JP5657201B2 - Dental composition having enzyme inhibitory action or enzyme inhibitory action and antibacterial action - Google Patents

Description

  The present invention relates to a dental composition. More specifically, the present invention relates to a dental composition suitable for a dental coating material, a dental adhesive, a dental root canal filling material, a dental composite resin, and the like applied to oral tissues.

  Collagen is a biomolecule that occupies about 30% of the total protein present in the living body, and is a main component constituting soft tissues such as skin, mucous membrane, and muscle. Collagen is also one of the elements necessary for inducing calcification of bone and dental hard tissues. In particular, in the dentin or cementum of bone and teeth, the ratio is about 20 to 30%. It is an occupying component.

  By the way, various enzymes exist in the living body. In particular, in the oral cavity, there are various enzymes produced by various oral microorganisms as well as enzymes derived from the human body. Among them, the peptide bond hydrolase belonging to EC3.4 is an enzyme that degrades collagen.

  Previous studies have revealed that collagen and other dental organic components present in dentin are degraded by the action of matrix metalloproteinase, one of the peptide bond hydrolases present in the oral cavity. It has become. As a result, it has been suggested that after the treatment of periodontal disease and caries, the risk of the occurrence of secondary caries and the accompanying prosthesis dropout increases.

  For example, periodontal disease which is one of oral diseases is an enzyme such as matrix metalloproteinase produced by periodontopathic bacteria such as Porphyromonas gingivalis present in the oral cavity, other proteins or compounds such as biogenic amines, It is a disease in which tissue destruction is caused indirectly by activating the immune system directly or in the body, resulting in softening of periodontal tissue and regression of alveolar bone.

  In general, soft tissues in the oral cavity are in an environment where bacterial colonization is difficult due to saliva secretion or cell cycle. However, it can be said that the boundary between the tooth and the gingival tissue such as the periodontal pocket has a low saliva buffering action and is structurally susceptible to colonization of bacteria. Periodontal disease mainly develops due to the influence of periodontopathic bacteria grown in this periodontal pocket.

  On the other hand, carious pathogenic bacteria represented by mutans bacteria adhere to the tooth surface by the adherent protein antigen present on the tooth surface, and produce insoluble glucan by sucrose (sucrose). This insoluble glucan prevents the diffusion of organic acids such as lactic acid produced in the plaque and avoids the buffering action of saliva. Therefore, when the plaque becomes below a certain pH, the tooth is decalcified and caries.

  In the case of dentine caries, after removing the carious site, a resin-impregnated layer, which is an artificial enamel, is formed from the collagen fibers present in the dentin and the resin contained in the dental material. The body is protected by bonding.

  For this reason, collagen fibers are decomposed after caries treatment, the artificial enamel is weakened, and the sealing property between the living body and the prosthesis is lowered, so that bacteria enter again through such gaps and secondary caries are caused. May occur.

According to Patent Document 1, matrix metalloproteinases are associated with rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermis and gastric ulcers; It has been implicated in many diseases that result from the destruction of connective tissue in vivo, such as neointimal proliferation leading to bloody heart failure; as well as tumor metastasis. Patent Document 1 describes that isophthalic acid derivatives are effective in treating these diseases by inhibiting matrix metalloproteinases. Specifically, isophthalic acid derivatives are used for dental applications. Is not specified.

Patent Document 2 discloses a composition for oral cavity having a broad antibacterial activity by combining chlorhexidine and other antibacterial agents. However, the oral composition does not have a useful enzyme inhibitory action.
JP 2005-503327 A JP-A-6-239723

  The object of the present invention is to (1) inhibit the decomposition of dental organic components by degrading enzymes and, in addition, inhibit the growth of bacteria, thereby exhibiting a preventive effect on periodontal disease and caries, and (2 ) To provide a dental composition capable of preserving teeth for a long period of time.

  From the above-mentioned knowledge of the prior art, for preventing periodontal disease or caries, collagen degradation enzyme around periodontal tissue or around alveolar bone is inhibited, collagen degradation is suppressed, periodontal pathogenic bacteria and caries are It is considered effective to suppress the growth of pathogenic bacteria.

  In addition, inhibition of such collagenolytic enzymes and suppression of bacterial growth also leads to suppression of weakening of artificial enamel such as a resin-impregnated layer after caries treatment. It is thought that preservation of tooth buds becomes possible.

  The present inventors have intensively studied to solve the above problems under the above-mentioned idea. As a result, by using enzyme inhibitors, it is possible to suppress the degradation of tooth organic components by degrading enzymes, and to prevent periodontal disease and caries, and to inhibit the long-term preservation of dental buds after treatment It has been found that a dental composition is provided.

  In addition, by using both an enzyme inhibitor and an antibacterial agent, it is possible to suppress the degradation of the organic components of the tooth by degrading enzymes, and in addition, it can suppress the growth of bacteria, and more effectively prevent periodontal disease and caries. It has been found that a dental composition having an enzyme inhibitory action and an antibacterial action capable of being preserved and capable of preserving tooth germs for a long time after treatment is provided.

That is, the present invention relates to the following [1] to [15].
[1] A dental composition comprising an enzyme inhibitor (A).
[2] The dental composition according to [1], wherein the enzyme inhibitor (A) is an enzyme inhibitor that inhibits a peptide bond hydrolase belonging to EC 3.4.

[3] The dental composition according to any one of [1] to [2], wherein the enzyme inhibitor (A) is an enzyme inhibitor that inhibits matrix metalloproteinase.
[4] The dental composition according to any one of [1] to [3], wherein the enzyme inhibitor (A) is an enzyme inhibitor (A1) having an acidic group.

  [5] The enzyme inhibitor (A) is at least one selected from a compound represented by the following general formula (1), a salt of the compound (1), and an acid anhydride of the compound (1) The dental composition according to any one of [1] to [3], which is a compound.

Wherein (1), X _1, X ₂ and X ₃ are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, trifluoromethyl, (meth) may have an acrylate group C ₁ ~ C ₆ alkyl, C ₁ -C ₆ alkoxy which may have a (meth) acrylate group, C ₂ -C ₆ alkenyl which may have a (meth) acrylate group, or a (meth) acrylate group Good C ₂ -C ₆ alkynyl, or NX ₄ X ₅
[X ₄ and X ₅ are each independently hydrogen or a (meth) acrylate group C _1-
C ₆ -alkyl, C ₂ -C ₆ alkenyl optionally having a (meth) acrylate group, C ₂ -C ₆ alkynyl optionally having a (meth) acrylate group, having a (meth) acrylate group Good C ₆ aryl, C ₃ -C ₆ cycloalkyl optionally having a (meth) acrylate group, 3-8 membered heteroaryl optionally having a (meth) acrylate group. X ₄ and X ₅ may combine to form a 3- to 8-membered heterocycle having at least one heteroatom selected from O, S and N as a ring atom. ];
E ₁ and E ₂ are each independently O or S;
A and B are each independently OX ₄ (where X ₄ has the same meaning as X ₄ above) or NX ₄ X ₅ (where X ₄ and X ₅ are the same as X ₄ and X ₅ above, respectively). Is.) ]
[6] The enzyme inhibitor (A) is at least one compound selected from an isophthalic acid derivative, a salt of the isophthalic acid derivative, and an acid anhydride of the isophthalic acid derivative. The dental composition according to any one of 1] to [3].

[7] The dental composition according to any one of [1] to [6], further comprising an antibacterial agent (B).
[8] The above-mentioned [7], wherein at least a part of the antibacterial agent (B) is at least one antibacterial agent selected from disinfectants and chemotherapeutic agents having a phenol coefficient of 0.001 to 300. The dental composition according to 1.

[9] The dental composition according to [7], wherein the antibacterial agent (B) is at least one antibacterial agent selected from chlorhexidines and salts thereof.
[10] The dental composition according to any one of [1] to [9], further comprising a polymerizable monomer (C) and a polymerization initiator (D).

[11] The dental composition according to [10], further comprising a filler (E).
[12] Any one of the above [1] to [11], which is used for a dental coating agent applied to an oral tissue selected from oral mucosa, periodontal tissue, alveolar bone and teeth. The dental composition as described.

[13] The dental composition according to any one of [1] to [11], which is used for a dental adhesive.
[14] The dental composition according to any one of [1] to [11], which is used for a dental root canal filling material.

  [15] The dental composition according to any one of [1] to [11], which is used for a dental composite resin.

  By using the dental composition containing the enzyme inhibitor according to the present invention, it is possible to inhibit peptide bond hydrolases such as matrix metalloproteinases, prevent periodontal disease and secondary caries after treatment, Long-term preservation of tooth germs becomes possible.

  Further, by using a dental composition containing both the enzyme inhibitor and the antibacterial agent according to the present invention, it inhibits peptide bond hydrolases such as matrix metalloproteinases, and further suppresses bacterial growth. It is possible to prevent periodontal disease and secondary caries after treatment more effectively and to preserve the tooth buds for a long time.

  In particular, the use of chlorhexidine as an enzyme inhibitor having an acidic group as an enzyme inhibitor (for example, isophthalic acid derivatives) and an antibacterial agent that suppresses the growth of periodontal pathogenic bacteria and cariogenic pathogenic bacteria is more effective. In addition, periodontal disease and secondary caries after treatment can be prevented, and tooth germs can be preserved for a long time.

  That is, according to the present invention, (1) suppressing the degradation of the organic component of the tooth by the degrading enzyme, and in addition, suppressing the growth of bacteria, exerting a periodontal disease and caries preventive effect, and (2) A dental composition capable of preserving tooth germs over a long period of time is provided.

  Hereinafter, the dental composition which has the enzyme inhibitory action which concerns on this invention, and the dental composition which has an enzyme inhibitory action and an antibacterial action are demonstrated. In the present invention, “(meth) acrylic acid” means a generic concept including acrylic acid and methacrylic acid, and the same applies to “(meth) acrylate” and the like.

  The dental composition according to the present invention contains the enzyme inhibitor (A) as an essential component (thereby exhibiting an enzyme inhibitory action), and preferably contains an antibacterial agent (B) (thereby an enzyme). An antibacterial effect is exhibited along with an inhibitory effect.)

The dental composition according to the present invention preferably further contains a polymerizable monomer (C) and a polymerization initiator (D), and may further contain a filler (E).
<Enzyme inhibitor (A)>
The enzyme inhibitor (A) is not particularly limited as long as it is a compound having an enzyme inhibitory action that can be used for dental use. For example, an enzyme belonging to EC 3.4, that is, generally inhibits a peptide bond hydrolase. An enzyme inhibitor is preferably used. Examples of the enzyme inhibitor that inhibits the peptide bond hydrolase include an enzyme inhibitor that inhibits matrix metalloproteinase.

More specifically, an enzyme inhibitor (A1) having an acidic group is preferably used as the enzyme inhibitor (A). Examples of the acidic group include a carboxyl group, a sulfo group, a phosphate group, and a thiophosphate group. Specific examples of the enzyme inhibitor (A1) having an acidic group include ethylenediaminetetraacetic acid, glycol etherdiaminetetraacetic acid, Tanomastat, R
ebimastat.

  As the enzyme inhibitor (A), a compound represented by the following general formula (1) (hereinafter also referred to as “compound (1)”), a salt of the compound (1), and the compound (1) It is also preferable to use an acid anhydride. Here, the salt of the compound (1) refers to a metal salt thereof when the compound (1) includes carboxy, amino and the like. The acid anhydride of the compound (1) refers to an acid anhydride dehydrated between or within the molecule when the compound (1) contains carboxy.

  Among these, it is preferable to use at least one compound selected from the compound (1), a salt of the compound (1), and an acid anhydride of the compound (1) as the enzyme inhibitor (A). .

In formula (1), X ₁ , X ₂ and X ₃ are each independently hydrogen, halogen, hydroxy, carboxy, cyano, nitro, trifluoromethyl, (meth) acrylate group (—OCOCR═CH ₂ ; R is hydrogen or methyl.) which may have a C ₁ -C ₆ alkyl, (meth)
C ₁ -C ₆ alkoxy which may have an acrylate group, C ₂ -C ₆ alkenyl which may have a (meth) acrylate group, C ₂ -C ₆ alkynyl which may have a (meth) acrylate group Or NX ₄ X ₅
[X ₄ and X ₅ are each independently hydrogen or a (meth) acrylate group C _1-
C ₆ -alkyl, C ₂ -C ₆ alkenyl optionally having a (meth) acrylate group, C ₂ -C ₆ alkynyl optionally having a (meth) acrylate group, having a (meth) acrylate group Good C ₆ aryl, C ₃ -C ₆ cycloalkyl optionally having a (meth) acrylate group, 3-8 membered heteroaryl optionally having a (meth) acrylate group. X ₄ and X ₅ may combine to form a 3- to 8-membered heterocycle having at least one heteroatom selected from O, S and N as a ring atom. ];
E ₁ and E ₂ are each independently O or S;
A and B are each independently OX ₄ (where X ₄ has the same meaning as X ₄ above) or NX ₄ X ₅ (where X ₄ and X ₅ are the same as X ₄ and X ₅ above, respectively). Is.)

However, in the general formula (1), among X ₁ , X ₂ , X ₃ , -CE ₁ A, and -CE ₂ B,
At least one is preferably carboxy, more preferably two are carboxy. Here, it is preferable that X ₁ and —CE ₁ A are carboxy, or X ₃ and —CE ₂ B are carboxy, and in this case, an acid anhydride group (that is, an acid of compound (1)) Anhydride.) May be formed.

Examples of the halogen include fluoro, chloro, bromo and iodo.
The C ₁ -C ₆ alkyl is preferably a linear or branched alkyl having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl.

Examples of the C ₁ -C ₆ alkoxy include methoxy, ethoxy, isopropoxy, and butoxy. The C ₁ -C ₆ alkoxy is —O— (CH ₂ ) ₂ —O—CH _3.
A polyether such as

The C ₂ -C ₆ alkenyl is preferably a linear or branched alkenyl having 2 to 6 carbon atoms, for example, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexene-1 -Yl.

The C ₂ -C ₆ alkynyl is preferably a linear or branched alkynyl having 2 to 6 carbon atoms, such as ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl. , 3-pentyn-1-yl.

Examples of the C ₆ aryl include phenyl and tolyl.
The C ₃ -C ₆ cycloalkyl is a cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

  The 3- to 8-membered heteroaryl is a heteroaryl having 3 to 8 ring atoms, at least a part of which is a heteroatom. Preferred heteroaryl has 1 to 4 ring atoms of at least one heteroatom selected from O, S and N, and more preferred heteroaryl is 1 or 2 in a 5- or 6-membered aromatic ring. It has the said hetero atom as a ring atom.

Specific examples of the 3- to 8-membered heteroaryl include pyridyl, benzothienyl, furanyl, pyrrole, pyrazole, imidazole, and thiazole.
Also, the above C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ aryl, C ₃ -C ₆ cycloalkyl, 3-8 membered heteroaryl These may have at least one, preferably one hydrogen contained therein, substituted with a (meth) acrylate group (that is, may have a (meth) acrylate group). In particular, in the case of linear C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, the hydrogen bonded to the terminal carbon contained therein is It is preferable that the (meth) acrylate group is substituted. Incidentally, carbon atoms of the (meth) acrylate groups, said C ₁ ~
It shall not be included in the carbon number such as C ₆ alkyl.

Specific examples of the NX ₄ X ₅ include amino, methylamino, diisopropylamino, 3-aminopropylamino, 3-ethylaminobutylamino, 3-di-n-propylamino-propylamino, 4-diethylaminobutylamino. Can be mentioned.

X ₄ and X ₅ , together with the nitrogen to which they are attached, are 3 to 8 membered heterocycles having at least one heteroatom selected from O, S and N as ring atoms May be formed. The 3- to 8-membered heterocycle preferably consists of one nitrogen, 1 to 7 carbons and the balance being at least one heteroatom selected from O, S and N.

Examples of the 3- to 8-membered heterocycle include pyrrolidinyl, piperazinyl, piperidinyl, and morpholinyl.
Among the compounds (1), an isophthalic acid derivative represented by the following general formula (2) (hereinafter also referred to as “isophthalic acid derivative (2)”), a salt of the isophthalic acid derivative (2), and the isophthalic acid It is preferable to use at least one compound selected from acid anhydrides of the acid derivative (2). Here, the salt of compound (2) refers to a metal salt thereof when carboxy is included in compound (2). Further, the acid anhydride of the compound (2) refers to an acid anhydride dehydrated between or within the molecule when the compound (2) contains carboxy.

In formula (2), X ₆ , X ₇ and X ₈ are each independently hydrogen, halogen, hydroxy or carboxy; X ₉ and X ₁₀ each independently have hydrogen or a (meth) acrylate group also a good C ₁ -C ₆ alkyl.

However, in the general formula (2), at least one of X ₆ , X ₇ , X ₈ , —COOX ₉ and —COOX ₁₀ is preferably carboxy, and more preferably two are carboxy. Where X ₇ and —COOX ₉ are carboxy or X ₈ and —COOX ₉
OX ₁₀ is preferably carboxy, and in this case, they may form an acid anhydride group (that is, an acid anhydride of compound (2)).

In the formula (2), the C ₁ -C ₆ alkyl is preferably a linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl, neopentyl, n -Hexyl. In particular, when a linear C ₁ -C ₆ alkyl, it is preferred that the hydrogen attached to the terminal carbon contained therein are replaced by (meth) acrylate groups.

  In particular, the enzyme inhibitor (A) is preferably a compound represented by the following general formula (3) (hereinafter also referred to as “compound (3)”).

Wherein (3), X _11, X ₁₂ and X ₁₃ are each independently hydrogen, halogen, hydroxy or carboxy; X ₁₄ is hydrogen or (meth) may have an acrylate group C ₁ ~
C ₆ alkyl; adjacent substituents of X ₁₁ , X ₁₂ , X ₁₃ and —COOX ₁₄ (
Where, for example, the moiety of X ₁₂ and —COOX ₁₄ ) is carboxy, these may form an acid anhydride group; X ₁₅ is C ₁ -C ₆ alkylene; R is hydrogen or methyl . Here, the C ₁ -C ₆ alkylene is preferably a linear or branched alkylene.

  Examples of the enzyme inhibitor (A) other than the enzyme inhibitor (A1) having an acidic group include, for example, succinyl hydroxamic acids such as Batimastat and Marimastat; sulfonamide hydroxamic acids such as MMI270; and tetracycline-based natural compounds such as Doxycyclin. Proteins such as TIMP (tissue inhibitor of metalloproteinases) -1, TIMP-2, TIMP-3, and TIMP-4.

An enzyme inhibitor (A) may be used individually by 1 type, and may use 2 or more types together.
<Antimicrobial agent (B)>
The antibacterial agent (B) is not particularly limited as long as it is a compound having an antibacterial action that can be used for dental use. Antibacterial agents are included.

As the antibacterial agent, chlorhexidines such as chlorhexidine gluconate and chlorhexidine hydrochloride and salts thereof are preferably used.
As the antibacterial agent, a disinfectant and a chemotherapeutic agent having a phenol coefficient of 0.001 to 300 are also preferably used. That is, it is also preferable to use at least one antibacterial agent selected from disinfectants and chemotherapeutic agents having a phenol coefficient of 0.001 to 300 for at least a part of the antibacterial agent (B).

These antibacterial agents (B) may be used alone or in combination of two or more.
≪Disinfectant with phenol coefficient 0.001-300≫
Examples of the disinfectant having a phenol coefficient of 0.001 to 300 include heavy metals having a specific gravity of 5.0 or more in the metal state such as mercury, silver, copper, gold, cobalt, lead, iron, aluminum, zinc, and the like. A compound, a salt of the compound having the heavy metal;
Oxidizing agents such as hydrogen peroxide (oxide) and potassium permanganate and their salts; chlorine compounds such as chlorine, sodium hypochlorite, chlorhexidine and chloramine and their salts; iodine, iodoglycerin, iodoform, povidone iodine, etc. Iodine compounds and their salts;
Methyl alcohol, ethyl alcohol, allyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, cyclopentanol, n-hexyl alcohol, cyclohexyl Primary alcohols such as sa-alcohol, n-heptyl alcohol, n-octyl alcohol, n-nonyl alcohol, n-decyl alcohol, benzyl alcohol, α-phenylethyl alcohol, β-phenylethyl alcohol, ethylene glycol, propylene glycol, glycerol Alcohols such as alcohol, secondary alcohol and tertiary alcohol;
Aldehydes such as formaldehyde, paraformaldehyde and glutaraldehyde; phenols and phenol derivatives such as phenol, cresol, thymol, guaiacol and Irgasan DP300; vegetable volatile oils such as eugenol, menthol and camphor;
Hydrophilic group is carboxylic acid, sulfate ester, sulfonate salt, phosphate ester salt, primary amine salt, secondary amine salt, tertiary amine salt, quaternary ammonium salt, amino acid, betaine, polyethylene glycol, many Anionic, cationic, zwitterionic and nonionic surfactants such as polyhydric alcohols (eg, benzethonium chloride, hexadecylpyridinium and its salts (eg, hexadecylpyridinium chloride));
Organic pigments such as acrinol and methyl rosaniline chloride;
Examples include water having a disinfecting action such as electrolytic acid water and ozone water.

  Among these, benzethonium chloride, hexadecylpyridinium and its salt (for example, hexadecylpyridinium chloride) are preferable. These disinfectants may be used alone or in combination of two or more.

≪Chemotherapeutic drugs≫
Examples of the chemotherapeutic agents include benzylpenicillin, phenoxymethylpenicillin, methicillin, oxacillin, pheneticillin, propicillin, cloxacillin, dicloxacillin, fluclosacillin, ampicillin, amoxiline, cyclacillin, bacampicillin, tarampicillin, lenbecicline, sulfencillin, , Penicillin chemotherapeutic drugs such as pepicillin and aspoxillin;
Cephalothin, Cefapirin, Cephalolidine, Cefazolin, Ceftezol, Cefacetril, Cephalexin, Cephaglycine, Cefradine, Cephatridine, Cefloxazine, Cefachlor, Cefatiam, Cefoxitin, Cefmetazole, Cefuroxime, Cefamidol, Cefetoxime, Cefetome, Cefetome Riaxon, ceftazidime, cefoperazone, cefbuperazone, latamoxef, cefminox, cefpimizole, cefpyramide, cefzonam, fromoxef, cefodizime, cefixime, ceftibutene, cefdinir, cefprozil, cefterim pivocifel, cefpodem · Pivoxil, Sefupiromu, Sefipimu, Cefozopran, Sefoserisu, cepham-based chemotherapeutic agents such as Sefurupurenamu;
Other β-lactam chemotherapeutic drugs such as carbapenem, monobactam;
Other cell wall synthesis inhibitors such as fosfomycin, bacitracin, vancomycin;
Aminoglucoside chemotherapeutic drugs such as streptomycin, kanamycin, bekanamycin, dibekacin, gentamicin, tobramycin, sisomicin, netilmycin, micromycin, amikacin, arbekacin, fradiomycin, paromomycin, ribostamycin, astromycin;
Macrolide chemotherapeutic drugs such as erythromycin, oleandomycin, roxithromycin, clarithromycin, azithromycin, kitasamycin, acetylspiramycin, midecamycin, josamycin, rokitamicin;
Lincosamide chemotherapy drugs such as lincomycin and clindamycin;
Tetracycline chemotherapeutic drugs such as tetracycline, chlortetracycline, oxytetracycline, demethylchlortetracycline, metacycline, doxycycline, minocycline;
Chloramphenicol chemotherapeutic drugs such as thianphenicol;
Quinolone chemotherapeutic drugs such as nalidixic acid, pyrometic acid, pipemic acid, enoxacin, tosufloxacin, norfloxacin, ofloxacin, ciprofloxacin, lomefloxacin, sparfloxacin, fleroxacin, pazufloxacin, valofloxacin, sinoxacin;
Ansamycin chemotherapeutic drugs such as rifampicin; Sulfonamide chemotherapeutic drugs such as paraaminobenzoic acid and sulfanilamide; ST combinations such as sulfamethoxazole and trimethopurine; Antituberculosis such as isoniazid, etionamide, ethambutol, and paraaminosalicylic acid Drugs; cell membrane damaging agents such as colistin and polymyxin B; polyene antifungals such as amphotericin B and nystatin; glycan antifungals such as griseofulvin; fluoropyrimidine antifungals such as flucytosine; clotrimazole, miconazole, ketoconazole Imidazole antifungals such as bifonazole; triazole antifungals such as fluconazole and itraconazole; antiprotozoal drugs such as metronidazole and pyrimesamine;
And antiviral drugs such as acyclovir, ganciclovir, halogenated pyridine, adenine arabinoside, cytosine arabinoside, amantadine, rimantadine, dibutodine, zalcitabine, ditanodine, nevirapine, delaviridin, saquinavir, indinavir, ritonavir, nelfinavir.

These chemotherapeutic drugs may be used alone or in combination of two or more.
<Polymerizable monomer (C)>
The polymerizable monomer (C) is not particularly limited as long as it is a monomer that is polymerized by a radical polymerization initiator, and examples thereof include a monofunctional polymerizable monomer, a bifunctional polymerizable monomer, and a trifunctional or more functional monomer. Polyfunctional polymerizable monomers, preferably monofunctional (meth) acrylic acid ester, bifunctional (meth) acrylic acid ester, trifunctional or higher polyfunctional (meth) acrylic acid ester It is appropriately selected depending on the above.

A polymerizable monomer (C) may be used individually by 1 type, and may use 2 or more types together.
≪Monofunctional (meth) acrylic acid ester≫
Examples of monofunctional (meth) acrylic acid esters include methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, isopropyl (meth) acrylate, butyl (meth) acrylate, pentyl (meth) acrylate, and isopentyl. Linear or branched alkyl (meth) acrylates such as (meth) acrylates;
Heterocyclic (meth) acrylates having oxygen atoms such as glycidyl (meth) acrylate and tetrafurfuryl (meth) acrylate; hydroxyalkyl (meta) such as 2-hydroxyethyl (meth) acrylate and 2-hydroxypropyl (meth) acrylate ) Acrylate; hydroxyalkyl (meth) acrylate with halogen (eg, chlorine) such as 3-chloro-2-hydroxypropyl (meth) acrylate;
Ethylene glycol mono (meth) acrylate, diethylene glycol mono (meth) acrylate, triethylene glycol mono (meth) acrylate, polyethylene glycol mono (meth) acrylate, methoxydiethylene glycol mono (meth) acrylate, methoxytetraethylene glycol (meth) acrylate, methoxy And alkoxy polyethylene glycol (meth) acrylates such as polyethylene glycol (meth) acrylate.

≪Bifunctional (meth) acrylic acid ester≫
Examples of the bifunctional (meth) acrylic acid ester include methylene glycol di (meth) acrylate, ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, and propylene glycol di (meth). ) Acrylate, tetraethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, 1,3-butylene glycol di (meth) acrylate, neopentyl glycol di (meth) acrylate, etc., linear or branched Examples include poly or monoalkylene glycol di (meth) acrylate and urethane di (meth) acrylate.

≪Polyfunctional (meth) acrylic acid ester≫
Examples of polyfunctional (meth) acrylic acid esters include trimethylolalkanetri (meth) acrylates such as trimethylolmethane tri (meth) acrylate, trimethylolethane tri (meth) acrylate, and trimethylolpropane tri (meth) acrylate. Representative trifunctional (meth) acrylic acid ester;
Tetrafunctional (meth) acrylic acid ester represented by tetra (meth) acrylate of polymethylolalkane ether such as pentaerythritol tetra (meth) acrylate and ditrimethylolpropane tetra (meth) acrylate;
And pentafunctional or higher (meth) acrylic acid esters represented by poly (meth) acrylates of ethers of polymethylolalkanes such as dipentaerythritol hydroxypenta (meth) acrylate.

  In addition, in the bifunctional or higher functional (meth) acrylic acid ester, for example, a methacrylate group and an acrylate group are combined with each other as in triethylene glycol acrylate methacrylate, trimethylolpropane monoacrylate dimethacrylate, pentaerythritol diacrylate dimethacrylate, and the like. Also included are compounds possessed in the molecule.

<Polymerization initiator (D)>
As the polymerization initiator (D), a polymerization initiator such as heat or a photopolymerization initiator is used.
≪Thermal polymerization initiator≫
As the thermal polymerization initiator, organic peroxides and diazo compounds are preferably used. Moreover, when it is desired to perform the polymerization efficiently in a short time, a thermal polymerization initiator having a decomposition half-life at 80 ° C. of 10 hours or less is preferable.

Examples of the organic peroxide include alkyl peroxides such as isobutyl peroxide and decanoyl peroxide; carboxylic acid anhydrides such as acetyl peroxide; aromatic peroxide carboxylic acid anhydrides such as benzoyl peroxide. ;
Peroxyanhydrides of polycarboxylic acids such as succinic acid peroxide; linear or branched aliphatic systems such as diisopropyl peroxydicarbonate, di-2-ethylhexyl peroxydicarbonate, diallyl peroxydicarbonate or the like Aromatic peroxydicarbonate;
linear or branched aliphatic or aromatic peroxides such as tert-butylperoxyisobutyrate, tert-butylperoxyneodecanate, cumeneperoxyneodecanate; acetylcyclohexylsulfonyl peroxide Peroxy anhydrides of carboxylic acid and sulfonic acid, and the like.

Examples of the diazo compound include 2,2′-azobisisobutyronitrile,
Examples include 4'-azobis (4-cyanovaleric acid), 2,2'-azobis (4-methoxy-2,4-dimethoxyvaleronitrile), and 2,2'-azobis (2-cyclopropylpropionitrile). .

  Of these thermal polymerization initiators, benzoyl peroxide and 2,2'-azobisisobutyronitrile are preferable. Moreover, reducing agents, such as an amine, can also be used together as a redox initiator. Moreover, these thermal polymerization initiators may be used individually by 1 type, and may use 2 or more types together.

≪Photopolymerization initiator≫
As the photopolymerization initiator, a photosensitizer may be used alone, or a photosensitizer and a photopolymerization accelerator may be used in combination. Among these, a combination of a photosensitizer and a photopolymerization accelerator is preferable.

Examples of the photosensitizer include camphorquinone compounds such as α-diketone compounds and camphorquinones; naphthyl compounds such as α-naphthyl; benzyl compounds such as benzyl and p, p′-dimethoxybenzyl; Β-diketone compounds of
And quinone compounds such as 1,4-phenanthrenequinone and naphthoquinone; and benzoylphosphine oxide compounds such as diphenyltrimethylbenzoylphosphine oxide. Of these, camphorquinone is preferred.

  These photosensitizers are known compounds that are excited by visible light or ultraviolet light irradiation to initiate polymerization. These photosensitizers may be used alone or in combination of two or more.

Examples of the photopolymerization accelerator include acylphosphine oxide and derivatives thereof; N, N-dialkyl (or aromatic) such as N, N-dimethylaniline, N, N-diethylaniline, and N, N-dibenzylaniline. Aniline; N, N-dialkyl (or aromatic) -p-toluidine such as N, N-dimethyl-p-toluidine;
pN, N-dimethylaminobenzoic acid, pN, N-diethylaminobenzoic acid, ethyl pN, N-dimethylaminobenzoate, pN, N-diethylaminobenzoic acid ethyl, pN, N- N, N-dialkylaminobenzoic acids and their alkyl esters such as methyl dimethylaminobenzoate, methyl p-N, N-diethylaminobenzoate;
pN, N-dialkylaminobenzaldehyde such as pN, N-dimethylaminobenzaldehyde; 2-n-butoxyethyl pN, N-dimethylaminobenzoate, 2-n p-N, N-diethylaminobenzoic acid An alkoxyalkyl ester of pN, N-dialkylaminobenzoic acid such as butoxyethyl;
pN, N-dialkylaminobenzonitrile such as pN, N-dimethylaminobenzonitrile and pN, N-diethylaminobenzonitrile; pN, N- such as pN, N-dihydroxyethylaniline Dihydroxyalkylaniline;
p-dialkylaminophenethyl alcohols such as p-dimethylaminophenethyl alcohol; N, N-dialkylaminoethyl methacrylates such as N, N-dimethylaminoethyl methacrylate;
Tertiary amines such as triethylamine, tributylamine, tripropylamine, N-ethylethanolamine; combinations of the tertiary amine with citric acid, malic acid or 2-hydroxypropanoic acid;
And barbituric acids such as 5-butylaminobarbituric acid and 1-benzyl-5-phenylbarbituric acid; and organic peroxides such as benzoyl peroxide and di-tert-butyl peroxide.

  Among these photopolymerization accelerators, aroma such as ethyl pN, N-dimethylaminobenzoate, 2-n-butoxyethyl pN, N-dimethylaminobenzoate, N, N-dimethylaminoethyl methacrylate, etc. An ester compound of a tertiary aromatic amine in which a nitrogen atom is directly bonded to the group, and an aliphatic tertiary amine acylphosphine oxide having a polymerizable group and derivatives thereof are preferably used. Moreover, these photopolymerization accelerators may be used individually by 1 type, and may use 2 or more types together.

  In addition, in the dental curable composition according to the present invention, the polymerization initiator (D) can be surely polymerized and cured without using an organic peroxide in combination, and further improve the adhesion to the tooth. It is also preferable to use an organic amine compound which is an aromatic amine having a carbonyl group.

  Specifically, N-phenylglycine (NPG), N-tolylglycine (NTG), N-methyl-N-phenylglycine (NMePG), N- (2-carboxyphenyl) glycine (N2CPG), N- (2 -Hydroxyphenyl) glycine (N2HPG), N- (4-carboxyphenyl) glycine (N4CPG), N- (4-hydroxyphenyl) glycine (N4HPG), N- (4-methoxyphenyl) glycine (N4MPG), N- Examples thereof include glycines such as (methoxycarbonyl) -N-phenylglycine (NMMCNPG) and N- (3-methacryloyloxy-2-hydroxypropyl) -N-phenylglycine (NPG-GMA), and salts thereof.

≪Initiator aid≫
Moreover, it is also preferable to mix | blend a sulfur-containing reducible compound as an initiator adjuvant, and an organic type sulfur-containing compound and an inorganic type sulfur-containing compound are mentioned as a specific example. These organic and inorganic sulfur-containing compounds may be used alone or in combination.

  Examples of the organic sulfur-containing compound include benzenesulfinic acid, o-toluenesulfinic acid, p-toluenesulfinic acid, ethylbenzenesulfinic acid, decylbenzenesulfinic acid, dodecylbenzenesulfinic acid, chlorobenzenesulfinic acid, and naphthalenesulfinic acid. Aromatic sulfinic acids and salts thereof; such as benzenesulfonic acid, o-toluenesulfonic acid, p-toluenesulfonic acid, ethylbenzenesulfonic acid, decylbenzenesulfonic acid, dodecylbenzenesulfonic acid, chlorobenzenesulfonic acid, naphthalenesulfonic acid, etc. Aromatic sulfonic acids and their salts are mentioned. Among these, p-toluenesulfinate is preferably used, and sodium p-toluenesulfinate is particularly preferably used.

  Examples of the inorganic sulfur-containing compound include sulfurous acid, bisulfurous acid, metasulfurous acid, metabisulfuric acid, pyrosulfurous acid, thiosulfuric acid, 1 dithionic acid, 1,2 thionic acid, hyposulfite, hydrosulfurous acid, and salts thereof. Is mentioned. Of these, sulfites are preferably used, and sodium sulfite, potassium sulfite, sodium hydrogen sulfite, and potassium hydrogen sulfite are particularly preferably used as the sulfite.

  In order to quickly complete the curing of the polymerizable monomer (C), a combination of a photosensitizer and a photopolymerization accelerator is preferable. Camphorquinone, ethyl pN, N-dimethylaminobenzoate, p A combination with an ester compound of a tertiary aromatic amine in which a nitrogen atom is directly bonded to an aromatic such as 2-N-butoxyethyl -N, N-dimethylaminobenzoate, or a combination with an acylphosphine oxide is particularly preferably used. It is done.

Moreover, it is also preferable to use together a camphorquinone, the organic amine compound which is an aromatic amine which has a carbonyl group, and an initiator adjuvant as a polymerization initiator (D).
<Filler (E)>
For example, when preparing a dental composite resin using the dental composition according to the present invention, in addition to the components (A) to (D), a filler (E) is further added to the composition. It is preferable. As such a filler (E), an inorganic filler and a composite filler are preferable, and both of them may be blended in the composition.

≪Inorganic filler≫
As the inorganic filler, known materials can be used, for example, (1) transition metals of groups 1, 2, 3, and 4 of the periodic rule and other metals having excellent X-ray contrast properties; (2) these (1) Oxides, hydroxides, chlorides, sulfates, sulfites, carbonates, phosphates, silicates; (3) mixtures of these (2), complex salts, metal salts.

  Specifically, glass powder such as silicon dioxide, strontium glass, lanthanum glass, barium glass; quartz powder, barium sulfate, aluminum oxide, titanium oxide, barium salt, glass beads, glass fiber, barium fluoride, lead salt, talc Glass filler, colloidal silica, silica gel, zirconium oxide, tin oxide, carbon fiber, calcium tungstate, bismuth carbonate, calcium molybdate, and other ceramic powders.

The average particle size of the inorganic filler is usually 0.01 to 5 μm, and when it is desired to impart gloss and transparency to the cured surface of the dental composite resin, the average particle size is preferably 0.00. The thickness is 01 to 3 μm, more preferably 0.01 to 1 μm, and particularly preferably 0.01 to 0.1 μm.

  To exhibit the above advantages (glossiness and transparency), hydrophobic aerosils such as R972, R972V, R972CF, RX200, RY200, R202, R805, R976, R812, R812S manufactured by Nippon Aerosil Co., Ltd .; OX-50 Silica called hydrophilic aerosil is preferred. Of these, R805, R972, R812, and R812S are preferable.

  Since the hydrophobic aerosil is commercially available as a hydrophobized product of high purity silicon dioxide aerosol, it does not need to be surface modified. Furthermore, the average particle diameter is 0.05 μm or less, which is smaller than the wavelength of visible light. For this reason, the hardened | cured material which mix | blended the said hydrophobic aerosil is hard to carry out irregular reflection of visible light, and is excellent in transparency.

  In addition, the inorganic filler may be subjected to a surface treatment with a surface treatment agent such as a silane coupling agent depending on the purpose. Examples of such a surface treatment agent include γ- (meth) acryloxypropyltrimethoxysilane, vinyltriethoxysilane, 3-aminopropylethoxysilane, 3-chloropropyltrimethoxysilanesilyl isocyanate, vinyltriene. Silane coupling agents such as dialkyldichlorosilanes such as chlorosilane, dimethyldichlorosilane, and dioctyldichlorosilane, and hexamethylene disilazane; zirconium coupling agents, titanium coupling agents, and aluminum coupling agents corresponding to these coupling agents are listed. It is done.

  The surface treatment agent is preferably used in an amount of 0.1 to 30 parts by weight, and more preferably 1 to 10 parts by weight with respect to 100 parts by weight of the inorganic filler. If the amount of the surface treatment agent used is less than the lower limit of the above numerical range, the familiarity between the inorganic filler and the liquid component will be worse, whereas if the amount exceeds the upper limit, the possibility of unreacted surface treatment agent will be increased. Sometimes.

≪Composite filler≫
The composite filler is a mixture obtained by mixing the inorganic filler and the polymerizable monomer and then polymerizing the polymerizable monomer by heating or a polymerization initiator until the desired particle size is obtained. This refers to the pulverized product. The composite filler may contain an enzyme inhibitor (A) (for example, an isophthalic acid derivative) or an antibacterial agent (B) (for example, chlorhexidine) (however, these include an enzyme inhibitor ( Calculated as the content of A) or antibacterial agent (B).

  A filler (E) may be used individually by 1 type, and may use 2 or more types together. Further, the shape of the filler (E) may be a spherical body or an indefinite shape, and is appropriately selected along with the particle diameter.

<Other components (F)>
The dental composition according to the present invention includes a polymerization inhibitor, a water-insoluble organic compound such as a water-insoluble organic solvent, a pigment such as titanium white and titanium yellow, and the like, as long as the object of the present invention is not impaired. Other components (F) such as agents; dyes; antioxidants may be blended. These other components (F) are blended in appropriate amounts.

Examples of the polymerization inhibitor include hydroquinone compounds such as hydroquinone and dibutyl hydroquinone; phenols such as hydroquinone monomethyl ether, 2,6-di-tert-butylphenol, and 2,6-di-tert-butyl-p-cresol. Is mentioned. These polymerization inhibitors are preferably blended in order to improve the storage stability of the dental composition. In particular, hydroquinone monomethyl ether and 2,6-di-ter
A combination with t-butyl-p-cresol is preferably used.

<Aqueous medium (G)>
The dental composition according to the present invention may contain an aqueous solvent (G) (excluding those having an antibacterial action). The aqueous medium (G) used here is water (however, excluding disinfecting water) alone, an organic solvent that can be mixed with water, or a solvent obtained by mixing water and the organic solvent.

  Examples of the water include distilled water (purified water) and ion-exchanged water. Moreover, physiological saline can also be used as an aqueous solvent. Among these, distilled water and ion exchange water are preferably used.

  The organic solvent that can be mixed with water is preferably an organic solvent that can be dissolved in 100 parts by weight of water in an amount of 5 parts by weight or more. For example, alcohols such as methanol, ethanol, and propanol; acetone, methyl ethyl ketone, and the like Ketones; Ethers such as tetrahydrofuran; Amides such as N, N-dimethylformamide. Among these organic solvents, it is particularly preferable to use ethanol or acetone in consideration of harmfulness and irritation to the dental pulp.

A water-based solvent (G) may be used individually by 1 type, and may use 2 or more types together.
<Preparation of dental composition>
The dental composition according to the present invention preferably contains an enzyme inhibitor (A) as an essential component, and further contains an antibacterial agent (B). In the dental composition according to the present invention, the content of the enzyme inhibitor (A) is preferably 0.01 to 50% by weight, more preferably 0.01% with respect to the total 100% by weight of the dental composition. ~ 30% by weight. Further, the content of the antibacterial agent (B) is preferably 0.01 to 50% by weight, more preferably 0.01 to 30% by weight, with respect to the total 100% by weight of the dental composition.

  Further, it is preferable to further contain a polymerizable monomer (C) and a polymerization initiator (D), and such a dental composition is prepared by mixing the above components at an appropriate ratio. For example, in a dental composition containing an enzyme inhibitor (A), an antibacterial agent (B), a polymerizable monomer (C) and a polymerization initiator (D), each of these components has a content in the following range. It is blended as follows.

  In addition, the enzyme inhibitor (A) may include an enzyme inhibitor (Ao) having no polymerizability and an enzyme inhibitor having a polymerizability. On the other hand, the polymerizable monomer (C) may also include a polymerizable monomer (Co) having no enzyme inhibitory action and a polymerizable monomer having an enzyme inhibitory action. That is, the component (AC) having the enzyme inhibitory action and polymerizability belongs to both the enzyme inhibitor (A) and the polymerizable monomer (C). Further, the polymerization initiator (D) having polymerizability does not belong to the polymerizable monomer (C) but belongs to the polymerization initiator (D).

  In the dental composition according to the present invention, the content of the enzyme inhibitor (A) (component (Ao) + (AC)) is the components (Ao), (B), (Co), (AC) and (D). ) Is preferably 0.01 to 70% by weight, more preferably 0.025 to 70% by weight, and still more preferably 0.25 to 50% by weight. If the content of the enzyme inhibitor (A) (component (Ao) + (AC)) is below the lower limit of the above numerical range, it will be difficult to exhibit the effect of preventing periodontal disease and caries and the effect of preserving tooth germs. If the above value is exceeded, the enzyme inhibitory activity becomes excessive and the irritation may increase.

The content of the component (Ao) is preferably 50% by weight or less, more preferably 100% by weight or less, more preferably 100% by weight of the total of the components (Ao), (B), (Co), (AC) and (D). It is 30% by weight or less, more preferably 10% by weight or less, and the lower limit thereof is preferably 0.001% by weight, more preferably 0.01% by weight. If the content of the component (Ao) exceeds the upper limit of the above numerical range, there is a high possibility of causing poor curing due to insufficient polymerization, and the elution amount of non-polymerized components may increase.

  In the dental composition according to the present invention, the content of the antibacterial agent (B) is preferably based on a total of 100% by weight of the components (Ao), (B), (Co), (AC) and (D). Is 0.01 to 50% by weight, more preferably 0.01 to 30% by weight. If the content of the antibacterial agent (B) is below the lower limit of the above numerical range, it will be difficult to exhibit the effect of preventing periodontal disease and caries and the preservation effect of dental buds. In some cases, the elution amount of non-polymerized components may increase.

  In the dental composition according to the present invention, the content of the polymerizable monomer (C) (component (Co) + (AC)) includes the components (Ao), (B), (Co), (AC) and Preferably it is 20-99 weight% with respect to the total of 100 weight% of (D), More preferably, it is 50-99.99 weight%. If the content of the polymerizable monomer (C) is below the lower limit of the above numerical range, there is a high possibility of causing poor curing due to insufficient polymerization, while if it exceeds the upper limit, the preventive effect of periodontal disease and tooth germ It may be difficult to preserve the storage effect.

  The weight ratio (Co) / (AC) is preferably 10/90 to 99.9 / 0.1, more preferably 30/70 to 99.9 / 0.1, and still more preferably 50/50 to 99. .9 / 0.1. If the weight ratio (Co) / (AC) is below the lower limit of the numerical range, the acidity of the liquid component may increase and irritation may increase, while if the upper limit is exceeded, periodontal disease and caries The preventive effect and the preservation effect of tooth buds may be difficult to be demonstrated.

  In the dental composition according to the present invention, the content of the polymerization initiator (D) is 100% by weight in total of the components (Ao), (B), (Co), (AC) and (D). Preferably it is 0.01 to 20 weight%, More preferably, it is 0.1 to 5 weight%. When the content of the polymerization initiator (D) is below the lower limit of the above numerical range, there is a high possibility of causing poor curing due to insufficient polymerization. On the other hand, when the content exceeds the upper limit, the operation time is shortened and used due to an increase in the polymerization rate. May be difficult.

Moreover, in this invention, it is preferable to mix | blend the filler (E) which is an arbitrary component, another component (F), and an aqueous solvent (G) so that it may become content of the following range.
In the dental composition according to the present invention, the content of the filler (E) is preferably 0 to 90% by weight with respect to 100% by weight of the whole composition. When content of a filler (E) exceeds the upper limit of the said numerical range, use of a dental composition may become difficult by a viscosity increase.

  In the dental composition according to the present invention, the total content of the other component (F) is 100 parts by weight in total of the components (Ao), (B), (Co), (AC) and (D). The amount is preferably 50 parts by weight or less, more preferably 10 parts by weight or less, and still more preferably 5 parts by weight or less. When the total content of the other components (F) exceeds the numerical range, it may be difficult to sufficiently exhibit the original performance of the present invention.

  In the dental composition according to the present invention, the content of the aqueous solvent (G) is preferably 0 to 90 parts by weight with respect to 100 parts by weight of the entire composition. When the content of the aqueous solvent (G) exceeds the upper limit of the numerical range, curing failure due to insufficient polymerization may be caused.

<Uses of dental composition>
The dental composition according to the present invention has an enzyme inhibitory action or an enzyme inhibitory action and an antibacterial action. For this reason, the dental composition is, for example, a dental coating agent applied to oral tissues such as oral mucosa, periodontal tissue, alveolar bone or teeth; a dental adhesive; a dental root canal filling material; It is suitably used for a dental composite resin. Further, it is also suitably used for dental cement, pit and fissure filling material, denture base resin and the like.

  EXAMPLES Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to these examples. In addition, the measurement of the enzyme activity and the antibacterial test of the dental compositions obtained in Examples and Comparative Examples were performed as follows.

[Measurement of enzyme activity]
Enzyme Gelatinase / Collagenase Assay Kit, an enzyme activity assay kit manufactured by Molecular Probes, was used for measurement of enzyme activity.

First, healthy dentin powder was prepared according to the following procedures (1a) to (1b).
(1a) Human teeth were frozen with liquid nitrogen to form frozen human teeth, and the frozen human teeth were pulverized for 5 minutes under the conditions of -120 ° C and 30 Hz using a steel mill.

(1b) The pulverized product obtained in (1a) above was sieved, and the pulverized product passed through a mesh size of 180 μm and not passed through 150 μm was recovered, and the recovered pulverized product was used as a healthy dentin powder.
Next, a sample for enzyme activity measurement was prepared by the following procedures (2a) to (2d) using the healthy dentin powder and the dental composition obtained in Examples 1 to 5 below.

(2a) 600 mg of healthy dentin powder and 0.7 ml of the dental composition obtained in Examples 1 to 5 below were mixed and kneaded in a dark room, and the kneaded product was spread on a glass plate.
(2b) A weak air blow was applied to the smelt spread on the glass plate to remove acetone and purified water contained in the smelt.

(2c) Furthermore, by placing another glass plate on the wrought product spread on the glass plate, the wrought product was sandwiched between the glass plates from both sides. Subsequently, the hydrate was irradiated with light through a glass plate (600 mW / cm ² for 40 seconds) to cure the hydrate, and a cured product having a length of 7 cm, a width of 4 cm, and a thickness of 0.4 mm was obtained. .

  (2d) The cured product was pulverized with a steel mill, and the obtained pulverized product was sieved, and a mesh size of 300 μm passed through and 225 μm not passed through was collected to obtain a sample for enzyme activity measurement.

  Using Enzchek Gelatinase / Collagenase Assay Kit, the enzyme activity values of the healthy dentin powder and the enzyme activity measurement sample were measured in the following manner (3a) to (3d).

(3a) Distilled water (8 mL) was added to 10X Buffer (2 mL) to dilute the 10X Buffer to prepare 1X Buffer.
(3b) Distilled water (10 mL) was added to NaN ₃ (1.3 mg) to prepare a NaN ₃ solution. Add the NaN ₃ solution (1 mL) to one DQ gelatin attached to the kit, and sonicate at 50 ° C. for 5 minutes to completely dissolve the DQ gelatin, and further dilute the volume to 2 times using 1 × Buffer. A DQ gelatin solution was prepared.

(3c) To one Collagenase (Type IV from Clostridium histolyticum 500U) attached to the Kit, distilled water (0.5 m
L) was added, and the volume was diluted 100 times with 1 × Buffer to prepare a collagenase solution. The collagenase solution was stored in a refrigerator until use.

  (3d) 1 × Buffer (60 μL), a sample for enzyme activity measurement (80 mg), and a DQ gelatin solution (20 μL) are mixed in a 96-well microplate, and a collagenase solution (100 μL) is added to the microplate. Incubated at room temperature for 24 hours in the dark. Thereafter, the fluorescence intensity was measured at an absorption maximum of 495 nm and an emission maximum of 515 nm, and the enzyme activity value was measured.

[Antimicrobial test]
Human oral bacteria are collected using a culture, and the bacteria are immediately dispersed in a phosphate buffer solution. A predetermined amount of the resulting dispersion is added to an anaerobic fungal blood agar medium (Nippon Becton Dickinson Co., Ltd.). )

  Next, 75 μl of the dental composition obtained in Examples 1 to 7 below was used as a sample for antibacterial testing, and soaked into a paper disk (diameter 8 mm, thickness 1.5 mm). The paper disk was placed on the agar medium, and the bacteria were cultured for 24 hours at 37 ° C. under anaerobic conditions. The growth state of the bacteria around the paper disk after 24 hours was observed and judged according to the criteria shown in Table 1 below.

[Example 1]
20 parts by weight of 4-methacryloyloxyethyl trimellitic anhydride (4-META) as an enzyme inhibitor (A) (this is a component (AC) having an enzyme inhibitory action and polymerizability); 20 parts by weight of urethane dimethacrylate (UDMA) and 2 parts by weight of 2-hydroxyethyl methacrylate (HEMA) as the body (Co); 0.2 parts by weight of camphorquinone (CQ) as the polymerization initiator (D), sodium N-phenylglycine A dental composition (1) comprising 0.3 part by weight and 0.3 part by weight of sodium p-toluenesulfinate; 40 parts by weight of acetone and 17.2 parts by weight of purified water as an aqueous solvent (G) was prepared. The dental composition (1) was used for enzyme activity measurement and antibacterial test. The results are shown in Table 2 and Table 3.

[Example 2]
To 100 parts by weight of the dental composition (1), 0.5 part by weight of chlorhexidine gluconate as an antibacterial agent (B) was blended to prepare a dental composition (2). The dental composition (2) was used for enzyme activity measurement and antibacterial test. The results are shown in Table 2 and Table 3.

[Example 3]
To 100 parts by weight of the dental composition (1), 1 part by weight of chlorhexidine gluconate as an antibacterial agent (B) was blended to prepare a dental composition (3). The dental composition (3) was used for enzyme activity measurement and antibacterial test. The results are shown in Table 2 and Table 3.

[Example 4]
To 100 parts by weight of the dental composition (1), 2 parts by weight of chlorhexidine gluconate as an antibacterial agent (B) was blended to prepare a dental composition (4). The dental composition (4) was used for enzyme activity measurement and antibacterial test. The results are shown in Table 2 and Table 3.

[Example 5]
To 100 parts by weight of the dental composition (1), 5 parts by weight of chlorhexidine gluconate as an antibacterial agent (B) was blended to prepare a dental composition (5). The dental composition (5) was used for enzyme activity measurement and antibacterial test. The results are shown in Table 2 and Table 3.

[Example 6]
To 100 parts by weight of the dental composition (1), 0.5 part by weight of benzethonium chloride as an antibacterial agent (B) was blended to prepare a dental composition (6). An antibacterial test was performed using the dental composition (6). The results are shown in Table 3.

[Example 7]
To 100 parts by weight of the dental composition (1), 0.5 part by weight of hexadecylpyridinium as an antibacterial agent (B) was blended to prepare a dental composition (6). An antibacterial test was performed using the dental composition (6). The results are shown in Table 3.

[Comparative Example 1]
A sample for enzyme activity measurement was prepared using only healthy dentin powder without using the dental composition obtained in Examples 1 to 5, and enzyme activity was measured. The results are shown in Table 2.

  As shown in Table 2, the dental composition containing the enzyme inhibitor (A) has a higher enzyme inhibitory ability than a normal healthy dentin powder. Moreover, as shown in Table 3, the antibacterial effect is also exhibited at the same time by further blending an antibacterial agent (B) such as chlorhexidine gluconate with such a dental composition having an enzyme inhibitory action.

Claims (5)

A compound having a polymerizable represented by the general formula (3), contact and at least one compound in which the enzyme inhibitor is selected from an acid anhydride of the compound (3) and (A),
At least one antibacterial agent (B) selected from chlorhexidines and salts thereof;
A polymerizable monomer (C) other than the enzyme inhibitor (A);
A dental composition containing a polymerization initiator (D),
The polymerizable monomer (C) is a linear or branched alkyl (meth) acrylate, glycidyl (meth) acrylate, tetrafurfuryl (meth) acrylate, hydroxyalkyl (meth) acrylate, or hydroxy having a halogen. Alkyl (meth) acrylate, alkoxy polyethylene glycol (meth) acrylate, linear or branched poly or monoalkylene glycol di (meth) acrylate, urethane di (meth) acrylate, trimethylolalkanetri (meth) acrylate, polymethylol Consisting of at least one selected from tetra (meth) acrylates of alkane ethers and poly (meth) acrylates of polymethylolalkane ethers,
A dental composition, which is a dental coating agent applied to an oral tissue selected from oral mucosa, periodontal tissue, alveolar bone and teeth.

Wherein (3), X _11, X ₁₂ and X ₁₃ are each independently hydrogen, halogen, hydroxy or carboxy; X ₁₄ is hydrogen or (meth) may have an acrylate group C ₁ ~ It is a C ₆ alkyl; X _11, when X _12, X ₁₃ and another substituent that is adjacent the -COOX ₁₄ is carboxy, may form these with an acid anhydride group; X ₁₅ is C it is ₁ -C ₆ alkylene; R is hydrogen or methyl. ]   The dental composition according to claim 1, wherein the enzyme inhibitor (A) is an enzyme inhibitor that inhibits a peptide bond hydrolase belonging to EC 3.4.   The dental composition according to claim 1, wherein the enzyme inhibitor (A) is an enzyme inhibitor that inhibits a matrix metalloproteinase.   The dental composition according to any one of claims 1 to 3, wherein the enzyme inhibitor (A) is an enzyme inhibitor (A1) having an acidic group. Furthermore, the dental composition according to claim 1, characterized in that a filler (E).