JP2009084160A - Composition for inducing expression of binding protein - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition inducing the expression of a binding protein on the surface of an organization, causing a biological bonding in a living body, prompting sealing, to keep the continuity of an epithelial organization. <P>SOLUTION: This composition for inducing the expression of binding protein comprises a (meth)acrylic compound and a radical polymerization initiator. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a composition that induces expression of an adhesion protein.

The epithelial tissue is a tissue that is continuously present on the outermost layer of the living body, and is a tissue that protects against stimulation from the outside world. For most people, cuts, abrasions, or damage to epithelial tissue caused by surgical procedures can cause discomfort. This is because the continuity of the epithelial tissue is not maintained and the external stimulus directly reaches the living body.
If epithelial tissue damage is mild, apply an artificial defense mechanism, such as covering the surface with an adhesive bandage, and select a method to wait for healing using the living body's regeneration mechanism. In many cases, when severe, a method such as suturing is performed to cause adhesion between epithelia and wait for regeneration. During these treatments, a microscopic gap is created by the method of applying the bandage or suturing, so that the epithelium is partially discontinuous and affected by external stimuli such as pathogenic bacteria, which may cause infection. Is always a problem.

  In addition, peri-implantitis is a problem in dental implants. In natural teeth, teeth are maintained by gingiva, cementum, periodontal ligament and alveolar bone, and the gingival epithelium and tooth enamel, which is also the epithelial tissue, are adhered by adhesive proteins such as laminin and integrin. In contrast, the continuity of epithelial tissue is maintained, whereas in implants, the gingiva and alveolar bone, especially the alveolar bone and the implant are maintained by osteointegration. The implant body, which is a tissue, is surrounded by an epithelial tissue called a peri-implant epithelium continuous from a gingival epithelium, which is a living tissue, and is only weakly joined, and the continuity of the epithelium is not maintained. Furthermore, unlike the damage described above, epithelial discontinuities are permanent after implant application. For this reason, there is a great risk that oral pathogens or irritants will enter the subepithelium, and once inflammation occurs, the progression is known to be smoother and more severe than natural teeth. In the department, it is important to prevent infection above all.

Regarding the epithelial continuity, Non-patent Document 1 describes that the adherent epithelium continuous from the gingival epithelium expresses a protein called laminin 5, adheres to the tooth enamel, and maintains the epithelial continuity. Various studies have been made.
As a technique for promoting the expression of tissue adhesion protein, Patent Document 1 or Patent Document 2 proposes an external medicine and a cosmetic that contain a plant extract that promotes the production of laminin in the tissue. Since it is obtained by extraction from the natural world, it is disadvantageous in terms of cost, and petrolatum, paraffin and the like have been proposed as a method for immobilization to the application site, and there are doubts about the sustainability of the effect.

In addition, as a technique for modifying the surface of a medical device and imparting physiological activity such as cell adhesion, Patent Document 3 discloses an organic compound containing a silyl group and a biopolymer such as heparin or fibronectin covalently bonded. However, since biopolymers such as heparin, which is the raw material, can be obtained only by extraction from organs of various animals, the productivity is low and the production cost is also low. This is a high burden on the patient's economy. In addition, since the raw material depends on the organs of various animals, the risk of contamination with impurities such as pathogenic bacteria cannot be denied, and there is a problem in terms of safety.
Japanese Patent Laid-Open No. 2004-262861 JP-A-2005-314230 JP-T-2004-505124 Journal of Periodontology, 72, 788-797, 2001

  The present invention has been made in view of the above-described problems. When an epithelial tissue that is a self-defense tissue in a living body lacks continuity due to an accident or a surgical procedure, the epithelial tissue adheres. An object of the present invention is to provide a composition that promotes protein expression, adheres other tissues or structures to epithelial tissues, and further activates a defense mechanism of a living body.

  As a result of intensive studies by the inventors, it has been found that the above object of the present invention can be achieved by an adhesive protein expression-inducing composition comprising a (meth) acrylic compound and a radical polymerization initiator. The invention has been completed.

  By using the adhesion protein expression-inducing composition of the present invention, the expression of the adhesion protein is induced on the tissue surface in direct contact with the composition, causing biological adhesion to the living body, promoting blockage, and maintaining the continuity of epithelial tissue. Can do.

The present invention is described in detail below. Hereinafter, unless otherwise specified, “part” or “%” in this specification indicates a weight basis. Also, “(meth) acryl ...” is used as a generic term for “acly ...” and “metaacryl ...”.
The (meth) acrylic compound in the present invention may be hereinafter referred to as (M) component. The component (M) is not particularly limited as long as it is a compound having a (meth) acryl group, but as a particularly preferred compound group, a monofunctional (meth) acrylate compound having no acidic group (hereinafter referred to as (M1) And a monofunctional (meth) acrylate compound having an acidic group (hereinafter, also referred to as (M2) component).

The component (M1) is a compound having one (meth) acryloyl group in the molecule and no acidic group. Specific compounds include
Alkyl or cycloalkyl (meth) such as methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, butyl (meth) acrylate, hexyl (meth) acrylate, dodecyl (meth) acrylate, cyclohexyl (meth) acrylate Acrylate;
Hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate;
Acetoacetoxyethyl (meth) acrylate;
(Poly) hydroxyalkyl (meth) acrylates such as 1,2- or 2,3-dihydroxypropyl (meth) acrylate, erythritol mono (meth) acrylate;
Polyalkylene glycol mono (meth) acrylates such as diethylene glycol mono (meth) acrylate, triethylene glycol mono (meth) acrylate, polyethylene glycol mono (meth) acrylate, polypropylene glycol mono (meth) acrylate;
Ethylene glycol monomethyl ether (meth) acrylate, ethylene glycol monoethyl ether (meth) acrylate, diethylene glycol monomethyl ether (meth) acrylate, diethylene glycol monoethyl ether (meth) acrylate, propylene glycol monomethyl ether (meth) acrylate or polyethylene glycol mono (meth) ) Polyalkylene glycol monoalkyl or monoalkenyl ether (meth) acrylate such as a compound in which 10-undecenyl alcohol is ether-added to acrylate;
(Meth) acrylate having a heterocyclic ring such as (tetrahydrofuran-2-yl) (meth) acrylate and 12- (meth) acryloyloxide decylpyridinium bromide and salts thereof;
Halogenated alkyl (meth) acrylates such as perfluorooctyl (meth) acrylate and hexafluorobutyl (meth) acrylate;
Can be mentioned. Also,
A compound in which (meth) acrylamide is used instead of (meth) acryl of the above (meth) acrylate, such as methyl (meth) acrylamide and 2,3-dihydroxypropyl (meth) acrylamide, can also be suitably used. .

Of these compounds, methyl (meth) acrylate can be preferably used.
These compounds as component (M1) can be used alone or in combination of two or more.
The component (M2) is a compound having one (meth) acryloyl group and at least one acidic group in the molecule. Examples of acidic groups include carboxylic acid groups, phosphoric acid groups, sulfonic acid groups, and acid anhydride groups thereof.

As a preferred compound, specifically,
(Meth) acrylic acid, maleic acid, 11- (meth) acryloyloxy-1,1-undecanedicarboxylic acid, 4- (2- (meth) acryloyloxyethyl) trimellitic acid, 2- (meth) acryloyloxyethyl acid Phosphate, 2-sulfoethyl (meth) acrylate, 2- or 1-sulfo-1- or 2-propyl (meth) acrylate, 1- or 3-sulfo-2-butyl (meth) acrylate, 1- or 2-methyl- (Meth) acrylates containing acidic groups such as 2-sulfopropyl (meth) acrylate;
Silane compounds having a (meth) acryloxyalkyl group such as 3- (trimethoxysilyl) propyl (meth) acrylate;
Vinyl compounds containing acidic groups such as 4-styrenesulfonic acid;
further,
Examples include compounds in which (meth) acrylamide is substituted for the above (meth) acrylate, such as 1,1-dimethyl-2-sulfoethyl (meth) acrylamide and 2- (meth) acrylamide-2-methylpropanesulfonic acid. it can.

Among these compounds, 4- (2- (meth) acryloyloxyethyl) trimellitic acid and / or its acid anhydride can be preferably used.
These compounds as component (M2) can be used alone or in combination of two or more.
As the (M) component, the (M1) component and the (M2) component can be used together.

  In the composition of the present invention, the content ratio of the component (M) is preferably 25 to 99.9% by weight, more preferably 30 to 99.5% by weight, still more preferably 35 to 5%, based on the total amount of the composition. It is 99% by weight, most preferably in the range of 40 to 98.8% by weight. Moreover, it is preferably 80 to 99.9% by weight, more preferably 85 to 99.5% by weight, and still more preferably 88 to 99% by weight based on the total amount of the components excluding the filler (F) described later. %, Most preferably in the range of 91-98.8% by weight. If it exceeds or falls below this range, the composition hardens in the application area and may not stay in the application area, leading to the inability to induce the expression of the adhesion protein, both being undesirable.

  Furthermore, as a use example of a suitable (M) component mainly in the oral cavity region, a method of using a combination of the (M1) component and the (M2) component can be given. In this case, the use of the (M1) component The amount is preferably in the range of 22 to 99% by weight, more preferably 27 to 98.5% by weight, still more preferably 32 to 98% by weight, and most preferably 36 to 97% by weight, based on the total amount of the composition. . The amount of component (M2) used is preferably 0.25 to 9.99% by weight, more preferably 0.3 to 9.95% by weight, and still more preferably 0.35 to 9%, based on the total amount of the composition. .8% by weight, most preferably in the range of 0.4 to 9.7% by weight. Of course, the sum of the usage amount of the component (M1) and the usage amount of the component (M2) is within the range of the usage amount of the component (M). The amount of the component (M1) used is preferably 72 to 99% by weight, more preferably 76 to 98.5% by weight, based on the total amount of the components excluding the filler (F) described later. The range is preferably 79 to 98% by weight, and most preferably 81 to 97% by weight. The amount of component (M2) used is preferably 0.8 to 9.99% by weight, more preferably 0.85 to 9.95% by weight, still more preferably 0.88 to 9.8% by weight, most preferably It is in the range of 0.9 to 9.7% by weight. Of course, also in this case, the sum of the usage amount of the component (M1) and the usage amount of the component (M2) is within the range of the usage amount of the component (M). . By preparing the composition within this range, the adhesion to the teeth and dental metal is improved, and a stable effect can be obtained even in a region where moisture is always present, such as in the oral cavity.

  In the present invention, the radical polymerization initiator is sometimes referred to as component (I) below. Examples of the component (I) include organic boron compounds, organic peroxides, inorganic peroxides, α-diketone compounds, phosphine oxides, organic amine compounds, organic sulfonic acids, organic sulfinic acids, inorganic sulfur compounds, organic phosphorus compounds and Mention may be made of compounds such as barbituric acids. These compounds as component (I) can be used alone or in combination of two or more.

These polymerization initiators can be classified into a room temperature chemical polymerization type and a photopolymerization type for convenience. As a specific example of the component (I), in the room temperature polymerization type,
Triethylboron, tri (n-propyl) boron, triisopropylboron, tri (n-butyl) boron, tri (s-butyl) boron, triisobutylboron, tripentylboron, trihexylboron, trioctylboron, tridecylboron , Trialkyl boron such as tridodecyl boron, tricyclopentyl boron, tricyclohexyl boron;
Alkoxyalkylborons such as butoxydibutylboron;
Dialkylboranes such as butyldicyclohexylborane, diisoamylborane, 9-borabicyclo [3.3.1] nonane;
Aryl borate compounds such as tetraphenyl boron sodium, tetraphenyl boron triethanolamine salt, tetraphenyl boron dimethyl-p-toluidine salt, tetraphenyl boron dimethylaminoethyl benzoate;
Partially oxidized trialkylboron such as partially oxidized tributylboron;
Diacetyl peroxide, dipropyl peroxide, dibutyl peroxide, dicapryl peroxide, dilauryl peroxide, benzoyl peroxide, p, p'-dichlorobenzoyl peroxide, p, p'-dimethoxybenzoyl peroxide, p, p Organic peroxides such as' -dimethylbenzoyl peroxide and p, p'-dinitrodibenzoyl peroxide;
Mention may be made of inorganic peroxides such as ammonium persulfate, potassium chlorate, potassium bromate and potassium perphosphate. Among these, it is preferable to use tributyl boron or partially oxidized tributyl boron. Of these, partially oxidized tributylboron is most preferable, and has an advantage that the composition can be sufficiently cured even in the presence of water or blood, for example, while the polymerization rate is set to an appropriate rate for application to the affected area.

In addition, as a specific example of the component (I), in the photopolymerization type,
Α-diketones such as 4,4-dichlorobenzyl, diacetyl, dl-camphorquinone;
Acetophenone, 2,2-dimethoxy-2-phenylacetophenone, 2,2-diethoxy-2-phenylacetophenone, 1,1-dichloroacetophenone, 2-methyl-1- [4- (methylthio) phenyl] -2-morpholino- Acetophenones such as propan-1-one, 2-benzyl-2-dimethylamino-1- (4-morpholinophenyl) -butan-1-one;
Benzoin / benzoin alkyl ethers such as benzoin, benzoin methyl ether, benzoin ethyl ether;
Anthraquinones such as 2-methylanthraquinone, 2-ethylanthraquinone, 2-t-butylanthraquinone, 1-chloroanthraquinone, 2-amylanthraquinone;
Benzophenones such as benzophenone;
Phosphine oxides such as trimethylbenzoyldiphenylphosphine oxide;
And so on.

  In the present invention, the amount of component (I) is preferably 0.1 to 20% by weight, more preferably 0.5 to 15% by weight, still more preferably 1 to 12% by weight, based on the total amount of the composition. Most preferably, it is in the range of 1.2 to 9% by weight. Moreover, it is preferably 0.1 to 20% by weight, more preferably 0.5 to 15% by weight, and further preferably 1 to 12% by weight, based on the total amount of the components except the filler (F) described later. Most preferably, it is in the range of 2 to 9% by weight. Below this numerical range, the composition hardens in the application area and may not be able to induce the expression of adhesion protein without staying in the application area. There is a possibility that significant heat generation may occur and cause burns. The composition of the present invention is preferably cured in 0.5 to 15 minutes, more preferably 1 to 10 minutes, and further preferably 1.5 to 8 minutes.

  In the present invention, if desired, a reducing compound (hereinafter sometimes referred to as (Ir)) can be used in combination. Examples of (Ir) include inorganic sulfur compounds such as sulfurous acid, metasulfurous acid, metabisulfurous acid, pyrosulfurous acid, thiosulfuric acid, dithionic acid, dithionic acid, hyposulfite, hydrosulfurous acid, and salts thereof. Among these reducing inorganic compounds, sulfites can be preferably used. Specific examples of preferred compounds include sodium sulfite, potassium sulfite, sodium hydrogen sulfite and potassium hydrogen sulfite.

Examples of the organic reducing compound include aromatic sulfinic acids such as benzenesulfinic acid, o- or p-toluenesulfinic acid, ethylbenzenesulfinic acid, decylbenzenesulfinic acid, dodecylbenzenesulfinic acid, chlorobenzenesulfinic acid, or salts thereof;
N, N-dimethylaniline, N, N-dimethyl-p-toluidine, N, N-dimethyl-p-toluidine, N, N-dihydroxymethyl-p-toluidine, N, N-dimethyl-pt-butyl In addition to aniline, N, N-dimethylanilysine, N, N-dimethyl-p-chloroaniline, etc., the following formula (1)

(Here, R ¹ and R ² are each independently a hydrogen atom or an alkyl group which may have a functional group or a substituent, and R ³ is a hydrogen atom or a metal atom.)
And / or the following formula (2)

(Where R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group, and R ⁶ is a hydrogen atom, an alkyl group which may have a functional group or a substituent, or a functional group or a substituent. Any of the alkoxyl groups that may be present.)
The compound represented by these can be mentioned.

  Specific compounds included in the above formula (1) include N-phenylglycine, N-tolylglycine, N- (3- (meth) acryloxy-2-hydroxypropyl) -N-phenylglycine and / or these Mention may be made of salts. Of these, N-phenylglycine and / or a salt thereof can be preferably used.

Specific compounds included in the above formula (2) include N, N-dimethylaminobenzoic acid and its alkyl ester, N, N-diethylaminobenzoic acid and its alkyl ester, and N, N-dipropyl. Aliphatic alkylaminobenzoic acid and its alkyl ester represented by aminobenzoic acid and its alkylester, N-isopropylaminobenzoic acid and its alkylester, N-isopropyl-N-methylaminobenzoic acid and its alkylester;
Aliphatic alkylaminobenzaldehydes represented by N, N-dimethylaminobenzaldehyde, N, N-diethylaminobenzaldehyde, N, N-dipropylaminobenzaldehyde, N-isopropyl-N-methylaminobenzaldehyde, and the like;
Fats represented by N, N-dimethylaminoacetylbenzene, N, N-diethylaminoacetylbenzene, N, N-dipropylaminoacetylbenzene, N-isopropylaminoacetylbenzene, N-isopropyl-N-methylaminoacetylbenzene, etc. Examples thereof include aliphatic alkylaminoacetylbenzenes and aliphatic alkylaminoacylbenzenes.
These reducing compounds (Ir) can be used alone or in combination of two or more.

  In the present invention, the amount of the (Ir) component that is optionally blended is preferably 0.01 to 15% by weight, more preferably 0.05 to 10% by weight, and still more preferably 0.8%, based on the total amount of the composition. It is in the range of 1 to 5% by weight. Moreover, it is preferably 0.1 to 15% by weight, more preferably 0.2 to 10% by weight, and further preferably 0.25 to 5%, based on the total amount of components of the composition excluding the filler (F) described later. It is in the range of wt%. Below this numerical range, the effect of blending may not appear, and when it exceeds, curing is extremely rapid and significant heat is generated at the application part, which may cause burns, both of which are not preferable.

In the present invention, a filler (F) may be used if desired. Examples of the component (F) include an organic filler (F1), an inorganic filler (F2), and an organic-inorganic composite filler (F3). (F) By mix | blending component, the fluidity | liquidity of a composition at the time of applying a composition directly to a biological body can be adjusted, and it prevents that a composition flows out to parts other than an affected part carelessly. At the same time, the operability of application can be improved.
Examples of (F1) include polyethylene glycol, polypropylene glycol, polyvinyl alcohol, etc., as well as single monomers listed as the (M) component such as poly (methyl (meth) acrylate) and poly (ethyl (meth) acrylate) Or a copolymer can be mentioned.

Specific examples of (F2) include metal oxide powders such as zirconium oxide, bismuth oxide, titanium oxide, zinc oxide and aluminum oxide particles, silica, bismuth carbonate, zirconium phosphate, barium sulfate, aluminum hydroxide or , CaHPO ₄ , Ca ₃ (PO ₄ ) ₂ , Ca ₅ (PO ₄ ) ₃ OH, Ca ₄ O (PO ₄ ) ₂ , Ca ₈ H ₂ (PO ₄ ) ₆ , Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , CaP ₄ O ₁₁ , Ca (PO ₃ ) ₂ , Ca ₂ P ₂ O ₇ , Ca (H ₂ PO ₄ ) ₂ , CaO, Ca (OH) ₂ , Ca (HCO ₃ ) ₂ , CaCO ₃ , CaCl ₂ Inorganic calcium salts such as 4- (2- (meth) acryloxyethyl) trimellitic acid calcium and 4-styrene calcium calcium , Metal salt powders such as calcium salts of organic acids, silica glass, aluminum-containing glass, barium-containing glass, strontium-containing glass, zirconium silicate glass, and other glass fillers, silver sustained-release fillers, fluorine sustained-release fillers Etc.
In order to improve the dispersibility in the component (M), these inorganic fillers (F2) may be used after being subjected to surface treatment such as silane treatment or polymer coating by a conventionally known method.

As an example of (F3), trimethylolpropane methacrylate and silica filler can be mixed and polymerized and then pulverized.
Among these components (F), it is preferable to use a homopolymer of the component (M), and it is most preferable to use poly (methyl methacrylate).
These (F) components can be used individually or in combination of 2 or more types.
As the particle size of the component (F) is smaller, the viscosity can be adjusted by adding a small amount, but the feeling of application and elongation at the time of application can also be adjusted. Preferably, fillers having an average particle diameter in the range of 1 nm to 50 μm, more preferably 5 nm to 30 μm, and still more preferably 10 nm to 20 μm are used.

The use amount of the component (F) optionally blended in the present invention is preferably 0.5 to 75% by weight, more preferably 1 to 70% by weight, further preferably 2 to 66% by weight based on the total amount of the composition. %, Particularly preferably in the range of 30 to 60% by weight. Below this numerical range, the effect of the blending cannot be confirmed, and when it exceeds, there is a possibility that the fluidity will remarkably increase and the operability may be affected, both of which are not preferable.
In the present invention, a polyfunctional (meth) acrylate compound (hereinafter sometimes referred to as (Mm) component) may be used as a compounding component of the (meth) acrylic compound ((M) component) as desired. Absent. By blending the (Mm) component, the rate of polymerization and curing can be adjusted, and the hardness of the composition after curing can be adjusted.

As a specific example of the component (Mm),
Poly (oxyalkylene) di (meth) acrylates such as ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate;
Glycerol di (meth) acrylate, trimethylolpropane di (meth) acrylate, meso-erythritol di (meth) acrylate or tri (meth) acrylate, pentanetriol di (meth) acrylate, tetramethylolmethane di (meth) acrylate or tri ( Di (meth) acrylates or tri (meth) acrylates of alkane polyols such as meth) acrylates, di (meth) acrylates of hexanetriol, di (meth) acrylates of hexanetetraol or tri (meth) acrylates;
A plurality of (meth) acryloyl groups such as N-benzyl-N, N-bis [(meth) acryloyloxyethyl] dodecylammonium chloride and N, N, N-tris [(meth) acryloyloxyethyl] dodecylammonium chloride Having an ammonium salt;
Or following formula (3)

[In the formula, R ⁷ is a divalent aromatic residue or cycloalkyl residue which has at least one aromatic ring and may have an oxygen atom or a sulfur atom in the molecule, preferably the following formula: Groups represented by each of (4):

R ⁸ and R ⁹ each independently represent a hydrogen atom or a methyl group, and j and k each independently represent an integer of 1 to 10, preferably 1 to 8. Polyfunctional (meth) acrylate,
Aliphatic, alicyclic or aromatic epoxy di (meth) acrylate represented by the following formula (5)

[Wherein R ¹⁰ has a divalent aromatic residue or cycloalkyl residue which has at least one aromatic ring and may have an oxygen atom or a sulfur atom in the molecule, preferably the above formula Any one selected from the groups represented by each of (4), R ¹¹ and R ¹² each independently represent a hydrogen atom or a methyl group, and l is an integer of 1 to 10, preferably 1 to 5. Show),
Furthermore, a polyfunctional (meth) acrylate having a urethane bond in the molecule represented by the following formula (6)

[In the formula, R ¹³ has a divalent aromatic residue or cycloalkyl residue which has at least one aromatic ring and may have an oxygen atom or a sulfur atom in the molecule, preferably the above-mentioned formula Any one selected from the groups represented by each of (4), R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom or a methyl group],
Furthermore, a compound having at least one acidic group such as bis (2- (meth) acryloxyethyl) hydrogen phosphate and a plurality of (meth) acryloyl groups can be exemplified.
These compounds as the component (Mm) can be used alone or in combination of two or more.

  In the present invention, the amount of the (Mm) component optionally blended is preferably 0.1 to 20% by weight, more preferably 0.5 to 15% by weight, and still more preferably 1 based on the total amount of the composition. It is in the range of -10% by weight. Further, it is preferably in the range of 1 to 20% by weight, more preferably 2 to 15% by weight, and further preferably 3 to 10% by weight, based on the total amount of the components of the composition excluding the filler (F). . Below this numerical range, the curing rate of the composition and the hardness after curing cannot be sufficiently increased, and when it exceeds, there is a possibility that the curing of the composition will be remarkably accelerated and the operability may be affected. It is not preferable.

  In addition, among the compounds included in the (Mm) component that is optionally blended in the present invention, the amount of the compound containing an acidic group is preferably 0.25 to 9.99 weight based on the total amount of the composition. %, More preferably 0.3 to 9.95% by weight, still more preferably 0.35 to 9.8% by weight, and most preferably 0.4 to 9.7% by weight. Preferably, the total amount of the components of the composition excluding (F) is 0.8 to 9.99% by weight, more preferably 0.85 to 9.95% by weight, and even more preferably 0.88 to 9.9. It is 8% by weight, most preferably in the range of 0.9 to 9.7% by weight. Furthermore, among the compounds included in the component (M2) and / or (Mm), the total amount of the compound containing an acidic group is preferably 0.25 to 9.99, based on the total amount of the composition. % By weight, more preferably 0.3 to 9.95% by weight, still more preferably 0.35 to 9.8% by weight, and most preferably 0.4 to 9.7% by weight. Of course, also in this case, the total use amount of these components shall not exceed the range of the use amount of the component (M). Further, based on the total amount of the components of the composition excluding the filler (F), preferably 0.8 to 9.99% by weight, more preferably 0.85 to 9.95% by weight, and still more preferably 0. The range is from .88 to 9.8% by weight, most preferably from 0.9 to 9.7% by weight. Below these numerical ranges, it is difficult for the composition to stay locally, and when it exceeds, the cured composition becomes brittle or the composition cures significantly faster, which may affect operability. In either case, expression of the adhesion protein may not be promoted, which is not preferable.

In the adhesive protein expression promoting composition of the present invention, as long as the effect is not impaired, as other components (hereinafter sometimes referred to as (X) component), for example, 4-methoxyphenol, 2,6-di-t -Polymerization inhibitors such as butyl-4-methylphenol;
Polymers such as polyethylene and polypropylene;
Inorganic pigments such as titanium mica, titanium oxide, bismuth oxychloride, synthetic phlogopite, mica, iron oxide;
Solvents such as acetone, ethanol, water;
Identification of compositions in the oral cavity such as Blue No. 1, Blue No. 404, Red No. 106, Red No. 201, Red No. 220, Red No. 225, Red No. 226, Red No. 227, Yellow No. 4, Gunjo, Conger, etc. Colorants to facilitate;
Metal salts such as magnesium chloride, magnesium acetate, magnesium sulfate, magnesium carbonate, barium sulfate;
Β-lactams such as ampicillin, aminoglycosides such as kanamycin, tetracyclines such as tetracycline hydrochloride, macrolides such as erythromycin, chloramphenicols, ketolides such as tethromycin, polyene macrolides such as amphotericin B, glycosyl such as vancomycin Antibiotics such as peptides, nucleic acids such as fosmidosine, pyridonecarboxylic acids such as levofloxacin, oxazolidinones such as linezolid;
anti-inflammatory agents such as β-glycyrrhetinic acid, glycyrrhizic acid, ε-aminocaproic acid, lysozyme chloride, indomethacin, ibuprofen, epidihydrocholesterin, dihydrocholesterol, hinokitiol, serrapeptase, pronase, buckwheat extract, allantoin;
Analgesics such as aspirin, acetaminophen, methyl salicylate, epilysole, naproxen, etodolac, flurbiprofen, loxoprofen sodium, mefenamic acid;
Hemostatic agents such as rutin, ascorbic acid, tranexamic acid, thrombin;
Blood circulation promoters such as vitamin E, sodium chloride, nicotinic acid-dl-α-tocopherol;
Antihistamines such as cimetidine, chlorferamine maleate, promethazine hydrochloride, diphenhydramine hydrochloride;
Bactericides such as chlorhexidine hydrochloride, cetylpyridinium chloride, chlorhexidine gluconate, dipotassium glycyrrhizinate, isopropylmethylphenol, triclosan, benzethonium chloride;
Disinfectants such as hydrogen peroxide, iodoglycerin, iodine tincture, chloramine, acrinol, and popidone iodine may be added.

When the composition thus obtained is applied, the adhesion protein is expressed on the surface of the epithelial tissue in contact with the composition and / or the regenerated epithelial tissue in contact with the composition, and biological sequestration is caused. Done.
There are no particular restrictions on the adhesion protein that induces expression in epithelial tissues, but preferred examples include laminin, integrin, nidogen, collagen, and perrican. Of these, laminin and / or integrin is preferably expressed.
Laminin is known to form a trimer and express its function. As components of laminin trimer, subunits such as α ₁ , α ₂ , α ₃ , α ₄ , α ₅ , β ₁ , β ₂ , β ₃ , γ ₁ , γ ₂ , γ ₃ are currently known. Among these, it is particularly preferable to express at least one laminin subunit selected from the group consisting of α ₁ , α ₃ , β ₁ , β ₂ , β ₃ , γ ₁ , γ ₂ , it is particularly preferred to express the gamma ₂ laminin subunits.

Integrins are also known to form dimers. The constituents include α ₁ , α ₂ , α ₃ , α ₄ , α ₅ , α ₆ , α ₇ , α ₈ , α _V , α _L , α _M , α _X , α _IEL , α _IIb , β ₁ , Β ₂ , β ₃ , β ₄ , β ₅ , β ₆ , β ₇ , β _8, etc. subunits are currently known, of which α ₁ , α ₂ , α ₃ , α ₆ , α ₇ Preferably, at least one subunit selected from the group consisting of, β ₁ and β ₄ is expressed, and in particular, at least one integrin selected from the group consisting of α ₃ , α ₆ , β ₁ , β ₄ It is particularly desirable that the subunit is expressed.
Furthermore, even if these adhesion proteins are 1 type, 2 or more types from which the subunit which comprises may differ may be expressed.

  The expression of these proteins can be confirmed by a conventionally known method. For example, a part of the tissue can be collected with a scalpel, an injection needle, etc., and can be identified by immunohistochemical staining or immunofluorescent staining after paraffin or frozen sections as necessary. In immunohistochemical staining, indirect methods such as ABC method, LSAB method, and enzyme-labeled polymer method are preferably used. In immunofluorescent staining, a primary antibody against the target protein is reacted and then labeled with a fluorescent dye. It is preferable to use an indirect method using a secondary antibody. Among these, an indirect method of immunohistochemical staining using a paraffin section fixed with formalin or paraformaldehyde can be preferably selected from the viewpoint of simplicity of identification. When using a paraffin section fixed with formalin or paraformaldehyde, it may be necessary to activate the antigen of the section. Conventionally known methods can be employed for antigen activation, and specifically, protease treatment, heat treatment, and microwave treatment can be exemplified. When identified by immunohistochemical staining or immunofluorescent staining, the surface of the epithelial tissue in contact with the composition and / or the regenerated epithelial tissue in contact with the composition and / Or it is preferable that the cell which contacts a composition obtains the dyeing | staining property equivalent to or more than a positive control. As a preferred positive control, the connective tissue side of normal gingival epithelium and normal adhering epithelium can be mentioned particularly in the oral cavity region.

In the present invention, `` configured '' is not limited to being mixed in the composition from the beginning, and if necessary, each component is appropriately sealed and stored, It includes mixing at the time of use.
As the form of use of the composition for inducing the expression of the adhesion protein of the present invention, the following modes are preferably selected.
(1) A method in which the component (M) and the component (I) are stored separately, mixed immediately before use, and applied and polymerized using a brush or the like;
(2) Among components (M) and (I), a composition containing a group selected from a photopolymerization initiator is stored in a bottle, applied directly using a brush or the like, using a light irradiator A method of polymerizing and curing the composition;
Etc. can be illustrated.

  When the composition for inducing the expression of the adhesion protein of the present invention is used, for example, for the purpose of blocking the wound surface, laminin or the like is expressed on the surface in contact with the epithelial composition regenerated under the composition, The wound surface is covered with the composition, and the composition and the regenerative epithelium are biologically adhered to each other, so that a coating without a minute gap is performed. In addition, for example, when applied to a dental implant body, cured, and implanted, laminin or the like is expressed on the implant surface in the epithelium in contact with the implant body, and the implant body and the epithelium are biologically bonded, The effect of suppressing the occurrence of peri-implantitis can be expected by eliminating the gap between the non-self tissue and the self tissue.

  EXAMPLES Hereinafter, although an Example further demonstrates this invention in detail, this invention is not limited at all by an Example.

<Preparation of composition>
A liquid A was obtained by dissolving 0.5 g of 4-methacryloxyethyl trimellitic anhydride in 9.5 g of methyl methacrylate and mixing well. Immediately before application as described later, 900 mg of liquid A, tributylborane partial oxide (manufactured by Sun Medical Co., Ltd., 0.5 mol per 1 mol of oxygen-added tributylboron), 60 mg of polymethyl methacrylate powder (number average molecular weight 40 The composition was obtained by thoroughly mixing 800 mg of an average particle size of about 25 μm, manufactured by Sun Medical Co., Ltd. with a brush.

Example 1
Sprague-Dawley male rats were anesthetized with sodium thiopental and the oral cavity was cleaned with physiological saline. Next, the palatal gingiva from the upper first molar to the second molar was excised with a width of about 1 mm with a scalpel, and about 10 mg of the above composition was applied. Immediately after application, the composition was able to modify its form. When the composition surface was pressed with a dental probe 6 minutes after the start of application, it was confirmed that the composition was cured. After 3, 5, 7, 14 days, the rats were sacrificed, perfusion-fixed with phosphate buffer containing 4% paraformaldehyde, EDTA decalcified, and 3 μm thick cheek-lingual paraffin sections were prepared according to the usual method. The obtained sections were stained with hematoxylin-eosin. Further, after antigen activation with 0.1% trypsin solution, color development is performed with diaminobenzidine tetrahydrochloride using anti-laminin γ ₂ antibody (Abcam) and anti-integrin β ₄ (Abcam) antibody. Immunohistochemical staining was performed according to the conventional method.
Three days after the treatment, a large number of lymphocytes and fibrin were present under the cured composition due to excision, but the epithelium without a keratinized layer was regenerated day by day from the fifth day. After the start of epithelial regeneration, localization of laminin γ ₂ and integrin β ₄ was observed on the surface in contact with the composition of the regenerating mucosa in any of the investigation periods.

Example 2
Sprague-Dawley male rats were treated in the same manner as in Example 1. After 14 days, the cured composition was removed with a dental probe, and the rats were sacrificed after 1, 3, 5, 7 days. Perfusion fixation with a phosphate buffer containing% paraformaldehyde and EDTA decalcification were carried out, and a buccal-lingual paraffin section having a thickness of 3 μm was prepared according to a conventional method, and the obtained section was stained with hematoxylin-eosin. Further, after antigen activation with 0.1% trypsin solution, color development is performed with diaminobenzidine tetrahydrochloride using anti-laminin γ ₂ antibody (Abcam) and anti-integrin β ₄ (Abcam) antibody. Immunohistochemical staining was performed according to the conventional method. In the oral findings on the first day after the removal, no significant difference was obtained from normal tissues, but the hematoxylin-eosin stained image confirmed that there was no keratinized layer in the regenerated epithelium, and the regenerated epithelium was weak However, after 3 days from the removal, both oral findings and hematoxylin-eosin-stained images obtained an image similar to a normal tissue with a keratinized layer. Laminin γ ₂ and integrin β ₄ were observed to be localized in the basement membrane and adherent epithelium. Thereby, it was shown that biological blockade was performed by the treatment of Example 1 and that epithelial tissue could be regenerated without causing infection with pathogenic bacteria.

Example 3
The above-mentioned composition was applied to an implant fixture made of titanium alloy having a diameter of 2 mm, a length of 5 mm, and a screw, which was ultrasonically cleaned for 10 minutes in acetone, dried, and allowed to cure at room temperature all day and night. Got. Sprague-Dawley male rats were anesthetized with sodium thiopental, and the maxillary first molar was extracted. The extraction cavity was enlarged with a # 120 reamer, the cavity was washed with physiological saline, and an implant specimen was immediately placed. After 1, 2, and 4 weeks after the operation, the rats were sacrificed, perfusion-fixed with a phosphate buffer containing 4% paraformaldehyde, EDTA decalcified, and the implant specimen was carefully removed. -A tongue-like paraffin section was prepared, and the obtained section was stained with hematoxylin-eosin. Further, after antigen activation with 0.1% trypsin solution, color development is performed with diaminobenzidine tetrahydrochloride using anti-laminin γ ₂ antibody (Abcam) and anti-integrin β ₄ (Abcam) antibody. Immunohistochemical staining was performed according to the conventional method. Around one week after the operation, the epithelium around the implant was observed, and a weak positive image of laminin γ ₂ was observed on the surface of the peri-implant epithelium in contact with the implant specimen. Further, after 2 weeks from the operation, strong positive images of laminin γ ₂ and integrin β ₄ were observed on the surface of the peri-implant epithelium in contact with the implant specimen. Thus, the treatment of Example 3 shows that even if the act of losing epithelial continuity called implant placement is performed, it is shown that biological blockage is performed, and there is a possibility that prognostic pathogen infection or the like will not occur It has been shown.

Claims (10)

  An adhesive protein expression-inducing composition comprising a (meth) acrylic compound and a radical polymerization initiator.   The composition according to claim 1, wherein expression of adhesion protein is induced in a tissue in contact with the composition.   The composition according to claim 1 or 2, wherein the adhesion protein is laminin and / or integrin. 4. The composition of claim 3, wherein the laminin has at least one subunit selected from [alpha] ₁ , [alpha] ₃ , [beta] ₁ , [beta] ₂ , [beta] ₃ , [gamma] _1, and [gamma] ₂ . _4. The composition of claim ₃ , wherein the integrin has at least one subunit selected from [alpha] ₃ , [alpha] ₆ , [beta] ₁ and [beta] ₄ .   The composition according to any one of claims 1 to 5, wherein the methacrylic compound is a monofunctional (meth) acrylate compound.   The composition according to any one of claims 1 to 5, wherein the methacrylic compound is a monofunctional (meth) acrylate compound (M2) containing an acidic group.   The composition according to any one of claims 1 to 7, wherein the radical polymerization initiator is an organic boron compound.   Furthermore, the composition in any one of Claims 1-8 containing a filler (F). Use of a combination of a (meth) acrylic compound and a radical polymerization initiator in an adhesive protein expression-inducing composition.