JP2002154941A - Composition for oral cavity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition which is used for oral cavities, exhibits an excellent antibacterial effect with small amounts of antibacterial agents, and can thereby reduce the intake of the antibacterial agents into the body of a user. SOLUTION: This composition for oral cavities, is characterized by containing a chlorhexidine derivative and at least one compound selected from the group consisting of dialkyldimethylammonium halides and quinolinium halides, especially chlorhexidine chloride and benzalkonium chloride, benzethonium chloride or decalinium chloride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an oral composition effective for preventing periodontal disease.

[0002]

2. Description of the Related Art Periodontal disease is used as a general term for gingivitis and periodontitis accompanied by alveolar bone resorption. Normally, the flora on the surface of healthy teeth is mainly composed of gram-positive bacteria, but when gingivitis is affected, the number of anaerobic gram-negative bacteria increases. As these bacteria grow, the gingiva expands and becomes edematous, and exudates leak into the gingival sulcus. Further, gingivitis that has become chronic destroys the gingival sulcus floor and inflammation spreads deep into the periodontal tissue, resulting in periodontitis. Actinobacillus actinomycetemcomitans (Actinobacillus actinomycetemcomitans), Prevotella intermedia (Prevotella intermedia), Porphyromonas gingivalis (Porphyromonas gingival)
is), Fusobacterium nucleatum
nucleatum) and the like are known.

[0003] When trying to prevent the onset of periodontal disease by using an oral composition, sterilizing periodontal pathogens is one powerful method. For this purpose, a large amount of a bactericide is required. However, if a large amount of the bactericide is blended, disadvantages such as deterioration of taste and the tendency to generate colored deposits (stain) on the tooth surface are caused. In addition, if you mix a large amount,
Problems arise in the safety of swallowing.

[0004] Chlorhexidine derivatives are widely used in oral compositions as cationic bactericides effective for preventing alveolar pyorrhea, cavity, and bad breath. However, chlorhexidine derivatives alone cannot exert sufficient bactericidal activity even in a small amount. On the other hand, cationic surfactants such as benzalkonium chloride, benzethonium chloride and decalinium chloride have surface activities such as emulsifying power and osmotic power, and further have a bactericidal action,
It also has an antistatic effect. Utilizing these properties, it is widely used as a rinse for cosmetics, a hair softener for treatment, a disinfectant / sterilizer, and the like. However, since compounds such as benzalkonium chloride, benzethonium chloride and decalinium chloride are cationic, a sufficient antibacterial effect may not be obtained due to their properties depending on the type of bacteria. Also, chlorhexidine derivatives may not be able to obtain a sufficient antibacterial effect due to their properties depending on the type of bacteria.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide an oral composition which can exert an effective bactericidal effect on a wide variety of fungi in a small amount.

[0006]

The present inventors have developed a chlorhexidine derivative and one or more compounds selected from dialkyldimethylammonium halide salts and quinolinium halide salts, especially benzalkonium chloride, benzethonium chloride or chloride. By combining with decalinium, compared to using them alone,
The present inventors have found that an unexpected synergistic effect is exerted on the bactericidal activity, and completed the present invention.

[0007] That is, the present invention is an oral composition comprising a chlorhexidine derivative and at least one compound selected from the group consisting of a dialkyldimethylammonium halide salt and a quinolinium halide salt.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The chlorhexidine derivative in the present invention means a compound such as chlorhexidine or an adduct of chlorhexidine and an acid. Preferred chlorhexidine derivatives are the gluconate and hydrochloride salts of chlorhexidine, and particularly preferred is the hydrochloride salt of chlorhexidine (ie, chlorhexidine hydrochloride).

The dialkyldimethylammonium halide salts include benzalkonium chloride and benzethonium chloride. Examples of the quinolinium halide include decalinium chloride.

A combination of a chlorhexidine derivative and at least one compound selected from the group consisting of a dialkyldimethylammonium halide salt and a quinolinium halide salt, particularly chlorhexidine hydrochloride and / or chlorhexidine gluconate, benzalkonium chloride, A fungicide comprising a combination with benzethonium chloride and / or decalinium chloride is contained in an amount of 0.001 to 10% by weight, preferably 0.005% by weight of the whole oral composition.
It is incorporated into oral compositions in amounts of up to 5% by weight. 0.0
If the amount is less than 01% by weight, the bactericidal effect required for the oral composition cannot be obtained. On the other hand, if it exceeds 10% by weight, unpleasant taste may be obtained, which is not preferable.

The compounding ratio of the chlorhexidine acid addition salt to benzalkonium chloride, benzethonium chloride and / or decalinium chloride is 1: 100 to 30: 1 in terms of weight ratio of chlorhexidine acid addition salt to hydrochloride. ,
Preferably it is 1:64 to 16: 1. The acid addition salt of chlorhexidine is present in an amount of 0.0001 to 1 in the whole oral composition.
It is preferably contained in the oral composition in an amount of from 0.0005 to 0.5% by weight. Benzalkonium chloride, benzethonium chloride and / or decalinium chloride are blended in the ratio described above with respect to the amount of the chlorhexidine derivative.
Preferably it is contained in an amount of from 005 to 5% by weight.

[0012] The oral composition of the present invention comprises toothpaste,
It can be used as a dosage form such as liquid toothpaste and mouthwash. The oral composition of the present invention, if necessary, within the range not impairing the effects of the present invention, ethanol, a binder, a wetting agent, a sweetener, a flavor, a surfactant, particularly a zwitterionic surfactant, Pharmaceutical ingredients, preservatives, abrasives and the like can be added.

In the composition of the present invention, the binders which can be used include alkali metal salts of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl hydroxyethyl cellulose.
Cellulose derivatives such as sodium alginate; alkali metal alginate such as sodium alginate; propylene glycol alginate; carrageenan, xanthan gum, tragacanth gum, karaya gum, gum such as arabia gum, polyvinyl alcohol, sodium polyacrylate, polyvinyl Use any binder used in the production of oral compositions, such as synthetic binders such as pyrrolidone, inorganic binders such as silica gel, aluminum silica gel, aluminum magnesium silicate and synthetic sodium magnesium silicate. Can also. One of these binders may be used alone, or two or more thereof may be used in combination. The proportion in these compositions is 0.3-5% by weight
It is.

Examples of the humectant that can be added to the oral composition of the present invention include glycerin, sorbitol, ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, and polypropylene glycol. And well-known wetting agents such as xyl, xylit, maltitol and lactit. The proportion of such humectants in the oral composition is from 5 to 80% by weight, preferably from 10 to 60% by weight.

The oral composition of the present invention comprises an anionic compound,
A zwitterionic or nonionic surfactant, particularly a zwitterionic surfactant, can be appropriately added.

Examples of the anionic surfactant include sodium alkyl sulfates such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates such as sodium N-lauroyl sarcosinate, sodium N-myristoyl sarcosinate, and dodecylbenzene sulfone. Sodium acid, hydrogenated coconut fatty acid sodium monoglyceride monosulfate, sodium lauryl sulfoacetate, N-acylglutamate such as sodium N-palmitoylglutamate, sodium N-methyl-N-acyltaurine, sodium N-methyl-N-acylalanine, Sodium α-olefin sulfonate, sodium dioctyl sulfosuccinate and the like are used.

Examples of the amphoteric surfactant include N-alkyldiaminoethylglycine such as N-lauryldiaminoethylglycine and N-myristyldiaminoethylglycine, N-alkyl-N-carboxymethylammonium betaine, and 2-alkyl-1-amine. Hydroxyethylimidazoline betaine sodium and the like are used.

Examples of the nonionic surfactant include sugar fatty acid esters such as sucrose fatty acid ester, maltol fatty acid ester and lactose fatty acid ester, and sugar alcohols such as multitolu fatty acid ester and lactitol fatty acid ester. Fatty acid esters such as fatty acid esters, decaglyceryl monolaurate, diglyceryl monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, and polyoxyethylene sorbitan Polyoxyethylene fatty acid esters such as oxyethylene hydrogenated castor oil, lauric acid mono- or diethanolamide, myristic acid mono- or diethanol-
Fatty acid alkanolamides such as amides, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene polyoxypropylene fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene alkyl phenyl ethers, etc. are used. .

The above surfactants may be used alone or in combination of two or more. The use amount of these surfactants is usually 0.01 to 50% by weight in the oral composition.

As fragrances, menthol, anetole,
Eugenol, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl salicylate, citronellyl acetate, cineole, linalool, ethyl linalool, crocodile, thymol , Spearmint oil, peppermint oil, lemon oil, orange oil,
Flavors such as sage oil, rosmari oil, cinnamon oil, pimento oil, cinnamon oil, perilla oil, winter green oil, clove oil, eucalyptus oil and the like can be used alone or in combination. The proportion of these fragrances in the oral composition is 0.01 to 10% by weight, preferably 0.01 to 5% by weight.

As sweeteners, sodium saccharin,
Stevioside, neohesperidyl dihydrochalcone,
Glycyrrhizin, perillartin, asparatylphenylalanine methyl ester, p-methoxycinnaldehyde, trehalose and the like can be used. The proportion of these sweeteners in the composition is usually from 0.001 to 1% by weight, preferably from 0.01 to 0.5% by weight.

In the oral composition of the present invention, as a medicinal ingredient other than the chlorhexidine derivative and benzalkonium chloride, benzethonium chloride and decalinium chloride, for example, dextranase, mutanase, lysothio-
Enzymes, such as enzymes, amylases, proteases, lytic enzymes,
Sodium monofluorophosphate, alkali metal monofluorophosphate such as potassium monofluorophosphate, sodium fluoride, fluoride such as stannous fluoride, vitamin Es such as tocopherol acetate, tocopherol succinate, tranexamic acid, Epsilon aminocaproic acid,
Uses medicinal ingredients such as aluminum chlorohydroxyl allantoin, dihydrocholesterol, glycyrrhizinates, glycyrrhetinic acid, pisaborol, glycerophosphate, chlorophyll, sodium chloride, water-soluble inorganic phosphate compounds, aluminum lactate, zinc chloride, etc. You can also.

As the preservative of the oral composition of the present invention,
Sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate,
For example, butyl paraoxybenzoate can be used.

When the dosage form of the oral composition of the present invention is toothpaste, examples of the abrasive include silica abrasives such as precipitated silica, silica gel, aluminosilicate and zirconosilicate; 2 of calcium diphosphate
Hydrates and anhydrides, tricalcium phosphate, calcium pyrophosphate, calcium carbonate, aluminum hydroxide,
Examples include alumina, magnesium carbonate, tribasic magnesium phosphate, insoluble sodium metaphosphate, insoluble potassium metaphosphate, titanium oxide, zeolite, aluminum silicate, zirconium silicate, and a synthetic resin-based abrasive. These may be used alone or in combination of two or more.

[0025]

The present invention will be described below in more detail with reference to Test Examples and Examples. As an index of the combined effect of the two agents of the present invention, FIC (fractional inh) was used.
using the concept of ibidory concentration index (the third edition of the Chemotherapy Handbook,
Edited by Yasuda Ueda and Kihachiro Shimizu, Nagai Shoten, p. 97). This means, for example, that the MIC (a _c ) (minimum growth inhibitory concentration) when the agent a and the agent b are used in combination at a certain ratio,
The value obtained by dividing by the MIC (a _o ) when agent a alone was used was FIC
Called (a _c / a _o), the FICindex calculated for both a agent and b agents, representation and more the sum _{a c / a o + b c} / b o is less smaller than 1, a large combined effect Is the way. Therefore, if the growth of bacteria was inhibited by using １ ／ of the minimum inhibitory concentration of each drug, the FICindex of each drug was 0.5, and the FICindex when two drugs were used together was 1. The combined effect is an additive effect. If the FIC index is smaller than this, it is considered that there is a synergistic effect.

Test Example 1 For each of the bacteria Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis, chlorhexidine hydrochloride (CHX) and benzalkonium chloride (BKC) were blended in the following proportions to minimize the growth. The inhibitory concentration was measured and the FIC index was calculated. The results are shown in Tables 1 and 2 below.

[0027]

[Table 1]

[0028]

[Table 2]

Test Example 2 Chlorhexidine hydrochloride (CHX) and benzethonium chloride (BZC) were blended at the following ratios, and the following bacteria were used: Actinobacillus actinomycetemcomitans, Prevotella intelmedia and Porphyromonas gingivalis. , Measuring the minimum inhibitory concentration and FICin
dex was calculated. The results are shown in Tables 3 to 5 below.

[0030]

[Table 3]

[0031]

[Table 4]

[0032]

[Table 5]

Test Example 3 Chlorhexidine hydrochloride (CHX) and decalinium chloride (DQC) were blended at the following ratios, and the following bacteria were used: Actinobacillus actinomycetemcomitans, Prevotella intelmedia and Porphyromonas gingivalis. , Measuring the minimum inhibitory concentration and FICin
dex was calculated. The results are shown in Tables 6 to 8 below.

[0034]

[Table 6]

[0035]

[Table 7]

[0036]

[Table 8]

As shown in Tables 1 to 8, in Test Examples 1 to 3, the FIC index was 1 or less, and a synergistic effect was observed when the two drugs were used in combination.

Example 1 Effect of Combination on Actinobacillus actinomycetemcomitans Actinobacillus actinomycetemcomitans, which is a pathogen of periodontal disease and resident in the oral cavity, was treated with chlorhexidine hydrochloride (CHX) and chloride. Benzalkonium (B
The minimum growth inhibitory concentration of the combined system of KC) was measured. In addition,
The minimum growth inhibitory concentration was determined by the following method. The agar plate dilution method was performed according to the standard method of the Japanese Society of Chemotherapy. That is, GA
BKC and CHX to a predetermined concentration in M agar medium.
A culture solution (10 ⁶ cells / ml) was inoculated on a plate to which a drug prepared by mixing an aqueous solution of
After anaerobic culture at 35 ° C. for 5 days, the minimum concentration at which no formation of colonies was observed with the naked eye was indicated by a titer (ppm). Table 9 shows the measurement results by a checkerboard method. In the checkerboard, −: no formation of settlement was observed with the naked eye, +: formation of settlement was observed with the naked eye.

[0039]

[Table 9]

Example 2 Effect of Combination on Porphyromonas gingivalis Porphyromonas gingivalis, which is a pathogen of periodontal disease and resident in the oral cavity, is compared with chlorhexidine hydrochloride (CHX) and benzalkonium chloride (BKC). The minimum growth inhibitory concentration of the combination system was measured. The minimum growth inhibitory concentration was determined by the method described in Example 1. Table 10 shows the measurement results.
The results are shown by the checkerboard method.

[0041]

[Table 10]

Example 3 Effect of Combination on Actinobacillus actinomycetemcomitans The minimum growth inhibitory concentration of a combined system of chlorhexidine hydrochloride (CHX) and benzethonium chloride (BZC) was measured for Actinobacillus actinomycetemcomitans. . The minimum growth inhibitory concentration was determined by the method described in Example 1. Table 11 shows the measurement results by a checkerboard method.

[0043]

[Table 11]

Example 4 Effect of Combination on Prevotella intermedia For prevotella intermedia, which is a pathogen of periodontal disease and is a bacterium resident in the oral cavity, a combination of chlorhexidine hydrochloride (CHX) and benzethonium chloride (BZC) was used. The minimum inhibitory concentration was determined. The minimum growth inhibitory concentration was determined by the method described in Example 1. Table 12 shows the measurement results by a checkerboard method.

[0045]

[Table 12]

Example 5: Combined effect on Porphyromonas gingivalis For porphyromonas gingivalis, chlorhexidine hydrochloride (CHX) and benzethonium chloride (BZC)
The minimum growth inhibitory concentration of the combination system was measured. The minimum growth inhibitory concentration was determined by the method described in Example 1. Table 13 shows the measurement results by a checkerboard method.

[0047]

[Table 13]

Example 6 Effect of Combination on Actinobacillus actinomycetemcomitans The minimum growth inhibitory concentration of a combined system of chlorhexidine hydrochloride (CHX) and decalinium chloride (DQC) was measured for Actinobacillus actinomycetemcomitans. .
The minimum growth inhibitory concentration was determined by the method described in Example 1. Table 14 shows the measurement results by a checkerboard method.

[0049]

[Table 14]

Example 7: Combination effect on Prevotella intelmedia The minimum growth inhibitory concentration of Prevotella intelmedia in a combined system of chlorhexidine hydrochloride (CHX) and decalinium chloride (DQC) was measured. The minimum growth inhibitory concentration was determined by the method described in Example 1. Table 15 shows the measurement results by a checkerboard method.

[0051]

[Table 15]

Example 8 Effect of Combination on Porphyromonas gingivalis The minimum growth inhibitory concentration of a combined system of chlorhexidine hydrochloride (CHX) and decalinium chloride (DQC) was measured for Porphyromonas gingivalis. The minimum growth inhibitory concentration was determined by the method described in Example 1. Table 16 shows the measurement results by a checkerboard method.

[0053]

[Table 16]

Reference Example: Regarding the combined system of chlorhexidine hydrochloride and cetylpyridium chloride described in JP-A-6-239723, the minimum value for Actinobacillus actinomycetemcomitans, Prevotella intelmedia and Porphyromonas gingivalis The growth inhibitory concentration was measured. The minimum growth inhibitory concentration was determined by the method described in Example 1. The measurement results are shown in Tables 17 to 19 by a checkerboard method.

[0055]

[Table 17]

[0056]

[Table 18]

[0057]

[Table 19]

Example 9 (Preparation example 1 of mouthwash) A mouthwash having the following composition was prepared by a conventional method. Ingredients Blended amount (% by weight) Chlorhexidine hydrochloride 0.03 Benzalkonium chloride 0.01 Polyoxyethylene hydrogenated castor oil 2 Glycerin 10 Ethyl alcohol 10 Saccharin sodium 0.05 Perfume 0.5 Purified water Residual total 100

Example 10: (Example 2 of preparation of mouthwash) A mouthwash having the following composition was prepared by a conventional method. Ingredients Blended amount (% by weight) Chlorhexidine hydrochloride 0.001 Benzethonium chloride 0.01 Polyoxyethylene sorbitan monooleate 1 Ethyl alcohol 15 Fragrance 1 Purified water Residual total 100

Example 11: (Mouthwash preparation example 3) A mouthwash having the following composition was prepared by a conventional method. Ingredients Blended amount (% by weight) Chlorhexidine hydrochloride 0.01 Decalinium chloride 0.01 Polyoxyethylene hydrogenated castor oil 1 Glycerin 8 Ethyl alcohol 5 Sorbitol 10 Perfume 10 Purified water Residual total 100

Example 12: (Preparation example 1 of toothpaste) A toothpaste having the following composition was prepared by a conventional method. Ingredients Compounding amount (% by weight) Dibasic calcium phosphate 40 Sodium carboxymethylcellulose 1.5 Sorbitol 20 Glycerin 10 Sodium lauryl sulfate 2 Chlorhexidine hydrochloride 0.04 Benzalkonium chloride 0.01 Butylparaben 0.01 Fragrance 1 Allantoinchlorohydroxyaluminum 0. 2 Sodium fluoride 0.2 Purified water Residual Total 100

Example 13: (Preparation example 2 of toothpaste) A toothpaste having the following composition was prepared by a conventional method. Ingredients Amount (% by weight) Aluminum hydroxide 20 Sodium carboxymethyl cellulose 1 Carrageenan 0.5 Glycerin 30 Polyoxyethylene hydrogenated castor oil 1 Chlorhexidine hydrochloride 0.001 Benzethonium chloride 0.01 Methyl paraben 0.1 Fragrance 0.5 ε-Aminocaproic acid 0.2 Tocopherol acetate 1 Purified water Residual Total 100

Example 14: (Preparation example 3 of toothpaste) A toothpaste having the following composition was prepared by a conventional method. Ingredients Blended amount (% by weight) Silicic anhydride 40 Hydroxyethyl cellulose 1 Saccharin sodium 0.2 Propylene glycol 3 Polyoxyethylene stearyl ether 2 Chlorhexidine hydrochloride 0.01 Decalinium chloride 0.01 Fragrance 0.8 Potassium glycyrrhizinate 0.2 Polyphosphoric acid Sodium 0.1 Purified water Residual Total 100

[0064]

Test Examples 1 to 3, Examples 1 to 8 and Table 9
From the results of ~ 16, compared to the chlorhexidine hydrochloride alone system, the combined system of chlorhexidine hydrochloride and benzalkonium chloride, the combined system of chlorhexidine hydrochloride and benzethonium chloride, and the combined system of chlorhexidine hydrochloride and decalinium chloride, It can be seen that a smaller or equal amount can provide a good growth inhibitory effect on oral bacteria. Since the oral composition of the present invention exhibits an excellent bactericidal effect with a small amount of bactericide, the amount of the bactericide taken into the body of the user can be reduced.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Masaru Matsumoto 6-12-18 Hiyoshidai, Tomisato-cho, Inba-gun, Chiba Prefecture (72) Inventor Ichiki ▲ Kyo ▼ Yu 7-1-1, Tamazo, Narita-shi, Chiba Pref. No. 301 F-term (reference) 4C083 AB172 AB222 AB282 AB292 AB472 AC102 AC122 AC132 AC182 AC432 AC442 AC482 AC622 AC682 AC691 AC692 AC741 AC742 AC782 AC851 AC852 AC862 AD272 AD282 AD352 AD532 AD662 CC41 EE33

Claims (6)

[Claims] 1. An oral composition comprising a chlorhexidine derivative and at least one compound selected from the group consisting of a dialkyldimethylammonium halide salt and a quinolinium halide salt. 2. The oral composition according to claim 1, wherein the chlorhexidine derivative is chlorhexidine hydrochloride or chlorhexidine gluconate. 3. The composition for oral cavity according to claim 1, wherein the chlorhexidine derivative is chlorhexidine hydrochloride. 4. The oral composition according to claim 1, wherein the dialkyldimethylammonium halide salt is benzalkonium chloride or benzethonium chloride, and the quinolinium halide salt is decalinium chloride. 5. The oral composition according to claim 4, comprising chlorhexidine hydrochloride and benzalkonium chloride, benzethonium chloride or decalinium chloride in a weight ratio of 1: 100 to 30: 1. 6. The oral composition according to claim 5, comprising chlorhexidine hydrochloride and benzalkonium chloride, benzethonium chloride or decalinium chloride in a weight ratio of 1:64 to 16: 1.