JP2011046633A - Two-agent type oral composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral composition that enhances adsorbability and retentivity in the oral cavity of a polymer compound exhibiting effectiveness in the oral cavity thereby to make the polymer compound exhibit the effects more. <P>SOLUTION: The two-agent type oral composition comprises a composition (A) comprising a positively charged polymer compound selected from among lysozyme, chitosan, lactoferrin, polylysine and a cationic monofluorophosphorylated polymer compound bearing a monofluorophosphoric acid residue and a composition (B) comprising a negatively charged polymer compound selected from among polyglutamic acid, hyaluronic acid, chondroitin sulfate, pectin and an anionic monofluorophosphorylated polymer compound bearing a monofluorophosphoric acid residue. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a composition for an oral cavity that exhibits a higher effect by adhering a polymer compound having a positive charge or a negative charge and exhibiting various effectiveness in the oral cavity to the oral cavity.

  As a technique for adhering substances that are effective in the oral cavity to the oral cavity, a composition containing a salt-sensitive polymer compound, an electrolyte, and an active ingredient is diluted with water, so that it is salt-sensitive together with the active ingredient. A technique for adhering an adhesive polymer compound in the oral cavity has been proposed (see Patent Document 1: Japanese Patent Application Laid-Open No. 2008-63334). However, electrolytes are essential for salt sensitivity, and it was necessary to dilute with water. For this reason, further improvement in the intraoral adsorptivity and retention has been desired by a simple method.

JP 2008-63334 A International Publication No. 2007/125980

  The present invention has been made in view of the above circumstances, and provides a composition for oral cavity that improves the adsorptive property / retention property in the oral cavity of a polymer compound that exhibits effectiveness in the oral cavity and exhibits its effect more effectively. For the purpose.

  As a result of intensive studies to achieve the above object, the inventors of the present invention contain a composition containing an ionic polymer compound that is effective in the oral cavity and a polymer compound having a charge opposite to this. It is a two-part oral composition having a composition, and the complex formed (precipitate) shows high oral absorption and retention by mixing and treating the oral cavity before use. It has been found and the present invention has been made.

Accordingly, the present invention provides the following two-pack oral composition.
[1]. A composition (A) containing a positively charged polymer compound selected from lysozyme, chitosan, lactoferrin, polylysine, and a cationic monofluorophosphorylated polymer compound having a monofluorophosphate residue;
A composition (B) containing a negatively charged polymer compound selected from polyglutamic acid, hyaluronic acid, chondroitin sulfate, pectin, and an anionic monofluorophosphorylated polymer compound having a monofluorophosphate residue; A two-part oral cavity composition.
[2]. The two-part oral cavity composition according to [1], wherein the pH of the mixture of the composition (A) and the composition (B) is 4 to 10, and the following charge concentration in the mixture is 1 to 30: object.
Charge concentration (mmol / L) = (Q ₁ / M ₁ × C ₁ −Q ₂ / M ₂ × C ₂ ) × 10
In the polymer compound having a positive charge in the composition (A),
Q ₁ (charge mmol / mol): “positive charge number−negative charge number” per molecule
M ₁ (g / mol): Molecular weight C ₁ (mass%): In the polymer compound having a negative charge in the blended concentration composition (B) in the mixture,
Q ₂ (charge mmol / mol): “number of negative charges−number of positive charges” per molecule
M ₂ (g / mol): molecular weight C ₂ (mass%): blending concentration in the mixture [3]. Furthermore, the composition for oral cavity of [1] or [2] containing an amphoteric surfactant.
[4]. The composition for oral cavity according to [3], wherein the amphoteric surfactant is a betaine amphoteric surfactant.

  According to the present invention, an object of the present invention is to provide a two-component oral composition in which an ionic polymer compound exhibiting effectiveness in the oral cavity exhibits oral absorption and retention.

Hereinafter, the present invention will be described in detail.
The ionic polymer compound exhibiting effectiveness in the oral cavity of the present invention may be a polymer compound having a positive charge or a polymer compound having a negative charge, and the composition (A), It may be contained in both of the compositions (B).

(A) Composition containing a polymer compound having a positive charge In composition (A), there is a cationic monofluorophosphorylated polymer compound having lysozyme, chitosan, lactoferrin, polylysine, and a monofluorophosphate residue. included. Lysozyme, chitosan and polylysine have oral bactericidal action, and lactoferrin has oral antibacterial action. The cationic monofluorophosphorylated polymer compound has fluorine and has an inhibitory action against caries.

(B) A composition containing a negatively charged polymer compound The composition (B) includes polyglutamic acid, hyaluronic acid, chondroitin sulfate, pectin, and anionic monofluorophosphoric acid having a monofluorophosphoric acid residue. Molecular compounds are included. Polyglutamic acid, hyaluronic acid, chondroitin sulfate, and pectin have a mucosal wetting action. The anionic monofluorophosphorylated polymer compound has fluorine and has an action of inhibiting caries.

  The combination of the polymer compound contained in (A) and the polymer compound contained in (B) can significantly improve the adsorptivity and retention in the oral cavity. Among them, a preferable combination is a combination of a composition (A) containing lysozyme and chitosan and a composition (B) containing an anionic monofluorophosphorylated polymer compound having a monofluorophosphate residue. High oral retention effect can be obtained.

  The weight average molecular weight of the polymer compound contained in the compositions (A) and (B) is preferably 1,000 to 10,000,000, and more preferably 5,000 to 5,000,000. The weight average molecular weight is converted by pullulan standard by gel permeation chromatography using water-soluble polymer compound after monofluorophosphorylation as a sample, water containing 10 mM sodium nitrate and 20 vol% acetonitrile as eluent. To calculate the weight average molecular weight.

（式中、Ｍは水素原子、アルカリ金属、アンモニウム、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン又はトリエチルアミンを示す。） A monofluorophosphoric acid residue in a cationic monofluorophosphorylated polymer compound having an monofluorophosphoric acid residue or an anionic monofluorophosphorylated polymer compound (hereinafter abbreviated as monofluorophosphorylated polymer compound) It is represented by the following general formula (1), and monofluorophosphoric acid may be any of acid type, neutralized type, and partially neutralized type.

(In the formula, M represents a hydrogen atom, an alkali metal, ammonium, monoethanolamine, diethanolamine, triethanolamine or triethylamine.)

  The monofluorophosphorylated polymer compound is, for example, a part of hydrogen atoms of the above-mentioned substituents of a synthetic polymer compound or a natural polymer compound having a hydroxyl group, a phosphate group, a carboxylic acid group, or a sulfonate group in the molecule, or The whole thing substituted by the said monofluoro phosphoric acid residue is mentioned. Although the monofluorophosphoric acid residue is an anionic group, whether the monofluorophosphorylated polymer compound is cationic or anionic is determined by the charge of the entire monofluorophosphorylated polymer compound.

  The synthetic polymer compound is preferably a (co) polymer containing an acrylamide derivative having a hydroxyl group as a structural unit, and the natural polymer compound is preferably a polysaccharide having a hydroxyl group.

（式中、Ｒ¹は水素原子又はメチル基、Ｒ²は炭素数１〜６の２価炭化水素基、ポリエチレンオキサイド基（エチレンオキサイド基の繰り返し数：１〜５）、ポリプロピレンオキサイド基（プロピレンオキサイド基の繰り返し数：１〜５）、ポリエチレンオキサイド基（エチレンオキサイド基の繰り返し数：１〜５）及びポリプロピレンオキサイド基（プロピレンオキサイド基の繰り返し数：１〜５）を含むポリアルキレンオキサイド又はジメトキシエチル基である。） The acrylamide derivative having a hydroxyl group is not particularly limited as long as it has a vinyl group, -C (= O) -NH- group, and a hydroxyl group in the molecule, and one kind alone or two or more kinds are appropriately combined. Can be used. Specifically, what is represented by the following general formula (2) is mentioned.

(Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a divalent hydrocarbon group having 1 to 6 carbon atoms, a polyethylene oxide group (the number of repeating ethylene oxide groups: 1 to 5), a polypropylene oxide group (propylene oxide) Group repeating number: 1 to 5), polyalkylene oxide or dimethoxyethyl group including polyethylene oxide group (ethylene oxide group repeating number: 1 to 5) and polypropylene oxide group (propylene oxide group repeating number: 1 to 5) .)

  As what is represented by the said General formula (2), N- (2-hydroxyethyl) (meth) acrylamide, N- (hydroxymethyl) (meth) acrylamide, N- (polyethylene glycol) (meth) acrylamide, N -(2,2-dimethoxy-1-hydroxyethyl) (meth) acrylamide, N- (2-hydroxypropyl) (meth) acrylamide, N- (diethylene glycol) (meth) acrylamide, N- (triethylene glycol) (meta And N- (polyethylene glycol) (meth) acrylamide such as N- (tetraethylene glycol) (meth) acrylamide.

  Examples of the acrylamide derivative having a hydroxyl group include N- [tris (hydroxymethyl) methyl] (meth) acrylamide, N, N′-dihydroxyethylene-bis (meth) acrylamide and the like.

  Among these, N- (2-hydroxyethyl) (meth) acrylamide, N- (hydroxymethyl) (meth) acrylamide, N- (diethylene glycol) (meth) acrylamide and N- [tris (hydroxymethyl) methyl] acrylamide are particularly preferable. N- (2-hydroxyethyl) (meth) acrylamide is most preferred. In the present invention, “(meth) acrylic acid” represents one or both of acrylic acid and methacrylic acid, and “(meth) acrylamide” represents one or both of acrylamide and methacrylamide.

  Any monomer other than the acrylamide derivative having a hydroxyl group can be used. Examples thereof include ionic monomers for improving the adsorptivity to mucous membranes, hydrophilic (water-soluble) nonionic monomers for improving water solubility, and hydrophobic nonionic monomers for improving retention. The acrylamide derivative having the above hydroxyl group is excluded.

  Examples of the ionic monomer include a cationic monomer, an anionic monomer, and an amphoteric monomer. Examples of the cationic monomer include N, N-dimethylaminoethyl (meth) acrylamide, N, N-dimethylaminopropyl (meth) acrylamide, N, N-diethylaminopropyl (meth) acrylamide, and dialkylaminoalkyl (meth) acrylamide. Dialkylaminoalkyl (meth) acrylamide (dialkyl (1 to 3 carbon atoms) aminoalkyl (1 to 3 carbon atoms) (meth) acrylamide), (meth) acrylic acid N, N-dimethylaminoethyl, (meth) acrylic acid N , N-diethylaminoethyl, N, N-dipropylaminoethyl (meth) acrylate, etc. Dialkylaminoalkyl (meth) acrylate (dialkyl (meth) acrylate (1 to 3 carbon atoms) aminoalkyl (1 to 1 carbon atoms) 3)), N, N-dimethyl (meth) aqua Ruamido, N, N-dimethylaminopropyl (meth) acrylamide, or quaternized product like these ammonium. Specific examples of ammonium quaternized compounds include trimethylammonium chloride and ethyldimethyl chloride. Among these, dialkylaminoalkyl (meth) acrylamide, dialkylaminoalkyl (meth) acrylate, and ammonium quaternized products thereof are preferable, dialkylaminoalkyl (meth) acrylamide and ammonium quaternized products thereof are more preferable, N, N -Dimethylaminopropylacrylamide methyl chloride is more preferred.

  As an anionic monomer, monomers having a phosphoric acid group such as acid phosphooxyethyl (meth) acrylate, 3-chloro-2-acid phosphooxypropyl (meth) acrylate, acid phosphooxypolyoxyethylene glycol mono (meth) acrylate , Monomers having a carboxylic acid group such as (meth) acrylic acid and maleic acid, and monomers having a sulfonic acid group such as 2-acrylamido-2-methylpropanesulfonic acid.

  Examples of amphoteric monomers include monomers having a phosphate group such as 3-dimethyl ((meth) acryloyloxyethyl) ammonium ethane phosphate, monomers having a carboxylic acid group such as 3-dimethyl (methacryloyloxyethyl) ammonium ethanecarboxylate, 3 -Monomers having a sulfonic acid group such as dimethyl (methacryloyloxyethyl) ammonium propane sulfonate.

  The lower limit of the ratio of the structural unit composed of ionic monomers to the structural unit composed of all monomers of the monofluorophosphorylated polymer compound may be 0% by mass, and the upper limit may be 50% by mass. Preferably it is 0.5-30 mass%, More preferably, it is 1-20 mass%. If it exceeds 50 mass%, the fluorine content may be lowered.

  Examples of the hydrophilic nonionic monomer include methoxypolyethylene glycol (meth) acrylate (p = 2 to 50; EO (ethylene oxide) addition mole number is 2 to 50). 0 mass% may be sufficient as the minimum of the ratio of the structural unit which consists of a water-soluble monomer with respect to the structural unit which consists of all the monomers of a monofluoro phosphorylated polymer compound, 0.5-50 mass% is preferable, More preferably, it is 1-30. % By mass. If it exceeds 50 mass%, the fluorine content may be lowered.

  Hydrophobic nonionic monomers include methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, butyl (meth) acrylate, pentyl (meth) acrylate, hexyl (meth) acrylate, Examples include 2-ethylhexyl (meth) acrylate, lauryl (meth) acrylate, octyl (meth) acrylate, stearyl (meth) acrylate, cyclohexyl (meth) acrylate, benzyl (meth) acrylate, and styrene. Among these, hexyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, lauryl (meth) acrylate, octyl (meth) acrylate, stearyl (meth) acrylate, and the like are preferable, lauryl (meth) acrylate, Stearyl (meth) acrylate is more preferred. However, the hydrophobic nonionic monomer is preferably copolymerized at a ratio that does not impair the water solubility of the polymer compound having a monofluorophosphate structure. 0 mass% may be sufficient as the minimum of the ratio of the structural unit which consists of a hydrophobic nonionic monomer with respect to the structural unit which consists of all the monomers of a monofluoro phosphorylated polymer compound, 0.05-50 mass% is preferable, More preferably, 0 It is 1-40 mass%, and 5-40 mass% is further more preferable. If it exceeds 50% by mass, the fluorine introduction rate and solubility may be lowered.

  Part or all of the hydrogen atoms of the hydroxyl group of the acrylamide derivative having a hydroxyl group becomes a monofluorophosphate residue (anion), and part or all of the hydrogen atoms of the hydroxyl group of the acrylamide derivative having a hydroxyl group is the above monofluorophosphate group. And having a structural unit of the formula (2), it is substituted with a monofluorophosphate group as in the following formula (3). Moreover, it becomes an acrylamide derivative (anion) having a hydroxyl group which is not substituted.

（式中、Ｒ¹、Ｒ²及びＭは上記と同じ。）

(Wherein R ¹ , R ² and M are the same as above)

  Whether the monofluorophosphorylated polymer compound is cationic or anionic is determined by the charge of the entire monofluorophosphorylated polymer compound. In order to obtain a cationic monofluorophosphorylated polymer compound, a cationic monomer is necessary and is appropriately selected. However, in the monofluorophosphorylated polymer compound, the monomer having a monofluorophosphate group is preferably 5 to 50% by mass, more preferably 10 to 30% by mass, and further preferably 12 to 29% by mass.

  The polysaccharide is a polymer compound having a hydroxyl group, specifically, starch, hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, glycogen, inulin, lichenin, hemicellulose, amylopectin, heparin, heparitin sulfate, chondroitin sulfate, hyaluron. Acid, keratosulfuric acid, chitin, chitosan, agar, carrageenan, alginic acid, fur celerin, locust bean gum, galactomannan, guar gum, cyrus gum, tamarind gum, gum arabic, tragacanth gum, caraya gum, pectin, arabinogalactan, xanthan gum, gellan gum, pullulan, Dextran, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium Bo carboxymethyl cellulose, methyl cellulose, ethyl cellulose, and cationic cellulose and the like. Among these, starch, hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, hydroxy starch, chondroitin sulfate, hyaluronic acid, chitin, chitosan, carrageenan, alginic acid, guar gum, tamarind gum, xanthan gum, dextran, cellulose, hydroxyethyl cellulose, hydroxy Propylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, cationized cellulose are preferred, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, cellulose, cationizedcellulose, hydroxystarch or hydroxypropyl Npun more preferably, hydroxypropyl cellulose, hydroxyethyl cellulose, more preferably cationized cellulose. Hydroxypropyl cellulose may have a low substitution degree. In view of fluorine retention, cationized cellulose is particularly preferable. Among these, the thing of 0.1-2.5 mass% of cationization degrees is preferable, and the thing of 0.4-2.0 mass% is more preferable. The degree of cationization in the present invention means the ratio (mass%) of nitrogen atoms per glucose ring unit of the cationized cellulose component.

  Whether the monofluorophosphorylated polymer compound is cationic or anionic is determined by the charge of the entire monofluorophosphorylated polymer compound. In order to obtain a cationic monofluorophosphorylated polymer compound, the degree of monofluorophosphorylation may be adjusted using a cationic polysaccharide so that the charge becomes positive.

The monofluorophosphorylated polymer compound can be prepared by the method described in International Publication No. 2007/125980 and the following steps.
(I) A (co) polymer or polysaccharide before monofluorophosphorylation is prepared.
(Ii) The (co) polymer or polysaccharide of (i) is monofluorophosphorylated.

  (I) A commercially available product may be used for the preparation of the (co) polymer or polysaccharide before monofluorophosphorylation, and the (co) polymer is an acrylamide derivative having a hydroxyl group or an acrylamide derivative having a hydroxyl group; Monomers containing monomers other than the above may be (co) polymerized.

  The polymerization method for polymerizing the monomer is not particularly limited, and a solution polymerization method, an emulsion polymerization method, a suspension polymerization method, a solid phase polymerization method and the like are used. When polymerized by a solution polymerization method, examples of the solvent include water, lower alcohols such as methanol, ethanol and isopropyl alcohol, aromatic, aliphatic or heterocyclic compounds such as benzene, toluene, xylene, cyclohexane, hexane and tetrahydrofuran, Various organic solvents such as ethyl acetate, acetone, and methyl ethyl ketone can be used. The polymerization concentration is not particularly limited, but it is usually preferable to polymerize the monomer at a total concentration of 10 to 50% by mass in the solvent. The copolymerization may be random copolymerization or block copolymerization.

  Examples of the polymerization initiator used in the monomer polymerization include persulfates such as ammonium persulfate, sodium persulfate and potassium persulfate, peroxides such as benzoyl peroxide and lauryl peroxide, cumene hydroperoxide, hydroperoxide. Hydroperoxides such as azo compounds such as azobisisobutyronitrile. The concentration of the polymerization initiator is usually preferably from 0.1 to 10 mol% based on the total amount of monomers used. Further, a chain transfer agent such as alkyl mercaptan, a polymerization accelerator such as a Lewis acid compound, and a pH adjuster such as phosphoric acid, citric acid, tartaric acid, and lactic acid may be used to regulate the molecular weight. The polymerization temperature is appropriately determined depending on the solvent used and the polymerization initiator, but is usually room temperature (25 ° C.) to 150 ° C. The polymerization time is 1 to 10 hours. The molecular weight of the polymer compound of the present invention can be controlled by adjusting the polymerization conditions such as the amount of initiator used, the type of polymerization solvent, and the monomer concentration during polymerization. A similar polymerization method can also be used when a monomer having a monofluorophosphate structure is covalently bonded.

(Ii) The (co) polymer or polysaccharide of (i) is monofluorophosphorylated.
The method for monofluorophosphorylating the (co) polymer or polysaccharide is not particularly limited, and examples thereof include a method of reacting the (co) polymer or polysaccharide with difluorophosphoric acid or a salt thereof. In the method of polymerizing a monomer having a monofluorophosphoric acid structure, the monofluorophosphoric acid may be hydrolyzed and eliminated during the polymerization reaction. Therefore, in order to increase the amount of monofluorophosphoric acid introduced, A method of reacting a (co) polymer or polysaccharide with difluorophosphoric acid or a salt thereof is preferable.

  By reacting the (co) polymer or polysaccharide with difluorophosphoric acid or a salt thereof, a part or all of the hydrogen atoms of the hydroxyl group in the (co) polymer or polysaccharide is the above monofluorophosphate group. The monofluorophosphate group is introduced into the (co) polymer or polysaccharide and monofluorophosphorylated.

  In reacting the (co) polymer or polysaccharide with difluorophosphoric acid or a salt thereof, it is desirable to remove a proton-donating solvent such as water and ethanol from the polymer compound. When it is not sufficiently removed, difluorophosphoric acid is hydrolyzed and cannot effectively react with the polymer compound. Examples of the method for removing the proton donating solvent include removal by leaving it under reduced pressure or under vacuum, removal using a drying agent such as silica gel and molecular sieve, and a dehydrating agent. In addition, from the viewpoint of reaction uniformity and operational safety, when the (co) polymer or polysaccharide is dissolved in various aprotic solvents, it is preferably dissolved and reacted. Examples of the aprotic solvent include ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane, esters such as ethyl acetate, dimethyl sulfoxide, acetonitrile and acetone. Among these, diethyl ether, tetrahydrofuran and 1,4 -Ethers such as dioxane, esters such as ethyl acetate, dimethyl sulfoxide and acetonitrile are preferred. Moreover, it is desirable to remove proton-donating solvents such as water and ethanol mixed in the aprotic solvent. Further, from the viewpoint of simplification of the process, the solvent for polymerizing the monomer is a solvent selected from dimethyl sulfoxide, 1,2-dimethoxyethane, acetonitrile, trimethyl phosphate and triphenyl phosphate, and after the copolymerization reaction. Difluorophosphoric acid or a salt thereof may be added to the reaction solution after the (co) polymerization reaction to react the (co) polymer with difluorophosphoric acid or a salt thereof.

  The reaction between the (co) polymer or polysaccharide and difluorophosphoric acid or a salt thereof is carried out in an inert atmosphere such as nitrogen or argon in order to prevent mixing of proton donating solvents such as water and ethanol from the outside. It is preferable. Further, since the reaction between the hydroxyl group and difluorophosphoric acid is exothermic, the reaction temperature is −20 to 50 ° C., preferably −10 to 40 ° C., and either or both of difluorophosphoric acid and the polymer compound solution are gradually added. It is preferable to mix while dropping. The proportion of difluorophosphoric acid in the reaction solution obtained by mixing the polymer compound solution and difluorophosphoric acid or a salt thereof is preferably 30 to 95% by mass, more preferably 35 to 90% by mass. . By setting this range, it is possible to further improve the fluorine content in the polymer compound having a monofluorophosphoric acid structure by increasing the difluorophosphoric acid concentration in the reaction solution. The molar ratio between the hydroxyl group in the polymer compound and difluorophosphoric acid or a salt thereof can be appropriately changed according to the ratio of the monofluorophosphate structure in the target polymer compound.

  The (co) polymer or polysaccharide is a non-polymer consisting of one or more solvents selected from dimethyl sulfoxide, trimethyl phosphate, triethyl phosphate, tripropyl phosphate, tributyl phosphate, and triphenyl phosphate. When making it react in a protic solvent, it is preferable that the difluoro phosphoric acid with respect to a hydroxyl group or its salt (molar ratio) shall be 5 or more, More preferably, it is 7-100, More preferably, it is 11-60. Also, the solvent for polymerizing the monomer is a solvent selected from dimethyl sulfoxide, 1,2-dimethoxyethane, acetonitrile, trimethyl phosphate and triphenyl phosphate, and the reaction after the (co) polymerization reaction after the copolymerization reaction When difluorophosphoric acid or a salt thereof is added to the liquid, the above ratio can be made 4 or less. The reaction temperature between the hydroxyl group and difluorophosphoric acid is preferably a reaction temperature equal to or higher than the melting point, particularly in the case of a solvent having a melting point of 0 ° C. or higher, such as dimethyl sulfoxide. -50 ° C, preferably 25-40 ° C. The reaction time is preferably 1 to 72 hours.

  Since unreacted difluorophosphoric acid remains in the reaction product, it should be removed by drying under reduced pressure, or reacted with a basic aqueous solution such as sodium hydroxide or potassium hydroxide to give a monofluorophosphate. Is preferred. The reaction solution may or may not be filtered, but is preferably filtered to remove trace insolubles. In the procedure for filtration, the monofluorophosphorylated polymer compound may be neutralized after filtration after dialysis, or may be filtered after dialysis and neutralization.

The two-component oral cavity composition of the present invention is used by mixing the composition (A) and the composition (B) before use and treating the oral cavity with this mixture. In the case of a one-part product made of a mixture of the composition (A) and the composition (B), improvement in the intraoral adsorptivity and retention of the polymer compound is insufficient. 4-10 are preferable and, as for pH (25 degreeC) of the mixture of a composition (A) and a composition (B), 5-9 are more preferable. Moreover, 1-30 are preferable, as for the following electric charge density | concentration in a mixture, 1-26 are more preferable, and 10-25 are more preferable from the point of the adsorptivity and staying property improvement in an intraoral area.
Charge concentration (mmol / L) = (Q ₁ / M ₁ × C ₁ −Q ₂ / M ₂ × C ₂ ) × 10
In the polymer compound having a positive charge in the composition (A),
Q ₁ (charge mmol / mol): “positive charge number−negative charge number” per molecule
M ₁ (g / mol): Molecular weight C ₁ (mass%): In the polymer compound having a negative charge in the blended concentration composition (B) in the mixture,
Q ₂ (charge mmol / mol): “number of negative charges−number of positive charges” per molecule
M ₂ (g / mol): Molecular weight C ₂ (mass%): Compounding concentration in the mixture

  The above indicates the charge concentration in the mixture. The oral mucosa is covered with a component mainly composed of glycoprotein such as mucin and has a negative surface potential. Therefore, it is preferable that the charge concentration is positive. If the charge concentration is too large, charge repulsion It is desirable that the value of the charge concentration is not too high because complex formation is unlikely to occur and solubility in water is improved.

  In order to have such a charge concentration, it can be obtained by adjusting the charge of the polymer compound in the composition (A) and the composition (B) and the blending amount thereof. The blending amount of the polymer compound having a positive charge and the polymer compound having a negative charge in each of the compositions (A) and (B) is 0.05 to 20% by mass, preferably so as to have the above charge concentration. It is suitably selected from the range of 0.07 to 10% by mass. Moreover, the ratio of the composition (A) and the composition (B) in the mixture is also adjusted as appropriate, and the blending amount of each polymer compound in the mixture is 0.02 to 10% by mass, preferably 0.05 to 5%. Each is appropriately selected from the mass% range.

  In the two-part oral cavity composition of the present invention, an amphoteric surfactant is preferably blended from the viewpoint that the charge balance for forming a complex between the polymer compounds is not impaired. The amphoteric surfactant may be added to either the composition (A) or the composition (B) or both. As the amphoteric surfactant, a betaine-type amphoteric surfactant is preferable, and examples thereof include a carboxybetaine surfactant, a sulfobetaine surfactant, and a phosphobetaine surfactant. A carboxybetaine surfactant is preferable, and lauric acid amide is particularly preferable. Preferred are alkylamidopropylbetaines such as propylbetaine and alkylcarboxymethylhydroxyethylimidazolium betaines. The compounding amount of the amphoteric surfactant is preferably 0.01 to 10% by mass, more preferably 0.03 to 1% by mass, and still more preferably 0.05 to 0.5% by mass in the mixture.

  Examples of the oral composition include dentifrices, mouthwashes, tooth surface coating agents, patches, denture cleaners, chewing gums, troches, and the like, but mouthwashes are preferred because of ease of mixing. Depending on the dosage form, other additives can be blended as optional components.

  As optional components, for example, active ingredients blended in the oral composition, surfactants other than amphoteric surfactants, cleaning agents, wetting agents, thickeners, abrasives, binders, thickeners, Oil, polymer compound other than the polymer compound of the present invention, preservative, inclusion compound, antioxidant / antioxidant, chelating agent, inorganic powder, gum base, acidulant, softener, colorant, brightener, Examples include emulsifiers, sweeteners, pH adjusters, fragrances, pigments, crude drugs, sugars, salts, amino acids, medicinal ingredients other than those mentioned above, antibacterial agents, and solvents such as water, ethanol, isopropyl alcohol, ethylene glycol, and glycerin. .

  The two-part oral cavity composition of the present invention can be obtained by mixing the polymer compound, water and other optional components together with the composition (A) and the composition (B).

  The method of using the two-part oral cavity composition of the present invention may be obtained by mixing the composition (A) and the composition (B) before use, and treating the oral cavity with this mixture, preferably a mixed solution, Mixing may be performed in a container before use or in the oral cavity. The mixing is not particularly limited as long as it is before use, but is preferably just before the treatment. The intraoral treatment time is 1 second to 10 minutes, preferably 3 seconds to 3 minutes. After the treatment, the composition for oral cavity may be discharged, and if it can be taken orally, it can be swallowed.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In addition, in the following examples, unless otherwise specified, the amount of each component in the table is an amount converted into a pure component.

[Production Example 1] Production of MFP-DMQ Preparation of N- (2-hydroxyethyl) acrylamide (HEAA) / N, N-dimethylaminopropylacrylamide methyl chloride (DMAPAA-Q) = 60/40 copolymer Stirrer, 85 g of ethanol was placed in a 300 mL four-necked separable flask equipped with a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, 18 g of N- (2-hydroxyethyl) acrylamide (manufactured by Kojin) and N, N-dimethylaminopropylacrylamide methyl chloride (DMAPAA-Q) (manufactured by Kojin) while heating in an oil bath at 90 ° C. ) A monomer solution in which 12 g is mixed with 50 g of ethanol and 2,8'-azobis (2-methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) 0.48 g dissolved in ethanol 35 g The agent solution was continuously added dropwise over 1 hour to carry out the polymerization reaction.
After completion of the dropwise addition, heating was continued for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (fraction molecular weight of dialysis membrane 14,000, manufactured by Sanko Junyaku Co., Ltd.). By removing water with an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.), N- (2-hydroxyethyl) acrylamide (HEAA) / N, N-dimethylaminopropylacrylamide methyl chloride (DMAPAA-Q) = 24 g of a 60/40 (mass ratio) copolymer was obtained.

1 g of N- (2-hydroxyethyl) acrylamide (HEAA) / N, N-dimethylaminopropylacrylamide methyl chloride (DMAPAA-Q) = 60/40 copolymer prepared as described above was added to 9 g of dimethyl sulfoxide (dry: manufactured by MERCK). Then, the mixture was placed in a 50 mL two-necked eggplant flask and nitrogen gas was introduced. While immersing the flask in a 25 ° C. water bath, 8 mL of difluorophosphoric acid (0.5 hydrate, manufactured by Shinquest, specific gravity 1.58) was gradually added dropwise (with the HEAA polymer hydroxyl group and difluorophosphoric acid). The molar ratio is hydroxyl group: difluorophosphoric acid = 1: 17.7). After stirring for 5 hours, a 25% by mass aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. The reaction solution was dialyzed in running water for 72 hours (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) and filtered using filter paper (101, manufactured by Advantech Toyo Co., Ltd.), and then aqueous sodium hydroxide solution To pH 7. Finally, water is removed by evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.), so that sodium monofluorophosphate N- (2-hydroxyethyl) acrylamide / N, N-dimethylaminopropylacrylamide methyl chloride 0.8 g of copolymer = 60/40 (F-HEAA / HEAA / DMAPAA-Q = 19/41/40) was obtained.
"F-" indicates that the hydrogen atom of the hydroxyl group is substituted with a monofluorophosphate group, and F-HEAA indicates N- (wherein the hydrogen atom of the hydroxyl group is substituted with a monofluorophosphate group. 2-hydroxyethyl) acrylamide.

[Production Example 2] Production of MFP-LMA Preparation of N- (2-hydroxyethyl) acrylamide (HEAA) / lauryl methacrylate (LMA) = 80/20 copolymer In Production Example 1, N- (2-hydroxyethyl) ) The amount of acrylamide (manufactured by Kojin) is 24 g, N, N-dimethylaminopropylacrylamide methyl chloride (DMAPAA-Q) (manufactured by Kojin) is 6 g of lauryl acrylate (LMA) (manufactured by Tokyo Chemical Industry), and 2,2 N- (2-hydroxyethyl) acrylamide (HEAA) was similarly used except that the amount of '-azobis (2-methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) was 0.44 g. ) / 25 g of lauryl methacrylate (LMA) = 80/20 copolymer was obtained.
N- (2-hydroxyethyl) acrylamide (HEAA) / N, N-dimethylaminopropylacrylamide methyl chloride (DMAPAA-Q) = 60/40 copolymer in Production Example 1 was converted to N- (2-hydroxyethyl) acrylamide ( HEAA) / Lauryl methacrylate (LMA) = 80/20 Copolymer was prepared in the same manner except that the copolymer was changed to 80/20 copolymer. Sodium monofluorophosphate N- (2-hydroxyethyl) acrylamide / lauryl methacrylate copolymer = 80 / 20 (hydroxyl group: difluorophosphoric acid = 1: 16.5) was obtained.

The polymer compound obtained in Production Example was subjected to the following measurement. The results are shown in Table 1.
1. Weight average molecular weight (Mw)
Water containing 10 mM sodium nitrate and 20 vol% acetonitrile was used as an eluent, measured by gel permeation chromatography, and converted to a pullulan standard (P-82, Showa Denko) with a molecular weight of 5,800 to 853,000. The average molecular weight was calculated. Specifically, the dried product was dissolved in water containing 10 mM sodium nitrate and 20 vol% acetonitrile to prepare a 0.5 mass% solution. Tosoh Co., Ltd. TSK-GelG2500PWXL and TSK-GelGMPWXL were connected and installed in the column, column oven set temperature was 40 ° C., eluent was water containing 10 mM sodium nitrate and 20 vol% acetonitrile, flow rate 0.5 mL / min, detection was performed by RI.

2. Fluorine introduction rate 2.4 g of a 1 mol / L perchloric acid aqueous solution was added to 1.6 g of a 0.1% by mass polymer compound aqueous solution, placed in a sealed tube with a lid made of PE, and heated at 105 ° C. for 10 minutes. . Thereafter, 0.4 g of the liquid was collected and mixed with 1.6 g of 1 mol / L potassium citrate buffer (pH 5.5), and then the fluorine amount was measured with a fluorine electrode meter (Expandable Ion Analyzer EA920, manufactured by Orion): X _p (ppm) was quantified. The mass concentration of fluorine (fluorine introduction rate: F (mass%)) relative to the total mass of the polymer compound was calculated by the following formula.
F = X _p × 1.25

[Examples 1 to 13]
A composition (A) and a composition (B) shown in Table 2 below were prepared by dissolving each polymer compound in water to prepare a two-part oral cavity composition. The charge concentration of a mixture (mixed solution) obtained by mixing equal amounts of the composition (A) and the composition (B) is shown in the table. The pH of the mixture (mixed solution) was 5 to 7 (room temperature: 25 ° C.). The following retention rate evaluation was performed about the obtained 2 agent type oral cavity composition. The results are also shown in the table.

[Charge concentration]
Charge concentration (mmol / L) = (Q ₁ / M ₁ × C ₁ −Q ₂ / M ₂ × C ₂ ) × 10
In the polymer compound having a positive charge in the composition (A),
Q ₁ (charge mmol / mol): “positive charge number−negative charge number” per molecule
M ₁ (g / mol): Molecular weight C ₁ (mass%): In the polymer compound having a negative charge in the blended concentration composition (B) in the mixture,
Q ₂ (charge mmol / mol): “number of negative charges−number of positive charges” per molecule
M ₂ (g / mol): Molecular weight C ₂ (mass%): Compounding concentration in the mixture

[Residence rate]
5 g of the composition (A) and 5 g of the composition (B) were simultaneously placed in the oral cavity, followed by a mouthwash treatment for 3 minutes, and then discharged to collect the liquid. The amount of fluorine in the discharge liquid is calculated from mass measurement and concentration measurement using a fluorine electrode, and the amount of fluorine decrease relative to the fluorine in the mixed liquid of composition (A) 5 g and composition (B) 5 g The retention rate of the polymer having a monofluorophosphate residue was calculated from the following equation.
Residence ratio (mass%) = (1−discharged liquid fluorine amount / mixed liquid fluorine amount) × 100

[Mass measurement and concentration measurement with fluorine electrode]
The mass M ₀ (g) of the liquid mixture before the mouth rinse treatment and the mass M ₁ (g) of the discharged liquid after the treatment are measured, and then the fluorine concentration F ₀ (ppm) of the liquid mixture before the mouth rinse treatment. The fluorine concentration F ₁ (ppm) of the discharged liquid after treatment was measured by the following fluorine concentration determination method. From the mass of the collected liquid and the fluorine concentration, the amount of fluorine in the liquid was calculated by the following equation.
Mixed liquid fluorine amount (μg) = F ₀ (ppm) × M ₀ (g)
Discharge liquid fluorine amount (μg) = F ₁ (ppm) × M ₁ (g)

[Fluorine concentration determination]
An equal amount of 2 mol / L hydrogen chloride aqueous solution was added to the sample solution, heated at 50 ° C. for 3 hours, and neutralized with 1 mol / L sodium hydroxide. Next, the fluorine concentration was quantified using a fluorine ion electrode (Orion 9609BNWP fluorine composite electrode manufactured by Thermo ELECTRON CORPORATEIO). The measurement was performed by diluting 5 times using a 1 mol / L potassium citrate solution as a buffer solution.

＊上段は、組成物（Ａ）又は（Ｂ）中の高分子化合物濃度（質量％）を示す。
下段は、混合物中の高分子化合物濃度（質量％）を示す。

* The upper row shows the polymer compound concentration (mass%) in the composition (A) or (B).
The lower row shows the polymer compound concentration (% by mass) in the mixture.

＊上段は、組成物（Ａ）又は（Ｂ）中の高分子化合物濃度（質量％）を示す。
下段は、混合物中の高分子化合物濃度（質量％）を示す。 [Examples 14 and 15]
The composition (A) and composition (B) shown in Table 3 below are prepared by dissolving each polymer compound in water (note that the amphoteric surfactant is blended in the composition (B)), two agents A composition for oral cavity was prepared. The charge concentration of the mixture of compositions (A) and (B) is shown in the table. The retention rate evaluation was performed on the obtained two-part oral cavity composition. The results are also shown in the table.

* The upper row shows the polymer compound concentration (mass%) in the composition (A) or (B).
The lower row shows the polymer compound concentration (% by mass) in the mixture.

[Comparative Examples 1-3]
A composition (A) and a composition (B) shown in Table 4 below were prepared by dissolving each polymer compound in water to prepare a two-part oral cavity composition. The charge concentration of the mixture of compositions (A) and (B) is shown in the table. The retention rate measurement was performed on the obtained two-part oral cavity composition. The results are also shown in the table.

[Comparative Example 4]
0.46% by mass of lysozyme (positive charge number per g 0.63 (mmol / mol)) and 0.09% by mass of MFP-LMA (negative charge number per g 1.10 (mmol / mol)) A one-pack oral composition was prepared. About the 1 agent type oral cavity composition, the said residence rate measurement was performed on the next day of preparation. The results are also shown in the table.

＊上段は、組成物（Ａ）又は（Ｂ）中の高分子化合物濃度（質量％）を示す。
下段は、混合物中の高分子化合物濃度（質量％）を示す。

* The upper row shows the polymer compound concentration (mass%) in the composition (A) or (B).
The lower row shows the polymer compound concentration (% by mass) in the mixture.

[Example 16]
A two-part mouthwash with the following composition was prepared, and the retention rate was measured by the above method. The charge concentration calculated from the composition (A) and the composition (B) was 5.

Claims (4)

A composition (A) containing a positively charged polymer compound selected from lysozyme, chitosan, lactoferrin, polylysine, and a cationic monofluorophosphorylated polymer compound having a monofluorophosphate residue;
A composition (B) containing a negatively charged polymer compound selected from polyglutamic acid, hyaluronic acid, chondroitin sulfate, pectin, and an anionic monofluorophosphorylated polymer compound having a monofluorophosphate residue; A two-part oral cavity composition. The two-part oral cavity according to claim 1, wherein the pH of the mixture of the composition (A) and the composition (B) is 4 to 10, and the following charge concentration in the mixture is 1 to 30. Composition.
Charge concentration (mmol / L) = (Q ₁ / M ₁ × C ₁ −Q ₂ / M ₂ × C ₂ ) × 10
In the polymer compound having a positive charge in the composition (A),
Q ₁ (charge mmol / mol): “positive charge number−negative charge number” per molecule
M ₁ (g / mol): Molecular weight C ₁ (mass%): In the polymer compound having a negative charge in the blended concentration composition (B) in the mixture,
Q ₂ (charge mmol / mol): “number of negative charges−number of positive charges” per molecule
M ₂ (g / mol): Molecular weight C ₂ (mass%): Compounding concentration in the mixture   Furthermore, the composition for oral cavity of Claim 1 or 2 containing an amphoteric surfactant.   The composition for oral cavity according to claim 3, wherein the amphoteric surfactant is a betaine amphoteric surfactant.