KR20130022379A - Composition for oral ointment and germicide for oral biofilm - Google Patents

Abstract

PURPOSE: An oral ointment composition and an oral biofilm germicide containing a cationic antibacterial agent, azulene, monovalent alcohol, and water soluble vinyl-based polymer compounds are provided to ensure a high germicidal effect. CONSTITUTION: An oral ointment composition contains a cationic antibacterial agent, azulene, monovalent alcohol, and water soluble vinyl-based polymer compounds. The cationic antibacterial agent is one or more kinds of quartenary ammonium salts selected from cetyl pyridinium chloride, benzethonium chloride, and benzalkonium chloride. The water soluble vinyl-based polymer compounds are polyvinyl pyrrolidone and/or carboxyvinyl polymers.

Description

Ointment composition and oral biofilm fungicide for oral cavity {COMPOSITION FOR ORAL OINTMENT AND GERMICIDE FOR ORAL BIOFILM}

The present invention relates to an oral ointment composition and oral biofilm sterilizing agent which is excellent in the oral biofilm sterilizing effect and whose sterilizing effect persists.

Periodontal disease is an inflammatory disease that begins when the periodontal causative bacteria, which is one of pathogenic bacteria in the oral cavity, settles in the oral cavity. Insufficient oral clearance causes plaque (oral bacteria and its metabolites) to adhere to the gum and tooth boundaries, to settle and proliferate. In response to this foreign matter, neutrophils and macrofuges infiltrate, and inflammation occurs. This inflammation is improved if the oral cavity can be cleaned by brushing or the like at an early stage. However, when the state where the plaque accumulates is left, inflammation increases, and when the periodontal pocket is formed, the plaque accumulated therein becomes difficult to remove by brushing or the like. Therefore, it is said that it is useful to suppress plaque, that is, to sterilize and sterilize pathogenic bacteria in the oral cavity as an effective means for preventing and improving periodontal disease.

In recent years, plaques have been identified as biofilms (see Non-Patent Document 1: Science 284, p1318-1322, 1999), and bacteria in oral biofilms (flags) have a protein expression pattern and drug resistance of bacteria as compared to floating bacteria. It has been evident that drugs that have been significantly different and that have been effective for suspended bacteria are not effective for biofilm constituting bacteria.

Many antibacterial agents, such as cation antibacterial agents such as cetylpyridinium chloride, benzetonium chloride, chlorhexidine, and nonionic antimicrobial agents such as triclosan, are known to be effective as a sterilizing means. For example, triclosan can be inhibited from plaque by blending it into a skirt composition as a plaque forming inhibitor (Patent Document 1: JP-A-60-239410) and phenolic compounds such as thymol in an oral composition. (Patent Document 2: Japanese Patent Laid-Open No. 2001-526202) is known.

However, it was evident that only these antibacterial agents could not obtain a sufficient biofilm inhibitory effect by the drug resistance mechanism of biofilm bacteria. In order to improve the bactericidal power of the antimicrobial agent, an improvement technique by improving the retention of the antimicrobial agent (Patent Document 3: Japanese Patent Application Laid-Open No. 08-26953) or use in combination with a flavor component (Patent Document 4: Japanese Patent Application Laid-Open No. 2002-370953) Although this has been proposed, no significant effect can be obtained due to poor drug penetration into the biofilm.

Moreover, as a biofilm suppression composition, the composition which mix | blended lactone and / or furan derivative (patent document 5: Unexamined-Japanese-Patent No. 2004-155681), the composition which mix | blended a nonionic antimicrobial agent and a dicarbon oxide compound (patent document 6: Japan) Japanese Patent Application Laid-Open No. 2005-015369), a composition in which cranberries or an extract thereof is blended (Patent Document 7: Japanese Patent Laid-Open No. 2009-155271) is proposed. However, these technologies have problems with cost, supplyability, formulation stability, and the like, and have not been introduced to the market yet.

On the other hand, it is known that oily components, such as asteraceae, camomile, changmok, and eucalyptus, have anti-inflammatory effects for a long time, and the anti-inflammatory components are azulene, such as camazulene and guai zulene. Originally, azulene insoluble in water becomes water-soluble by chemical synthesis such as sulfonation. In particular, azulenesulfonate, a derivative of guazulene, has anti-inflammatory action, anti-allergic action, anti-ulcer action, tissue repair action, and the like, and thus is widely used for treatment or prevention in various medical fields.

Azulene is a dark blue crystal or liquid, and when sodium azulene sulfonate is dissolved in water, it becomes a blue violet aqueous solution. However, it is known that azulene in an azulene aqueous solution decomposes under the influence of light, heat, oxygen, and the like, and the aqueous solution discolors. Therefore, as a method of stabilizing an azulene liquid formulation, a method in which a hydrogen carbonate is blended with an alcohol having a concentration of 30 to 100% by weight in a liquid formulation containing azulene (Patent Document 8: Japanese Patent Application Laid-Open No. 7). -35342 has been proposed, but this method requires the addition of a large amount of alcohol as a solvent, and there is room for improvement in terms of irritation when used in the oral cavity. In addition, a method of improving azulene stability in a liquid formulation by dissolving a water-soluble azulene in a buffer solution and adding a condensed phosphate (Patent Document 9: Japanese Patent Application Laid-Open No. 58-144365), a positive amount in an azulene aqueous solution A method for stabilizing by combining a theoretical surfactant or chlorhexidine with a nonionic surfactant (Patent Document 10: Japanese Patent Laid-Open No. 59-196816) is disclosed. However, these stabilization methods are insufficient in terms of long-term stability. Thus, although various examination is made about stabilization of azulene, all are limited to examination in aqueous solution.

Patent Document 1: Japanese Patent Application Laid-Open No. 60-239410 Patent Document 2: Japanese Patent Application Laid-Open No. 2001-526202 Patent Document 3: Japanese Patent Application Laid-Open No. 08-26953 Patent Document 4: Japanese Patent Application Laid-Open No. 2002-370953 Patent Document 5: Japanese Patent Application Laid-Open No. 2004-155681 Patent Document 6: Japanese Patent Application Laid-Open No. 2005-015369 Patent Document 7: Japanese Patent Application Laid-Open No. 2009-155271 Patent Document 8: Japanese Patent Application Laid-Open No. 7-35342 Patent Document 9: Japanese Patent Application Laid-Open No. 58-144365 Patent Document 10: Japanese Patent Application Laid-Open No. 59-196816

Non-Patent Document 1: Science 284, p1318-1322, 1999

Because of this current state, new sterilization techniques effective against bacteria in oral biofilms are desired instead of conventional techniques.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an oral ointment composition and oral biofilm sterilizing agent which achieves a high oral biofilm sterilizing effect and the effect is continued.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to achieve the said objective, when using together (A) cationic antibacterial agent and (B) azulene, high oral biofilm sterilization effect is expressed, and such a combination system and (C) lower grade 1 By blending the dihydric alcohol and the (D) water-soluble vinyl polymer compound, the azulene is stabilized over time in the ointment composition, particularly in the water-soluble ointment composition, and the oral biofilm sterilization effect is maintained, thereby providing a high The present invention has been accomplished by finding that an oral ointment composition and oral biofilm sterilizing agent can be provided which achieves oral biofilm sterilization effect and the germicidal effect is continued.

That is, cationic antimicrobial agents such as cetylpyridinium chloride and benzetonium chloride have high antibacterial effect in the oral cavity, but the oral biofilm sterilization effect is very weak. When used together, it unexpectedly discovered that the oral biofilm sterilization effect was expressed effectively. However, it has also been found that there is a problem that it is difficult to stably blend azulene in the ointment composition for oral cavity in this case. That is, the present inventors blended water-soluble azulene, such as sodium guazulene sulfonate, with a water-soluble ointment mainly composed of a cellulose-based water-soluble high molecular compound, which is a general water-soluble high molecular compound. And disassembly was confirmed. Therefore, the present inventors conducted further studies to stably blend azulene in an ointment composition. As a result, when a lower monohydric alcohol and a water-soluble vinyl polymer compound are combined with azulene, decomposition of azulene is suppressed and stabilized. In particular, in the water-soluble ointment composition, it has been found that the oral biofilm sterilization effect by the combination system lasts and achieves a high sterilization effect even after long-term storage.

Accordingly, the present invention provides the following oral ointment compositions and oral biofilm fungicides.

[One]

An oral ointment composition comprising (A) a cationic antimicrobial agent, (B) azulene, (C) a lower monohydric alcohol and (D) a water-soluble vinyl polymer compound.

[2]

The composition as described in [1] whose (A) component / (B) component is 0.2-50 as mass ratio.

[3]

(A) The composition as described in [1] or [2] whose cationic antibacterial agent is 1 or more quaternary ammonium salts chosen from cetylpyridinium chloride, benzetonium chloride, and benzalkonium chloride.

[4]

(D) The composition as described in [1] or [2] whose water-soluble vinyl polymer compound is a polyvinylpyrrolidone and / or a carboxyvinyl polymer.

[5]

The composition as described in [1] or [2] whose content of (A) component is 0.01-1 mass%, and content of (B) component is 0.01 mass% or more and less than 0.4 mass%.

[6]

[1] or [2], wherein the composition does not contain petroleum hydrocarbons.

[7]

An oral biofilm fungicide comprising (A) a cationic antibacterial agent, (B) azulene, (C) lower monohydric alcohol and (D) a water-soluble vinyl polymer compound.

[8]

[7] The sterilizing agent described in [7] whose (A) component / (B) component is 0.2-50 as mass ratio.

According to the present invention, it is possible to provide an oral ointment composition and oral biofilm sterilizing agent which achieves a high oral biofilm sterilization effect and which the sterilizing effect lasts.

Hereinafter, the present invention will be described in more detail. The ointment composition for oral cavity of this invention contains (A) cationic antibacterial agent, (B) azulene, (C) lower monohydric alcohol, and (D) water-soluble vinyl type polymer.

(A) Component: Cationic Antibacterial Agent

As the cationic antimicrobial agent, bisguanides or quaternary ammonium salts are used, and for example, chlorhexidines such as cetylpyridinium chloride, benzogenium chloride, benzalkonium chloride, dequalinium chloride, chlorhexidine gluconate, embrittled domiphene, and the like are used. Can be mentioned. One type selected from these can be mix | blended individually or in combination of 2 or more types. Preferably, it is a quaternary ammonium salt, Specifically, cetylpyridinium chloride, benzetonium chloride, and benzalkonium chloride are mentioned.

The amount of the cationic antimicrobial agent is preferably 0.01% to 1% (mass% or less), particularly 0.02% to 1%, particularly 0.02% to 0.5%, in terms of biofilm sterilization. If the blending amount is less than 0.01%, sufficient biofilm sterilization effect may not be obtained. Even if it mix | blends more than 1%, the improvement of a biofilm sterilization effect cannot already be desired, the bitter taste may be reversed, and it may be unsatisfactory for use in an oral cavity. It is preferable not to exceed 1% in order to achieve compatibility with the efficacy of the formulation.

(B) Ingredient: Azulene

Azulene is an ingredient contained in the Asteraceae plant Camolena, Rhubarb, Eucalyptus, etc., and has been used for various anti-inflammatory diseases for a long time as a folk medicine.

Here, azulene also includes derivatives of azulene, water-soluble salts thereof, and the like. Representatives of such azulene include azulene derivatives such as camazulene (1,4-dimethyl-7-ethylazulene) and guiazulene (1,4-dimethyl-7-isopropylazulene) The water-soluble salt which introduce | transduced the sulfonic acid group into the 3rd position of these azulene derivatives is mentioned, These are also called water-soluble azulene and guai zulensulfate. Although a water-soluble salt is not specifically limited, A sodium salt, potassium salt, an ammonium salt, etc. can be illustrated, It is preferable to use a sodium salt especially. Among these azulenes, sodium azulene sulfonate is more suitable.

As for the compounding quantity of azulene, 0.01% or more and less than 0.4% of the whole composition, especially 0.02 to 0.3%, and especially 0.02 to 0.2% are preferable. If the blending amount is less than 0.01%, sufficient biofilm sterilization effect may not be obtained. Even if 0.4% or more is blended, the biofilm sterilization effect cannot be enhanced, and consequently, the sweetness peculiar to azulene may come out, which may not be good for use in the oral cavity. Less than 0.4% is desirable in achieving both effectiveness and use.

As for the compounding ratio of (A) cationic antibacterial agent and (B) azulene, it is preferable that (A) / (B) is 0.2 or more, especially 0.25 or more as a mass ratio from the point of expression of a biofilm sterilization effect, and a preferable range Is 0.2 to 50, more preferably 0.25 to 30, still more preferably 0.25 to 20. By setting it as said range, a biofilm sterilization effect can be acquired more.

(C) Component: Lower Monohydric Alcohol

In the present invention, by combining the lower monohydric alcohol (C) in combination with the (D) water-soluble vinyl polymer, the azulene is stabilized, whereby the oral biofilm sterilization effect of the combination system is increased and high sterilization even after long-term storage. Effect.

As the lower monohydric alcohol, as a compound represented by the general formula ROH, R is preferably a linear or branched alkyl group having 6 or less carbon atoms, especially 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. Specifically, methanol, ethanol, propanol, isopropanol, butanol, etc. are mentioned, One type selected from these can be used individually or in combination of 2 or more types. In particular, ethanol is suitable.

As for the compounding quantity of a lower monohydric alcohol, 0.1-25%, especially 0.1-20% of the whole composition are preferable at the point of stabilization of azulene. If the amount is less than 0.1%, the stability of azulene may not be ensured. When it exceeds 25%, even if the stability of azulene can be secured, the stability as an ointment formulation may not be secured. In order to make stabilization of azulene and stabilization of a formulation compatible, and to raise the oral biofilm sterilization effect, it is preferable not to exceed 25%.

Moreover, it is preferable to mix | blend a lower polyhydric alcohol with this composition further. In addition to the lower monohydric alcohol of the said (C) component, mix | blending a lower polyhydric alcohol is effective for improving stability of azulene. Specifically, lower polyhydric alcohols, such as glycerin, ethylene glycol, propylene glycol, are mentioned, Especially, glycerin is preferable.

When mix | blending a lower polyhydric alcohol, the compounding quantity will not be specifically limited if it is a range which does not prevent the effect of this invention, but 5 to 60%, especially 10 to 45% of the whole composition is preferable.

(D) component: Water-soluble vinyl polymer compound

Specific examples of the (D) water-soluble vinyl polymer compound include polyvinylpyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, polyacrylate, and the like, and one or two or more selected from these can be used. . In particular, polyvinylpyrrolidone and carboxyvinyl polymers are suitably used. In particular, polyvinylpyrrolidone is suitable in terms of formulation uniformity in preparation of the formulation.

As polyvinylpyrrolidone, the weight average molecular weight (by the light scattering method) is preferably 2,000 to 1,600,000, more preferably 20,000 to 1,400,000, and those of various grades as long as they do not interfere with the effects of the present invention. Can be used. For example, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K60, polyvinylpyrrolidone K90, etc. are mentioned, These 1 type, or 2 or more types can be used.

As a specific commercial product, Plusdon K-25, Plusdon K-90, Plusdon K-90D, Plusdon K-90M, Plusdon K-29 / 32 (manufactured by ISP), Coreidon 12PF, Coreidone 17PF, corridone 25, corridone 30, corridone 90F (made by BASF), etc. are mentioned.

As carboxyvinyl polymer, the range of viscosity (BH type | mold rotational viscometer, density | concentration 0.2 mass%, rotor No. 7, rotation speed 20 rpm, 25 degreeC) is preferable that it is 3,000-80,000 mPa * s, and is 5,000-50,000 mPa * s. It is more preferable. Carboxyvinyl polymers also include salts thereof. Specific commercially available products include Carbopol 914, 934, 934P, 971P, 974P, 980, 981, 2984, 5984, ETD2050, Ultre10 (manufactured by NOVEON), Juron PW-110, PW-111, PW-150, PW. -302, PW-310, PW-350 (made by Nihon Junyaku Co., Ltd.), Hibiswako 103, 104, 105 (made by Wako Junya Co., Ltd.), AQUPECHV-501, HV-504, HV-505 (Sumitomo Seika Co., Ltd. product) etc. can be mentioned, These 1 type, or 2 or more types can be used.

As for the compounding quantity of a water-soluble vinyl type high molecular compound, 0.05-15% of the whole composition, especially 0.1-10%, especially 0.2-5% are preferable at the point of stabilization of azulene. If the blending amount is less than 0.05%, the stability of azulene may not be secured. If it exceeds 15%, the stability of the azulene may be secured, but the stability as an ointment formulation may not be secured. In order to make stabilization of azulene and stabilization of a formulation compatible, and to raise the oral biofilm sterilization effect, it is preferable not to exceed 15%.

Although the compounding ratio of (C) lower monohydric alcohol and (D) water-soluble vinyl polymer compound is not restrict | limited, (C) / (D) is 0.05-130 as mass ratio, especially 0.1-100, Especially 0.5-75 Is preferably. If the ratio is outside the above range, the stability of azulene may not be satisfactorily obtained.

The ointment composition for oral cavity of this invention can be prepared in shape, such as a paste form and a gel form. Moreover, the well-known component normally mix | blended with an ointment composition can be mix | blended with the composition of this invention other than the said component according to the shape etc. arbitrarily. Specifically, a wetting agent, a surfactant, a thickener, a solvent, and, as necessary, a medicinal ingredient, a preservative, a pH adjuster, a flavoring agent, and the like are added, but these components can be blended in a range that does not interfere with the effects of the present invention. .

As an ointment base, a water-soluble base and an oil-soluble base are used, but the composition of this invention is prepared suitably as a water-soluble ointment, and for this reason, a water-soluble base is used suitably. In the present invention, in particular, the decomposition of azulene when the water-soluble azulene is blended with the water-soluble ointment can be effectively suppressed and the stability of the azulene can be improved. Here, in this invention, the water-soluble ointment is what gelatinized the water-soluble high molecular compound with the solvent (water, alcohol, macrogol (polyethylene glycol), etc.), or uses water-soluble bases, such as macrogol. Moreover, especially the composition of this invention does not need to contain useful bases, such as petroleum hydrocarbons, such as a liquid paraffin and solid paraffin.

Examples of the humectant include sugar alcohols such as sorbitol, xylitol, erythritol, maltitol and lactitol in addition to the lower polyhydric alcohol.

Examples of the thickener include cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl cellulose sodium, alginate derivatives such as alginate such as sodium alginate and propylene glycol esters of alginate, xanthan rubber, and tragacanth rubber. And rubbers such as gellan rubber, karaya rubber, and arabian rubber. Among them, alginate is said to have an effect of improving retention in the oral cavity, but in the present invention, it is not necessary to blend the alginate as an essential component.

Although it does not restrict | limit especially as surfactant, A nonionic surfactant is preferable. For example, polyoxyethylene hardened castor oil, sucrose fatty acid ester, stearic acid polyoxyethylene sorbitan ester, stearic acid sorbitan, oleic acid polyoxyethylene sorbitan, etc. are mentioned. Particularly preferred are polyoxyethylene sorbitan fatty acid esters such as sucrose fatty acid ester and stearic acid polyoxyethylene sorbitan.

Examples of the solvent include water, 1,3-butylene glycol, polyethylene glycol such as polyethylene glycol 200 to 20,000, and the like.

Examples of the active ingredient include antimicrobial agents, fungicides, anti-inflammatory agents, antihistamines, tissue repair agents, local anesthetics, herbal medicines, vitamins, and blood circulation promoters.

The pH of the composition is not particularly limited, but a pH at 25 ° C. is 4.5 to 9.6, in particular 5.5 to 9.0.

In addition, although the viscosity of a composition is not specifically limited, 50-300 Pa.s, especially 60-200 Pa by the measured value by BH-type rotational viscometer (measurement conditions: rotor No. 7, rotation speed 20rpm, 60 second after rotation 60 second). It is preferable to adjust to s.

The preparation method of the ointment composition of this invention is not specifically limited, It can prepare according to a daily method, For example, when it is a water-soluble ointment, (A)-(D) component, Furthermore, arbitrary components, such as a water-soluble base, It can prepare by mixing by a normal method.

Moreover, this invention provides the oral biofilm sterilizing agent which consists of (A) cationic antibacterial agent, (B) azulene, (C) lower monohydric alcohol, and (D) water-soluble vinyl type polymer. In this case, the components (A) to (D) are the same as described above, and the blending ratio of each component is the same.

[Example]

Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not limited to the following Example. In addition, in the following example,% represents the mass% unless there is particular notice.

In addition, preparation of the test composition was performed by a routine method.

The detail of the used compound raw material is as follows.

Cetylpyridinium chloride (made by Tokyo Kasei Co., Ltd.)

Benzethonium chloride (made by Tokyo Kasei Co., Ltd.)

Benzalkonium chloride (made by Tokyo Kasei Co., Ltd.)

Azulene sulfonate sodium (made by Alps Pharmaceutical Co., Ltd.)

Ethanol (manufactured by Wako Pure Chemical Industries, Ltd.)

Polyvinylpyrrolidone (ISP, brand name: PLASDONEK-90)

Carboxy vinyl polymer (NOVEON company make, product name: Carbopol980)

[Example, Comparative Example]

The ointment composition for oral cavity of the composition shown to Tables 1-5 was prepared, and the obtained composition was used as a test composition, and the biofilm bactericidal effect and the stability of sodium azulene sulfonate were evaluated by the following method by the following method. The results are shown in Tables 1-5.

And the viscosity of the ointment composition of the obtained Example is 50-100 Pa.s (BH type | mold rotational viscometer, rotor No. 7, rotation speed 20rpm, the measured value at 25 degreeC after 60 second of rotation.), PH is 5.0-0- 7. It was in the range of 0.

(1) Evaluation method of biofilm sterilization effect

The ointment composition for oral cavity prepared as a test composition was provided immediately after preparation (before the preservation test) and after the test described below, and stored at 50 ° C. for 1 month (after the preservation test). Evaluated.

Three species of Actinomyces viscocus ATCC43146, Fusobacterium nucleatum ATCC10953, and Porphyromonas gingivalis ATCC33277 purchased from the American Type Culture Collection (ATCC) 40 microliters of the bacteria solution were autoclaved at 121 ° C. for 15 minutes, respectively. 4) It was added to 4 ml of culture solution (THBHM ^{* 1} ), and it was anaerobic-cultured (80 vol% nitrogen, 10 vol% carbon dioxide, 10 vol% hydrogen) overnight at 37 degreeC.

Similarly, 80 µl of the Bayonella parvula ATCC17745 bacterial solution stored was 4 ml of Tod-Hewitt-Bros (manufactured by Becton and Dickinson) containing 1.26% sodium lactate (manufactured by Sigma) (THBL ^{* 2} ) Was added and cultured in the same manner.

After incubation, 300 µl of each of three bacterial strains except Bayonella parbula was collected, added to 30 ml of THBHM, and incubated overnight. Similarly, 300 µl was collected from Bayonella parbula bacteria, added to 30 ml of THBL, and incubated overnight.

After the culture, each bacterial solution was centrifuged (10,000 rpm, 10 minutes) to discard the supernatant. For each acupuncture (bacteria), a besaldium mucin culture medium (BMM ^{* 3} ) autoclaved at 121 ° C. for 15 minutes was added and resuspended, followed by a culture tank (140 mm in diameter × 200 in height BMM). Mm), each of the bacteria was ingested to be 1 × 10 ⁷ / ml, and stirred with a steerer (rotated at about 100 rpm), at 37 ° C., anaerobic conditions (95 vol% nitrogen, 5 vol% carbon dioxide). Incubated overnight.

Thereafter, BMM was supplied at a rate of 100 mL / h, and the culture solution was discharged at the same rate. The culture liquid discharged | emitted from the said culture tank was continuously supplied to the other culture tank in which liquid quantity was hold | maintained at 300 ml. A rotating plate (rotated at about 80 rpm) in this culture tank was equipped with a 7-mm diameter hydroxyapatite plate treated with human irritant saliva filtered with a 0.45 μm filter for 2 hours as an attachment carrier. It took 21 days on the surface to form a biofilm.

In order to evaluate the biofilm sterilization effect of the test composition, the hydroxyapatite plate to which the biofilm was attached was taken out of the culture tank, transferred to a chalet (35 mm in diameter x 14 mm in height), and the test composition 5 g ^{* 4} shown in the table. After soaking in for 10 minutes, it was washed three times with 5 g of physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.), and the hydroxyapatite to which the biofilm was attached was transferred to a test tube (diameter 13 mm x 100 mm) to which 4 ml of THBHM was added. Immediately by ultrasonic crushing (for 10 seconds at an output of 200 kPa), step dilution (10-fold dilution of 6 steps) was performed, and smeared onto blood agar plate medium ^{* 5} in accordance with the usual method. The flat medium was subjected to anaerobic culture (80 vol% nitrogen, 10 vol% carbon dioxide, 10 vol% hydrogen) until the colonies could be visually identified, and the number of colonies was counted to calculate viable cells.

The result was computed by the following formula of the effect of the test composition which made comparative example 1 the control, and was determined based on the following evaluation criteria from the calculated value.

Biofilm sterilization effect of test composition based on Comparative Example 1 =

 -log (Viable cell number after treatment with test composition / viable cell number after treatment with composition of Comparative Example 1)

Evaluation standard ;

◎: 3.0 or more (high biofilm sterilization effect is recognized.)

(Circle): 2.0 or more and less than 3.0 (Slightly biofilm sterilization effect is recognized.)

(Triangle | delta): 1.0 or more and less than 2.0 (Slight biofilm sterilization effect is recognized.)

X: less than 1.0 (biofilm sterilization effect is equivalent to or inferior to control)

* 1 Composition of THBHM: Shown as the mass in 1 liter.

Todd-Hewitt-Bros (Becton and Dickinson): 30 g / l

Hemin (manufactured by Sigma-Aldrich): 5 mg / l

Vitamin K (made by Wakojunyaku Co., Ltd.): 1mg / ℓ

Distilled Water: Rest

(The volume was made up to 1 L and autoclaved at 121 ° C. for 15 minutes.)

* 2 Composition of THBL: indicated by mass in 1 L.

Todd-Hewitt-Bros (Becton and Dickinson): 30 g / l

60% sodium lactate aqueous solution (manufactured by Sigma Aldrich): 21 g / l

Distilled Water: Rest

(The volume was made up to 1 L and autoclaved at 121 ° C. for 15 minutes.)

* 3 Composition of BMM: Shown as the mass in 1 L.

Proteospeptone (manufactured by Becton and Dickinson): 4 g / l

Tryptone (Becton and Dickinson): 2g / ℓ

Yeast Extract (Becton and Dickinson): 2g / ℓ

Mutin (Sigma-Aldrich): 5 g / ℓ

Hemin (manufactured by Sigma Aldrich): 2.5 mg / l

Vitamin K (manufactured by Wako Pure Chemical Industries, Ltd.): 0.5 mg / l

KCl (manufactured by Wako Pure Chemical Industries, Ltd.): 1g / ℓ

Cysteine (manufactured by Wako Pure Chemical Industries, Ltd.): 0.2 g / ℓ

Distilled Water: Rest

(The volume was made up to 1 L and autoclaved at 121 ° C. for 15 minutes.)

* 4 5 g test composition

10 g of physiological saline was added to 5 g of the test composition using a 20 ml beaker and dispersed at 360 rpm for 3 hours (37 ° C).

* 5 Composition of blood agar plate medium: Shown as the mass in 1 L.

Todd-Hewitt-Bros (Becton and Dickinson): 30 g / l

Agar (Becton and Dickinson): 15g / ℓ

Hemin (manufactured by Sigma-Aldrich): 5 mg / l

Vitamin K (made by Wakojunyaku Co., Ltd.): 1mg / ℓ

Distilled Water: Rest

(The volume was made up to 1 L and autoclaved at 121 ° C. for 15 minutes.)

Matal bleeding blood (manufactured by Nippon Biotest Lab): 50g / ℓ

(After autoclave, cooled to 50 ° C and added)

(2) Evaluation of stability of sodium azulene sulfonate

The test composition was subjected to the harsh test described below. The content of sodium azulene sulfonate was measured one month after the start of the harsh test, and the proportion of sodium azulene sulfonate remaining as compared to before the start of the harsh test was calculated as the residual rate (%) by the following formula. Stability was determined based on the following criteria from the calculated residual rate.

Harsh test;

In the severe test, 20 g of the composition was filled in an epoxy-phenol resin coated coating aluminum tube, and stored at 50 ° C. for 1 month.

The content of sodium azulene sulfonate was measured by high performance liquid chromatography.

Measurement conditions are as follows.

Detector: ultraviolet absorption photometer (measured wavelength: 246 nm).

Column: A 5 µm octadecylsilylated silica gel for a liquid chromatograph was packed into a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm.

Column temperature: constant temperature around 40 ° C.

Mobile phase: After distilled water 900 ml was added to 0.7 ml of triethylamine, the pH was adjusted to 7.5 by adding phosphoric acid, and acetonitrile was added at a ratio of 7: 3 to 1,000 ml of distilled water.

Residual percentage of sodium azulene sulfonate =

                         (Content after harsh test / content before severe test) × 100

Criteria ;

◎: 95% or more and 100% or less

○: 90% or more but less than 95%

×: less than 90%

From the results in Tables 1 to 5, when the (A) cationic antimicrobial agent or (B) azulene is lacking, the biofilm bactericidal effect is not expressed, and even if azulene is used in combination with triclosan or isopropyl methyl phenol, the bio The film sterilization effect was not expressed, but it was found that the biofilm sterilization effect was effectively expressed when the (A) component and the (B) component were used together. Moreover, even if it mix | blends (C) component or (D) component with the combined system of (A) and (B) component, sodium azulene sulfonate cannot be stabilized, but (C) and (D) component are added to the said combined system. It was found that the formulation inhibited and stabilized the degradation of sodium azulene sulfonate over time, and achieved a biofilm sterilization effect even after storage. Therefore, by blending the components (A) to (D), it was confirmed that a high biofilm sterilization effect was achieved and that the sterilization effect continued.

Claims (8)

An oral ointment composition comprising (A) a cationic antimicrobial agent, (B) azulene, (C) a lower monohydric alcohol and (D) a water-soluble vinyl polymer compound. The method of claim 1,
(A) component / (B) component is 0.2-50 as mass ratio, The composition characterized by the above-mentioned. 3. The method according to claim 1 or 2,
(A) A composition wherein the cationic antimicrobial agent is at least one quaternary ammonium salt selected from cetylpyridinium chloride, benzetonium chloride and benzalkonium chloride. 3. The method according to claim 1 or 2,
(D) The composition characterized in that the water-soluble vinyl polymer compound is polyvinylpyrrolidone and / or carboxyvinyl polymer. 3. The method according to claim 1 or 2,
Content of (A) component is 0.01-1 mass%, and content of (B) component is 0.01 mass% or more and less than 0.4 mass%, The composition characterized by the above-mentioned. 3. The method according to claim 1 or 2,
A composition comprising no petroleum hydrocarbons. An oral biofilm fungicide comprising (A) a cationic antimicrobial agent, (B) azulene, (C) a lower monohydric alcohol and (D) a water-soluble vinyl polymer compound. 8. The method of claim 7,
(A) component / (B) component is 0.2-50 as mass ratio, The sterilizing agent characterized by the above-mentioned.