JPH0899849A - Composition for oral cavity - Google Patents

Abstract

PURPOSE: To provide a composition for oral cavity showing increased active oxygen-removing effect and increased absorption into gingiva tissues of ascorbic phosphate and increased prophylactic and remedial effect for periodontal diseases. CONSTITUTION: This composition for oral cavity comprises (A) at least one selected from ascorbic 2-phosphate, ascorbic 3-phosphate, ascorbic 5-phosphate, ascorbic 6-phosphate, ascorbic 2-polyphosphate, ascorbic 3-polyphosphate, ascorbic 5-polyphosphate, ascorbic-6-polyphosphate and their salts and (B) at least one selected from menthone, carvone, cineol, limonene, menthane, anethole, eugenol, cinnamaldehyde and, when needed, in combination of menthol.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention provides a method of combining ascorbic acid phosphoric acid ester with a specific monoterpenoid or a specific phenylpropanoid to eliminate the active oxygen of ascorbic acid phosphoric acid ester and absorb into the gum tissue. The present invention relates to a composition for oral cavity, which is characterized by improving the effect of preventing and treating periodontal disease.

[0002]

BACKGROUND OF THE INVENTION Most periodontal diseases are considered to be infections caused by bacteria mainly of obligate anaerobic Gram-negative bacilli. As a histologic image characteristic of chronic periodontal disease, neutrophil accumulation in the periodontal pocket,
In recent years, periodontal disease has been observed in patients with gingival tissue infiltration of lymphocytes, and in patients with diseases that cause neutrophil hypofunction (such as diabetes and AIDS). Diseases have been recognized as a result of the interaction between the body's defense function centered on neutrophils and bacterial infection.

[0003] Neutrophils in the living body are exuded from blood vessels when infected with bacteria and migrate to the inflamed area to sterilize the bacteria by releasing bacterial hypophages or active oxygen and lysosomal enzymes to protect the living body from infection. To do. As described above, neutrophils originally protect the living body, but when they are chronically or acutely stimulated, they leak cell components and produce excessive active oxygen, which damages living tissues. Giving it, on the contrary, will make the inflammation worse.

Therefore, in order to prevent the above-mentioned tissue damage due to active oxygen, utilization of various antioxidants has been studied. Ascorbic acid phosphate is one of them,
Prevention of periodontal disease by a composition for oral cavity containing ascorbic acid phosphoric acid ester as an antioxidant is disclosed in, for example, JP-A-62-96408.

However, the active oxygen scavenging effect when ascorbic acid phosphoric acid ester is used alone as an antioxidant is not so high, and ascorbic acid phosphoric acid ester is metabolized in the oral cavity. Although the effect is enhanced, there is a problem that it cannot reach the affected area and exert a high effect due to poor absorption into the mucous membrane.

The present invention has been made to solve the above problems, and is a composition for oral cavity which is effective for more effectively eliminating active oxygen in periodontal inflamed tissues and for preventing / treating periodontal diseases. The purpose is to provide.

[0007]

Means and Actions for Solving the Problems As a result of intensive studies to achieve the above object, the present inventor used ascorbic acid phosphate in combination with a specific monoterpenoid or a specific phenylpropanoid. By doing so, it was found that each active oxygen scavenging effect and absorbability to mucous membranes are synergistically increased, and that it is more effective if menthol is further used in combination with the above-mentioned combination, and the present invention has been completed. It was

That is, according to the present invention, ascorbic acid phosphoric acid ester is used in combination with one or more selected from menthone, carvone, cineole, limonene, menthane, anethole, eugenol and cinnamic aldehyde. A featured oral composition is provided.

The present invention will be described in more detail below. The ascorbic acid phosphoric acid ester used in the present invention is a derivative having a phosphoric acid group at any of the 2, 3, 5 and 6 positions of ascorbic acid. , For example, ascorbic acid-2-phosphate ester, ascorbic acid-3-phosphate ester, ascorbic acid-5-phosphate ester, ascorbic acid-6-phosphate ester, ascorbic acid-2-
Examples thereof include polyphosphoric acid ester, ascorbic acid-3-polyphosphoric acid ester, ascorbic acid-5-polyphosphoric acid ester, ascorbic acid-6-polyphosphoric acid ester and water-soluble salts thereof. One of these ascorbic acid phosphoric acid esters may be used alone or two or more thereof may be used in combination, and ascorbic acid-2-phosphoric acid ester magnesium salt is particularly preferably used from the viewpoint of stability of the composition. .

The compounding amount of ascorbic acid phosphoric acid ester in the oral composition of the present invention is not particularly limited, but 0.001 to 10% (wt%, the same applies hereinafter) of the entire composition,
In particular, 0.01 to 5% is preferable. If it is less than 0.001%, the effect of the ascorbic acid phosphate ester as an antioxidant may not be sufficient, and if it exceeds 10%, the usability of the oral composition may be adversely affected.

The oral composition of the present invention comprises the ascorbic acid phosphoric acid ester in combination with one or two of a specific monoterpenoid and a specific phenylpropanoid.

The specific monoterpenoids in the present invention are menthone, carvone, cineole, limonene and menthane, and one of these monoterpenoids can be used alone or in combination of two or more kinds.
As menthone, carvone, cineol, limonene, and menthane, those isolated from essential oils or those synthesized, or the essential oils containing them may be used.

Further, the specific phenylpropanoids used in the present invention are anethole, eugenol and cinnamic aldehyde, and one of these phenylpropanoids can be used alone or in combination of two or more kinds. . The amount of the above monoterpenoid and phenylpropanoid is 0.0001-based on the total composition.
5%, especially 0.001-1% is preferable. 0.0001
If it is less than 5%, the effect of using it together with ascorbic acid phosphoric acid ester may not be sufficient, and if it exceeds 5%, the usability of the oral composition may be adversely affected.

In the present invention, it is desirable to further add menthol, which can further improve the active oxygen scavenging effect of ascorbic acid phosphoric acid ester and the absorbability to gingival tissue.

The menthol content is preferably 0.0001 to 5%, and more preferably 0.001 to 1% of the total composition. If the amount is less than 0.001%, the above effect may not be sufficient, and if the amount exceeds 0.001%, the usability of the oral composition may be adversely affected.

As menthol, those isolated from essential oils or those synthesized, or the essential oils containing them may be used.

The oral composition of the present invention can be made into various dosage forms such as a dentifrice such as a toothpaste, a mouthwash, a gum massage cream, a liquid or pasty topical application agent, and a chewing gum. In this case, the oral composition of the present invention may be mixed with various bases used for ordinary dentifrices and other medicinal components in addition to the above-mentioned components.

For example, in the case of dentifrice, dibasic calcium phosphate dihydrate and anhydride, monobasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium pyrophosphate, aluminum hydroxide, alumina, silicic acid anhydride, silicic acid. Aluminum, insoluble sodium metaphosphate, tribasic magnesium phosphate, magnesium carbonate, calcium sulfate, polymethylmethacrylate, bentonite,
One or more kinds of zirconium silicate, synthetic resin, etc. may be blended (the compounding amount is usually 5 to 80%, and in the case of toothpaste, 8 to
50%).

In the case of a paste-form oral composition such as toothpaste, a cellulose derivative such as carrageenan, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl hydroxyethyl cellulose sodium, etc. as a binder,
Alginate, propylene glycol alginate, xanthan gum, tragacanth gum, karaya gum,
Gums such as arabic gum, polyvinyl alcohol, sodium polyacrylate, carboxyvinyl polymer,
Synthetic binder such as polyvinylpyrrolidone, silica gel,
One or two or more kinds of inorganic binders such as aluminum silica gel, bee gum, and laponite may be blended (blending amount is usually 0.1 to 5% in the case of toothpaste).

Further, in the production of toothpaste and other liquid or paste oral compositions, as a viscous agent, sorbit, glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, polypropylene glycol, xylitol. ,
One kind or two or more kinds of maltitol, lactitol and the like can be blended (the blending amount is usually 5 to 80% in the case of dentifrice).

As the surface active agent, one or more of an anionic surface active agent, a nonionic surface active agent and a zwitterionic surface active agent may be compounded (the compounding amount is usually 0.1-0.1%).
10%, preferably 0.5-5%).

Here, as the anionic surfactant, sodium alkylsulfates such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acylsarcosinates such as sodium N-lauroylsarcosinate and sodium N-myristoylsarcosinate, N-acylglutamates such as sodium dodecylbenzene sulfonate, hydrogenated coconut fatty acid monoglyceride sodium monosulfate, sodium lauryl sulfoacetate and sodium N-palmitoyl glutamate, N-methyl-
N-acyl taurine sodium, N-methyl-N-acyl alanine sodium, sodium α-olefin sulfonate, sodium dioctyl sulfosuccinate and the like are used.

As the nonionic surfactant, sugar fatty acid esters such as sucrose fatty acid ester, maltose fatty acid ester and lactose fatty acid ester, sugar alcohol fatty acid ester such as maltitol fatty acid ester and lactitol fatty acid ester, and polyoxyethylene sorbitan. Monolaurate, polyoxyethylene sorbitan monostearate and other polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil and other polyoxyethylene fatty acid esters, lauric acid mono- or diethanolamide, myristic acid mono- or diethanolamide fatty acid Ethanolamide, sorbitan fatty acid ester, fatty acid monoglyceride, polyoxyethylene higher alcohol ether, polyoxyethylene polyoxyp Pyrene copolymer, polyoxyethylene polyoxypropylene fatty acid ester or the like is used.

Further, as the zwitterionic surfactant, N
-N-alkyldiaminoethylglycine such as lauryldiaminoethylglycine and N-myristyldiaminoethylglycine, N-alkyl-N-carboxymethylammonium betaine, 2-alkyl-1-hydroxyethylimidazoline betaine sodium and the like are used.

The oral composition of the present invention further comprises saccharin sodium, stevioside, neohesperidyl dihydrochalcone, glycyrrhizin, perillartin, thaumatin, asparatyl phenylalanine methyl ester,
A sweetener such as p-methoxycinnamic aldehyde, a preservative, a fragrance, etc. may be added, and for example, in the case of toothpaste, it can be produced by kneading the desired components described above with an appropriate amount of water.

Also, in the case of producing other oral compositions, it can be produced according to a conventional method using appropriate components usually used.

In the present invention, cationic bactericides such as chlorhexidine, benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride and decalinium chloride, phenolic compounds such as triclosan, hinokitiol and biozole, and dextranase. , Enzymes such as mutanase, lysozyme, amylase, protease, lytic enzyme, superoxide dismutase, alkali metal monofluorophosphates such as sodium monofluorophosphate, potassium monofluorophosphate, sodium fluoride, stannous fluoride, etc. Compound, tranexamic acid, epsilon aminocaproic acid, aluminum chlorhydroxyl allantoin, dihydrocholestanol, glycyrrhizic acids, glycyrrhetinic acid, Sabororu, glycerophosphate, chlorophyll, sodium chloride, a known active ingredient, such as water-soluble inorganic phosphoric acid compounds may be formulated alone or in combination.

[0028]

INDUSTRIAL APPLICABILITY The oral composition of the present invention enhances the absorption of ascorbic acid phosphoric acid ester into the mucosa by using the ascorbic acid phosphoric acid ester in combination with a specific monoterpenoid or a specific phenylpropanoid. At the same time, it is useful for effectively eliminating active oxygen produced excessively by the biological defense reaction and preventing or treating the destruction of gingival tissue in periodontal disease.

[0029]

EXAMPLES The present invention will be specifically described below by showing experimental examples and examples, but the present invention is not limited to the following examples.

[Experimental Example 1] Reactive oxygen scavenging experiment 2% casein was intraperitoneally injected into a mouse, and 16 hours later, the peritoneal cells were washed with HBSS and 2.5 x 10 ⁶
Adjusted to individual / ml. To 50 μl of this peritoneal cell suspension, 50 μl of the drug shown in Table 1 was added, and the mixture was allowed to stand at 35 ° C. for 5 hours.
Incubated for minutes. Furthermore, Luminol solution 100μ
l and Porphyromonas gingivalis 381 suspension (O
50 μl of D ₅₅₀ = 1.0) was added and the mixture was further incubated for 5 minutes, and the produced active oxygen was measured by a Lumiphotometer.

Table 1 also shows the results of the active oxygen production inhibitory action of various drugs. In Table 1, APM represents magnesium ascorbyl phosphate magnesium salt (the same applies hereinafter), and the drug concentrations in the combination of APM and other drugs are the same as in the case of using them alone.

[0032]

[Table 1]

From the results shown in Table 1, ascorbic acid phosphate, carvone, menthone, cineol, limonene,
It was found that active oxygen was synergistically eliminated by the combined use of anethole and eugenol. Also, if you use menthol in combination with these,
It was also found that the active oxygen was more effectively eliminated.

[Experimental Example 2] Rat gingivitis improvement experiment ODU rats (7 weeks old) were used as experimental animals and were bred for 2 months with powdered feed to accumulate plaque on the anterior part of the lower jaw. Caused it. From this time point (zero days), one group consisting of 5 animals was given a gel containing the drugs shown in Table 2 per day.
The left and right gingiva of the lower jaw was rubbed with a spatula on the right and left sides of the lower anterior part for 20 days, and the gingival inflammation areas on days 0 and 20 were measured under a stereoscopic microscope, and the degree of improvement of inflammation was determined by the following formula. Gingivitis improvement rate (%) = (A−B) × 100 / A A: Inflamed area on day 0 B: Inflamed area on day 20 Table 2 also shows the results of rat gingivitis improving effects of various drugs. .

[0035]

[Table 2]

From the results shown in Table 2, it was confirmed that gingivitis was synergistically improved by the combined use of ascorbic acid phosphate and carvone or eugenol.
It was also found that gingivitis was more effectively improved by using menthol in combination with these.

[Experimental Example 3] Mucosal absorption promoting experiment Ascorbic acid phosphate magnesium salt (10 m
M) (25 ml), carvone (5 mM), eugenol (5 mM), or menthol was pre-incubated at 37 ° C. for 5 minutes and then allowed to soak in the oral cavity for 5 minutes. Spit this into a beaker,
Furthermore, what rinsed the inside of the oral cavity with 10 ml of distilled water for 5 seconds was added, and the whole was made up to 50 ml. This solution was centrifuged at 3000 × g for 10 minutes, the supernatants were collected, and analyzed and quantified by HPLC under the following analysis conditions. HPLC analysis conditions; Column: Shiseido CAPCELL PAK AG-120
(0.6 × 25 cm) CAPCELL PAK AG-120 (0.6 × 3.
5 cm) Mobile phase: 0.1M KH ₂ PO ₄ /0.1MH ₂ PO
₄ (pH2) Detector: 240 nm Flow rate: 0.7 ml / min Table 3 shows the results of mucosal absorption promoting effect of various drugs.

[0038]

[Table 3]

From the results of Table 3, it was confirmed that carvone and eugenol promote the mucosal absorbability of magnesium ascorbyl phosphate ester. Further, it was confirmed that when menthol was further added, the mucosal absorbability of magnesium ascorbyl phosphate ester was further promoted.

Examples will be shown below. [Example 1] Toothpaste Precipitable silica 25.0% Solbit 25.0 Glycerin 25.0 Polyvinylpyrrolidone 1.0 Lauroyl polyglycerin ester 1.0 Polyoxyethylene (60 mol) sorbitan monolaurate 0.5 Saccharin sodium 0 .2 ethyl paraoxybenzoate 0.1 chlorhexidine hydrochloride 0.1 ascorbic acid phosphate magnesium salt 0.1 carvone 0.05 menthol 0.1 fragrance 1.0 water balance 100.0%

Example 2 Toothpaste Dicalcium Phosphate Dihydrate 20.0% Dicalcium Phosphate Anhydrate 20.0 Gelling Silica 2.0 Solbit 20.0 Propylene Glycol 2.5 Sodium Carboxymethyl Cellulose 1.0 Lauryl diethanolamide 1.0 Sodium lauryl sulfate 1.5 Lauroyl sarcosine sodium 0.9 Saccharin sodium 0.1 Ethyl paraoxybenzoate 0.1 Ascorbic acid phosphoric acid ester magnesium salt 0.05 Menthol 0.1 Eugenol 0.1 05 Fragrance 0.8 Water Residual 100.0%

Example 3 Oral Pasta Cetanol 5.0% Squalane 20.0 Precipitating Silica 5.0 Polyoxyethylene (40 mol) Hydrogenated Castor Oil 0.1 Sorbitan Monooleate 1.0 Sodium Lauryl Sulfate 0.2 Glycyrrhetinic acid 0.1 Sodium saccharin 0.6 Ascorbic acid phosphoric acid ester 0.2 Menthol 0.2 Carvone 0.1 Fragrance 0.6 Water balance 100.0%

Example 4 Oral pasta Liquid paraffin 15.0% Cetanol 7.0 Glycerin 20.0 Sorbitan monopalmitate 0.6 Polyoxyethylene (40 mol) sorbitan monostearate 5.0 Saccharin sodium 0.5 Cetylpyridinium chloride 0.05 Ascorbic acid phosphate 0.5 Menthol 0.2 Anethole 0.05 Perfume 0.5 Water Residual 100.0%

Example 5 Mouthwash Sorbit 10.0% Ethanol 5.0 Polyoxyethylene (60 mol) hydrogenated castor oil 0.1 Sucrose monopalmitate 0.2 Saccharin sodium 0.2 Triclosan 0.03 Cetyl chloride Pyridinium 0.05 Ascorbic acid phosphate 0.05 Cynamic aldehyde 0.1 Carvone 0.1 Fragrance 0.6 Water Residual 100.0%

[Example 6] Chewing gum Gum base 20.0% Sugar 15.0 Isomaltose 20.0 Palatinose 20.0 Corn syrup 12.0 Syrup 11.9 Ascorbic acid phosphate 0.02 Limonene 0.1 Mentone 0 0.03 Fragrance 0.6 Total 100.0%

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[Procedure amendment]

[Submission date] November 22, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0003

[Correction method] Change

[Correction content]

[0003] Neutrophils in the living body are leached from blood vessels when infected with bacteria and migrate to the inflammatory site to sterilize the bacteria by releasing bacterial hypophages or active oxygen and lysosomal enzymes to protect the living body from infection. To do. As described above, neutrophils originally protect the living body, but when they are chronically or acutely stimulated, they leak cell components and produce excessive active oxygen, which damages living tissues. Giving it, on the contrary, will make the inflammation worse.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0015

[Correction method] Change

[Correction content]

The menthol content is preferably 0.0001 to 5%, and more preferably 0.001 to 1% of the total composition. If it is less than 0.0001% , the above effect may not be sufficient, and if it exceeds 5% , the usability of the oral composition may be adversely affected.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction content]

The oral composition of the present invention can be made into various dosage forms such as dentifrice such as toothpaste, mouthwash , gingival massage cream, liquid or pasty topical application agent, chewing gum and the like. In this case, the oral composition of the present invention may be mixed with various bases used for ordinary dentifrices and other medicinal components in addition to the above-mentioned components.

[Procedure amendment 4]

[Document name to be amended] Statement

[Name of item to be corrected] 0030

[Correction method] Change

[Correction content]

[0030]

[Experimental Example 1] Reactive oxygen scavenging experiment 2% casein was intraperitoneally injected into a mouse, and after 16 hours, the peritoneal cells were washed with HBSS and 2.5 x 10 ⁶
Individual / ml was adjusted. To 50 μl of this peritoneal cell suspension, 50 μl of the drug shown in Table 1 was added, and the mixture was allowed to stand at 35 ° C. for 5 hours.
Incubated for minutes. Furthermore, Luminol solution 100μ
1 and Porphyromonas gingivalis 381 suspension (O
50 μl of D ₅₅₀ = 1.0) was added and incubated for 5 minutes , and the produced active oxygen was measured with a Lumiphotometer.

Claims (3)

[Claims] 1. An oral cavity comprising a combination of ascorbic acid phosphate and one or more selected from menthone, carvone, cineole, limonene, menthane, anethole, eugenol and cinnamic aldehyde. Composition. 2. Ascorbic acid phosphoric acid ester is ascorbic acid-2-phosphoric acid ester or ascorbic acid-3.
-Phosphate ester, ascorbic acid-5-phosphate ester, ascorbic acid-6-phosphate ester, ascorbic acid-2-polyphosphate ester, ascorbic acid-3-
The oral composition according to claim 1, which is one or more selected from polyphosphoric acid ester, ascorbic acid-5-polyphosphoric acid ester, ascorbic acid-6-polyphosphoric acid ester and salts thereof. 3. The oral composition according to claim 1, which further comprises menthol.