JPH0417930B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an oral composition containing carbazochromes, and more specifically, it has an excellent hemostatic effect,
Therefore, the present invention relates to an oral composition suitable for use in preventing periodontal diseases such as gingivitis. Many people suffer from periodontal diseases such as gingivitis and pyorrhea, and the majority of tooth loss in adults in particular is caused by periodontal diseases. It is clear that the prevention and treatment of periodontal disease will become an increasingly important issue. Symptoms of periodontal disease include redness, swelling, and bleeding of the gums.
The main causes include pus drainage and alveolar bone resorption, but currently no drug has been recognized that exhibits a therapeutic effect that satisfies all of these simultaneously. It is difficult to improve these symptoms all at once, and it is therefore appropriate to select preventive and therapeutic agents that suit each individual symptom. The present inventors investigated the symptoms of periodontal diseases from this perspective and found that in periodontal diseases such as gingivitis and alveolar pyorrhea, bleeding from the gums occurs from the early stages to the late stages. It was concluded that gingival bleeding is the most important symptom, and that it is necessary to develop active ingredients that effectively suppress gingival bleeding and are effective in preventing and curing bleeding. . In addition, many hemostatic agents have been developed at present, and their mechanisms of action include promoting coagulation, antiheparin, antiplasmin, vasoconstriction, and strengthening capillaries.The present inventors also investigated the pathophysiology of periodontal disease. As a result, we came to the conclusion that it was most desirable to strengthen the capillaries inside the tissue, rather than using symptomatic treatment, and conducted intensive research on carbazocchromes, which are capillary strengthening agents. As a result, one or two of carbazochromes, a solvent extract of Kouka, glycyrrhetinic acid and its salts were obtained.
When used in combination with these species, it has an extremely excellent hemostatic effect, and oral compositions containing these as active ingredients have a high hemostatic effect, making it effective for the prevention and treatment of gingivitis, alveolar pyorrhea, etc. We found that it is used for. That is, according to the results of the studies conducted by the present inventors, when carbazocchromes were used alone as shown in the experimental examples described later, the hemostatic effect was not necessarily sufficient. When extracts, glycyrrhetinic acid, or its salts are combined, although these compounds do not have a hemostatic effect, these compounds act synergistically with carbazocchromes, and the effect is more pronounced than when carbazocromes are used alone. The present invention was based on the discovery that carbazocchromes exhibit a hemostatic effect and the capillary strengthening effect of carbazochromes is more effectively exerted. The present invention will be explained in more detail below. The oral composition according to the present invention is made by combining carbazochromes with one or more synergist ingredients selected from a solvent extract of Koka and glycyrrhetinic acid and its salts, and is used in the oral cavity such as gingival pine surge cream. ointment, mouthwash, toothpaste,
It is used as troches, chewing gum, etc. The oral composition of the present invention has a very high hemostatic effect due to the combination of carbazochromes and the synergist component, and therefore can be suitably used for the prevention of periodontal diseases such as gingivitis. . Here, examples of carbazochromes include carbazochrome, sodium carbazochrome sulfonate,
Examples include adrenochrome monoaminoguanidine methanesulfonate, and one or more of these may be used. The amount of carbazochromes is 0.001 to 1% (weight%, same hereinafter) of the entire composition,
In particular, it is preferably 0.01 to 0.5%. In addition, in the present invention, one or more of Kouka extract, glycyrrhetinic acid and its salts are blended as a synergist component.
In this case, the solvents used to obtain the Koka solvent extract include water, lower alcohols such as methanol and ethanol, polyhydric alcohols such as propylene glycol, ethylene glycol, and glycerin, and polar solvents such as acetone, ethyl ether, and ethyl acetate. Solvents such as nonpolar solvents such as benzene, hexane, and petroleum ether, and mixed solvents that combine two or more of these solvents can be used.The solvent extract of Koka is extracted by extracting Koka with these solvents and removing the extraction residue. However, if necessary, it can be produced by distilling off the solvent from the extract. In this case, when water, ethanol, etc. or a mixed solvent thereof is used as a solvent, the extract or concentrated extract thereof can be blended into the oral composition as it is. Note that a known method can be used as the extraction method, for example, a method such as digesting dry powder of Koka in the above-mentioned solvent can be used. In the present invention,
This extract can be used as is, but
Furthermore, a residue obtained by carrying out two or more stages of extraction with the above-mentioned solvent, or subjecting this extract to steam distillation treatment or molecular distillation treatment, or by applying this extract or the above-mentioned residue to an adsorbent such as activated carbon, diatomaceous earth, or acid clay. Further, after treating the extract with an adsorbent, a residue obtained by steam distillation treatment or molecular distillation treatment, or a fractionated product of these by column chromatography are also suitable as extracts of the plant. It can be used for. The amount of Koka solvent extract to be incorporated into the oral composition is not necessarily limited, but
It is preferably 0.001 to 5%, particularly 0.01 to 2%. Further, the amount of glycyrrhetinic acid or its salt blended is preferably 0.001 to 5%, particularly 0.1 to 2% of the total. Here, examples of the salt of glycyrrhetinic acid include dipotassium glycyrrhetinate, monoammonium glycyrrhetinate, and the like. In addition to the above-mentioned components, the oral composition of the present invention may further contain appropriate components depending on the purpose, type of composition, etc. For example, in the case of pasty compositions such as ointments, binders include carrageenan, cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, and sodium carboxymethylhydroxyethylcellulose, alkali metal alginates such as sodium alginate, and propylene glycol alginate. Gums such as ester, xanthan gum, tragacanth gum, karaya gum, gum arabic, synthetic binders such as polyvinyl alcohol, sodium polyacrylate, carboxyvinyl polymer, polyvinylpyrrolidone, inorganic binders such as silica gel, aluminum silica gel, vegum, laponite, etc. One or more of these may be blended (the blending amount is usually 0.3 to 5%). Furthermore, in the production of pasty or liquid oral compositions, sorbitol, glycerin,
ethylene glycol, propylene glycol,
One or more of 1,3-butylene glycol, polyethylene glycol, polypropylene glycol, xyrite, maltite, lactite, etc. may be blended (the blending amount is usually 10 to 70%). Furthermore, surfactants such as nonionic surfactants, anionic surfactants, and amphoteric surfactants can be blended into the composition of the present invention. Nonionic surfactants include fatty acid esters of sugars or sugar alcohols, for example, each fatty acid residue has 12 to 18 carbon atoms and an average degree of esterification of 1.1.
~2.5, more preferably 1.2 to 1.9 sucrose fatty acid ester, maltose fatty acid ester, maltitol fatty acid ester, maltotriitol fatty acid ester, maltotetraitol fatty acid ester, maltopentitol fatty acid ester, maltohexitol fatty acid ester , maltoheptitol fatty acid ester, sorbitan fatty acid ester, lactose fatty acid ester, lactitol fatty acid ester, etc., polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, etc., and polyoxyethylene In addition to fatty acid esters such as polyoxyethylene hydrogenated castor oil, fatty acid diethanolamides such as lauric acid mono- or diethanolamide, fatty acid monoglycerides, polyoxyethylene higher alcohol ethers, polyoxyethylene polyoxypropylene copolymers, polyoxy Ethylene polyoxypropylene fatty acid esters and the like may also be used. Examples of anionic surfactants include water-soluble salts of higher alkyl sulfates whose alkyl group has 8 to 18 carbon atoms, such as sodium lauryl sulfate and sodium myristyl sulfate, α-olefin sulfonate, sodium lauryl monoglyceride sulfonate, and sodium lauryl monoglyceride sulfonate. Water-soluble salts of higher fatty acid monoglyceride sulfonates in which the fatty acid group has 10 to 18 carbon atoms such as diium coconut monoglyceride sulfonate, higher fatty acid sodium monoglyceride monosulfate, sodium-N-methyl-N-
Examples include palmitoyl tauride, sodium N-lauroyl sarcosinate, sodium N-lauroyl-β-alanine, and sodium N-long chain acylamino acid. Furthermore, examples of amphoteric surfactants include 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, alkyldiaminoethylglycine hydrochloride, and lauryldimethylaminoacetic acid betaine. In addition, these surfactants may be used alone or in combination of two or more. In addition, the amount of surfactant added is usually 0.01 to 5 of the total amount.
%, more preferably 0.05 to 3%. The oral composition of the present invention further includes menthol,
Carvone, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol,
Methyl acetate, citronellyl acetate, methyl eugenol, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla Flavoring agents such as oil, winter oil, clove oil, eucalyptus oil, etc., alone or in combination, have a total of 0 to 10.
%, preferably about 0.5 to 5%, and
Satucalin sodium, stevioside, neohesperidyl dihydrochalcone, glycyrrhizin,
Sweeteners (0 to 1%, preferably 0.01 to 0.5%) such as perillartine, thaumatin, asparatylphenylalanine methyl ester, and p-methoxycinnamic aldehyde may be blended. In the case of toothpaste, dibasic calcium phosphate dihydrate and anhydride, dibasic calcium phosphate, dibasic calcium phosphate, calcium carbonate, calcium pyrophosphate, aluminum hydroxide, alumina, silicic anhydride, silica gel, aluminum silicate , insoluble sodium metaphosphate, tertiary magnesium phosphate, magnesium carbonate, calcium sulfate, polymethyl methacrylate, bentonite, zirconium silicate, synthetic resin, etc. (the amount usually ranges from 20% to 90% and 20% to 60% for toothpaste). In addition, in the present invention, as active ingredients, enzymes such as dextranase, amylase, protease, mutanase, lysozyme, and lytic enzyme (retate enzyme), and alkalis such as sodium monofluorophosphate and potassium monofluorophosphate are used. Metal monofluorophosphate, sodium fluoride, fluorides such as stannous fluoride, tranexamic acid and epsilon aminocaproic acid, aluminum chlorohydroxyallantoin, dihydrocholesterol, glycyrrhizin salts, chlorhexidine, glycerophosphate, chlorophyll, sodium chloride, One or more active ingredients such as calopeptide and water-soluble inorganic phosphoric acid compounds may be blended. The oral composition of the present invention can be used in a known manner depending on its type. For example, in the case of gingival pine surge cream, the amount of carbazochromes per dose for adults is about 0.1 to 5 mg. This cream can be applied by massaging the gums with this cream about three times a day. Next, experimental examples will be shown to specifically explain the effects of the present invention. Experimental example: Hair was removed from the back of a domestic rabbit (weight 2.5-3.0 kg), and 24 hours later, 0.1 ml of antiserum against whole rabbit serum diluted with the same amount of physiological saline was applied to the hair-removed area. was injected intravenously to induce inflammation. The first part is in this area.
0.2 g of a hydrophilic ointment (manufactured by Sanko Pharmaceutical Industries, Ltd.) having the active ingredients shown in the table was applied once a day from the day of intradermal injection of the antiserum until the day of hemostatic effect measurement. Twenty-four hours after the intradermal injection, a cross-shaped incision of 10 mm on each side was made in the center of the inflamed area using a scalpel. 48 hours after creating the cut, measure the cut area using a purpurameter for 300 minutes.
Bleeding was induced by suctioning at mmHg for 30 seconds. The hemostatic effect of the active ingredient was measured by sucking up the bleeding blood onto absorbent cotton, measuring its weight, and determining the amount of bleeding. The results are shown in Table 1.

【table】

[Table] For the water extract of Kouka, add 1000 ml of water to 100 g of dry Kouka powder, reflux for 1 hour on a water bath at 80 to 90°C with a cooling tube attached, and then separate the water fraction. After adding fresh water to the residue and repeating the same reflux twice for a total of three extraction operations,
A powder obtained by concentrating the water extracts together under reduced pressure was used. From the results shown in Table 1, it was found that although Koka water extract and glycyrrhetinic acid do not have a hemostatic effect by themselves, the hemostatic effect is significantly increased by using these compounds in combination with carbazocchrome. Examples are shown below. Example 1 O/W emulsion type ointment oral preparation Liquid paraffin 10% Setanol 13 Glycerin 20 Microcrystalline wax 4.0 Sorbitan monopalmitate 0.6 Polyoxyethylene (20 mol) monostearate
5.0 Kouka water extract 0.1 Carbazochrome 0.1 Fragrance 1.0 Water Remaining 100.0% Example 2 W/O/W type cream oral preparation Beeswax 10% Ceresin 10 Vaseline 15 Lanolin 5 Cosbiol 15 Olive oil 12% Sorbitan monooleate 4 Sorbitan monooleate Stearate 3 Dipotassium glycyrrhetinate 0.2 Carbazochrome 0.1 Kouka water extract 0.1 Fragrance 0.6 Water Remaining 100.0% 78 parts by weight of the W/O emulsion with the above composition
It was dispersed in 22 parts by weight of a 10% aqueous solution of sucrose fatty acid ester of HLB12, and re-emulsified at 70°C using a homomixer to obtain a W/O/W type creamy oral composition. Example 3 Mouthwash 95% glycerin aqueous solution 20% 60% sorbitol aqueous solution 20 Carbopol/neutralizing agent 0.001 Polyoxyethylene sorbitan monolaurate
1.0 Polyoxyethylene (40 mol) stearate
1.0 Satucalin sodium 0.1% Flavoring 1.0 Tranexamic acid 0.05 Koukamethanol extract 0.05 Carbazochrome 0.1 Water Remaining total 100.0% Example 4 Toothpaste precipitated silica (ZeO49) 20% Precipitated silica (Vitaseal) 0.5 95% glycerin aqueous solution 36.0 60 % Sorbit aqueous solution 27.0 polyethylene glycol 3.0 Calboximethylcerus natrium 1.0 sodium laurelil sodium 1.2 Satsukarin sodium 0.1 タROM 0.1 Total water residual 100.0 % Examples Sident20) 25 % sedimentary silica (vitasile) 0.3 95 % glycerin aqueous solution 28.5 60 % solubitar aqueous solution 30.7 polyethylene glycol 4.0 Calvopol 0.5 neutralizer 0.2 hydroxyethyl cellulose 0.5 laurelil sodium sodium 1.2 Satsukarinna Torium 0.1 Penus 1.0 Sodium Monoflull Olorinate 0.76 Koka water extract 0.2 Carbazochrome 0.1 Water Total balance 100.0% Example 6 Toothpaste dicalcium phosphate 45% Precipitated silica (Vitaseal) 0.1 60% sorbitol aqueous solution 30.0 Sodium carboxymethyl cellulose 1.0 Hydroxyethyl cellulose 1.0 Sucrose dipalmitate 1.2 Polyoxyethylene ( 40 mol) stearate
0.3 Satucharin sodium 0.1 Flavor 1.0 Dextrase 1.0 Dipotassium glycyrrhetinate 0.2 Carbazochrome 0.05 Kouka water-ethanol (1:1) extract 0.1 Water Total balance 100.0% Example 7 Toothpaste aluminum hydroxide 35.0% Precipitated silica (Vitaseal) ) 0.1 60% sorbitan aqueous solution 40.0 Xanthan gum 1.0% Sodium lauryl sulfate 1.2 Polyoxyethylene sorbitan monolaurate
0.1 Satucharin sodium 0.1 Flavoring 1.2 Sodium monofluorophosphate 0.76 Glycyrrhetinic acid monoammonium salt 0.1 Carbazochrome 0.05 Koka water-ethanol (1:1) extract 0.2 Water Total balance 100.0% Example 8 Mouthwash 60% sorbitol aqueous solution 40 % Hydroxyethyl cellulose 0.1 Sucrose dipalmitate 1.0 Polyoxyethylene (40 mol) stearate
0.1 Satucalin sodium 0.2 Flavor 1.5 Tranexamic acid 0.05 Ethane hydroxy diphosphate 0.05 Kouka water extract 0.3% Carbazochrome 0.05 Water Total balance 100.0% Example 9 Mouthwash 60% sorbitol aqueous solution 30% Hydroxyethyl cellulose 0.1 Sucrose dipalmitate 1 .0 poly Oxyethylene (40 mol) stearate
0.1 Satucalin sodium 0.1 Flavor 0.7 Chlorhexidine hydrochloride 0.05 Monoammonium gluconate 0.1 Carbazochrome 0.05 Koka water-ethanol (1:1) extract 0.3 Water Total balance 100.0% Example 10 Chewing gum gum base 43.75% Calcium carbonate 2.0 Water Candy 15.0% Powdered sugar 30.0 Sucrose palmitate 1.0 Fructose 4.0 Maltose 3.0 Carbazochrome 0.05 Koka water extract 0.2 Flavoring 1.0 100.0% Example 11 Oral ointment Polyoxyethylene monostearate 2.0% Sorbitan monooleate 2.0 Cetyl alcohol 2.0% Paralcohol Methyl alcohol 3.0 Propylene glycol 15.0 Carboxymethyl cellulose 5.0 Gelatin 1.0 Satucalin 0.2 Carbazochrome 0.1 Glycyrrhetinic acid 0.1 Chlorhexidine hydrochloride 0.01% Fragrance 0.3 Lysozyme chloride 5000 units/g water Balance 100.0% Example 12 Pastille Gum Arabic 6.0% Glucose 72.0 Gelatin 3.0 Flavoring 0.2 Dextranase 0.1 Chlorhexidine gluconate 0.01 Carbazochrome 0.1 Koka water extract 0.2 Water Remaining 100.0% All of the compositions of Examples have good hemostatic effect.

Claims (1)

[Scope of Claims] 1. An oral composition characterized in that it contains one or more synergist components selected from a solvent extract of Kouka and glycyrrhetinic acid and its salts, in combination with carbazochromes. 2. The amount of Koka solvent extract in the entire composition is
The oral composition according to claim 1, wherein the amount is 0.001 to 5% by weight. 3. The oral composition according to claim 1, wherein the amount of glycyrrhetinic acid or its salt is 0.001 to 5% by weight of the entire composition. 4 The amount of carbazochromes in the entire composition
The oral composition according to any one of claims 1 to 3, wherein the content is 0.001 to 1% by weight.