JP2009137895A - Composition for oral cavity - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a composition for oral cavity, which is useful for preventing and treating periodontal disease since the composition is stably mixed with gabexate mesylate that inhibits argingipain being a cysteine protease produced by Porphyromonas gingivalis being a causative microorganism of periodontal disease specifically in high activity and effectively exhibits its inhibitory effect. <P>SOLUTION: The composition for oral cavity includes gabexate mesylate and an extract of at least one of plant selected from pine, cranberry and rose. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention is a composition containing gabexate mesilate, which is excellent in the activity-inhibiting effect of algin dipain produced by Porphyromonas gingivalis, which is a causative agent of periodontal disease, and is stable in periodontal disease. The present invention relates to an oral composition suitable for prevention or treatment.

  Proteases are broadly classified into serine proteases, cysteine proteases, metalloproteases, and aspartic proteases based on their catalytic mechanisms, and have important functions in life activities and are involved in the onset and progression of many diseases. Has become the target of.

  Argindipine is a cysteine protease that exhibits trypsin-like activity that specifically cleaves the arginine C-terminus of proteins. In the classification of proteases, a unique group is formed because there is no homology with other proteases in the primary structure comparison. Therefore, research on the three-dimensional structure and function of protease has been actively conducted, and development of a specific protease inhibitor is required as a protease inhibitor.

  Argindipine is a major virulence factor of this bacterium produced by the Gram-negative anaerobic gonococci Porphyromonas gingivalis, which is a causative agent of periodontal disease, and is essential for the growth of the bacterium. Furthermore, since it has an action of degrading extracellular matrix such as collagen constituting periodontal tissue, it is considered that the periodontal tissue is directly destroyed. Moreover, it is thought that the said microbe escapes immunity from the function reduction effect | action of the neutrophil which has an important function in an immune system, and an antibody decomposition | disassembly effect | action, and has an important function in order to continue an infection. Therefore, an algin dipain activity inhibitor is expected as a novel periodontal disease therapeutic and preventive agent that acts specifically on a pathogenic factor.

  The present applicant has found that gabexate mesylate, which is used as a therapeutic agent for pancreatitis and generalized intravascular blood coagulation, is a protease produced by Porphyromonas gingivalis, a causative agent for periodontal disease, algin dipine Have been found to have a very high specific activity-inhibiting effect, and proposed an algin dipine inhibitor containing gabexate mesylate and a composition for oral cavity containing the same (see Japanese Patent Application No. 2006-340035).

However, gabexate mesylate has a problem in stability in water and has been conventionally supplied as a lyophilized preparation and dissolved in a solution at the time of use and administered to a patient as an injection or infusion. Therefore, as a stable solution that does not require a freeze-drying step and does not need to be prepared at the time of use, a stabilized solution obtained by dissolving in a substantially anhydrous organic solvent in the presence of an acid (Patent Document 1) And a liquid agent that is dissolved in a non-aqueous solvent and stabilized by the coexistence of amino acids (see Patent Document 2). However, the effects of these techniques are not sufficient, and Patent Document 1 uses an acid that demineralizes teeth, and thus cannot be applied to an oral composition.
Therefore, a technique capable of stably incorporating gabexate mesylate into an oral composition is desired.

JP 2001-163776 A JP 2003-171273 A

  This invention is made | formed in view of the said situation, and it aims at providing the composition for oral cavity suitable for periodontal disease prevention or the treatment which the stable mixing | blending of the gabexate mesilate improved and the storage stability improved.

  As a result of intensive studies to achieve the above object, the present inventor has found that polyphenols contained in a specific plant extract have an inhibitory action on the degradation of gabexate mesylate, and as a result of further investigation, gabexate mesylate and By combining and combining at least one plant extract selected from pine plant extract, cranberry plant extract, and rose plant extract, degradation of gabexate mesylate in the oral composition is suppressed. The inventors have found that the storage stability is improved, and have made the present invention.

  In addition, as apparent from the experimental results described later, the grape seed extract of the grape family plant contained in the same rose subnet as rose does not have such a stability-improving action, so that the degradation suppression of gabexate mesylate, The stability improvement effect is considered to be an action specific to the above-mentioned polyphenol derived from a plant extract.

  Accordingly, the present invention provides an oral composition comprising gabexate mesylate and an extract of at least one plant selected from pine, cranberry and rose.

  The composition for oral cavity of the present invention suppresses the degradation of gabexate mesilate, which specifically and highly inhibits argindipine, which is a cysteine protease produced by Porphyromonas gingivalis, a periodontal disease-causing bacterium, and is stable in storage. It has excellent properties and exhibits its inhibitory effect effectively, and is useful for the prevention and treatment of periodontal disease.

  Hereinafter, the present invention will be described in more detail. The oral composition of the present invention comprises gabexate mesylate and at least one selected from a pine plant extract, a cranberry plant extract and a rose plant extract. It contains.

  The gabexate mesylate used in the present invention is represented by the following chemical structural formula.

  As gabexate mesylate, commercially available products can be used. For example, FOWY from Ono Pharmaceutical Co., Ltd., Probitol from Nippon Pharmaceutical Industry Co., Ltd., Allodate from Sawai Pharmaceutical Co., Ltd., Mesyl from Wako Pure Chemical Industries, Ltd. Acid gabexate or the like can be used.

  The plant extract used in the present invention is a plant extract of a pine of a pine family, a cranberry of an azalea family, or a rose of a rose family.

  In the present invention, the plant extract may be extracted by a known extraction method using a raw or dried plant as it is, or a pulverized and powdered raw material. Specifically, it is possible to employ a method in which extraction is carried out usually by heating for 10 minutes to 4 hours at room temperature or under heating using an extraction solvent. In addition to the above raw materials, an extract or an extraction residue obtained by solvent extraction may be used as the raw material for the extraction.

  As the extraction solvent, a normal polar or nonpolar solvent can be used, for example, lower alcohols such as water, ethanol, methanol, propanol and butanol, polyhydric alcohols such as glycerin, 1,3-butylene glycol and propylene glycol, acetic acid. Arbitrary solvents such as lower alkyl esters such as ethyl ester, hydrocarbons such as benzene and hexane, acetone and carbon dioxide can be used. These solvents can be used alone or in combination of two or more. Also good. In addition, when performing the said extraction, you may perform a de-essential oil and a decoloring before or after extraction as needed, and you may perform the solvent extraction process by the same solvent or a different solvent in multiple times.

  In the present invention, the finally obtained extract may be used as it is, but if necessary, an extract obtained by distilling off the solvent and further concentrating may be used. In addition, the extract can be used after being purified using a conventional purification method such as a counter-current distribution method or liquid chromatography. In addition, the plant extract can be used as a dried product, and the drying method in this case is not particularly limited. For example, the obtained extract is dried by reduced pressure, freeze-dried or the like by a normal means such as plant extract. The method of making it a dry material is mentioned.

  The pine plant extract used in the present invention can be prepared from a plant of a pine family plant (scientific names: Pinus Pinaster, Pinus Strobus, Pinus maritima), in particular, bark, by the above method. As the pine bark extract, a commercial product commercially available from Hofa Research (trade name, Pycnogenol) can also be used.

  The plant extract of cranberries used in the present invention can be prepared from a plant of cranberries (scientific name: Vaccinium macrocarpon), particularly fruits, by the above method. Moreover, the cranberry extract marketed from Kikkoman Corporation (brand name, cranberry extract) can also be used.

  The rose plant extract used in the present invention is a plant of rose family plants (scientific names: Rosa hybrida, Rosa centifolia, Rosa specials, Rosa Canina (dog rose), Rosa coana (wild rose)), in particular, before petals or flowering. It can be prepared by the above method from the flower bud. Moreover, the commercial item marketed from Maruzen Pharmaceutical Co., Ltd. (brand name, rose butts) and Maruei Trading Co., Ltd. (brand name, rose extract) can also be used.

  In the present invention, one of the above plant extracts can be singly or in combination of two or more. However, the content of polyphenols contained in these plant extracts is not particularly specified, but is usually a plant extract. It is preferable that it is 1 to 99% of the whole product (hereinafter, unless otherwise specified,% represents mass%), particularly 5 to 90%. If it is less than 1%, the stabilizing action of gabexate mesylate may not be sufficiently exerted, and it is difficult to ensure that it contains more than 99% polyphenol.

  In addition, you may use what diluted the said plant extract as needed, As a solvent to dilute, for example, water-based solvents, such as purified water, physiological saline, glucose injection solution, Ringer's solution, propylene glycol, Nonaqueous solvents such as glycerin and ethanol, or a mixture thereof can be used. In this case, the dilution concentration is appropriately selected and adjusted according to the use conditions, etc., but it is desirable to adjust so that the content of polyphenol in the plant extract is within the above range.

  The compounding amount of gabexate mesylate to the composition of the present invention is preferably 0.001 to 5%, particularly 0.01 to 2% of the whole composition. If the blending amount is less than 0.001%, the blending effect may not be sufficiently exhibited, and if it exceeds 5%, it may be difficult to stabilize the preparation.

Moreover, the compounding quantity of the said plant extract is 0.001-2% of the whole composition, Preferably it is 0.01-0.5%. When the amount is less than 0.001%, the blending effect is not sufficiently exhibited, and when it exceeds 2%, the astringency is strong and the usability may be deteriorated.
Furthermore, the blending amount of the plant extract is preferably in a range where the content of polyphenol in the composition is 0.0001 to 2%, particularly 0.001 to 0.5%, and is 0.0001%. If it is not satisfied, the blending effect may not be sufficiently exhibited, and if it exceeds 2%, the astringency is strong and the usability may be deteriorated.

  In the present invention, the mixing ratio of gabexate mesylate and plant extract is not particularly limited, but gabexate mesylate: plant extract is in a mass ratio of 1: 0.01 to 1: 100, particularly 1: 0.1 to 0.1. It is preferable to select and adjust appropriately within the range of 1:20. If the proportion of plant extract used is less than 0.01 with respect to gabexate mesylate 1, the blending effect may not be sufficiently exhibited. There may not be.

  The composition for oral cavity of the present invention contains gabexar mesylate and at least one plant extract selected from pine, cranberry, and rose as described above, and is used for toothpaste, toothpaste, liquid toothpaste, and the like. It can be prepared into various dosage forms such as dentifrices, mouthwashes, gels, ointments, mouth fresheners, gargle tablets, oral pasta, gum, etc. In addition to the above essential ingredients, the dosage form Depending on the case, other components can be blended within a range not impairing the effects of the present invention, and can be prepared by a usual method.

  As other components, for example, in the case of dentifrice, various abrasives, wetting agents, binders, surfactants, sweeteners, fragrances, coloring agents, preservatives, other active ingredients, etc. It can be used in a normal amount as long as the effect is not hindered.

  As abrasives, precipitated silica, silica gel, aluminosilicate, zeolite, zirconosilicate, dicalcium phosphate dihydrate and anhydride, calcium pyrophosphate, calcium carbonate, aluminum hydroxide, alumina, magnesium carbonate, tertiary phosphorus Examples thereof include magnesium acid, insoluble sodium metaphosphate, insoluble potassium metaphosphate, titanium oxide, hydroxyapatite, and synthetic resin-based abrasive (mixing amount: usually 5 to 50% based on the entire composition).

  Examples of the wetting agent include polyhydric alcohols such as glycerin, sorbitol, propylene glycol, polyethylene glycol, and 1,3-butylene glycol, sugar alcohols, and the like (blending amount: usually 10 to 50% based on the entire composition). .

  As binder, carrageenan, hydroxyethylcellulose sodium, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol ester alginate, polyacrylic acid, sodium polyacrylate, xanthan gum, tara gum, Guam gum, locust bean gum, gellan gum, gelatin, curdlan, gum arabic, agar, pectin, polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, etc. (blending amount: usually 0.1 to 5% based on the whole composition) .

  As the surfactant, an anionic surfactant, a nonionic surfactant, a cationic surfactant, and an amphoteric surfactant can be blended. Anionic surfactants include sodium alkyl sulfates such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosine such as sodium N-lauroyl sarcosine, sodium N-myristoyl sarcosine, sodium dodecylbenzenesulfonate, hydrogenated coconut fatty acid N-acyl glutamate such as sodium monoglyceride monosulfate, sodium lauryl sulfoacetate, sodium N-palmitoyl glutamate, sodium N-methyl-N-acyl taurate, sodium N-methyl-N-acylalanine, sodium α-olefin sulfonate Is mentioned. Nonionic surfactants include sugar alcohol fatty acid esters such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol Polyester alcohol fatty acid ester such as fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene alkylphenyl ether, ester type surfactant such as polyoxyethylene hydrogenated castor oil, lauric acid And fatty acid alkanolamides such as diethanolamide. Examples of the cationic surfactant include alkyl ammonium and alkyl benzyl ammonium salts. Examples of amphoteric surfactants include betaine acetate, imidazolinium betaine, and lecithin (blending amount: usually 0.5 to 5% based on the entire composition).

  As active ingredients, in addition to gabexate mesylate and the above plant extracts, for example, antiplasmin agents such as tranexamic acid and epsilon aminocaproic acid, anti-inflammatory agents such as glycyrrhizin, glycyrrhizinate and allantoins, ascorbate and tocopherol Vitamins such as esters, enzymes such as dextranase, mutanase, and lysozyme, herbal extracts, hornon extract, herbal extracts such as clove extract, cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, decalinium chloride, chlorhexidine hydrochloride , Bactericides such as chlorhexidine gluconate, triclosan, isopropylmethylphenol, hinokitiol, sodium chloride, sodium polyphosphate, sodium metaphosphate, sodium orthophosphate, tripolyline Sodium, aluminum lactate, and inorganic salts or organic salts of chitosan such as a possible formulation. In addition, the compounding quantity of these active ingredients can be made into an effective quantity in the range which does not prevent the effect of this invention.

  Examples of the sweetening agent include saccharin sodium, stevioside, stevia extract, paramethoxycinnamic aldehyde, neohesperidyl hydrochalcone, and perilartin. Examples of the colorant include blue No. 1, yellow No. 4, titanium dioxide and the like. Examples of the preservative include paraoxybenzoic acid ester and sodium benzoate.

Examples of the fragrances include terpenes such as l-menthol, carvone, anethole and limonene, or derivatives thereof, peppermint oil, and the like.
Examples of the pH adjuster include citric acid, fumaric acid, malic acid, tartaric acid, and lactic acid.

  Hereinafter, the present invention will be described more specifically with reference to experimental examples and examples. However, the present invention is not limited to these examples.

[Experimental example]
The storage stability of gabexate mesylate was evaluated by the following method. In addition, the gabexate mesylate manufactured by Wako Pure Chemical Industries, Ltd. and the plant extract shown in Table 1 were used.

Evaluation of storage stability of gabexate mesylate;
In order to evaluate the storage stability of gabexate mesylate, an accelerated storage test was conducted.
Gabexate mesylate 0.25% and the plant extract of the kind and blending amount shown in Table 2 were dissolved in propylene glycol and stored in a constant temperature bath at 60 ° C. for 2 weeks. After storage, the remaining amount of gabexate mesylate was measured by the following method, and the inhibition rate of gabexate mesilate degradation was calculated by the following formula.

The residual amount of gabexate mesylate was measured by liquid chromatography according to the quantitative method of the Japanese Pharmacopoeia. The stored gabexate mesylate solution was diluted 5-fold with a 50% ethanol solution, and an equal amount of a 50% ethanol solution containing 0.02% butyl paraoxybenzoate was added as an internal standard to prepare a test solution. A column (trade name, TSK-GEL ODS-80Ts, manufactured by Tosoh Corporation) in which 100 μL of a test solution was packed in a stainless tube having an inner diameter of 5 mm and a length of 15 cm and having a particle size of 5 μm and octadecylsilylated silica gel for liquid chromatography. Injection was performed under conditions of a temperature of 25 ° C. and a mobile phase ^{* 1} flow rate of 1.0 mL / min. Detection was carried out with absorbance at a wavelength of 245 nm.

Calculation formula for inhibition rate of gabexate mesilate degradation

* 1: Mobile phase composition Methanol 540 mL
0.1% sodium lauryl sulfate aqueous solution 200mL
0.5% 1-heptane sodium sulfonate aqueous solution 20 mL
Glacial acetic acid 1mL
Total 761mL

  From the results in Table 2, it was found that the use of pine bark extract, cranberry extract, and rose extract together suppresses the degradation of gabexate mesylate.

[Example 1] Ointment gabexate mesilate 0.05
Pine bark extract (trade name, Pycnogenol, manufactured by Hofa Research) 0.05
Glyceryl monomyristate 5
Citric acid 0.1
Liquid paraffin 15
White petrolatum balance
Total 100.0%

Example 2 Gel Agent Gabexate Mesilate 0.01
Pine bark extract (trade name, Pycnogenol, manufactured by Hofa Research) 0.05
Hydroxyethylcellulose 1.5
Polyethylene glycol 4000 15
Sodium monofluorophosphate 0.1
Ethyl paraoxybenzoate 0.03
Water balance
Total 100.0%

Example 3 Dentifrice Calcium Phosphate 25.0
Silicic anhydride 5.0
Sodium lauryl sulfate 1.2
Carboxymethylcellulose 0.8
Carrageenan 0.5
Sodium fluoride 0.2
Gabexate mesylate 0.05
Rose extract (trade name, rose bud extract, Maruei Trading) 0.01
Sorbitol 15.0
Fragrance 1.0
Water balance
Total 100.0%

[Example 4] Dentifrice Silicic anhydride 15.0
Sodium lauryl sulfate 1.0
Xanthan gum 0.5
Sodium alginate 0.5
Saccharin sodium 0.1
Sodium monofluorophosphate 0.1
Gabexate mesylate 0.02
Pine bark extract (trade name, Pycnogenol, manufactured by Hofa Research) 0.05
Epsilon aminocaproic acid 0.05
Sorbitol 10.0
Xylitol 5.0
Fragrance 1.0
Water balance
Total 100.0%

[Example 5] Pastacetanol for oral cavity 5.0
Squalane 20.0
Precipitated silica 5.0
Polyoxyethylene (40) hydrogenated castor oil 0.1
Sorbitan monooleate 1.0
Sodium lauryl sulfate 0.2
Saccharin sodium 0.6
Gabexate mesylate 0.5
Pine bark extract (trade name, Pycnogenol, manufactured by Hofa Research) 0.05
Sorbitol 10.0
Fragrance 0.6
Water balance
Total 100.0%

[Example 6] Mouthwash ethanol 10.0
Gabexate mesylate 0.05
Cranberry extract (trade name, cranberry extract, manufactured by Kikkoman) 0.01
Tranexamic acid 0.05
Sodium fluoride 0.1
Sorbitol 5.0
Xylitol 5.0
Polyoxyethylene (60) hydrogenated castor oil 0.5
Saccharin sodium 0.2
Fragrance 0.8
Water balance
Total 100.0%

[Example 7] Gum gum base 20.0
Fragrance 1.0
Minamata 20.0
Powdered sugar 10.0
Trisodium citrate 1.5
Gabexate mesylate 0.1
Pine bark extract (trade name, Pycnogenol, manufactured by Hofa Research) 0.5
Sorbitol 15.0
Xylitol 10.0
Water balance
Total 100.0%

Claims (1)

  An oral composition comprising gabexate mesylate and an extract of at least one plant selected from pine, cranberry and rose.