JP2002003369A - Methionase and/or protease inhibitor and composition for oral cavity application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a methionase and/or protease inhibitor capable of effectively preventing or suppressing the halitosis, or the like, caused by methionase and/or protease and usable as an ingredient of pharmaceuticals, cosmetics, mouth- refreshing candy, or the like, and to obtain a composition for oral cavity application effective for preventing or suppressing the halitosis, or the like, caused by methionase and/or protease. SOLUTION: The methionase and/or protease inhibitor contains one or more substances selected from cinnamaldehyde, citral, n-hexanal, heliotropin, indole, n-octanal, n-nonanal, n-decanal, n-dodecanal, γ-methylindole and their mixture as active components. The composition for oral cavity application contains the inhibitor, a quaternary ammonium salt and a bisbiguanide compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a methionase and / or protease inhibitor which can effectively inhibit methionase and / or protease, and which can be blended in various pharmaceuticals, cosmetics, oral soft drinks and the like. The present invention relates to an oral composition containing the inhibitor and capable of effectively suppressing and preventing bad breath caused by methionase and protease.

[0002]

2. Description of the Related Art In recent years, there has been an increasing interest in odors such as bad breath in daily life, and a number of products for bad breath containing a fragrance or the like for masking the odor and suppressing the odor have been marketed. . Such fragrances are usually blended for the purpose of masking bad breath and the like, and therefore are often used after eating foods and the like that cause bad breath. On the other hand, halitosis caused by periodontal disease and the like has also become a problem, especially in middle-aged and elderly people. Such bad breath is often not noticed by oneself, and products for bad breath that suppress the above-mentioned bad breath are rarely used. Moreover, it is not considered that such bad breath caused by periodontal disease or the like can be suppressed by a conventional bad breath product which masks the above-mentioned bad breath. As the cause of bad breath caused by such periodontal disease, for example, cysteine desulfidase that produces hydrogen sulfide from L-cysteine and methionase that produces methyl mercaptan from L-methionine are known. Therefore, the search for substances that inhibit these enzymes is ongoing. In addition, the above L-
Cysteine and L-methionine are derived from proteins such as exfoliated epithelial cells in the oral cavity, salivary proteins and food residues, and proteases that degrade these proteins are also one of the causes of bad breath caused by periodontal disease and the like. It is considered, and the search for a substance that inhibits such a protease is also in progress.

Conventionally, cinnamaldehyde, citral, n-hexanal, heliotropin, indole, n-octanal, n-nonanal, n-decanal, n-dodecanal, γ-methylindole and the like have been well known as fragrances. It may be blended into various oral products as a fragrance. Some of these fragrances have been found to have effects other than fragrances. For example, citral has a blood flow promoting effect (JP-A-2000-44).
467), and that the cinnamic aldehydes have a dustproof action (Japanese Patent Application Laid-Open No. 7-187793). However, it is not known that these flavors have a methionase and / or protease inhibitory action.

Heretofore, many oral compositions have been proposed which can be blended into toothpastes, mouthwashes, oral fresheners, oral ointments, oral refreshments and the like. And
It is also known to blend various fragrances and blend bactericides according to the purpose. However, there are few compositions that can prevent or suppress the production of methionase and protease, which are considered to be the cause of bad breath caused by periodontal disease, and the development of oral compositions that can effectively prevent such bad breath is needed. Is desired.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to effectively prevent or suppress bad breath caused by methionase and / or protease, and to be incorporated in pharmaceuticals, cosmetics, refreshing confections in the mouth, and the like. To provide a methionase and / or protease inhibitor that can be used as a methionase. Another object of the present invention is to provide an oral composition which can effectively prevent or suppress bad breath caused by methionase and / or protease.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, a specific compound known as a fragrance has become a problem, especially in middle-aged people and the like. It has been found that it has the ability to inhibit methionase and / or protease, which is a part of the cause of bad breath caused by periodontal disease and the like. In addition, they have found that a composition containing a specific compound known as a fragrance and two specific types of fungicides can effectively prevent the above-mentioned bad breath, and completed the present invention. That is, according to the present invention, cinnamamic aldehyde (Cinnamic Aldehyde), citral (Citral), n-hexanal (n-Hexanal), heliotropin (Heliotropin), indole (Indol), n-octanal (n-Octanal), n-Nonanal, n
-N-Decanal, n-Dodecanal
a methionase and / or a protease inhibitor comprising, as an active ingredient, one or more selected from the group consisting of canal), γ-methylindole and a mixture thereof. You. Further, according to the present invention, there is provided an oral composition comprising the methionase and / or protease inhibitor, a quaternary ammonium salt, and a bisbiguanide compound.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. The methionase and / or protease inhibitor of the present invention includes cinamic aldehyde, citral, n-hexanal, heliotropin, indole, n-octanal, n-nonanal, n-decanal, n-dodecanal, γ-methylindole and the like. One or more selected from the group consisting of a mixture is contained as an active ingredient. These compounds are known as fragrances and can be obtained by known methods. The methionase and / or protease inhibitor of the present invention may contain a compound having another methionase and / or protease inhibitory ability in addition to the above-mentioned active ingredient.

[0008] The methionase and / or protease inhibitor of the present invention includes, for example, various pharmaceuticals, foods, and cosmetics, in particular, mouth refreshing sweets, mouth refreshing agents (spray type, etc.), mouthwashes, tooth brushes, bad breath preventing agents, and oral agents. By blending in an ointment or the like, it is possible to effectively prevent and suppress bad breath caused by methionase and / or protease caused by periodontal disease and the like. Therefore, it can be expected to be blended into various middle-aged and elderly products in which periodontal disease and the like are likely to occur. In the methionase and / or protease inhibitor of the present invention, the effective concentration of the above-mentioned essential active ingredient can be appropriately selected according to the kind and combination thereof.
0.0001 mass% or more, preferably 0.01 to 1.0
% By mass is desirable. If it exceeds 10% by mass, the stability, aroma, flavor, etc. of the formulation or product to be compounded may be significantly impaired, which is not preferred.

The oral composition of the present invention contains the methionase and / or protease inhibitor described above, a quaternary ammonium salt, and a bisbiguanide compound, and a desired effect can be remarkably obtained by a combination thereof. . Examples of the quaternary ammonium salt include cetylpyridium chloride, benzethonium chloride, benzalkonium chloride, and mixtures thereof. Examples of the bisbiguanide compound include chlorhexidine gluconate, chlorhexidine hydrochloride, alexidine, and mixtures thereof. The quaternary ammonium salt and the bisbiguanide compound are both compounds known as fungicides, and can be obtained by known methods.

In the oral composition of the present invention, the mixing ratio of the above-mentioned methionase and / or protease inhibitor, quaternary ammonium salt and bisbiguanide compound is indispensable in the case of methionase and / or protease inhibitor. In conversion, the amount is usually 0.0001% by mass or more, preferably 0.01 to 1.0% by mass, based on the formulation or product containing the oral composition, 0.0001% by mass or more, preferably 0.001% by mass or
The amount of the bisbiguanide compound is usually 0.0001% by mass or more, preferably 0.1% by mass, based on the total amount of the preparation or product containing the oral composition.
001 to 0.3% by mass. The total blending ratio of the methionase and / or protease inhibitor, the quaternary ammonium salt and the bisbiguanide compound is not particularly limited, but a desired bad odor can be prevented without impairing the stability and aroma of the formulation or product to be blended. 0.01
１．５1.5% by mass is desirable.

[0011] The oral composition of the present invention is formulated into, for example, a mouth refreshing confection, a mouth refreshing agent (spray type, etc.), a mouthwash, a toothpaste, an oral malodor preventive, an oral ointment, and the like to effectively treat bad breath, especially Bad breath caused by methionase and / or protease caused by periodontal disease or the like can be prevented or suppressed. Therefore, it is useful as various products for middle-aged and elderly people in which periodontal disease and the like easily occur. In the oral composition of the present invention, other components are appropriately compounded according to the type of each product or preparation, in a range that does not impair the desired purpose, and in order to improve the desired effect or other effects. can do. For example, a surfactant, an abrasive, a wetting agent, a lower alcohol, a thickener, a flavoring agent, a pH adjuster, a coloring agent and the like can be mentioned. Further, a compound having a methionase and / or protease inhibitory ability other than the essential methionase and / or protease inhibitor, a bactericide other than the quaternary ammonium salt and the bisbiguanide compound, and the like can be added. The proportion of each of these other components can be appropriately determined according to the intended oral product.

Examples of the surfactant include alkyl sulfates, polyoxyethylene alkyl sulfates, N-acylamino acid surfactants, alkyl sulfo acetates, α
Anionic surfactants such as olefin sulfonates, sulfosuccinic acid derivatives, and taurate derivatives; polyoxyethylene hydrogenated castor oil, sucrose fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, fatty acid alkanolamides Surfactants, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers and other nonionic surfactants;
Examples include amphoteric surfactants such as betaine type, imidazolinium type, imidazolinium betaine type, amino acid type and amine oxide type. As the abrasive, for example,
Calcium carbonate, dicalcium phosphate, silicic anhydride,
Examples include aluminum hydroxide, calcium pyrophosphate, sodium metaphosphate, magnesium carbonate and the like. Examples of the wetting agent include glycerin, polyethylene glycol, polypropylene glycol, ethylene glycol, 1,3-butylene glycol, sorbitol, xylitol, polyhydric alcohols such as mannitol, and the like. Examples of the lower alcohol include ethanol, propyl alcohol, and isopropyl alcohol. Examples of the thickener include cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose and hydroxypropylcellulose; polysaccharides such as sodium alginate, carrageenan and xanthan gum; synthetic polymers such as sodium polyacrylate; bentonite and laponite And other inorganic clay minerals. Examples of the flavoring agent include saccharin sodium, menthol, peppermint oil, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, perilla oil, eucalyptus oil,
Clove oil, glycyrrhizic acid and its derivatives, perfumes and the like. Examples of the pH adjuster include citric acid, malic acid, phosphoric acid, and salts thereof.

[0013]

Industrial Applicability The methionase and / or protease inhibitor of the present invention can effectively inhibit methionase and / or protease causing bad breath and the like, and its active ingredient is a safe fragrance known as a fragrance. Since it is a compound, it can be widely used in the fields of pharmaceuticals, cosmetics, foods and the like. The oral composition of the present invention,
A methionase and / or protease inhibitor of the present invention,
Because quaternary ammonium salt and bis-biguanide compound are combined and compounded, it is mixed with mouth soft drink, mouth softener (spray type, etc.), mouthwash, toothpaste, bad breath preventive agent, oral ointment, etc. Can prevent and suppress bad breath caused by methionase and / or protease caused by methionase. In particular, it can be expected to be used as various products for middle-aged and elderly people in which periodontal disease and the like are likely to occur.

[0014]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples, but the present invention is not limited thereto. Example 1 The methionase inhibitory effect and protease inhibitory effect of various test compounds shown in Table 1 were measured by the following methods. These results are shown in Table 1 as an average of two measurements. <Methionase inhibitory effect> 0.025 ml of each test compound shown in Table 1 was dissolved in 0.475 ml of ethanol.
Porp, an anaerobic bacterium that produces enzymes and proteases that generate methyl mercaptan and hydrogen sulfide in this solution
hyromonas gingivalis (hereinafter referred to as Pg bacteria) cell suspension
(OD of 610 nm = 1.4) 1 ml was added and stirred.
Incubated at 0 ° C for 5 minutes. After adding 0.5 ml of the L-methion solution thereto and further incubating for 10 minutes, the amount of methyl mercaptan present in the head space of the container was measured using a methyl mercaptan detector tube. The control was 0.025 m of each of the test compounds described above.
The operation was performed in the same manner as described above except that 0.025 ml of distilled water was used instead of 1 to measure the amount of methyl mercaptan. The methionase inhibition rate was determined according to the following equation. Methionase inhibition rate (%) = [(amount of methyl mercaptan in control solution−amount of methyl mercaptan in solution containing test compound) / (amount of methyl mercaptan in control solution)]
× 100 <Protease inhibitory effect> Dissolve 0.03 ml of each of the test compounds shown in Table 1 in 0.3 ml of ethanol, add 0.5 ml of a Pg cell suspension to this solution, and stir.
Incubated at 5 ° C for 5 minutes. Add casein solution 2
ml was added and incubated at 35 ° C. for 10 minutes. Thereafter, 2.5 ml of a trichloroacetic acid solution was added to stop the reaction, and a Folin reagent was added to develop a color. Then, the absorbance at 660 nm was measured, and the titer of the protease was determined from a previously prepared calibration curve. The control is 0.03 m of various test compounds.
The same procedure as above was repeated except that 0.03 ml of distilled water was used instead of 1 to determine the protease titer. The protease inhibition rate was determined according to the following equation. Protease inhibition rate (%) = [(Protease titer of control solution−Protease titer of test compound-containing solution)
/ (Protease titer of control solution)] × 100

[0015]

[Table 1]

From the results in Table 1, it was found that all the compounds shown in Table 1 have methionase and / or protease inhibitory activity and can be used as an active ingredient of these inhibitors.

Examples 2 to 11 Methionase and / or methionase having the composition shown in Table 2 (a) to (j).
Or a protease inhibitor and a bactericide, polyoxyethylene (POE) hydrogenated castor oil (100EO) 2% by mass, concentrated glycerin 8% by mass, denatured ethanol 5% by mass, saccharin sodium 0.04% by mass, pH adjuster A mouthwash was prepared according to a conventional method using the purified water residue.

[0018]

[Table 2]

Next, ten subjects who felt bad breath were used with each of the above prepared mouthwashes, and the degree of bad breath was measured by a specialized panel. That is, the degree of the smell of breath of each subject was evaluated by a specialized panel at a distance of about 60 cm from the subject before using the mouthwash, and 5 minutes and 2 hours after using the mouthwash. The ratio of the number of persons whose degree of bad breath decreased compared to before use was taken as the evaluation result. Table 3 shows the results.

[0020]

[Table 3]

Comparative Examples 1 to 6 Methionase and / or methionase having the composition shown in (a) to (j) of Table 2
Or, instead of protease inhibitors and bactericides,
Examples 2-1 except that the compositions shown in (k) to (p) were used.
Mouthwash was prepared in the same manner as in Example 1, and the degree of bad breath was evaluated. Table 5 shows the results.

[0022]

[Table 4]

[0023]

[Table 5]

Examples 12 to 21 Methionase and / or methionase having the composition shown in Table 2 (a) to (j).
Or a protease inhibitor and a bactericide, coconut oil fatty acid amidopropyl betaine 0.75% by mass, POE hydrogenated castor oil (100EO) 2% by mass, concentrated glycerin 8% by mass, denatured ethanol 5% by mass, saccharin sodium 0.04
Using the mass%, the appropriate amount of the pH adjuster, and the remainder of purified water,
Water toothpaste was prepared according to a conventional method. Next, the degree of bad breath intensity was evaluated in the same manner as in Examples 2 to 11, using the above-mentioned water toothpastes instead of the mouthwash. Table 6 shows the results.

[0025]

[Table 6]

Comparative Examples 7 to 12 Methionase and / or methionase having the composition shown in Table 2 (a) to (j).
Or, instead of protease inhibitors and bactericides,
Examples 12 to except that the compositions shown in (k) to (p) were used
Water toothpaste was prepared in the same manner as in Example 21, and the degree of bad breath was evaluated. Table 7 shows the results.

[0027]

[Table 7]

Examples 22 to 31 Methionase and / or methionase having the composition shown in (a) to (j) of Table 2
Or a protease inhibitor and a bactericide, l-menthol 0.1% by mass, mentha oil 0.1% by mass, polyglycerin fatty acid ester 4% by mass, ethanol 45% by mass, saccharin sodium 0.01% by mass, pH adjuster appropriate amount, In addition, a mouth freshener was prepared according to a conventional method using the purified water residue. Next, the degree of bad breath intensity was evaluated in the same manner as in Examples 2 to 11, except that the above-mentioned mouth fresheners were used instead of the mouthwash. Table 8 shows the results.

[0029]

[Table 8]

Comparative Examples 13 to 18 Methionase and / or methionase having the compositions shown in (a) to (j) of Table 2
Or, instead of protease inhibitors and bactericides,
Examples 22 to 20 except that the compositions shown in (k) to (p) were used.
In the same manner as in No. 31, an oral freshener was prepared, and the degree of bad breath intensity was evaluated. Table 9 shows the results.

[0031]

[Table 9]

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61K 31/44 A61K 31/44 A61P 1/02 A61P 1/02 43/00 111 43/00 111 C12N 9/99 C12N 9 / 99 F term (reference) 4C083 AC211 AC691 AC841 CC41 DD23 DD27 EE34 4C086 AA01 AA02 BC13 BC17 MA01 MA02 MA04 MA57 NA14 ZA67 ZB35 ZC20 4C206 AA01 AA02 CB02 CB05 HA31 MA01 MA02 MA04 MA77 NA14 ZA67 ZB35

Claims (3)

[Claims] 1. A cinnamaldehyde, citral,
n-hexanal, heliotropin, indole, n-
Octanal, n-nonanal, n-decanal, n-
A methionase and / or protease inhibitor comprising, as an active ingredient, one or more selected from the group consisting of dodecanal, γ-methylindole, and a mixture thereof. 2. An oral composition comprising the methionase and / or protease inhibitor according to claim 1, a quaternary ammonium salt, and a bisbiguanide compound. 3. The oral composition according to claim 2, wherein the quaternary ammonium salt contains at least cetylpyridium chloride, and the bisbiguanide compound contains at least chlorhexidine gluconate.