JP2003342140A - Bacteria adsorption inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a bacteria adsorption inhibitor capable of effectively inhibiting the adsorption of bacteria to teeth surface, and to provide a composition for oral cavity containing the inhibitor. <P>SOLUTION: The bacteria adsorption inhibitor comprises a hydrophilic polymer bearing on one end thereof a residue resulted by eliminating one hydrogen atom from at least one phosphorus-based acid selected from phosphoric acid, polyphosphoric acid, phosphonic acid, polyphosphonic acid, phosphinic acid and partial esters thereof and salts thereof. The composition for oral cavity comprises the inhibitor and water and/or a 1-5C lower alcohol. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bacterial adsorption inhibitor useful for an oral care agent, which effectively inhibits the adsorption of bacteria on the tooth surface, and an oral composition containing the same.

[0002]

2. Description of the Related Art It is a known fact that dental plaque is a cause of periodontal disease and tooth decay, and plaque that is difficult to remove if the dental plaque is left unattended ( Change to crystalline calcium). The formation of plaque begins when proteins in saliva are adsorbed on the tooth surface, a film called a pellicle is formed, and bacteria are adsorbed to the pellicle. Therefore, agents that inhibit the adsorption of bacteria and microorganisms have been conventionally proposed.

For example, JP-A-9-175965 discloses a homopolymer of dimethyldiallylammonium chloride and at least 1 part of dimethyldiallylammonium chloride.
Disclosed is that a composition comprising a polymer selected from copolymers with a polymerizable monomer having a certain ethylenically unsaturated hydrocarbon bond and a betaine-type surfactant is effective in suppressing adhesion of microorganisms to tooth surfaces. However, this composition does not have a sufficient effect of inhibiting the adsorption of bacteria.

Further, JP-A-57-135817 discloses a water-soluble copolymer composed of a unit having a molecular arrangement of units derived from vinylphosphonic acid and a unit derived from vinylphosphonyl fluoride. It is disclosed that bacteria can be prevented from adsorbing to the hydroxyapatite beads coated with saliva, but the effect is not yet sufficient.

An object of the present invention is to provide a bacterial adsorption inhibitor capable of inhibiting the adsorption of bacteria on the tooth surface more effectively, and an oral composition containing the same.

[0006]

According to the present invention, one or more phosphorus compounds selected from phosphoric acid, polyphosphoric acid, phosphonic acid, polyphosphonic acid, phosphinic acid and partial esters thereof and salts thereof are attached to one end of a hydrophilic polymer. Adsorption inhibitor consisting of a hydrophilic polymer having a residue obtained by removing one hydrogen atom from a system acid (hereinafter referred to as phosphorus acid residue), and the bacterial adsorption inhibitor, and water and / or carbon number It relates to an oral composition containing 1 to 5 lower alcohols.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION [Hydrophilic Polymer] In the present invention, a polymer is hydrophilic in that it means an organic conceptual diagram-basic and applied- (Yoshio Koda, Sankyo Publishing Co., Ltd., 1984).
In the first edition, issued on the 10th of October, the ratio of inorganic (I) and organic (O) of the monomers constituting the polymer [I /
O] is 0.6 or more, preferably 1.0 or more, and more preferably 1.5 or more.

As the hydrophilic polymer, the following (i) to (xii)
Polymers and the like having a structural unit selected from the monomer group of are preferable.

(I) (meth) acrylamide, (ii) alkyl such as N-methyl (meth) acrylamide, N-ethyl (meth) acrylamide, Nn-propyl (meth) acrylamide, N-isopropyl (meth) acrylamide, etc. (C1-C3) (meth) acrylamide, (iii)
Having a dialkyl (total carbon number of 2 to 8) (meth) acrylamide such as N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, and (iv) hydroxyalkyl (having 1 to 3 carbon atoms) groups Monomers having sulfonic acid groups such as (meth) acrylic acid ester or (meth) acrylamide, (v) (meth) acrylic acid and salts thereof, (vi) styrenesulfonic acid, acrylamidopropanesulfonic acid (AMPS), and methacrylsulfonic acid. Or a salt thereof, (vii) ethylene-based amines, amine monomers such as allylamine, (viii) alkylene oxides such as ethylene oxide and propylene oxide, (ix) vinyl alcohol, monomers having a hydroxy group such as allyl alcohol, (x) vinyl Pyrrolidone, (xi) epichlorohydrin,
(xii) Glycidyl ether and its alkyl (1 carbon atom
~ 3) Ether and the like can be mentioned. Examples of the salt include ammonium salts, alkali metal salts, alkaline earth metal salts and the like.

The hydrophilic polymer may be copolymerized with the above-mentioned monomer and other monomer which is copolymerizable,
In order to maintain hydrophilicity, the ratio of the constituent units consisting of the monomer groups (i) to (xii) is 70 to 10 in the hydrophilic polymer.
0 mass% is preferable, 80-100 mass% is still more preferable, 90-100 mass% is especially preferable, 100 mass%
Is most preferred.

Particularly among these, poly (meth) acrylamide, poly (meth) acrylic acid and salts thereof, polyethyleneimine, polyallylamine, polyoxyalkylene, polyvinyl alcohol, polyvinylpyrrolidone, polyepichlorohydrin, polyglycidyl ether. And homopolymers of its alkyl (C1 to C3) ethers and the like are preferable, and polyoxyalkylene is more preferable because the production method is easy. The polyoxyalkylene is preferably polyoxyethylene, polyoxypropylene, or a random or block copolymer thereof, and more preferably polyoxyethylene.

[Phosphoric acid residue] As the phosphorus acid residue,
Phosphoric acid residue (1), phosphoric acid monoester residue (2), diphosphoric acid residue (3), diphosphoric acid monoester residue (4), as described in WO98 / 26749. Phosphate group or diphosphate group having at least one hydroxyl group such as diphosphoric acid diester residue (5) or a salt thereof; phosphonic acid residue (6), phosphonic acid monoester residue (7), diphosphonic acid residue (8), a phosphonate group having at least one hydroxyl group such as a diphosphonic acid monoester residue (9) or a diphosphonate group or a salt thereof; a phosphinic acid residue (phosphinate group) (10) or a salt thereof, etc. Can be mentioned. Among the groups represented by the above (1) to (10), (1) to (5) or salts thereof are more preferable from the viewpoint of availability and safety, and phosphoric acid residue (1) or salts thereof. Is particularly preferable. It may be a halide in which one or more of the hydroxyl groups in the phosphorus acid residue are substituted with a chlorine atom, a bromine atom, a fluorine atom or the like. The ester has 1 to 22 carbon atoms.
The linear or branched alkyl ester or alkenyl ester of is preferable. Examples of the salt include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts, ammonium salts, alkanol ammonium salts (eg, monoethanol ammonium salt, diethanol ammonium salt, etc.), and the like. preferable.

[Hydrophilic Polymer Having Phosphoric Acid Residue at One Terminal] In the present invention, the hydrophilic polymer having a phosphorus acid residue at one terminal is preferably a hydrophilic polymer represented by the following general formula (I). Is.

[0014]

[Chemical 1]

[In the formula, R ¹ represents a linear or branched alkyl group or alkenyl group having 1 to 22 carbon atoms. R
² and R ³ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, and n R ² and n R ³ may be the same or different. good. n shows the number of 2-200. X is the formula (II) or (III)

[0016]

[Chemical 2]

(M ¹ and M ² are the same or different and each is a hydrogen atom, a metal, ammonium, an alkyl or alkenyl ammonium having 1 to 22 carbon atoms, an alkyl or alkenyl-substituted pyridinium having 1 to 22 carbon atoms, and a total carbon number. 1 to 22 represents an alkanol ammonium or a basic amino acid, and R ⁴ represents a phosphoric acid residue represented by a C 1 to C 22 linear or branched alkyl group or alkenyl group.). ] In the general formula (I), R ¹ preferably has 1 to 5 carbon atoms.
Is a linear or branched alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group or an i-propyl group, and particularly preferably a methyl group. R ² and R ³ are the same or different and are preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom. n is preferably 20 to 200,
40-120 is more preferable. M ¹ and M ² are the same or different and are preferably a hydrogen atom or an alkali metal such as sodium or potassium. R ⁴ preferably has 1 carbon atom
To 5 linear or branched alkyl groups, more preferably a methyl group, an ethyl group, an n-propyl group or an i-propyl group.

The molecular weight of the hydrophilic polymer having a phosphoric acid residue at one end of the present invention is preferably 1,000 to 20,000, and preferably 1,000 to 10 in terms of weight average molecular weight according to the measuring method described later. 1,000 is more preferred. Within this range, the effect of inhibiting the adsorption of bacteria is high, the viscosity of the aqueous solution is moderate, and it is easy to handle.

In this specification, the molecular weight is a value measured by the following method.

<Molecular Weight Measuring Method> Using gel permeation chromatography (GPC), the weight average molecular weight was determined under the following conditions.・ Condition column: G4000PWXL + G2500PWXL (manufactured by Tosoh Corporation) Eluent: 0.2M phosphoric acid aqueous solution / acetonitrile = 9 /
1 Detection: RI Flow rate: 1 mL / min Column temperature: 40 ° C. Reduced molecular weight: Polyethylene glycol.

[Synthesis Method of Hydrophilic Polymer Having Phosphoric Acid Residue at One Terminal] The synthesis method of the polymer of the present invention is not particularly limited, and a known method can be selected. Among these, a method of introducing a predetermined phosphorus acid residue into the hydroxyl group at the terminal of the polyoxyalkylene chain having one end protected by an alkyl group is preferable.

To introduce the phosphorus acid residue, phosphoric acid, polyphosphoric acid, phosphorylating agents such as phosphorus oxychloride and the like are used, but phosphorus oxychloride is preferably used. The solvent to be used is not limited as long as it is an inert solvent in which the polyoxyalkylene having one end protected by an alkyl group and the phosphorylating agent are dissolved, and tetrahydrofuran, chloroform, methylene chloride, diethyl ether, dimethoxyethane are used. preferable. Alternatively, the reaction may be performed without a solvent.

The amount of the phosphorylating agent used is preferably 1.0 to 1.2 equivalents with respect to the hydroxyl group of the polyoxyalkylene whose one end is protected by an alkyl group because it suppresses side reactions.

As an agent for trapping the generated hydrochloric acid gas, an organic tertiary amine such as triethylamine, tripropylamine, tributylamine, pyridine or picoline,
Metal hydroxides such as sodium hydroxide and potassium hydroxide,
Alternatively, metal salts such as sodium perchlorate, potassium perchlorate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydrogen phosphate, sodium acetate, sodium citrate, sodium glutamate, sodium succinate, and sodium dichloroacetate may be used. Is preferred. The amount of the trapping agent used is preferably 1.0 to 1.1 equivalents with respect to the phosphorylating agent used. The temperature for phosphorylation is preferably −30 ° C. to 5 ° C. in terms of reactivity and suppression of side reactions.

[Bacterial Adsorption Inhibitor] The bacterial adsorption inhibitory property of the bacterial adsorption inhibitor of the present invention comprising a hydrophilic polymer having a phosphorus acid residue at one end is the bacterial adsorption inhibition value defined by the following formula (IV). Indicated by.

Bacterial adsorption inhibition value = [(AX) / (AB)] × 100 (IV) [wherein A is saliva in a labeled bacterial fluid not containing the bacterial adsorption inhibitor of the present invention. The number of bacteria (× 10 ⁷ cells / cm ² ) attached to the treated hydroxyapatite plate is shown as B
Indicates the number of bacteria (× 10 ⁷ cells / cm ² ) attached to the hydroxyapatite plate not subjected to saliva treatment in the labeled bacterial liquid containing no bacterial adsorption inhibitor of the present invention, and X is 0.5% by mass. 3 shows the number of bacteria (× 10 ⁷ cells / cm ² ) attached to the saliva-treated hydroxyapatite plate in the labeled bacterial solution containing the bacterial adsorption inhibitor of the present invention. ] That is, in the labeled bacterial liquid not containing the bacterial adsorption inhibitor of the present invention, the number of bacteria (A) attached to the saliva-treated hydroxyapatite plate and the labeled bacterial liquid not containing the bacterial adsorption inhibitor of the present invention , The difference from the number of bacteria (B) adhering to the hydroxyapatite plate that has not been treated with saliva is the standard value (1
00), the difference in the number of bacteria (X) attached to the saliva-treated hydroxyapatite plate in the labeled bacterial solution containing (A) and 0.5% by mass of the bacterial adsorption inhibitor of the present invention,
The quantified value as shown in formula (IV) was used as the bacterial adsorption inhibition value.

The bacterial adsorption inhibitor of the present invention preferably has a bacterial adsorption inhibition value of 10 or more, more preferably 15 or more.

[Oral Composition] The oral composition of the present invention contains the bacterial adsorption inhibitor of the present invention and water and / or a lower alcohol. Here, the lower alcohol is preferably a linear or branched saturated alcohol having 1 to 5 carbon atoms, more preferably ethanol or isopropyl alcohol, and particularly preferably ethanol. It is also possible to use a combination of two or more selected from water and lower alcohols.

The content of the bacterial adsorption inhibitor according to the present invention in the oral composition of the present invention is preferably 0.05 to 20% by mass, more preferably 0.1 to 5% by mass. Water and /
Alternatively, the content of the lower alcohol is preferably 0.1 to 99.9% by mass, more preferably 5 to 80% by mass.

In the oral composition of the present invention, it is preferable that 0.1 to 5% by mass, particularly 0.01 to 1% by mass, of a bactericide be added to the entire composition from the viewpoint of inhibiting plaque. Examples of such bactericides include benzethonium chloride, chlorhexidine hydrochloride, triclosan, cetylpyridinium chloride, isopropylmethylphenol, decalinium chloride and alkyldiaminoethylglycine hydrochloride.

The oral composition of the present invention further comprises components usually used in oral compositions such as surfactants, abrasives, sweeteners such as oligosaccharides or sugar alcohols, fragrances, preservatives, and whitening agents. Wetting agents, binders and the like can be appropriately added within a range that does not impair the effects of the present invention. In addition, it is also preferable to contain a medicinal agent such as a blood circulation promoter, an anti-inflammatory agent, a hemostatic agent, an analgesic agent, an antihistamine, and a plant extract having these actions. Examples of blood circulation promoters include vitamin E, dl-α-tocopherol nicotinate, sodium chloride and the like; examples of anti-inflammatory agents include allantoin, β-glycyrrhetinic acid, glycyrrhizic acid, epidihydrocholesterin, dihydrocholesterol, ε-aminocaproic acid, hinokitiol, lysozyme chloride, indomethacin, ibuprofen and the like; hemostatics such as tranexamic acid, thrombin, ascorbic acid, rutin and the like; analgesics such as aspirin, acetaminophen, Methyl salicylate and the like; antihistamines, such as cimetidine, chlorpheniramine maleate, diphenhydramine hydrochloride, promethazine hydrochloride, and the like; plant extracts, such as fennel extract, urine extract N'ekisu, Scutellaria root extract, Hypericum extract, Kamomiraekisu, kumazasa extract, mint extract, sage extract, clove extract, ginseng extract, witch hazel extract, bladderwrack extract, horse chestnut extract, peach leaf extract, rosemary extract, eucalyptus extract, and the like. One or more medicinal agents can be used, and it is preferable to add 0.01 to 5% by mass, particularly 0.1 to 1% by mass in the total composition.

The oral composition of the present invention is produced by a conventional method. Further, it can be applied to the oral cavity by a usual method, and the gum can be massaged using the same.

The oral composition of the present invention can be used in a dosage form such as toothpaste, powder toothpaste, water toothpaste, mouthwash, tooth coating agent and chewing gum. Particularly, toothpaste is preferable.

[0034]

EXAMPLES In the examples,% means mass% unless otherwise specified.

Synthesis Example 1 (Synthesis of Polymer 1) A 200 ml two-necked eggplant-shaped flask was equipped with a cooling tube, a nitrogen introducing tube and a stirring blade, and 20.0 g (4 mmo of polyethylene glycol monomethyl ether (made by Aldrich, average molecular weight 5000))
l), acetonitrile 20 ml, triethylamine 0.44 g (4.4
mmol) was added. With stirring, the atmosphere was replaced with nitrogen and then cooled with ice.
0.67 g (4.4 mmol) of phosphorus oxychloride was added all at once, and at 0 ° C
Stir for 5 hours. After filtration, the filtrate contains 70 g of acetonitrile.
Then, 10 g of ion-exchanged water was added and the mixture was stirred at room temperature overnight. After concentrating, it was washed with ethyl acetate and dried to obtain 16 g of a colorless solid.

The obtained product was treated with 10% heavy aqueous solution as ¹ H
As a result of NMR measurement, the results shown in FIG. 1 were obtained. The proton of the methyl group bonded to the end of the polyoxyethylene chain was found at δ = 3.3 ppm, and the polyoxyethylene chain was found at δ = 3.4 to 3.6 ppm. The proton of methylene was confirmed. Also, P
-When NMR measurement was performed, the results shown in FIG. 2 were obtained, and the triplet derived from -0.2 ppm of phosphate ester was confirmed,
The compound is a phosphoric acid monoester of polyethylene glycol monomethyl ether [in the formula (I), R ¹ ═CH ₃ ,
R ² = R ³ = H, n = 113, and X is a group represented by the formula (II), and M ¹ = M ² = H. From NMR, the purity is 87% for polymer, 5% for phosphoric acid,
Water was 2%. The weight average molecular weight was 5,500 by gel permeation chromatography (GPC: polyethylene glycol conversion).

Example 1 Polymer 1 synthesized in Synthesis Example 1 and the comparative polymers shown in Table 1 were used as a bacterial adsorption inhibitor, and the bacterial adsorption inhibitory property was evaluated by the following method.

<Evaluation Method for Bacterial Adsorption Inhibition> 10 μCi / mL methylated [ ³ H] -thymidine 0.2% glucose-containing Brain Heart Infusion Medium (DIFCO) 10 mL of S. mutans preserved cells isolated from human oral cavity Inoculate and then at 37 ℃ for 2
Anaerobic culture was carried out for 4 hours. Buffered KCl solution (50 mM KCl, 1 mM CaC
l ₂ and 1 mM phosphate buffer containing 0.1 mM MgCl ₂ ) and then washed 3 times with 5 mg / mL bovine serum albumin containing buffered KCl solution
It was dispersed at a concentration of × 10 ⁹ CFU / mL to prepare a ³ H-labeled S. mutans solution.

Asahi Optical Co., Ltd. hydroxyapatite (HA
p) A plate 1 cm × 1 cm × 2 mm was treated with 1 mL of a 0.5% aqueous solution of a bacterial adsorption inhibitor at 37 ° C. for 1 hour. After washing twice with 2 mL of buffered KCl solution, parotid saliva 1 collected from 7 healthy male subjects
Treated in mL at 4 ° C. for 24 hours. After washing 3 times with 2 mL of buffered KCl solution, buffered KCl solution containing 5 mg / mL bovine serum albumin
Add 0.5 mL and 0.5 mL of the ³ H-labeled S. mutans solution at 37 ° C for 1
Time processed. After washing 3 times with buffered KCl solution, the HAp plate was
Treated in 1 mL of NaOH for 1 hour. After neutralization with 1 mL of 2N HCl, ³ H radioactivity was measured with a liquid scintillation counter, and the number of adsorbed bacteria was calculated. Define this value as X,
The results are shown in Table 1.

In the above experiment, the number of bacteria adsorbed when the same treatment was carried out using 1 mL of a buffered KCl solution instead of the 0.5% aqueous solution of the bacteria adsorption inhibitor was defined as A. A = 5.67
(× 10 ⁷ cells / cm ² ).

After washing the HAp plate twice with 2 mL of buffered KCl solution,
5 mg / mL bovine serum albumin-containing buffered KCl solution 0.5 mL,
0.5 mL of the ³ H-labeled S. mutans solution was added, and the mixture was treated at 37 ° C for 1 hour. After washing 3 times with buffered KCl solution, the HAp plate was washed with 2N NaOH.
Treated in 1 mL for 1 hour. After neutralization with 1 mL of 2N HCl, ³ H radioactivity was measured with a liquid scintillation counter to give the number of adsorbed bacteria. This value is defined as B. B =
It was 0.33 (× 10 ⁷ cells / cm ² ).

From the values of A, B and X, the bacterial adsorption inhibition value defined by the above formula (IV) was determined. The results are shown in Table 1.

[0043]

[Table 1]

Prescription example 1: Toothpaste A toothpaste was produced according to a conventional method according to the following formulation.

Polymer 1 5.0% Silica 30.0% Sorbitol 30.0% Sodium lauryl sulfate 1.0% Carboxymethylcellulose ^{* 1} 1.0% Saccharin 0.1% Benzethonium chloride 0.5% Perfume 0.3% Water 32.1% Total 100% * 1: Carboxymethyl cellulose (Brand name Sunrose F
20-HC, manufactured by Nippon Paper Industries Co., Ltd.

Prescription example 2: mouthwash A mouthwash was manufactured by the following method according to a conventional method.

Polymer 1 5.0% Ethanol 20.0% Sodium Pyrophosphate 2.0% Saccharin 0.1% Chlorhexidine Hydrochloride 0.3% Perfume 0.3% Water 72.3% Total 100%

[0048]

INDUSTRIAL APPLICABILITY The bacterial adsorption inhibitor of the present invention has an effective bacterial adsorption inhibiting effect.

[Brief description of drawings]

FIG. 1 ¹ H-NM of polymer 1 synthesized in Synthesis Example 1
It is an R spectrum.

FIG. 2 P-NMR of Polymer 1 synthesized in Synthesis Example 1
It is a spectrum.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C083 AB011 AB012 AB051 AB172                       AB281 AB282 AC101 AC102                       AC132 AC692 AC782 AC862                       AD011 AD041 AD042 AD272                       CC41 DD22 DD23 DD27 EE32                       EE33

Claims (4)

[Claims] 1. A hydrogen atom from one or more phosphorus-based acids selected from phosphoric acid, polyphosphoric acid, phosphonic acid, polyphosphonic acid, phosphinic acid and partial esters thereof, and salts thereof at one end of the hydrophilic polymer. A bacterial adsorption inhibitor consisting of a hydrophilic polymer having a residue except one (hereinafter referred to as a phosphoric acid residue). 2. The bacterial adsorption inhibitor according to claim 1, wherein the hydrophilic polymer is a polymer containing an oxyalkylene group as a constituent unit. 3. The bacterial adsorption inhibitor according to claim 2, wherein the oxyalkylene group is an oxyethylene group and / or an oxypropylene group. 4. An oral composition containing the bacterial adsorption inhibitor according to any one of claims 1 to 3 and water and / or a lower alcohol having 1 to 5 carbon atoms.