JP2009102283A - Oral composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral composition adsorbed with plaque, mucosa and teeth in an oral cavity, preventing and improving caries continuously and effectively by gradually decomposing the F-P bond of fluorophosphoric acid by a phosphoric acid hydrolase in the oral cavity to gradually releasing fluoride ion for a long period of time, improving peculiar use feeling of the water-soluble polymer covalently bonded with a monofluorophosphoric acid residue and excellent in effectiveness, use feeling and using property. <P>SOLUTION: This oral composition comprises (A) a water-soluble monofluorophosphoric acid polymer compound obtained by covalently bonding the monofluorophosphoric acid with the polymer molecule selected from a hydroxyethyl(meth)acrylamide polymer, hydroxypropyl cellulose, polyvinyl alcohol and polyhydroxyethyl (meth)acrylate and having 5,000 to 500,000 weight-average molecular weight and (B) a surfactant selected from anionic surfactants, nonionic surfactants and amphoteric surfactants in 0.5 to 30 mass ratio of (A)/(B). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an oral cavity containing a water-soluble polymer compound and a surfactant, to which monofluorophosphoric acid is covalently bonded, which is excellent in fluoride retention in the oral cavity, fluoride ion releasing property, usability and usability of the preparation. The present invention relates to a composition for use.

  Conventionally, the use of a fluoride-containing dentifrice has been recommended as a daily self-care behavior for the purpose of preventing dental caries, which is one of the diseases of the oral cavity. The mechanism for preventing dental caries is to reinforce the acid resistance of the tooth by fluorapatite or to restore the initial caries by remineralization to restore the original healthy tooth. Examples of fluorides include sodium fluoride, sodium monofluorophosphate and tin fluoride. Development of technologies to increase the retention of these substances in the oral cavity in order to improve their effectiveness (in combination with coating substances) (Patent Document 1; JP 2006-511553 A, Patent Document 2; JP 2006-16424 A). However, these temporarily suppress the adhesion of bacteria on the tooth surface and temporarily improve the retention of fluorine in the oral cavity, and there are still many problems to prevent caries continuously and effectively.

  In order to prevent caries continuously and effectively, it is important to retain several ppm level of fluoride ions in the oral cavity over a long period of time, and has such high retention and fluoride sustained release function. Oral compositions are desired.

  Patent Document 3 (Japanese Patent Laid-Open No. 2002-145715) exemplifies an organic filler containing a fluorine sustained-release component, an acrylic monomer, a polymerization initiator, and a metal oxide, but these substances are close to physical mixing. However, the efficient sustained release function of fluoride ions into the oral cavity remains highly questionable.

  Patent Documents 4 and 5 (Japanese Patent Laid-Open Nos. 57-88106 and 62-12706) propose fluoride ion sustained-release polymers having vinyl monomer units having acid fluoride groups as constituent units. Although these compositions are water-insoluble dental fillers that polymerize in the mouth, the cleavage of carbon-fluorine covalent bonds and the penetration of phosphate hydrolases that cleave phosphorus-fluorine covalent bonds is not It is extremely difficult and it is unlikely that fluoride ions will be released slowly and efficiently. In addition, when used in a composition for oral cavity, the feeling of use is poor because it is insoluble in water.

  When considering application to the oral cavity, both technologies have a feeling of use, compoundability in the composition, fluoride retention in the oral cavity, and long-term sustained fluoride ion sustained release function in the oral cavity. The design is not comprehensively considered, and there are problems in effectiveness, usability, and convenience of obtaining usability as an oral composition.

JP 2006-511553 A JP 2006-16424 A JP 2002-145715 A JP 57-88106 A Japanese Patent Laid-Open No. 62-12706

  The present invention has been made in view of the above circumstances, and provides an oral composition having excellent retention of fluoride in the oral cavity, sustained release of fluoride ions in the oral cavity, and good usability and usability. The purpose is to do.

  As a result of intensive studies to achieve the above object, the present inventors have found that at least one polymer selected from hydroxyethyl (meth) acrylamide polymer, hydroxypropyl cellulose, polyvinyl alcohol, and polyhydroxyethyl (meth) acrylate. , A water-soluble monohydrate having a weight average molecular weight of 5,000 to 500,000, in which part or all of the hydrogen atoms of the hydroxyl group in the polymer molecule are substituted with a monofluorophosphate residue, and the monofluorophosphate is covalently bonded to the molecule. A fluorophosphorylated polymer compound (A) and at least one surfactant (B) selected from an anionic surfactant, a nonionic surfactant and an amphoteric surfactant are (A) / (B ) Mass ratio of 0.5 to 30 in a composition for oral cavity, fluoride retention in the oral cavity and fluoride a It has excellent sustained-release properties, has a good feeling of use, has excellent shape retention when prepared as a dentifrice, and is easy to pour from a container when prepared as a liquid formulation such as a mouthwash. Thus, an oral composition excellent in usability was obtained, and it was found that caries can be effectively prevented / improved, and the present invention has been made.

  In the oral composition of the present invention, the water-soluble monofluorophosphorylated polymer compound is adsorbed to plaques, mucous membranes and teeth in the oral cavity, and the water-soluble monofluorophosphorylated polymer compound is absorbed by the oral phosphate hydrolase. Since the FP bond of the fluorophosphate group therein is gradually decomposed and the fluoride ions are gradually released over a long period of time, caries can be prevented and improved continuously and effectively. Furthermore, according to the present invention, there is provided an oral composition that can improve the unique feeling of use derived from a water-soluble polymer compound to which a monofluorophosphate residue is covalently bonded, and is excellent in effectiveness, feeling of use and usability. be able to.

  Accordingly, in the present invention, monofluorophosphoric acid is covalently bonded to a polymer molecule of at least one polymer selected from hydroxyethyl (meth) acrylamide polymer, hydroxypropyl cellulose, polyvinyl alcohol, and polyhydroxyethyl (meth) acrylate. A water-soluble monofluorophosphorylated polymer compound (A) having a weight average molecular weight of 5,000 to 500,000 and at least one interface selected from an anionic surfactant, a nonionic surfactant and an amphoteric surfactant The composition for oral cavity characterized by mix | blending an active agent (B) with the mass ratio of 0.5-30 of (A) / (B) is provided.

  In the composition for oral cavity of the present invention, the water-soluble monofluorophosphorylated polymer compound is adsorbed to plaques, mucous membranes and teeth in the oral cavity, and the FP bond of the fluorophosphate group is formed by the phosphate hydrolase in the oral cavity. It is gradually decomposed and can release and release fluoride ions over a long period of time to prevent and improve caries continuously and effectively. The unique feeling of use is also improved, and it is excellent in effectiveness, feeling of use and usability.

  Hereinafter, the present invention will be described in more detail. The composition for oral cavity of the present invention is at least one polymer selected from hydroxyethyl (meth) acrylamide polymer, hydroxypropyl cellulose, polyvinyl alcohol, and polyhydroxyethyl (meth) acrylate. A water-soluble monofluorophosphorylated polymer compound (A) having a weight average molecular weight of 5,000 to 500,000 in which monofluorophosphoric acid is covalently bonded to the polymer molecule, an anionic surfactant, and a nonionic surfactant And (A) / (B) at a mass ratio of 0.5 to 30 containing at least one surfactant (B) selected from agents and amphoteric surfactants.

  The water-soluble monofluorophosphorylated polymer compound (A) used in the present invention comprises at least one polymer selected from hydroxyethyl (meth) acrylamide polymer, hydroxypropyl cellulose, polyvinyl alcohol, and polyhydroxyethyl (meth) acrylate. A water-soluble polymer compound in which part or all of the hydrogen atoms of the hydroxyl group in the polymer molecule are substituted with a monofluorophosphate residue. Monofluorophosphorylated hydroxyethyl (meth) acrylamide polymer, monofluorophosphorylated hydroxypropyl It is one or more selected from cellulose, monofluorophosphorylated polyvinyl alcohol, and monofluorophosphorylated polyhydroxyethyl (meth) acrylate. Of these, monofluorophosphorylated hydroxyethyl (meth) acrylamide polymer and monofluorophosphorylated hydroxypropylcellulose are preferable. In addition, (meth) acrylamide means either one or both of methacrylamide and acrylamide. The same applies to (meth) acrylate. In the present invention, hydroxyethyl (meth) acrylamide is N- (2-hydroxyethyl) (meth) acrylamide, and hydroxyethyl (meth) acrylate is (2-hydroxyethyl) (meth) acrylate. Furthermore, the polyvinyl alcohol includes a partially saponified product in which a part of the structural unit is vinyl acetate.

  The water-soluble monofluorophosphorylated polymer compound is a water-soluble polymer compound in which monofluorophosphoric acid is covalently bonded. Specifically, a monofluorophosphate residue represented by the following general formula (1) is used. , A water-soluble polymer compound in the molecule through a covalent bond.

（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。）

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

  The polymer compound can have one or more monofluorophosphoric acid residues represented by the general formula (1), and may be a partially neutralized product.

The water-soluble polymer compound of the present invention has a structural unit having a monofluorophosphoric acid structure via a covalent bond, and a part or all of the hydrogen atoms of the hydroxyl group in the polymer compound are as described above. It is a water-soluble polymer compound substituted with a monofluorophosphate residue.
When the hydrogen atom of the hydroxyl group in the polymer compound is substituted with the monofluorophosphate residue, it has a group represented by the general formula (1).

As described above, the water-soluble monofluorophosphorylated polymer compound may be a partial monofluorophosphorus oxide. The monofluorophosphoric acid may be any of acid type, neutralization type, and partial neutralization type. The types of counter ions in the neutralization type and partial neutralization type are alkali metal, ammonium, monoethanolamine, diethanolamine. Any of triethanolamine and triethylamine may be used.
Furthermore, the water-soluble monofluorophosphorylated polymer compound may have a monofluorophosphoric acid structure in the main chain or in a side chain.

  The water-soluble monofluorophosphorylated polymer compound according to the present invention can be prepared by employing the production method described in International Application PCT / JP2007 / 59023.

  The preparation methods can be broadly classified as follows: (1) a method of polymerizing a monomer having a monofluorophosphoric acid structure via a covalent bond, and (2) a monofluorophosphoric acid shared with a polymer compound having a hydroxyl group in the molecule. The method of combining etc. is mentioned. As a method of covalently bonding monofluorophosphoric acid to a polymer compound having a hydroxyl group in the molecule of (2), specifically, a polymer compound having a hydroxyl group in the molecule is reacted with difluorophosphoric acid or a salt thereof. A method of reacting a polymer compound having a hydroxyl group in the molecule with monofluorophosphoric acid, a polymer compound having a hydroxyl group in the molecule, phosphorus oxychloride and fluorine such as sodium fluoride or triethylamine trifluoride The method of making a source react is mentioned. Among these, in the method of polymerizing a monomer having a monofluorophosphoric acid structure, the monofluorophosphoric acid may be hydrolyzed and eliminated during the polymerization reaction, and from the viewpoint of the simplicity of the reaction operation, A method of reacting a polymer compound having a hydroxyl group in the molecule with difluorophosphoric acid or a salt thereof to covalently bond monofluorophosphoric acid to the polymer compound is preferable.

  Here, when the polymer compound having a hydroxyl group in the molecule is reacted 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, the above polymer compound is preferably reacted in various aprotic solvents. 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.

  The reaction between the polymer compound having a hydroxyl group in the molecule and difluorophosphoric acid or a salt thereof is performed under an inert atmosphere such as nitrogen or argon in order to prevent contamination of proton donating solvents such as water and ethanol from the outside. Preferably it is done. Further, since the reaction between the hydroxyl group and difluorophosphoric acid is exothermic, it is cooled in an ice bath, and the reaction temperature is -20 to 50 ° C, preferably -10 to 30 ° C, and either difluorophosphoric acid or a polymer solution is used. It is preferable to mix while gradually dropping both. The molar ratio between the hydroxyl group present 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, but the hydroxyl group: difluorophosphoric acid Or its salt (molar ratio) = 1: 1 to 1:60, particularly 1: 1 to 1:20 is preferable.

  However, in the case of reacting a polymer compound having a hydroxyl group in the molecule by dissolving it in dimethyl sulfoxide, the difluorophosphoric acid or its salt (molar ratio) with respect to the hydroxyl group is preferably 5 or more, more preferably a hydroxyl group. : Difluorophosphoric acid or a salt thereof (molar ratio) = 1: 7 to 1:60.

  Since unreacted difluorophosphoric acid remains in the reaction product of the polymer compound having a hydroxyl group in the molecule and difluorophosphoric acid or a salt thereof, it is removed by drying under reduced pressure, or sodium hydroxide or potassium hydroxide. It is preferable to make it react to monofluorophosphate by adding a basic aqueous solution or the like. Moreover, it is preferable to neutralize a reaction liquid, for example, it is preferable to neutralize to about pH 5-9 by addition, such as basic aqueous solutions, such as sodium hydroxide and potassium hydroxide. In addition, when using basic aqueous solution for the removal of unreacted difluorophosphoric acid, it is preferable to carry out as the same process as subsequent neutralization. Then, you may refine | purify by dialysis, ultrafiltration, etc.

  In the present invention, the polymer compound having a hydroxyl group in the molecule is a polymer selected from hydroxyethyl (meth) acrylamide polymer, hydroxypropyl cellulose, polyvinyl alcohol, and polyhydroxyethyl (meth) acrylate. In order to prepare a water-soluble monofluorophosphorylated polymer compound by reacting the compound with difluorophosphoric acid or a salt thereof, the above before (i) introducing monofluorophosphoric acid (hereinafter referred to as monofluorophosphorylation). A step of preparing a raw material polymer (a polymer compound having a hydroxyl group in the molecule) and a step of (ii) monofluorophosphorylating the polymer of (i) are performed. In addition, as a raw material polymer, for example, a commercially available polymer can be used as hydroxypropyl cellulose. In this case, the step (ii) can be performed using the commercially available polymer without performing the step (i).

Here, in the step of preparing the raw material polymer before introducing the monofluorophosphoric acid, a usual polymer synthesis method can be employed.
The raw material water-soluble polymer compound is prepared by polymerization of monomers corresponding to the raw material polymer compound, specifically, hydroxyethyl (meth) acrylamide, vinyl alcohol, vinyl acetate, and hydroxyethyl (meth) acrylate. . As for the method for preparing polyvinyl alcohol, vinyl acetate is used as a monomer at the time of polymerization, which is a method often used for industrial purposes. A method of forming a vinyl alcohol polymer by decomposing is also preferably used.

Examples of the polymerization method include a solution polymerization method, an emulsion polymerization method, a suspension polymerization method, and a solid phase polymerization method. When polymerized by the 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 and hexane, and ethyl acetate. Various organic solvents such as acetone and methyl ethyl ketone can be used. The polymerization concentration is not particularly limited, but it is preferable that the polymerization is usually performed when the total monomer concentration in the solvent is 3 to 90% (mass%, the same applies hereinafter), particularly 10 to 80%.
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 polymerization initiator concentration is usually 0.01 to 30%, particularly preferably 0.01 to 3%, 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 and the polymerization initiator used, and is usually room temperature to 150 ° C. The polymerization time is 1 to 10 hours. The molecular weight of the polymer compound according to 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.
The outline of the preparation method of the water-soluble monofluorophosphorylated polymer compound according to the present invention is illustrated below.

a. Preparation of monofluorophosphorylated hydroxyethyl (meth) acrylamide polymer A 4-necked separable flask equipped with a stirrer, reflux condenser and nitrogen inlet tube was charged with a solvent such as ethanol, isopropyl alcohol, water, etc., and nitrogen was introduced while stirring. Nitrogen gas is introduced from the tube. Next, while heating to 60 to 90 ° C. in an oil bath, a hydroxyethyl (meth) acrylamide (manufactured by Kojin Co., Ltd.) solution is added thereto so that the monomer concentration in the reaction solution is 3 to 50%. . When the solvent is ethanol or isopropyl alcohol, 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.), and when the solvent is water, A polymerization initiator solution such as 2,2′-azobis (2-methylpropionamidine) dihydrochloride (trade name V-50, manufactured by Wako Pure Chemical Industries, Ltd.) is used in a polymerization initiator concentration of 0. Add so that it becomes 01 to 5%. In addition, it is preferable that the hydroxyethyl (meth) acrylamide solution and the polymerization initiator solution are continuously dropped to perform a polymerization reaction. After completion of the dropwise addition, heating was continued at 60 to 100 ° C. for 3 to 8 hours while introducing nitrogen, and then the reaction solution was dialyzed in running water for 1 to 5 days (fraction molecular weight of dialysis membrane 2,000 to 14). )) And finally the water is removed by evaporator and lyophilization to obtain the hydroxyethyl (meth) acrylamide polymer before introduction of monofluorophosphoric acid.

  Next, the hydroxyethyl (meth) acrylamide polymer is dissolved in a solvent such as dimethyl sulfoxide (dry: manufactured by MERCK, hereinafter abbreviated as DMSO) and then placed in a two-necked eggplant flask, and nitrogen gas is introduced (polymer concentration). 1-30%). Next, while immersing the flask in a water bath at room temperature, 0.8 to 50 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) is gradually added dropwise to 1 g of the polymer. After stirring for 2 to 48 hours, an aqueous sodium hydroxide solution is added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut off 2,000 to 14,000), and after removing water insolubles using a filter paper (101, manufactured by Advantech Toyo Co., Ltd.). The water-soluble part is adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, water is removed by evaporator and lyophilization to obtain a water soluble monofluorophosphorylated hydroxyethyl (meth) acrylamide polymer.

b. Preparation of monofluorophosphorylated hydroxypropylcellulose Commercially available hydroxypropylcellulose is dissolved in tetrahydrofuran (dehydrated, manufactured by Kanto Chemical Co., Inc., hereinafter abbreviated as THF), then placed in a two-necked eggplant flask, and nitrogen gas is introduced. (Polymer concentration 1-20%). Next, while immersing the flask in a room temperature water bath, 0.7 to 40 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) is gradually added dropwise to 1 g of the polymer. After stirring for 2 to 48 hours, an aqueous sodium hydroxide solution is added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut off 2,000 to 14,000), and after removing water insolubles using a filter paper (101, manufactured by Advantech Toyo Co., Ltd.). The water-soluble part is adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, the water-soluble monofluorophosphorylated hydroxypropyl cellulose can be obtained by removing water by an evaporator and lyophilization.
In addition, as commercially available hydroxypropyl cellulose, HPC-SLL, HPC-SL, HPC-L, HPC-M (manufactured by Nippon Soda Co., Ltd.), KLUCEL-GF (manufactured by HERCULES) and the like are used.

c. Preparation of monofluorophosphorylated polyvinyl alcohol A solvent such as methanol is placed in a four-necked separable flask equipped with a stirrer, reflux condenser and nitrogen inlet tube, and nitrogen gas is introduced from the nitrogen inlet tube while stirring. Next, while heating to 60 to 90 ° C. in an oil bath, the monomer concentration in the reaction solution of the vinyl acetate (manufactured by Tokyo Chemical Industry Co., Ltd.) solution is 3 to 90%, particularly 3 to 80%. Add to. In addition, a polymerization initiator solution such as 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.), the polymerization initiator concentration in the reaction solution is 0. Add to be 01-1%. The vinyl acetate solution and the polymerization initiator solution are preferably dripped continuously to carry out the polymerization reaction. After completion of the dropwise addition, heating is continued at 60 to 90 ° C. for 3 to 8 hours while introducing nitrogen, and the reaction solution is dialyzed in running water for 1 to 5 days (fraction molecular weight of dialysis membrane is 2,000 to 14,000). ) Finally, the polyvinyl acetate is obtained by removing the water by evaporator and lyophilization.
Next, the polyvinyl acetate is saponified (hydrolyzed). 2 g of the resulting polyvinyl acetate is dissolved in 80 to 200 mL of methanol and heated to 30 to 45 ° C., then 1.5 to 3 mL of 40% aqueous sodium hydroxide solution is added, and the mixture is stirred and allowed to stand. After standing for 20 to 60 minutes, the reaction solution is filtered with suction, the residue is washed several times with methanol, extracted with a Soxhlet extractor for 2 to 5 hours, and finally the methanol is removed by evaporator and lyophilization. Polyvinyl alcohol (including partially saponified product) before introduction of fluorophosphoric acid is obtained.

  Next, polyvinyl alcohol is put into a two-necked eggplant flask and nitrogen gas is introduced. Next, while immersing the flask in a water bath at room temperature, 2-110 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) is gradually added dropwise to 1 g of the polymer. After stirring for 2 to 48 hours, an aqueous sodium hydroxide solution is added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut off 2,000 to 14,000), and after removing water insolubles using a filter paper (101, manufactured by Advantech Toyo Co., Ltd.). The water-soluble part is adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, water is removed by evaporator and lyophilization to obtain water-soluble monofluorophosphorylated polyvinyl alcohol.

d. Preparation of monofluorophosphorylated polyhydroxyethyl (meth) acrylate A four-necked separable flask equipped with a stirrer, reflux condenser and nitrogen inlet tube was charged with a solvent such as ethanol and water, and nitrogen was stirred from the nitrogen inlet tube. Introduce gas. Subsequently, hydroxyethyl (meth) acrylate (manufactured by Kojin Co., Ltd.) is added thereto so that the monomer concentration in the reaction solution is 3 to 50% while heating to 60 to 100 ° C. in an oil bath. When the solvent is ethanol, 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.), and when the solvent is water, 2,2′- A polymerization initiator solution such as azobis (2-methylpropionamidine) dihydrochloride (trade name V-50: manufactured by Wako Pure Chemical Industries, Ltd.) is used with a polymerization initiator concentration of 0.01 to 5% in the reaction solution. Add to be. In addition, it is preferable that the hydroxyethyl (meth) acrylate solution and the polymerization initiator solution are continuously dropped to perform a polymerization reaction. After completion of the dropwise addition, heating was continued at 60 to 100 ° C. while introducing nitrogen, and the reaction solution was dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut off 2,000 to 14,000). By removing water by an evaporator and lyophilization, polyhydroxyethyl (meth) acrylate before introduction of monofluorophosphoric acid is obtained.

  Next, after dissolving polyhydroxyethyl (meth) acrylate in a solvent such as dimethyl sulfoxide (dry: manufactured by MERCK, DMSO), the solution is placed in a two-necked eggplant flask and nitrogen gas is introduced (polymer concentration: 1 to 30%) . Next, 1-50 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) is gradually added dropwise to 1 g of the polymer while the flask is immersed in a water bath at room temperature. After stirring for 2 to 48 hours, an aqueous sodium hydroxide solution is added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut off 2,000 to 14,000), and after removing water insolubles using a filter paper (101, manufactured by Advantech Toyo Co., Ltd.). The water-soluble part is adjusted to pH 7 with an aqueous sodium hydroxide solution. Finally, water is removed by evaporator and lyophilization to obtain water soluble monofluorophosphorylated polyhydroxyethyl (meth) acrylate.

The definition of water solubility of the water-soluble polymer compound used in the present invention is defined by the following method.
0.5 g of the prepared polymer compound is precisely weighed and dissolved in 10 g of distilled water that has been precisely weighed in advance at room temperature for 24 hours (using a 1 cm × 0.5 cm stirrer chip, 200 to 300 rpm). This polymer compound is defined as water-soluble when it becomes a clear solution.

The water-soluble monofluorophosphorylated polymer compound used in the present invention has a weight average molecular weight of 5,000 to 500,000, preferably 10,000 to 300,000. When the weight average molecular weight is less than 5,000, irritation is felt or other components in the composition are disturbed, and sufficient fluoride retention is not obtained. (F by intraoral phosphate hydrolase ^- ion release) usability and enzymatic reactivity problems.

The weight average molecular weight is a value measured by the following method.
The weight average molecular weight of the water-soluble monofluorophosphorylated polymer compound was measured by gel permeation chromatography (GPC) using water containing sodium nitrate and acetonitrile as an eluent, and calculated based on a pullulan standard. For example, a dried product of the polymer compound was dissolved in water containing 10 mM sodium nitrate and 20% by volume acetonitrile to prepare a 0.5% solution. Tosoh Co., Ltd. TSK-GelG2500PWXL and TSK-GelGMPWXL are connected and installed in the column, column oven set temperature is 40 ° C. (CO-8020, manufactured by Tosoh), eluent is water containing 10 mM sodium nitrate and 20% by volume acetonitrile. The flow rate is 0.5 mL / min (pump: DS-4, manufactured by Shodex), and RI (RI-71, manufactured by Shodex) is used for detection.

  The monofluorophosphorylated hydroxyethyl (meth) acrylamide polymer, monofluorophosphorylated polyvinyl alcohol, and monofluorophosphorylated polyhydroxyethyl (meth) acrylate according to the present invention are before introduction of monofluorophosphoric acid in the step (i). In the polymer preparation step, the weight average molecular weight can be controlled within the above range by adjusting the polymerization conditions such as the amount of initiator to be used, the type of polymerization solvent, and the monomer concentration during polymerization. Moreover, monofluoro phosphorylated hydroxypropyl cellulose can adjust a weight average molecular weight to the said range by selecting suitably the weight average molecular weight of the commercial polymer used for monofluoro phosphorylation.

  Furthermore, the fluorine introduction rate of the water-soluble monofluorophosphorylated polymer compound is preferably 0.1 to 18%, particularly preferably 0.5 to 15%, and particularly preferably 1 to 5%. If the fluorine introduction rate is less than 0.1%, a sufficient fluorine release amount may not be obtained, and if it exceeds 18%, it may be difficult to synthesize fluorine. The fluorine introduction rate of the water-soluble monofluorophosphorylated polymer compound can be appropriately adjusted by selecting the type of reaction solvent, the amount of difluorophosphoric acid, the reaction time, and the reaction temperature.

The fluorine introduction rate can be obtained by dividing the introduced fluorine atom weight by the polymer mass.
Specifically, an aqueous solution of perchloric acid is added to an aqueous solution in which a known amount of a water-soluble monofluorophosphorylated polymer compound is dissolved, and all monofluorophosphate groups are hydrolyzed by boiling for 10 to 20 minutes. Thereafter, potassium citrate buffer (pH 5.5) was added, and the fluoride ion concentration was measured with a fluorine ion electrode. Finally, the amount of fluorine obtained by conversion from the measured fluoride ion concentration was determined as the polymer mass. The fluorine introduction rate is calculated by dividing by.

  The oral composition of the present invention desirably contains the water-soluble monofluorophosphorylated polymer compound in an amount of 0.1 to 10%, particularly 0.2 to 5%, based on the entire composition. If the content is less than 0.1%, a satisfactory blending effect cannot be obtained, and if it exceeds 10%, the usability of the composition may be inferior.

  Next, the surfactant is at least one selected from an anionic surfactant, a nonionic surfactant and an amphoteric surfactant, and one type may be used alone or two or more types may be combined. Good.

Examples of the anionic surfactant include alkali metal salts of fatty acids, sulfates of higher alcohols, and sulfonates of alkanes.
Examples of these anionic surfactants include sodium oleate, potassium oleate, sodium stearate, potassium stearate, sodium lauryl sulfate, sodium oleyl sulfate, sodium myristyl sulfate, sodium dodecane sulfonate, sodium hexadecane sulfonate, and dodecyl. Examples thereof include sodium benzenesulfonate.

  Examples of the nonionic surfactant include polyoxyethylene alkyl ether, sucrose fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester and the like.

  As these nonionic surfactants, for example, polyoxyethylene (average added mole number of ethylene oxide (average added EO) 5 moles) stearyl ether and the like have 14 to 18 carbon atoms and an average of ethylene oxide Fatty acid residues having 14 to 18 carbon atoms such as polyoxyethylene alkyl ether, sucrose stearic acid ester, sucrose palmitic acid ester, sucrose myristic acid ester, sucrose oleic acid ester and the like having an addition mole number of 3 to 8 Polyglycerin fatty acid ester having a fatty acid residue having 14 to 18 carbon atoms such as decaglyceryl monomyristate, decaglyceryl monostearate, decaglyceryl monoisostearate, polyoxyethylene (average addition EO60) Mol) hydrogenated castor oil, polyoxye Polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene (average added EO 40 mol) hydrogenated castor oil, polyoxyethylene (average added EO 20 mol) hydrogenated castor oil, and the like. Polyoxyethylene sorbitan fatty acid ester having a fatty acid residue having 14 to 18 carbon atoms, such as ethylene (average added EO 20 mol) sorbitan, polyoxyethylene monooleate (average added EO 20 mol) sorbitan, sorbitan monooleate, monostearate Examples include sorbitan fatty acid esters having a fatty acid residue having 14 to 18 carbon atoms, such as acid sorbitan and sorbitan sesquioleate.

  As the amphoteric surfactant, N-alkyldiaminoethylglycine such as N-lauryldiaminoethylglycine, N-myristyldiaminoethylglycine, N-alkyl-N-carboxymethylammonium betaine, 2-alkyl-1-hydroxyethylimidazo Linium betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, etc. are mentioned.

  Among these surfactants, sodium oleate, potassium stearate, sodium lauryl sulfate, sucrose stearate, decaglyceryl monomyristate, polyoxyethylene stearyl ether, polyoxyethylene hydrogenated castor oil, 2-alkyl -N-carboxymethyl-N-hydroxyethyl imidazolinium betaine is preferably used, more preferably sodium lauryl sulfate as an anionic surfactant, polyoxyethylene hydrogenated castor oil (average addition EO20 as a nonionic surfactant) ˜80 mol), 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine is used as the amphoteric surfactant.

  Furthermore, when prepared as a dentifrice, those having an average added EO mole number of 20 to 30 as polyoxyethylene hydrogenated castor oil, and in the case of mouthwash, average added EO moles as polyoxyethylene hydrogenated castor oil 50 to 80 are preferably used.

  Specifically, examples of sodium lauryl sulfate include NIKKOL SLS (manufactured by Nikko Chemicals Co., Ltd.), and Scope LN-140 (manufactured by Toho Chemical Industry Co., Ltd.). As castor oil, NIKKOL HCO-20 (manufactured by Nikko Chemicals Co., Ltd., average addition EO 20 mol), EMALEX HC-20 (manufactured by Nippon Emulsion Co., Ltd.), BLAUNON RCW-20 (manufactured by Aoki Oil & Fat Co., Ltd., the same) , NIKKOL HCO-30 (manufactured by Nikko Chemicals Co., Ltd., average added EO 30 mol), EMALEX HC-30 (manufactured by Nihon Emulsion Co., Ltd.), NIKKOL HCO-50 (manufactured by Nikko Chemicals Co., Ltd., average added EO 50 mol), EMALEX HC-50 (Japan Emulsion Co., Ltd.), NIKKOL HCO-60 (Nikko Chemicals Co., Ltd., average addition EO 60 mol), EMALEX HC-60 (Nippon Emulsion Co., Ltd.), BLAUNON RCW-60 (Aoki Yushi Kogyo Co., Ltd.) NIKKOL HCO-80 (manufactured by Nikko Chemicals Co., Ltd., average addition EO 80 mol), EMALEX HC-80 (manufactured by Nihon Emulsion Co., Ltd.), BLAUNON RCW-80 (manufactured by Aoki Yushi Kogyo Co., Ltd.), etc. Is mentioned. As 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, a 30% aqueous solution of 2-coconut oil alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine sodium (Enadicol C-40H, Lion Corporation).

  The compounding quantity of surfactant is 0.1 to 5% of the whole composition, and 0.1 to 3% is especially preferable. Further, in the case of a dentifrice composition, 0.1 to 5%, particularly 0.1 to 3%, and in the case of a mouthwash composition, 0.1 to 3%, particularly 0.1 to 2% may be blended. preferable. If it is less than 0.1%, the irritation of the monofluorophosphorylated polymer cannot be improved, or the viscosity of the preparation becomes high, resulting in a problem in use. If it exceeds 5%, the viscosity of the preparation may be lowered and appropriate usability may not be obtained, or the retention property in the oral cavity of the monofluorophosphorylated polymer compound may be deteriorated.

  Furthermore, in the composition for oral cavity of the present invention, the mass ratio ((A) / (B)) between the water-soluble monofluorophosphorylated polymer compound (A) and the surfactant (B) is 0.5 to 30, preferably 0.5 to 20, and more preferably 1 to 10. When (A) / (B) is less than 0.5, there are too many surfactants, the usability of the preparation, the retention in the oral cavity of the water-soluble polymer compound (A), or the surfactant-derived Irritation is felt and the feeling of use is inferior, and the usability of the agent is also inferior. If it exceeds 30, the surfactant decreases, the viscosity of the preparation increases, the usability deteriorates, and the improvement effect of mucous membrane irritation can be satisfied Therefore, the effect of the present invention cannot be achieved.

The composition for oral cavity of the present invention can be prepared in various forms such as paste, liquid, liquid, gum and the like, and toothpaste such as toothpaste, liquid toothpaste, liquid toothpaste, and toothpaste, mouthwash, chewing gum, It can be prepared as a troche or the like, and is particularly suitable as a dentifrice (especially a toothpaste) and a mouthwash. Furthermore, other additives can be blended as optional components in addition to the essential components according to the dosage form. In the case of dentifrices, for example, abrasives, binders, surfactants, wetting agents, fragrances, sweeteners, preservatives, various active ingredients, colorants, etc. can be blended, and these ingredients are mixed with water and manufactured. can do.
Moreover, when preparing into liquid dosage forms, such as a mouthwash, it can prepare by a conventional method by mix | blending a binder, a wetting agent, a fragrance | flavor, an active ingredient etc. as an arbitrary component, for example.

As abrasives, precipitated silica, silica gel, aluminosilicate, calcium hydrogen phosphate anhydrate, calcium hydrogen phosphate dihydrate, calcium pyrophosphate, calcium carbonate, aluminum hydroxide, alumina, magnesium carbonate, tertiary phosphate Examples include magnesium, zeolite, zirconium silicate, tricalcium phosphate, hydroxyapatite, quaternary calcium phosphate, and synthetic resin-based abrasive.
The blending amount of these abrasives can be a normal amount, 2 to 20% of the whole with a dentifrice composition, particularly 5 to 15%, and 0 to 10% with a liquid dentifrice or mouthwash, in particular. 0 to 5% is preferable.

Examples of the binder include cellulose derivatives such as sodium carboxymethyl cellulose and hydroxyethyl cellulose, carrageenan, guar gum, alginic acid, montmorillonite, gelatin, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, tragacanth gum, karaya gum, bee gum, xanthan gum and the like.
The compounding amount of these binders can be a normal amount as long as the effect of the present invention is not hindered. However, in the case of a dentifrice composition, it is 0.1 to 2%, particularly 0.3. ~ 1% is preferred. Liquid dentifrices and mouthwashes can contain 0-5%.

  Examples of the wetting agent include sorbitol (including sorbitol liquid), glycerin, propylene glycol, xylitol, maltitol, lactit and the like, and sorbitol and xylitol are particularly preferable. These blending amounts are preferably 5 to 50%, particularly 20 to 45% of the entire composition.

  Examples of the sweetener include saccharin sodium, and examples of the preservative include paraoxybenzoic acid ester and sodium benzoate.

  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, grapefruit oil, sweetie Natural fragrances such as oil, bran oil, Iris concrete, absolute peppermint, absolute rose, orange flower, and processing of these natural fragrances (front reservoir cut, rear reservoir cut, fractional distillation, liquid extraction, essence, powder Perfumes, etc.) and menthol, Rubon, Anethole, Cineol, Methyl salicylate, Synamic aldehyde, Eugenol, 3-l-Mentoxypropane-1,2-diol, Thymol, Linalol, Linarel acetate, Limonene, Menthone, Menthyl acetate, N-Substituted-paramenthane 3-carboxamide, pinene, octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allyl cyclohexane propionate, methyl anthranilate, ethyl methyl phenyl glycidate, vanillin, undecalactone, Hexanal, butanol, isoamyl alcohol, hexenol, dimethyl sulfide, cycloten, furfural, trimethylpyrazine, ethyl lactate, ethyl Oral compositions such as single flavors such as o-acetate, and other flavors such as strawberry flavor, apple flavor, banana flavor, pineapple flavor, grape flavor, mango flavor, butter flavor, milk flavor, fruit mix flavor, tropical fruit flavor, etc. It can be used in combination with known perfume materials used in the above.

  Other active ingredients include fluorides such as sodium fluoride, sodium monofluorophosphate, stannous fluoride, and ammonium fluoride, water-soluble phosphate compounds such as potassium salt and sodium salt of orthophosphoric acid, dextra Glucanases such as nuclease and mutanase, allantoinchlorohydroxyaluminum, ascorbic acid, lysozyme chloride, glycyrrhizic acid or salts thereof, sodium chloride, tranexamic acid, epsilon aminocaproic acid, copper chlorophyllin sodium, copper gluconate and other copper compounds, aluminum lactate, chloride Strontium, potassium nitrate, berberine, hydroxamic acid or its derivatives, sodium tripolyphosphate, amylase, methoxyethylene, epidihydrocholesterin, isopropylmethylphenol, triclosan Hinokitiol, thymol, chlorhexidine, cetylpyridinium chloride, benzethonium chloride, dihydrocholesterol, trichlorocarbanilide, zinc citrate, Japanese angelica root soft extract, Phellodendron bark extract, clove, rosemary, scutellaria root, include extracts, such as safflower. In addition, the said active ingredient can be mix | blended in an effective amount in the range which does not prevent the effect of this invention.

  As the colorant, blue 1, No. 4, green 3, No. 3, titanium dioxide and the like can be blended in usual amounts.

The pH of the composition for oral cavity of the present invention is not particularly limited as long as it is within the range of safety in the oral cavity and human body, but the stability of the water-soluble monofluorophosphorylated polymer compound is not limited. From the aspect, the pH is preferably 6-9, and more preferably pH 7-9. When the pH is less than 6, the stability of the water-soluble monofluorophosphorylated polymer compound may be lowered, and when the pH exceeds 9, the usability and taste may be deteriorated. If necessary, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, citric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium acetate, sodium carbonate, sodium citrate, sodium hydrogen citrate, phosphorus An appropriate amount of sodium acid, sodium hydrogen phosphate, or the like can be blended.
Further, ethanol, water or the like can be blended as a solvent.

  EXAMPLES Hereinafter, although a preparation example, an Example, a comparative example, and a formulation example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In addition, all the mixing | blending% in each example is a mass percentage.

[Preparation Example]
Preparation of water-soluble monofluorophosphorylated polymer compound:
a-1) Preparation 1 of sodium monofluorophosphate hydroxyethylacrylamide polymer
[Synthesis of polymer compounds]
55 g of isopropyl alcohol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 90 ° C. in an oil bath, a monomer solution in which 15 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) was dissolved in 20 g of isopropyl alcohol, and 2,2′-azobis (2- Methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) 0.25 g of a solution in which 10 g of isopropyl alcohol was dissolved was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 100 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 2,000, manufactured by Spectrum Laboratories). By removing the water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.), 12 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid was obtained. This series of operations was repeated a total of 7 times to obtain a total of 84 g of hydroxyethylacrylamide polymer before the introduction of monofluorophosphoric acid.

  Next, 5 g of hydroxyethyl acrylamide polymer was dissolved in 45 g of dimethyl sulfoxide (Dry: manufactured by MERCK, hereinafter abbreviated as DMSO), put into a two-necked eggplant flask, and nitrogen gas was introduced. Next, 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize the solution to pH 7. Then, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories), and filter paper ( 101, manufactured by Advantech Toyo Co., Ltd.), the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution, and finally the water was freeze-dried (NEOCOOL, manufactured by Yamato Science Co., Ltd.). By removing, 4.1 g of water-soluble monofluorophosphorylated hydroxyethylacrylamide polymer was obtained. This series of operations was repeated a total of 20 times to obtain a total of 82 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.

(Measurement of weight average molecular weight)
The weight average molecular weight was measured by gel permeation chromatography (GPC) using water containing 10 mM sodium nitrate and 20 volume% acetonitrile, and a pullulan standard (P-82, Showa Denko) with a molecular weight of 5,800 to 853,000. The product was converted and calculated. Specifically, 0.05 g of a dried product of monofluorophosphorylated hydroxyethyl acrylamide polymer was dissolved in 10 g of water containing 10 mM sodium nitrate and 20 volume% acetonitrile to prepare a 0.5% solution. TSK-GelG2500PWXL and TSK-GelGMPWXL manufactured by Tosoh Corporation were connected to the column and installed, the column oven set temperature was 40 ° C., the flow rate was 0.5 mL / min, and the detection was measured using RI. As a result, the weight average molecular weight was 10,400.

[Evaluation of water solubility]
The water solubility of the polymer compound prepared in the present invention was evaluated by the following method.
0.5 g of the prepared polymer compound was precisely weighed and dissolved in 10 g of distilled water weighed in advance at room temperature for 24 hours (300 rpm) using a 1 cm × 0.5 cm stirrer chip. When in solution, this polymer compound was determined to be water-soluble.

[Calculation of fluorine introduction rate]
2.4 g of 1M perchloric acid aqueous solution was added to 1.6 g of a 0.1% by mass aqueous solution of the polymer compound, 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 1M potassium citrate buffer (pH 5.5), and then the amount of fluorine: Xp (ppm) using a fluoride ion electrode (Expandable Ion Analyzer EA920, manufactured by Orion). ) Was quantified. The mass concentration of fluorine with respect to the mass of the polymer (fluorine introduction rate): F (mass%) was calculated by the following equation.
F = Xp × 1.25
As a result, Xp was 2.32 ppm, and the fluorine introduction rate was 2.9%.

a-2) Preparation 2 of sodium monofluorophosphate hydroxyethylacrylamide polymer
30 g of ethanol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser, and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 90 ° C. in an oil bath, a monomer solution in which 40 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) was dissolved in 20 g of ethanol, and 2,2′-azobis (2-methyl) as a polymerization initiator were used. Butyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) A solution obtained by dissolving 0.05 g of ethanol in 10 g of ethanol was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 90 ° C. for 5 hours while introducing nitrogen, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) Finally, 14 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid was obtained by removing water with an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 8 times to obtain a total of 112 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid.

Next, 5 g of hydroxyethyl acrylamide polymer was dissolved in 45 g of dimethyl sulfoxide (dry: manufactured by MERCK, DMSO) and then placed in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 8 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) After removing water insolubles using filter paper (101, manufactured by Advantech Toyo Co., Ltd.), the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution, and finally the water was freeze-dried (NEOCOOL, Yamato Science Co., Ltd.). To obtain 4.2 g of a water-soluble monofluorophosphorylated hydroxyethylacrylamide polymer. This series of operations was repeated a total of 20 times to obtain a total of 84 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.
Furthermore, as a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 153,000 and the fluorine introduction rate was 3.1%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

a-3) Preparation 3 of sodium monofluorophosphate hydroxyethylacrylamide polymer 3
30 g of distilled water was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 60 ° C. in an oil bath, a monomer solution prepared by dissolving 40 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) with 20 g of distilled water and 2,2′-azobis (2- A solution in which 0.08 g of methylpropionamidine) dihydrochloride (trade name V-50: manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 10 g of distilled water was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 60 ° C. for 5 hours while introducing nitrogen, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) Finally, water was removed by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.) to obtain 35 g of a hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid. This series of operations was repeated a total of 3 times to obtain a total of 105 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid.

Next, 5 g of hydroxyethylacrylamide polymer was dissolved in 45 g of dimethyl sulfoxide (dry: manufactured by MERCK, DMSO), and then dissolved in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 10 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) After removing water insolubles using filter paper (101, manufactured by Advantech Toyo Co., Ltd.), the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution, and finally the water was freeze-dried (NEOCOOL, Yamato Science Co., Ltd.). To obtain 4.3 g of water-soluble monofluorophosphorylated hydroxyethylacrylamide polymer. This series of operations was repeated a total of 20 times to obtain a total of 86 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.
Furthermore, as a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 298,000, and the fluorine introduction rate was 3.2%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

a-4) Preparation 4 of sodium monofluorophosphate hydroxyethylacrylamide polymer
65 g of isopropyl alcohol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 90 ° C. in an oil bath, a monomer solution prepared by dissolving 5 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) with 20 g of isopropyl alcohol, and 2,2′-azobis (2- Methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) 0.5 g of a solution in which 10 g of isopropyl alcohol was dissolved was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 90 ° C. for 5 hours while introducing nitrogen, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories). By removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.), 4 g of a hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid was obtained. This series of operations was repeated a total of 20 times to obtain a total of 80 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid.

Next, 5 g of hydroxyethylacrylamide polymer was dissolved in 45 g of dimethyl sulfoxide (dry: manufactured by MERCK, DMSO), and then dissolved in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories), and filter paper ( 101, manufactured by Advantech Toyo Co., Ltd.), the water-soluble portion was adjusted again to pH 7 with an aqueous sodium hydroxide solution, and finally the water was freeze-dried (NEOCOOL, manufactured by Yamato Science Co., Ltd.). Removal of 3.9 g of a water-soluble monofluorophosphorylated hydroxyethylacrylamide polymer was obtained. This series of operations was repeated a total of 15 times to obtain a total of 58.5 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.
Furthermore, as a result of measuring the weight average molecular weight and fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 5,200, and the fluorine introduction rate was 2.8%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

a-5) Preparation 5 of sodium monofluorophosphate hydroxyethylacrylamide polymer
20 g of water was put into a four-necked separable flask equipped with a stirrer, a reflux condenser, and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 60 ° C. in an oil bath, a monomer solution prepared by dissolving 50 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) with 20 g of water, and 2,2′-azobis (2-methyl) as a polymerization initiator. Propionamidine) dihydrochloride (trade name V-50: manufactured by Wako Pure Chemical Industries, Ltd.) 0.05 g dissolved in 10 g of water was continuously added dropwise to carry out the polymerization reaction. After completion of dropping, heating was continued at 60 ° C. for 5 hours while introducing nitrogen, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) Finally, 40 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid was obtained by removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 2 times to obtain a total of 80 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid.

Next, 5 g of hydroxyethylacrylamide polymer was dissolved in 45 g of dimethyl sulfoxide (dry: manufactured by MERCK, DMSO), and then dissolved in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) After removing water insolubles using filter paper (101, manufactured by Advantech Toyo Co., Ltd.), the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution, and finally the water was freeze-dried (NEOCOOL, Yamato Science Co., Ltd.). 3.8 g of water-soluble monofluorophosphorylated hydroxyethylacrylamide polymer was obtained. This series of operations was repeated a total of 15 times to obtain a total of 57 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.
Furthermore, as a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 404,000 and the fluorine introduction rate was 2.9%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

a-6) Preparation 6 of sodium monofluorophosphate hydroxyethylacrylamide polymer
65 g of isopropyl alcohol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser, and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 90 ° C. in an oil bath, a monomer solution in which 5 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) was dissolved in 20 g of isopropyl alcohol and 2,2′-azobis (2- (Methylbutyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) A solution in which 1.25 g of butyl alcohol was dissolved in 10 g of isopropyl alcohol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 90 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories). By removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.), 4.2 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid was obtained. This series of operations was repeated 20 times in total to obtain a total of 84 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid.

Next, 5 g of hydroxyethylacrylamide polymer was dissolved in 45 g of dimethyl sulfoxide (dry: manufactured by MERCK, DMSO), and then dissolved in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories), and filter paper ( 101, manufactured by Advantech Toyo Co., Ltd.), the water-insoluble portion was removed, and the water-soluble portion was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Thereafter, ultrafiltration was performed using an ultrafiltration membrane having a fractional molecular weight of 3,000 (Amicon Ultra-15, manufactured by Nippon Millipore Co., Ltd.) (centrifugation: 5000 G, 15 minutes), and the filtrate was recovered. Finally, 3.9 g of monofluorophosphorylated hydroxyethylacrylamide polymer was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 15 times to obtain a total of 58.5 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.
Furthermore, as a result of measuring the weight average molecular weight and fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 1,200 and the fluorine introduction rate was 3.0%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

a-7) Preparation 7 of sodium monofluorophosphate hydroxyethylacrylamide polymer 7
20 g of water was put into a four-necked separable flask equipped with a stirrer, a reflux condenser, and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 55 ° C. in an oil bath, a monomer solution prepared by dissolving 50 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) with 20 g of water and 2,2′-azobis (2-methyl) as a polymerization initiator Propionamidine) dihydrochloride (trade name V-50: manufactured by Wako Pure Chemical Industries, Ltd.) 0.03 g dissolved in 10 g of water was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 60 ° C. for 5 hours while introducing nitrogen, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) Finally, 39 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid was obtained by removing water with an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 3 times to obtain a total of 117 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.

Next, 5 g of hydroxyethylacrylamide polymer was dissolved in 45 g of dimethyl sulfoxide (dry: manufactured by MERCK, DMSO), and then dissolved in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) After removing water insolubles using filter paper (101, manufactured by Advantech Toyo Co., Ltd.), the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution, and finally the water was freeze-dried (NEOCOOL, Yamato Science Co., Ltd.). To obtain 3.7 g of water-soluble monofluorophosphorylated hydroxyethylacrylamide polymer. This series of operations was repeated 20 times in total to obtain a total of 74 g of sodium monofluorophosphate (including a partially neutralized product) hydroxyethylacrylamide polymer.
Furthermore, as a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 603,500, and the fluorine introduction rate was 2.5%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

a-8) Preparation of non-monofluorophosphorylated hydroxyethyl acrylamide polymer 30 g of ethanol was placed in a four-necked separable flask equipped with a stirrer, reflux condenser and nitrogen inlet tube, and nitrogen gas was added from the nitrogen inlet tube while stirring. Introduced. Next, while heating to 90 ° C. in an oil bath, a monomer solution in which 40 g of hydroxyethylacrylamide (manufactured by Kojin Co., Ltd.) was dissolved in 20 g of ethanol, and 2,2′-azobis (2-methyl) as a polymerization initiator were used. Butyronitrile) (trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) A solution obtained by dissolving 0.05 g of ethanol in 10 g of ethanol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, the mixture was heated to 90 ° C. while introducing nitrogen and continued for 5 hours, and then the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, Sanko Junyaku Co. ) Finally, water was removed by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.) to obtain 35 g of hydroxyethylacrylamide polymer before introduction of monofluorophosphoric acid. This series of operations was repeated a total of 3 times to obtain a total of 105 g of hydroxyethylacrylamide polymer.
Further, distilled water was added to 100 g of this polymer to dissolve it, and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Finally, 102 g of hydroxyethylacrylamide polymer was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.)
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 147,000, and the fluorine introduction rate was 0%. As a result of the evaluation of sex, it was determined that there was water solubility.

b-1) Preparation 1 of sodium monohydroxyphosphate hydroxypropylcellulose
5 g of commercially available hydroxypropyl cellulose (HPC-SLL, manufactured by Nippon Soda Co., Ltd.) was dissolved in 45 g of THF (manufactured by Kanto Chemical Co., Inc.), and then was placed in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 30 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Thereafter, ultrafiltration was performed using an ultrafiltration membrane (Amicon Ultra-15, manufactured by Nippon Millipore Co., Ltd.) having a molecular weight cut off of 30,000 (centrifugation: 5000 G, 15 minutes), and the filtrate was recovered. Finally, 4.1 g of water-soluble monofluorophosphorylated hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 82 g of sodium monofluorophosphate (including a partially neutralized product) hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 14,000 and the fluorine introduction rate was 3.1%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

b-2) Preparation 2 of sodium monohydroxyphosphate hydroxypropylcellulose
5 g of commercially available hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.) was dissolved in 45 g of THF (manufactured by Kanto Chemical Co., Ltd.), and then put into a two-necked eggplant flask, and nitrogen gas was introduced. Next, 30 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.2 g of water-soluble monofluorophosphorylated hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 84 g of sodium monofluorophosphate (including a partially neutralized product) hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 140,000 and the fluorine introduction rate was 3.2%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

b-3) Preparation 3 of sodium monofluorophosphate hydroxypropylcellulose
5 g of commercially available hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was dissolved in 45 g of THF (manufactured by Kanto Chemical Co., Inc.), and then was put into a two-necked eggplant flask, and nitrogen gas was introduced. Next, 30 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.0 g of water-soluble monofluorophosphorylated hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 80 g of sodium monofluorophosphate (including a partially neutralized product) hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 250,000 and the fluorine introduction rate was 3.0%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

b-4) Preparation 4 of sodium monohydroxyphosphate hydroxypropylcellulose
5 g of commercially available hydroxypropyl cellulose (HPC-SLL, manufactured by Nippon Soda Co., Ltd.) was dissolved in 45 g of THF (manufactured by Kanto Chemical Co., Inc.), and then was placed in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 30 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Thereafter, ultrafiltration was performed using an ultrafiltration membrane (Amicon Ultra-15, manufactured by Nippon Millipore Co., Ltd.) having a fractional molecular weight of 10,000 (centrifugation: 5000 G, 15 minutes), and the filtrate was recovered. Finally, 3.8 g of water-soluble monofluorophosphorylated hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 76 g of sodium monofluorophosphate (including a partially neutralized product) hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 5,300 and the fluorine introduction rate was 2.9%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

b-5) Preparation 5 of sodium monofluorophosphate hydroxypropylcellulose
5 g of commercially available hydroxypropylcellulose (KLUCEL-GF, manufactured by HERCULES) was dissolved in 45 g of THF (manufactured by Kanto Chemical Co., Inc.) and then placed in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 30 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 4 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 3.8 g of water-soluble monofluorophosphorylated hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 76 g of sodium monofluorophosphate (including a partially neutralized product) hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 450,000 and the fluorine introduction rate was 2.8%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

b-6) Preparation 6 of sodium monohydroxyphosphate hydroxypropylcellulose
5 g of commercially available hydroxypropyl cellulose (HPC-SLL, manufactured by Nippon Soda Co., Ltd.) was dissolved in 45 g of THF (manufactured by Kanto Chemical Co., Inc.), and then was placed in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 30 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Thereafter, ultrafiltration was performed using an ultrafiltration membrane having a fractional molecular weight of 3,000 (Amicon Ultra-15, manufactured by Nippon Millipore Co., Ltd.) (centrifugation: 5000 G, 15 minutes), and the filtrate was recovered. Finally, 3.7 g of water-soluble monofluorophosphorylated hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated 20 times in total to obtain a total of 74 g of sodium monofluorophosphate (including a partially neutralized product) hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 1,300 and the fluorine introduction rate was 3.0%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

b-7) Preparation 7 of sodium monofluorophosphate hydroxypropylcellulose
5 g of commercially available hydroxypropyl cellulose (HPC-M, manufactured by Nippon Soda Co., Ltd.) was dissolved in 45 g of THF (manufactured by Kanto Chemical Co., Ltd.), and then was placed in a two-necked eggplant flask, and nitrogen gas was introduced. Next, 30 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually dropped while the flask was immersed in a water bath at room temperature. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 3.8 g of water-soluble monofluorophosphorylated hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 76 g of sodium monofluorophosphate (including a partially neutralized product) hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 700,000 and the fluorine introduction rate was 2.6%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

b-8) Preparation of non-monofluorophosphorylated hydroxypropyl cellulose 5 g of commercially available hydroxypropyl cellulose (HPC-SL, Nippon Soda Co., Ltd.) was dissolved in 100 g of distilled water and dialyzed in running water for 3 days (dialysis membrane). Molecular weight of 14,000, manufactured by Sanko Junyaku Co., Ltd.), filter paper (101, manufactured by Advantech Toyo Co., Ltd.), water-insoluble matter was removed, and the water-soluble portion was adjusted to pH 7 again using an aqueous sodium hydroxide solution. did. Finally, 4.9 g of water-soluble hydroxypropylcellulose was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 98 g of non-monofluorophosphorylated hydroxypropylcellulose.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 136,000, and the fluorine introduction rate was 0%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

c-1) Preparation 1 of sodium monofluorophosphate polyvinyl alcohol
85 g of methanol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 62 ° C. in an oil bath, 10 g of vinyl acetate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: Wako Pure Chemical Industries, Ltd.) 0.2 g and a polymerization initiator solution consisting of 5 g of methanol were continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 62 ° C. for 6 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories). Was removed by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.) to obtain 9.0 g of polyvinyl acetate. This series of operations was repeated a total of 25 times to obtain a total of 225 g of polyvinyl acetate.
Next, 20 g of the obtained polyvinyl acetate was dissolved in 1000 mL of methanol and heated to 40 ° C., 20 mL of 40% aqueous sodium hydroxide solution was added, and the mixture was stirred and allowed to stand. After standing for 30 minutes, the reaction solution is suction filtered, the residue is washed several times with methanol, extracted with a Soxhlet extractor for 3 hours, and finally methanol is removed by evaporator and lyophilization to introduce monofluorophosphoric acid. 10 g of the previous polyvinyl alcohol was obtained. This series of operations was repeated a total of 10 times to obtain a total of 100 g of polyvinyl alcohol.

Further, 5 g of polyvinyl alcohol was put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually added while the flask was immersed in a water bath at room temperature. It was dripped in. After further stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Finally, 4.1 g of water-soluble monofluorophosphorylated polyvinyl alcohol was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 82 g of sodium monofluorophosphate (including a partially neutralized product) polyvinyl alcohol.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 10,100 and the fluorine introduction rate was 1.8%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

c-2) Preparation 2 of sodium monofluorophosphate polyvinyl alcohol
20 g of methanol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 62 ° C. in an oil bath, 75 g of vinyl acetate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: A polymerization initiator solution consisting of 0.03 g (manufactured by Wako Pure Chemical Industries, Ltd.) and 5 g of methanol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropping, heating was continued at 62 ° C. for 6 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.). In addition, 60 g of polyvinyl acetate was obtained by removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 4 times to obtain a total of 240 g of polyvinyl acetate.
Next, 20 g of the obtained polyvinyl acetate was dissolved in 1000 mL of methanol and heated to 40 ° C., and then 20 mL of a 40% by mass aqueous sodium hydroxide solution was added, stirred and allowed to stand. After standing for 30 minutes, the reaction solution is suction filtered, the residue is washed several times with methanol, extracted with a Soxhlet extractor for 3 hours, and finally methanol is removed by evaporator and lyophilization to introduce monofluorophosphoric acid. 10 g of the previous polyvinyl alcohol was obtained. This series of operations was repeated a total of 10 times to obtain a total of 100 g of polyvinyl alcohol.

Further, 5 g of polyvinyl alcohol was put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually added while the flask was immersed in a water bath at room temperature. It was dripped in. After further stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.2 g of water-soluble monofluorophosphorylated polyvinyl alcohol was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 84 g of sodium monofluorophosphate (including a partially neutralized product) polyvinyl alcohol.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 154,000, and the fluorine introduction rate was 1.5%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

c-3) Preparation 3 of sodium monofluorophosphate polyvinyl alcohol
20 g of ethyl acetate was put into a four-necked separable flask equipped with a stirrer, a reflux condenser, and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Subsequently, 75 g of vinyl acetate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: A polymerization initiator solution comprising 0.01 g of Wako Pure Chemical Industries, Ltd. and 5 g of methanol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 62 ° C. for 6 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.). In addition, 61 g of polyvinyl acetate was obtained by removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 4 times to obtain a total of 244 g of polyvinyl acetate.
Next, 20 g of the obtained polyvinyl acetate was dissolved in 1000 mL of methanol and heated to 40 ° C., and then 20 mL of a 40% by mass aqueous sodium hydroxide solution was added, stirred and allowed to stand. After standing for 30 minutes, the reaction solution is suction filtered, the residue is washed several times with methanol, extracted with a Soxhlet extractor for 3 hours, and finally methanol is removed by evaporator and lyophilization to introduce monofluorophosphoric acid. 10 g of the previous polyvinyl alcohol was obtained. This series of operations was repeated a total of 10 times to obtain a total of 100 g of polyvinyl alcohol.

Further, 5 g of polyvinyl alcohol was put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually added while the flask was immersed in a water bath at room temperature. It was dripped in. After further stirring for 10 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.2 g of water-soluble monofluorophosphorylated polyvinyl alcohol was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 84 g of sodium monofluorophosphate (including a partially neutralized product) polyvinyl alcohol.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 297,000 and the fluorine introduction rate was 2.0%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

c-4) Preparation 4 of sodium monofluorophosphate polyvinyl alcohol
90 g of methanol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, 5 g of vinyl acetate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: Wako Pure Chemical Industries, Ltd.) 0.15 g and a polymerization initiator solution consisting of 5 g of methanol were continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 62 ° C. for 6 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories). Was removed by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.) to obtain 4 g of polyvinyl acetate. This series of operations was repeated 50 times in total to obtain a total of 200 g of polyvinyl acetate.
Next, 20 g of the obtained polyvinyl acetate was dissolved in 1000 mL of methanol and heated to 40 ° C., and then 20 mL of a 40% by mass aqueous sodium hydroxide solution was added, stirred and allowed to stand. After standing for 30 minutes, the reaction solution is suction filtered, the residue is washed several times with methanol, extracted with a Soxhlet extractor for 3 hours, and finally methanol is removed by evaporator and lyophilization to introduce monofluorophosphoric acid. 10 g of the previous polyvinyl alcohol was obtained. This series of operations was repeated a total of 10 times to obtain a total of 100 g of polyvinyl alcohol.

Further, 5 g of polyvinyl alcohol was put into a two-necked eggplant flask, nitrogen gas was introduced, and 40 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually added while the flask was immersed in a water bath at room temperature. It was dripped in. After further stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Finally, 3.9 g of water-soluble monofluorophosphorylated polyvinyl alcohol was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 78 g of sodium monofluorophosphate (including a partially neutralized product) polyvinyl alcohol.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 5,100 and the fluorine introduction rate was 1.2%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

c-5) Preparation 5 of sodium monofluorophosphate polyvinyl alcohol
90 g of methanol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 62 ° C. in an oil bath, 5 g of vinyl acetate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: Japanese A polymerization initiator solution consisting of 0.20 g (manufactured by Kojun Pharmaceutical Co., Ltd.) and 5 g of methanol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 62 ° C. for 6 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories). Was removed by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.) to obtain 4 g of polyvinyl acetate. This series of operations was repeated 50 times in total to obtain a total of 200 g of polyvinyl acetate.
Next, 20 g of the obtained polyvinyl acetate was dissolved in 1000 mL of methanol and heated to 40 ° C., and then 20 mL of a 40% by mass aqueous sodium hydroxide solution was added, stirred and allowed to stand. After standing for 30 minutes, the reaction solution is suction filtered, the residue is washed several times with methanol, extracted with a Soxhlet extractor for 3 hours, and finally methanol is removed by evaporator and lyophilization to introduce monofluorophosphoric acid. 10 g of the previous polyvinyl alcohol was obtained. This series of operations was repeated a total of 10 times to obtain a total of 100 g of polyvinyl alcohol.

Further, 5 g of polyvinyl alcohol was put into a two-necked eggplant flask, nitrogen gas was introduced, and 7 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually added while the flask was immersed in a water bath at room temperature. It was dripped in. After further stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Thereafter, ultrafiltration was performed using an ultrafiltration membrane having a fractional molecular weight of 3,000 (Amicon Ultra-15, manufactured by Nippon Millipore Co., Ltd.) (centrifugation: 5000 G, 15 minutes), and the filtrate was recovered. Finally, 3.7 g of water-soluble monofluorophosphorylated polyvinyl alcohol was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated 20 times in total to obtain a total of 74 g of sodium monofluorophosphate (including a partially neutralized product) polyvinyl alcohol.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 1,100 and the fluorine introduction rate was 1.5%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

c-6) Preparation 6 of sodium monofluorophosphate polyvinyl alcohol
20 g of methanol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 62 ° C. in an oil bath, 100 g of vinyl acetate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 2,2′-azobis (2-methylbutyronitrile) (trade name V-59: A polymerization initiator solution consisting of 0.03 g (manufactured by Wako Pure Chemical Industries, Ltd.) and 5 g of methanol was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 62 ° C. for 8 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.). Then, 80 g of polyvinyl acetate was obtained by removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 3 times to obtain a total of 240 g of polyvinyl acetate.
Next, 20 g of the obtained polyvinyl acetate was dissolved in 1000 mL of methanol and heated to 40 ° C., and then 20 mL of a 40% by mass aqueous sodium hydroxide solution was added, stirred and allowed to stand. After standing for 30 minutes, the reaction solution is suction filtered, the residue is washed several times with methanol, extracted with a Soxhlet extractor for 3 hours, and finally methanol is removed by evaporator and lyophilization to introduce monofluorophosphoric acid. 10 g of the previous polyvinyl alcohol was obtained. This series of operations was repeated a total of 10 times to obtain a total of 100 g of polyvinyl alcohol.

Further, 5 g of polyvinyl alcohol was put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0.5 hydrate, manufactured by Synquest) was gradually added while the flask was immersed in a water bath at room temperature. It was dripped in. After further stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.0 g of water-soluble monofluorophosphorylated polyvinyl alcohol was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 80 g of sodium monofluorophosphate (including a partially neutralized product) polyvinyl alcohol.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 604,000, and the fluorine introduction rate was 1.6%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

d-1) Preparation 1 of sodium monofluorophosphate polyhydroxyethyl acrylate
55 g of isopropyl alcohol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 100 ° C. in an oil bath, a monomer solution consisting of 15 g of hydroxyethyl acrylate (manufactured by Kojin Co., Ltd.) and 20 g of isopropyl alcohol was added to 2,2′-azobis (2-methylbutyronitrile). (Product name V-59: Wako Pure Chemical Industries, Ltd.) A polymerization initiator solution consisting of 0.25 g and 10 g of isopropyl alcohol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 100 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories). By removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.), 12 g of polyhydroxyethyl acrylate before introduction of monofluorophosphoric acid was obtained. This series of operations was repeated a total of 8 times to obtain a total of 96 g of polyhydroxyethyl acrylate before the introduction of monofluorophosphoric acid.

Next, 5 g of polyhydroxyethyl acrylate was dissolved in 45 g of DMSO, put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0. Pentahydrate (manufactured by Synquest) was gradually added dropwise. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Finally, 4.1 g of water-soluble monofluorophosphorylated polyhydroxyethyl acrylate was obtained by removing the water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 82 g of sodium monofluorophosphate (including a partially neutralized product) polyhydroxyethyl acrylate.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 10,400 and the fluorine introduction rate was 3.2%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

d-2) Preparation 2 of sodium monofluorophosphate polyhydroxyethyl acrylate
30 g of ethanol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser, and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 90 ° C. in an oil bath, a monomer solution consisting of 40 g of hydroxyethyl acrylate (manufactured by Kojin Co., Ltd.) and 20 g of ethanol was added to 2,2′-azobis (2-methylbutyronitrile) ( (Trade name V-59: manufactured by Wako Pure Chemical Industries, Ltd.) A polymerization initiator solution composed of 0.05 g and 10 g of ethanol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 90 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.) Finally, 33 g of polyhydroxyethyl acrylate before introduction of monofluorophosphoric acid was obtained by removing water with an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 3 times to obtain a total of 99 g of polyhydroxyethyl acrylate before the introduction of monofluorophosphoric acid.

Next, 5 g of polyhydroxyethyl acrylate was dissolved in 45 g of DMSO, put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0. Pentahydrate (manufactured by Synquest) was gradually added dropwise. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.2 g of water-soluble monofluorophosphorylated polyhydroxyethyl acrylate was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 84 g of sodium monofluorophosphate (including a partially neutralized product) polyhydroxyethyl acrylate.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 152,000 and the fluorine introduction rate was 3.3%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

d-3) Preparation 3 of sodium monofluorophosphate polyhydroxyethyl acrylate 3
30 g of distilled water was placed in a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 60 ° C. in an oil bath, 2,2′-azobis (2-methylpropionamidine) dihydro was added to a monomer solution consisting of 40 g of hydroxyethyl acrylate (manufactured by Kojin Co., Ltd.) and 20 g of distilled water. A polymerization initiator solution consisting of 0.08 g of chloride (trade name V-50: manufactured by Wako Pure Chemical Industries, Ltd.) and 10 g of distilled water was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 60 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 1 to 5 days (fraction molecular weight of dialysis membrane 14,000, manufactured by Sanko Junyaku Co., Ltd.). Finally, 35 g of polyhydroxyethyl acrylate before introduction of monofluorophosphoric acid was obtained by removing water with an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 3 times to obtain a total of 105 g of polyhydroxyethyl acrylate before the introduction of monofluorophosphoric acid.

Next, 5 g of polyhydroxyethyl acrylate was dissolved in 45 g of DMSO, put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0. Pentahydrate (manufactured by Synquest) was gradually added dropwise. After stirring for 8 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.0 g of water-soluble monofluorophosphorylated polyhydroxyethyl acrylate was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 80 g of sodium monofluorophosphate (including a partially neutralized product) polyhydroxyethyl acrylate.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 295,000, and the fluorine introduction rate was 3.5%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

d-4) Preparation 4 of sodium monofluorophosphate polyhydroxyethyl acrylate
20 g of distilled water was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 60 ° C. in an oil bath, 2,2′-azobis (2-methylpropionamidine) dihydro was added to a monomer solution consisting of 50 g of hydroxyethyl acrylate (manufactured by Kojin Co., Ltd.) and 20 g of distilled water. A polymerization initiator solution consisting of 0.05 g of chloride (trade name V-50: manufactured by Wako Pure Chemical Industries, Ltd.) and 10 g of distilled water was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 60 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 1 to 5 days (fraction molecular weight of dialysis membrane 14,000, manufactured by Sanko Junyaku Co., Ltd.). Finally, 40 g of polyhydroxyethyl acrylate before introduction of monofluorophosphoric acid was obtained by removing water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 3 times to obtain a total of 120 g of polyhydroxyethyl acrylate before the introduction of monofluorophosphoric acid.

Next, 5 g of polyhydroxyethyl acrylate was dissolved in 45 g of DMSO, put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0. Pentahydrate (manufactured by Synquest) was gradually added dropwise. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.0 g of water-soluble monofluorophosphorylated polyhydroxyethyl acrylate was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 80 g of sodium monofluorophosphate (including a partially neutralized product) polyhydroxyethyl acrylate.
As a result of measuring the weight average molecular weight and the fluorine introduction rate under the same conditions as in the above a-1), the weight average molecular weight was 402,000 and the fluorine introduction rate was 2.9%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

d-5) Preparation 5 of sodium monofluorophosphate polyhydroxyethyl acrylate
60 g of isopropyl alcohol was put into a four-necked separable flask equipped with a stirrer, a reflux condenser, and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 100 ° C. in an oil bath, a monomer solution consisting of 5 g of hydroxyethyl acrylate (manufactured by Kojin Co., Ltd.) and 20 g of isopropyl alcohol was added to 2,2′-azobis (2-methylbutyronitrile). (Product name V-59: Wako Pure Chemical Industries, Ltd.) A polymerization initiator solution consisting of 0.30 g and 10 g of isopropyl alcohol was continuously added dropwise to carry out a polymerization reaction. After completion of the dropwise addition, heating was continued at 100 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 1 to 5 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories). By removing the water by an evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.), 4.2 g of polyhydroxyethyl acrylate before introduction of monofluorophosphoric acid was obtained. This series of operations was repeated a total of 30 times to obtain a total of 126 g of polyhydroxyethyl acrylate before the introduction of monofluorophosphoric acid.

Next, 5 g of polyhydroxyethyl acrylate was dissolved in 45 g of DMSO, put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0. Pentahydrate (manufactured by Synquest) was gradually added dropwise. After further stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution is dialyzed in running water for 3 days (dialysis membrane molecular weight cut-off 2,000, manufactured by Spectrum Laboratories) and filter paper (101, manufactured by Advantech Toyo Co., Ltd.) to remove water-insoluble matter. The neutral part was again adjusted to pH 7 with aqueous sodium hydroxide solution. Thereafter, ultrafiltration was performed using an ultrafiltration membrane having a fractional molecular weight of 3,000 (Amicon Ultra-15, manufactured by Nippon Millipore Co., Ltd.) (centrifugation: 5000 G, 15 minutes), and the filtrate was recovered. Finally, 3.8 g of monofluorophosphorylated polyhydroxyethyl acrylate was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated 20 times in total to obtain a total of 76 g of sodium monofluorophosphate (including a partially neutralized product) polyhydroxyethyl acrylate.
Thereafter, the weight average molecular weight and the fluorine introduction rate were measured under the same conditions as in the above a-1). As a result, the weight average molecular weight was 900, and the fluorine introduction rate was 2.8%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

d-6) Preparation 6 of sodium monofluorophosphate polyhydroxyethyl acrylate 6
20 g of distilled water was put into a four-necked separable flask equipped with a stirrer, a reflux condenser and a nitrogen introduction tube, and nitrogen gas was introduced from the nitrogen introduction tube while stirring. Next, while heating to 60 ° C. in an oil bath, 2,2′-azobis (2-methylpropionamidine) dihydro was added to a monomer solution consisting of 50 g of hydroxyethyl acrylate (manufactured by Kojin Co., Ltd.) and 20 g of distilled water. A polymerization initiator solution consisting of 0.03 g of chloride (trade name V-50, manufactured by Wako Pure Chemical Industries, Ltd.) and 10 g of distilled water was continuously added dropwise to carry out a polymerization reaction. After completion of dropping, heating was continued at 60 ° C. for 5 hours while introducing nitrogen, and the reaction solution was dialyzed in running water for 1 to 5 days (fraction molecular weight of dialysis membrane 14,000, manufactured by Sanko Junyaku Co., Ltd.). Finally, water was removed by evaporator and freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.) to obtain 41 g of polyhydroxyethyl acrylate before introduction of monofluorophosphoric acid. This series of operations was repeated a total of 3 times to obtain a total of 121 g of polyhydroxyethyl acrylate before the introduction of monofluorophosphoric acid.

Next, 5 g of polyhydroxyethyl acrylate was dissolved in 45 g of DMSO, put into a two-necked eggplant flask, nitrogen gas was introduced, and 70 g of difluorophosphoric acid (0. Pentahydrate (manufactured by Synquest) was gradually added dropwise. After stirring for 5 hours, an aqueous sodium hydroxide solution was added dropwise to neutralize to pH 7. Thereafter, the reaction solution was dialyzed in running water for 3 days (dialysis membrane molecular weight cut off 14,000, manufactured by Sanko Junyaku Co., Ltd.), and water insolubles were removed using filter paper (101, manufactured by Advantech Toyo Co., Ltd.). Thereafter, the water-soluble part was adjusted again to pH 7 with an aqueous sodium hydroxide solution. Finally, 4.0 g of water-soluble monofluorophosphorylated polyhydroxyethyl acrylate was obtained by removing water by freeze-drying (NEOCOOL, manufactured by Yamato Scientific Co., Ltd.). This series of operations was repeated a total of 20 times to obtain a total of 80 g of sodium monofluorophosphate (including a partially neutralized product) polyhydroxyethyl acrylate.
Thereafter, the weight average molecular weight and fluorine introduction rate were measured under the same conditions as in the above a-1). As a result, the weight average molecular weight was 604,000 and the fluorine introduction rate was 3.0%.
Further, as in the case of the above a-1), as a result of water-soluble evaluation, it was determined that water-soluble.

Hydroxyethylacrylamide polymer obtained in Preparation Example a-8), monofluorophosphorylated hydroxyethylacrylamide polymer obtained in Preparation Example a-2), before introduction of monofluorophosphoric acid obtained in Preparation Example d-2) 1% by mass of the monofluorophosphorylated hydroxyethyl acrylate polymer obtained in Preparation Example d-2) in heavy water was dissolved in proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR; 270 MHz, JNM). -EX270, manufactured by JEOL Datum). The results are shown in FIGS. A polymer compound having a hydroxyl group in the molecule, in the case of forming a monofluorophosphate ester by reaction with difluorophosphate, since the peak of the proton of the hydroxyl group adjacent methylene shifts, the covalent bond formed by the ¹ H-NMR measurement It is possible to determine.
In the case of “hydroxyethylacrylamide polymer (FIG. 1)”, the proton peak of methylene adjacent to the hydroxyl group appeared at 3.5 to 3.7 ppm (peak area relative value: 2.00), but the reaction product with difluorophosphoric acid In the “monofluorophosphorylated hydroxyethylacrylamide polymer (FIG. 2)”, the peak of 3.5 to 3.7 ppm is reduced (peak area relative value: 1.23), and 3.7 to 4 instead. A peak appeared at 1 ppm (peak area relative value: 0.57). And other peaks did not shift.
In the case of “hydroxyethyl acrylate polymer (FIG. 3)”, the proton peak of the methylene adjacent to the hydroxyl group appeared at 3.6 to 3.8 ppm (peak area relative value: 2.00), but the reaction product with difluorophosphoric acid In the “monofluorophosphorylated hydroxyethyl acrylate polymer (FIG. 4)”, the peak of 3.6 to 3.8 ppm decreases (peak area relative value: 1.14), and instead of 4.1 to 4 A peak appeared at 3 ppm (peak area relative value: 0.81). And other peaks did not shift.
From this result, in the monofluorophosphorylated hydroxyethylacrylamide polymer obtained in Preparation Example a-2), the hydroxyl group of the hydroxyethylacrylamide polymer forms a covalent bond with monofluorophosphoric acid, and in Preparation Example d-2) In the obtained monofluorophosphorylated hydroxyethyl acrylate polymer, it was confirmed that the hydroxyl group of the hydroxyethyl acrylate polymer formed a covalent bond with monofluorophosphoric acid.

  With respect to the polymer compounds prepared above, the weight average molecular weight, fluorine introduction rate, and water-soluble evaluation results are summarized in Table 1 below.

[Examples and Comparative Examples]
Dentifrices and mouthwashes having the compositions shown in Tables 2 and 3 were prepared by the following methods and evaluated as follows.

Toothpaste preparation method:
A phase A was prepared by mixing and dissolving water-soluble components (water-soluble monofluorophosphorylated polymer compound, nonionic surfactant, amphoteric surfactant, pH adjuster, sodium saccharin, etc.) in purified water at room temperature. On the other hand, a B phase was prepared by dissolving and dispersing sodium polyacrylate, xanthan gum, sodium carboxymethyl cellulose and the like in propylene glycol at room temperature. Next, the B phase was added and mixed in the A phase under stirring to prepare the C phase.
Furthermore, using a small vacuum crusher (Ishiyama Kogakusho), phase C and sodium lauryl sulfate, fragrance, silicic acid anhydride, and other active ingredients (dextranase) are mixed at room temperature and decompressed to 4 kPa for removal. Foaming was performed to obtain 100 g of dentifrice (pH was in the range of 6 to 9).
Sodium lauryl sulfate is NIKKOL (registered trademark) SLS (manufactured by Nikko Chemicals Co., Ltd.), polyoxyethylene (average addition EO 20 mol) hydrogenated castor oil is NIKKOL (registered trademark) HCO-20 (manufactured by Nikko Chemicals Co., Ltd.) As the 30% aqueous solution of 2-coconut oil alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine sodium, Enazicol C-40H (manufactured by Lion Corporation) was used.

Mouthwash preparation method:
The mouthwash was prepared as follows.
A specified amount of purified water is put into a stainless steel container equipped with a three-one motor and a stirrer with rotating blades. Among the ingredients, water-soluble monofluorophosphorylated polymer compound, surfactant, pH adjuster, saccharin sodium, etc. A water-soluble component was added and dissolved while stirring to obtain Phase A. On the other hand, in a separate stainless steel container equipped with a three-one motor and a stirrer with rotating blades, a specified amount of organic solvent such as ethanol or glycerin is added, and oil-soluble components such as fragrances are added while stirring. And dissolved to obtain a phase B. Furthermore, B phase was added to A phase, and it stirred for 1 minute-30 minutes, and it was set as the uniform solution, and 100g of mouthwashes (pH is the range of 6-9) was obtained.
In addition, NIKKOL (registered trademark) HCO-60, manufactured by Nikko Chemicals Co., Ltd. was used as the polyoxyethylene (average added EO 60 mol) hydrogenated castor oil.

In addition, the chewing gum of the below-mentioned formulation example was manufactured by the conventional method as follows.
Chewing gum preparation method:
The gum base was heated to 80 to 90 ° C. and added to the mixing kettle in a dissolved state, and then a sweetener, surfactant, plasticizer, softener and the like were added and mixed. Further, the mixing kettle was cooled to 40 to 45 ° C., and a fragrance, a water-soluble monofluorophosphorylated polymer and the like were added and mixed until homogeneous to obtain 100 g of chewing gum.

Mucosal irritation suppression effect confirmation experiment:
The following in vitro test method was adopted as a method for evaluating mucosal irritation of the composition. Regarding this in vitro test method, it has been reported that the cytotoxicity of the test substance against rabbit cornea-derived cells (SIRC cells) correlates well with irritation to the skin and mucous membranes. Report of the first validation study on mucosal irritation test alternatives (1994). Details of the test method according to the above report are described below.

For the dentifrice, the dentifrice: pure water = 1: 2 dilution of each Example and Comparative Example was centrifuged at 3000 rpm for 20 minutes at room temperature, and the resulting supernatant was used as a test solution. For the mouthwash, the mouthwash: pure water = 10: 1 dilution of each Example and Comparative Example was used as the test solution. The dentifrice: pure water 1: 2 dilution and mouthwash: pure water 10: 1 dilution means that the dentifrice and mouthwash are diluted with saliva when brushing and using the mouthwash. Was assumed. Then, further dilute the test solution to 2 ^-1 , 2 ^-2 , 2 ^-3 , 2 ^-4 , 2 ^-5 , 2 ^-6 , 2 ^-7 , 2 ^-8 , 2 ^-9 , 2 ^-10 with distilled water Then, 100 μL of the diluted solution was applied to a 96-well microplate (manufactured by Sumitomo Bakelite Co., Ltd.). Thereafter, 100 μL of SIRC cell suspension (manufactured by Dainippon Sumitomo Pharma Co., Ltd.) was added and cultured at 37 ° C. for 72 hours. Thereafter, the culture solution was discarded, 100 μL of a 0.1 mass% neutral red aqueous solution was added, and the mixture was cultured at 37 ° C. for 3 hours in a CO ₂ incubator. After discarding the 0.1% by weight neutral red aqueous solution, 200 μL of a cell fixing solution (1% by weight formalin aqueous solution containing 1% by weight calcium chloride) was added and allowed to stand for 1 minute, and the fixing solution was discarded. Subsequently, 100 microliters of pigment | dye extract (50 mass% ethanol aqueous solution containing 1 mass% acetic acid) was added, and it stirred and incubated at room temperature for 20 minutes. Finally, the dye extract was discarded, and the absorbance at 550 nm was measured using a microplate reader (Model 550, manufactured by BIORAD). The absorbance of wells not containing the test substance was taken as 100%, and the dilution concentration (EC ₅₀ ) of the test substance showing 50% absorbance was determined and judged according to the following criteria. The determination was made with an average value of N = 2.

Criteria ◎: EC ₅₀ is 2 ⁻³ or more ○: EC ₅₀ is 2 ⁻⁶ or more and less than 2 ⁻³ Δ: EC ₅₀ is 2 ⁻⁹ or more and less than 2 ⁻⁶ ×: EC ₅₀ is less than 2 ⁻⁹

Evaluation of long-term enzyme reactivity of monofluorophosphorylated polymer compounds:
After preparing the preparations described in Examples and Comparative Examples by a conventional method, in the case of dentifrice, 10 g of artificial saliva (CaCl ₂ = 1.5 mmol / L, KH ₂ PO ₄ = 5.0 mmol / L, acetic acid) = 100 mmol / L, NaCl = 100 mmol / L; pH 7.0) and mixed (assuming a dentifrice diluted 3-fold in the oral cavity). After stirring, the mixture was centrifuged (3000 rpm, 10 minutes) with a centrifuge (Centifige 5804R, Hamburg, Germany), and the resulting supernatant was used as a treatment solution. In the case of a mouthwash, 0.5 g of artificial saliva was mixed with 5 g of the agent and stirred (assuming a mouthwash that is slightly diluted in the oral cavity) as a treatment liquid. 5 g of each treatment solution was injected into a 6-hole petri dish (manufactured by Nippon Becton Dickinson Co., Ltd.), and 6 mL of 1 mL phosphate buffer solution (pH 5) containing 5 units / mL acid phosphatase (from potato; Sigma) was added. Fluoride ions were released by injecting into a hole petri dish and shaking at 37 ° C. for 12 hours. By measuring the fluoride ion concentration in the phosphate buffer with an ion chromatograph (ICS-2000; Dionex), the enzyme reactivity (long-term release) with respect to the monofluorophosphorylated polymer was evaluated.
The enzyme reactivity was evaluated by calculating the monofluorophosphate group decomposition rate from the measured fluoride ion concentration after 12 hours from the following formula. The measurement was performed at N = 2, and the average value was used for the determination.

<Ion chromatograph measurement conditions>
Separation column: IonPac AS20,
Guard column: NG-1, Column temperature: 30 ° C
Detector temperature: 35 ° C., eluent: 55 mM potassium hydroxide,
Flow rate: 1.2 mL / min, introduction amount: 20 μL

<Criteria>
A: Decomposition rate of monofluorophosphate group after 12 hours of enzyme introduction is 40% or more and less than 80%, and enzyme reactivity is appropriate (exhibiting long-term fluoride ion release property)
○: Monofluorophosphoric acid group decomposition rate after 20 hours of enzyme input is 20% or more and less than 40%, or 80% or more and less than 90%, and is moderate enzyme reactivity ×: 12 hours after enzyme input Decomposition rate of monofluorophosphate group is 90% or more, enzyme reactivity is too high, enzyme reaction is not recognized for a long time, or less than 20%, enzyme reactivity is low

Evaluation of fluoride retention immediately after treatment (immediately after fluoride retention):
After preparing the preparations described in Examples and Comparative Examples by a conventional method, in the case of dentifrice, 10 g of artificial saliva (CaCl ₂ = 1.5 mmol / L, KH ₂ PO ₄ = 5.0 mmol / L, acetic acid) = 100 mmol / L, NaCl = 100 mmol / L, balance = water; pH 7.0) was mixed and stirred (assuming a dentifrice diluted 3-fold in the oral cavity). After stirring, the mixture was centrifuged (3000 rpm, 10 minutes) with a centrifuge (Centifige 5804R, Hamburg, Germany), and the resulting supernatant was used as a treatment solution. In the case of a mouthwash, 0.5 g of artificial saliva was mixed with 5 g of the agent and stirred (assuming a mouthwash that is slightly diluted in the oral cavity) as a treatment liquid. 5 g of each treatment solution is injected into a 100 mm diameter standard dish (Nippon Becton Dickinson Co., Ltd .; assuming oral environment such as oral mucosa, pellicle, etc.). The liquid was discarded and washed with 2 g of ultrapure water. In the case of a mouthwash, the treatment liquid was discarded after being held for 30 seconds, and washing was not performed.
After each treatment, 1 mL of phosphate buffer (pH 5) containing 5 units / mL of acid phosphatase (from potato; Sigma) was injected into the dish and shaken at 37 ° C. for 24 hours. Fluoride ions were released from the retained monofluorophosphorylated polymer. The fluoride ion concentration in the phosphate buffer was measured with an ion chromatograph (ICS-2000; Dionex). The measurement was performed at N = 2, and the average value was used for the determination.

<Ion chromatograph measurement conditions>
Separation column: IonPac AS20,
Guard column: NG-1, column temperature: 30 ° C, detector temperature: 35 ° C,
Eluent: 55 mM potassium hydroxide, flow rate: 1.2 mL / min, introduction volume: 20 μL

<Criteria>
◎: Fluoride ion concentration 0.5 ppm or more and less than 1.0 ppm ○: Fluoride ion concentration 0.2 ppm or more and less than 0.5 ppm Δ: Fluoride ion concentration 0.1 ppm or more and less than 0.2 ppm X: Fluoride ion Concentration is less than 0.1ppm

Evaluation of drug use:
Usability tests were conducted as follows.
Dentifrice;
The dentifrices of each Example and Comparative Example were each enclosed in a dentifrice laminate tube. Thereafter, using 5 subjects, the extrudability of the dentifrice was sensory-evaluated by using about 5 cm of the paste of the dentifrice contained in the tube on a fine paper. The judgment criteria are as follows, and an average value of 5 subjects was used.

Judgment criteria ◎: Can be extruded normally with moderate shape retention ○: Slightly hard or slightly soft, but can be extruded without pain ×: Extrusion is difficult, or if it is placed on a toothbrush

Mouthwash;
The mouthwash of each Example and Comparative Example was put into a PET bottle (500 mL) for mouthwash. Thereafter, using five test subjects, the usability of the bottle mouthwash was tilted about 100 degrees, and the sensory evaluation of the ease of pouring when the contents were poured into a 10 mL plastic cup was performed. The evaluation criteria are as follows, and an average value of 5 subjects was used.

Criteria ◎: Can be poured normally ○: Slightly time consuming, but can be poured without pain ×: Difficult to pour

  The above results are shown in Table 2 (dentifrice) and Table 3 (mouth wash). The overall criteria were as follows.

Overall criteria ◎: All evaluation items are ◎ ○: All evaluation items are ◎ or ○, and ○ is 1 item or more ×: Among all evaluation items, Δ or × is 2 items or more

  In Table 2, MFP-modified HEAA is monofluorophosphorylated hydroxyethylacrylamide polymer, MFP-modified HPC is monofluorophosphorylated hydroxypropylcellulose, MFP-modified PVA is monofluorophosphorylated polyvinyl alcohol, and MFP-modified HEA is monofluorophosphorylated poly Represents hydroxyethyl acrylate. In addition, about 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine which is a surfactant component, it is 30 of 2-coconut oil alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine sodium. % Aqueous solution was used, and the compounding amount in the table indicates the compounding amount in terms of pure content. A / B (mass ratio) indicates a blending ratio of water-soluble monofluorophosphorylated or non-monofluorophosphorylated polymer compound (A) / surfactant (B). Moreover, about 70% sorbit liquid, the compounding quantity with the figure was shown.

  In Table 3, MFP-modified HEAA is monofluorophosphorylated hydroxyethylacrylamide polymer, MFP-modified HPC is monofluorophosphorylated hydroxypropylcellulose, MFP-modified PVA is monofluorophosphorylated polyvinyl alcohol, and MFP-modified HEA is monofluorophosphorylated poly Represents hydroxyethyl acrylate. A / B (mass ratio) indicates a blending ratio of water-soluble monofluorophosphorylated or non-monofluorophosphorylated polymer compound (A) / surfactant (B). In addition, about 85% glycerin, the compounding quantity with the figure was shown.

  As shown in the above table, the water-soluble monofluorophosphorylated polymer compound (A) according to the present invention and the surfactant (B) have a mass ratio of (A) / (B) of 0.5 to 30. It was found that an oral composition excellent in usability and usability and excellent in fluoride retention in the oral cavity and long-term sustained release of fluoride ions was obtained.

  In addition to the above examples, other formulation examples of the composition of the present invention are shown below.

[Prescription Example 1] Dentifrice (pH 7.0)
Silica anhydride 10.0
Sodium monofluorophosphate hydroxyethylacrylamide polymer prepared in Preparation Example a-1) 1.5
Sodium lauryl sulfate 1.0
(NIKKOL SLS, manufactured by Nikko Chemicals Corporation)
Propylene glycol 3.0
Sodium alginate 0.6
85% glycerin 5.0
70% sorbite solution 30.0
Xylitol 5.0
Saccharin sodium 0.02
Fragrance 0.8
Purified water remaining
Total 100.0%

[Prescription Example 2] Dentifrice (pH 7.5)
Silicic anhydride 20.0
Sodium fluoride 0.1
Sodium monofluorophosphate hydroxypropylcellulose prepared in Preparation Example b-1) 3.0
Sodium lauryl sulfate 1.0
(NIKKOL SLS, manufactured by Nikko Chemicals Corporation)
Polyoxyethylene (average addition EO 20 mol) hydrogenated castor oil 0.25
(NIKKOL (registered trademark) HCO-20, manufactured by Nikko Chemicals Corporation)
Polyoxyethylene (average addition EO 5 mol) stearyl ether 0.25
(EMALEX 605, manufactured by Nippon Emulsion Co., Ltd.)
Propylene glycol 5.0
Sodium polyacrylate 0.85
70% sorbite solution 40.0
Saccharin sodium 0.02
Fragrance 0.8
Purified water remaining
Total 100.0%

[Prescription Example 3] Dentifrice (pH 7.0)
Sodium monofluorophosphate hydroxyethylacrylamide polymer prepared in Preparation Example a-2) 4.0
Sodium lauryl sulfate 0.5
(NIKKOL SLS, manufactured by Nikko Chemicals Corporation)
2-coconut oil alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine 30% aqueous solution (Enazicol C-40H, manufactured by Lion Corporation)
0.5
Propylene glycol 3.0
Carrageenan 0.7
Xanthan gum 0.6
85% glycerin 15.0
70% sorbite solution 20.0
Sodium hydroxide 0.5
Dextranase 0.3
Saccharin sodium 0.02
Fragrance 0.8
Purified water remaining
Total 100.0%

[Prescription Example 4] Dentifrice (pH 7.8)
Silicic anhydride 15.0
Sodium monofluorophosphate 0.3
Sodium monofluorophosphate hydroxypropylcellulose prepared in Preparation Example b-2) 5.0
Sodium lauryl sulfate 1.0
(NIKKOL SLS, manufactured by Nikko Chemicals Corporation)
Polyoxyethylene (average addition EO 20 mol) hydrogenated castor oil 0.5
(NIKKOL (registered trademark) HCO-20, manufactured by Nikko Chemicals Corporation)
Propylene glycol 10.0
Sodium polyacrylate 0.8
Xanthan gum 0.5
70% sorbite solution 20.0
Cetylpyridinium chloride 0.02
Xylitol 5.0
Isopropylmethylphenol 0.05
Fragrance 0.5
Purified water remaining
Total 100.0%

[Prescription Example 5] Dentifrice (pH 8.5)
Silicic anhydride 15.0
Sodium monofluorophosphate hydroxyethylacrylamide polymer prepared in Preparation Example a-3) 1.0
Sodium lauryl sulfate 0.5
(NIKKOL SLS, manufactured by Nikko Chemicals Corporation)
Polyoxyethylene (average addition EO 20 mol) hydrogenated castor oil 0.5
(NIKKOL (registered trademark) HCO-20, manufactured by Nikko Chemicals Corporation)
Propylene glycol 3.0
Carrageenan 0.7
Xanthan gum 0.6
85% glycerin 10.0
Xylitol 20.0
Sodium hydroxide 0.5
Saccharin sodium 0.02
Fragrance 0.8
Purified water remaining
Total 100.0%

[Prescription Example 6] Dentifrice (pH 7.0)
Sodium monofluorophosphate hydroxypropylcellulose prepared in Preparation Example b-3) 0.5
Sodium lauryl sulfate 0.5
(NIKKOL SLS, manufactured by Nikko Chemicals Corporation)
2-coconut oil alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine 30% aqueous solution (Enazicol C-40H, manufactured by Lion Corporation)
0.3
Propylene glycol 3.0
Carrageenan 0.7
Xanthan gum 0.6
85% glycerin 15.0
70% sorbite solution 20.0
Sodium hydroxide 0.5
Dextranase 0.3
Saccharin sodium 0.02
Fragrance 0.8
Purified water remaining
Total 100.0%

[Prescription Example 7] Mouthwash (pH 7.0)
Sodium monofluorophosphate hydroxypropylcellulose prepared in Preparation Example b-2) 0.5
Polyoxyethylene (average addition EO 50 mol) hydrogenated castor oil 1.0
(EMALEX HC-50, manufactured by Nippon Emulsion Co., Ltd.)
Citric acid 0.01
Trisodium citrate 0.3
Benzalkonium chloride 0.01
Saccharin sodium 0.1
Xylitol 3.0
85% glycerin 5.0
Ethanol 3.0
0.1% green No.3 0.8
Fragrance 0.3
Purified water remaining
Total 100.0%

[Prescription Example 8] Mouthwash (pH 7.5)
Sodium monofluorophosphate hydroxyethylacrylamide polymer prepared in Preparation Example a-1) 1.0
Polyoxyethylene (average addition EO 60 mol) hydrogenated castor oil 0.3
(NIKKOL (registered trademark) HCO-60, manufactured by Nikko Chemicals Corporation)
Citric acid 0.01
Trisodium citrate 0.3
Sodium fluoride 0.05
Saccharin sodium 0.1
Xylitol 5.0
Propylene glycol 5.0
0.1% green No.3 0.8
Fragrance 0.3
Purified water remaining
Total 100.0%

[Formulation Example 9] Sodium monofluorophosphate hydroxyethylacrylamide polymer prepared in Chewing Gum Preparation Example a-2) 0.3
Polyoxyethylene (average addition EO 80 mol) hydrogenated castor oil 0.5
(BLAUNON RCW-80, Aoki Yushi Kogyo Co., Ltd.)
Gum base material 25.0
Sorbitol powder 30.0
Mannitol powder 15.0
Maltitol powder 10.0
Fragrance 1.5
Glycerin 3.5
Saccharin 0.1
Purified water remaining
Total 100.0%

^{1 is} a ¹ H-NMR spectrum chart of a hydroxyethylacrylamide polymer obtained in Preparation Example a-8). Preparation a-2) is a ¹ H-NMR spectrum chart of the sodium monofluorophosphate hydroxyethyl acrylamide polymer obtained in. Preparation Example d-2) is a ¹ H-NMR spectrum chart of monofluorophosphate before introduction of hydroxyethyl acrylate polymer obtained in. It is a ¹ H-NMR spectrum chart of monofluorophosphate sodium-ized hydroxyethyl acrylate polymer obtained in Preparation Example d-2).

Claims (2)

  Weight average molecular weight of 5,000 of at least one polymer selected from hydroxyethyl (meth) acrylamide polymer, hydroxypropyl cellulose, polyvinyl alcohol, and polyhydroxyethyl (meth) acrylate, in which monofluorophosphoric acid is covalently bonded in the polymer molecule. ~ 500,000 water-soluble monofluorophosphorylated polymer compound (A) and at least one surfactant (B) selected from anionic surfactants, nonionic surfactants and amphoteric surfactants; Is formulated with a mass ratio of (A) / (B) of 0.5 to 30.   Surfactants include sodium oleate, potassium stearate, sodium lauryl sulfate, sucrose stearate, decaglyceryl monomyristate, polyoxyethylene stearyl ether, polyoxyethylene hydrogenated castor oil, and 2-alkyl-N-carboxyl The oral composition according to claim 1, wherein the composition is at least one selected from methyl-N-hydroxyethylimidazolinium betaine.

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