JP2005187377A - Oral cavity biofilm inhibitory composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral cavity biofilm inhibitory composition excellent in the effect of inhibiting oral cavity biofilm contributing to oral cavity diseases, therefore effective for reducing and preventing gingivitis, periodontoses, dental caries and foul breath. <P>SOLUTION: The oral cavity biofilm inhibitory composition comprises 0.0001-10 mass% of a histidine kinase inhibitor selected from ofloxacin of formula(1) and closantel of formula(2) and one or more kinds from among phenolic bactericides, surfactants and alcohols. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention is an innovative oral biofilm inhibitory composition that is excellent in suppressing the oral biofilm that is the cause of oral diseases, and can effectively reduce and prevent gingivitis, periodontal disease, caries, bad breath Related to things.

  In recent years, dental plaque has been perceived as a biofilm (see Non-Patent Document 1), and the bacteria in the biofilm have a bacterial protein expression pattern (see Non-Patent Documents 2 and 3) and drug resistance (non-patent documents). It has become clear that the patent documents 4 and 5) are greatly different. So far, phenolic fungicides (see Patent Document 1) and the like have been developed to sterilize bacteria. However, since bacteria in biofilm have a strong drug resistance mechanism, this alone is not effective in suppressing biofilm. It was sufficient and it was difficult to eliminate the risk of oral disease.

  Moreover, in order to enhance these bactericidal powers, a technique for improving the retention of bactericides has been proposed (see Patent Document 2), but due to the low drug permeability of biofilms, a significant effect could not be expected. Under such circumstances, there is a strong demand for the development of a biofilm inhibitory composition that is effective against bacteria in biofilms.

  On the other hand, in recent years, histidine kinase functions as a part of an external environment recognition system (two-component control system) such as staphylococci, and it has been suggested that the inhibitor may be effective in the prevention and treatment of infectious diseases ( Non-patent document 6). A histidine kinase inhibitor having a specific structure has been developed for antibacterial activity of Gram-positive bacteria (see Patent Document 3).

  However, a histidine kinase inhibitor alone could not be expected to have a sufficient biofilm inhibitory effect on drug-resistant biofilms. In addition, unlike other biofilms, oral biofilms have 300 to 400 types of bacterial species (see Non-Patent Document 7), so that the inhibitory effect of histidine kinase inhibitors on oral biofilms is sufficiently satisfactory. It wasn't. From such a current situation, development of an oral biofilm suppressing composition that is more effective for oral biofilms is strongly desired.

Costerton, J.M. W. , Stewart, P.M. S. and Greenberg, E.A. P. : Bacterial biofilms: a common cause of persistent influences. Science 284: 1318-1322, 1999. Costerton, J.M. W. Lewandowski, Z .; Caldwell, D .; E. Korber, D .; R. and Lappin-Scott, H .; M.M. : Microbiological biofilms. Annu. Rev. Microbiol. 49: 711-745, 1995. Hudson, M.M. C. Curtiss, R .; III: Regulation of expression of Streptococcus mutans genes important to virus. Infect. Immun. 58: 464-470, 1990. Stewart, P.M. S. : Mechanicals of antibiotic resistance in bacterial biofilms. Int. J. et al. Med. Microbiol. 292: 107-113, 2002. Philip Marsh and Michael V. Martin "Oral Microbiology", Wright Publishing, 2000, p. 58-81 (Dental plaque) Hilliard, J.M. J. et al. Goldschmidt, R .; M.M. , Licata, L .; Baum, E .; Z. and Bush, K .; : Multiple mechanisms of action for inhibitors of his protein protein kinases, two-component systems. Antimicrob. Agents. Chemother. 43: 1693-1699, 1999. Okuda Katsumi, “Dental Plaque Bacteria: A Microscopic World Even Aiming for Life”, Ishiyaku Shuppan, 1999, p. 1-26 (Chapter 1 Bacteria turned to reverse with weapons) JP 02-11511 A JP 04-139119 A JP 2002-69034 A

  The present invention has been made in view of the above circumstances, and is excellent in suppressing the oral biofilm which is the cause of oral diseases, and can effectively reduce and prevent gingivitis, periodontal disease, caries and bad breath. An object is to provide an oral biofilm inhibitory composition.

  As a result of intensive research to achieve the above object, the present inventor has shown that the histidine kinase inhibitor alone or the phenolic fungicide alone does not show a remarkable oral biofilm inhibitory activity, whereas the following formula ( Inhibiting the above histidine kinase by combining a combination of a histidine kinase inhibitor selected from ofloxacin represented by 1) and closantel represented by the following formula (2), a phenolic fungicide, a surfactant and / or an alcohol For the first time that the antibacterial agent and the phenolic fungicide act synergistically, and the inhibitory effect is hardly lowered due to drug resistance, and shows a very excellent oral biofilm inhibitory effect. It came.

  Therefore, the present invention contains an ofloxacin represented by the following formula (1) and a histidine kinase inhibitor selected from closantel represented by the following formula (2) at a concentration of 0.0001 to 10% by mass with respect to the entire composition. And an oral biofilm suppressing composition comprising a phenolic fungicide, one or more of surfactants and alcohols.

  The composition for suppressing an oral biofilm of the present invention is excellent in the effect of suppressing an oral biofilm which is a cause of oral diseases, and is effective in reducing and preventing gingivitis, periodontal disease, dental caries and bad breath.

  Hereinafter, the present invention will be described in more detail. The oral biofilm inhibitory composition of the present invention contains a specific histidine kinase inhibitor, a phenolic fungicide, a surfactant, and / or an alcohol, and the like. , Can be manufactured and prepared by various methods such as solids, liquids, liquids, gels, pastes, gums, etc., for example, toothpastes such as toothpastes, liquid dentifrices, mouthwashes, mouthwashes, gums, etc. Can be prepared into various dosage forms that can be used for oral use.

  In the present invention, ofloxacin represented by the following formula (1) and closantel represented by the following formula (2) are used as the histidine kinase inhibitor, and these may exist as salts. The said histidine kinase inhibitor may be used individually by 1 type, or may use 2 types together.

  The blending amount of the histidine kinase inhibitor is preferably 0.0001 to 10% (mass%, the same applies hereinafter), more preferably 0.0001 to 5%, especially 0.001 to 1% with respect to the entire composition. is there. When the blending amount is less than 0.0001%, a sufficient biofilm suppressing effect may not be obtained. When the blending amount exceeds 10%, there may be a problem in formulation in terms of cost, palatability and the like.

  Examples of the phenolic fungicide include triclosan, 3-methyl-4-isopropylphenol (biosol), 2-isopropyl-5-methylphenol (thymol), phenoxyethanol, phenol and the like. In consideration of safety, it is particularly preferable to use triclosan, 3-methyl-4-isopropylphenol, 2-isopropyl-5-methylphenol, and phenoxyethanol. These phenolic fungicides can be blended alone or in combination of two or more.

  The blending amount of the phenolic fungicide is preferably 0.0001 to 10%, more preferably 0.0001 to 5% of the entire composition. When the blending amount is less than 0.0001%, a satisfactory biofilm suppressing effect may not be obtained, and when it exceeds 10%, there may be a problem in formulation in terms of palatability and cost.

  In the present invention, it is essential to contain both a histidine kinase inhibitor and a phenolic fungicide, and the blending ratio (mass ratio) of the histidine kinase inhibitor and the phenolic fungicide is 1: 100000-100: 1 is preferable, More preferably, it is 1: 10000-10: 1. If the blending ratio is out of the above range, a satisfactory biofilm suppressing effect may not be obtained.

  Although there is no particular limitation on the combination of the histidine kinase inhibitor and the phenolic fungicide, from the viewpoint of safety ofloxacin and / or closantel, triclosan, 3-methyl-4-isopropylphenol, 2-isopropyl-5-methyl It is desirable to combine one or more selected from phenol and phenoxyethanol.

  Moreover, in this invention, in order to solubilize the said histidine kinase inhibitor and a phenolic microbicide, and to exhibit a sufficient biofilm inhibitory effect, it is essential to mix | blend surfactant and / or alcohol.

  As the surfactant, one or more of an anionic surfactant, a nonionic surfactant and an amphoteric surfactant can be blended. Examples of the anionic surfactant include sodium alkyl sulfates such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinate such as sodium N-lauroyl sarcosinate, sodium N-myristoyl sarcosinate, sodium dodecylbenzene sulfonate, Hydrogenated coconut fatty acid monoglyceride sodium monosulfate, sodium lauryl sulfoacetate, N-acyl glutamate such as sodium N-palmitoyl glutamate, N-methyl-N-acyl taurine sodium, N-methyl-N-acylalanine sodium, α-olefin Sodium sulfonate, sodium dioctyl sulfosuccinate and the like are used. Nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters, sugar alcohol fatty acid esters such as maltitol fatty acid esters and lactitol fatty acid esters, and polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate, polyoxyethylene fatty acid esters such as polyoxyethylene hydrogenated castor oil, lauric acid mono- or diethanolamide, fatty acid diethanolamides such as myristic acid mono- or diethanolamide, For sorbitan fatty acid ester, fatty acid monoglyceride, polyoxyethylene higher alcohol ether, polyoxyethylene polyoxypropylene Coalescence, polyoxyethylene polyoxypropylene fatty acid ester or the like is used. Examples of zwitterionic surfactants include N-alkyldiaminoethylglycine such as N-lauryldiaminoethylglycine and N-myristyldiaminoethylglycine, N-alkyl-N-carboxymethylammonium betaine, and 2-alkyl-1-hydroxyethylimidazoline. Betaine sodium and the like are used.

  The blending amount of the surfactant is preferably 0.01 to 30%, more preferably 0.1 to 10% of the entire composition. When the blending amount is less than 0.01%, the histidine kinase inhibitor and / or the phenolic fungicide cannot be solubilized, and a sufficient biofilm suppressing effect may not be obtained. There may be a problem in formulation in terms of palatability.

  Examples of alcohols include ethanol, isopropanol, butanol, propanol, glycerin, ethylene glycol, diethylene glycol, hexylene glycol, butylene glycol, pentanediol, propylene glycol, 1,3-butylene glycol, sorbit, polyethylene glycol 200 to 20,000. Polyhydric alcohols such as polypropylene glycol 300 to 4,000 can be mentioned, and one of these can be used alone or in combination of two or more.

  The blending amount of the alcohol is preferably 0.01 to 70%, more preferably 0.1 to 50% with respect to the entire composition. When the blending amount is less than 0.01%, the histidine kinase inhibitor and / or the phenolic fungicide cannot be solubilized and a sufficient biofilm inhibitory effect may not be obtained, which exceeds 70%. In terms of palatability and the like, it may be a problem in formulation.

  In the present invention, a surfactant or alcohol may be blended alone (blending only surfactant or blending only alcohol), or a surfactant and alcohol may be blended in combination, The combination of surfactants and / or alcohols can be appropriately adjusted according to the shape, dosage form, composition, etc. of the composition so that the histidine kinase inhibitor and the phenolic fungicide can be solubilized. What is necessary is just to mix | blend. For example, when the biofilm suppressing composition of the present invention is prepared as a dentifrice composition, it is preferable to use a surfactant alone, and when it is prepared as a mouthwash composition, alcohols alone or an interface is used. An activator and alcohols can be used in combination.

  In addition to the above-described components, the oral biofilm suppressing composition according to the present invention may further contain appropriate components according to the purpose of use, the dosage form of the composition, and the like.

  For example, when prepared as a dentifrice, dibasic calcium phosphate dihydrate and anhydride, primary calcium phosphate, tertiary calcium phosphate, calcium carbonate, calcium pyrophosphate, aluminum hydroxide, alumina, anhydrous silicic acid, silicic acid One or more of aluminum, insoluble sodium metaphosphate, tribasic magnesium phosphate, magnesium carbonate, calcium sulfate, polymethyl methacrylate, bentonite, zirconium silicate, synthetic resin and the like can be blended (blending amount usually 5 to 5) 90%, 10-60% for toothpaste).

  In the case of a paste-like composition such as toothpaste, carrageenan, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylhydroxyethylcellulose, etc. as a binder, alginates, propylene glycol alginate, xanthan gum, One kind of gums such as tragacanth gum, karaya gum, arabiya gum, synthetic binders such as polyvinyl alcohol, sodium polyacrylate, carboxyvinyl polymer, polyvinylpyrrolidone, inorganic binders such as silica gel, aluminum silica gel, bee gum, laponite, etc. Two or more kinds can be blended (the blending amount is usually 0.3 to 10%).

  Further, when prepared as a paste or liquid oral composition such as dentifrice, xylitol, maltitol, lactitol as a thickener, or polyhydric alcohol (sorbite, glycerin, One or more of ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol 200 to 20,000, and polypropylene glycol 300 to 4,000) can be blended (blending amount is usually 10 to 70%).

  As perfumes, peppermint oil, spearmint oil, anise oil, eucalyptus oil, winter green oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander oil, mandarin oil , Lime oil, lavender oil, rosemary oil, laurel oil, camomil oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, Iris concrete, Natural fragrances such as absolute peppermint, absolute rose and orange flower, and fragrances processed by these natural fragrances (front cut, rear cut, fractional distillation, liquid-liquid extraction, essence, powder fragrance, etc.), and , Menthol, carvone, anethole, cineole, salichi Acid methyl, cinnamic aldehyde, eugenol, 3-l-mentoxypropane-1,2-diol, thymol, linalool, linalyl acetate, limonene, menthone, menthyl acetate, N-substituted-paramentane-3-carboxamide, pinene, Octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allyl cyclohexane propionate, methyl anthranilate, ethyl methyl phenyl glycidate, vanillin, undecalactone, hexanal, ethyl alcohol, propyl Alcohol, butanol, isoamyl alcohol, hexenol, dimethyl sulfide, cycloten, furfural, trimethylpyrazine, ethyl lactate, ethyl thiol For oral compositions such as single flavors such as acetate, and other flavors such as strawberry flavor, apple flavor, banana flavor, pineapple flavor, grape flavor, mango flavor, butter flavor, milk flavor, fruit mix flavor, tropical fruit flavor, etc. The known fragrance | flavor raw material used can be used, It is not limited to the fragrance | flavor of an Example.

  Moreover, although the compounding quantity of a fragrance | flavor is not specifically limited, It is preferable to use said fragrance | flavor raw material 0.000001 to 1% in a formulation composition. Moreover, as a fragrance | flavor for fragrance | flavor using the said fragrance | flavor raw material, it is preferable to use 0.1 to 2.0% in a formulation composition.

  In the present invention, as an active ingredient, cationic fungicides such as chlorhexidine, benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride, decalinium chloride, phenolic compounds such as hinokitiol, dextranase, mutanase, Enzymes such as lysozyme, amylase, protease, lytic enzyme, superoxide, mutase, alkali metal monofluorophosphates such as sodium monofluorophosphate and potassium monofluorophosphate, fluorides such as sodium fluoride and stannous fluoride, Tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholestanol, glycyrrhizic acids, glycyrrhetinic acid, bisabolol, glycerophos Eto, chlorophyll, sodium chloride, active ingredients such as water-soluble inorganic phosphoric acid compounds may be formulated alone or in combination.

EXAMPLES Hereinafter, although an experiment example and an Example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, the blending amount is mass%.
[Experimental example]

  Cryopreserved Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, 40 μL of Porphyromonas gingivalis, 5 mg / L L Vitamin K (manufactured by Wako Pure Chemical Industries, Ltd.) Todd Hewit broth (manufactured by Becton and Dickinson) added to 4 mL of culture solution (THBHM) and anaerobic culture overnight at 37 ° C (80 vol% nitrogen, 10 vol% carbon dioxide 10 vol% hydrogen). 80 μL of the frozen Bayonella parvula culture solution was added to 4 mL of Todd Hewitt broth (Becton and Dickinson) culture solution (THBL) containing 1.26% sodium lactate (Sigma), Culture was performed in the same manner.

After culturing, 300 μL was collected from each of the three bacterial strains excluding Bayonella pervula, added to 30 mL of THBHM, and further cultured overnight. Similarly, 300 μL was collected from the bacterial solution of Bayonella pervula, added to 30 mL of THBL, and cultured overnight. After re-culture, each bacterial solution was centrifuged (10000 rpm, 10 min), and the supernatant was discarded. For each sediment (bacteria), basal medium mucin culture medium (BMM) ^* was added and resuspended so that the absorbance (550 nm) was approximately 0.1. Four types of bacterial solutions were mixed in equal amounts, and stirred, and then dispensed in an amount of 1 mL into each well of a 24-well multi-dish (manufactured by Sumitomo Bakelite, culture area per well; about 1.9 cm ² ). After anaerobic culture for one day, the whole culture broth was discharged and 1 mL of BMM ^* was added. The same operation was continued for 6 days to form a biofilm on the plate.

  On the 6th day of culture, an aqueous solution having the composition shown in Table 1 was added and left for 3 minutes. Then, it was washed 12 times with physiological saline, 1 mL of BMM was added, and anaerobic culture was performed again. The same treatment was performed on the seventh day of culture, and the remaining biofilm was dispersed in 4 mL of THBHM and transferred to a test tube (diameter 1.3 cm × 10 cm).

In this experiment, in order to evaluate the biofilm inhibitory effect, the number of viable bacteria remaining in the biofilm after drug treatment was measured. The biofilm was subjected to ultrasonic disruption (10 seconds, 200 μA), serial dilution (× 10) was performed, and each bacterial solution was smeared on a blood agar plate ^** . The plate was anaerobically cultured until colonies could be confirmed with the naked eye. After counting the number of colonies on each plate, the number of viable bacteria (unit: cfu / well, abbreviation for colon forming unit) was calculated by a conventional method. The results are shown in Table 1.

* BMM composition: Expressed by mass in 1 liter.
Proteose peptone (Becton and Dickinson):
5g / L
Yeast extract (Becton and Dickinson): 2.5 g / L
Tryptone (Becton and Dickinson): 2.5 g / L
Mucin (manufactured by Sigma): 6.25 g / L
Hemin (manufactured by Sigma): 2.5 mg / L
Vitamin K (manufactured by Wako Pure Chemical Industries, Ltd.): 0.5mg / L
KCl (manufactured by Wako Pure Chemical Industries): 1.25 g / L
Cysteine (manufactured by Wako Pure Chemical Industries): 0.25 g / L
Distilled water: Residue (The volume was increased so that the total volume was 1 liter.)
** Composition of blood agar plate medium: expressed in mass per liter.
Todd Hewitt Broth (Becton and Dickinson):
30g / L
Agar (Becton and Dickinson): 15g / L
Hemin (manufactured by Sigma): 5mg / L
Vitamin K (manufactured by Wako Pure Chemical Industries): 1mg / L
Distilled water: Residue (The volume was increased so that the total volume was 1 liter.)

  Preparation method of aqueous solutions of Comparative Examples and Examples in Table 1 above: A 1.5 mg / mL albumin aqueous solution was prepared by dissolving 0.15 g of bovine serum albumin (manufactured by Sigma) in 100 mL of distilled water. Ethanol (manufactured by Wako Pure Chemical Industries, Ltd.), triclosan (manufactured by Wako Pure Chemical Industries, Ltd.), 3-methyl-4-isopropylphenol (manufactured by Wako Pure Chemical Industries, Ltd.), and a histidine kinase inhibitor at the blending ratios shown in Table 1. After the addition, the volume was made up with an aqueous solution of 1.5 mg / mL bovine serum albumin (manufactured by Sigma) so that the total amount became 100 mL. As the histidine kinase inhibitor, closantel (manufactured by Wako Pure Chemical Industries, Ltd.) and ofloxacin (manufactured by Sigma) were used.

From the above results, histidine kinase inhibitor and phenolic fungicide alone, which are comparative examples, survive 6.0 × 10 ⁷ cfu / well or more of bacteria, but the histidine kinase inhibitor and phenol according to the present invention When combined with a fungicidal agent, the total was 6.0 × 10 ⁶ cfu / well or less, compared with Comparative Example 3 (the number of remaining biofilm remaining 6.8 × 10 ⁷ cfu / well), which was the most effective. It has been found that more than 90% of the bacteria in the biofilm are killed.

[Example 6] Toothpaste dicalcium phosphate 47.0%
Silicic anhydride 2.5
Sorbit liquid (70% aqueous solution, manufactured by Kao Corporation) 24.0
Propylene glycol (Dow Chemical Co.) 3.0
Sodium carboxymethylcellulose 1.0
Sodium alginate 0.2
Sodium lauryl sulfate (manufactured by Nippon Surfactant Co., Ltd.) 1.5
Saccharin sodium 1.0
Ethyl paraoxybenzoate 0.1
Fragrance A 1.0
Closantel (Wako Pure Chemical Industries, Ltd.) 0.05
3-Methyl-4-isopropylphenol (manufactured by Wako Pure Chemical Industries, Ltd.) 0.1
Triclosan 0.1
(Calbiochem-Novabiochem)
Ammonium chloride 0.5
Purified water remaining
Total 100.0%

[Example 7] Toothpaste aluminum hydroxide 50.0%
Glycerin (made by Lion) 8.0
Sorbit liquid (70% aqueous solution, manufactured by Nikken Kasei Co., Ltd.) 15.0
Propylene glycol (Showa Denko) 2.0
Sodium carboxymethylcellulose 1.0
Sodium alginate 0.2
Sodium lauryl sulfate (manufactured by Toho Chemical Industry Co., Ltd.) 1.8
Saccharin sodium 0.2
Ethyl paraoxybenzoate 0.2
Fragrance B 1.0
Ofloxacin (manufactured by Sigma) 0.01
3-Methyl-4-isopropylphenol (manufactured by Wako Pure Chemical Industries, Ltd.) 0.1
Cetylpyridinium chloride 0.1
Ammonium sulfate 1.0
Purified water remaining
Total 100.0%

[Example 8] Toothpaste neutralization treatment aluminum hydroxide 42.0%
Silicic anhydride 2.5
Sorbit liquid (70% aqueous solution, manufactured by Kao Corporation) 23.0
Carrageenan 0.5
Sodium myristyl sulfate (Wako Chemical Co., Ltd.) 1.3
Sodium alginate 0.5
Glycerol calcium phosphate 0.8
Saccharin sodium 0.1
Ethyl paraoxybenzoate 0.05
Dextranase (17.5 u / g) 0.1
Triclosan 0.05
(Calbiochem-Novabiochem)
Sodium monofluorophosphate 0.75
Fragrance C 1.0
Potassium nitrate 5.0
3-Methyl-4-isopropylphenol (manufactured by Wako Pure Chemical Industries, Ltd.) 0.1
Ofloxacin (manufactured by Sigma) 0.01
Purified water remaining
Total 100.0%

[Example 9] Toothpaste glycerin (manufactured by Lion) 20.0%
Silicic anhydride 20.0
Sorbit liquid (70% aqueous solution, manufactured by Towa Kasei Kogyo Co., Ltd.) 40.0
Propylene glycol (Asahi Glass Co., Ltd.) 2.5
Sodium carboxymethylcellulose 1.0
Gelatin 0.3
Sodium lauryl sulfate (manufactured by Kao) 1.2
Saccharin sodium 1.0
Phytate 5 sodium 0.8
Fragrance D 1.0
Potassium nitrate 3.3
Triclosan (Promochem) 0.3
3-methyl-4-isopropylphenol (Wako Pure Chemical Industries, Ltd.) 0.05
Closantel (Wako Pure Chemical Industries, Ltd.) 0.005
Ofloxacin (manufactured by Sigma) 0.05
Ammonium sulfate 2.0
Purified water remaining
Total 100.0%

[Example 10] Toothpaste zirconosilicate 25.0%
Silica anhydride 2.0
Sorbit liquid (70% aqueous solution, manufactured by Nikken Kasei) 40.0
Polyethylene glycol 400 (Lion Corporation) 5.0
Sodium polyacrylate 1.0
Sodium lauryl sulfate (manufactured by Kao Corporation) 1.0
Saccharin sodium 0.1
Fragrance E 1.1
Methyl paraoxybenzoate 0.1
Butyl paraoxybenzoate 0.1
Chlorhexidine gluconate 0.05
Potassium nitrate 1.0
3-Methyl-4-isopropylphenol (manufactured by Wako Pure Chemical Industries, Ltd.) 0.1
2-Isopropyl-5-methylphenol (Wako Pure Chemical Industries, Ltd.) 0.05
Ofloxacin (manufactured by Sigma) 0.01
Purified water remaining
Total 100.0%

[Example 11] Toothpaste silicic acid 20.0%
Sorbit liquid (70% aqueous solution, manufactured by Sanmatsu Kogyo Co., Ltd.) 22.0
Propylene glycol (Asahi Denka) 3.5
Sodium α-olefin sulfonate (manufactured by Lion) 1.8
Saccharin sodium 1.0
Methyl paraoxybenzoate 0.1
Fragrance F 1.0
Allantoin 0.05
Zeolite 0.1
Sodium fluoride 0.02
Ofloxacin (manufactured by Sigma) 0.1
Potassium nitrate 5.0
Tranexamic acid 1.0
Phenoxyethanol (Wako Pure Chemical Industries, Ltd.) 0.5
Ammonium sulfate 1.5
Purified water remaining
Total 100.0%

[Example 12] Toothpaste calcium carbonate 40.0%
Propylene glycol (Asahi Denka) 3.0
Glycerin (Sakamoto Pharmaceutical Co., Ltd.) 20.0
Sodium carboxymethylcellulose 1.5
Titanium oxide 0.5
Sodium lauryl sulfate (Nippon Surfactant Kogyo Co., Ltd.) 0.2
Saccharin sodium 0.1
Ethyl paraoxybenzoate 0.1
Fragrance G 1.0
Phenoxyethanol 0.75
(Avocado Research chemicals)
Closantel (Wako Pure Chemical Industries, Ltd.) 0.1
Glycerol calcium phosphate 1.2
Purified water remaining
Total 100.0%

[Example 13] Toothpaste calcium carbonate 40.0%
Propylene glycol (Asahi Glass Co., Ltd.) 3.0
Glycerin (made by Lion) 20.0
Sodium carboxymethylcellulose 1.5
Titanium oxide 0.2
Sodium lauryl sulfate (manufactured by Toho Chemical Industry Co., Ltd.) 2.5
Saccharin sodium 1.0
Ethyl paraoxybenzoate 0.1
Fragrance A 1.0
Sodium chloride 1.0
Potassium nitrate 5.0
3-methyl-4-isopropylphenol (Wako Pure Chemical Industries, Ltd.) 0.005
Benzethonium chloride 0.1
Ofloxacin (manufactured by Sigma) 0.005
Purified water remaining
Total 100.0%

Example 14 Toothpaste precipitated silica 20.0%
Thickening silica 3.0
Sorbit liquid (Sanmatsu Kogyo Co., Ltd.) 35.0
Propylene glycol (Showa Denko) 2.0
Glycerin (made by Lion) 10.0
Titanium dioxide 0.5
Carrageenan 1.0
Vinyl methyl ether / maleic acid copolymer 1.0
(Gantrez ES-225)
Sodium lauryl sulfate (manufactured by Kao) 1.5
Saccharin sodium 1.0
Ethyl paraoxybenzoate 0.1
Fragrance B 1.0
Potassium nitrate 5.0
3-Methyl-4-isopropylphenol (Wako Pure Chemical Industries, Ltd.) 0.02
Triclosan (Ciba-Geigy) 0.05
Closantel (Wako Pure Chemical Industries, Ltd.) 0.01
Purified water remaining
Total 100.0%

[Example 15] Liquid dentifrice glycerin (manufactured by Sakamoto Product Co., Ltd.) 35.0%
Propylene glycol (Dow Chemical Co.) 5.0
Sodium polyacrylate 0.5
Silicic anhydride 15.0
Sodium lauryl sulfate (manufactured by Toho Chemical Industry Co., Ltd.) 1.0
Saccharin sodium 0.3
Sodium benzoate 0.3
Triclosan (Promochem) 0.1
β-glycyrrhetinic acid 0.05
Fragrance C 4.0
Potassium nitrate 3.0
Tranexamic acid 0.1
Tryptophan 0.5
Ofloxacin (manufactured by Sigma) 0.05
Purified water remaining
Total 100.0%

[Example 16] Mouthwash glycerin (manufactured by Lion) 15.0%
Ethanol (made by New Energy and Industrial Technology Development Organization) 15.0
Polyoxyethylene (20) hydrogenated castor oil 1.0
(Nippon Surfactant Kogyo Co., Ltd.)
Saccharin sodium 0.01
Sodium benzoate 0.3
Fragrance D 4.0
Dye 0.004
Sodium monoglyceride sulfate 0.3
Disodium phosphate 0.05
Potassium nitrate 1.0
Sodium inosinate 1.0
Glycerol sodium phosphate 1.5
Triclosan 0.15
(Calbiochem-Novabiochem)
Ofloxacin (manufactured by Sigma) 0.001
Purified water remaining
Total 100.0%

[Example 17] Mouthwash ethanol (manufactured by New Energy and Industrial Technology Development Organization) 50.0%
Glycerin (made by Lion) 30.0
Polyoxyethylene (10) hydrogenated castor oil (Wako Chemical Co., Ltd.) 1.0
Saccharin sodium 0.3
Dye 0.0002
Fragrance E 3.0
Lysozyme chloride 0.3
Potassium nitrate 5.0
Ofloxacin (manufactured by Sigma) 0.005
Triclosan (Ciba-Geigy) 0.01
Ammonium sulfate 0.2
Purified water remaining
Total 100.0%

[Example 18] Gum gum agent Xylitol 30%
Maltitol 30
Lysozyme 0.1
Ofloxacin (manufactured by Sigma) 0.015
3-methyl-4-isopropylphenol (Wako Pure Chemical Industries, Ltd.) 0.05
Fragrance F 2
Gum base remaining
Total 100.0%

  The fragrances A to G are as follows.

* Fruit mix flavor FM3000 (mixed fragrance)
Strawberry flavor 40%
Apple flavor 15
Melon Flavor 17
Banana Flavor 10
Peach flavor 5
Orange oil 2.5
Raspberry flavor 2.0
Pineapple flavor 15
Grape flavor 1.0
Tropical fruit flavor 1.5
Milk flavor 1.0
Grapefruit oil 0.5
Lemon oil 0.5
Rose oil 0.2
Ethanol ** remaining
Total 100%
** New Energy and Industrial Technology Development Organization

As described above, the same evaluations as in the experimental examples were performed on Examples 6 to 18, and as a result, the number of remaining biofilms was 6.0 × 10 ⁶ cfu / well or less, and good results were obtained. .

Claims (1)

A phenolic fungicide containing an ofloxacin represented by the following formula (1) and a histidine kinase inhibitor selected from closantel represented by the following formula (2) at a concentration of 0.0001 to 10% by mass relative to the whole composition: And one or more of surfactants and alcohols.