JP2000229825A - Composition for oral cavity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a composition which permits users to expect excellent effects for preventing and treating periodontal diseases, is safe, and has a good touch, by adding a specific arginine derivative. SOLUTION: This composition for oral cavities contains one or more compounds selected from an arginine derivative of the formula (R1-R3 are each H, an alkyl or the like) and its salts preferably in an amount of 0.01-3 wt.% based on the whole amount of the composition. The composition is prepared in the form of dentifrice such as a tooth paste, a liquid-like tooth polish or a liquid tooth polish, an ointment for oral cavities, a mouth wash, or the like. The dentifrice may be compounded with a polishing agent (for example, precipitated silica), a thickener (for example, glycerol), a surfactant (for example, sodium laurylsulfate), a sweetener (for example, saccharin sodium), an antiseptic (for example, para-hydroxybenzoic acid ester), a perfume (for example, peppermint), a coloring agent (for example, Food Blue No.1), and the like. The dentifrice may further be compounded with a dental caries-preventing agent, a tartar- preventing agent, a tissue-activating agent, a wound-curing agent, and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an oral composition suitably used for prevention and treatment of periodontal disease.

[0002]

BACKGROUND OF INVENTION Problems to be Solved] Periodontal disease is present in the subgingival plaque Porphyromonas gingivalis (Porphyromonas gingi
valis ), Prevoterra Intel Media ( Pre
votella intermedia ), Fusobacterium nucleatum ( Fusobacterium)
It is known to be caused by periodontal pathogens such as N. nucleatum . Therefore, as a means for preventing and treating periodontal disease in daily care such as dentifrice and mouthwash, oral care using a dentifrice containing a bactericide against these pathogenic bacteria and a mouthwash is widely performed. . Furthermore, in addition to fungicides, anti-inflammatory agents, protease inhibitors and the like have also been used in combination, but none of them can exert high efficacy, and the periodontal disease incidence remains high. .

The following three are considered to be particularly significant as reasons why these conventional techniques cannot exhibit high effectiveness. It is difficult to sterilize and remove subgingival plaque, and it is difficult to remove pathogenic bacteria. Therefore, the periodontal tissue continues to receive the inflammatory stimulus and exhibits the pathology of chronic inflammation. Periodontal disease characterized by chronic inflammation cannot be expected to be effective with an anti-inflammatory approach that assumes acute inflammation. In the case of a multi-drug combination, there is a problem in the combination of the active ingredients, and the original effect cannot be exhibited.
Among them, the reason is particularly problematic. It is difficult to improve chronic inflammation not only for periodontal disease, but it is expected to establish an effective prevention and treatment method.

[0004] In recent years, attention has been paid to the importance of nitric oxide as an inflammatory mediator.
Nitric oxide is synthesized by nitric oxide synthase using L-arginine as a substrate. Its physiological actions are diverse, but in inflammation, in both acute and chronic inflammation,
An important mediator. Regarding chronic inflammation, McCartney-Francis et al. Have reported that the nitric oxide synthase inhibitor ^NG -methyl-L-arginine (L-NMMA) improves experimental arthritis in rats (McCartney- Francis, N. et
al . , J. et al. Exp. Med. , 1993;
178: 749-754). In the periodontal disease field, Actinobacills actinomycetemcomitans, which is a causal bacterium of juvenile periodontitis, is also known as Actinobacill.
rus actinomycetemcomitan
s) the production of nitric oxide from macrophages by derived lipopolysaccharide is a nitric oxide synthase inhibitor N ^G -
Brix and Kristen report that nitroarginine methyl ester (L-NAME) is inhibited (Blix, IJS. And Krist).
en, H .; , Eur. J. Oral Sc
i. , 1998; 106: 576-581).

As described above, many studies have been made on nitric oxide synthase inhibitors which are expected as a new type of anti-inflammatory agent, but the above-mentioned L-NMMA, L-N
There have been many reports on ^NG -substituted forms of L-arginine represented by AME. L-arginine derivatives inhibit enzymatic action by competing with L-arginine which is a substrate for nitric oxide synthase, but are classified into reversible inhibitors and irreversible inhibitors according to the inhibition mode. For example, L-NAM
E is a reversible inhibitor and L-NMMA is an irreversible inhibitor. Reversible inhibitors have a problem that when L-arginine is present at a high concentration, the inhibitory effect is greatly reduced. In contrast, irreversible inhibitors are less susceptible to L-arginine.

[0006] It has been reported that L-arginine is sufficiently supplied in vivo and that L-arginine concentration increases in inflammatory sites. In addition, it has been confirmed that the L-arginine concentration increases depending on the contents of the meal and the state of eating. Furthermore, in order to utilize the wound healing action, bleeding prevention action, anti-inflammatory action, and antibacterial action of L-arginine, L-arginine has also been incorporated into the preparation,
JP-A-3-178926 and JP-A-8-15132
No. 4 discloses the technique. Therefore, considering the presence of L-arginine in living organisms and preparations, there is a concern that reversible nitric oxide synthase inhibitors may not be able to achieve sufficient efficacy.

[0007] The present invention has been made in view of the above circumstances,
An object of the present invention is to provide an oral composition that is expected to have excellent periodontal disease prevention and treatment effects, is safe, and has a good feeling in use.

[0008]

Means for Solving the Problems and Embodiments of the Invention The present inventors have made intensive studies to achieve the above object, and as a result, have been selected from arginine derivatives represented by the following general formula (I) and salts thereof. It has been found that an oral composition effective for the prevention and treatment of periodontal disease can be obtained by combining one or more kinds, and the present invention has been completed.

[0009]

Embedded image (In the formula, R ¹ and R ² represent a hydrogen atom, an alkyl group or an alkenyl group, but R ¹ and R ² do not simultaneously represent a hydrogen atom. R ³ represents a hydrogen atom or an alkyl group.)

The above-mentioned Japanese Patent Application Laid-Open No. Hei 3-178926 discloses an oral composition containing an arginine derivative. However, the invention was made by paying attention to the protease inhibitory effect of the arginine derivative. The effects of the invention cannot be easily analogized. Also, JP-A-8-15
No. 1324 also discloses an oral composition containing an arginine derivative. However, this is an invention made by focusing on the antibacterial effect, and the effect of the present invention cannot be easily analogized.

Hereinafter, the present invention will be described in more detail.
The oral composition of the present invention contains one or more selected from arginine derivatives represented by the following general formula (I) and salts thereof.

[0012]

Embedded image

Here, R ¹ and R ² are a hydrogen atom, an alkyl group or an alkenyl group, but R ¹ and R ² are not simultaneously a hydrogen atom. The alkyl group and the alkenyl group may be linear, branched, or cyclic, but may be a lower alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, or 2 to 6 carbon atoms, particularly 2 carbon atoms. And lower alkenyl groups such as methyl, ethyl, propyl, butyl, vinyl, allyl, propenyl, and butenyl.

R ³ is a hydrogen atom or an alkyl group, and the alkyl group is preferably a lower alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms.
Examples include a propyl group and a butyl group.

Further, salts of the arginine derivative represented by the general formula (I) are also included in the present invention. Although all pharmaceutically acceptable salts can be used, mineral salts such as hydrochloride, phosphate and sulfate, and carboxylate such as acetate, tartaric acid and citric acid are particularly preferable.

Although the L-form is generally highly effective optically, a racemic form can also be blended. Further, depending on the type of the substituent, the D-form may exhibit the same effectiveness as the L-form and may be used.

As the formulation, it is possible to use only one arginine derivative alone, but it is also possible to obtain even higher effectiveness by using two or more arginine derivatives in combination.

The oral composition of the present invention contains one or more of the arginine derivative represented by the general formula (I) and a salt thereof as an active ingredient, and includes toothpaste, liquid dentifrice, and liquid dentifrice. And dentifrices, oral ointments, mouthwashes, mouthwashes, mouthwash tablets, injection preparations, troches, chewing gums and the like.

The amount of the above-mentioned active ingredient is preferably 0.001 to 10% (% by weight, hereinafter the same), particularly 0.01 to 3% of the whole oral composition.

In the oral composition of the present invention, components used in ordinary oral compositions can be used as components other than the arginine derivative. The amount of these components depends on the effect of the present invention. Normal amounts can be used as long as they do not interfere.

In the case of dentifrices, for example, abrasives, binders,
Thickeners, surfactants, sweeteners, preservatives, flavors, coloring agents,
Various active ingredients other than those described above can be blended in a usual dose, and can be produced by mixing these ingredients with water.

Here, as the abrasive, precipitated silica,
Silica-based abrasives such as silica gel, aluminosilicate and zirconosilicate, dibasic calcium phosphate dihydrate and anhydrate, calcium pyrophosphate, calcium carbonate, aluminum hydroxide, alumina, magnesium carbonate, tertiary magnesium phosphate, zeolite , Zirconium silicate, synthetic resin-based abrasives and the like are preferably used.

As the thickener, glycerin, sorbitol, xylitol, propylene glycol, polyethylene glycol, maltitol, lactit and the like are preferably used.

As the surfactant, an anionic surfactant, a cationic surfactant, a nonionic surfactant and the like can be blended, and specific examples thereof include sodium lauryl sulfate, sodium α-olefin sulfonate, and N-acyl sulfonate. Cosinate, N-acyl glutamate, 2-alkyl-N-carboxymethyl-N-hydroethylimidazolinium betaine, N-acyl taurate, sucrose fatty acid ester,
Alkylol amide, polyoxyethylene hydrogenated castor oil, polyglycerin fatty acid ester, pluronic, polyoxyethylene sorbitan monostearate and the like are preferably used.

As sweeteners, sodium saccharin,
Examples include stevioside, stevia extract, aspartame, paramethoxycinnamic aldehyde, xylitol, neohesperidyl dihydrochalcone, and perillartin.

Examples of the preservative include paraoxybenzoate, sodium benzoate and the like.

As the fragrance, terpenes such as peppermint, spearmint, l-menthol, carvone, anethole, limonene and the like or derivatives thereof are preferable.

As the colorant, Blue No. 1, Yellow No. 4, titanium dioxide and the like are appropriately used.

Other active ingredients include caries preventives, tartar inhibitors, tissue activators, wound healing agents, immunostimulants, astringents, anti-inflammatory agents, blood flow improvers, hemostatic agents, bactericides, antibacterials Agent,
As a hypersensitivity inhibitor etc., fluorides such as sodium fluoride, potassium fluoride, ammonium fluoride, stannous fluoride, sodium monofluorophosphate, orthophosphate,
Tripolyphosphate, hexametaphosphate, allantoin, arginine and its salts, ascorbic acid and its derivatives, sodium chloride, tranexamic acid and its salts, epsilon aminocaproic acid and its salts, dl-tocopherol acetate, azulene, α-bisabolol, glycyrrhizinate And derivatives thereof, glycyrrhetinic acid, hydroxymic acid and derivatives thereof, zeolite, dextranase,
Mutanase, amylase, lysozyme chloride, methoxyethylene-maleic anhydride copolymer, polyvinylpyrrolidone, corn extract, oak extract, clove extract,
Rosemary extract, ogre extract, safflower extract, chlorhexidine salt, cetylpyridinium chloride,
Benzethonium chloride, copper chlorophyllin, gluconate, hinokitiol, trichlorocarbanilide, aluminum lactate, strontium chloride, potassium nitrate and the like can be appropriately selected and used.

[0030]

The oral composition containing the arginine derivative or a salt thereof according to the present invention suppresses the occurrence and progress of periodontal disease and contributes to the maintenance of healthy periodontal tissue. The indications widely include periodontal tissue lesions such as gingivitis, periodontitis, alveolar abscess, and apical lesions.

[0031]

EXAMPLES Next, the present invention will be described specifically with reference to examples, but the present invention is not limited thereto. Hereinafter, examples in which the L-arginine derivatives represented by the formulas (II) to (IV) are blended, and L represented by the formula (V)
Explanation will be made using a comparative example in which an arginine derivative is blended. In addition, the compounding amount in each composition was shown by weight%.

[0032]

Embedded image

[Experimental example] Syrian hamster (male, 8
Weekly) using 10 animals per group. After ligating the string to the lower first molar of the hamster, a bacterial suspension of Porphyromonas gingivalis ATCC 33277 strain (550) was obtained.
0.1 ml prepared using a THB medium so that the absorbance in nm becomes 1.0) was dropped once a day around the ligation part for three consecutive days. From the day after the end of bacterial administration,
0.1 ml of a sample of each formulation described in Table 1 was twice a day,
It was dropped around the lower first molar for two consecutive weeks. 1 after administration
Drinking water within hours was banned.

The animals were sacrificed the day after the last day of the administration of the specimens, and after preparation of jaw specimens, the amount of alveolar bone resorption was measured. The value obtained by subtracting the alveolar bone resorption amount of the untreated group from the alveolar bone resorption amount of the sample administration group was defined as the alveolar bone resorption amount. From the comparison with the alveolar bone resorption amount of the control group, the bone resorption inhibition rate (%) was calculated. The results are shown in Table 2.

[0035]

[Table 1]

[0036]

[Table 2]

Example 5 Toothpaste Calcium carbonate 50.0% by weight Glycerin 20.0 Carrageenan 0.50 Carboxymethylcellulose 1.00 Lauryldiethanolamide 1.00 Sucrose monolaurate 2.00 Fragrance 1.00 Saccharin sodium 0 .10 Phosphate of formula (III) 0.50 Purified water Remainder total 100.0% by weight

Example 6 Toothpaste Dicalcium phosphate dihydrate 50.0% by weight Glycerin 20.0 Carboxymethylcellulose 2.00 Sodium lauryl sulfate 2.00 Fragrance 1.00 Saccharin sodium 0.10 Monofluorophosphoric acid Sodium 0.70 Acetate of formula (II) 0.60 Purified water Remainder total 100.0% by weight

Example 7 Toothpaste 45.0% by weight of aluminum hydroxide Sorbit 25.0 Gelling silica 2.00 Carboxymethylcellulose 1.00 Sodium lauryl sulfate 2.00 Fragrance 1.00 Palatinose 0.25 Monofluoro Sodium phosphate 0.70 Acetate of formula (II) 0.50 Purified water Remainder total 100.0% by weight

Example 8 Toothpaste Precipitable silica 25.0% by weight Glycerin 25.0 Sorbit 25.0 Lauroyl polyglycerin ester 0.20 Polyoxyethylene sorbitan monolaurate 2.00 Sodium lauryl sulfate 1.50 Xylitol 8.00 Fragrance 1.00 Saccharin sodium 0.10 Hinokitiol 0.20 Sodium fluoride 0.21 Hydrochloride of formula (IV) 0.50 Arginine hydrochloride 1.50 Purified water Remaining total 100.0% by weight

Example 9 Liquid Toothpaste Precipitated Silica 20.0% by Weight Glycerin 25.0 Sorbit 35.0 Xanthan Gum 0.20 Propylene Glycol 2.00 Sodium Lauryl Sulfate 1.50 Decaglyceryl Monolaurate 2.00 Fragrance 1 0.000 Sodium saccharin 0.10 Sodium fluoride 0.21 Hydrochloride of formula (II) 0.45 Hydrochloride of formula (IV) 0.30 Purified water Remainder 100.0% by weight

Example 10 Oral ointment Liquid paraffin 15.0% by weight Cetanol 10.0 Glycerin 20.0 Polyoxyethylene sorbitan fatty acid ester 5.00 Fragrance 0.50 Saccharin sodium 0.02 Hydrochloride of formula (IV) 0.60 Arginine hydrochloride 1.50 Purified water Remainder total 100.0% by weight

Example 11 Mouthwash Ethanol 20.0% by weight Polyoxyethylene hydrogenated castor oil 0.30 Fragrance 1.00 Sodium monofluorophosphate 0.10 Saccharin sodium 0.05 Sodium fluoride 0.021 Formula ( II) Hydrochloride 0.05 Arginine hydrochloride 0.50 Dye Appropriate amount Purified water Remainder total 100.0% by weight

Example 12 Gargle Tablets Sodium Bicarbonate 50.5% by Weight Citric Acid 15.0 Sodium Anhydrous Sulfate 12.0 Sodium Dibasic Phosphate 10.0 Polyethylene Glycol 3.00 Oleic Acid 0.10 Flavor 2 0.000 Sodium monofluorophosphate 0.10 Hydrochloride of formula (IV) 0.50 Purified water Remainder 100.0% by weight

Example 13 Lozenges Glucose 35.0% by weight Palatinose 35.0 Gum arabic 6.00 Fragrance 1.00 Hydrochloride of formula (II) 0.30 Purified water Remaining total 100.0% by weight

Example 14 Chewing Gum Sugar 45.0% by Weight Gum Base 20.0 Glucose 10.0 Syringe 16.0 Fragrance 0.50 Citrate of Formula (III) 0.50 Purified Water Remaining Total 100.0% %

Example 15 Preparation for Injection Hydrochloride of Formula (IV) 0.25% by weight Arginine hydrochloride 0.50 Physiological saline Remainder 100.0% by weight

 ──────────────────────────────────────────────────続 き Continued from the front page F term (reference) 4C083 AB032 AB172 AB282 AB312 AB322 AB332 AB352 AC022 AC072 AC102 AC122 AC132 AC242 AC302 AC422 AC432 AC442 AC581 AC582 AC642 AC732 AC782 AC862 AD112 AD202 AD212 AD222 AD242 AD272 AD352 AD552 BB55 CC41 DD15 DD22 DD23 DD23 EE32 EE33 4H006 AA03 AB20

Claims (1)

[Claims] 1. An oral composition comprising one or more arginine derivatives represented by the following general formula (I) and salts thereof. Embedded image (In the formula, R ¹ and R ² represent a hydrogen atom, an alkyl group or an alkenyl group, but R ¹ and R ² do not simultaneously represent a hydrogen atom. R ³ represents a hydrogen atom or an alkyl group.)