JP3486930B2 - Oral composition - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition for the oral cavity which is effective for preventing and preventing the progress of oral diseases such as periodontal disease, dental caries, tartar and the like. [0002] Periodontal disease and dental caries, which are typical diseases in the oral cavity, are infections caused by pathogenic bacteria, and the pathogenic bacteria adhere to the tooth surface when they occur. Start with things. The attached bacteria form plaque in a visible form through aggregation and growth between the bacteria. [0003] Regarding the initial adhesion, it is known that a hydrophobic bond, an ionic bond, and a lectin-like bond are formed between a proteinaceous adhesin on the cell surface and a pellicle on the tooth surface to establish the adhesion. . In addition, it has been reported that the agglutination reaction between bacteria also depends on a binding mode similar to the initial attachment. [0004] With respect to the proteinaceous adhesin, research on separation, purification, and structure determination of the adhesin has been progressing in accordance with recent advances in molecular biology. In particular, Porphyromonas gingivalis, which is a representative pathogen of adult periodontitis, is known as Porphyromonas gingivalis.
lis), Streptococcus mutans, the main pathogen of caries
tans) and Streptococcus sobrinas (St)
(reptococcus sobrinus) has been studied in considerable detail. The main adhesin of Porphyromonas gingivalis is fimbriae
It is said that a protein having a molecular weight of about 42K is polymerized. Streptococcus adhesins have a similar structure for each serotype, and c-type Streptococcus mutans and g-type Streptococcus sobrinus each have protein antigen c (Protei c).
n Antigen c, hereinafter referred to as PAc), Protein Antigen g (Protein Antigen g)
g, hereinafter referred to as PAg) on the cell surface. Both PAc and PAg have a molecular weight of about 190
It is said that K is deeply involved in the initial adhesion and the aggregation between bacteria. [0005] Regarding the adherence of cells of the genus Streptococcus, it is well known that the cells themselves adhere to the polysaccharide produced by the bacterium. On the other hand, plaque formed by the above-mentioned process is mainly composed of bacterial cells and metabolites thereof, and serves as a scaffold for growth of microorganisms and causes various diseases. For example, periodontal disease is caused by pathogenic bacteria present in plaque existing above the gingival margin (supragingival plaque) and in plaque below the gingival margin (subgingival plaque), which is more anaerobic. Caused by pathogenic bacteria present in In particular, subgingival plaque is more anaerobic due to the presence of supragingival plaque, and gram-negative anaerobic bacteria that grow there are large in the progression of periodontal disease as pathogens of periodontitis. Involved. [0007] Regarding caries, Streptococcus mutans and Streptococcus
It has been clarified that sobrinus produces organic acids by carbohydrate metabolism while growing in dental plaque, and the acid demineralizes the tooth surface, thereby causing and progressing caries. [0008] Further, calculus formed by calcification of plaque is also known to be directly involved in plaque. As described above, by suppressing the formation and accumulation of plaque causing various diseases in the oral cavity, it is possible to expect an effect of eliminating pathogenic bacteria and eliminating the site of their proliferation. Furthermore, by reducing the amount of accumulated plaque and reducing the anaerobicity of subgingival plaque, it can also contribute to the inhibition of the growth of anaerobic bacteria that are the causative bacteria of periodontal disease. In other words, suppressing the formation and accumulation of plaque greatly contributes to the prevention and progress of oral diseases such as periodontal disease, dental caries and tartar. Conventionally, various measures have been taken to suppress the formation of plaque, but at present there is no satisfactory method. For example, brushing using a toothbrush is performed to suppress plaque formation, but because the shape of the oral cavity is complicated, plaque in the interproximal area and fissures should be removed by brushing alone. It is difficult. [0011] Further, as a method for chemically inhibiting plaque formation,
It is known to directly kill pathogenic bacteria, and the use of dentifrices and mouthwashes containing a disinfectant, or the disinfection of plaque microorganisms by administration of antibiotics can be effective in inhibiting plaque formation. It has been disclosed (JP-A-61-200905).
No. 61-148125). However, it has been pointed out that the use of powerful fungicides and antibiotics disrupts the normal oral flora, resulting in an abnormal increase in certain pathogenic bacteria, and a risk of harmful effects. Furthermore, the emergence of drug-resistant bacteria is also considered,
This is not necessarily the preferred method. [0012] Therefore, there is a demand for an oral composition which can exhibit an excellent plaque formation inhibitory effect without such problems. The present inventors have conducted intensive studies to meet the above-mentioned demands. As a result, the hydroxy-2-pyridone derivative represented by the following general formula (1) or a salt thereof has been developed. Unlike conventional fungicides, which inhibit plaque formation with strong antibacterial activity, Streptococcus sobrinus bacteria are used at low concentrations that do not exhibit antibacterial activity.
It has been found that it has an excellent plaque formation inhibitory effect on the formation of plaque formed by body adhesion and can be stably compounded in various oral compositions. The present invention has been found that an oral composition containing a pyridone derivative or a salt thereof has an excellent plaque formation inhibitory effect and is effective for preventing or preventing progress of oral diseases such as periodontal disease, dental caries and tartar. It came to do. Embedded image (Wherein, R ¹ and R ² are each a hydrogen atom or a hydroxyl group, and at least one of R ¹ and R ² is a hydroxyl group.
R ³ , R ⁴ and R ⁵ are each a hydrogen atom or a monovalent organic group. As for the hydroxy-2-pyridone derivative, Japanese Patent Publication No. 48-35077 discloses that the 1-hydroxy-2-pyridone derivative has an antifungal activity and is applicable to the treatment of dermatomycosis. Have been. In addition, Tokubo Sho 5
8-39805 discloses an application technique for hair care and hair dressing products applied to the scalp and hair by using the derivative, which has an excellent antiscalp effect. In addition, the anti-scalp effect of the derivative is (1) antibacterial activity against scalp resident bacteria, (2) antioxidant activity for suppressing oxidation of epidermal lipids, (3) peroxide decomposition against peroxide generated from epidermal lipids. It is reported that it comes from power. These known techniques are limited to applications related to skin, scalp or hair, and no application to oral compositions has been reported. Further, the 3-hydroxy-2-pyridone structure has not been reported to have the above-mentioned activity, and there has been no report on its application to oral compositions. Hereinafter, the present invention will be described in more detail. The oral composition of the present invention includes dentifrices such as toothpaste, powdered toothpaste, liquid dentifrice, liquid dentifrice, gel dentifrice, mouthwash, coating agent, and spray agent. , Lozenges, foods (including gums, candies, etc.)
It contains a hydroxy-2-pyridone derivative represented by the following general formula (1) or a salt thereof as an active ingredient as an active ingredient for suppressing plaque formation. Embedded image In the above formula (1), R ¹ and R ² are each a hydrogen atom or a hydroxyl group, and at least one of R ¹ and R ² is a hydroxyl group. R ³ , R ⁴ and R ⁵ each represent a hydrogen atom or a monovalent organic group (preferably having 1 to 1 carbon atoms).
8), and the monovalent organic group is an alkyl group,
Alkenyl, cycloalkyl, bicycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, arylalkenyl, aryloxyalkyl, arylmercaptoalkyl, benzhydryl, phenylsulfonylalkyl, furyl, furylalkenyl And the like.
Preferred are an alkyl group having 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, a cycloalkyl group having 3 to 18 carbon atoms, a cycloalkyl-alkyl group, and a benzyl group. The hydroxy-2-pyridone derivative of the above formula (1) has a 1-hydroxy-2-pyridone or 3-hydroxy-2-pyridone skeleton, and each has a tautomer. In the case of a 1-hydroxy-2-pyridone skeleton, a 2-hydroxypyridine-N-oxide skeleton or the like exists as an isomer, and 3-hydroxy-2-pyridone is present.
In the case of a pyridone skeleton, a 2,3-dihydroxypyridine skeleton or the like exists. The present invention can include these isomers. It is also possible to use a salt using an appropriate base. Examples of the salt form include sodium, potassium, calcium, magnesium, strontium, zinc, copper, aluminum, lanthanum, iron, tin and other monovalent or polyvalent metal salts, ammonium salts, monoethanolamine, diethanolamine, triethanolamine, Salts with amines such as ethylenediamine and hydroxylamine, salts with basic amino acids such as arginine and lysine, and salts with basic peptides and basic proteins containing basic amino acids are widely available. It can be appropriately selected from a range that is acceptable in terms of quality. The compounding amount of the hydroxy-2-pyridone derivative of the formula (1) or a salt thereof is 0.0005 to 0.5% of the whole composition.
20% (% by weight, hereinafter the same), particularly 0.01 to 10%,
More preferably, it is preferably 0.1 to 5%, and more preferably 0.1 to 5%.
If it is less than 0005%, plaque formation may not be able to be suppressed, and if it exceeds 20%, there may be problems in use feeling and formulation. The oral composition of the present invention may contain other optional components according to the dosage form. For example,
In the case of dentifrices, abrasives, binders, thickeners, surfactants, sweeteners, preservatives, coloring agents, fragrances, foaming agents, medicinal components other than the above essential components, and the like can be blended. As the abrasive, dicalcium phosphate 2
Phosphate abrasives such as water salts, calcium pyrophosphate and insoluble sodium metaphosphate, carbonate abrasives such as calcium carbonate and magnesium carbonate, silicate abrasives such as silica and zirconosilicate, and aluminum hydroxide One or two or more kinds can be appropriately selected from hydroxide-based abrasives and the like. Examples of the binder include carrageenan, sodium alginate, xanthan gum, pullulan, gelatin,
Carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, gum arabic, guar gum, locust bean gum, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, montmorillonite, kaolin, hydrated silica, aluminum silicate, magnesium silicate, hectorite, etc. One or two or more of them can be appropriately selected. As the thickener, propylene glycol,
One or more of sorbitol, glycerin, polyethylene glycol and the like can be appropriately selected. As the surfactant, one or more of sodium lauryl sulfate and sarcosinate can be appropriately selected. As the preservative, one or more of methyl paraben, ethyl paraben, butyl paraben, sodium benzoate and the like can be appropriately selected. Other medicinal components include fluorides such as sodium fluoride, sodium monofluorophosphate and tin fluoride; bactericidal / antibacterial agents such as chlorhexidine, triclosan and cetylpyridinium chloride; condensed phosphates; Calculus prevention agents such as hydroxydiphosphonate, anti-inflammatory agents such as tranexamic acid and glycyrrhizin dipotassium salt, enzyme agents such as dextranase and mutanase, astringents such as sodium chloride and aluminum lactate, potassium nitrate and strontium chloride One or more plaque inhibitors such as a hypersensitivity inhibitor, zinc citrate, and gluconic acid can be appropriately selected and used according to the purpose within a pharmaceutically acceptable range. In addition, the addition amount of the optional component can be a normal amount within a range that does not impair the effects of the present invention. The oral composition of the present invention has excellent plaque formation inhibitory activity and is effective for preventing and preventing progress of oral diseases such as periodontal disease, dental caries and tartar. EXAMPLES Hereinafter, the present invention will be described specifically with reference to experimental examples and examples, but the present invention is not limited to the following examples. [Experimental Examples] The plaque formation inhibitory effect and antibacterial activity of the test samples shown in Table 1 were evaluated by the following methods. Table 1 shows the results. Plaque formation inhibitory effect: Streptococcus sobrinus 6
Using 715 strain, a plaque formation model test in a test tube was performed. Streptococcus sobrinus 6715
Share 3.7% Brain Heart Infusion (B
rain Heart Infusion, hereafter BHI
) Was centrifuged to obtain a culture supernatant and cells. The culture supernatant is passed through a membrane filter (Amicon, Diaflow Membrane PM10).
Ultrafiltration using phosphate buffered saline (pH
7.0, hereinafter referred to as PBS) to exchange the buffer in the same manner to obtain a 20-fold concentrated culture supernatant. Cells are PBS
The suspension was treated in a boiling water bath for 20 minutes to obtain a heat-killed suspension. After cooling to room temperature, 550 n using PBS
A heat-killed suspension having an absorbance at m (hereinafter referred to as _A550 ) of 4.5 was prepared. A 20-fold concentrated culture supernatant (PA
g concentration: about 20 μg / ml) 1 ml, heat-killed bacterial suspension 1
ml, 10% sucrose (in PBS) solution 0.4 ml, 2%
A test sample (in dimethyl sulfoxide) solution was added to a predetermined concentration, and the final volume was adjusted to 4 ml with PBS. After standing 16 hours at maintaining and 37 ° C. The tubes inclination of 60 degrees, measures the A ₅₅₀ of the heat killed suspension of killed bacteria adhering to the test tube wall obtained by dispersing sonicated And the amount of dead bacteria attached was measured. The amount of dead bacteria adhered at this time was regarded as the amount of plaque formed in the test tube, and the same experiment was carried out for a sample without addition as a control, and the plaque formation inhibition rate was calculated according to the following equation. Plaque formation inhibition rate (%) = {A ₅₅₀ (control) -A ₅₅₀ (sample)} / A ₅₅₀ (control) × 100 [0034] Antibacterial Test: a glass test tube culture 4ml
, And the concentration of the test sample aqueous solution at the time of culturing was 0.5, 1, 5, 10, 50, 1
After the addition, the total amount was adjusted to 4.5 ml using purified water. Using a pre-previous Streptococcus sobrinus 6715 strain had been cultured broth, A ₅₅₀ is prepared cell suspension of 1, 1-day culture in addition to the glass tube test sample was added to the 40μl After that, _A550 was measured to determine the minimum growth inhibitory concentration range. As a culture solution, 3.7% BHI was used, and all the cultures were carried out in a gas phase at 37 ° C. [Table 1] As shown in Table 1, the hydroxy-2-pyridone derivative according to the present invention showed an excellent plaque formation inhibitory effect in an in vitro plaque formation test using heat-killed bacteria. 4-Hydroxy-2-pyridone did not show any inhibitory effect, nor did chlorhexidine show any effect. Furthermore, the hydroxy-2-pyridone derivative according to the present invention exhibited a plaque formation inhibitory effect even at such a low concentration as not to exhibit antibacterial activity. Example 1 Toothpaste Dibasic calcium phosphate dihydrate 30 parts by weight Propylene glycol 3.0 Carboxymethylcellulose 1.0 Glycerin 25 Sodium lauryl sulfate 1.0 Fragrance 1.0 Saccharin sodium 0.15 Monofluorophosphoric acid sodium 0.73 1-hydroxy-4-methyl-6- (2,4,4-trimethyl-1.0-pentyl) -2-pyridone monoethanolamine salt water remaining in total 100 parts by weight [0039] example 2 kneading Toothpaste 20 parts by weight Propylene glycol 3.0 Carboxymethylcellulose 1.0 Sorbit 30 Sodium lauryl sulfate 1.0 Fragrance 1.0 Sodium saccharin 0.15 Sodium fluoride 0.21 1-hydroxy-4-methyl-6- (2, 4,4-trimethyl 1.0 Pentyl) -2-pyridone monoethanolamine salt water remaining in total 100 parts by weight [0040] Example 3 Liquid dentifrice Propylene glycol 2.0 parts by weight xanthan gum 0.2 Sodium polyacrylate 0.15 sorbitol 30 glycerol 20 silica 15 Saccharin sodium 0.1 Sodium lauryl sulfate 1.0 Sodium fluoride 0.21 Fragrance 1.0 butyl paraben 0.01 1-hydroxy-4-methyl-6- (2,4,4-trimethyl 0.2 pentyl) -2 - 100 parts by weight in total remaining pyridone monoethanolamine salt water [0041] example 4 mouthwash ethanol 20 parts by weight of sodium saccharin 0.02 1-hydroxy-4-methyl-6- (2,4,4-trimethyl 0 .1 pentyl) -2-pyridone monoethanolamine 0.1 Water balance Total 100 parts by weight of salt of sodium 0.14 coloring qs perfume monofluorophosphate [0042] Example 5 mouthwash saccharin sodium 0.02 parts by weight of 3-hydroxy-2-pyridone 0.1 hydrofluoric Sodium chloride 0.022 Butyl paraben 0.01 Coloring agent Appropriate amount of flavoring agent 0.1 Water Remaining total 100 parts by weight [Example 6] Lozenge gum arabic 7.0 parts by weight Glucose 40 Maltose 40 Magnesium stearate 1.0 Saccharin sodium 0.02 Perfume 0.2 1-Hydroxy-2-pyridone 0.1 Water Remaining 100 parts by weight [Example 7] Toothpaste propylene glycol 2.5 parts by weight Carrageenan 1.0 Sorbit 20 Saccharin sodium 0.15 Butylparaben 0.01 monofluorophosphoric acid Thorium 0.73 Aluminum 40 perfume 0.9 Sodium lauryl sulphate 1.0 1-hydroxy-4-methyl-hydroxide-6- (2,4,4-trimethyl-5.0-pentyl) -2-pyridone monoethanolamine salt water The remaining 100 parts by weight in total [0045] example 8 coating agent carboxymethylcellulose 3.0 part by weight sorbit 20 polyethylene glycol 2.0 perfume 1.0 Sodium saccharin 0.05 butylparaben 0.01 1-hydroxy-2-pyridone 1 .0 water balance total 100 parts by weight [0046] example 9 toothpaste calcium carbonate 30 parts by weight glycerin 15 sorbitol 15 carboxymethylcellulose 1.0 sodium lauryl sulfate 1.0 perfume 1.0 sodium saccharin 0.1 monofluorophosphate Sodium .73 1-hydroxy-3,4-dimethyl-6-benzyl-2 2.0 pyridone water remaining in total 100 parts by weight [0047] Example 10 mouth sprays Glycerin 10 parts by weight Ethanol 40 Saccharin sodium 0.3 Perfume 3.0 1-Hydroxy-4-methyl-6- (2,4,4-trimethyl 2.0 pentyl) -2-pyridone monoethanolamine salt Coloring agent Suitable amount of water Remaining 100 parts by weight

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K ^7/ 00-7/50 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claim 1] A hydroxy-2-pyridone derivative represented by the following general formula (1) or a salt thereof is contained as an active ingredient in an amount of 0.0005 to 20% by weight of the whole composition. A cell of Streptococcus sobrinus
An oral composition for inhibiting plaque formation due to adhesion . Embedded image (Wherein, R ¹ and R ² are each a hydrogen atom or a hydroxyl group, and at least one of R ¹ and R ² is a hydroxyl group.
R ³ , R ⁴ and R ⁵ are each a hydrogen atom or a monovalent organic group. )