JP5004505B2 - Oral composition - Google Patents

Description

  The present invention relates to an oral composition for preventing dental caries by promoting remineralization of tooth enamel.

For dental caries, Streptococcus mutans, Streptococcus sobrinaus, and other oral streptococci (carious fungi) adhere to the tooth surface, and these bacteria produce insoluble glucan and form plaques. Begins. In the plaque, the acid produced by the bacteria metabolizing food demineralizes the tooth enamel and enters an initial caries state.
The enamel on the tooth surface is composed of hydroxyapatite crystals, and this hydroxyapatite is composed of calcium phosphate and is considered to be effective as a source of calcium and phosphate. So far, in order to remineralize the demineralized portion, a dentifrice containing a fine particle of hydroxyapatite having a crystal structure similar to that of fluoride or an inorganic component of a tooth has been developed.
However, remineralization was not sufficient only by the use of fluoride or hydroxyapatite.

  Thus, hydroxyapatite has been improved by blending other components. For example, water-soluble cellulose (patent document 1), temperature-sensitive polymer compound (patent document 2), xylitol (patent document 3), isoflavone (patent document 4), trehalose (patent document 5). Plant extract protein (Patent Document 6), royal jelly (Patent Document 7), and the like.

  On the other hand, hyaluronic acid is a kind of glycosaminoglycan and is known as a biological component contained in vitreous, joint fluid and the like. This hyaluronic acid is used not only for pharmaceuticals, cosmetics and foods but also for oral use. For oral use, for example, it is used in combination with an antioxidant for prevention of periodontal disease (Patent Document 8), and is added to a drug, soft anhydrous silicic acid, a hydrophobic soft base for improving adhesion to the oral mucosa. (Patent Document 9), and a composition for oral cavity containing a zinc compound for preventing tartar, anti-caries, and the like (Patent Document 10) containing hyaluronic acid as an astringency improving agent.

  Until now, as compositions used in the oral cavity in which hydroxyapatite and hyaluronic acid are blended, there are those described as applications for tooth substitutes or bone repair materials (Patent Documents 11 and 12). Is a composition that uses hydroxyapatite with a large particle size and contains a large amount of hyaluronic acid, and is intended to correct or replace missing teeth. It is used to prevent caries such as toothpaste and mouthwash. It was different. In addition, these documents did not describe that hyaluronic acid was used in combination with hydroxyapatite and was effective in promoting remineralization of enamel.

JP 10-59814 A JP-A-10-109915 JP-A-9-175963 JP 2005-68093 A JP 2001-213746 A JP 2004-18396 A JP 2005-314266 A Japanese Patent Laid-Open No. 10-182390 Japanese Patent Laid-Open No. 10-245329 JP 2002-29950 A JP 2005-530525 A JP 2005-538757 A

  The object of the present invention is to provide an oral composition excellent in preventing dental caries by promoting remineralization of decalcified enamel.

  The present inventors have found that remineralization of tooth enamel is promoted by using hyaluronic acid or sodium hyaluronate in combination with hydroxyapatite, and have completed the present invention.

That is, the present invention comprises (1) a composition for oral cavity for preventing caries containing hyaluronic acid or a salt thereof and hydroxyapatite, and (2) 0.001 to 5% by weight of hyaluronic acid or a salt thereof, hydroxyapatite. Is a composition for oral cavity for preventing dental caries according to (1) above.
Furthermore, the present invention is (3) a dentifrice or mouthwash containing the composition for oral cavity prevention for caries as described in (1) or (2) above.

  As is apparent from the results of the remineralization acceleration test, the oral composition of the present invention is a comparative example of sodium hyaluronate alone, hydroxyapatite alone or sodium hyaluronate and other calcium phosphates in combination. It was found that the remineralization rate of tooth enamel was significantly different. From this fact, the present invention using hyaluronic acid or a salt thereof and hydroxyapatite in combination can remarkably promote the remineralization of the demineralized tooth enamel, and thus actively suppresses caries. It has become possible to provide an oral composition having a very excellent effect.

  The composition for oral cavity prevention of caries of the present invention contains hyaluronic acid or a salt thereof and hydroxyapatite, and is used as a toothpaste such as toothpaste, toothpaste, liquid toothpaste, mouthwash, and the like.

(Hydroxyapatite)
Hydroxyapatite used in the present invention is a kind of calcium phosphate, and is obtained from fish bones, pork bones, cow bones, etc. of edible fish such as salmon as natural hard tissues, in addition to those synthesized by ordinary methods.
Usually, hydroxyapatite is stoichiometrically represented by a composition composed of Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , but is non-stoichiometric with a Ca / P molar ratio of not 1.67. Even if it has the properties of hydroxyapatite, it can take an apatite structure, and such hydroxyapatite having a Ca / P molar ratio of about 1.4 to 1.8 is also included in the hydroxyapatite in the present invention. It is.

  The hydroxyapatite of the present invention may be crystalline, low crystalline or amorphous, but is preferably low crystalline or amorphous hydroxyapatite from the viewpoint of caries prevention effect (hereinafter referred to as “low hydroxyapatite”). Crystalline hydroxyapatite and amorphous hydroxyapatite are referred to as “amorphous hydroxyapatite”). “Low crystallinity” means that the X-ray diffraction peak is broader than that of highly crystalline powder, and “amorphous” means that the X-ray diffraction pattern has a wide halo. The diffraction pattern showing the characteristics of the crystal cannot be obtained. Such amorphous hydroxyapatite can be obtained, for example, by freeze-drying apatite synthesized by a wet synthesis method, drying at a temperature of 100 ° C. or lower, or baking at about 300 ° C. or lower.

The hydroxyapatite of the present invention is usually in powder form or suspended in water, and has a maximum particle size measured with a laser diffraction / scattering particle size distribution analyzer (LS 130) (manufactured by Beckman Coulter, Inc.). , Preferably 40 μm or less, particularly preferably 1 μm or less. The lower limit of the maximum particle size is 0.08 μm in production. The average particle size measured with a Microtrac 7340UPA particle size distribution meter (manufactured by Nikkiso Co., Ltd.) is preferably 0.01 to 10 μm, particularly preferably 0.02 to 5 μm.
In addition, the specific surface area by the BET method of the hydroxyapatite used normally is about 100 m < ² > / g or less. Moreover, you may give a drying process, a porous process, an electrostatic process, etc. after powdering as needed.
The compounding amount of hydroxyapatite in the present invention is preferably 0.001 to 50% by weight, particularly preferably 0.01 to 30% by weight, based on the caries prevention effect, production cost, and usability. %.

(hyaluronic acid)
Hyaluronic acid or a salt thereof used in the present invention is a mucopolysaccharide having a disaccharide in which glucuronic acid and N-acetylglucosamine are bound as a repeating unit. As used herein, hyaluronic acid includes free hyaluronic acid and its derivatives.
Although there is no restriction | limiting in particular as an average molecular weight, Usually, the thing of about 10,000 to 5 million is used, and especially the thing of the range of 500,000-3,500,000 is suitable.
The origin is not particularly limited, and may be any animal-derived product, microbial-derived product (eg, Streptococcus spp.), Or synthetic product extracted from, for example, umbilical cord, animal skin, eyeglass band, chicken hen's crown, etc. . There are no particular restrictions on the extraction method and the purification treatment method in the case of natural origin.

The derivative of hyaluronic acid is not particularly limited as long as it can be used in the oral cavity. For example, sulfated hyaluronic acid (see Japanese Patent Laid-Open No. 10-195107), acetylated hyaluronic acid (Japanese Patent Laid-Open No. 8-53501), hyaluronic acid substituted with an in vivo organic acid such as lactic acid (see JP-A-6-16702), and crosslinked hyaluronic acid (see JP-A-7-97401). .
The salt of hyaluronic acid is not particularly limited as long as it can be used in the oral cavity. Metal salts such as sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt, lysine salt, arginine salt, histidine salt, etc. The basic amino acid salts, ammonium salts, triethanolamine salts, diisopropanolamine salts, and the like are suitable as hyaluronic acid salts. Particularly preferred is a sodium salt.

Commercially available products include sodium hyaluronate Q-5 (Cuppy), bio sodium hyaluronate (Shiseido Co., Ltd.), bio hyaluronic acid (Asahi Kasei Co., Ltd.), hyaluronic acid FCH (Kibun Food Chemifa Corporation) Etc., and any of them can be suitably used.
The said hyaluronic acid and / or its salt can also be used individually, and can also be used in combination of 2 or more type.
The amount of hyaluronic acid or a salt thereof is preferably 0.001 to 5% by weight, particularly preferably 0.01 to 3% by weight, based on the caries prevention effect and the feeling of use.

(Other additives)
The oral composition of the present invention comprises, in addition to the above-mentioned components, abrasives, wetting agents, foaming agents, thickeners, preservatives, fragrances, sweeteners and additives that are usually used in oral compositions. Various medicinal ingredients can be contained. Specific examples of these components are shown below.
Abrasive: calcium carbonate, calcium hydrogen phosphate, calcium pyrophosphate, silica, aluminum silicate, aluminum hydroxide, alumina, zeolite, titanium oxide, zirconium silicate and the like.
Wetting agent: glycerin, propylene glycol, polyethylene glycol, sorbitol, xylitol, etc.
Foaming agent: sodium lauryl sulfate, sodium N-lauroyl sarcosine, nonionic surfactant and the like.
Thickener: hydroxyethyl cellulose, sodium carboxymethyl cellulose, carrageenan, carboxyvinyl polymer, xanthan gum, gelatin, pullulan, sodium alginate and the like.
Preservatives: paraoxybenzoic acid ester, alkyldiaminoethylglycine hydrochloride, methylparaben, ethylparaben, sodium benzoate and the like.
Perfume: menthol, spearmint oil, lemon oil, eucalyptus oil, etc.
Sweetening agents: sodium saccharin, stevia extract, aspartame, etc.
Other medicinal ingredients: allantoin, tocopherol acetate, isopropylphenol, β-glycyrrhetinic acid, triclosan, chlorhexidine, dextranase, chlorophyll, flavonoid, tranexamic acid, hinokitiol and the like.
In addition, the compounding quantity of these arbitrary components is used suitably in the range accept | permitted pharmacologically, without preventing the effect of this invention.

(Preparation method)
In the present invention, as a method of adding hyaluronic acid or a salt thereof or hydroxyapatite to the composition, it may be added at any time during the production process of the product, and may be mixed with the remaining raw materials at any time. However, it is most preferable that hyaluronic acid or a salt thereof and hydroxyapatite are mixed in advance and then mixed with other raw materials.

EXAMPLES Examples and test examples of the present invention will be described below, but the scope of the present invention is not limited thereby. “%” Means% by weight unless otherwise specified.
(Preparation of amorphous hydroxyapatite)
A phosphate solution was dropped into the stirring calcium hydroxide solution, and the precipitated product was collected and blown and dried at 100 ° C. or lower to obtain amorphous hydroxyapatite. The obtained amorphous hydroxyapatite had a maximum particle size of about 1 μm, a minimum particle size of about 0.01 μm, and an average particle size of about 0.03 μm.
(Preparation of crystalline hydroxyapatite)
A part of the amorphous hydroxyapatite obtained above was baked in air at 800 ° C. for 2 hours to obtain crystalline hydroxyapatite.
The obtained crystalline hydroxyapatite had a maximum particle size of about 40 μm, a minimum particle size of about 0.1 μm, and an average particle size of about 3.7 μm.
(Sodium hyaluronate)
In the examples and comparative examples, sodium hyaluronate 1% aqueous solution of biohyaluronate sodium (MP-PE) manufactured by Shiseido Co., Ltd. was used.

(Preparation of oral compositions of Examples and Comparative Examples)
A toothpaste and a mouthwash having the following composition were produced according to a conventional method.
In Examples, Examples 1 to 11 are toothpastes, and Examples 12 to 16 are mouthwashes. Among these, Example 4 uses crystalline hydroxyapatite, and the other examples are examples using amorphous hydroxyapatite. In Comparative Examples, Comparative Examples 1 to 11 are toothpastes, and Comparative Examples 12 and 13 are mouthwashes. Among these, Comparative Examples 1-2 and Comparative Examples 4-5 are examples of amorphous hydroxyapatite alone, Comparative Example 3 is an example of crystalline hydroxyapatite alone, Comparative Example 6 is an example of using calcium carbonate instead of hydroxyapatite, Comparative Example 7 is an example using dicalcium phosphate instead of hydroxyapatite, Comparative Example 8 is an example using tricalcium phosphate instead of hydroxyapatite, Comparative Examples 9-11 are examples of sodium hyaluronate alone, Comparative Example 12 is an example of hydroxyapatite alone, and Comparative Example 13 is an example of sodium hyaluronate alone.

[Recalcification promotion test]
In the remineralization acceleration test, the “control surface” in the figure is a part for comparing the degree to which the “oral composition” in Examples and Comparative Examples has a remineralization effect, The state of “artificial initial caries” is maintained. It is a half of the artificial initial caries (3.5 × 3.0 mm window) region.
The “treated surface” (“test surface” in FIG. 1) in the figure is a portion where the specimens of the example and the comparative example are operated as follows.
(1) The test substance was prepared by preparing a dentifrice and mouthwash in suspension with artificial saliva.
(2) In the remineralization promotion test, the artificial initial caries test specimen was immersed in each test solution for 24 hours.

(Recalcification promotion test method)
In order to confirm the effect of promoting remineralization, an artificial initial caries test sample prepared in advance was used.
Preparation of the artificial initial caries test sample is performed by removing the dirt and deposits on the enamel surface using the crown of a human extracted tooth that has not undergone dental preservation and prosthesis treatment, and then testing the enamel surface. A 3.5 × 3.0 mm window was created with Nail Enamel (Maybelin) as a target site, and 0.1 M lactate buffer (pH 4.5, 3.0 mm CaCl ₂ , 1.8 mm KH ₂ PO ₄ , 0 .5% CMC) at 37 ° C. for 7 days to prepare artificial initial caries. For control of the test, a half of the top of the crown of the 3.5 × 3.0 mm window was further masked with Nail Enamel (manufactured by Maybelline) to obtain a comparison target site (control).
The test substance was prepared by using a dentifrice and mouthwash in suspension with artificial saliva as a test solution.

  In the remineralization acceleration test, the artificial initial caries test specimen prepared above was immersed in each test solution for 24 hours, and then the specimen was about 500 μm thick so as to be parallel to the tooth axis with a microcutter. After cutting, this piece was polished using a kneading stone and a natural whetstone so as to obtain a parallel thin piece having a thickness of about 100 μm under water injection. After polishing, contact microradiogram (CMR) imaging was performed to confirm the remineralization effect of the teeth (see FIGS. 1 and 2), and the effect of the remineralization of the artificial initial caries site using a computer Analysis.

  Computer image analysis was performed using the formula of Angmer et al. (B. Angmer, D. Carlstrom and JE. Glas: Studies on Ultrastructure of Dental Enemel IV: The Mineralization of normal Human Enamel, J. Ultrastructure. Res. 8, 12-23. , 1963) to calculate the amount of remineralized minerals, and the method of Damato et al. (FA Damato, R. Stang and KW Stephen: Effect of Fluoride Concentration on Reminerelization of Carious Enamel Res, 24, 174-180, 1990), the amount of mineral loss ΔZ (% volume mineral · μm) between the control surface and the treated surface of each section was calculated. In addition, the remineralization rate was computed by the following formula | equation.

(Test results)
Table 6 shows the results of confirming the effect of promoting remineralization of the oral composition by the above-described remineralization promotion test method.

It is a photograph which shows the control surface and processing surface of a crown part by a contact microradiogram (CMR). In the figure, “HAP” is an abbreviation for hydroxyapatite. FIG. 2 is a diagram in which the photograph shown in FIG. 1 is drawn using dark ink and a description of the state of each part is added.

Claims (4)

  An oral composition for preventing dental caries comprising hyaluronic acid or a salt thereof and hydroxyapatite.   The oral composition for preventing dental caries according to claim 1, wherein 0.001 to 5% by weight of hyaluronic acid or a salt thereof and 0.001 to 50% by weight of hydroxyapatite are blended.    A dentifrice containing the composition for oral cavity for prevention of caries according to claim 1 or 2. A mouthwash containing the composition for oral cavity for preventing caries according to claim 1 or 2.