JP5663292B2 - Aqueous liquid preparation for oral cavity and aqueous liquid preparation for oral cavity in container - Google Patents

Description

  The present invention relates to an aqueous preparation and an aqueous preparation in a container.

About 70% of the causes of tooth loss are periodontal disease, and it is said that it is useful to use oral preparations containing bactericides and anti-inflammatory agents to prevent periodontal disease. Yes. The root cause of periodontal disease is a pathogenic bacterium that exists in the narrow part of the bottom of the periodontal pocket.
Therefore, in order to prevent the onset of periodontal disease, it is important for the self-care to infiltrate and retain the preparation to the depth of the periodontal pocket to kill pathogenic bacteria.

Conventionally, various devices and preparations have been proposed for the purpose of preventing periodontal disease.
For example, a drug supply device for a periodontal pocket that includes a nozzle that is inserted into the periodontal pocket to supply the drug into the periodontal pocket and a regulating means that regulates the insertion depth of the nozzle with respect to the periodontal pocket has been proposed. (For example, Patent Document 1). According to the invention of Patent Document 1, although the medicine can be infiltrated into the bottom of the periodontal pocket, the operation is complicated. In addition, a drug with high fluidity that can enter the periodontal pocket is likely to be washed away by saliva and the like, and the effect is not sustained.

In order to solve these problems, a preparation that can be easily applied to an affected area and has improved drug durability has been proposed.
For example, a composition for treating an oral cavity disease for insertion comprising a copolymer of lactide and glycolide, an active agent and propylene carbonate has been proposed (for example, Patent Document 2). According to the invention of Patent Literature 2, after being applied to the affected area, the copolymer gradually hydrolyzes to release the active agent continuously, thereby improving the durability of the drug effect.
In addition, a locally administered biodegradable sustained-release periodontitis pharmaceutical composition comprising microspheres containing an active substance and a water-soluble polymer in the form of a film or strip has been proposed (for example, Patent Document 3). . According to the invention of Patent Document 3, the active substance is gradually released to improve the sustainability of the drug effect.
Or the composition for oral cavity which mix | blended the active ingredient, the carboxy vinyl polymer, polyvinyl pyrrolidone, and sucrose fatty acid ester is proposed (for example, patent document 4). According to the invention of Patent Document 4, the sustainability of the drug effect is improved because the oral composition stays in the oral cavity for a long time.

JP 2001-340363 A Japanese Patent No. 3051154 JP-T-2001-504439 JP 2006-182699 A

However, since the techniques of Patent Documents 2 to 4 increase the viscosity of the composition and improve the adhesion to the affected area, there is a problem that the composition is difficult to enter the periodontal pocket. On the other hand, a composition simply having a reduced viscosity can easily enter into a narrow gap such as a periodontal pocket (highly permeable), but is easily washed away by saliva and the like, and the drug effect is not sustained (retention property). Is low).
Then, this invention aims at the aqueous | water-based formulation with high infiltration property and retention.

For the prevention and improvement of periodontal disease, a preparation having a contradictory function of high penetration into a narrow gap such as a periodontal pocket and high retention is required.
As a result of intensive studies, the present inventors have found that by combining a specific carboxyvinyl polymer and a specific water-soluble polymer at a specific ratio, it is possible to achieve both infiltration properties and retention properties, leading to the present invention. It was.

That is, the aqueous preparation of the present invention contains a carboxyvinyl polymer (A) having a viscosity of 20 Pa · s or less of a 0.5 mass% aqueous solution measured at 20 rpm and 25 ° C. using a B-type viscometer, and nitrogen. An aqueous preparation containing the water-soluble polymer (B), wherein the mass ratio represented by (A) / (B) is 0.2 to 5, the pH at 25 ° C. is 5 to 9, and the water content is It is 30 to 85% by mass.
It is preferably used in the oral cavity, and the water-soluble polymer (B) is preferably polyvinylpyrrolidone, preferably contains a cationic fungicide (C), contains a chelating agent (D), ( The mass ratio represented by C) / (D) is more preferably 0.3 to 5, and the viscosity measured at 20 rpm and 25 ° C. using a B-type viscometer is 1 to 20 Pa · s. It is preferable that the yield value is increased by contact with water.

 The container-containing aqueous preparation of the present invention is a container-containing aqueous preparation obtained by filling the aqueous preparation of the present invention into a dispensing container, and the dispensing container includes a container main body in which the aqueous preparation is stored; And a nozzle body that projects from the container main body and pours out the aqueous preparation.

  According to the aqueous preparation of the present invention, both infiltration and retention can be achieved.

It is a top view which shows an example of the extraction container concerning one Embodiment of this invention. It is the elements on larger scale of the extraction container of FIG.

(Aqueous preparation)
The aqueous preparation of the present invention contains a carboxyvinyl polymer (A) (hereinafter sometimes referred to as component (A)) and a water-soluble polymer (B) (hereinafter sometimes referred to as component (B)). It is an aqueous formulation. The aqueous preparation is a concept including an aqueous solution in which the component (A) and / or the component (B) are dissolved in water, and an aqueous dispersion in which the component (A) and / or the component (B) are dispersed in water.
The aqueous preparation of the present invention contains, for example, a bactericidal agent, an anti-inflammatory agent and the like, and is a periodontal disease preventive agent or periodontal disease improving agent applied to a periodontal pocket, a toothpaste, a liquid dentifrice, a mouthwash. It contains aqueous preparations for oral cavity such as bactericides, and is used as an aqueous preparation for wounds such as a skin disinfectant applied to wounds.

The viscosity of the aqueous preparation is preferably from 0.1 to 20 Pa · s, more preferably from 1.5 to 7 Pa · s. If it is less than 0.1 Pa · s, there is a risk that the retention in the application target such as the periodontal pocket may be insufficient, and if it exceeds 20 Pa · s, the penetration property into the application target such as the periodontal pocket may be insufficient. May be insufficient.
The viscosity of the aqueous preparation was measured under the following measurement conditions using a BH rotary viscometer (product name: TVB-10) manufactured by Toki Sangyo Co., Ltd.
Rotor: No. 5. Number of revolutions: 20 rpm, measurement temperature: 25 ° C., measurement time: 180 seconds later

The aqueous preparation has a pH of 5 to 9 at 25 ° C, preferably a pH of 6 to 8. Within the above range, it is possible to achieve both penetration and retention.
The pH was measured using a pH meter (product name: SevenEasy, manufactured by METTLER TOLEDO) and a pH electrode (product name: InLab, manufactured by METTLER TOLEDO), and the pH electrode was inserted into an aqueous preparation at 25 ° C. This is done by reading the indicated value after elapse of seconds.

It is preferable that the aqueous preparation has a yield value that increases by contact with water (purified water). [Yield value after contact with water] ÷ [Yield value before contact with water] × 100 The rate of increase in value (%) is preferably more than 100%, more preferably 105% or more, still more preferably 108% or more, and particularly preferably 110% or more.
In addition, the yield value of the aqueous preparation in this paper is a value measured at 37 ° C. at a sensor C of 35/4 degrees, 0 to 20 Pa (30 seconds) using a viscoelasticity measuring device RheoStress RS50 (manufactured by HAAKE).

 In general, an aqueous preparation in which a water-soluble polymer compound is dispersed in water is a pseudoplastic fluid with a yield value among non-Newtonian fluids. In a stationary state, strong binding due to intermolecular stress and interparticle stress Even if it is liquid, it acts like a solid. If the external force is less than the stress acting inside the material, the material will only undergo elastic deformation. When the external force becomes greater than the stress acting inside the substance, the bond due to the internal stress is broken, and the molecules and particles in the substance begin to move and move irregularly, changing to the properties of the liquid. That is, the yield value is a value of external stress when a substance having both solid and liquid properties changes from solid to liquid, that is, when external force and internal stress are equal.

<Carboxyvinyl polymer (A)>
The component (A) of the present invention has a viscosity of a 0.5 mass% aqueous solution (hereinafter sometimes referred to as component (A)) measured at 20 rpm and 25 ° C. using a B-type viscometer, and is 20 Pa · s. The following are preferable, and are preferably 2 to 20 Pa · s, more preferably 5 to 16 Pa · s. (A) If a carboxyvinyl polymer having a component viscosity of more than 20 Pa · s is used, the staying property is lowered, and the component tends to flow out. When the viscosity of the component (A) is increased, the carboxyvinyl polymer has a higher degree of crosslinking and lower cation resistance. For this reason, the carboxyvinyl polymer having a high degree of crosslinking such that the viscosity of the component (A) exceeds 20 Pa · s is easily destroyed by the addition of the component (B) which is a cationic substance, and the retention property of the aqueous preparation Reduce.

Examples of such component (A) include Carbopol 941, 981, ETD2050, 2984 (trade name, manufactured by Lubrizol Corporation), HV501, 501E (trade name, manufactured by Sumitomo Seika Co., Ltd.), and the like.
These (A) components can be used individually by 1 type or in combination of 2 or more types.

 The content of the component (A) in the aqueous preparation can be determined in consideration of the type of the component (A), etc., preferably 0.2 to 2.0% by mass, more preferably 0.4 to 1.5% by mass. preferable. If it is less than 0.2% by mass, the retention may be reduced, and if it is more than 2.0% by mass, the infiltration may be reduced.

<Water-soluble polymer (B)>
The component (B) of the present invention contains nitrogen. “Water-soluble” means that the solubility in water (20 ° C.) is 0.1 g / 100 g or more of water. “Polymer” has a weight average molecular weight of 1000 or more.

The component (B) is not particularly limited as long as it is a water-soluble polymer having a nitrogen atom in the molecule, and examples thereof include hydroxyethyl cellulose dimethyl diallyl ammonium chloride, dimethyl diallyl ammonium chloride polymer, polyvinyl pyrrolidone, and the like. From the viewpoint of further improving the retention, polyvinylpyrrolidone is preferable.
As hydroxyethyl cellulose dimethyl diallylammonium chloride, CELQUAT L-200 (trade name, manufactured by Nippon SC Co., Ltd.), as dimethyl diallylammonium chloride polymer, MERQUAT 100 (trade name, manufactured by Nalco Corp.), as polyvinylpyrrolidone , Rubiscol K-30, 90 (trade name, manufactured by BASF Japan Ltd.) and the like are commercially available.
These (B) components can be used individually by 1 type or in combination of 2 or more types.
The weight average molecular weight of (B) component is not specifically limited, For example, 10000-15500 are preferable. In addition, the said weight average molecular weight converts K value prescribed | regulated in the United States Pharmacopeia (USP) into the weight average molecular weight measured by the light-scattering method.

 The content of the component (B) in the aqueous preparation is preferably 0.2 to 5% by mass, and more preferably 0.4 to 3% by mass. If the amount is less than 0.2% by mass, the retention may decrease, and even if the amount exceeds 5% by mass, the retention cannot be further improved.

 The mass ratio ((A) / (B)) of the component (A) to the component (B) is 0.2 to 5, preferably 0.4 to 3. If it is less than 0.2, sufficient retention cannot be obtained, and if it exceeds 5, impregnation and retention are impaired.

<Cationic fungicide (C)>
The aqueous preparation may contain a cationic fungicide (C) (hereinafter referred to as component (C)). By containing the component (C), the aqueous preparation is suitable for uses that require bactericidal activity, such as periodontal disease preventive agents, periodontal disease improving agents, skin disinfectants, and the like. Further improvement is achieved.

The component (C) excludes the component (B), and examples thereof include cetylpyridinium chloride, benzalkonium chloride, and benzethonium chloride. Among them, cetylpyridinium chloride having high bactericidal activity is preferable.
These (C) components can be used singly or in appropriate combination of two or more.

 The content of the component (C) in the aqueous preparation can be determined in consideration of the bactericidal power required for the aqueous preparation, the content of the component (B), and the like. For example, 0.01 to 0.3% by mass is preferable. 0.02-0.1 mass% is more preferable. If the amount is less than 0.01% by mass, sufficient sterilizing power may not be obtained or the effect of improving the retention property may not be obtained. If it exceeds 0.3% by mass, the infiltration property and the retention property are impaired. It is.

<Chelating agent (D)>
When an aqueous formulation contains (C) component, it is preferable to contain (D) component. By using the component (C) and the component (D) in combination, the bactericidal power of the aqueous preparation can be further improved.

The component (D) is not particularly limited as long as it has a chelating action. For example, edetate disodium, edetate trisodium, ethylenediamine, N-methylethylenediamine, N, N′-dimethylethylenediamine, N, N, N ′, N′-tetramethylethylenediamine, trimethylenediamine, cis-1,2-diaminocyclohexane, 1,2,3-triaminopropane, diethylenetriamine, triethylenetetramine, pyridine-2,6-dicarboxylic acid, nicotinic acid Hydrazide, histamine, iminodiacetic acid, hydroxyethylacetic acid, nitrilotriacetic acid, N, N′-ethylenediaminediacetic acid, N′-hydroxyethyl-N, N, N′-triacetic acid, ethylenediamine-N, N′-diacetic acid-N , N'-dipropionic acid, ethylenediaminetetrapro On acid, 1,2-propylenediaminetetraacetic acid, trimethylenediaminetetraacetic acid, trans-cyclohexane-1,2-diaminetetraacetic acid, ethyl etherdiaminetetraacetic acid, diethylenetriaminepentaacetic acid, glycol etherdiaminetetraacetic acid, glycine, sarcosine, Alanine, leucine, serine, cysteine, glutamic acid, tryptophan, adenine, acetylacetone, 2-nitroso-1-naphthol-8-hydroxynazoline, citric acid, malic acid, tartaric acid, diethylenetriaminepentaacetic acid, or monovalent metal salts thereof (Alkali metal salts such as sodium salts and potassium salts), amine salts and ammonium salts are preferred. Among these, edetate disodium and edetate trisodium are preferable.
These (D) components can be used singly or in appropriate combination of two or more.
Examples of disodium edetate include disolvin NA2 (trade name, manufactured by Lion Corporation), and examples of edetate trisodium include Zonone T (trade name, manufactured by Daiichi Chemicals Co., Ltd.).

 The content of the component (D) in the aqueous preparation is preferably from 0.01 to 0.2% by mass, more preferably from 0.02 to 0.1% by mass, from the viewpoint of the effect of improving bactericidal activity. If it is less than 0.01%, a sufficient effect of improving the sterilizing power may not be obtained, and if it exceeds 0.3% by mass, the retention may be deteriorated.

 The mass ratio ((D) / (C)) of the component (D) to the component (C) is 0.3 to 5, preferably 0.5 to 3. If it is less than 0.3, the retention may decrease, and if it exceeds 5, the effect of improving the sterilizing power may not be obtained.

<Dispersion medium>
The dispersion medium of the aqueous preparation is not particularly limited as long as it is water, and examples thereof include tap water, well water, purified water treated by distillation, ion exchange, filtration, or a combination thereof.
The water content (water content) in the aqueous preparation is 30 to 85% by mass, preferably 40 to 75% by mass. When the amount is less than 30% by mass, the penetration property is insufficient, and when it exceeds 85% by mass, the retention property is insufficient.

<Other optional components>
In addition to the components (A) to (D), the aqueous preparation of the present invention can contain optional components as long as the effects of the present invention are not hindered. As an optional ingredient, for example, when an aqueous preparation is an aqueous preparation for oral cavity, an active ingredient (optional active ingredient) other than the component (C), a thickener, a binder, a surfactant, a sweetener, an antiseptic Agents, pigments, fragrances, abrasives and the like.

Optional active ingredients include fungicides such as hinokitiol, isopropylmethylphenol, and triclosan, and fluoride having a remineralizing effect such as sodium fluoride, potassium fluoride, stannous fluoride, strontium fluoride, and sodium monofluorophosphate. Anti-inflammation such as fluoride, tranexamic acid, epsilon-aminocaproic acid, allantoinchlorohydroxyaluminum, hinokitiol, ascorbic acid, dl-tocopherol acetate, dihydrocholesterol, α-bisabolol, azulene, dipotassium glycyrrhizinate, glycyrrhetinic acid, copper chlorophyllin sodium, chlorophyll Agents, copper compounds such as copper gluconate, ingredients for suppressing hypersensitivity such as aluminum lactate, strontium chloride, potassium nitrate, soft sugar beet extract, buckwheat extract, chamomile, cho Di, rosemary, scutellaria root extract, etc. safflower and the like. These arbitrary active ingredients can be used individually by 1 type or in combination of 2 or more types.
The content of the optional active ingredient in the aqueous preparation can be determined within a range that does not impair the effects of the present invention in consideration of the type of the optional active ingredient.

Examples of the thickening agent include glycerin, sorbit, propylene glycol, polyethylene glycol having a molecular weight of 200 to 6000, ethylene glycol, polyhydric alcohol such as reduced starch saccharified product, and the like. These thickeners can be used singly or in appropriate combination of two or more.
Although content of the thickener in an aqueous formulation is not specifically limited, For example, you may be 5-50 mass%.

Examples of the binder include water-soluble polymers excluding component (A) and component (B), such as sodium polyacrylate, xanthan gum, sodium alginate, propylene glycol ester alginate, sodium carboxymethyl cellulose, hydroxyethyl cellulose, guar gum. And organic binders such as gelatin and Avicel, and inorganic binders such as montmorillonite, kaolin and bentonite. These binders can be used individually by 1 type or in combination of 2 or more types as appropriate.
Although content of the binder in an aqueous formulation is not specifically limited, For example, you may be 5 mass% or less.

Examples of the surfactant include anionic surfactants such as sodium lauryl sulfate, sodium lauroyl sarcosine, polyoxyethylene alkyl sulfate, N-lauroyl taurate, α-olefin sulfonate, N-acyl glutamate, 2- Amphoteric surfactants such as alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, polyoxyethylene hydrogenated castor oil, alkylglycoside, alkylol amide, polyoxyethylene sorbitan monostearate, polyoxyethylene polyoxypropylene Nonionic surfactants such as glycol, polyoxyethylene alkyl ether, decaglyceryl laurate and the like can be mentioned.
When the aqueous preparation contains the component (C) or an optional active ingredient, the HLB value is 10 as a surfactant in order to solubilize these components, reduce adhesion to the dispensing container described later, and further increase the infiltration property. It is preferable to use polyoxyethylene (20 to 100) hydrogenated castor oil (average added mole number of ethylene oxide: 20 to 100 mol) of ˜17.
In addition, HLB is a value calculated | required by the method of Griffin (see Yoshida, Shindo, Ogaki, Yamanaka co-edit, "New edition surfactant handbook", Kogyoshosho, 1991, 234 pages). These surfactants can be used individually by 1 type or in combination of 2 or more types as appropriate.
The content of the surfactant in the aqueous preparation can be determined in consideration of the type of the surfactant and the like, for example, 0.1 to 5% by mass. When polyoxyethylene (20 to 100) hydrogenated castor oil is used as the surfactant, the content of the surfactant in the aqueous preparation is, for example, 0.5 to 5% by mass.

Examples of sweeteners include saccharin sodium, aspartame, stevioside, stevia extract, paramethoxycinnamic aldehyde, neohesperidyl dihydrochalcone, and perilartin. Examples of preservatives include parabens such as butylparaben and ethylparaben (paraoxybenzoate esters). ), Sodium benzoate and the like. These sweeteners can be used singly or in appropriate combination of two or more.
The content of the sweetener in the aqueous preparation can be determined within a range that does not impair the effects of the present invention in consideration of the type of sweetener.

Perfumes include peppermint oil, spearmint oil, anise oil, eucalyptus oil, winter green oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander oil, mandarin oil, Lime oil, lavender oil, rosemary oil, laurel oil, camomil oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, iris concrete, absolute Natural fragrances such as peppermint, absolute rose, orange flower, and fragrances, menthol, carvone that have been processed by these natural fragrances (front reservoir cut, rear reservoir cut, fractional distillation, liquid extraction, essence, powder fragrance, etc.) , Anethole, cineol, methyl salicylate, Namic aldehyde, eugenol, 3-l-menthoxypropane-1.2-diol, thymol, linalool, linalyl acetate, limonene, menthone, menthyl acetate, N-substituted-paramentane-3-carboxamide, pinene, octylaldehyde, Citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allylcyclohexane propionate, methyl anthranilate, ethyl methyl phenyl glycidate, vanillin, undecalactone, hexanal, propyl alcohol, butanol, isoamyl alcohol , Hexenol, dimethyl sulfide, cycloten, furfural, trimethylpyrazine, ethyl lactate, methyl lactate, ethylthioacetate Separately perfume, strawberry flavor, apple flavor, banana flavor, pineapple flavor, grape flavor, mango flavor, butter flavor, milk flavor, fruit mix flavors, blended fragrance such as tropical fruit flavors and the like, include known perfume. These fragrance | flavors can be used individually by 1 type or in combination of 2 or more types as appropriate.
Content of the fragrance | flavor in an aqueous formulation can be determined according to the kind of fragrance | flavor, for example, 0.000001-1 mass% is preferable. Moreover, when using the fragrance | flavor formulation which melt | dissolved the said fragrance | flavor in the fragrance | flavor solvent, 0.1-2.0 mass% of content of the fragrance | flavor formulation in an aqueous formulation is preferable, for example.

Examples of the abrasive include anhydrous silicic acid, silica gel, aluminosilicate, zirconosilicate, dicalcium phosphate dihydrate, dibasic calcium phosphate anhydride, calcium pyrophosphate, aluminum hydroxide, alumina, titanium dioxide, crystalline zirconium. Silicate, polymethyl methacrylate, insoluble calcium metaphosphate, light calcium carbonate, heavy calcium carbonate, magnesium carbonate, tertiary magnesium phosphate, zeolite, zirconium silicate, tertiary calcium phosphate, hydroxyapatite, fluoroapatite, calcium deficient apatite Examples thereof include tricalcium phosphate, fourth calcium phosphate, eighth calcium phosphate, and synthetic resin-based abrasive. These abrasive | polishing agents can be used individually by 1 type or in combination of 2 or more types as appropriate.
The content of the abrasive in the aqueous preparation is, for example, 2 to 50% by mass.

 Examples of the colorant include Blue No. 1, Responsible Color No. 4, Green No. 3, and the like.

(Production method)
The production method of the aqueous preparation is not particularly limited as long as the components (A) to (B) can be dissolved or dispersed in water. For example, using a vessel equipped with a stirring blade, (A) to (A B) Component, (C)-(D) component and the method of melt | dissolving or disperse | distributing arbitrary component as needed are mentioned.

(how to use)
Next, a method for using the aqueous preparation of the present invention will be described.
The aqueous preparation is stored, for example, in a resin, metal, or glass container, and an appropriate amount is taken out from the container and applied to an application target.
The method for applying the aqueous preparation is not particularly limited, and examples thereof include a method in which the aqueous preparation in the container is inhaled into a dropper or a syringe, and then the aqueous preparation is poured out to the application target.
Moreover, the method of apply | coating to an application | coating object is mentioned, for example using the extraction container provided with the container main body which accommodates the aqueous | water-based preparation, and the nozzle body which pours out the stored aqueous | water-based preparation.
An example of such a dispensing container will be described with reference to FIG.

The dispensing container 1 of FIG. 1 includes a container main body 2 that stores an aqueous preparation and a nozzle body 3 connected to the container main body 2, and has a long shape as a whole.
The container main body 2 is formed by forming a flexible resin film into a substantially cylindrical shape, with the inner surfaces of one open end butting each other, and forming a bottom 22 fused by heat sealing or the like. A dome-shaped mouth and neck portion 24 that protrudes in the direction of the axis O of the container body 2 is formed at the opening end opposite to the bottom portion 22, and the inside and outside of the container body 2 communicate with the projecting end of the mouth and neck portion 24. An opening (not shown) is formed. A long nozzle body 3 extending in the direction of the axis O is connected to the opening of the mouth / neck portion 24.
The nozzle body 3 is reduced in diameter as it goes from the proximal end portion 34, which is a connection portion with the mouth-and-neck portion 24, toward the distal end portion 32, and the inside of the nozzle body 3 passes through the opening portion of the mouth-and-neck portion 24. The container body 2 communicates with the inside.

 If the size of the container body 2 is too large, the operation is complicated, and if it is too small, the aqueous preparation as the contents is consumed in a short period of time. For this reason, the magnitude | size of the container main body 2 can be determined in consideration of the dosage and usage of an aqueous formulation, for example, 10-200 mL capacity is preferable.

 The material of the container body 2 may be any material as long as it is flexible and can be poured out by a finger so that the stored aqueous preparation can be poured out. Polyolefin such as polyethylene and polypropylene, polyester such as polyethylene terephthalate, nylon Examples thereof include a single layer film made of polyamide, etc., and a multilayer film obtained by laminating these single layer films.

 As for the nozzle body 3, 20-60 mm is preferable and, as for the length L from the front-end | tip part 32 to the base end part 34, 30-50 mm is more preferable. If it is less than 20 mm, it is difficult to apply the aqueous preparation to the periodontal spot of the back tooth, and if it is more than 60 mm, the operation in the oral cavity becomes complicated, and it becomes particularly difficult to apply the aqueous preparation to the periodontal pocket of the front tooth.

  The inner diameter R (FIG. 2) of the tip 32 of the nozzle body 3 can be determined in consideration of the viscosity of the aqueous preparation and the like, for example, 0.2 to 2 mm is preferable, and 0.4 to 1.2 mm is more preferable. If it is less than 0.2 mm, it is troublesome to pour out an arbitrary volume, and there is a risk of pain when the tip 32 hits the gums. If it exceeds 2 mm, it tends to be difficult to control the dispensing amount of the aqueous preparation.

The material of the nozzle body 3 is not particularly limited, but it is preferable that the nozzle body 3 is not easily irritate to the user when the nozzle body 3 comes into contact with the gums or teeth and has flexibility. By having flexibility, the tip part 32 of the nozzle body 3 is brought into contact with the boundary between the tooth and the gingiva, and the aqueous preparation is poured out while moving in the oral cavity. Can be applied.
Examples of the material of the nozzle body 3 include relatively soft resins such as polyolefins such as polyethylene and polypropylene, vinyl chloride, silicon elastomer, and urethane.

Next, the usage method of the container-containing aqueous preparation which accommodated the periodontal disease prevention agent in the extraction container of this embodiment is demonstrated.
The container body 2 is gripped with fingers, the tip 32 of the nozzle body 3 is brought into contact with the boundary between the teeth and gums, and the container body 2 is pressed with the gripped fingers to pour out the aqueous preparation from the tip 32. While pouring out the aqueous preparation, the tip 32 is moved according to the boundary between the teeth and gums, thereby applying the aqueous preparation over a wide range.
Since the aqueous preparation applied at the boundary between the tooth and the gingiva has fluidity, it penetrates to the bottom of the periodontal pocket. When the aqueous preparation comes into contact with water contained in saliva or the like in the oral cavity, the yield value increases, the fluidity decreases, and the aqueous preparation stays in the periodontal pocket.

 As described above, since the water content of the present invention is 30 to 85% by mass, it has excellent fluidity and can penetrate into narrow gaps such as periodontal pockets. In addition, since the aqueous preparation contains the component (A) and the component (B), the yield value increases by entering the narrow gap and then coming into contact with water, thereby exhibiting high retention.

The mechanism by which the yield value of the aqueous preparation increases when the aqueous preparation comes into contact with water is not clear, but can be estimated as follows.
The water in which the component (A) is dispersed has an increased viscosity as compared with water not containing the component (A). Here, the viscosity resulting from (A) component falls because (A) component and (B) component couple | bond together. For this reason, the aqueous preparation of the present invention has fluidity and penetrates well into narrow gaps.
In the aqueous preparation of the present invention, when water from saliva or the like in the oral cavity is supplied, the bond between the component (A) and the component (B) is dissociated, and the component (A) is dispersed independently in water. Thus, the yield value is increased. For this reason, it is thought that the aqueous formulation restores the retention property derived from the component (A).
Furthermore, the coupling | bonding and dissociation of (A) component and (B) component are accelerated | stimulated more by presence of (C) component. For this reason, an aqueous formulation is equipped with (C) component, and while providing bactericidal power, it exhibits more favorable infiltration property and better retention property.

 Furthermore, the aqueous preparation can be easily applied to the application target by storing the aqueous preparation in a dispensing container having a container body and a nozzle body.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited by the following description.

(Raw materials used)
The raw materials used in the aqueous preparations of each example are as follows.
The viscosity ((A) component viscosity) of the 0.5 mass% aqueous solution of the components (A) and (A ′) is described as “0.5 mass% viscosity” in each table.
<(A) component>
A-1: Carboxyvinyl polymer (trade name; Carbopol 981, viscosity of 0.5 mass% aqueous solution; 6 Pa · s, manufactured by Lubrizol Corporation)
A-2: Carboxyvinyl polymer (trade name; Carbopol ETD2050, viscosity of 0.5 mass% aqueous solution; 15 Pa · s, manufactured by Lubrizol Corporation)

<(A ′) component: Comparative product of component (A)>
A′-1: Carboxyvinyl polymer (trade name: HV504E, viscosity of 0.5 mass% aqueous solution; 28 Pa · s, manufactured by Sumitomo Seika Co., Ltd.)
A′-2: Carboxyvinyl polymer (trade name; HV505E, viscosity of 0.5 mass% aqueous solution: 42 Pa · s, manufactured by Sumitomo Seika Co., Ltd.)
A′-3: Carboxymethylcellulose (trade name; CMC Daicel 1260, manufactured by Daicel Chemical Industries, Ltd.)
A'-4: Xanthan gum (trade name; Monato Gum DA, manufactured by Dainippon Sumitomo Pharma Co., Ltd.)

<(B) component>
B-1: Polyvinylpyrrolidone (trade name; Rubiscol K-90, manufactured by BASF Japan Ltd.)
B-2: Hydroxyethylcellulose dimethyl diallylammonium chloride (trade name; CELQUAT L-200, manufactured by NSC Japan)
B-3: Dimethyldiallylammonium chloride polymer (trade name; MERQUAT 100, manufactured by Nalco Corporation)

<(C) component>
C-1: Cetylpyridinium chloride (Wako Pure Chemical Industries, Ltd.)
C-2: Benzalkonium chloride (manufactured by Kanto Chemical Co., Inc.)
C-3: Benzethonium chloride (manufactured by Kanto Chemical Co., Inc.)

<(D) component>
D-1: Disodium edetate (trade name; Dissolvin NA2, manufactured by Lion Corporation)
D-2: Trisodium edetate (trade name; Zonon T, manufactured by Daiichi Chemicals Co., Ltd.)

<Others>
For other ingredients, standard products of quasi-drug raw material standards were used.

(Evaluation method)
<Invasion evaluation method>
A tooth model made of acrylic was fixed to the mandibular first molar part of the jaw model with a screw from the back surface at a depth of 10 mm to obtain an infiltration evaluation model. The infiltration length 10 seconds after the aqueous preparation of each example was poured from the container and applied to the tooth neck of the jaw model was measured. This test was repeated, the average value of 3 times was calculated | required, the average value was classified into the following references | standards, and the penetration property was evaluated.
◎: Average penetration length 8 mm or more ◎: Average penetration length 7 mm or more and less than 8 mm ○: Average penetration length 6 mm or more and less than 7 mm △: Average penetration length 4 mm or more and less than 6 mm ×: Average penetration depth 4 mm or less

<Residence evaluation method>
The retention was evaluated based on “preparation of dissolution of the preparation” and “feeling of retention in the oral cavity after standing” described below.
≪Evaluation method for suppression of drug dissolution≫
1 mL of the aqueous preparation of each example was added to 3 mL of artificial saliva, and the dissolved state after 3 minutes was visually observed. 5 points for "almost elute", 4 points for "elute about 1/4", 3 points for "elute about 1/2", 2 points for "elute about 3/4", "almost elute" Was evaluated as the drug elution suppression based on the following criteria based on the average of three repetitions.
◎: Average point 4.5 points or more ◎: Average point 4.0 points or more and less than 4.5 points ○: Average point 3.5 points or more and less than 4.0 points △: Average point 2.0 points or more and 3.5 points Less than point x: Average score of 1.0 point or more and less than 2.0 point

≪Evaluation method for the feeling of retention in the oral cavity after standing still≫
Contain 1 mL of each aqueous preparation in the oral cavity, and get a response in 4 stages of “I feel very”, “I feel”, “I feel a little”, “I don't feel” about the staying feeling after standing for 1 minute and exhaling It was. Of these answers, 4 points are “I feel very”, 3 points are “I feel”, 2 points are “I feel a little”, and 1 point is “I don't feel”. Then, the feeling of staying in the oral cavity after standing was evaluated.
◎: Average point 3.5 points or more ◎: Average point 3.0 points or more and less than 3.5 points ○: Average point 2.5 points or more and less than 3.0 points △: Average point 2.0 points or more and 2.5 points Less than point x: Average score of 1.0 point or more and less than 2.0 point

<Method for evaluating sterilizing power>
50 μL of the Porphyromonas gingivalis culture solution that had been cryopreserved was Todd Hewitt broth (Becton and) containing 5 mg / L hemin (Sigma) and 1 mg / L vitamin K (Wako Pure Chemical Industries). Dickinson's) culture solution (THBHM) was added to 4 mL, and anaerobic culture was performed at 37 ° C. overnight (80 vol% nitrogen, 10 vol% carbon dioxide, 10 vol% hydrogen) to obtain a bacterial solution. After adding 49 mL of THBHM medium to 1 g of the aqueous preparation of each example and stirring, a THBHM medium was further added to prepare a diluted medium containing each aqueous preparation so that the aqueous preparation had a dilution ratio of 400 to 4000 times. 50 μL of the bacterial solution was added to 3 mL of each diluted medium containing the aqueous preparation, and after anaerobic culture at 37 ° C. for 7 days, the presence or absence of the growth of the bacteria was determined by appearance, smell, and microscope. The bactericidal power is a value indicated by the highest dilution factor in a diluted medium containing an aqueous preparation in which no bacterial growth was observed.

<Evaluation method of infiltration>
Inject the aqueous preparation of each case from the dispensing container into the periodontal pocket. Regarding the feeling of intrusion into the periodontal pocket, “I feel a very intrusive feeling”, “I feel a feeling of intruding”, “I feel a little intruding feeling”, respectively. , “No feeling of intrusion” was answered in four stages. Of these answers, 4 points are “I feel a very intrusion”, 3 points are “I feel a feeling of intrusion”, 2 points are “I feel a little intrusion”, and 1 point is “I do not feel a feeling of intrusion”. The average score of 10 people was classified into the following criteria to evaluate the feeling of penetration.
◎: Average point 3.5 points or more ◎: Average point 3.0 points or more and less than 3.5 points ○: Average point 2.5 points or more and less than 3.0 points △: Average point 2.0 points or more and 2.5 points Less than point x: Average score of 1.0 point or more and less than 2.0 point

<Evaluation method for staying feeling>
Inject the aqueous preparation of each case from the dispensing container into the periodontal pocket. Regarding the feeling of retention in the periodontal pocket, “I feel a feeling of staying”, “I feel a feeling of staying”, and “I feel a feeling of staying a little”, respectively. , "No feeling of stay" was obtained in four stages. Out of these answers, 4 points are “I feel a feeling of staying in”, 3 points are “I feel a feeling of staying”, 2 points are “feeling a feeling of staying a little”, and 1 point is “I do not feel a feeling of staying” The average score of 10 people was classified into the following criteria to evaluate the feeling of stay.
◎: Average point 3.5 points or more ◎: Average point 3.0 points or more and less than 3.5 points ○: Average point 2.5 points or more and less than 3.0 points △: Average point 2.0 points or more and 2.5 points Less than point x: Average score of 1.0 point or more and less than 2.0 point

<Evaluation method of operability>
Regarding the ease of injection when injecting the aqueous preparation of each case into the periodontal pocket, it is divided into four stages: “Very easy to inject”, “Easy to inject”, “Slightly difficult to inject”, and “Difficult to inject”. Got an answer. Of these answers, the average score of 10 people was 4 points for “very easy to inject”, 3 points for “easy to inject”, 2 points for “easy to inject”, 1 point for “not easy to inject” Were classified into the following criteria to evaluate operability.
◎: Average point 3.5 points or more ◎: Average point 3.0 points or more and less than 3.5 points ○: Average point 2.5 points or more and less than 3.0 points △: Average point 2.0 points or more and 2.5 points Less than point x: Average score of 1.0 point or more and less than 2.0 point

<Yield increase rate>
First, 2 mL of a sample to be measured is placed on a sample stage, and using a viscoelasticity measuring device RheoStress RS50 (manufactured by HAAKE), sensor C35 / 4 degrees, 0 to 20 Pa (30 seconds) at 37 ° C. with water The yield value before contact was measured.
Next, 2 mL of the sample to be measured is placed on the sample stage, and immediately after 200 μL of water is dropped on the sample, using a viscoelasticity measuring device RheoStress RS50 (manufactured by HAAKE), sensor C35 / 4 degrees (cone type), The yield value after contact with water was measured at 0 to 20 Pa (30 seconds) at 37 ° C.
From the yield value obtained, the yield value increase rate was determined by the following equation (1).

  Yield value increase rate (%) = [yield value after contact with water] ÷ [yield value before contact with water] x 100 (1)

(Examples 1-20, Comparative Examples 1-12)
According to the composition of Tables 1-3, each component was added to water and stirred to obtain an aqueous preparation of each example. About this aqueous formulation, penetration property, formulation elution suppression, the feeling of staying in the oral cavity after standing were evaluated, and the results are shown in the table. In the evaluation of penetration, the aqueous preparations of each example were stored in containers of the following specifications, and the stored aqueous preparations were applied to the application target while pouring out.

<Container specifications>
-Container body: Laminated tube for dentifrice (inner diameter 19 mm, mouth and neck (height 10 mm, opening 5 mm)) (low density polyethylene 72 μm / ethylene / acrylic acid copolymer resin 90 μm / aluminum 10 μm / ethylene / acrylic) Acid copolymer resin 35 μm / linear low density polyethylene 50 μm, thickness 257 μm), manufactured by Dai Nippon Printing Co., Ltd.

As shown in Tables 1 to 3, in Examples 1 to 20 to which the present invention was applied, the penetrability was “◯” to “◎◎”, the formulation elution suppression was “○” to “◎”, and static The feeling of staying in the oral cavity after placement was “◯” to “◎”. In addition, when the yield value increase rate was measured for Example 6, it was 109% (yield value after contact with water: 3.781 Pa, yield value before contact with water: 3.463 Pa).
On the other hand, in Comparative Example 1 containing no component (A), the penetration property was “◎”, but the dissolution of the preparation and the feeling of staying in the oral cavity after standing were both “x”. In Comparative Example 2 containing no component (B), the penetration property, the dissolution of the preparation, and the retention in the oral cavity after standing were all “Δ”, and the yield value increase rate was 94% (after contact with water). Yield value: 10.59 Pa, yield value before contact with water: 11.21 Pa). In Comparative Example 6 using A′-2 instead of the component (A), the penetration property was “◎◎”, but the dissolution of the preparation and the feeling of staying in the oral cavity after standing were both “×”. there were. Comparative Example 6 did not show a yield value because the swelling of A′-2 was destroyed by the addition of component (B).
In Comparative Example 3 where the water content was less than the lower limit of the present invention, the formulation elution suppression was “◯” and the oral retention after standing was “◎◎”, but the penetration property was “×”. It was. In Comparative Example 4 in which the water content exceeds the upper limit of the present invention, the penetration property was “◯”, but the formulation elution suppression was “Δ”, and the oral residence feeling after standing was “×”. .
In Comparative Example 9 in which the mass ratio of (A) / (B) is less than the lower limit of the present invention, the penetration property was “◯”, but the formulation elution suppression and the feeling of retention in the oral cavity after standing were “×”. "Met. In Comparative Example 10 in which the mass ratio of (A) / (B) exceeds the upper limit value of the present invention, the penetration property is “◯”, and the dissolution in the oral cavity after the preparation dissolution and standing is “Δ”. there were.
From the above results, it has been found that the aqueous preparation to which the present invention is applied can achieve both infiltration and retention.

(Examples 21 to 38)
According to the composition of Tables 4-5, the aqueous formulation of each example was prepared like Example 1 according to the aqueous formulation. This aqueous preparation was evaluated in the same manner as in Example 1 for invasiveness, preparation elution suppression, standing in the oral cavity after standing, and bactericidal power, and the results are shown in the table.

  As shown in Tables 4 to 5, in Examples 21 to 38 to which the present invention was applied, the penetration property was “◎”, the dissolution of the preparation was inhibited, and the feeling of staying in the oral cavity after standing was “◎” or “◎”. there were. In addition, all of Examples 21 to 38 had a sterilizing power of 1200 or more, and showed a good sterilizing power.

(Examples 39 to 52)
According to the composition of Tables 6 to 7, each component was added to water and stirred to obtain an aqueous preparation of each example. A nozzle body with the specifications shown in the table (the inner diameter of the base end is 5 mm for each) is attached to the mouth and neck of the container body with the following specifications to produce a dispensing container similar to the dispensing container 1 shown in FIG. did. 30 g of the aqueous preparation of each example was stored in this dispensing container to obtain an aqueous preparation in a container. About this water-based preparation in a container, penetration property, preparation elution suppression, a feeling of staying in the oral cavity after standing, a feeling of penetration, a feeling of staying, and operability are evaluated, and the results are shown in the table. In addition, about Examples 51-52 containing (C) component, the bactericidal power was measured.

<Specification of the dispensing container>
-Container body: Laminated tube for dentifrice (inner diameter 19 mm, mouth and neck (height 10 mm, opening 5 mm)) (low density polyethylene 72 μm / ethylene / acrylic acid copolymer resin 90 μm / aluminum 10 μm / ethylene / acrylic) Acid copolymer resin 35 μm / linear low density polyethylene 50 μm, thickness 257 μm), manufactured by Dai Nippon Printing Co., Ltd.

  As shown in Tables 6 to 7, all of Examples 39 to 52 to which the present invention is applied have an invasion property of “◎” or “◎◎”, and suppresses dissolution of the preparation and has a feeling of staying in the oral cavity after standing. It was “◎” or “◎◎”. In addition, in Examples 39 to 52, the feeling of penetration, the feeling of stay, and the operability were “」 ”or“ 「”.

1 Dispensing container 2 Container body 3 Nozzle body

Claims (8)

Carboxyvinyl polymer (A) in which the viscosity of a 0.5 mass% aqueous solution measured at 20 rpm and 25 ° C using a B-type viscometer is 5 to 20 Pa · s , and a water-soluble polymer (B) containing nitrogen an aqueous solution formulation in the oral cavity containing bets,
The content of (A) is 0.2 to 2.0% by mass,
The content of (B) is 0.2 to 4.0% by mass, and (B) is at least one selected from hydroxyethyl cellulose dimethyl diallyl ammonium chloride, dimethyl diallyl ammonium chloride polymer and polyvinyl pyrrolidone. ,
(A) / pH 5 to 9 mass ratio represented by (B) is at 0.2～5,25 ° C., water content Ri 30-85% by mass, and with a B-type viscometer 20rpm the aqueous solution formulation in the oral cavity that is viscosity measured at 25 ° C. and wherein 0.1 to 20 Pa · s der Rukoto. Characterized in that it is used for periodontal pockets, the aqueous solution formulation in the oral cavity according to claim 1. Wherein (B) is characterized by a polyvinylpyrrolidone, intraoral aqueous liquid preparation according to claim 1 or 2. Characterized in that it contains a cationic bactericidal agent (C), the aqueous solution formulation in the oral cavity according to any one of claims 1-3. Contain a chelating agent (D), (C) / mass ratio represented by (D) is characterized in that 0.3 to 5, the aqueous solution formulation in the oral cavity according to claim 4. Viscosity measured at 20 rpm, 25 ° C. using a B-type viscometer, characterized in that it is a 1~20Pa · s, aqueous solution formulation in the oral cavity according to any one of claims 1 to 5 . By contact with water, yield value, characterized in that the rising, the aqueous solution formulation in the oral cavity according to any one of claims 1-6. An aqueous solution formulation containers the mouth comprising the aqueous liquid preparation for the oral cavity was filled in a dispensing container according to claim 1, wherein the dispensing container, for the oral cavity a container body the aqueous liquid preparation is accommodated, the container protrudes from the body, the aqueous liquid pharmaceutical containers in the oral cavity, characterized in that it comprises a nozzle body which dispense the aqueous liquid formulation for the oral cavity.

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