JPH11139948A - Dental plaque formation inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor free from irritating odor, capable of suppressing the dental plaque formation without killing normal oral bacteria and capable of preventing the occurrence of dental caries and periodontal diseases by compounding a specific isothiocyanate compound. SOLUTION: An isothiocyanate compound having the formula: CH1 =CH (CH2 )m NCS [(m)=2-10] (e.g. 3-butenyl isothiocyanate or 4-pentenyl isothiocyanate) or an isothiocyanate compound having the formula: RS(CH2 )n NCS [(n)=1-10; R is a 1-4C alkyl] (e.g. methylthiomethyl isothiocyanate or ethylthiomethyl isothiocyanate) is compounded in an oral hygienic agent or a drink in a concentration of about 0.01-100 ppm.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a plaque formation inhibitor comprising an isothiocyanate compound. By mixing the plaque formation inhibitor of the present invention with various confectionery, foods and drinks such as juices, or toothpastes and oral hygiene agents such as mouthwashes, plaque formation is inhibited, and dental caries and teeth are prevented. Peripheral disease can be prevented.

[0002]

2. Description of the Related Art Recent studies have revealed that dental caries and periodontal disease are triggered by oral bacteria. That is, oral microorganisms, especially Streptococcus
Glucosyltransferase (GTase), an extracellular enzyme of Streptococcus mutans (S. mutans), converts sucrose (sucrose) in food into sticky glucan, which adheres to the tooth surface. To form plaque, which is an aggregate of bacterial cells,
S. in plaque Microorganisms such as mutans and gram-negative bacteria proliferate, and these microorganisms produce organic acids such as lactic acid by fermentation. This organic acid lowers the pH of the tooth surface,
Tooth demineralization occurs, caries is induced, and periodontal disease is caused by gram-negative bacterial toxins. Therefore, S.
By stopping the activity of mutans and inhibiting the production of GTase and thus the production of sticky glucan, the occurrence of dental caries and periodontal disease can be prevented.

Conventionally, S.I. Various fungicides and antibiotics have been used to suppress the activity of mutans, but each has drawbacks and has not always produced satisfactory results. For example, antibiotics such as tetracycline and minocycline are unsuitable for long-term use because of their side effects and resistance, and bactericides such as chlorhexidine have the disadvantages of being highly toxic and coloring teeth and tongue. Furthermore, since antibiotics and bactericides generally kill normal bacteria in the oral cavity, the normal bacterial flora changes, resulting in abnormal reproduction of fungi and the like, which is undesirable for living organisms.

On the other hand, allyl isothiocyanate, a kind of isothiocyanate compound, is known to have an antibacterial activity against Bacillus subtilis and Aspergillus niger, and is used as a plaque formation inhibitor. (US Patent 3,940,476). However,
Allyl isothiocyanate is the main ingredient of wasabi spicy, has a strong pungent odor, and does not have a strong inhibitory effect on plaque formation. It is difficult to use. In addition, benzyl isothiocyanate is used in S.P. It has been reported that it is effective in suppressing the growth of mutans and acid production (Microbios
Letters 39, 143-151, 1988), since this compound has extremely poor stability in aqueous solution and has a strong pungent odor,
The use in the oral cavity is considerably restricted in terms of the amount added.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to eliminate the above-mentioned disadvantages in the prior art, to have no irritating odor, to be able to mix foods and drinks and mouth washes, and to have a normal oral cavity. An object of the present invention is to provide a plaque formation inhibitor capable of suppressing plaque formation without killing various bacteria and preventing the occurrence of dental caries and periodontal disease.

[0006]

According to the present invention, there is provided a compound of the formula (I) CH ₂ 2CH— (CH ₂ ) _m —NCS (I) wherein m is an integer of 2 to 10; _{R-S- (CH 2) n} -NCS (II) ( wherein, n represents an integer of 1 to 10, R represents a C ₁ -C ₄ alkyl group) plaque consisting of isothiocyanate compounds with Consists of a formation inhibitor.

In the above formula (I), m represents an integer of 2 to 10, preferably 3 to 8, particularly preferably 3 to 5. In the above formula (II), n represents an integer of 1 to 10;
An integer of 8, especially 4 to 7, is preferred. R represents a C ₁ -C ₄ alkyl group, and preferred examples include methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl and the like.

Examples of compounds having the formula (I) include 3-
Butenyl isothiocyanate, 4-pentenyl isothiocyanate, 5-hexenyl isothiocyanate, 6-
Heptenyl isothiocyanate, 7-octenyl isothiocyanate and the like can be mentioned. Examples of compounds having the formula (II) include methylthiomethylisothiocyanate,
Ethyl thiomethyl isothiocyanate, n-propyl thiomethyl isothiocyanate, isopropyl thiomethyl isothiocyanate, n-butyl thiomethyl isothiocyanate, 2-methyl thioethyl isothiocyanate,
2-ethylthioethyl isothiocyanate, 2-n-propylthioethyl isothiocyanate, 3-methylthiopropyl thioisothiocyanate, 4-methylthiobutyl isothiocyanate, 5-methylthiopentyl isothiocyanate, 6-methylthiohexylisothiate Ocyanate, 7-methylthioheptyl isothiocyanate, 8
-Methylthiooctyl isothiocyanate, 9-methylthiononyl isothiocyanate and the like.

In the above formula (I) or (II), compounds wherein m is 5 or less or n is 8 or less are known to be contained in aroma components such as wasabi and horseradish. Since the amount is very small, it is appropriate to use a synthesis for industrial production.

The compound having the formula (I) can be prepared by reacting the compound of the formula (III) CH ₂ ＣＨCH— (CH ₂ ) _m -X (III) in an inert solvent according to the method described in, for example, JP-A-2-221255. (Wherein m has the same meaning as described above, and X represents a halogen atom such as bromine, chlorine or iodine), and the resulting alkenyl thiocyanate is reacted with a thiocyanate. By isomerization in a polar aprotic solvent.

[0011] Compounds having the formula (II), for example according to the method described in JP-A-7-215931, in an inert solvent, formula _{(IV) CH 2 = CH- (} CH 2) n-2 -NCS ( IV) ω-alkenyl isothiocyanate having the formula (V) R-SH (V) wherein n has the same meaning as described above, wherein R has the same meaning as described above. ) Is obtained by reacting with an alkyl mercaptan having

The plaque formation inhibitor of the present invention is blended with an oral hygiene agent or food or drink at a concentration of about 0.01 to 100 ppm according to a conventional method. The dosage form of the oral hygiene agent containing the plaque formation inhibitor of the present invention may be a liquid, a solid, or a semi-solid, a dentifrice, a troche, a liquid or powdery mouthwash, a coating solution, It is applied to chewing gum and the like. Suitable foods and drinks containing the plaque formation inhibitor of the present invention include soft drinks such as juices and confectionery such as candy and chewing gum.

Next, S.I. The effect of the plaque formation inhibitor of the present invention is shown by a test of the rate of adhesion of glucan generated by mutans to a smooth glass surface.

Suppression of adhesion to glass smooth surface Mutant with sucrose-containing Brain heart infusi
It is known that glucan firmly adheres to a smooth surface such as a test tube wall when cultured in an on medium (BHI medium) (manufactured by Nissui Pharmaceutical Co., Ltd.). When the isothiocyanate compound of the present invention is used in SHI in a BHI medium containing sucrose. The following method was used to test how much the smooth surface adhesion exhibited by the mutans was suppressed. In the following tests, all percentages are by weight.

5 ml of the BHI medium was dispensed into a test tube, and the S. cerevisiae which had been frozen and stored was used. Mutans IFO 13955 was inoculated and precultured at 37 ° C. for 24 hours. A sample of the isothiocyanate compound was prepared as an N, N-dimethylsulfoxide solution or an ethanol solution. 0.05 ml of each isothiocyanate sample was added to BH containing 1.0% sucrose.
The medium was added to 4.94 ml of I medium, and the pre-cultured bacteria were diluted to about 1.0 × 10 ⁶ CFU / ml in the medium, and 10 μl of the bacterial solution was inoculated. The culture was performed at 37 ° C. at an elevation angle of 30 ° with respect to the horizontal plane, for 24 to 48 hours. After the completion of the culture, the medium was removed and carefully washed with distilled water so as not to peel off the attached glucan, and dried at 60 ° C. for 3 hours. Then
The weight of glucan adhering to the test tube was measured, and the relative adhesion rate (%) was calculated according to the following equation, when the glucan adhering weight of the control to which no isothiocyanate compound was added was taken as 100%.

[0016]

(Equation 1)

Each of the isothiocyanate compounds was added to 50
When 0 ppm was added, glucan adhesion inhibitory action was observed in all compounds, and the relationship between structure and activity was not clear. Therefore, the relative adhesion rate of glucan when 125 ppm was added.
(%) Is shown in Table 1. From Table 1, it was found that ω-alkenyl isothiocyanate compounds and ω-methylthioalkyl isothiocyanate compounds having long carbon chains had stronger activity than alkenyl compounds having short carbon chains.

[0018]

[Table 1]

Next, the relationship between the carbon chain of the ω-alkenyl isothiocyanate compound and the ω-methylthioalkyl isothiocyanate compound and the relative adhesion ratio of glucan to the smooth glass surface is shown in FIGS. 1 and 2, respectively. As a result, it became clear that the effect of glucan on the smooth surface of the glass increases as the carbon chain becomes longer.

[0020]

EXAMPLES Next, the present invention will be described more specifically with reference to Reference Examples and Examples.

Synthesis Example of Plaque Formation Inhibitor Reference Example 1 Synthesis of 4-pentenyl isothiocyanate 16 g of 4-pentenyl iodide was treated with 1,3-dimethyl-2.
-Dissolved in 16 g of imidazolidinone, 8 g of potassium thiocyanate and 2.7 g of calcium carbonate were added, and the mixed solution was heated and stirred at 75 ° C for 1 hour. Then, the internal temperature is 155 ° C
Then, the mixture was heated and stirred for 6 hours. After removing insolubles, extraction with methylene chloride was performed to obtain a crude oil. The crude oil was distilled under reduced pressure to obtain 2.1 g of 4-pentenyl isothiocyanate. Yield 20%. Boiling point 83 ° C / 96mm
Hg.

Reference Example 2 Synthesis of 6-methylthiohexyl isothiocyanate 0.2 g of TBHP was added to a mixture of 14.1 g of 5-hexenyl isothiocyanate and 48 g of a methanol solution of methyl mercaptan (30%), and the mixture was stirred at room temperature for 2 hours. .
Ethyl acetate was added, washed with water and distilled to obtain 16.1 g of 6-methylthiohexyl isothiocyanate. 82% yield. Boiling point 119 ° C / 0.5 mmHg.

Example 1 Candy A candy containing the plaque formation inhibitor of the present invention was obtained by a conventional method using a candy composition comprising the following components. Sugar 50 Water candy 33 Organic acid 2 Flavor 0.2 Water balance 6-methylthiohexyl isothiocyanate 0.002 Total 100g

Example 2 Chewing gum A chewing gum containing the plaque formation inhibitor of the present invention was obtained by a conventional method using a chewing gum composition comprising the following components. Gum base 20.095 Sugar 53 Glucose 10 Water candy 16.4 Fragrance 0.5 4- Butenyl isothiocyanate 0.0005 Total 100g

Example 3 Toothpaste A toothpaste containing the plaque formation inhibitor of the present invention was obtained by a conventional method using a toothpaste composition comprising the following components. Calcium hydrogen phosphate 20 Silicic anhydride 10 Sorbit liquid 40 Glycerin 10 Benzalkonium chloride 0.01 Thickener 0.6 Fragrance 0.8 Water balance 7-Methylthioheptyl isothiocyanate 0.0001 Total 100 g

Example 4 Mouthwash A mouthwash containing the plaque formation inhibitor of the present invention was obtained by a conventional method using a mouthwash composition comprising the following components. Ethyl alcohol 10.0 Polyoxyethylene hydrogenated castor oil 2.0 Saccharin sodium 0.2 Sodium benzoate 0.1 Glycerin 5.0 Fragrance 0.2 Sodium citrate Appropriate amount (pH adjusted) Water balance 6-methylthiohexylisothiate Oceanate 0.00005 Total 100g

[0027]

EFFECT OF THE INVENTION The plaque formation inhibitor of the present invention comprises Since the formation of plaque due to mutans is effectively suppressed, it can be used as a preventive agent for dental caries and periodontal disease. The plaque formation inhibitor of the present invention is a natural product which is contained in a small amount in the flavor component of wasabi, so that the safety is high, and the difference between the threshold value of the flavor and the effective amount showing the plaque formation inhibitory action is large, It is suitable for use in foods and drinks such as confectionery and juice, or oral hygiene such as toothpaste and mouthwash. The compound having the formula (I) or (II) of the present invention has a feature that the larger the integer of m or n, the less the pungent odor and the stronger the plaque formation inhibitory action.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows that when 31.5 ppm of the ω-alkenyl isothiocyanate compound of the present invention having the above formula (I) is added to a sucrose-containing medium. It is a graph which shows the effect which suppresses glucan adhesion by mutance. The vertical axis represents the relative adhesion rate of glucan, and the horizontal axis represents m in the above formula (VI).

FIG. 2 shows that when R in the above formula (II), 62.5 ppm of the ω-methylthioalkylisothiocyanate compound of the present invention was added to a sucrose-containing medium. It is a graph which shows the effect which suppresses glucan adhesion by mutance. The vertical axis represents the glucan relative adhesion rate, and the horizontal axis represents n in the above formula (VIII).

Claims (3)

[Claims] 1. A formula _{(I) CH 2 = CH- (} CH 2) m -NCS (I) ( wherein, m represents an integer of 2 to 10) or formula (II) R-S- (CH 2 ) _n -NCS (II) (wherein, n represents an integer of 1 to 10, R is plaque formation inhibitor consisting of isothiocyanate compounds having a representative) a C ₁ -C ₄ alkyl group. 2. An oral hygiene agent comprising the plaque formation inhibitor according to claim 1. 3. A food or drink comprising the plaque formation inhibitor according to claim 1.