selected and used.
- antibacterial agents examples include organic synthetic antibacterial agents, natural antibacterial agents, and inorganic antibacterial agents.
- Antibacterial components contained in the antibacterial agent include, for example, cetylpyridinium chloride (CPC), chlorhexidine, benzalkonium chloride, benzethonium chloride, depotassium chloride, chlorhexidine gluconate, protamine, dodecyldiaminoethylglycine, triclosan, 3-methyl- 4-isopropylmethylphenol (IPMP), thymol, carvacrol, farnesol, bisabolol, cineol, hinokitiol, sodium lauroyl sarcosinate, l-menthol, and the like.
- CPC cetylpyridinium chloride
- IPMP 3-methyl- 4-isopropylmethylphenol
- IPMP 3-methyl- 4-isopropylmethylphenol
- these antibacterial agents may be used singly or in combination of two or more.
- the concentration of these antibacterial ingredients is appropriately determined for each antibacterial ingredient in consideration of the purpose of use and antibacterial activity. , preferably in the range of 0.0001 to 0.01% by mass.
- an acidic antibacterial agent is used, it is used in the range of 0.01 to 0.5% by mass.
- the range is preferably 0.1 to 5.0% by mass, more preferably 1.0 to 4.0% by mass.
- composition for oral care of the present embodiment contains these antibacterial agents in predetermined specifications and amounts, thereby enhancing the effect of suppressing or inhibiting the binding of oral bacteria and salivary biopolymers.
- the antimicrobial agent may be included in a reduced formulation below the amounts (concentrations) described herein. In this case as well, it is possible to enhance the action of suppressing or inhibiting the binding of oral bacteria to salivary biopolymers while reducing the side effects of the antibacterial agent.
- the synergistic effect of the myrrhaceae algae extract and the antibacterial agent is not bound by any theory, but the synergistic effect of the ionic antibacterial agent is greater than that of the nonionic antibacterial agent. It is believed that the active ingredient of the present invention and the antibacterial agent form a complex in some form to further enhance the lectin activity.
- the active ingredient of the present invention is thought to inhibit the interaction between saliva-derived biopolymers, particularly sugar chains containing galactose at the end, and oral bacteria. It is also possible that the cell membrane structure changes and the binding force of lectin-like substances derived from oral bacteria on the membrane surface decreases.
- biofilms formed by microorganisms It can be used as a means to solve various problems caused by For example, in the medical field, it has been pointed out that biofilms formed on the surface of catheters cause serious infections. It is also possible to suppress biofilm formation on the medical device surface by treating the medical device with
- the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
- the unit % of numerical values indicating the addition amount of various components means % by mass (w/v %).
- Example 1 Preparation of Myrraceae Algae Extract (Mill Extract Liquid)
- Mill Extract Liquid As a raw material, alga bodies of Codium fragile were used. This raw material was purchased from a grower as fresh seaweed that was not dried. The purchased raw seaweed was dried and pulverized by a predetermined method and used as a raw material. Add 10 times the amount of Dulbecco's phosphate-buffered saline (pH 7.3, D5652, Sigma-Aldrich, Ca- and Mg-free, hereinafter referred to as "PBS") to 50 g of the raw material, and allow to stand at room temperature for 30 minutes. and mill extract was prepared.
- PBS Dulbecco's phosphate-buffered saline
- the extract was centrifuged at 37000 ⁇ g for 15 minutes and the supernatant was collected.
- the protein concentration of the extract was measured using a BCA protein assay kit (Thermo Fisher Scientific Co.).
- a 2-fold dilution series of the extract was prepared with PBS, and subjected to an experiment to evaluate the effect on adhesion and growth of Streptococcus mutans.
- Example 2 Fractionation of mill extract 10 mL of the mill extract prepared in Example 1 was sequentially treated with Vivaspin 20 (manufactured by Sartorius) having molecular weight cutoffs of 50 k, 30 k, and 5 k, respectively. Four fractions of ⁇ 30,000, ⁇ 30,000 and ⁇ 50,000, and ⁇ 50,000 were obtained. The protein concentration of these four fractions was measured using a BCA protein assay kit (Thermo Fisher Scientific Co., Ltd.), diluted with PBS to a predetermined concentration, and subjected to the following bacterial adsorption test. rice field.
- Vivaspin 20 manufactured by Sartorius
- Example 1 The protein concentration of the mill extract prepared in Example 1 was 765 ⁇ g/mL. This was diluted with PBS to a concentration of 1% and used in the following tests. Each antimicrobial agent used in this study was prepared at twice the test concentration because it was mixed 1:1 with mill extract, its predetermined molecular weight fraction, or PBS.
- the CPC solution was prepared by dissolving 0.2 g of CPC in 10 mL of ethanol solution to prepare a storage solution (2% CPC). This was diluted 20-fold with purified water to prepare a 0.1% CPC (5% ethanol) solution. This was further diluted with a 5% ethanol solution to prepare 0.05% CPC (5% ethanol) and 0.02% CPC (5% ethanol), respectively.
- the benzalkonium chloride solution was prepared by dissolving 0.2 g of benzalkonium chloride in 10 mL of ethanol solution to prepare a storage solution (2% benzalkonium chloride). This was diluted 5-fold with ethanol to prepare an ethanol solution of 0.4% benzalkonium chloride solution. This was further diluted 20-fold with purified water to prepare 0.02% benzalkonium chloride (5% ethanol). This was further diluted 2-fold with a 5% ethanol solution to give a 0.01% benzalkonium chloride (5% ethanol) solution, and further diluted 2-fold with 5% ethanol to give a 0.005% benzalkonium chloride (5% ethanol) solution. ) becomes a solution.
- chlorhexidine solution a 20% aqueous solution was used as the stock solution, diluted 20-fold with ethanol and purified water to obtain a 0.1% chlorhexidine (5% ethanol) solution. Further dilute this 5-fold with a 5% ethanol solution to obtain a 0.02% chlorhexidine (5% ethanol) solution, which is further diluted 10-fold with 5% ethanol to prepare a 0.002% chlorhexidine (5% ethanol) solution. did.
- IPMP solution was prepared by dissolving 0.4 g of IPMP in 10 mL of ethanol solution to prepare a storage solution (4% IPMP). This was diluted 20-fold with ethanol and purified water to obtain a 0.2% IPMP (20% ethanol) solution. This was further diluted twice with 20% ethanol to prepare a 0.1% IPMP (20% ethanol) solution, and further diluted with 20% ethanol to prepare a 0.04% IPMP (20% ethanol) solution.
- Saliva was collected 2 hours or more after brushing teeth. Stimulated saliva secreted by chewing Parafilm was collected and centrifuged at 4° C. and 2000 ⁇ g for 30 minutes. The supernatant was suction-filtered through a cellulose mixed ester (0.1 ⁇ m, 90 mm) membrane filter, and the saliva was diluted to an appropriate concentration using PBS.
- the bacterial solution was discarded from each well of this plate, washed twice with 300 ⁇ L of PBS, and fixed with 100 ⁇ L of 0.25% glutaraldehyde solution at room temperature for 30 minutes. Thereafter, the liquid was discarded, 100 ⁇ L of 0.1% crystal violet solution was added to each well, and the plate was allowed to stand at room temperature for 30 minutes.
- the staining solution was aspirated and discarded with a pipette, and the plate was thoroughly washed with purified water and dried in a constant temperature bath at 37°C. 100 ⁇ L of 30% acetic acid solution was added to each well, and the dye was eluted using a plate shaker. To quantify the number of cells, the dye concentration in the 30% acetic acid solution in each well was measured at an absorption wavelength of 570 nm using a plate reader.
- FIG. 1 is a graph showing the inhibitory effect of mill extract (ML), cetylpyridinium chloride (CPC) and a mixture thereof (CPC+ML) on adhesion of Streptococcus mutans to saliva-coated substrates.
- the adhesion rate in the graph is shown as an average value of five repeated measurements under the same conditions. The smaller the adhesion rate, the more suppressed the adhesion of Streptococcus mutans.
- Cont. Groups are shown for samples containing PBS only.
- the BSA group on the horizontal axis is a group to which 100 ⁇ g/mL bovine serum albumin (BSA) was added as a positive control.
- BSA bovine serum albumin
- FIG. 1 Cont.
- Table 1 shows the numerical values (adhesion rate) of each group shown in FIG.
- FIG. 2 shows similar test results when using benzalkonium chloride instead of CPC as the antibacterial component.
- Cont The relative value of each sample when the group is set to 100 is shown.
- Table 2 shows the numerical values (adhesion rate) of each group shown in FIG.
- FIG. 3 shows similar test results when using chlorhexidine instead of CPC or benzalkonium chloride as the antibacterial component.
- Cont The relative value of each sample when the group is set to 100 is shown.
- Table 3 shows the numerical values (adhesion rate) of each group shown in FIG.
- FIG. 4 shows similar test results when IPMP was used instead of each of the above antibacterial agents.
- Cont. The relative value of each sample when the group is set to 100 is shown.
- Table 4 shows the numerical values (adhesion rate) of each group shown in FIG.
- FIG. 5 shows four fractions of the mill extract (unfractionated extract) of Example 1 and the mill extract subjected to molecular weight fractionation in Example 2 (molecular weight less than 5000, 5000 or more and less than 30000, 30000 or more 50000 or less and 50000 or more), the results of a bacterial adsorption test performed under the same conditions as above using samples with a protein concentration of 10 ⁇ g/mL are shown.
- ** indicates data showing a significant difference (p ⁇ 0.01) from the control by Student's T-test.
- Table 5 shows the numerical values (adhesion rate) of each group shown in FIG.
- a group of mill extracts (no fractionation) of Example 1 As shown in FIG. 5 and Table 5, a group of mill extracts (no fractionation) of Example 1, a group of mill extract fractions with a molecular weight of 50000 or more (50 k or more), and a mill extract with a molecular weight of 5000 or more and less than 30000 It was confirmed that the adherence rate of fungi decreased in the liquid fraction group. Therefore, in the experiment according to FIG. 5 and Table 5, the three groups of mill extract fractions (molecular weight less than 5000, 5000 or more and less than 30000, and 30000 or more and less than 50000) for which a decrease in the adhesion rate was not confirmed, the protein concentration was raised for further analysis.
- a bacteria adsorption test was performed using a higher concentration sample (diluted from a protein concentration of 50 ⁇ g/mL in a 2-fold dilution series) to confirm concentration dependence.
- the results of this test are shown in FIG. 6 and Table 6.
- Table 6 shows the numerical values (adhesion rate) of each group shown in FIG.
- Test Example 2 Bacteria adsorption test Furthermore, using the mill extract of Example 1 and a commercially available mouthwash, a bacteria adsorption test was performed in the same manner as in Test Example 1 above, and the mill extract and the mouthwash were tested. We confirmed the effect of the combined use of The mill extract from Example 1 was added to a final concentration of 1.0%. In Test Example 2, gum dental rinse (regular type, Sunstar) was used as a commercially available mouthwash. Ingredients contained in the mouthwash are described below.
- Solvent Concentrated glycerin, ethanol / Flavor: Fragrance (herb mint type), saccharin Na / Solubilizer: POE hydrogenated castor oil / Medicinal ingredients: Cetylpyridinium chloride (bactericide CPC), glycyrrhizic acid 2K (anti-inflammatory agent GK2) , benzalkonium chloride (bactericide BKC) / pH adjuster: sodium citrate, anhydrous citric acid / cleaning aid: coconut oil fatty acid acyl arginine ethyl DL-PCA salt
- Example 1 10 mL of the mill extract prepared in Example 1 above was prepared to prepare the following three samples.
- ⁇ Myrraceae algae extract containing proteins with molecular weights of 5000 or more and less than 30000 extracts containing no proteins with molecular weights other than 5000 or more and less than 30000, hereinafter referred to as "5000 or more and less than 30000 ML”
- ⁇ Myrraceae algae extract containing proteins with a molecular weight of 30,000 or more and less than 50,000 extracts containing no proteins with a molecular weight other than 30,000 or more and less than 50,000, hereinafter referred to as "30,000 or more and less than 50,000 ML”
- ⁇ Myrraceae algae extract containing protein with a molecular weight of 50,000 or more extract containing no protein with a molecular weight other than 50,000 or more, hereinafter referred to as "50,000 or more ML”
- Example 1 10 mL of the mill extract prepared in Example 1 was sequentially treated with Vivaspin 20 (manufactured by Sartorius) having a molecular weight cutoff of 50 k, 30 k, and 5 k, respectively, to obtain 5000 or more and less than 30,000 ML, 30,000 or more and less than 50,000 ML, 50,000 or more ML, Three fractions were obtained.
- Vivaspin 20 manufactured by Sartorius
- a given CPC solution was prepared as follows. First, 0.2 g of CPC was dissolved in 10 mL of ethanol solution to prepare a stock solution (2% CPC). This stock solution was diluted 20-fold with purified water to prepare a 0.1% CPC (5% ethanol) solution. This was further diluted with a 5% ethanol solution to prepare 0.05% CPC (5% ethanol), 0.025% CPC (5% ethanol), and 0.0125% CPC (5% ethanol), respectively.
- Saliva (approximately 2 mL) was collected from a healthy human in his thirties (1 male) by a predetermined method. The collected saliva was centrifuged (2000 ⁇ g, 10 minutes, 25° C. (room temperature)). After the centrifugation, the supernatant was collected. The supernatant was added to 30 mL of Todd Hewitt Broth (Becton, Dickinson and Company, 249240) and incubated at 37° C. for 16 hours. The turbidity (OD660 nm) of the culture solution after this cultivation was measured, and this culture solution was diluted with PBS so that the turbidity was 0.125. The diluted solution (oral bacterial culture solution) was used for the test.
- Halitosis is defined as "the offensive odor of gases exhaled through the mouth or nose that exceeds socially acceptable limits". Most of the bad breath (80% or more) is considered to be derived from gas in the oral cavity, and the main causative substance is hydrogen sulfide (H 2 S), which is a volatile sulfur compound (VSC). It is considered to be methyl mercaptan (CH 3 SH) and dimethyl sulfide [(CH 3 ) 2 S] (Ministry of Health, Labor and Welfare e-Healthnet, Causes and actual conditions of bad breath, URL: https://www.e-healthnet. mhlw.go.jp/information/teeth/h-07-001.html). Therefore, in this Test Example 3, by measuring the VSC concentration, the effect of suppressing halitosis by a predetermined mill extract or the like was confirmed.
- Test 3-1 After preparing samples for each group as shown in Table 9, the groups of Test 3-1, Test 3-2, and Test 3-3 were each left at 25°C (room temperature) for 10 minutes.
- VSC concentration contained in each group was measured three times with a halimator (RH17K, Taiyo), and the average value was calculated. An average value of the obtained results (numerical values) was calculated. Table 10 shows the calculated results.
- Test 3-1 group In the calculation results, the relative value compared to the 3-1 control group is shown, and "*" is Student's T test compared to the 3-1 control group "p ⁇ 0.05" indicates ⁇ Test 3-2 group: In the calculation results, the relative value compared to the 3-2 control group is shown, and "**" is Student's T test compared to the 3-2 control group "p ⁇ 0.05 ” is shown.
- Test 3-3 group In the calculation results, the relative value compared to the 3-3 control group is shown, and "***" indicates "p ⁇ 0. 05”.
- ⁇ Test method> First, the following reagents are listed. - Apatite particles: Bio RAD CHT Ceramic Hydroxyapatite Type I (80 ⁇ m), Cat. #158-8000, Lot. M401076 ⁇ Coffee: commercially available canned coffee, craft boss black (Suntory Foods Co., Ltd.) ⁇ Measuring instrument for color difference measurement: CR-400, Konica Minolta, color difference meter ⁇ Saliva added in the following test process (solution of saliva 1): Prepared as follows. The saliva of a healthy adult human male (30s) was used. Two hours or more after brushing the teeth, saliva was collected with paraffin gum stimulation.
- the collected saliva was centrifuged (4° C., 2000 g, 30 min) to collect the supernatant.
- the supernatant was diluted with PBS to prepare a diluted solution.
- the diluted solution was filtered through a cellulose mixed ester (0.1 ⁇ m, 90 mm) membrane filter.
- the diluted solution after the filtration was used as saliva to be added in the following test steps.
- the collected saliva was centrifuged (2000 ⁇ g, 10 minutes, 25° C. (room temperature)). After the centrifugation, the supernatant was collected.
- apatite particles 100 mg were weighed into a 1.5 mL tube. 1 mL of PBS was added to the tube containing the particles and stirred at 25° C. with a vortex mixer. After the stirring, the tube was spun down and the supernatant was discarded. After discarding, 1 mL of saliva was added to the tube and stirred at 25° C. with a vortex mixer. After the stirring, the mixture was allowed to stand at 37°C for 1 hour. After standing and spinning down, the supernatant was discarded from the tube. The particles in the tubes were rinsed twice (vortex, spin down, discard supernatant) by adding 1 mL of PBS to each tube.
- the particles in the tubes were rinsed twice by adding 1 mL of PBS to each tube (rinsing in the process of vortexing, spinning down, and discarding the supernatant).
- the particles were transferred from the tube to a Petri dish for each group. After transferring to the petri dish, the particles were dried at 50° C. for 2 hours. After drying, each group was subjected to color difference measurement using the measuring instrument. The background color during color measurement was white, and the particles were placed on a standard white board for measurement. The colorimetric value obtained by measuring the color of the particles before adding the coffee was used as the reference value.
- the L * a * b * color system (CIE1976 L * a * b * uniform color space) was used for color specification.
- the L * value represents the brightness, and ranges from 0 to 100, and the larger the value, the brighter the image.
- Color is represented by a * b * , and when both a * b * are 0, the color is achromatic.
- the more positive a * the more reddish, the more negative a*, the more greenish, the more positive b * , the more yellowish, and the more negative b*, the more bluish.
- the value of ⁇ E* (Delta E Star), which is used to express the difference between colors, is obtained by calculating how far the straight line distance between two colors is in this color space. .
- Table 12 lists the mean values calculated from the values measured three times in each group. "*" in Table 12 indicates “p ⁇ 0.01" compared to group 4-3 by Student's T-test. In the "oral bacterial culture”, group 4-2 (group to which mill extract or the like was added) showed better results (especially L * value (brightness) results) than group 4-3. rice field.
- Toothpaste containing the mill extract prepared in Example 1 of Formulation Examples 1 to 3 listed in Table 13 below was prepared.
- Comparative Example 1 a toothpaste not containing the mill extract shown in Table 13 below was prepared. Toothbrushing was performed using the toothpastes of Formulation Examples 1 to 3 and Comparative Example 1 shown in Table 13 to confirm the effect.
- a mouthwash containing the mill extract prepared in Example 1 of Formulation Examples 4 to 6 listed in Table 14 below was prepared.
- Comparative Example 2 a mouthwash not containing the mill extract shown in Table 14 below was prepared. Mouthwashes were performed using the mouthrinses of Formulation Examples 4 to 6 and Comparative Examples shown in Table 14 to confirm the effect.
- composition of the present invention may be used as oral care cosmetics, quasi-drugs, and the like.
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Abstract
Description
[1]ミル科藻類抽出物を有効成分として含有する口腔ケア用組成物。ミル科藻類抽出物に含まれる分子量5000以上のタンパク質画分を有効成分として含有する口腔ケア用組成物。このタンパク質画分は、分子量が5000以上で50000未満であることが好ましく、当該分子量が5000以上で30000未満であることがさらに好ましい。あるいは、分子量が50000以上の高分子画分に存在するタンパク質であってもよい。
[2]さらに抗菌成分を含む[1]に記載の口腔ケア用組成物。
[3]抗菌成分が、塩化セチルピリジニウム(CPC)、クロルヘキシジン、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化デカリウム、グルコン酸クロルヘキシジン、プロタミン、ドデシルジアミノエチルグリシン、トリクロサン、3-メチル-4-イソプロピルメチルフェノール(IPMP)、チモール、カルバクロール、ファルネソール、ビサボロール、シネオール、ヒノキチオール、ラウロイルサルコシンナトリウム、l-メントールからなる群から選ばれる1種又は2種以上である、[1]又は[2]に記載の口腔ケア用組成物。
[4]有効成分が、ミル科藻類抽出物換算で組成物の全量に対して0.001~5質量%含有される[1]から[3]のいずれかに記載の口腔ケア用組成物。
[5]抗菌成分が、組成物の全量に対して0.0001~1質量%含有される[2]から[4]のいずれかに記載の口腔ケア用組成物。
本明細書において、「口腔ケア用組成物」は、例えば以下である。
・通常の使用方法において、特定の治療剤の全身投与を目的として意図的に飲み込むのではなく、むしろ、口腔内活動の目的で実質的にすべての歯面及び/又は口腔組織に接触するのに十分な時間、口腔内に保持される製品(口腔ケア用製品)。
・当該製品に含有される素材。当該素材に、ミル科藻類抽出物が含有される。
本発明の一実施形態で用いられるミル科藻類抽出物(以下、「本実施形態の抽出物」と称する。)は、緑藻綱(Chlorophyceae)、ミル目(Codiales、最近の分類ではハネモ目(Bryopsidalesとされる場合がある。)のミル科(Codiaceae)に属する藻類から抽出されたものである。この藻類は、ミル(Codium fragile)、イセモミル(Codium tomentosum)、タマミル(Codium minus)、コブシミル(Codium spongiosum)、クロミル(Codium subtubulosum)、モツレミル(Codium intricatum)、ハイミル(Codium adhaerens)、ナンバンハイミル(Codium arabicum)、ネザシミル(Codium coactum)、ヒゲミル(Codium barbatum)、サキブトミル(Codium contractum)、ヒラミル(Codium latum)及びナガミル(Codium cylindricum)を含むが、これらに限られない、ミル属(Codium)の生物種に属する場合がある。
続いて、上記本実施形態の抽出物をそのままで、あるいは精製若しくは濃縮することにより、口腔ケア用組成物としての有効成分を得ることができる。好ましい実施形態において、この有効成分は、分子量5000以上のタンパク質画分中に存在する。より好ましくは分子量5000以上50000未満の画分、さらに好ましくは分子量5000以上30000未満の画分、である。
いかなる理論にも拘束されないが、本発明の有効成分は、唾液の生体高分子に含まれる多糖類によって形成される膜の表面に存在するGalNAcに結合し、これに対する口腔細菌の付着を阻害すると考えられる。
本実施形態の口腔ケア用組成物は所定量の抗菌成分を含むことが好ましい。抗菌成分は、抗菌作用のある成分である。抗菌作用は、例えば、滅菌作用、殺菌作用、消毒作用、静菌作用、制菌作用、除菌作用、防腐作用、防菌作用、防カビ作用である。抗菌剤は、抗菌成分が含有される剤である。抗菌剤としては、例えば、殺菌剤、抗菌剤、防カビ剤、抗カビ剤、防腐剤、消臭剤、殺虫剤が挙げられ、中でも、殺菌剤、抗菌剤、防カビ剤、抗カビ剤等の微生物制御剤や消臭剤を好適に用いることができる。本実施形態の口腔ケア用組成物に含有される抗菌成分としては、上記の作用を有する公知の化合物を適宜選択して使用すればよい。
原料として、ミル(Codium fragile)の藻体を用いた。この原料は、乾燥されない生の海藻を栽培業者から購入した。所定の方法で、当該購入した生の海藻を乾燥及び粉砕して、原料として用いた。原料50gに10倍量のDulbeccoリン酸緩衝生理食塩水(pH7.3、D5652、シグマアルドリッチ、Ca及びMgを含まないもの、以下、「PBS」という。)を添加し、室温で30分間静置し、ミル抽出液を調製した。抽出液は、37000×gで15分間遠心分離し、上清を採取した。抽出液のタンパク質濃度は、BCAプロテインアッセイキット(サーモフィッシャーサイエンティフィック株式会社)を用いて測定した。抽出液のPBSによる2倍希釈系列を調製し、ミュータンス菌の付着及び増殖に対する効果を評価する実験などに供した。
実施例1で調製したミル抽出液10mLを、それぞれ分画分子量50k、30k、及び5kのビバスピン20(ザルトリウス製)で順に処理し、分子量5000未満、5000以上30000未満、30000以上50000未満、及び50000以上の4つの画分を得た。この4つの画分のタンパク質濃度をBCAプロテインアッセイキット(サーモフィッシャーサイエンティフィック株式会社)を用いて測定し、所定の濃度となるようにPBSを用いて希釈し、以下の菌吸着試験などを行った。
<菌液の調製>
ミュータンス菌(Streptococcus mutans(NBRC13955))は、独立行政法人製品評価技術基盤機構(NITE)から購入した。Todd-Hewitt Brothで37℃、一晩(約16時間)培養後、660nmで測定した吸光度OD660が0.8~1.4になるまで増殖したものを用いた。測定された吸光度を基に、PBSでOD660が0.125になるように希釈して以下の試験に用いる菌液を調製した。
実施例1で調製したミル抽出液のタンパク質濃度は、765μg/mLであった。これを1%の濃度となるようにPBSで希釈し、以下の試験に用いた。
本試験に用いた各抗菌剤は、ミル抽出液、その所定の分子量画分又はPBSと1:1で混合されるため試験濃度の2倍の濃度で調製した。
歯磨き後2時間以上経過後の唾液を採取した。パラフィルムを咀嚼することによって分泌される刺激唾液を採取し、4℃、2000×gで30分間遠心分離した。セルロース混合エステル(0.1μm、90mm)のメンブレンフィルターにて上清を吸引ろ過し、PBSを用いて適切な濃度に唾液を希釈した。
更に、実施例1のミル抽出液及び市販の洗口液を用いて、上述の試験例1と同じように菌吸着試験により、ミル抽出液と当該洗口液との併用した場合の効果などを確認した。実施例1のミル抽出液を最終濃度1.0%となるように添加した。この試験例2では、市販の洗口液として、ガム・デンタルリンス(レギュラータイプ、サンスター)を用いた。当該洗口液の含有成分を以下に記載する。
溶剤:濃グリセリン、エタノール/香味剤:香料(ハーブミントタイプ)、サッカリンNa/可溶化剤:POE硬化ヒマシ油/薬用成分:塩化セチルピリジニウム(殺菌剤CPC)、グリチルリチン酸2K(抗炎症剤GK2)、塩化ベンザルコニウム(殺菌剤BKC)/pH調整剤:クエン酸Na、無水クエン酸/清掃助剤:ヤシ油脂肪酸アシルアルギニンエチル・DL-PCA塩
所定のミル抽出液などによる当該効果の有無の確認を行った。以下試験方法などを記載する。
(所定のミル抽出液の準備)
分子量5000以上のタンパク質を含有するミル科藻類抽出物(分子量5000未満のタンパク質は含有しない抽出物、以下「5000以上ML」と記載)を作製するために、上述の実施例1で調製したミル抽出液10mLを準備した。分画分子量5kのビバスピン20(ザルトリウス製)を用いて、5000以上MLを作製した。
・分子量5000以上30000未満のタンパク質を含有するミル科藻類抽出物(分子量5000以上30000未満以外の分子量のタンパク質は含有しない抽出物、以下「5000以上30000未満ML」と記載)
・分子量30000以上50000未満のタンパク質を含有するミル科藻類抽出物(分子量30000以上50000未満以外の分子量のタンパク質は含有しない抽出物、以下「30000以上50000未満ML」と記載)
・分子量50000以上のタンパク質を含有するミル科藻類抽出物(分子量50000以上以外の分子量のタンパク質は含有しない抽出物、以下「50000以上ML」と記載)
所定のCPC溶液を、次のように作製した。まず、10mLのエタノール溶液に0.2gのCPCを溶解して保存液(2%CPC)を作製した。この保存液を精製水で20倍希釈して0.1%CPC(5%エタノール)溶液を調製した。これをさらに5%エタノール溶液で希釈して、それぞれ、0.05%CPC(5%エタノール)、0.025%CPC(5%エタノール)、0.0125%CPC(5%エタノール)を調製した。
所定の方法で30代の健常なヒト(男性1名)の唾液(約2mL)を採取した。採取した唾液を遠心分離(2000×g、10分間、25℃(室温))した。当該遠心分離後、上清を回収した。当該上清を、Todd Hewitt Broth (Becton, Dickinson and Company、249240)を30mLに加え、37℃で16時間培養した。この培養後の培養液の濁度(OD660nm)を測定し、当該濁度が0.125となるように、この培養液を、PBSを用いて希釈した。当該希釈した液(口腔細菌培養液)を試験に用いた。
口臭は「口あるいは鼻を通して出てくる気体のうち、社会的容認限度を超える悪臭」と定義されている。当該口臭の大部分(8割以上)は口腔内の気体由来であると考えられており、その主要原因物質は揮発性硫黄化合物(VSC:Volatile Sulfur Compounds)である硫化水素(H2S)、メチルメルカプタン(CH3SH)、ジメチルサルファイド[(CH3)2S]であるとされている(厚生労働省e-ヘルスネット、口臭の原因・実態、URL:https://www.e-healthnet.mhlw.go.jp/information/teeth/h-07-001.html)。よって、この試験例3では、VSC濃度を測定することにより、所定のミル抽出液などによる口臭抑制効果の確認を行った。
96ウェルのマルチプレート(ポリスチレン製、サーモフィッシャーサイエンティフィック製、マルチソープ)に、試験例1に記載のように、調製したヒト唾液を100μL添加し、プレートをシールして、37℃で1時間インキュベートした。その後、各ウェルを300μLのPBSで2回洗浄した。なお、以下表9に記載の各群にて、各5ウェル使用するように、以下も含め準備した。
・試験3-1の群:算出結果において、3-1コントロール群と比べての相対値を示し、「*」はStudentのT検定で3-1コントロール群と比べて「p<0.05」を示す。
・試験3-2の群:算出結果において、3-2コントロール群と比べての相対値を示し、「**」はStudentのT検定で3-2コントロール群と比べて「p<0.05」を示す。
・試験3-3の群:算出結果において、3-3コントロール群と比べての相対値を示し、「***」はStudentのT検定で3-3コントロール群と比べて「p<0.05」を示す。
例えば、前歯部に用いられる歯冠補綴物において、審美性が要求される(非特許文献1、非特許文献2)。そこで、実施例1で調製したミル抽出液及びCPCを含む組成物(溶液)により、アパタイト粒子を用いて色素沈着を抑制できるかを試験した。当該試験は、非特許文献1及び非特許文献2の記載に基づき以下記載のように行った。
先ず、以下の試薬などを列記する。
・アパタイト粒子:Bio RAD CHT Ceramic Hydroxyapatite Type I(80μm)、Cat.#158-8000、Lot.M401076
・コーヒー:市販の缶コーヒー、クラフトボスブラック(サントリーフーズ株式会社)
・色差測定のための測定機器:CR-400、コニカミノルタ、色彩色差計
・以下試験工程で添加する唾液(唾液の溶解液その1):以下のように作製した。
健常なヒト成人男性(30歳代)の唾液を用いた。歯磨きしてから2時間以上経過後の唾液をパラフィンガム刺激で回収した。当該回収した唾液を、遠心分離(4℃、2000g、30min)を行い、上清を回収した。当該上清をPBSにより希釈して希釈液を作製した。当該希釈液をセルロース混合エステル(0.1μm、90mm)のメンブレンフィルターにより濾過した。当該濾過後の希釈液を以下試験工程で添加する唾液とした。
・以下試験工程で添加する口腔細菌培養液:所定の方法で30代の健常なヒト(男性1名)の唾液(約2mL)を採取した。採取した唾液を遠心分離(2000×g、10分間、25℃(室温))した。当該遠心分離後、上清を回収した。当該上清を、Todd Hewitt Broth(Becton,Dickinson and Company、249240)を30mLに加え、37℃で16時間培養した。この培養後の培養液の濁度(OD660nm)を測定し、当該濁度が0.125となるように、この培養液を、PBSを用いて希釈した。当該希釈した液を以下試験工程で添加する口腔細菌培養液とした。
・CPC:試験例1で用いたCPC
当該廃棄後、チューブに唾液1mL添加して、ボルテックスミキサーにより25℃で攪拌した。当該攪拌後、37℃で1時間静置した。当該静置してスピンダウン後に、チューブから上清を廃棄した。
当該チューブに入っている当該粒子に対して、各チューブにPBS1mLを添加することにより2回リンス(ボルテックス、スピンダウン、上清廃棄という過程のリンス)を行った。
当該チューブに入っている当該粒子に対して、各チューブにPBS1mLを添加することにより2回リンス(ボルテックス、スピンダウン、上清廃棄という過程のリンス)を行った。
当該チューブに入っている当該粒子に対して、各チューブに精製水1mLを添加することにより3回リンス(ボルテックス、スピンダウン、上清廃棄という過程のリンス)を行った。
色差測定の結果を以下表12に示す。表12では、各群において3回測定した値から算出された平均値を記載する。表12に記載の「*」は、StudentのT検定で、群4-3と比べて「p<0.01」を示す。当該「口腔細菌培養液」において、群4-3に比べ、群4-2(ミル抽出液などを添加した群)では、良好な結果(特にL*値(明るさ)の結果)が得られた。
実施例1で調製したミル抽出液を含有する練り歯磨きをヒト口腔内で用いた際の効果を確認した。健常なヒト成人男性(30歳代)の3名での試験にて効果を確認した。
実施例1で調製したミル抽出液を含有する洗口液をヒト口腔内で用いた際の効果を確認した。健常なヒト成人男性(30歳代)の3名での試験にて効果を確認した。
Claims (5)
- ミル科藻類抽出物を含有し、当該ミル科藻類抽出物に含まれる分子量5000以上のタンパク質を有効成分として含有する、口腔ケア用組成物。
- さらに抗菌成分を含む請求項1に記載の口腔ケア用組成物。
- 前記抗菌成分が、塩化セチルピリジニウム(CPC)、クロルヘキシジン、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化デカリウム、グルコン酸クロルヘキシジン、プロタミン、ドデシルジアミノエチルグリシン、トリクロサン、3-メチル-4-イソプロピルメチルフェノール(IPMP)、チモール、カルバクロール、ファルネソール、ビサボロール、シネオール、ヒノキチオール、ラウロイルサルコシンナトリウム、l-メントールからなる群から選ばれる1種又は2種以上である、請求項1又は2に記載の口腔ケア用組成物。
- 前記有効成分が、前記ミル科藻類抽出物換算で前記組成物の全量に対して0.001~5質量%含有される請求項1~3のいずれか一項に記載の口腔ケア用組成物。
- 前記抗菌成分が、前記組成物の全量に対して0.0001~1質量%含有される、請求項2~4のいずれか一項に記載の口腔ケア用組成物。
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