WO2008038503A1 - Blend type photocurable chitosan adhesive or coating agent - Google Patents

Abstract

Disclosed is an adhesive or coating agent, particularly a medical adhesive or coating agent, which is excellent in adhesiveness, biocompatibility and convenience. Also disclosed is use of such an adhesive or coating agent. Specifically disclosed is a photocurable adhesive or coating agent, which contains a chitosan derivative having a photopolymerizable functional group and a photopolymerizable resin.

Description

 Specification

 Blended photo-curing chitosan adhesive or coating

 Technical field

 [0001] The present invention relates to a photocurable adhesive or coating used for a living body. Specifically, the present invention relates to a photocurable adhesive or coating agent containing a chitosan derivative having a photopolymerizable functional group and a photopolymerizable resin, particularly a medical adhesive or coating agent, and uses thereof.

 Background art

 [0002] Regarding the treatment of wounds and surgical sites in recent years, the use of adhesives has attracted attention, and several synthetic adhesives and natural product-derived adhesives have been used. As a synthetic adhesive, cyanate-based medical adhesives are widely used. However, taking the representative `` Alon Alpha A '' as an example, it has adhesive strength but has poor biocompatibility and flexibility. Depending on the location, vascular lesions such as occlusion of blood vessels are observed, and there are restrictions on the location and method of use due to side effects such as severe inflammation. Examples of natural products include gelatin-formaldehyde (Non-patent Document 1), fibrindale (Non-Patent Document 1), and chitosan (see Patent Document 1). Although both are excellent in biocompatibility, the gelatin-formaldehyde system uses harmful formaldehyde as a cross-linking agent, so its safety has been questioned. The chitosan system had a problem in adhesive strength. In addition, gelatin-formaldehyde-based fiber glue adhesives have restrictions on the time and timing until bonding. Therefore, the current situation is that the development of medical adhesives with excellent adhesiveness, biocompatibility, and convenience is still desired.

 Patent Document 1: Japanese Patent Laid-Open No. 2005-154477

 Non-Patent Document 1: Techniques in Gastrointestinal Endoscopy, 8, p.33-37, (2006). Int. J. Adhesion and adhesives, 16, p.17-20, (1996).

 Disclosure of the invention

Problems to be solved by the invention [0003] The problem to be solved by the present invention is to provide an adhesive or coating agent, particularly a medical adhesive or coating agent, which is excellent in adhesiveness, biocompatibility, convenience!

 Means for solving the problem

 [0004] The inventors of the present invention have intensively studied to solve the above problems, and can solve the above problems by mixing a photopolymerizable resin with a chitosan derivative having a photopolymerizable functional group. The inventors have found that a mold adhesive or coating agent can be obtained, and have completed the present invention. Since the chitosan derivative having a photopolymerizable functional group and a photopolymerizable resin are mixed, the adhesive or coating material of the present invention may be referred to as a “bend-type” photocurable chitosan-based adhesive or covering agent. it can.

 [0005] That is, the present invention provides the following:

 (1) a photocurable adhesive or coating agent comprising a chitosan derivative having a photopolymerizable functional group and a photopolymerizable resin;

 (2) An ultraviolet curable adhesive or coating agent comprising a chitosan derivative having an ultraviolet polymerizable functional group and an ultraviolet polymerizable resin, wherein the chitosan derivative is represented by the following formula (I):

 [Chemical 1]

[Wherein l + m + n = l; and

 1, m, n are independently 0 <1 <1, 0 <m <l, 0 <η <1;

 Ac is a acetyl group;

 R1 is the following formula (II):

(式中、 R2は水素または C；! 3アルキル基である）で示される]で示されるものである 接着剤または被覆剤；

(Wherein R2 is hydrogen or C;! 3 is an alkyl group)] an adhesive or coating agent;

 (3) The adhesive or coating agent according to (2), wherein 1 m n is independently 0 <1 <0 · 8 0 <m <0.8.8 0 · 2 <η <0.8.

 (4) The adhesive or coating agent according to (2) or (3), wherein R2 is hydrogen or methyl;

(5) The ultraviolet-polymerizable resin is a glycerin monometatalylate resin (2)! / In (4), the displacement force, or the adhesive or coating agent according to item 1;

 (6) Further containing a polymerization initiator (1) The adhesive or coating agent according to any one of (5)! /;

(7) It is a medical adhesive (1) The adhesive or coating agent according to (6)!

(8) The adhesive or coating agent according to (7), which is a medical coating agent;

 (9) The adhesive or covering agent according to (8), which is a wound protective agent;

 (10) The adhesive or coating agent according to (9) having an antibacterial effect;

 (11) The adhesive or coating agent according to (8), which is a sealer for a catheter insertion site;

(12) The adhesive or coating agent according to (8), which is a sealer for the nipple mouth and nipple tube; and

 (13) The adhesive or coating agent according to (1) or (2), which is curable by visible light.

 The invention's effect

 [0006] According to the present invention, there are provided adhesives, biocompatibility, convenience! /, Adhesives or coatings excellent in deviation, particularly medical adhesives, and uses thereof.

 Brief Description of Drawings

[0007] FIG. 1 shows the FT / IR spectrum of UV-curable chitosan derivatives with different degrees of substitution of side chains. _a , bcdefg, (corresponding to derivative numbers 1 2 3 4 5 6 7 8 in Table 1 respectively) chitosan is a raw material chitosan, chitin is a 100% acetylated sample of raw material chitosan. Peripheral absorption peaks indicated by arrows are due to the polymerizable side chain: 1) 1720cm— ¹ , C = 〇; 2 6) 1640cm—814cm— ¹ , C = C; 3) 1510cm—benzene ring; 1660cm— Acetyl group. 2) 4) 5) 6) Peak disappearing after photopolymerization.

BEST MODE FOR CARRYING OUT THE INVENTION [0008] The present invention provides a photocurable adhesive or coating agent comprising a chitosan derivative having a photopolymerizable functional group and a photopolymerizable resin. Here, light includes not only light rays such as visible light rays and ultraviolet rays but also electromagnetic waves such as X-rays. Photopolymerizable functional groups and photopolymerizable resins are well known to those skilled in the art, and those skilled in the art can select and use them as appropriate. Examples of the photopolymerizable functional group include a (meth) atalyloyl group, a butyl ether group, a cinnamoyl group, an azide group, and a maleimide group. Examples of the photopolymerizable monomer resin include (meth) acrylic acid and hydroxyethyl. (Meth) acrylate, polyethylene glycol di (meth) acrylate, polyethylene glycol diglycidyl ether di (meth) acrylate, methacrylate, N-methoxymethyl acrylamide, N-dimethylaminoethyl (meth) acrylate, attaroyl Examples include S, such as morpholine, glycosylethyl methacrylate, 2-acrylamide-2-methylpropanesulfonic acid, N, N-dimethylacrylamide, N-butylpyrrolidone. There are many types of photopolymerizable polymer resins, but systematically, epoxy (meth) acrylate, urethane (meth) acrylate, polyester (meth) acrylate, copolymer (meth) acrylate, There are polybutadiene (meth) acrylate, silicon (meth) acrylate, and amino resin (meth) acrylate. Examples of cationic polymerization include alicyclic epoxy resins and butyl ether resins. Among photopolymerizable functional groups and photopolymerizable resins, particularly widely used are UV-polymerizable functional groups and UV-polymerizable resins. Hereinafter, chitosan derivatives having UV-polymerizable functional groups (also referred to as UV-curable chitosan derivatives; hereinafter referred to as “UVCC”) and UV-curable adhesives containing UV-polymerizable resins Alternatively, the present invention will be described by taking a coating agent (hereinafter sometimes referred to as “the adhesive or coating agent of the present invention”) as an example. However, the present invention is limited to an ultraviolet curable adhesive or a coating material. is not.

[0009] As described above, in one aspect, the present invention provides an ultraviolet curable adhesive or coating agent containing UVCC and an ultraviolet polymerizable resin. U used in the present invention

VCC has an ultraviolet polymerization functional group in a part of the sugar residue of chitosan.

[0010] The position of the UV-polymerizable functional group is preferably // of chitosan, or may be a shifted part! /, But is preferably bonded to nitrogen at the 2-position of the sugar residue. The UV-polymerizable functional group (hereinafter referred to as “R1”) that binds to the nitrogen at the 2-position of the sugar residue can cause a polymerization reaction upon UV irradiation. There are various known groups. A group in which the obtained UVCC is less toxic to a living body or non-toxic is preferred. Power, Karu R1 is preferably a group derived from UV-polymerizable aldehyde. As the UV-polymerizable aldehyde, a (meth) acrylic acid derivative having an aldehyde group capable of reacting with the amino group at the 2-position of chitosan is preferable. The (meth) acrylic acid derivative may be any compound as long as it has an alicyclic group or methacryloyl group that cures when irradiated with ultraviolet rays. I like things! Such aromatic aldehydes can be synthesized by methods known in the art (see, for example, J. Polym. S., Part A: Polym. Chem., Vol. 25, 3063-3077 (1987)) or JP 2005 — It can be carried out according to the method described in Example 1 of Japanese Patent No. 154477. As an example of such an aromatic aldehyde, there is one represented by the following formula (II).

 Therefore, a typical example of a preferable UVCC used in the present invention is represented by the formula (I):

 [Chemical 3]

に示す構造を有するものが挙げられる。式中、 1はキトサンの糖残基のうち 2位がアミノ 基であるもの（ダルコサミン）であるものの割合、 mはキトサンの糖残基のうち 2位が N ーァセチル基であるもの（N—ァセチルダルコサミン）であるものの割合、 nはキトサン の糖残基のうち 2位の窒素（GlcN)が紫外線重合性官能基 R1で置換されたものの 割合である。 1および mの値は使用するキトサンにより異なる。また、 1および mの値は、 公知の方法を用いて脱ァセチル化反応ゃァセチル化反応行うことによって変化させ ること力 Sできる。 l + m + n= lである。好ましい 1、 m、 nの値は 0<1< 1、 0<m< l、 0 <η< 1であり、さらに好ましい 1、 m、 nのィ直は 0<1< 0. 8、 0<m< 0. 8、 0. 2<n< 0. 8である。

Those having the structure shown in FIG. In the formula, 1 is the proportion of chitosan sugar residues whose amino group is at the 2-position (darcosamine), and m is the chitosan sugar residue whose 2-position is at the N-acetyl group (N-A). Cetyldarcosamine), and n is the ratio of the chitosan sugar residue in which the nitrogen (GlcN) at position 2 is substituted with the UV-polymerizable functional group R1. The values of 1 and m depend on the chitosan used. The values of 1 and m can be changed by performing a deacetylation reaction or a acetylation reaction using a known method. l + m + n = l. Preferred values of 1, m, n are 0 <1 <1, 0 <m <l, 0 <η <1, and more preferred values of 1, m, n are 0 <1 <0.8, 0 < m <0.8 and 0.2 <n <0.8.

 A typical example of R1 in formula (I) is formula (II):

に示す官能基が挙げられる。 R1官能基中の R2は水素または C；!〜 3アルキル基であ り、 C；!〜 3アルキル基はメチル、ェチル、プロピル、イソプロピルを包含する。好まし V、R2は水素またはメチル基である。 [Chemical 4]

The functional group shown in these is mentioned. R2 in the R1 functional group is hydrogen or C;! To 3 alkyl group, and C;! To 3 alkyl group includes methyl, ethyl, propyl, and isopropyl. V and R2 are preferably hydrogen or a methyl group.

 [0013] R1 other than the above that can be used in the UVCC of the present invention includes 3 methoxy-4 1 (2 hydroxy 3 methacryloyloxypropoxy) benzyl, 3, 4 bis (2 hydroxy-3- methacryloyloxypropoxy) benzyl 3,5-bis (2hydroxy-3methacryloyloxypropoxy) benzyl, 3-methoxy-4-methacryloyloxybenzyl, 3,4-dimethacryloyloxybenzyl, 3,5-dimethacryloyloxybenzyl group, etc. (See Special Publication 2002-226503).

 [0014] UVCC used for the adhesive or coating of the present invention can be obtained by adding an ultraviolet polymerizable functional group R1 to chitosan. The addition of the R1 group to chitosan can be carried out, for example, according to the method outlined below or the method shown in Example 1 of the present specification). As the chitosan, a commercially available chitosan may be used which can be obtained by deacetylating chitin by a known method, for example. First, chitosan is dissolved in a dilute organic acid aqueous solution such as formic acid or acetic acid, a hydrophilic solvent such as methanol is added, and then a solution of a (meth) acrylic acid derivative is added. Stir for about 6 to about 12 hours, then add a solution of a reducing agent such as sodium borohydride and stir for another about 6 to about 12 hours. These reaction temperatures may be from about 0 ° C. to room temperature.

 [0015] The ratio of chitosan and (meth) acrylic acid derivative to be reacted depends on the desired degree of substitution of GlcN. For example, if the target value of n in the above formula (I) is 0.6, the molar ratio of the (meth) acrylic acid derivative to the GlcN residue of chitosan should be 1: 0 · 6! /.

[0016] In the synthesis of UVCC in which R2 is hydrogen in the formula (II), 2-hydroxy-3- (4-formyl-2-methoxy) phenoxypyrutalylate is used as a (meth) acrylic acid derivative having an aldehyde group. In the synthesis of UVCC, which is R2 force S methyl in formula (II), 2-hydroxy 3- (4 formyl as a (meth) acrylic acid derivative having an aldehyde group 2-Methoxy) phenoxypropinoremethacrylate is used.

[0017] The UVCC used in the adhesive or coating agent of the present invention may be one kind or a combination of two or more kinds. The amount of UVCC in the adhesive or coating of the present invention depends on the type of UVCC, the amount of other components (such as an ultraviolet polymerizable resin and a photopolymerization initiator), and the properties of the target adhesive or coating. Force that can be determined The preferred amount of UVCC is from about 0.5 to about 5% by weight.

 [0018] Another essential component of the adhesive or coating agent of the present invention is an ultraviolet polymerizable resin.

 The present inventors prepared an adhesive containing UVCC, water, DMSO and a photopolymerization initiator (see JP-A-2005-154477), embedded the adhesive cured under the skin of the skin, When the tissue was examined, biocompatibility was shown, but the adhesive strength as an adhesive was weak, and water and DMSO were not involved in the curing reaction, so water and DMSO were liberated after polymerization. It was. In the present invention, the above-mentioned drawbacks are overcome by using UVCC and an ultraviolet polymerizable resin in combination. In other words, mixing with UV-polymerizable resin improves adhesion and covering ability, and mixing UVCC with an ultraviolet-polymerizable resin alone may lower the inflammatory reaction in vivo. Proven.

 [0019] Various ultraviolet-polymerizable resins are known, and any resin may be used. By appropriately selecting the solvent, it is possible to use not only water-soluble resins but also water-insoluble resins. Further, the ultraviolet polymerizable resin may be in the form of a monomer or a polymer. Examples of the UV-polymerizable resin that can be used in the adhesive or coating of the present invention include methyl methacrylate, ethyl methacrylate, butyl methacrylate, dodecyl methacrylate, keihylic acid, methacrylamide, attalyloylmorpholine, and N-methyl. Acrylamide, N, N dimethylaminoethyl (meth) acrylate, N, N-jetylaminoethyl (meth) acrylate, N, N dimethylamino neopentyl acrylate, N bulyl 2-pyrrolidone, N methylol attaly Amides, methoxypolyethyleneglycol (meth) acrylate, -methacryloyloleoxyschichinole hydrogen phthalate, butanediolenomonoacrylate

, 2-hydroxypropyl metatalylate, polyethylene glycol dimetatalylate and the like. The UV-polymerizable resin used in the adhesive or coating agent of the present invention is preferably one that has low toxicity to living organisms, or one that is hypoallergenic! Low toxicity to living body Examples of UV-polymerizable resins that are V or low-irritant include glycerin monometatalylate resin, talyloylmorpholine, polymethylmetatalylate, hydroxyethyl (meth) atrelate, N-bulol-2-pyrrolidone, diacetone acrylamide 2-acrylamidomethylpropane sulfonic acid and the like, and glycerin monometatalylate resin (Nippon Yushi Co., Ltd .; hereinafter referred to as “GLM”) is preferred among others!

 [0020] The ultraviolet polymerizable resin used in the adhesive or coating agent of the present invention may be one kind or a combination of two or more kinds. The amount of the UV polymerizable resin in the adhesive of the present invention is determined according to the type of the UV polymerizable resin, the amount of other components (such as UVCC and a photopolymerization initiator), and the properties of the target adhesive. However, the preferred amount of UV-polymerizable resin is greater than 0% by weight and up to about 95.7% by weight.

[0021] Depending on the type and concentration of components such as UVCC and UV-polymerizable resin used in the adhesive or coating agent of the present invention, it may be difficult to polymerize or may not polymerize. In such a case, a photopolymerization initiator may be used. Various photopolymerization initiators are known, and any substance can be used as long as it generates a radical that becomes a polymerization initiation group upon irradiation with light. Photopolymerization initiators that can be used in the adhesive or coating agent of the present invention include hydroxyketone-based, aminoketone-based, and bisacinorefhosphoxide-based materials, such as benzophenone, benzoinethyl ether, Acetophenone, benzoin methyl ether, hydroxycyclohexyl phenyl ketone, 2-hydroxy-2-methylphenylpropanone 1 [4 (2-hydroxyethoxy) phenyl] 2 hydroxy-2-methylpropanone, etc. in the visible light region Examples of the initiator having an absorption maximum include camphorquinone and a metaguchisen polymerization initiator. The photopolymerization initiator used in the adhesive or coating agent of the present invention is preferably a photopolymerization initiator that has low toxicity to the living body or low irritation. Examples of such photopolymerization initiators include, for example, Irgacure (registered trademark) 2959 (2 hydroxy 1 [4 (hydroxyethoxy) phenyl] 2-methyl-1 propanone). Other examples include IrlOOO (Irgacure (registered trademark) 1000; Chino 'Specialty Chemicals Co., Ltd.), Ir819 (Irgacure (registered trademark) 819; Chino' Specialty Chemicals Co., Ltd.), Ir 184 (Irgacure (registered trademark)) 184; Chinoku 'Specialty Chemicals Co., Ltd.). If the amount of GLM is less than 50% by weight, water-soluble photopolymerization It is preferable to use a combination of initiators (for example, Irgacure 2959).

[0022] The photopolymerization initiator used in the adhesive or coating agent of the present invention may be one kind or a combination of two or more kinds. The amount of the photopolymerization initiator in the adhesive or coating of the present invention includes the type of photopolymerization initiator, the amount of other components (UVCC, UV-polymerizable resin, etc.), and the target adhesive or coating agent. The preferred amount of photoinitiator is from about 0.5 to about 4% by weight, although it can be determined depending on the properties. When an electron beam or the like is used as a light source, it is not always necessary to add a photopolymerization initiator.

[0023] Depending on the type and amount of UVCC used, UVCC may not dissolve well in the adhesive or coating of the present invention. In such a case, the UVCC is blended after it is dissolved in a substance that is highly soluble or highly dispersible in UVCC. Examples of substances with high solubility or dispersibility of UVCC include acetic acid (aqueous solution), methacrylic acid (aqueous solution), acrylic acid (aqueous solution), DMSO, etc. Low toxicity to living organisms or low irritation ! / In view of this, 2-acrylamido-2-methylpropanesulfonic acid (A MPS) is preferred. AMPS is one of UV-polymerizable acidic substances. It is preferable to previously dissolve or disperse UVCC in the aqueous solution (for example, 3% aqueous solution). The amount of the substance capable of dissolving or dispersing UVCC to the adhesive or coating agent of the present invention may be an amount that can dissolve or disperse UVCC. Since the AMPS aqueous solution is strongly acidic, it is preferable to mix it so that it is neutralized when mixed with UVCC and the pH of the mixed solution is about 4 to about 8, and further about 6 to about 7. For example, it is preferred to use from about 3.8 to about 45% by weight of a 3% aqueous solution for the adhesive or coating of the present invention.

 [0024] Preferable amount of each component in the adhesive or coating of the present invention described above! /, The amount is just a guideline, and UVCC does not precipitate or precipitate when mixed, Any amount is acceptable.

 [0025] The adhesive or coating agent of the present invention may contain other components, for example, an aqueous or non-aqueous solvent such as water or DMSO depending on the purpose. Furthermore, it may contain a disinfectant, a local anesthetic, a wound treatment, epidermal growth factor, and other medicinal ingredients.

[0026] The adhesive or coating agent of the present invention can also be used for adhesion and coating of substances other than living organisms. The adhesive or coating agent of the present invention can be used as a medical product by selecting a component having low toxicity or irritation to the living body or non-toxicity. The adhesive or coating agent of the present invention can be applied to a desired part of a living body. Here, the term “medical use” includes not only human medical treatment but also veterinary use. The adhesive or coating of the present invention has an adhesive strength or covering ability that can withstand practical use when used on a living body such as skin, and has a sufficient flexibility after curing and has a sealing property. Is excellent. In addition, the adhesive or coating agent of the present invention is excellent in hemostatic effect. In particular, the adhesive or coating of the present invention is effective for skin adhesion and coating.

 In view of the above properties of the adhesive or coating agent of the present invention, the adhesive or coating agent of the present invention is also suitable as a medical coating material. A preferable use as a medical coating agent is a use as a wound protective agent. Examples of the wound protection agent include antibacterial agents such as mercurochrome, iodine tincture, chlorhexidine dalconate, benzalkonium chloride, alkyldiaminoethinoglycine, penicillin, gentamicin, chloramphenicol, tetracycline, neomycin, and lidocaine. , Local anesthetics such as xylocaine, mer force in, and carbo force in may also be included. The wound protective agent may include an anti-inflammatory agent such as indomethacin and a growth factor such as epidermal growth factor (EGF)! /. A person skilled in the art can appropriately select these drugs and determine the amount of addition.

 [0028] The adhesive or coating agent of the present invention as a medical coating material may be a sealer at the catheter insertion position. Furthermore, the adhesive or coating material of the present invention as a medical coating material can be used as a sealer for a teat mouth and a teat tube.

 [0029] The adhesive or coating agent of the present invention, particularly those using GLM as an ultraviolet-polymerizable resin, is highly useful in the field of cosmetic surgery because of its high transparency after curing.

 [0030] It is possible to formulate the adhesive, coating, medical adhesive, and medical coating material of the present invention into various forms. These may be formulated as powder and dissolved in water or DMSO before use, or may be formulated in a tube. Since the adhesive or coating of the present invention is photocurable, it is preferable to formulate it in a light-shielding sealed container!

[0031] In order to cure the adhesive or coating agent of the present invention, an ordinary ultraviolet irradiation device is sufficient. For example, when UV irradiation is performed from a distance of 10 mm using a UV lamp with output lKw In this case, the adhesive or coating agent of the present invention can reach a sufficient adhesive strength or exhibit a sufficient covering ability by uv irradiation within a few seconds.

 As described above, the adhesive or coating agent of the present invention has been described mainly with respect to the ultraviolet curable adhesive or coating agent. However, the photopolymerizable functional group, the photocurable resin, or the photopolymerization initiator, and others. It goes without saying that by selecting these components, it is possible to obtain an adhesive or a coating that is cured by visible light, electron beam or the like. Those skilled in the art can appropriately select and use such photopolymerizable functional groups, photocurable resins, and photopolymerization initiators. The present invention also includes an adhesive or a coating agent that is cured by such visible light or electron beam.

[0033] As described above, the photocurable adhesive or coating agent containing the chitosan derivative having a photopolymerizable functional group of the present invention and a photopolymerizable resin includes those that can be cured by visible light. Furthermore, the ultraviolet curable adhesive or coating agent containing a chitosan derivative having an ultraviolet polymerizable functional group and an ultraviolet polymerizable resin of the present invention includes those that can be cured by visible light. The adhesive or coating material of the present invention that can be cured by visible light is preferable because irradiation light is visible light that is gentle to the living body when applied to the living body.

 [0034] The visible light polymerizable functional groups that can be used in the adhesive or coating agent of the present invention that is cured by visible light are not limited to those exemplified above.

 [0035] The visible light polymerizable resin that can be used in the adhesive or coating agent of the present invention that is cured by visible light includes monofunctional or polyfunctional (meth) acrylate, for example, hydroxyethyl (meth) acrylate, hydroxy Long chain alkyl (meth) acrylates such as propyl (meth) acrylate, methyl (meth) acrylate, methoxypolyethylene glycol methacrylate, stearyl methacrylate, butanediol (meth) acrylate, glycidyl methacrylate , 2-Acrylamide-2-Methylpropane sulfonic acid, methacrylamide, triethylenedalicol dimetatalylate (Tri-EDMA), 2, 2-bis (p-2'-hydroxy 1 3'-methacryloxypropoxyphene Nole) propane (Bis—GMA), 2,2-bis (4-methacryloxy polyester) Kishifue two Norre) propane (Bis- MPEPP), G (methacryloxydiethoxyphenyl shell chill) trimethyl

 4E

[5. 2. 1. 0 ² ' ⁶ ] Decane (TCDDMA) and the like are exemplified, but not limited thereto. This Visible light polymerizable resins that have low toxicity or low irritation to living organisms are preferred. Long-chain alkynole (meth) atalylate such as methoxypolyethylene glycol metatalylate and stearyl metatalylate, butanediol (meta ) Atarylate, glycidyl metatalylate, 2-acrylamide-2-methylpropanesulfonic acid, and the like, but are not limited thereto.

 [0036] Visible light polymerization initiators that can be used in the adhesives or coatings of the present invention that are cured by visible light include eosin Y, coumarin, rose bengal, erythemacin, camphorquinone, 9 fluorenone, titanocene compounds such as biscyclohexane. Examples thereof include, but are not limited to, pentagebirubis (difluoropyroylenyl) titanium. Among them, camphorquinone, 9fluorenone, etc., which are preferred as visible light polymerization initiators that have low toxicity or low irritation to living organisms, are not limited to these.

 [0037] A normal visible light irradiation device is sufficient as the irradiation device used for curing the adhesive or coating material of the present invention with visible light to obtain an adhesive or coating material. These visible light irradiation conditions can be appropriately selected by those skilled in the art according to the types and amounts of the individual components and the uses of the adhesive and the covering material. Those skilled in the art will readily manufacture the adhesives or coatings of the present invention that are cured by visible light, based on the general knowledge and capabilities and explanations of the UV curable adhesives or coatings described above, Can be used.

 [0038] Hereinafter, the present invention will be described in more detail and specifically with reference to examples, but the examples are merely illustrative and do not limit the scope of the present invention.

 Example 1

 [0039] Synthesis of UV-curable chitosan derivatives

800 mg of chitosan was dissolved in acetate buffer (ρΗ4, 5, 60 ml), diluted with 40 ml of methanol, and cooled to 0 ° C. To this solution, 0.2 mole equivalent of acetic anhydride per darcosamine residue of chitosan was added and allowed to react overnight at room temperature. UV-curing side chain aldehyde (3-methoxy 4- (2-hydroxy-3 metatalyloxyloxypropoxy) benzaldehyde (also known as: 2-hydroxy-3- (4 formyl-2-methoxy) phenoxypropyl methacrylate)) (chitosan Dissolved in 20 ml of THF. The solution was added dropwise to the above solution at room temperature, reacted at room temperature overnight, cooled again to 0 ° C., and sodium cyanoborohydride dissolved in 10 ml of water was slowly added. The reaction solution is stirred at room temperature and then neutralized with a 10% aqueous sodium hydroxide solution. The resulting precipitate is collected by centrifugation, ethanol is added and repeated centrifugal washing, followed by desalting by dialysis. I did it. Finally, freeze-drying was performed! / \ A purified product of an ultraviolet curable chitosan derivative was obtained.

 [0040] Further, the amount of acetic anhydride and aldehyde to be added is adjusted to 0 to 1 molar equivalent per darcosamine residue of chitosan, and ultraviolet curable chitosan derivatives having different functional group substitution degrees (DS) are obtained. Synthesized. Table 1 shows reagent addition amounts and derivative abbreviations.

 [0041] [Table 1]

 Table 1 Reagent addition amounts and derivative abbreviations

 Amount of reagent added per derivatized GlcN residue

 Body number Derivative symbol

 No. Acetic anhydride Aldehydride

 1 0. 8 Gl cNPsO, 8

 2 0. 6 Gl cNPsO. 6

 3 0. 4 Gl cNPs O. 4

 4 0. 2 Gl cNPsO, 2

 5 0. 2 0. 8 Gl cNAcO. 2- GlcNPsO. 8

 6 0. 4 0. 6 Gl cNAcO. 4- GlcNPsO. 6

 7 0. 6 0. 4 Gl cNAcO, 6- GlcNPsO. 4

 8 0. 8 0. 2 Gl cNAcO, 8- GlcNPsO. 2

[0042] When elemental analysis was performed on the obtained derivatives 1 to 8, the calculated values and the measured values were in good agreement. The degree of substitution of the N-alkyl side chains of these derivatives also corresponded well to the amount of aldehyde used in the synthesis. Figure 1 shows the FT / IR spectra of each derivative. From these results, it was confirmed that the desired derivative was obtained. The yield of each derivative was in the range of 63-83%.

 Example 2

[0043] Preparation of test and test solution

 (a) Comparative sample (Test solution 1)

The purified UVCC was dissolved with the following composition 1 to give test solution 1. Water and DMSO were added to UVCC, stirred until dissolved, and a photopolymerization initiator was added to obtain Test Solution 1. [0044] [Table 2]

 Table 2 Composition of test solution 1

 Ingredient name (weight ratio)

 UVCC 5

 Water 11

 DMSO 84

 Photopolymerization initiator M000 1 Irgacure 1000 (weight ratio 1) is used as the photopolymerization initiator.

 [0045] (b) March wording (phrase, trial ^^ night 2)

 The purified UVCC was dissolved in the following composition 2 to prepare test solution 2. 3% AMPS (9g) was added to UVCC (lg) and stirred for! ~ 2 days to make UVCC emulsion or solution. Table 4 summarizes the results of testing the solubility of purified UVCC in DMSO, 2% acetic acid aqueous solution, 3% AMPS aqueous solution, and 3% AMPS aqueous solution + GLM. To this solution, GLM (20 g) was added and stirred until homogeneous to obtain a single brown transparent UVCC 'resin mixed solution. Test solution 2 was prepared by adding 20% DMSO solution of photopolymerization initiator so that the amount of polymerization initiator was 2% of GLM.

 [0046] [Table 3]

 Table 3 Composition of test solution 2

 Ingredient name (weight ratio)

 UVCC 1

 3% AMPS 9

 GLM 20

 Photoinitiator Ir819 + Irl 84 0.4

The ratio of Ir819 and Irl84 was 1: 5 (weight ratio).

 [0047] Composition 2 is merely an example, and UVCC is about 0.5 to about 5% by weight, 3% AMPS is about 3.8 to about 45%, GLM is less than about 95.7% by weight (UVCC precipitates and precipitates) If the photoinitiator is in the range of about 0.5 to about 4% by weight, a test solution mixed in the same manner as above can be obtained.

[0048] [Table 4] Table 4 Solvent solubility of chitosan derivatives

 uvcc 3% AMPS

DMS 0 ^a 2% AcOH 3% AMPS ^C

+ GLM ^d

1

 2

 3 ―

 Four -

 Five

 6

 7

 8

 ++, dissolved; +-, suspended;-'insoluble.

 a, composition 1.b, 1% derivative Z% AcOH.

 c, 10% derivative / / 3% AM Ρ S.

 d, composition 2. e, dissolves but has high viscosity and is easily separated,

Example 3

Tensile strength test

Horse skin was collected from the waste horse and cut into 5 cm (H) _x 2 cm ( _W ) after shaving. A pseudo-incision was created by making an incision of about 7 mm in the lateral direction in the center. About 100 a 1 of the test solution of Composition 1 and Composition 2 was applied to the incision, and UV irradiation was performed for 4 seconds at an irradiation distance of 10 mm to cure the test solution and close the incision site. The UV irradiation device is EYE CURE LIGHT

SPOT UP 150M (Eye Graphics Co., Ltd.) was used, and a short arc metal halide lamp was used as the UV lamp. The irradiation distance was 10 mm and the irradiation time was 4 seconds. Immediately after the UV irradiation, the upper and lower specimens were fixed to a tensile tester and a tensile strength test was conducted. As a control, a commercially available surgical adhesive: Alon Alpha A (Cyanacrylate Surgical Adhesive (Sankyo Co., Ltd.); hereinafter referred to as “CA”) was applied to the incision, and a pull test was conducted after 4 seconds. It was. The tensile strength measuring instrument Measurement Innovator (Aiko Engineering Co., Ltd.) was used, and the traction machine was Test Stand Model— 1356 (Aiko Engineering Co., Ltd.). The pulling speed is expressed as 5 mm / min, the tensile strength is expressed as N (Newton), and the tensile strength is defined as the load applied when the incision point fixed with the test solution is opened by pulling the test piece. The results of the test solution of composition 1 are shown in Table 5, and the results of the test solution of composition 2 are shown in Table 6. [0050] [Table 5]

 Table 5 Tensile strength test results with composition 1 test solution (Unit: N, n = 3)

UVCC CA 1 2 5 6 7 Average 0.30 0.54 0.58 0.95 3.08 0.48

 CA, medical adhesive

 1. Cured product with composition 1 UVCC of 1 (G 1 NP 5; 0.8)

 2. Cured product with composition 1 UVCC of 2 (G 1 NP 5; 0.6)

 5. Cured product with composition 1 UVCC of 5 (G 1 NA c: 0.2-G 1 c N P s 0

6. Cured product with composition 1 UVCC of 6 (G 1 NA c; 0.4—G 1 c N P s 0

7. Cured product with composition 1 UVCC of 7 (G1NAc: 0.6-G1cNPs0)

[0051] [Table 6]

 Tensile strength test results with composition 2 test solution (unit: N,

 UVCC 1 2 3 4 5 6 7 8

 Average 2.75 3.92 4.84 3.56 3.33 4.12 5.49 4.57

CA, medical adhesive.

 1 Cured product with composition 2 UVCC of 1 (G1CNPSO.8)

 2.Hardened product with UVCC of composition 2 (GlcNPsO.6)

 3. Hardened product with composition 2 UVCC of 3 (GlcNPsO.4)

 4, Cured product with composition 2 UVCC of 4 (GlcNPsO.2)

 5, Cured product with composition 2 UVCC of 5 (GlcNAcO.2—GlcNPsO.8)

 6, Cured product with composition 2 UVCC of 6 (GlcNAcO.4—GlcNPsO.6)

 7. Cured product with composition 2 UVCC of 7 (GlcNAcO.6—GlcNPsO.4)

 8, Cured product with composition 2 UVCC of 8 (GlcNAcO.8—GlcNPsO.2)

 [0052] In the tensile strength test, when compared with the curing time of 4 seconds, the UV CC in the test solution composition showed stronger adhesive strength than that of Cyanol KCA). Even in the case of misalignment, the adhesive strength of composition 2 to which an ultraviolet curable resin was added was improved compared to composition 1. In particular, the cured product having composition 2, UVCC of 3, 6, 7, and 8 had high adhesive strength.

Example 4 [0053] Biosafety test

 (a) Ushimoto's language, test words

 100 1 each of test solutions were poured into a 96-microwell plate, irradiated with ultraviolet rays, and a disk-shaped UVCC cured product with a diameter of about 6 mm and a height of about 2 mm was used as an embedded test piece.

 [0054] (b) Burial test

 Anesthetize mice (female, 8 weeks old, weight 25 ± 5 g) (Nembutal (50 mg / kg, administered intraperitoneally)), after shaving the incision, make an incision with the scalp on the back and undercut with a spatula A pocket for sample embedding was created in a pocket-like shape, and a hardened sample was embedded in the subcutaneous pocket, and the incision wound was sutured by simple stitching with 40 nylon sutures and used as a test model. Individuals who underwent similar surgical procedures without implanting specimens served as controls, and the surgical adhesive, Aron Alpha A (CA) and surgical absorbable sutures (Maxon (absorbed for polydalconate surgery) Synthetic suture thread 3—0) (Tyco Healthcare Japan Co., Ltd.) (hereinafter referred to as “AS”) was embedded in the mouse subcutaneously as a comparative product with UVCC cured product. In the clinical inflammation Abnormal conditions such as pain, heat, swelling, and redness, which were reactions, were not observed.After treatment, antibiotics, anti-inflammatory agents, etc. were not administered, and normal samples were fed freely. The tissue including the epidermis and muscle layer around the specimen embedding site was sampled under anesthesia, and the tissue was searched.

The sampled tissue was fixed in formalin, embedded in norafine, and sliced into slices. The slices were stained with hematoxylin-eosin and used as histological specimens. The specimens were observed under a microscope, and fibroblasts, neutrophils, and other inflammatory mononuclear cells in 200 visual fields (1 visual field = 625 111 ² ) randomly extracted from around the embedded area were counted to obtain inflammatory cells. The smaller the number, the smaller the inflammatory reaction and the higher the biocompatibility. Table 7 shows the results of counting the number of inflammatory cells in the test solution composition 1 cured product embedment test, and Table 8 shows the results of the inflammatory cell count in the test solution composition 2 test curable material embedding test.

[0056] [Table 7] Table 7 Inflammatory cell count results from test solution composition 1 cured product embedding test (n = 3) Control CA AS DMSO 1 2 5 6 7

 A 38 112 172 77 100 189 181 26 523

 B 296 267 72 168 458 361 309 140 165

 C 172 259 454 161 120 65 130 63 470

 A, neutrophils; B,; fibroblasts; C, Ryukyu (li, pamphlet, plasma cells, etc.) o

 Control, incision suture only.

 CA, medical adhesive; AS, surgical absorbable suture; DM so,.

 1. Cured product with composition 1 UVCC of 1 (G 1 <: NP s 0.8)

 2. Cured product with composition 1 UVCC of 2 (G 1 (: NP s 0.6)

 5, Cured product with composition 1 UVCC of 5 (G 1 <: NA c 0. 2- G 1 c N P s 0.8)

6, Cured product with composition 1 UVCC of 6 (G 1 (: NA c 0.4.4-G 1 cNPs 0.6))

7. Cured product with composition 1 UVCC of 7 (G 1 (: NA c 0.6 G 1 c N P s0. 4)

[0057] [Table 8]

 Table 8 Counting results of inflammatory cells in test solution composition 2 cured product embedding test (n = 3)

GLM GLM 1 2 5 6 7 8

 + AMPS

 1 315 160 218 140 152 93 150 226

2 150 334 217 233 313 260 210 178

3 447 297 304 128 86 91 180 219

1, neutrophils; 2, fibroblasts; 3, Ryukyu (V nno, plasma cells, etc.);

 GLM, composition 2 to 3% cured sample excluding AMP S and U V C C;

 G L M + 10 AM P S, Sample cured product obtained by removing UVCC from composition 2.

 1. Cured product with composition 2 UVCC of 1 (G1: NP50.8)

 2, Cured product with composition 2 UVCC of 2 (G 1; NP 5 0.6)

 5, Cured product with composition 2 UVCC of 3 (G 1 2 NA c: 0.2-G 1 c N P s 0.8)

6, Cured product with composition 2 UVCC of 6 (G 1: NA c; 0.4—G 1 c N P s 0.6)

7, Cured product with composition 2 UVCC of 7 (G 1 2 NA c: 0.6-G 1 c N P s 0.4)

8, Cured product with composition 2 UVCC of 8 (G 1: NA c: 0. 8- G 1 c N P s 0. 2)

[0058] From the results of the in-vivo embedment test of the test solution after curing, there was no significant difference in the number of inflammatory cells in the composition 1 sample and the cured product of composition 2 (with UVCC of composition 1 being 6). The cured product has a smaller number of inflammatory cells. The cured product with UVCC of 7 with a larger number of inflammatory cells had a higher number of inflammatory cells). The number of inflammatory cells of GL M + AMPS and composition 2 The number of inflammatory cells of cured products with UVCC of 1, 2, 5, 6, 7, 8 was compared. (Table 8). Cured products with composition 2, UVCC of 1, 2, 5, 6, 7, 8 are surgical adhesive (CA) and Compared to the surgical absorbable suture (AS), the total number of inflammatory cells around the implant is rather small and it is judged that there is no severe inflammatory reaction. In addition, there were few inflammatory reactions compared to GLM, a biocompatible material. In particular, the cured product with UVCC of 6 (GlcNAcO. 4-GlcNPs 0.6) showed mild results for the living body with the smallest total number of inflammatory cells.

 Example 5

[0059] Male cat, Os, Siam. After removing the pleural effusion by thoracentesis for pleural effusion (using a 16G vein indwelling needle), apply approximately 10011 1 of the test solution of composition 2 (UVCC No. 6) to the skin puncture hole, and irradiate with UV for 4 seconds at an irradiation distance of 10 mm Then, the test solution was cured and the incision site was closed. EYE CURE LIGHT SPOT UP 150M (Eye Graphics Co., Ltd.) was used as the UV irradiation device, and a short arc metal halide lamp was used as the UV lamp. Sealed for over a week, and the skin puncture hole was closed and healed under the seal.

[0060] (b) Clinical trial example 2

 Cat, female, Japanese cat. Diaphragmatic hernia: The diaphragm ruptures and the abdominal intestinal tract moves into the thoracic cavity. The intestinal tract is returned to the abdominal cavity by surgery, a drain is placed in the chest cavity, and the drain is removed on the second day. Install the drain again, and immediately after removing the air, apply about 100 Γ of the test solution of composition 2 (UVCC No. 6) to the skin puncture hole, irradiate with UV for 4 seconds at an irradiation distance of 10 mm, and cure and cut the test solution. The place was occluded. EYE CURE LIGHT SPOT UP 150M (Eye Graphics Co., Ltd.) was used as the UV irradiation device, and a short arc metal halide lamp was used as the UV lamp. In addition, since the invasion of air from the sutured part of the abdominal wall was suspected, the entire skin of the sutured part was similarly sealed. After that, there was no recurrence of pneumothorax, and it was completely cured.

 Example 6

[0061] Curing by visible light

Resins having the compositions shown in Table 9 were prepared. Visible light irradiation device: Elipar (trademark) Fr _ee Light2 (3M ESPE) (High power LED photopolymerizer; light intensity 1000mW / cm ² ; irradiation wavelength: 430-4 80 nm), a light guide diameter of 8 mm and an irradiation distance of about 1 cm was irradiated for 10 to 20 seconds to obtain a rubber-like cured product.

 [Table 9

Table ⁹ Composition of visible light curable resin

U VC C (No. 6) ^a 10 0 mg

 3% AMP S 90 0 mg

 G LM 200 0 mg

 Strength nhuaquinone 1%

 Triethylamine 0.1% a G 1 c NA c 0.4--G 1 c NP s 0.6

[0063] From the above results, the overall adhesive force is improved by mixing UVCC with synthetic resin, and the inflammatory reaction in vivo is lower when UVCC is mixed than when synthetic resin is used alone. It became clear that In other words, UVCC is a substance with sufficient performance as an ideal bioadhesive, and mixing with existing resin has been shown to have the effect of reducing the biostimulation of the resin alone.

 Industrial applicability

 [0064] The present invention provides adhesives and coatings that are excellent in all of adhesiveness, biocompatibility, and convenience, especially medical adhesives and coatings, and uses thereof. ! /, I can use S for IJ.

Claims

The scope of the claims  [1] A photocurable adhesive or coating agent comprising a chitosan derivative having a photopolymerizable functional group and a photopolymerizable resin.  [2] An ultraviolet curable adhesive or coating agent comprising a chitosan derivative having an ultraviolet polymerizable functional group and an ultraviolet polymerizable resin, wherein the chitosan derivative is represented by the following formula (I):  [Chemical 1]

(Wherein R2 is hydrogen or C;! To 3 alkyl group)] is an adhesive or coating agent.  [3] The adhesive or coating agent according to claim 2, wherein 1, m and n are independently 0 <1 <0 · 8, 0 <m <0.8, 0.2 <n <0.8. . [4] The adhesive or coating agent according to claim 2 or 3, wherein R2 is hydrogen or methyl.  [5] The adhesive or coating agent according to any one of claims 2 to 4, wherein the ultraviolet polymerizable resin is a glycerin monometatalylate resin. [6] The force according to any one of claims 1 to 5, further comprising a polymerization initiator, or the adhesive or coating agent according to 1. [7] The adhesive or coating agent according to [1], which is a medical adhesive.  [8] The adhesive or coating according to claim 7, which is a medical coating.  [9] The adhesive or coating agent according to claim 8, which is a wound protective agent.  10. The adhesive or coating agent according to claim 9, which has an antibacterial effect.  11. The adhesive or coating agent according to claim 8, which is a sealer for a catheter insertion site.  12. The adhesive or coating agent according to claim 8, which is a sealer for a nipple mouth and a nipple tube.  [13] The adhesive or coating agent according to claim 1 or 2, which can be cured by visible light.