KR19990079220A - Oral composition containing triclosan - Google Patents

Abstract

The present invention relates to an oral composition comprising 2,4,4'-trichloro-2'-hydroxy diphenyl ether (hereinafter referred to as "triclosan"). More specifically, the oral cavity increases the rate of diffusion of triclosan in the oral cavity, adsorption to the oral mucosa and teeth, and extends the retention time in the oral cavity, thereby acting more continuously on the causative agents of oral disease, thereby increasing plaque formation and preventing gingivitis. It relates to a composition for.

Description

Oral composition containing triclosan

The present invention relates to an oral composition comprising 2,4,4'-trichloro-2'-hydroxy diphenyl ether (hereinafter referred to as "triclosan"). More specifically, the oral cavity increases the rate of diffusion of triclosan in the oral cavity, adsorption to the oral mucosa and teeth, and extends the retention time in the oral cavity, thereby acting more continuously on the causative agents of oral disease, thereby increasing plaque formation and preventing gingivitis. It relates to a composition for.

2,4,4'-trichloro-2'-hydroxydiphenyl ether of the following general formula (I) is an antimicrobial agent exhibiting excellent antimicrobial activity against various periodontal disease-causing bacteria, and is commonly used as "triclosan". :

(Ⅰ)

Triclosan has been formulated in oral compositions such as toothpaste for a long time due to its excellent antibacterial action, and is widely known as a technique for inhibiting plaque formation and preventing gingivitis by its potent bactericidal action (pp. 科學 す る, pp 84-85). For example, Japanese Patent Application Laid-Open No. 60-239409 discloses triclosan and a surfactant, Japanese Patent Publication No. 60-239410 discloses triclosan and zinc citrate, and Japanese Patent Publication No. 62-89614 discloses triclosan and copper compounds. In Japanese Patent Application Laid-Open No. 62-126116, oral composition comprising triclosan and polyethylene glycol, and Japanese Patent Application Laid-Open No. 63-233909 in combination with triclosan and potassium salt have been proposed.

As a result of intensive studies on the composition for oral cavity containing triclosan, the present inventors also added tocopherol acetate having a blood-promoting action to the combination of triclosan and potassium chloride to further improve the interaction between triclosan and potassium chloride, even at low concentrations. In particular, the filing effect of inhibiting the growth of periodontal disease-causing bacteria and causal causative bacteria has been filed as of November 16, 1995 for the composition for oral cavity that can provide an increased effect on the prevention of periodontal disease and caries prevention. (Korean Patent Application 95-41702: Publication 97-25596).

However, triclosan is hardly soluble in water, and the molecule itself is non-ionic, so it has little adsorption to oral mucosa or teeth, so that the amount of triclosan stays in oral tissue or teeth after use is very small. For this reason, the above-described oral compositions did not exhibit sufficient bactericidal or antimicrobial activity, so that the contained triclosan did not sufficiently exhibit the effect of inhibiting plaque and preventing periodontal disease.

Therefore, the research direction in the related art related to triclosan is to increase the adsorption and adsorption rate of triclosan to oral mucosa and teeth, and to increase the oral mucosa and antibacterial effect of triclosan for a sufficient time for various oral diseases causing bacteria in the oral cavity. The focus is on ways to increase my residence time.

As an example, Japanese Patent Laid-Open No. 4-139118 mixes alginic acid made with a specific molecular weight into a composition for oral cavity containing triclosan. However, in the case of sodium alginate, the adsorption to oral mucosa and teeth is not so high that the technical limitations of the triclosan compounded toothpaste described above cannot be completely solved.

In contrast, techniques for encapsulating triclosan to form liposomes for effective delivery of triclosan have been introduced (European Patent Publication No. 481701), and for oral compositions in which trichloroic acid is dissolved and formulated using a sufficient amount of ethanol. (US Pat. No. 5,256,401).

Accordingly, the present inventors increase triclosan diffusion rate and adsorption to oral mucosa and teeth and increase the intraoral diffusion rate of triclosan so that the triclosan-blended composition for oral cavity can sufficiently exhibit bactericidal or antimicrobial and tartar control effects against oral disease-causing bacteria. While exploring ways to prolong the residence time, triclosan and intraoral mucosa and teeth of triclosan are formed by homogeneous mixing of triclosan and intramolecular carboxyl groups and substances having one or more polar functional groups in aqueous solution. It has been found that the mobility to the can be increased. Furthermore, in blending the complex into the composition for oral cavity, by using carboxy alkyl cellulose of a certain degree of substitution as a mediator of triclosan, it is possible to increase the adsorption of triclosan to oral mucosa and teeth. The present invention has been completed by considering that the residence time can be increased.

Accordingly, an object of the present invention is to increase the rate of intraoral diffusion of triclosan and adsorption to oral mucosa and teeth in the composition for oral cavity containing triclosan, and to extend the residence time in the oral cavity more continuously to cause oral diseases. It acts to provide a composition for oral cavity that has increased plaque formation and gingivitis prevention effect.

In order to achieve the above object, the composition for oral cavity according to the present invention,

Triclosan,

1 to 3 times the molar amount of triclosan of a substance having at least one polar functional group in an aqueous solution with an intramolecular carboxyl group, and

It is characterized by containing the carboxy alkyl cellulose and its salt whose average substitution degree is 1.2 or more in the quantity of 0.2-5 weight% of the total amount of a composition.

Hereinafter, each component which comprises this invention is demonstrated.

First, in the composition for oral cavity according to the present invention, triclosan compounded for the purpose of preventing plaque formation and gingivitis by showing excellent antimicrobial activity against the causative agent of oral disease is not particularly limited in the amount thereof, but is usually used in the composition for oral cavity. It is compounded in an amount of 0.001 to 2% by weight of the total weight of the composition, preferably in an amount of 0.01 to 1.0% by weight.

In addition, as a substance having at least one polar functional group in the aqueous solution state with an intramolecular carboxyl group, which is formulated to enhance the mobility of triclosan to promote oral diffusion rate and instant adsorption, α-hydroxy propanoic acid (α-hydroxypropionic acid), fumaric acid, DL-maleic acid, citric acid, gluconic acid, DL-alanine, DL-glutamic acid , L-thiamine and at least one selected from the group consisting of metal salts thereof. The compounding quantity of this is suitably in the range of 1 to 3 times the molar amount of triclosan blended into the composition for oral cavity. If the compounding amount is less than the number of moles of triclosan compound, sufficient effect cannot be obtained. If the amount of molar amount exceeds 3 times the number of moles of triclosan compound, these substances present more than necessary, which may have a bad effect on the texture of the oral composition including taste. It can be crazy and economically undesirable.

In addition, the carboxyl alkyl cellulose and the salt thereof in a specific substitution range blended in the composition for oral cavity according to the present invention have excellent solubility in water and adsorption to oral mucosa and teeth, and thus, triclosan in oral mucosa and teeth. It acts as a mediator to increase the adsorption of triclosan. If the average degree of substitution is less than 1.2, since the retention and adsorption property to the oral mucosa is not good, and triclosan cannot serve as an oral retention time enhancer, it is preferable to use an average degree of substitution of 1.2 or more. More preferably, the average substitution degree exists in the range of 1.2-1.6. Specific examples include those selected from the group consisting of carboxy methyl cellulose, carboxy ethyl cellulose, carboxy propyl cellulose and sodium salts thereof, and the compounding amount thereof is 0.2 to 5% by weight, preferably 0.5 to 2% by weight of the total weight of the composition for oral cavity. The range of% is suitable. If the compounding amount is less than 0.2%, triclosan does not sufficiently maintain the oral residence time. If the compounding amount is more than 5%, the viscosity of the composition becomes so high that it is difficult to squeeze into the toothbrush when formulated as a toothpaste. Dispersibility also worsens, which adversely affects the overall feel of toothpaste.

The composition for oral cavity according to the present invention is a cationic agent such as chlorohexidine, benzethonium chloride, benzalkonium chloride, cetylpyridium chloride, etc. for the purpose of prevention of tooth decay as well as triclosan as an active ingredient. Fungicides, alkali metal monofluorophosphates such as sodium monofluoro phosphate, potassium monofluoro phosphate, fluorides such as sodium fluoride and tin fluoride, tranexamic acid, ε-amino capronic acid, aluminum chloro hydroxyl allantoin, Efficacy ingredients such as dehydrocholesterol, glycyrrhizin, glycerophosphate, sodium chloride, water-soluble inorganic phosphate compounds, ascorbic acid (sodium), acetate l- α-tocopherol, polyvinyl pyrrolidone It can contain further 1 type or 2 types or more from among them.

In addition, the composition for oral cavity of the present invention may be formulated in the form of paste toothpaste, liquid toothpaste, mouthwash, gingival massage cream, liquid or paste topical coating or chewing gum. In addition to the components described above, the composition for oral cavity of the present invention may further contain suitable components that are usually used in the composition for oral cavity, depending on the use and formulation of the composition.

For example, when formulated as a toothpaste, it may contain an abrasive or a moisturizer commonly used in toothpaste compositions. Abrasives include dicalcium phosphate dihydrate and anhydride, tricalcium phosphate, calcium carbonate, calcium pyrophosphate, aluminum hydroxide, silicic anhydride, aluminum silicate, insoluble sodium metaphosphate, tricalcium phosphate, magnesium carbonate, calcium sulfate, polycarbonate Methyl methacrylate, other synthetic resins, etc. are used, and these abrasives are used alone or in combination of two or more kinds (a compounding amount is usually 20 to 90%, in the case of soft toothpaste 20 to 60%). As a moisturizer to be blended into a paste or liquid composition, one or two or more polyhydric alcohols such as sorbitol, glycerin, ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol are selected and used (compound amount is usually 10 to 70%). ).

In addition, as an additive used in small amounts, for example, when formulated as a toothpaste, components commonly used in toothpaste compositions include a binder, a perfume, a sweetener, an active ingredient, a foaming agent, and the like. In the case of paste compositions such as soft toothpaste, gums such as carrageenan, various incremental cellulose derivatives, xanthan gum and tragacanth gum, polyvinyl alcohol, sodium polyacrylate, and polyacrylic acid / maleic acid copolymer are used as caking additives. And one or two or more selected from organic binders such as synthetic polymer derivatives such as carboxyvinyl polymers and inorganic binders such as silica and laponite are used (compound amount is usually 0.3 to 5%). As the fragrance component, menthol, anetol, eugenol, limonene, ocimene, n-dodecyl alcohol, citronenol, α-terpineol ( α-terpineol, methylsalicylate, methyl acetate, citronelyl acetate, citronelyl, cineol, linalool, ethyl linalool, vanillin, thymol ), Spearmint oil, sage oil, rosemary oil, cinnamon oil, etc. may be used alone or in combination (the amount is usually 0-10%, preferably 0.5-5%). . As a sweetener, saccharin sodium, stevioside, aspartame, D-xylose, etc. are used individually or in combination (the compounding quantity is 0-1% normally, Preferably it is 0.01-0.5%).

In addition, the surfactant used as the foaming component includes sodium alkyl sulfates such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-lauroyl sarcosinate, and sodium N-myristyl sarcosinate (Sodium N). anionic surfactants such as sodium N-acyl sarcosinate such as -myristyl sarcosinate); Sugar-derived fatty acid esters such as sugar fatty acid esters, maltose fatty acid esters, lactose fatty acid esters, polyoxyethylene hardened castor oil, polyoxyethylene higher alcohol ethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene polypropylene Nonionic surfactants such as fatty acid esters; N-alkyl di-aminoethylglycines such as N-lauryl di-aminoethylglycine, N-myristyl di-aminoethylglycine, N-alkyl-N-carboxy methyl ammonium betaine, 2-alkyl-1-hydroxy Zwitterionic surfactants such as ethyl imidazoline betaine sodium can be used. Among them, anionic surfactants are mainly used, and sodium alkyl sulfates such as sodium lauryl sulfate are most widely used. These surfactant are used individually or in mixture of 2 or more types, and compounding quantity is normally used in 0.01-5% of the total weight of a composition, More preferably, 0.05 to 3% of range.

Hereinafter, with reference to the experimental examples and examples will be described in more detail with respect to the composition and effect of the composition for oral cavity according to the present invention.

Experimental Example 1 Adsorption Time and Retention of Triclosan to Teeth

10 mg of hydroxyapatite was washed with PBS (10 mM: pH = 7.2) and then immersed in saliva for 1 hour to coat the HA surface with saliva. After the saliva-coated HA was washed again with PBS, the HA plate was immersed in 100 ml of the composition solution of Table 1, and stirred slowly for 5 minutes, 10 minutes, 20 minutes, and 30 minutes, respectively. After stirring, triclosan adsorbed on HA was washed with PBS, extracted with ethanol, quantified triclosan by HPLC, and quantified triclosan attached to HA plate.

HPLC quantitative conditions

Column: YMC J'sphere ODS-H80 (Diameter 4.6 × 250mm) S-4μm, 80A

Eluent: methanol / water / phosphate = 80/20 / 0.1

Detection: UV 280nm

The results of this experiment are shown in Table 1 below. As can be seen from the results of Table 1, one polar functional group in the carboxyl group and the aqueous solution in the aqueous solution than in the case of using triclosan alone (Experiment No. 2) or only triclosan and carboxy methyl cellulose (Experiment No. 3) In the case where the above-mentioned substances are used in combination, triclosan not only adsorbs HA more quickly, but also has a great amount of adsorption. In addition, it can be seen that the adsorption amount of triclosan increases as the degree of substitution of carboxymethyl cellulose increases.

Experimental Example 2 Plaque Formation Inhibitory Effect of Triclosan Adsorbed / Retained on Teeth

After producing a 10-mm-diameter HA disk using the IR tablet molding machine which normally uses hydroxy apatite 200 mg, it sintered at 1300 degreeC for 1 hour, and the test body was produced. This disk was immersed in saliva for 24 hours (37 DEG C), and the surface was sufficiently coated with a saliva component (pellicle). The saliva-coated HA disk plate was washed with PBS, and then treated with test solution of Experimental Example 1 for 30 minutes. 0.3 processing after sufficiently washing a Visco then immersed in a HA test samples in liquid THB medium 2.7㎖, and evil Martino My process suspension (A. viscosus) T14V and Streptococcus mutans (S. mutans) 6715-41 bacterial solution in PBS, respectively ML was added to inoculate. After culturing under anaerobic conditions at 37 ° C for 24 hours, the HA test plate was washed with PBS, and the amount of DNA attached was quantified by the fluorescence method described by Paul & Myers, and the value was determined as the amount of attached plaque. It was. For reference, the DNA quantification method is briefly described as follows.

① The HA disk plate is sonicated in PBS solution to remove the plaque.

② The dispersed plaque solution is removed and treated with lysozyme (1㎍ / mL) and incubated for 1 hour and 30 minutes at 37 ° C.

③ Hesostost dye (Hoeschost Dye) 33258 was added to measure the DNA using a spectrofluorometer (spectrofluorometer).

The results of this experiment are shown in Table 1 below. As can be seen from the results of Table 1, one polar functional group in the carboxyl group and the aqueous solution in the aqueous solution than in the case of using triclosan alone (Experiment No. 2) or only triclosan and carboxy methyl cellulose (Experiment No. 3) When used in combination with the above materials, the plaque suppression effect was excellent. In addition, it can be seen that as the substitution degree of carboxymethyl cellulose increases, the plaque suppression effect also increases.

Raw material name Experiment number One 2 3 4 5 6 7 8 9 10 11 Propylene glycol - 5 5 5 5 5 5 5 5 5 5 glycerin - 3 3 3 3 3 3 3 3 3 3 D-sorbitol - 20 20 20 20 20 20 20 20 20 20 Triclosan - 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 α-hydroxy propanoic acid - - - 0.18 - - - 0.18 0.18 0.18 0.18 Ca- (L) -2-hydroxy propanoic acid - - - - 0.35 - - - - - - Zn- (L) -2-hydroxy propanoic acid - - - - - 0.40 - - - - - DL-maleic acid - - - - - - 0.26 - - - - Sodium Lauryl Sulfate - 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 CMC-Na (average degree of substitution = 0.7) - - - - - - - One - - - CMC-Na (average degree of substitution = 0.9) - - - - - - - - One - - CMC-Na (average degree of substitution = 1.2) - - - - - - - - - One - CMC-Na (average degree of substitution = 1.4) - - One One One One One - - - - CMC-Na (average degree of substitution = 1.6) - - - - - - - - - - One Purified water Adjust to 100 system 100 100 100 100 100 100 100 100 100 100 100 Triclosan adsorption amount (㎍ / 10mg HA) 5 minutes - 1.2 4.8 28.3 36.6 30.4 23.1 8.4 12.7 22.4 33.6 10 minutes - 6.4 10.2 45.6 49.8 46.6 36.7 14.6 18.5 38.4 49.5 20 minutes - 11.3 22.6 61.5 66.4 64.4 52.4 22.8 28.4 53.5 65.7 30 minutes - 15.6 28.3 70.5 72.5 69.2 68.5 36.3 38.5 60.5 72.6 Plaque Suppression Effect (Μg DNA / HA disc) ^{* 1} 56.5 43.2 30.6 8.4 10.6 8.8 14.2 28.8 24.5 16.3 8.0 % Inhibitory effect ^{* 2} - 23.5 45.8 85.1 81.2 84.4 74.8 49.0 56.6 71.1 85.8 (Note) ^{* 1 This} is the arithmetic mean value of 5 experiments. ^{* 2} Inhibition rate compared to the control group using only distilled water (test No. 11).

Hereinafter, examples of a paste-type toothpaste, a mouse wash, and a liquid toothpaste, which are representative oral compositions, are shown. These embodiments are merely illustrative of the composition for oral cavity of the present invention, the present invention is not limited to these embodiments can be applied to all oral compositions commonly used.

1. Paste Toothpaste

Raw material name Example One 2 3 4 5 6 7 8 9 10 Sodium fluoride trixamic acid precipitated silica Dicalcium phosphate Dihydrate Potassium pyrophosphate Sodium pyrophosphate (anhydrous) Water Soluble Silicate Sorbitol liquid (non-crystalline) Propylene glycol Polyoxyethylene glycol 1500 Sodium phosphate monohydrate (anhydrous) Paraoxybenzoic Acid Methyl Flavor 0.22 0.1 18.0-4.61.53.020.05.02.00.10.20.20.31.0 0.22 0.118.0-4.51.53.020.05.02.00.10.20.20.31.0 0.22 0.118.0-4.51.53.020.05.02.00.10.20.20.31.0 0.22 0.118.0-4.51.53.020.05.02.00.10.20.20.31.0 0.22 0.118.0-4.51.53.020.05.02.00.10.20.20.31.0 0.22 0.1-35.04.51.53.020.05.02.00.10.20.20.31.0 0.22 0.1-35.04.51.53.020.05.02.00.10.20.20.31.0 0.22 0.1-35.04.51.53.020.05.02.00.10.20.20.31.0 0.22 0.1-35.04.51.53.020.05.02.00.10.20.20.31.0 0.22 0.1-35.04.51.53.020.05.02.00.10.20.20.31.0 Triclosan 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 α-hydroxy propanoic acid 0.18 - - - - 0.18 - - - - Ca- (L) -2-hydroxy propanoic acid - 0.35 - - - - 0.35 - - - Zn- (L) -2-hydroxy propanoic acid - - 0.40 - - - - 0.40 - - Al- (L) -2-hydroxy propanoic acid - - - 0.45 - - - - 0.45 - DL-maleic acid - - - - 0.26 - - - 0.26 Sodium Lauryl Sulfate 1.5 1.5 1.5 1.5 1.5 1.8 1.8 1.8 1.8 1.8 CMC-Na (average degree of substitution = 1.4) 1.0 1.0 1.0 1.0 1.0 1.2 1.2 1.2 1.2 1.1 Purified water Adjust to 100 system 100 100 100 100 100 100 100 100 100 100

2. Liquid Toothpaste

Raw material name Example 11 12 13 14 15 Glycerin Propylene Glycol Ethanol Tranexamic Acid Saccharin Sodium 30.08.04.02.00.1 30.08.04.02.00.1 30.08.04.02.00.1 30.08.04.02.00.1 30.08.04.02.00.1 Triclosan 0.3 0.3 0.3 0.3 0.3 α-hydroxy propanoic acid 0.18 - - - - Ca- (L) -2-hydroxy propanoic acid - 0.35 - - - Zn- (L) -2-hydroxy propanoic acid - - 0.40 - - Al- (L) -2-hydroxy propanoic acid - - - 0.45 - DL-maleic acid - - - - 0.26 Sodium Lauryl Sulfate 0.05 0.05 0.05 0.05 0.05 CMC-Na (average degree of substitution = 1.4) 0.8 0.8 0.8 0.8 0.8 Purified water Adjust to 100 system 100 100 100 100 100

3. Mouse Wash

Raw material name Example 16 17 18 19 20 Sorbitol (70%) Ethanol (90%) Polyoxyethylene glycol 1500 Glycerin Polyoxyethylene (60 mol) 10.05.00.20.22.00.20.30.20.2 10.05.00.20.22.00.20.30.20.2 10.05.00.20.22.00.20.30.20.2 10.05.00.20.22.00.20.30.20.2 10.05.00.20.22.00.20.30.20.2 Triclosan 0.05 0.05 0.05 0.05 0.05 α-hydroxy propanoic acid 0.03 - - - - Ca- (L) -2-hydroxy propanoic acid - 0.05 - - - Zn- (L) -2-hydroxy propanoic acid - - 0.06 - - Al- (L) -2-hydroxy propanoic acid - - - 0.07 - DL-maleic acid - - - - 0.04 Sodium Lauryl Sulfate 0.05 0.05 0.05 0.05 0.05 CMC-Na (average degree of substitution = 1.4) 0.1 0.1 0.1 0.1 0.1 Purified water Adjust to 100 system 100 100 100 100 100

The composition for oral cavity of this invention contains the triclosan, the substance which has one or more polar functional groups in an aqueous carboxyl group and an aqueous solution, and carboxy alkyl cellulose of specific substitution degree, and the intraoral mobility of triclosan increases, Since it is adsorbed on the oral mucosa and teeth in a short time and the oral retention time is extended, the bactericidal or antimicrobial effect of triclosan is effectively and continuously exerted, which shows excellent oral disease suppression effect and high plaque suppression effect.

Claims (3)

In the composition for oral cavity containing 2,4,4'-trichloro-2'-hydroxy diphenyl ether, It contains 1 to 3 times the molar amount of 2,4,4'-trichloro-2'-hydroxy diphenyl ether as a substance having at least one polar functional group in an aqueous solution with an intramolecular carboxyl group. The composition for oral cavity which further contains the carboxy alkyl cellulose and its salt whose average substitution degree is 1.2 or more in the quantity of 0.2-5 weight% of the total amount of a composition. According to claim 1, wherein the substance having at least one polar group in the aqueous solution of the intramolecular carboxyl group and the aqueous solution, α-hydroxypropionic acid (α-hydroxypropionic acid, fumaric acid, DL-maleic acid (DL-maleic acid), citric acid, gluconic acid, DL-alanine, DL-glutamic acid, L-thiamine and metal salts thereof Oral composition, characterized in that selected from. The carboxyalkyl cellulose having a mean substitution degree of 1.2 or higher and its salt are selected from the group consisting of carboxy methyl cellulose, carboxy ethyl cellulose, carboxy propyl cellulose and their sodium salts. Oral composition.