JP2019188149A - Medical adhesive - Google Patents

Abstract

To provide a medical adhesive applicable for devices having low viscosity and having small injection diameter, capable of reducing air bubbles in a cured coated film, and excellent in adhesiveness with biological tissues.SOLUTION: There is provided a medical adhesive containing an urethane prepolymer (UP) having an isocyanate group and a diluent (C), the urethane prepolymer (UP) having an isocyanate group is a reaction product of a polyisocyanate component (A) containing a fluorine-containing non-aromatic polyisocyanate compound (A1) as an essential component, and a polyol component (B) containing polyol (B1) having at least 30 wt.% of an oxyethylene group as an essential component, HLB of the diluent (C) is 10 to 25, and chemical formula amount or number average molecular weight of the diluent (C) is 76 to 1500.SELECTED DRAWING: None

Description

  The present invention relates to a medical adhesive.

  As a medical adhesive for bonding biological tissues such as blood vessels, heart, respiratory organs, and digestive organs, conventionally, isocyanate group-terminated hydrophilic urethane prepolymers obtained by reaction of fluorine-containing polyisocyanates and hydrophilic polyether polyols, etc. It is known to use (patent documents 1 to 4).

On the other hand, in recent years, endoscopic surgery has been performed for reasons such as small surgical traces, less pain, quick postoperative recovery, and short-term hospitalization. In endoscopic surgery, a medical adhesive is injected into an affected area through a small injection diameter such as a trocar, cannula, and catheter. However, conventional isocyanate group-terminated hydrophilic urethane prepolymers and the like have a high viscosity, and there is a problem that they cannot be successfully injected with a device having a small injection diameter.
In addition, since the conventional isocyanate group-terminated hydrophilic urethane prepolymer has a high viscosity, a large amount of carbon dioxide gas generated at the time of moisture curing becomes bubbles and exists in the film and at the film interface, resulting in a decrease in film strength and adhesion. Often caused defects. Furthermore, since the viscosity is high and the spreadability is low, the range of use is limited only to the vascular anastomosis, making it difficult to use it for organs such as the heart, respiratory organs and digestive organs.

JP-A-1-227762 International Publication No. 03/051952 JP 2005-124808 A International Publication No. 2012/056179

  It is an object of the present invention to provide a medical adhesive that can be applied to a device having a low viscosity and a small injection diameter, and that can reduce bubbles in a cured coating and has excellent adhesion to living tissue. To do.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have reached the present invention. That is, the present invention provides a medical adhesive containing a urethane prepolymer (UP) having an isocyanate group and a diluent (C), wherein the urethane prepolymer (UP) having an isocyanate group is a fluorine-containing non-aromatic. A reaction product of a polyisocyanate component (A) having an aromatic polyisocyanate compound (A1) as an essential component and a polyol component (B) having a polyol (B1) having at least 30% by weight of an oxyethylene group as an essential component, The HLB of the diluent (C) is 10 to 25, and the chemical formula amount or number average molecular weight of the diluent (C) is 76 to 1500.

  The medical adhesive of the present invention can be applied to a device having a low viscosity and a small injection diameter, and can reduce bubbles in the cured coating and has excellent adhesiveness to living tissue.

It is the figure which showed arrangement | positioning of the collagen fragment | piece in the adhesiveness evaluation-3, and the application part of the medical adhesive agent.

The medical adhesive of the present invention contains a urethane prepolymer (UP) having an isocyanate group and a diluent (C).
The urethane prepolymer (UP) having an isocyanate group in the present invention is obtained by reacting a polyisocyanate component (A) having a fluorine-containing non-aromatic polyisocyanate compound (A1) as an essential component with a polyol component (B). It is done.

The polyisocyanate component (A) in the present invention contains a fluorine-containing non-aromatic polyisocyanate compound (A1) as an essential component, but does not contain a fluorine atom and a fluorine-containing aromatic polyisocyanate compound (A3). ) Etc. may be used in combination.
As a fluorine-containing non-aromatic polyisocyanate compound (A1), C3-C24 fluorine-containing aliphatic diisocyanate (A11), C8-C21 fluorine-containing alicyclic diisocyanate, and C9-C72. Fluorine-containing poly (3- to 6-valent) isocyanate (A13) and the like can be used.

The fluorinated aliphatic diisocyanates 24 carbon atoms (A11), those represented by OCN-Rf-NCO (. Rf represents a perfluoroalkylene group having 1 to 22 carbon atoms), and OCN-CH ₂ - Those represented by Rf—CH ₂ —NCO (Rf represents a perfluoroalkylene group having 1 to 20 carbon atoms) and the like are included.
Examples of OCN-Rf-NCO include difluoromethylene diisocyanate, perfluorodimethylene diisocyanate, perfluorotrimethylene diisocyanate, perfluorooctyl diisocyanate, and perfluoroeicosylene diisocyanate.

OCN—CH ₂ —Rf—CH ₂ —NCO includes bis (isocyanatomethyl) difluoromethane, bis (isocyanatomethyl) perfluoroethane, bis (isocyanatomethyl) perfluoropropane, bis ( Examples include isocyanatomethyl) perfluorobutane, bis (isocyanatomethyl) perfluoropentane, bis (isocyanatomethyl) perfluorohexane, and bis (isocyanatomethyl) perfluoroeicosane.

  Examples of the fluorine-containing alicyclic diisocyanate having 8 to 21 carbon atoms (A12) include diisocyanatoperfluorocyclohexane, bis (isocyanatomethyl) perfluorocyclohexane, bis (isocyanatomethyl) perfluorodimethylcyclohexane, and bis (isocyanato). Perfluorocyclohexyl) perfluoropropane and bis (isocyanatomethylperfluorocyclohexyl) perfluoropropane.

  Examples of the fluorine-containing poly (3- to 6-valent) isocyanate (A13) having 9 to 72 carbon atoms include the diisocyanate nurate, the diisocyanate adduct and tris (isocyanatotetrafluorocyclohexyl) methane.

In addition, the position of the isocyanate group in the fluorine-containing non-aromatic polyisocyanate compound (A1) is a position with less steric hindrance from the viewpoint of reactivity with the polyol component (B) and reactivity with blood, body fluids, and the like. A terminal position with less steric hindrance is more preferable and more preferable.
Further, the fluorine-containing non-aromatic polyisocyanate compound (A1) may be one type or a mixture of two or more types.
Further, among the fluorine-containing non-aromatic polyisocyanate compound (A1), those having two isocyanate groups are preferable from the viewpoint that side reactions such as a crosslinking reaction hardly occur.

Of the fluorine-containing non-aromatic polyisocyanate compound (A1), fluorine-containing aliphatic polyisocyanate (A11) is preferable from the viewpoint of safety such as mutagenicity, and OCN—CH ₂ —Rf—CH is more preferable. Fluorine-containing aliphatic polyisocyanate represented by ₂ -NCO and fluorine-containing aliphatic polyisocyanate represented by OCN-Rf-NCO, particularly preferred are difluoromethylene diisocyanate, perfluorodimethylene diisocyanate, and perfluorotrimethylene. Diisocyanate, perfluorooctyl diisocyanate, perfluoroeicosylene diisocyanate, bis (isocyanatomethyl) perfluoropropane, bis (isocyanatomethyl) perfluorobutane, bis (isocyanatomethyl) perfluoropentane and Bis (isocyanatomethyl) perfluorohexane.

  From the viewpoint of adhesive strength and the like, the proportion (% by weight) of fluorine atoms in the fluorine-containing non-aromatic polyisocyanate compound (A1) is preferably 35 to 70, more preferably, based on the weight of (A1). It is 38-70, Most preferably, it is 40-56.

  The content (% by weight) of the fluorine-containing non-aromatic polyisocyanate compound (A1) in the raw material constituting the urethane prepolymer (UP) having an isocyanate group is determined from the viewpoint of adhesive strength. UP) is preferably 5 to 60, based on the total weight of the raw materials constituting UP).

  Examples of the polyisocyanate compound (A2) not containing a fluorine atom include an aliphatic polyisocyanate (A21) not containing a fluorine atom having 3 to 24 carbon atoms, and an alicyclic polyisocyanate containing no fluorine atom having 8 to 21 carbon atoms ( A22), an araliphatic polyisocyanate (A23) not containing a fluorine atom having 10 to 21 carbon atoms, an aromatic polyisocyanate (A24) not containing a fluorine atom having 8 to 21 carbon atoms, and a modified product thereof (A25) Is mentioned.

  Examples of the aliphatic polyisocyanate (A21) not containing a fluorine atom having 3 to 24 carbon atoms include tetramethylene diisocyanate, hexamethylene diisocyanate (HDI), 2,2,4-trimethylhexamethylene diisocyanate, and lysine diisocyanate.

  Examples of the alicyclic polyisocyanate (A22) containing no fluorine atom having 8 to 21 carbon atoms include isophorone diisocyanate (IPDI), dicyclohexylmethane-4,4′-diisocyanate (hydrogenated MDI), cyclohexylene diisocyanate, and methylcyclohexylene. Examples thereof include diisocyanate (hydrogenated TDI).

  Examples of the araliphatic polyisocyanate (A23) containing no fluorine atom having 10 to 21 carbon atoms include m- or p-xylylene diisocyanate (XDI) and α, α, α ′, α′-tetramethylxylylene diisocyanate ( TMXDI) and the like.

  Examples of the aromatic polyisocyanate (A24) containing no fluorine atom having 8 to 21 carbon atoms include 1,3- or 1,4-phenylene diisocyanate (PDI), 2,4- or 2,6-tolylene diisocyanate (TDI). ), 2,4′- or 4,4′-diphenylmethane diisocyanate (MDI) and crude MDI.

  Examples of these modified products (A25) include urethane modified products, isocyanurate modified products, allophanate modified products, biuret modified products, uretdione modified products, uretonimine modified products, and uretdione / isocyanurate modified products. Examples of modified HDI include urethane-modified HDI, carbodiimide-modified HDI, and trihydrocarbyl phosphate-modified HDI. Examples of modified MDI include urethane-modified MDI, carbodiimide-modified MDI, and TDI. TDI etc. are mentioned.

Of these polyisocyanate compounds (A2), the aromatic polyisocyanate (A24) containing no fluorine atom is preferred from the viewpoint of reactivity, and more preferred are MDI and TDI.
From the viewpoint of safety, aliphatic polyisocyanate (A21) containing no fluorine atom is preferred, and HDI is more preferred.
In addition, the polyisocyanate compound (A2) which does not contain a fluorine atom may be one type or a mixture of two or more types.

  In the case of using a polyisocyanate compound (A2) that does not contain a fluorine atom, from the viewpoint of safety such as mutagenicity, the content (% by weight) of (A2) is the fluorine-containing non-aromatic polyisocyanate compound (A1). 0.1 to 20 is preferable, 0.2 to 10 is more preferable, and 0.3 to 5 is particularly preferable.

  Examples of the fluorinated aromatic polyisocyanate compound (A3) include fluorinated aromatic polyisocyanates in which some or all of the hydrogen atoms in the aromatic polyisocyanate (A24) not containing fluorine atoms are substituted with fluorine atoms. Can be mentioned.

  The fluorine-containing aromatic polyisocyanate (A31) is obtained by substituting all the hydrogen atoms of the aromatic ring with fluorine atoms, specifically, 1,3- or 1,4-perfluorophenylene diisocyanate, 3, Examples include 5,6- or 3,4,5-trifluoro-2,4- or 2,6-tolylene diisocyanate, tetrafluoro-2,4'- or 4,4'-diphenylmethane diisocyanate.

  The fluorine-containing aromatic polyisocyanate (A32) is obtained by substituting a part of hydrogen atoms of an aromatic ring with a fluorine atom, specifically, trifluoromethyl-monofluoro-phenylene-1, 3 or 1, Examples include 4-diisocyanate and 2,4′- or 4,4′-diphenyldifluoromethane diisocyanate.

  The fluorine-containing aromatic polyisocyanate (A33) is one in which all hydrogen atoms are substituted with fluorine atoms. Specifically, 2,4- or 2,6-perfluorotolylene diisocyanate and 2,4′- Alternatively, 4,4′-perfluorodiphenylmethane diisocyanate and the like can be mentioned.

Among these fluorine-containing aromatic polyisocyanate compounds (A3), from the viewpoint of reactivity, etc., the fluorine-containing aromatic polyisocyanate (A31) in which all hydrogen atoms of the aromatic ring are substituted with fluorine atoms, The fluorine-containing aromatic polyisocyanate (A32) in which some hydrogen atoms are substituted with fluorine atoms and the fluorine-containing aromatic polyisocyanate (A33) in which all hydrogen atoms are substituted with fluorine atoms are preferable, and all hydrogen is more preferable. This is a fluorine-containing aromatic polyisocyanate (A33) in which atoms are substituted with fluorine atoms.
The fluorine-containing aromatic polyisocyanate compound (A3) may be one type or a mixture of two or more types.

  When the fluorine-containing aromatic polyisocyanate compound (A3) is used, from the viewpoint of safety such as mutagenicity, the content (% by weight) of (A3) is the same as that of the fluorine-containing non-aromatic polyisocyanate compound (A1). Based on weight, 0.1-5 are preferable, More preferably, it is 0.2-3, Most preferably, it is 0.3-2.

  The polyol component (B) in the present invention comprises a polyol (B1) containing at least 30% by weight of an oxyethylene group as an essential component.

  As the polyol (B1), a polyether polyol (B1-1) containing at least 30% by weight of an oxyethylene group and a polyester polyol containing at least 30% by weight of an oxyethylene group obtained by using (B1-1) as an essential component ( B1-2) and the like.

As the polyether polyol (B1-1), an ethylene oxide adduct or ethylene oxide and a C3-C8 alkylene oxide (1,2- or 1,3-propylene oxide) to a compound having at least two active hydrogens. 1, 2-, 1,3-, 2,3- or 1,4-butylene oxide and styrene oxide).
In the case of a co-adduct, the addition form may be any of random, block, and combinations thereof, but is preferably random from the viewpoint of adhesive strength.
Moreover, as a C3-C8 alkylene oxide, a 1, 2- propylene oxide is preferable from a viewpoint of adhesive strength.

As the compound having at least two active hydrogens, water, diol, 3 to 8 valent polyol, dicarboxylic acid, 3 to 4 valent polycarboxylic acid, monoamine, polyamine, polythiol and the like can be used.
A divalent polyol is obtained when a compound having two active hydrogens is used, and a trivalent or higher polyol is obtained when a compound having three or more active hydrogens is used.

  Examples of the diol include alkylene glycols having 2 to 30 carbon atoms (ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,6-hexanediol, octanediol, decanediol, Dodecanediol, tetradecanediol, neopentyl glycol, 2,2-diethyl-1,3-propanediol, etc.); C6-C24 alicyclic diol (1,4-cyclohexanedimethanol, hydrogenated bisphenol A, etc.) Bisphenols having 15 to 30 carbon atoms (such as bisphenol A, bisphenol F and bisphenol S); dihydroxybenzenes (such as catechol and hydroquinone).

  Examples of the trivalent to octavalent polyol include aliphatic polyhydric alcohols having 3 to 8 carbon atoms (such as glycerin, trimethylolethane, trimethylolpropane, pentaerythritol, sorbitan, diglycerin, and sorbitol).

  Examples of the dicarboxylic acid include alkane dicarboxylic acids having 4 to 32 carbon atoms (such as succinic acid, adipic acid, sebacic acid, azelaic acid, sebacic acid, dodecanedicarboxylic acid, octadecanedicarboxylic acid, dodecyl succinic acid, and octadecyl succinic acid); Alkene dicarboxylic acids having 4 to 32 (maleic acid, fumaric acid, citraconic acid, mesaconic acid, dimer acid, dodecenyl succinic acid and pentadecenyl succinic acid, etc.); aromatic dicarboxylic acids having 8 to 20 carbon atoms (phthalic acid, isophthalic acid) Acid, terephthalic acid, naphthalenedicarboxylic acid and the like).

  Examples of the trivalent to tetravalent polycarboxylic acid include aromatic polycarboxylic acids having 9 to 20 carbon atoms (such as trimellitic acid and pyromellitic acid).

  Monoamines include ammonia and aliphatic primary amines having 1 to 20 carbon atoms {alkylamines having 1 to 20 carbon atoms (such as methylamine, ethylamine, propylamine, hexylamine, dodecylamine, and eicosylamine)}, carbon Examples thereof include alicyclic amines having 4 to 15 carbon atoms (piperidine, aminocyclohexane, isophorone monoamine, 4-methylenedicyclohexane monoamine and the like); aliphatic ring-containing aliphatic amines having 6 to 15 carbon atoms (benzylamine and the like) and the like.

  Examples of polyamines include aliphatic polyamines having 2 to 18 carbon atoms (alkylene diamines having 2 to 12 carbon atoms (ethylenediamine, propylenediamine, trimethylenediamine, hexamethylenediamine, N, N′-diethylethylenediamine, undecylenediamine, etc.)) and polyamines. Alkylene (alkylene having 2 to 6 carbon atoms) polyamine (diethylenetriamine, dipropylenetriamine, triethylenetetramine, pentaethylenehexamine and the like); alicyclic polyamine having 4 to 15 carbon atoms (1,3-diaminocyclohexane, isophoronediamine) And 4,4′-methylenedicyclohexanediamine and the like; heterocyclic polyamines having 4 to 15 carbon atoms (piperazine, N-aminoethylpiperazine, 1,4-diaminoethylpiperazine and N-aminoethylpi). Jin, etc.) and the like.

  Examples of the polythiol include dithiols having 2 to 24 carbon atoms (such as ethanedithiol, 1,4-butanedithiol and 1,6-hexanedithiol), polythiols having 3 to 6 carbon atoms and 5 to 3000 carbon atoms [trade name: Capcure 3800 ( Japan Epoxy Resin Co., Ltd.) and polyvinyl thiol etc.].

As the compound having at least two active hydrogens, in addition to the above, amino acids, oxycarboxylic acids, amino alcohols and the like can also be used.
The compound having at least two active hydrogens may be one kind or a mixture of two or more kinds.
As the compound having at least two active hydrogens, water and diol are preferable from the viewpoint of safety to the living body and adhesive strength, water and alkylene glycol are more preferable, water and carbon number 2 to 4 are particularly preferable. Of alkylene glycol.

  Preferred examples of the polyether polyol (B1-1) include ethylene oxide adducts to diols (such as ethylene oxide adducts to ethylene glycol and ethylene oxide adducts to propylene glycol), and ethylene oxide to diols. Coadducts of alkylene oxides having 3 to 8 carbon atoms (random and / or block coadducts of ethylene oxide and propylene oxide to ethylene glycol, and random and / or of ethylene oxide and butylene oxide to ethylene glycol) Block co-adducts, etc.).

As the polyether polyol (B1-1), from the viewpoint that the reaction with water is accelerated and the adhesive strength is further improved, the ethylene oxide adduct to the diol and the co-addition of ethylene oxide and propylene oxide to the diol And particularly preferred is a co-adduct of ethylene oxide and propylene oxide to a diol.
The polyether polyol (B1-1) may be a single type or a mixture of two or more types.

The hydroxyl group equivalent (number average molecular weight per hydroxyl group) of the polyether polyol (B1-1) is preferably 50 to 5000, more preferably 100 to 4000, and particularly preferably 200 to 3000. Within this range, the adhesive strength and the like are further improved.
In addition, the hydroxyl group equivalent in this invention can measure a hydroxyl value based on JISK1557-1: 2007, and can be calculated | required by a following formula.
Hydroxyl equivalent = 1,000 × 56.1 / value of hydroxyl value

Polyester polyol (B1-2) containing at least 30% by weight of oxyethylene groups obtained by using polyether polyol (B1-1) as an essential component includes polyether polyol (B1-1) and at least two active hydrogens. And dicarboxylic acids and acid anhydrides thereof (such as maleic anhydride and phthalic anhydride) and / or lower alkyl (carbon number 1 to 4) esters (methyl esters, ethyl esters, isopropyl esters and t-butyl esters) Etc.) and polyester. The terminal of these polyesters is a hydroxyl group.
As a part of dicarboxylic acid, dicarboxylic acid anhydride and / or dicarboxylic acid lower alkyl ester, trivalent or higher polycarboxylic acid, trivalent or higher polycarboxylic acid anhydride and trivalent or higher polycarboxylic acid. Acid lower alkyl ethers and the like can also be used, and when these are used, the amount used (mol%) is based on the total number of moles of all carboxylic acids, acid anhydrides of carboxylic acids and carboxylic acid lower alkyl esters, 0.1-10 are preferable, More preferably, it is 0.1-5, Most preferably, it is 0.1-2. Within this range, the adhesive strength and the like are further improved.

Preferred examples of polyester polyol (B1-2) include ethylene oxide adducts to diol (ethylene oxide adducts to ethylene glycol, ethylene oxide adducts to propylene glycol, etc.) and dicarboxylic acids (adipic acid, sebacic acid) , Maleic acid and phthalic acid), polyester diols with dicarboxylic acid anhydrides and / or dicarboxylic acid lower alkyl esters (such as methyl or ethyl esters of dicarboxylic acids), and ethylene oxides to diols and 3 to 8 carbon atoms Of alkylene oxides (random and / or block coadducts of ethylene oxide and 1,2- or 1,3-propylene oxide to ethylene glycol, ethylene oxide and 1,4-butylene to propylene glycol) Random and / or block copolymer adduct) a dicarboxylic acid with Kisaido, acid anhydrides of dicarboxylic acids and / or polyester diol of dicarboxylic acid lower alkyl esters.
Among these, from the viewpoint of adhesive strength and the like, polyester diols of ethylene oxide adducts to diols and dicarboxylic acids, acid anhydrides of dicarboxylic acids and / or lower alkyl esters of dicarboxylic acids, and ethylene oxide and propylene oxide to diols Polyester diols of co-adducts of dicarboxylic acids with dicarboxylic acids, dicarboxylic acid anhydrides and / or dicarboxylic acid lower alkyl esters are preferred, more preferred are ethylene oxide adducts to diols with dicarboxylic acids and dicarboxylic acid anhydrides. And / or a polyester diol with a dicarboxylic acid lower alkyl ester.
These polyester polyols (B1-2) may be one kind or a mixture of two or more kinds.

  The hydroxyl equivalent of the polyester polyol (B1-2) is preferably 50 to 5000, more preferably 100 to 4000, and particularly preferably 200 to 3000. Within this range, the adhesive strength and the like are further improved.

The HLB of the polyol (B1) is preferably 4 to 20, more preferably 4.5 to 20, from the viewpoints of reactivity and adhesive strength.
“HLB” in the present invention is an index indicating a balance between hydrophilicity and lipophilicity, and is described in, for example, “Introduction to Surfactants” (published by Sanyo Chemical Industries, Ltd., 2007, Takehiko Fujimoto), page 212. Can be calculated from the ratio between the organic value and the inorganic value of the organic compound.
HLB = 10 × inorganic / organic The organic value and the inorganic value for deriving HLB can be calculated using the values in the table described in the above “Introduction to Surfactant” page 213.

As the polyol (B1), polyether polyol (B1-1) is preferable from the viewpoint that the reaction with water becomes faster and the adhesive strength and the like are further improved, and more preferable is an ethylene oxide adduct to a diol and A co-adduct of ethylene oxide and propylene oxide to a diol, particularly preferably a co-adduct of ethylene oxide and propylene oxide to a diol.
The polyol (B1) may be a single type or a mixture of two or more types.

  The content (% by weight) of the oxyethylene group in the polyol (B1) is at least 30, preferably 40 or more, particularly preferably 50 or more, based on the weight of (B1), from the viewpoint of adhesive strength and the like. is there.

  The polyol component (B) can contain a polyol other than (B1), that is, a polyol (B2) having an oxyethylene group content of less than 30% by weight.

  The polyol (B2) includes a diol and a trivalent to hexavalent polyol described above as a compound having at least two active hydrogens. In addition to this, a polyol containing an oxyalkylene group and having an oxyethylene group content of less than 30% by weight based on the weight of the polyol (B2) is included, a polyether polyol (B2-1), A polyester polyol (B2-2) obtained using the polyether polyol (B2-1) as an essential component, a polyester polyol (B2-3) not containing an oxyethylene group and an oxyalkylene group having 3 to 8 carbon atoms, and the like can be used.

  As the polyether polyol (B2-1), a (co) adduct of an alkylene oxide having 3 to 8 carbon atoms and an ethylene oxide and an alkylene oxide having 3 to 8 carbon atoms to a compound having at least two active hydrogens. Coadducts and the like can be used. However, the content of oxyethylene groups is less than 30% by weight based on the weight of the polyol (B2-1).

Suitable examples of the polyether polyol (B2-1) include polypropylene glycol (1,2- or 1,3-propylene oxide adduct of propylene glycol), ethylene oxide adduct (polyethylene glycol or propylene) to polyalkylene glycol. Block adducts of ethylene oxide and propylene oxide to glycol having an ethylene oxide content of 5 wt% or more and less than 30 wt%, and an ethylene oxide adduct of polypropylene glycol, containing ethylene oxide Random copolymer of propylene oxide and ethylene oxide (ethylene glycol or propylene oxide polymer to ethylene glycol or propylene glycol) A dam adduct having an ethylene oxide content of 10 to 25% by weight, polytetramethylene glycol (1,4-butylene glycol 1,2-, 1,3-, 2,3- and / Or 1,4-butylene oxide adduct) and a copolymer of 1,4-butylene oxide and ethylene oxide (ethylene glycol or ethylene oxide to butylene glycol 10-25 weight and 1,4-butylene oxide 75-90 weight) % Block and / or random adduct having an ethylene oxide content of 10 to 25% by weight).
Among these, from the viewpoint of adhesiveness and the like, polypropylene glycol and ethylene oxide adducts to polypropylene glycol (ethylene oxide content of 5 wt% or more and less than 30 wt%) are preferable, and polypropylene glycol and more preferable It is an ethylene oxide adduct (polyethylene glycol content of 15% by weight or more and less than 30% by weight) to polypropylene glycol.
These polyether polyols (B2-1) may be one kind or a mixture of two or more kinds.

  The preferred range of the hydroxyl group equivalent of the polyether polyol (B2-1) is the same as that of the polyether polyol (B1-1).

  As the polyester polyol (B2-2) obtained by using the polyether polyol (B2-1) as an essential component, the polyether polyol (B2-1), the dicarboxylic acid, the acid anhydride of the dicarboxylic acid and / or the dicarboxylic acid described above. Polyester polyols that can be derived from lower alkyl esters can be used.

Preferable examples of the polyester polyol (B2-2) include polypropylene glycol (1,2- or 1,3-propylene oxide adduct to propylene glycol), ethylene oxide adduct to polyalkylene glycol (ethylene glycol or propylene) Block adducts of ethylene oxide and propylene oxide to glycols having an ethylene oxide content of 5 to 30% by weight, and polypropylene glycol ethylene oxide adducts having an ethylene oxide content of 5% by weight % And less than 30% by weight), random copolymer of propylene oxide and ethylene oxide (random addition of ethylene oxide and propylene oxide to ethylene glycol or propylene glycol) Wherein ethylene oxide content is 10 to 25% by weight, etc.), polytetramethylene glycol (1,4-butylene glycol 1,2-, 1,3-, 2,3- and / or 1 , 4-butylene oxide adduct) and / or a copolymer of 1,4-butylene oxide and ethylene oxide (ethylene glycol or ethylene oxide to ethylene glycol or butylene glycol 10 to 25 weight and 1,4-butylene oxide 75 to 90 weight%) Block and / or random adducts having an ethylene oxide content of 10 to 25% by weight), dicarboxylic acids (such as adipic acid, sebacic acid, maleic acid, and phthalic acid), and acid anhydrides of dicarboxylic acids And / or dicarboxylic acid lower alkyl esters (such as methyl and ethyl esters of dicarboxylic acids) Polyester polyols, and the like, which may be derived from a.
These polyester polyols (B2-2) may be one kind or a mixture of two or more kinds.

  As the polyester polyol (B2-3) not containing an oxyethylene group and an oxyalkylene group having 3 to 8 carbon atoms, the above diol and / or 3 to 6 valent polyol, the above dicarboxylic acid, and acid anhydride of dicarboxylic acid Polyesters derived from products and / or lower alkyl esters of dicarboxylic acids, polyesters derived from ring-opening polymerization of caprolactone, and the like can be used.

Preferable examples of the polyester polyol (B2-3) include polyester diols derived from butanediol and adipic acid; polyester diols derived from ethylene glycol and adipic acid; polyester diols derived from hexamethylene glycol and adipic acid A polyester diol derived from ethylene glycol, butanediol and adipic acid; a polyester diol derived from ethylene glycol and sebacic acid; a polyester diol derived from cyclohexanediol and phthalic acid; and a ring-opening polymerization of caprolactone Examples include polycaprolactone.
These polyester polyols (B2-3) may be one kind or a mixture of two or more kinds.

  Of these polyols (B2), polyether polyols (B2-1) having an oxyethylene group content of less than 30% by weight are preferred from the viewpoint of adhesive strength and the like, and more preferred are polypropylene glycol and polypropylene glycol. An adduct of 5 to 15% by weight of ethylene oxide, particularly preferably polypropylene glycol.

The content (% by weight) of the oxyethylene group in the entire polyol component (B) is preferably 30 to 100, more preferably 35 to 98, particularly preferably 40 to 95, most preferably based on the weight of (B). Is 50-90. Within this range, the adhesive strength and the like are further improved.
Moreover, 50-5000 are preferable, as for the average hydroxyl equivalent of the whole polyol component (B), More preferably, it is 100-4000, Most preferably, it is 200-3000. Within this range, the adhesive strength and the like are further improved.

  When the polyol (B1) and the polyol (B2) are used in combination, the polyol (B1) is preferably a polyether polyol (B1-1), more preferably an ethylene oxide adduct (ethylene to ethylene glycol) to a diol. Oxide adducts and ethylene oxide adducts to propylene glycol, etc.) and co-adducts of ethylene oxide and alkylene oxides having 3 to 8 carbon atoms to diol (random and / or ethylene oxide and propylene oxide to ethylene glycol) Block co-adducts, and random and / or block co-adducts of ethylene oxide and butylene oxide to ethylene glycol), particularly preferred are co-adducts of ethylene oxide and propylene oxide to diols, Preferred are random copolymers adduct of ethylene oxide and propylene oxide to diols.

  When (B1) and (B2) are used in combination, the polyol (B2) has a diol, a trivalent to hexavalent polyol, and an oxyethylene group content of less than 30% by weight based on the weight of (B2). Polyether polyols are preferred, more preferred are polyether polyols containing an oxypropylene group and having an oxyethylene group content of less than 30% by weight based on the weight of (B2), and particularly preferred is polypropylene glycol. is there.

  When (B1) and (B2) are used in combination, as the polyol component (B), from the viewpoint of adhesiveness, the content of the polyether polyol (B1-1) and the oxyethylene group is in the weight of (B2). It is preferably a mixture with a polyether polyol of less than 30% by weight, more preferably a co-adduct of ethylene oxide and propylene oxide to a diol, an oxypropylene group containing an oxyethylene group Mixtures of polyether polyols whose amount is less than 30% by weight based on the weight of (B2), particularly preferred are mixtures of random coadducts of ethylene oxide and propylene oxide to diols and polypropylene glycol It is.

When (B1) and (B2) are used in combination, the content (% by weight) of (B1) in the polyol component (B) is 20 to 99 based on the weight of (B) from the viewpoint of adhesiveness. Is more preferable, and 30-95 is more preferable.
The content (% by weight) of (B2) in the polyol component (B) is preferably from 1 to 80, more preferably from 5 to 70, based on the weight of (B), from the viewpoint of adhesiveness.

The urethane prepolymer (UP) having an isocyanate group is obtained by reacting the polyisocyanate component (A) and the polyol component (B).
The amount ratio of the polyisocyanate component (A) to the polyol component (B) is preferably 1.5 to 3 as the equivalent ratio of the isocyanate group of (A) to the hydroxyl group of (B) (NCO group / hydroxyl group). More preferably, it is 1.8 to 2.3, and particularly preferably 1.9 to 2.1. Within this range, the viscosity is relatively low, it becomes easier to handle as an adhesive, and the wet adhesive strength is further improved.

As a method for producing a urethane prepolymer (UP) having an isocyanate group, a conventionally known method (method described in International Publication No. 03/051952) may be used. For example, a polyisocyanate component (A) and a polyol component ( And a method in which B) is reacted at 50 to 100 ° C. for 1 to 10 hours. In this case, the method of adding the polyisocyanate component (A) and the polyol component (B) may be a method of adding from the beginning or a method of gradually lowering.
The urethane prepolymer (UP) having an isocyanate group preferably has a structure having at least two (preferably two) isocyanate groups in the molecule and no active hydrogen.
In addition, the position of the isocyanate group in the urethane prepolymer (UP) having an isocyanate group is preferably a position with less steric hindrance from the viewpoint of reactivity with blood, body fluid, etc., and more preferably a terminal with less steric hindrance. Position.

Further, the isocyanate group content (% by weight) in the urethane prepolymer (UP) having an isocyanate group (the weight ratio of the isocyanate group in the total weight of the (UP)) is preferably 1 to 10, more preferably 1. It is 2 to 8, particularly preferably 1.5 to 6. Within this range, the wet adhesive strength is further improved.
The isocyanate group content can be measured by a method in which an excess di-n-butylamine solution is added to the sample and reacted, and unreacted di-n-butylamine is back titrated with a hydrochloric acid standard solution. For example, JISK7301 -Measured according to 1995, 6.3 isocyanate group content.

From the viewpoint of adhesive strength, the content (% by weight) of fluorine in the urethane prepolymer (UP) having an isocyanate group is preferably 1 to 30, more preferably 1 to 29, based on the weight of (UP). is there.
The content (% by weight) of oxyethylene groups in the urethane prepolymer (UP) having an isocyanate group is preferably from 25 to 65, more preferably from 30 to 65, based on the weight of (UP), from the viewpoint of reactivity. 60.

  The number average molecular weight (hereinafter abbreviated as Mn) of the urethane prepolymer (UP) having an isocyanate group is preferably 500 to 30,000, more preferably 800 to 20,000, particularly preferably 1,000 to 10,000, Most preferably, it is 1,200 to 8,000. Within this range, the wet adhesive strength is further improved.

In addition, Mn in this invention is measured on condition of the following, for example by gel permeation chromatography (GPC).
Apparatus: Gel permeation chromatograph Solvent: Tetrahydrofuran Reference substance: Polyoxyethylene glycol Sample concentration: 0.25% by weight
Column stationary phase: TSKgelSuperH4000
Column temperature: 40 ° C
The Mn of the urethane prepolymer (UP) is a value obtained by reacting methanol with the isocyanate group of (UP).

  The medical adhesive of the present invention contains a diluent (C) having an HLB of 10 to 25 and a chemical formula amount or Mn of 76 to 1500. By containing the diluent (C), an adhesive having low viscosity and excellent adhesiveness can be obtained.

  The HLB of the diluent (C) needs to be 10 to 25 from the viewpoints of adhesiveness and curing rate, preferably 10.5 to 24, and more preferably 11.0 to 23.

  The chemical formula amount or Mn of the diluent (C) needs to be 76 to 1500 from the viewpoint of viscosity and adhesiveness, preferably 100 to 1000, more preferably 100 to 800.

The diluent (C) in the present invention can be used as long as it satisfies the HLB and the chemical formula amount or Mn. From the viewpoint of adhesiveness, the alkylene glycol dialkyl ether (C1) and the polyoxyalkylene diol dialkyl ether are used. (C2) is preferred.
The number of carbon atoms of the alkylene group in (C1) and (C2) is preferably 1 to 8, more preferably 1 to 6, particularly preferably 1 to 4, from the viewpoints of viscosity and adhesiveness.
Moreover, as for carbon number of the alkyl group in (C1) and (C2), 1-8 are preferable from a viscosity and adhesive viewpoint, More preferably, it is 1-6, Most preferably, it is 1-4.

As the diluent (C), the compound (C3) represented by the following general formula (1) is more preferable from the viewpoints of curing time, viscosity and adhesiveness.

R ¹ —O— (AO) _n —R ² (1)

R ¹ and R ² in the general formula (1) each independently represent an alkyl group having 1 to 4 carbon atoms, and a methyl group is preferable from the viewpoint of curing time and adhesiveness.
A in the general formula (1) represents an alkylene group having 1 to 4 carbon atoms, and an ethylene group is preferable from the viewpoints of viscosity and adhesiveness.
When there are a plurality of A in the general formula (1), they may be the same or different. Further, when there are a plurality of AOs, the combination format may be a block format or a random format.
N in the general formula (1) represents an integer of 1 to 35, and is preferably 1 to 10 from the viewpoint of viscosity.

  Specific examples of the compound (C3) represented by the general formula (1) include polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polyethylene glycol dibutyl ether, polypropylene glycol dimethyl ether, polypropylene glycol diethyl ether, polypropylene glycol dibutyl ether, poly (oxy Ethylene / oxypropylene) diol dimethyl ether, poly (oxyethylene / oxypropylene) diol diethyl ether, poly (oxyethylene / oxypropylene) diol dibutyl ether, and the like. From the viewpoint of curing time and adhesiveness, polyethylene is particularly preferable. Glycol dimethyl ether.

From the viewpoint of fluidity, the viscosity (mPa · s) of the diluent (C) is preferably 0.5 to 100, and more preferably 1.0 to 90.
The viscosity in the present invention is a viscosity measured at a measurement temperature of 25 ° C. using an E-type viscometer [manufactured by Toki Sangyo Co., Ltd., model TVE-22H].

The absolute value of the difference between the solubility parameter of the urethane prepolymer (UP) having an isocyanate group and the solubility parameter of the solubility parameter of the urethane prepolymer (UP) is 1.9 or less from the viewpoint of adhesiveness and curing speed. Preferably, it is 0.2 to 1.9, particularly preferably 0.3 to 1.8, particularly preferably 0.3 to 1.6, and most preferably 0.3. -1.0.
In the present application, the solubility parameter (hereinafter abbreviated as SP value) is described in Polymer Engineering and Science Vol. 14, pages 151 to 154, by Robert F Faders et al. It is calculated by the method.

  The weight ratio [(C) / (UP)] of the diluent (C) to the urethane prepolymer (UP) having an isocyanate group is preferably from 5 to 150% by weight, more preferably from the viewpoint of viscosity and adhesiveness. ~ 110% by weight.

  The medical adhesive of the present invention may further contain a phenol radical scavenger (PRS). When PRS is contained, it is possible to suppress degradation over time of the cured product produced by the reaction of the urethane prepolymer (UP) having an isocyanate group and moisture, and to prevent a decrease in adhesive strength.

  Examples of the phenol-based radical scavenger (PRS) include monophenol-based, bisphenol-based, or polymer-type phenol-based radical scavengers.

  Examples of the monophenol-based radical scavenger include 2,6-di-t-butyl-p-cresol {for example, ANTAGE BHT manufactured by Kawaguchi Chemical Co., Ltd.), butylated hydroxyanisole {for example, Orient BHT manufactured by Orient Chemical Co., Ltd.), 2,6-di- t-Butyl-4-ethylphenol {for example Nouchira M-17, manufactured by Ouchi Shinsei Chemical Co., Ltd.) and stearyl-β- (3,5-di-t-butyl-4-hydroxyphenyl) propionate {for example, ADK STAB AO- manufactured by Asahi Denka 50} and the like.

  Examples of the bisphenol radical scavenger include 2,2′-methylenebis (4-methyl-6-tert-butylphenol) {for example, ANTAGE W-400 manufactured by Kawaguchi Chemical Co., Ltd.), 2,2′-methylenebis (4-ethyl-6-t). -Butylphenol) {eg Kawaguchi Chemical Antage W-500}, 4,4'-butylidenebis (3-methyl-6-t-butylphenol) {eg Kawaguchi Chemical Antage Crystal}, 4,4'-thiobis (3- Methyl-6-tert-butylphenol) {for example, ANTE W-300} manufactured by Kawaguchi Chemical Co., Ltd., 1,6-hexanediol-bis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] {for example Irganox s259} manufactured by Ciba Specialty Chemicals and 3,9-bis [1,1-dimethyl-2- [β- (3 t- butyl-4-hydroxy-5-methylphenyl) propionyl] ethyl] 2,4,8,10-tetraoxaspiro [5.5] undecane {e.g. Asahi Denka Ltd. STAB AO-80}, and the like.

  As a polymer type phenol radical scavenger, tetrakis- [methylene-3- (3 ′, 5′-di-t-butyl-4′-hydroxyphenyl) propionate] methane {for example, Irganox 1010 manufactured by Ciba Specialty Chemicals} 1,3,5-trimethyl-2,4,6-tris (3,5-di-t-butyl-4-hydroxybenzyl) benzene {for example, ADK STAB AO-330 manufactured by Asahi Denka Co., Ltd., 1,1,3- Tris (2-methyl-4-hydroxy-5-t-butylphenyl) butane {for example, ADK STAB AO-30 manufactured by Asahi Denka Co., Ltd.], bis [3,3′-bis- (4′-hydroxy-3′-t-butyl) Phenyl) butyric acid] glycol ester {eg Hoechst antioxidant TMOZ} and 1,3,5-tris (3 ′, 5′- -t- butyl-4'-hydroxybenzyl)-sec-triazine -2,4,6- (1H, 3H, 5H) trione {e.g. Asahi Denka Ltd. STAB AO-20}, and the like.

  The phenolic radical scavenger (PRS) preferably has a chemical formula amount or Mn of 500 to 1200, more preferably 600 to 1100, and particularly preferably 700 to 1000. When it is within this range, the cured product is less likely to deteriorate and decompose over time.

  The phenol-based radical scavenger (PRS) preferably has at least two hydroxyl groups, more preferably 2 to 5, and particularly preferably 3 to 4. When it is within this range, the cured product is less likely to deteriorate and decompose over time.

  Among these phenol-based radical scavengers, bisphenol-based radical scavengers and polymer-type phenol-based radical scavengers are preferable from the viewpoint of suppressing degradation and degradation with time of the cured product, and tetrakis- [methylene-3 is more preferable. -(3 ', 5'-di-tert-butyl 4'-hydroxyphenyl) propionate] methane, 1,1,3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, 1, 3,5-trimethyl-2,4,6-tris (3,5-di-t-butyl-4-hydroxybenzyl) benzene, 1,3,5-tris (3 ′, 5′-di-t-butyl) -4'-hydroxybenzyl) -sec-triazine-2,4,6- (1H, 3H, 5H) trione and 1,6-hexanediol-bis [3- (3,5-di-t-butyl- - hydroxy phenyl) propionate].

In addition, even in the same radical scavenger, radical scavengers other than phenol-based [for example, aromatic amine-based radical scavenger {octylated diphenylamine, Nn-butyl-p-aminophenol, phenothiazine, etc.}, sulfur-based radical scavenger {Dilauryl-3,3′-thiodipropionate, distearyl-3,3′-thiodipropionate, pentaerythritol tetrakis (3-laurylthiopropionate, etc.)} and phosphorus radical scavenger {trisnonylphenyl Phenolic radical scavengers (PRS) are preferred to phosphites, tris (2,4-di-t-butylphenyl) phosphites, distearyl pentaerythritol diphosphites, etc.}]. When a phenol-based radical scavenger (PRS) is used, it is possible to suppress degradation and degradation of the cured urethane prepolymer (UP) having an isocyanate group over time and to exhibit excellent adhesion durability.
Note that a phenol-based radical scavenger (PRS) and a radical scavenger other than (PRS) may be used in combination.

The content (% by weight) of these phenol-based radical scavengers (PRS) is preferably 0.01 to 3, more preferably 0.02 based on the weight of the urethane prepolymer (UP) having an isocyanate group. 1, particularly preferably 0.05 to 0.5. Within this range, deterioration of the cured body over time can be suppressed, and the human body is not adversely affected.
The phenol-based radical scavenger (PRS) may be added to the urethane prepolymer (UP) having an isocyanate group, or added in advance to the polyisocyanate component (A) and / or the polyol component (B). A urethane prepolymer (UP) having a group may be obtained.

In addition to the urethane prepolymer (UP) having an isocyanate group, the diluent (C) and the phenol radical scavenger (PRS), the medical adhesive of the present invention can contain other components as necessary.
Other components include physiologically active drugs (central nervous system drugs, allergy drugs, cardiovascular drugs, respiratory system drugs, gastrointestinal drugs, hormone drugs, metabolic drugs, antineoplastic agents, antibiotics Preparations and chemotherapeutic agents), fillers (carbon black, bengara, calcium silicate, sodium silicate, titanium oxide, acrylic resin powders and various ceramic powders) and plasticizers (DBP, DOP, TCP, tributoxyethyl) Phosphate and other various esters). When other components are included, the content thereof is appropriately determined depending on the application.

  The viscosity (mPa · s) at 25 ° C. of the medical adhesive is preferably 100 to 20,000, more preferably 200 to 15,000, and particularly preferably 300 to 20,000, from the viewpoint of fluidity and adhesiveness. 11,000.

The urethane prepolymer (UP) having an isocyanate group contained in the adhesive of the present invention produces an amino group and carbon dioxide by reacting an isocyanate group with water (water in a body fluid such as blood or lymph). The amino group further reacts with an isocyanate group to increase the molecular weight (polymerization). The carbon dioxide generated during the reaction forms a foam (sponge), and a film containing a foam having wet adhesive strength and flexibility is generated. At that time, by using the diluent (C), it is possible to suppress the remaining of excessive bubbles inside and on the surface of the coating, and it is possible to prevent a decrease in adhesive strength.
Therefore, when the adhesive of the present invention is brought into contact with a body fluid such as blood in a medical practice such as surgery, the water is rapidly polymerized and the adhesive strength is expressed. Moreover, the initial adhesive strength can be increased by replenishing moisture by spraying, for example, physiological saline as necessary.

  In the operation, the bonding method when bonding the living tissue with the adhesive of the present invention is a direct bonding method in which the adhesive of the present invention is directly applied to the incision; a highly peelable film such as a silicone film and a fluorine film. Examples include a transfer adhesion method in which the incision is covered with the film after the adhesive is applied, and the film is removed after the reaction.

  In endoscopic surgery, endoscopic surgery involves incising several small holes of about 0.5 cm in the abdominal cavity, chest cavity, retroperitoneal cavity, etc., and then inserting a video camera and special surgical instruments for monitoring. Compared with conventional thoracotomy and abdominal surgery, this is a technique that is less invasive and reduces the burden on the patient. In addition to the digestive organs and general surgical fields, it is also applied to surgeries such as the chest (thoracic cavity) such as the lungs and heart, the neck such as the neck, gynecology, urology, plastic surgery, orthopedics and otolaryngology. The medical adhesive of the present invention has a low viscosity and can be suitably used for those having a small injection diameter such as trocars, cannulas and catheters. Further, the medical adhesive of the present invention may be used for endoscopic surgery that does not require incision (surgery in which a video camera and a special surgical instrument are inserted from the nose and mouth).

  The medical adhesive of the present invention is preferably used for adhesion of a living tissue from the viewpoint of safety to the living body and adhesive strength to the living body, and preferable as the living tissue is a blood vessel, nerve, heart, respiratory organ. And the gastrointestinal tract, more preferably the lung, artery, heart, vein, trachea, esophagus, stomach, duodenum, small intestine, large intestine, rectum, liver, spleen, kidney, pancreas and nerve.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples. In the following, “%” means “wt%” and “part” means “part by weight” unless otherwise specified.

Mn in the examples was measured by gel permeation chromatography (GPC) under the following conditions.
Apparatus: Gel permeation chromatograph Solvent: Tetrahydrofuran Reference substance: Polyoxyethylene glycol Sample concentration: 0.25% by weight
Column stationary phase: TSKgelSuperH4000
Column temperature: 40 ° C

<Production Example 1>
An autoclave was charged with 15.5 parts of ethylene glycol and 3.8 parts of potassium hydroxide, purged with nitrogen (oxygen concentration in the gas phase part: 450 ppm), and dehydrated under reduced pressure (100 kPa) at 120 ° C. for 60 minutes. Next, after injecting a mixture of 784.5 parts of ethylene oxide and 200 parts of propylene oxide at 100 to 130 ° C. in about 10 hours, the reaction was continued at 130 ° C. for 3 hours to obtain a liquid crude polyether. 1,000 parts of this liquid crude polyether was charged into an autoclave, nitrogen substitution (oxygen concentration in the gas phase part 450 ppm) was performed, 30 parts of ion-exchanged water was added, and then synthetic magnesium silicate (sodium content 0.2%) ) Was added and nitrogen was substituted again, followed by stirring at 90 ° C. for 45 minutes at a stirring speed of 300 rpm. Subsequently, it filtered under nitrogen using the glass filter (GF-75: product made from Toyo Roshi), and obtained the ethylene oxide / propylene oxide random coadduct (B1-1). Mn of this ethylene oxide / propylene oxide random co-adduct (B1-1) was 4,000, and the content of oxyethylene groups was 80%.

<Production Example 2>
The autoclave was charged with 141.8 parts of prolene glycol and 3.8 parts of potassium hydroxide, and after nitrogen substitution (oxygen concentration of 450 ppm in the gas phase part) was vacuum dehydrated at 120 ° C. for 60 minutes.
Subsequently, after injecting a mixture of 781 parts of ethylene oxide and 193 parts of propylene oxide at 100 to 130 ° C. for about 10 hours, the reaction is continued at 130 ° C. until the volatile content is 0.1% by volume or less. Got.
This liquid crude polyether was treated with synthetic magnesium silicate in the same manner as in Production Example 1 to obtain an ethylene oxide / propylene oxide random co-adduct (B1-2). The number average molecular weight of this (B1-2) was 600, and the content of oxyethylene groups was 70% by weight.

<Production Example 3>
The autoclave was charged with 362 parts of propylene glycol and 3.8 parts of potassium hydroxide, purged with nitrogen (oxygen concentration in the gas phase part: 450 ppm), and dehydrated under reduced pressure (100 kPa) for 60 minutes at 120 ° C. Next, 632 parts of propylene oxide was injected at about 100 to 130 ° C. for about 10 hours, and then the reaction was continued at 130 ° C. until the volatile content became 0.1% or less to obtain a liquid crude polyether. This liquid crude polyether was treated with synthetic magnesium silicate in the same manner as in Production Example 1 to obtain a propylene oxide adduct (B2-1). The propylene oxide adduct (B2-1) had an Mn of 210 and an oxyethylene group content of 0%.

<Production Example 4>
A mixture of 90 parts of the ethylene oxide / propylene oxide random coadduct (B1-1) obtained in Production Example 1 and 10 parts of the propylene oxide adduct (B2-1) obtained in Production Example 3 as a polyol component (B). In a nitrogen atmosphere, dehydration was performed under reduced pressure at 100 ° C. for 2 hours, followed by cooling to 50 ° C., and 0.5 part of tetrakis- [methylene-3- (3 ′) as a phenolic hydroxyl group-containing radical scavenger (PRS). , 5′-di-t-butyl-4′-hydroxyphenyl) propionate] methane (Irganox 1010, manufactured by BASF). Stir uniformly for 30 minutes. After further cooling to 40 ° C., bis (isocyanatomethyl) perfluorobutane {OCN—CH ₂ — (CF ₂ ) ₄ —CH ₂ which is a fluorine-containing non-aromatic polyisocyanate (A1) as the polyisocyanate component (A). -NCO} 45.6 parts (NCO group / hydroxyl ratio = 2/1) was added and stirred uniformly, then the temperature was raised to 80 ° C. and reacted at 80 ° C. for 6 hours to give a urethane prepolymer having an isocyanate group. (UP-1) was obtained. This (UP-1) had an isocyanate group content of 4.0%. In addition, the content of oxyethylene groups in (B) is 72%, and the content of oxyethylene groups in (UP-1) is 49%.

<Production Examples 5 to 7 and Comparative Production Example 1>
In Production Example 4, as the polyol component (B), the compounds described in Table 1 were used in the number of parts described in Table 1, and as the polyisocyanate component (A), the compounds described in Table 1 were used as the number of parts described in Table 1. The urethane prepolymers (UP-2) to (UP-4) having an isocyanate group and the urethane prepolymer (UPR-1) having an isocyanate group for comparison were carried out in the same manner as in Production Example 4 except that Got.
For each urethane prepolymer, the number average molecular weight of (UP), the content of isocyanate groups in (UP) (% by weight), the content of oxyethylene groups in (B) (% by weight), and in (UP) Table 1 shows the oxyethylene group content (% by weight) and the fluorine atom content (% by weight) in (UP).

<Production Example 8>
An autoclave was charged with 505 parts of diethylene glycol monomethyl ether and 0.2 part of potassium hydroxide, and after nitrogen substitution (oxygen concentration of 450 ppm in the gas phase part), 495 parts of ethylene oxide was injected at 175 to 185 ° C. in about 5 hours, and then 180 parts. The reaction was continued for 1 hour at ° C. Next, 0.2 parts of 90% aqueous acetic acid solution was charged and neutralized at 90 to 100 ° C. to obtain liquid crude polyethylene glycol monomethyl ether. 945 parts of this liquid crude polyethylene glycol monomethyl ether was charged into an autoclave, nitrogen substitution (oxygen concentration in the gas phase part: 200 ppm) was performed, 0.2 part of ion-exchanged water, 0.005 part of a 48% sodium hydroxide aqueous solution, and borohydride. 0.05 part of sodium was charged. Next, after charging 181 parts of sodium hydroxide, nitrogen substitution (oxygen concentration in the gas phase part of 200 ppm) was performed, and 239 parts of methyl chloride was injected at 30 to 65 ° C. in about 10 hours. Thereafter, the reaction was continued at 65 ° C. for 2 hours. Subsequently, demethyl chloride was performed while blowing nitrogen into the liquid at a flow rate of 100 L / min at 60 to 70 ° C. Next, 30 parts of ion-exchanged water was added, 10 parts of synthetic magnesium silicate (sodium content 0.2%) was added, and the atmosphere was purged with nitrogen again, and then stirred at 70 to 80 ° C. for 45 minutes at a stirring speed of 300 rpm. . Subsequently, it filtered under nitrogen using the glass filter (GF-75: product made from Toyo Roshi), and the diluent (C-1) was obtained. Mn of this diluent (C-1) was 240, HLB was 15.5, and SP value was 10.3.

<Production Example 9>
An autoclave was charged with 95 parts of diethylene glycol monomethyl ether and 0.2 part of potassium hydroxide, and after nitrogen substitution (oxygen concentration of 450 ppm in the gas phase part), 495 parts of ethylene oxide was injected at 175 to 185 ° C. in about 5 hours, and then 180 parts. The reaction was continued for 1 hour at ° C. Next, 0.2 parts of 90% aqueous acetic acid solution was charged and neutralized at 90 to 100 ° C. to obtain liquid crude polyethylene glycol monomethyl ether. 945 parts of this liquid crude polyethylene glycol monomethyl ether was charged into an autoclave, purged with nitrogen (oxygen concentration in the gas phase part 200 ppm), 0.2 parts of ion-exchanged water, 0.005 part of a 48% sodium hydroxide aqueous solution, and borohydride. 0.05 part of sodium was charged. Next, after charging 181 parts of sodium hydroxide, nitrogen substitution (oxygen concentration in the gas phase part 200 ppm) was performed, and 239 parts of methyl chloride were injected at 30 to 65 ° C. in about 10 hours. Thereafter, the reaction was continued at 65 ° C. for 2 hours. Subsequently, demethyl chloride was performed while blowing nitrogen into the liquid at a flow rate of 100 L / min at 60 to 70 ° C. Next, after adding 30 parts of ion-exchanged water, 10 parts of synthetic magnesium silicate (sodium content 0.2%) was added, and the atmosphere was purged with nitrogen again. . Subsequently, it filtered under nitrogen using the glass filter (GF-75: product made from Toyo filter paper), and the diluent (C-4) was obtained. Mn of this diluent (C-4) was 730, HLB was 16.9, and SP value was 9.7.

<Comparative Production Example 2>
A comparative diluent (CR-1) was obtained in the same manner as in Production Example 8 except that the amount of diethylene glycol monomethyl ether was changed to 100 parts and the amount of ethylene oxide was changed to 1575 parts in Production Example 8. Mn of this diluent (CR-1) was 2012, HLB was 18.0, and SP value was 9.50.

<Examples 1-8 and Comparative Examples 1-4>
Urethane prepolymer (UP) having an isocyanate group, diluent (C-1), diluent (C-2) [“Diethylene glycol dimethyl ether” manufactured by Tokyo Chemical Industry Co., Ltd., Mn: 134, HLB: 12. 5, SP value: 8.10], diluent (C-3) ["Diethylene glycol dibutyl ether" manufactured by Toho Chemical Industry Co., Ltd., Mn: 218, HLB: 23.8, SP value: 8.29], dilution Agent (C-4), Comparative Diluent (CR-1) or Comparative Diluent (CR-2) [Shin-Etsu Chemical Co., Ltd. “Silicone Oil KF-96-5CS”, Mn: 892, HLB: 4.2, SP value: 7.2] were blended in the number of blending parts described in Table 2 to prepare medical adhesives of Examples 1 to 8 and Comparative Examples 1 to 4.
About the produced medical adhesive, it measured or evaluated about the viscosity, hardening time, and adhesiveness by the method as described below. The results are shown in Table 1.
In addition, the medical adhesive of Comparative Example 4 was separated into two phases, and various evaluations could not be performed.

<Evaluation 1: Viscosity>
The viscosity at 25 ° C. was measured using an E-type viscometer [manufactured by Toki Sangyo Co., Ltd., model TVE-22H].
Generally, when the viscosity is 20,000 mPa · s or less, it can be suitably used for a small-diameter medical device.

<Evaluation 2: Curing time>
Under an environment of 25 ± 5 ° C., 1.0 g of a medical adhesive was weighed into a polyethylene cup, and 1.0 mL of ion-exchanged water was added thereto, and the time at which the ion-exchange water was added was defined as a measurement time start time. The mixture was quickly stirred with a glass rod so that the medical adhesive and ion-exchanged water became uniform. When the glass rod is pulled up from the mixture, the mixture continues to pull the yarn between the mixture and the glass rod.However, if it is recognized that the mixture can break without breaking the yarn due to the progress of curing, it is determined that the curing is complete. The time from the start of stirring to this point was taken as the curing time. The curing time was measured in seconds.

<Evaluation 3: Adhesive evaluation-1>
ePTFE tape (product name: PTFE gasket tape, count: Pillar No. 3330, manufactured by Japan Gore-Tex Co., Ltd.) (1 cm x 4 cm) end part 1 cm x 1 cm in width about 0.02 g of medical adhesive is spatula Was applied using.
After applying the medical adhesive, an end portion of 1 cm × 1 cm of another ePTFE tape was bonded. The test piece was covered with a sufficiently dampened cloth, and a weight of 100 g / cm ² was applied to the portion where the ePTFE tape was bonded, and the sample was left for 5 minutes and then removed.
Next, the tensile shear stress of the test piece was measured according to JIS K6850-1999 under the environment of 25 ± 5 ° C. and humidity 65 ± 5% RH, and the stress at break (N / mm ² ) was defined as the adhesive strength. Adhesion was evaluated.
The tensile tester used was Autograph AGS-500D manufactured by Shimadzu Corporation, and the tensile speed was 300 mm / min. Moreover, the location fixed with the gripping tool was a 1 cm end portion where the ePTFE tape was not bonded and a 1 cm end portion where the other ePTFE tape was not bonded.

<Evaluation 4: Adhesion evaluation-2>
“Adhesion evaluation-1” “operation of covering the test piece with a sufficiently damp cloth and leaving it on for 5 minutes with a weight of 100 g so that a load of 100 g / cm ² is applied to the bonded portion of the ePTFE tape” Except that the test piece is covered with a sufficiently moistened cloth and a 100 g weight is applied to the bonded part of the ePTFE tape to leave it in water for 5 minutes so that a load of 100 g / cm ² is applied. Adhesiveness was evaluated in the same manner as Adhesiveness Evaluation-1.

<Evaluation 5: Adhesive evaluation-3>
Collagen fragments (trade name: manufactured by Nippi Co., Ltd., length 4 cm, width 1 cm, thickness 0.2 cm), another collagen fragment (trade name: manufactured by Nippi Co., Ltd., length) The end part 1 cm × 1 cm of 4 cm, width 1 cm, thickness 0.2 cm) was superposed as shown in FIG. 1, and the following bonding operation (1) was performed.
[Adhesion operation (1)]
Next, as shown in FIG. 1, about 0.02 g of medical adhesive was spread using a spatula so as to cover the overlapped collagen fragments. After covering with a silicon sheet, the specimen was covered with a sufficiently damp cloth. Applying a medical adhesive material, after leaving the portion covered with the silicon sheet topped with 100g of weight to load of 100g / cm ² is applied for 5 minutes, remove the weight, only the silicon steel sheet from the test strip It peeled off [The operation so far is set as adhesion | attachment operation (1)].
Next, the test piece was turned over, and the same operation as the bonding operation (1) was performed on the back surface, and a coating film of a medical adhesive was produced so as to cover the surface and the back surface of the overlapped collagen fragments.
Next, the tensile shear stress of the test piece was measured according to JIS K6850-1999 under the environment of 25 ± 5 ° C. and humidity 65 ± 5% RH, and the stress at break (N / mm ² ) was defined as the adhesive strength. Adhesion was evaluated.
The tensile tester used was Autograph AGS-500D manufactured by Shimadzu Corporation, and the tensile speed was 300 mm / min. Moreover, the location fixed with the gripping tool was a 1 cm end portion where the collagen fragment was not adhered and a 1 cm end portion of the other collagen fragment.

From the results in Table 2, it can be seen that the medical adhesives of Examples 1 to 8 have low viscosity and excellent adhesiveness. On the other hand, although the adhesive for medical use of Comparative Example 1 has excellent adhesive strength in Adhesiveness Evaluation-1, it has poor adhesive strength in Adhesiveness Evaluation-3 and has a high viscosity and is used for a small-caliber medical device. Can not.
Moreover, although the medical adhesive of the comparative example 2 is a viscosity which can be used for a small diameter medical device, it turns out that it is inferior to adhesive strength.
Further, the medical adhesive of Comparative Example 3 is inferior in adhesion hardness (particularly, adhesion evaluation-2 and adhesion evaluation-3) and has a slow curing rate.
Moreover, the medical adhesive of Comparative Example 4 was separated into two phases and could not be used as a medical adhesive.

  Since the medical adhesive of the present invention is excellent in adhesive strength, it can be particularly effectively used for adhesion of a moving biological tissue, for example, arteries, veins, lungs, heart, trachea, esophagus, stomach, duodenum, small intestine, large intestine. It is extremely effective as a medical adhesive used for adhesion of rectum, liver, spleen, kidney, pancreas and nerves, prevention of bleeding, prevention of enzyme leakage from digestive organs, temporary fixation prior to suturing and reinforcement of affected area. In addition, it exhibits high reliability and high performance for joints such as wound surfaces and wounds, and adhesive treatment in dentistry. Further, since the medical adhesive of the present invention has a low viscosity, it can be suitably used for medical devices having a small injection diameter such as trocars, cannulas and catheters, and is particularly useful for endoscopic surgery using these. .

1. Collagen fragment (top)
2. Collagen fragment (bottom)
3. Medical adhesive application part

Claims (9)

A medical adhesive containing a urethane prepolymer having an isocyanate group (UP) and a diluent (C),
The urethane prepolymer (UP) having an isocyanate group is a polyisocyanate component (A) having a fluorine-containing non-aromatic polyisocyanate compound (A1) as an essential component, and a polyol (B1) having at least 30% by weight of an oxyethylene group. Is a reaction product with the polyol component (B) having an essential component, and the diluent (C) has an HLB of 10 to 25,
The medical adhesive whose chemical formula quantity or number average molecular weight of the said diluent (C) is 76-1500.   The medical adhesive according to claim 1, wherein the isocyanate group-containing urethane prepolymer (UP) has an isocyanate group content of 1 to 10% by weight based on the weight of the (UP).   The medical adhesive according to claim 1 or 2, wherein the polyol (B1) is a polyether polyol.   The medical adhesive according to any one of claims 1 to 3, wherein the diluent (C) is an alkylene glycol dialkyl ether (C1) and / or a polyoxyalkylenediol dialkyl ether (C2). The medical adhesive according to any one of claims 1 to 4, wherein the diluent (C) is a compound (C3) represented by the following general formula (1).
R ¹ —O— (AO) _n —R ² (1)
[Wherein, R ¹ and R ² each independently represent an alkyl group having 1 to 4 carbon atoms, A represents an alkylene group having 1 to 4 carbon atoms, and when there are a plurality of A groups, they may be the same or different. Well, n represents the integer of 1-35. ] The medical adhesive according to claim 5, wherein R ¹ and R ² in the general formula (1) are methyl groups, and A is an ethylene group.   The weight ratio [(C) / (UP)] of the diluent (C) to the urethane prepolymer (UP) having an isocyanate group is 5 to 150% by weight. Medical adhesive.   The medical adhesive according to any one of claims 1 to 7, which is used for adhesion of a living tissue.   The medical adhesive according to claim 8, wherein the biological tissue is at least one tissue selected from the group consisting of blood vessels, nerves, heart, respiratory organs and digestive organs.

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