JP2021006140A - Medical adhesive - Google Patents

Abstract

To provide a medical adhesive which can be applied to a tool having low viscosity and a small injection diameter and is excellent in adhesion to a biological tissue.SOLUTION: A medical adhesive contains urethane prepolymer (UP) having an isocyanate group, in which viscosity at 25°C of the medical adhesive is 5,000-30,000 mPa s, the (UP) is a reactant of a polyol component (A) and a polyisocyanate component (B), the (A) contains polyoxyalkylene glycol (A1) containing an oxyethylene group and an oxyethylene group as essential constitutional units, a weight ratio of the oxyethylene group of the (A1) is 30 wt.% or more based on the weight of the (A1), a number average molecular weight of the (A1) is 800-5,000, and the (B) has at least one selected from the group consisting of an aromatic ring and a fluorine atom.SELECTED DRAWING: None

Description

The present invention relates to medical adhesives.

As a medical adhesive for adhering biological tissues such as blood vessels, heart, respiratory organs and digestive organs, conventionally, isocyanate group-terminated hydrophilic urethane prepolymer obtained by reaction of fluorine-containing polyisocyanate and hydrophilic polyether polyol is used. It is known to be used (Patent Documents 1 to 4).

On the other hand, in recent years, endoscopic surgery has been performed because of small surgical scars, less pain, quick postoperative recovery, and the ability to perform surgery with short-term hospitalization. In endoscopic surgery, medical adhesives are injected into the affected area through small injection diameter objects such as trocars, cannulas and catheters. However, conventional isocyanate group-terminated hydrophilic urethane prepolymers and the like have a high viscosity, and there is a problem that they cannot be injected well with an instrument having a small injection diameter.
Further, since the conventional isocyanate group-terminated hydrophilic urethane prepolymer has a high viscosity, a large amount of carbon dioxide gas generated during moisture curing becomes bubbles and is present in a large amount in the coating film and at the coating film interface, resulting in a decrease in coating strength and adhesion. It often caused defects. Furthermore, since the viscosity is high and the ductility is low, the range of use is limited only to the anastomotic site of blood vessels, and it is difficult to use it for organs such as the heart, respiratory organs and digestive organs.

Japanese Unexamined Patent Publication No. 1-227762 International Publication No. 03/051952 Japanese Unexamined Patent Publication No. 2005-124808 International Publication No. 2012/056179

An object of the present invention is to provide a medical adhesive which has low viscosity, can be applied to an instrument having a small injection diameter, and has excellent adhesiveness to living tissues.

The present inventors have arrived at the present invention as a result of diligent studies to solve the above problems. That is, the present invention is a medical adhesive containing a urethane prepolymer (UP) having an isocyanate group.
The medical adhesive has a viscosity at 25 ° C. of 5,000 to 30,000 mPa · s.
The urethane prepolymer (UP) having an isocyanate group is a reaction product of the polyol component (A) and the polyisocyanate component (B).
The polyol component (A) contains a polyoxyalkylene glycol (A1) containing an oxyethylene group and an oxypropylene group as essential constituent units.
The weight ratio of the oxyethylene group contained in the polyoxyalkylene glycol (A1) is 30% by weight or more based on the weight of the polyoxyalkylene glycol (A1).
The polyoxyalkylene glycol (A1) has a number average molecular weight of 800 to 5,000.
The polyisocyanate component (B) is a medical adhesive having at least one selected from the group consisting of an aromatic ring and a fluorine atom.

The medical adhesive of the present invention can be applied to an instrument having a low viscosity and a small injection diameter, and has excellent adhesiveness to living tissues.

The medical adhesive of the present invention contains a urethane prepolymer (UP) having an isocyanate group.
The urethane prepolymer (UP) having an isocyanate group in the present invention is a reaction product of the polyol component (A) and the polyisocyanate component (B).

The polyol component (A) in the present invention contains a polyoxyalkylene glycol (A1) containing an oxyethylene group and an oxypropylene group as essential constituent units.

The polyoxyalkylene glycol (A1) includes an alkylene glycol having 2 to 30 carbon atoms, ethylene oxide and propylene oxide (1,2- or 1,3-propylene oxide), and if necessary, 4 to 8 carbon atoms. Examples thereof include compounds obtained by adding alkylene oxide (1,2-, 1,3-, 2,3- or 1,4-butylene oxide, styrene oxide, etc.).
The addition form may be random, block or a combination thereof, but from the viewpoint of adhesive strength, random is preferable.

Examples of the alkylene glycol having 2 to 30 carbon atoms include ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,6-hexanediol, octanediol, decanediol, and dodecanediol. , Tetradecanediol, neopentyl glycol and 2,2-diethyl-1,3-propanediol, etc.); alicyclic diol having 6 to 24 carbon atoms (1,4-cyclohexanedimethanol, hydrogenated bisphenol A, etc.); carbon Numbers 15 to 30 of bisphenols (bisphenol A, bisphenol F, bisphenol S, etc.); dihydroxybenzene (catechol, hydroquinone, etc.) and the like can be mentioned.

Among the above-mentioned alkylene glycols having 2 to 30 carbon atoms, alkylene glycols having 2 to 4 carbon atoms are preferable from the viewpoint of safety to a living body and adhesive strength.
The polyoxyalkylene glycol (A1) may be one kind or a mixture of two or more kinds.

The weight ratio of the oxyethylene group to the oxypropylene group [oxyethylene group / oxypropylene group] of the polyoxyalkylene glycol (A1) is preferably 3 to 5 from the viewpoint of adhesive strength.

The number average molecular weight (hereinafter, may be abbreviated as Mn) of the polyoxyalkylene glycol (A1) is 800 to 5,000.
If the number average molecular weight is less than 800, the medical adhesive may flow from the bonding target site before the reaction with water proceeds and the medical adhesive is cured.
Further, if it exceeds 5,000, it becomes difficult to inject the medical adhesive with an instrument having a small injection diameter.

Mn in the present invention is measured by gel permeation chromatography (GPC) under the following conditions, for example.
Equipment: Gel Permeation Chromatograph Solvent: Tetrahydrofuran Reference Material: Polyoxyethylene Glycol Sample Concentration: 0.25% by Weight
Column stationary phase: TSKgelSuperH4000
Column temperature: 40 ° C

The HLB of the polyoxyalkylene glycol (A1) is preferably 4 to 20, more preferably 4.5 to 20, from the viewpoint of reactivity and adhesive strength.
The "HLB" in the present invention is an index showing the balance between hydrophilicity and lipophilicity, and is described in, for example, "Introduction to Surfactants" [published by Sanyo Chemical Industries, Ltd. in 2007, by Takehiko Fujimoto] on page 212. According to the Oda method, it can be calculated from the ratio of the organic value and the inorganic value of the organic compound.
HLB ≈ 10 × Inorganic / Organic The organic value and the inorganic value for deriving the HLB can be calculated using the values in the table described on page 213 of the above-mentioned "Introduction to Surfactants".

The content (% by weight) of the oxyethylene group contained in the polyoxyalkylene glycol (A1) is at least 30 and preferably 40 or more, particularly preferably 40 or more, based on the weight of (A1) from the viewpoint of adhesive strength and the like. It is 50 or more.

The polyol component (A) may contain polypropylene glycol (A2) and other polyols (A3) in addition to the polyols other than (A1).

The number average molecular weight of polypropylene glycol (A2) is preferably 100 to 1200 from the viewpoint of the viscosity of the medical adhesive.

Other polyols (A3) include compounds having at least two active hydrogens (alkylene glycols having 2 to 30 carbon atoms, 3- to 8-valent polyols, dicarboxylic acids, 3- to 4-valent polycarboxylic acids, monoamines, and polyamines. And polythiol, etc.) with an alkylene oxide adduct (A31) having 2 to 8 carbon atoms [excluding (A1) and (A2)], and from the group consisting of (A1), (A2) and (A31). Examples thereof include polyester polyol (A32), which is a reaction product of at least one selected polyol and a dicarboxylic acid.

Examples of the 3- to 8-valent polyol include aliphatic polyhydric alcohols having 3 to 8 carbon atoms (glycerin, trimethylolethane, trimethylolpropane, pentaerythritol, sorbitan, diglycerin, sorbitol, etc.).

Examples of the dicarboxylic acid include alcandicarboxylic acids having 4 to 32 carbon atoms (succinic acid, adipic acid, sebacic acid, azelaic acid, sebacic acid, dodecanedicarboxylic acid, octadecanediocarboxylic acid, dodecylsuccinic acid, octadecylsuccinic acid, etc.); 4-32 arcendicarboxylic acids (maleic acid, fumaric acid, citraconic acid, mesaconic acid, dimeric acid, dodecenyl succinic acid, pentadecenyl succinic acid, etc.); aromatic dicarboxylic acids having 8 to 20 carbon atoms (phthalic acid, isophthalic acid, etc.) Acids, terephthalic acids, naphthalenedicarboxylic acids, etc.) and the like.

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

Examples of monoamines include ammonia, aliphatic primary amines having 1 to 20 carbon atoms {alkyl amines having 1 to 20 carbon atoms (methylamine, ethylamine, propylamine, hexylamine, dodecylamine, eicosylamine, etc.)}, carbon. Examples thereof include alicyclic amines having numbers 4 to 15 (piperidin, aminocyclohexane, isophorone monoamine, 4-methylenedicyclohexane monoamine, etc.); aromatic ring-containing aliphatic amines having 6 to 15 carbon atoms (benzylamine, etc.).

Examples of polyamines include aliphatic polyamines having 2 to 18 carbon atoms {alkylenediamines having 2 to 12 carbon atoms (ethylenediamine, propylenediamine, trimethylenediamine, hexamethylenediamine, N, N'-diethylethylenediamine, undecylenediamine, etc.) and polyamines. Alkylene (2 to 6 carbon atoms) polyamines (diethylenetriamine, dipropylenetriamine, triethylenetetramine, pentaethylenehexamine, etc.), etc.}; Aliphatic polyamines with 4 to 15 carbon atoms (1,3-diaminocyclohexane, isophoronediamine and 4) , 4'-Methylenedicyclohexanediamine, etc.); Examples thereof include heterocyclic polyamines having 4 to 15 carbon atoms (piperazine, N-aminoethyl piperazine, 1,4-diaminoethyl piperazine, N-aminoethylpyridine, etc.).

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

The content (% by weight) of the oxyethylene group in the entire polyol component (A) is preferably 30 to 98, more preferably 40 to 95, and particularly preferably 50 to 90, based on the weight of (A). Within this range, the adhesive strength and the like are further improved.

When (A1) and (A2) are used in combination, the content (% by weight) of (A1) in the polyol component (A) is 50 to 100 based on the weight of (A) from the viewpoint of adhesiveness. Is preferable, more preferably 50 to 99, and particularly preferably 70 to 95.
The content (% by weight) of (A2) in the polyol component (A) is preferably 0 to 50, more preferably 1 to 50, and particularly preferably 1 to 50, based on the weight of (A) from the viewpoint of adhesiveness. It is 5 to 30.

The polyisocyanate component (B) in the present invention has at least one selected from the group consisting of an aromatic ring and a fluorine atom. That is, the polyisocyanate component (B) in the present invention includes a fluorine-containing non-aromatic polyisocyanate compound (B1), a fluorine atom-free aromatic polyisocyanate compound (B2), and a fluorine-containing aromatic polyisocyanate compound (B3). ), At least one polyisocyanate compound selected from the group consisting of) is an essential component.
The medical adhesive of the present invention can exhibit sufficient adhesiveness by using a polyisocyanate component (B) having at least one selected from the group consisting of an aromatic ring and a fluorine atom, and can be compared. It can be cured in a short time.
Further, the polyisocyanate component (B) in the present invention includes an aliphatic polyisocyanate compound (b1) containing no fluorine atom and an alicyclic polyisocyanate compound containing no fluorine atom (B1) to (B3). b2) and the like may be used together.
Examples of the fluorine-containing non-aromatic polyisocyanate compound (B1) include fluorine-containing aliphatic diisocyanate (B11) having 3 to 24 carbon atoms, fluorine-containing alicyclic diisocyanate (B12) having 8 to 21 carbon atoms, and 9 to 72 carbon atoms. Fluorine-containing poly (3 to 6 valent) isocyanate (B13) and the like can be used.

Fluorine-containing aliphatic diisocyanates (B11) having 3 to 24 carbon atoms are 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, perfluorooctyldiisocyanate, and perfluoroeicosylene diisocyanate.

OCN-CH _2- Rf-CH _2- NCO represents bis (isocyanatomethyl) difluoromethane, bis (isocyanatomethyl) perfluoroethane, bis (isocyanatomethyl) perfluoropropane, bis ( Examples thereof include isocyanatomethyl) perfluorobutane, bis (isocyanatomethyl) perfluoropentane, bis (isocyanatomethyl) perfluorohexane and bis (isocyanatomethyl) perfluoroeikosan.

Examples of the fluorine-containing alicyclic diisocyanate (B12) having 8 to 21 carbon atoms include diisocyanatoperfluorocyclohexane, bis (isocyanatomethyl) perfluorocyclohexane, bis (isocyanatomethyl) perfluorodimethylcyclohexane, and bis (isocyanato). Perfluorocyclohexyl) perfluoropropane and bis (isocyanatomethylperfluorocyclohexyl) perfluoropropane and the like can be mentioned.

Examples of the fluorine-containing poly (3 to 6-valent) isocyanate (B13) having 9 to 72 carbon atoms include the nurate form of the diisocyanate, the adduct form of the diisocyanate, and tris (isocyanatotetrafluorocyclohexyl) methane.

The position of the isocyanate group in the fluorine-containing non-aromatic polyisocyanate compound (B1) is such that there is little steric hindrance from the viewpoint of reactivity with the polyol component (A) and reactivity with blood, body fluids, etc. Preferably, more preferred is a terminal position with less steric hindrance.
Further, the fluorine-containing non-aromatic polyisocyanate compound (B1) may be one kind or a mixture of two or more kinds.
Further, among the fluorine-containing non-aromatic polyisocyanate compounds (B1), those having two isocyanate groups are preferable from the viewpoint that side reactions such as a cross-linking reaction are unlikely to occur.

Among the fluorine-containing non-aromatic polyisocyanate compounds (B1), the fluorine-containing aliphatic polyisocyanate (B11) is preferable, and OCN-CH _2- Rf-CH is more preferable from the viewpoint of safety such as mutagenicity. Fluoroaliphatic polyisocyanate represented by ₂ -NCO and fluorine-containing aliphatic polyisocyanate represented by OCN-Rf-NCO are particularly preferable, with difluoromethylene diisocyanate, perfluorodimethylene diisocyanate, and perfluorotrimethylene. Diisocyanate, perfluorooctyldiisocyanate, perfluoroeicosylene diisocyanate, bis (isocyanatomethyl) perfluoropropane, bis (isocyanatomethyl) perfluorobutane, bis (isocyanatomethyl) perfluoropentane and bis (isocyanatomethyl) par Fluorohexane.

From the viewpoint of adhesive strength and the like, the ratio (% by weight) of the weight of the fluorine atom in the fluorine-containing non-aromatic polyisocyanate compound (B1) is preferably 35 to 70, more preferably 35 to 70, based on the weight of (B1). It is 38 to 70, particularly preferably 40 to 56.

Examples of the above-mentioned aromatic polyisocyanate compound (B2) containing no fluorine atom include aromatic polyisocyanate [m- or p-xylylene diisocyanate (XDI), α, α, which does not contain a fluorine atom having 8 to 21 carbon atoms. α', α'-tetramethylxylylene diisocyanate (TMXDI), 1,3- or 1,4-phenylenediocyanate (PDI), 2,4- or 2,6-tolylene diisocyanate (TDI), 2,4' -Or 4,4'-diphenylmethane diisocyanate (MDI), crude MDI, etc.] and the like.

The polyisocyanate compound (B2) containing no fluorine atom may be one kind or a mixture of two or more kinds.

Examples of the fluorine-containing aromatic polyisocyanate compound (B3) include fluorine-containing aromatic polyisocyanates in which some or all of the hydrogen atoms of the aromatic polyisocyanate (B2) containing no fluorine atom are replaced with fluorine atoms. Can be mentioned.

The fluorine-containing aromatic polyisocyanate (B31) is obtained by substituting all hydrogen atoms in the aromatic ring with fluorine atoms, and specifically, 1,3- or 1,4-perfluorophenylenediisocyanate, 3, Examples thereof include 5,6- or 3,4,5-trifluoro-2,4- or 2,6-tolylene diisocyanate, tetrafluoro-2,4'-or 4,4'-diphenylmethane diisocyanate and the like.

The fluorine-containing aromatic polyisocyanate (B32) is obtained by substituting a hydrogen atom of a part of the aromatic ring with a fluorine atom, and specifically, trifluoromethyl-monofluoro-phenylene-1,3 or 1, Examples thereof include 4-diisocyanate and 2,4'-or 4,4'-diphenyldifluoromethane diisocyanate.

Fluorine-containing aromatic polyisocyanate (B33) is obtained by substituting all hydrogen atoms with fluorine atoms, and 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 polyisocyanates (B3), from the viewpoint of reactivity and the like, the fluorine-containing aromatic polyisocyanate (B31) in which all hydrogen atoms in the aromatic ring are replaced with fluorine atoms, and the aromatic ring Fluorine-containing aromatic polyisocyanate (B32) in which some hydrogen atoms are replaced with fluorine atoms and fluorine-containing aromatic polyisocyanate (B33) in which all hydrogen atoms are replaced with fluorine are preferable, and all hydrogen atoms are more preferable. Is a fluorine-containing aromatic polyisocyanate (B33) in which is substituted with a fluorine atom.
The fluorine-containing aromatic polyisocyanate compound (B3) may be one kind or a mixture of two or more kinds.

The aliphatic polyisocyanate compound (b1) containing no fluorine atom includes an aliphatic polyisocyanate containing no fluorine atom having 3 to 24 carbon atoms ([tetramethylene diisocyanate, hexamethylene diisocyanate (HDI), 2, 2, 2). 4-trimethylhexamethylene diisocyanate, lysine diisocyanate, etc.] and the like.

Examples of the alicyclic polyisocyanate compound (b2) containing no fluorine atom include alicyclic polyisocyanate [isophorone diisocyanate (IPDI), dicyclohexylmethane-4,4'-, which does not contain a fluorine atom having 8 to 21 carbon atoms. Diisocyanate (hydrogenated MDI), cyclohexylene diisocyanate, methylcyclohexylene diisocyanate (hydrogenated TDI), etc.] and the like.

Further, these polyocyanate compounds may be modified products, and urethane modified products, isocyanurate modified products, allophanate modified products, biuret modified products, uretdione modified products, uretonimine modified products, uretdione / isocyanurate modified products and the like may be used. Can be mentioned. Which of (B1) to (B3) and (b1) to (b2) the modified product belongs to is determined by the presence or absence of a fluorine atom and an aromatic ring.
For example, the modified products of HDI include urethane-modified HDI, carbodiimide-modified HDI and trihydrocarbyl phosphate-modified HDI, the modified products of MDI include urethane-modified MDI, carbodiimide-modified MDI, and the modified products of TDI include urethane-modified TDI and Examples thereof include carbodiimide-modified TDI.

The urethane prepolymer (UP) having an isocyanate group can be obtained by reacting the polyol component (A) with the polyisocyanate component (B).
The ratio of the amount of the polyisocyanate component (B) to the polyol component (A) used is preferably 1.5 to 3 as the equivalent ratio of the isocyanate group of (B) to the hydroxyl group of (A) (NCO group / hydroxyl group). , More preferably 1.8 to 2.3, and particularly preferably 1.9 to 2.1. Within this range, the viscosity is relatively low, the adhesive is more easily handled, 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 (such as the method described in International Publication No. 03/051952) may be used, and for example, a polyisocyanate component (B) and a polyol component ( Examples thereof include a method of reacting A) with and at 50 to 100 ° C. for 1 to 10 hours. In this case, the method of adding the polyisocyanate component (B) and the polyol component (A) may be a method of adding the polyisocyanate component (B) from the beginning or a method of gradually lowering the amount.
The urethane prepolymer (UP) having an isocyanate group has a structure having at least two (preferably two) isocyanate groups in the molecule and no active hydrogen.
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. The position.

Further, the isocyanate group content (% by weight) {weight ratio of the isocyanate group to the total weight of (UP)} in the urethane prepolymer (UP) having an isocyanate group is preferably 1 to 10, and more preferably 1. It is 2 to 8, particularly preferably 1.5 to 6. Within this range, the wet adhesive strength becomes even better.
The isocyanate group content can be measured by adding an excess di-n-butylamine solution to the sample to cause a reaction, and back-titrating the unreacted di-n-butylamine with a hydrochloric acid standard solution, for example, JIS K7301. -1995, 6.3 Measured according to the isocyanate group content.

The content (% by weight) of the oxyethylene group in the urethane prepolymer (UP) having an isocyanate group is preferably 25 to 65, more preferably 30 to 65, based on the weight of (UP) from the viewpoint of reactivity. It is 60.

The 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, and most preferably 1,200 to 8. It is 000. Within this range, the wet adhesive strength becomes even better.
The Mn of the urethane prepolymer (UP) is a value obtained by reacting the isocyanate group of (UP) with methanol.

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

Examples of the phenol-based radical trapping agent (PRS) include monophenol-based, bisphenol-based, and polymer-based phenol-based radical trapping agents.

Examples of the monophenol radical trapping agent include 2,6-di-t-butyl-p-cresol {for example, Antage BHT manufactured by Kawaguchi Chemical Industry Co., Ltd.} and butylated hydroxyanisole {for example, Orient BHT manufactured by Orient Chemical Industry Co., Ltd. }, 2,6-di-t-butyl-4-ethylphenol {for example, Noclizer M-17 manufactured by Ouchi Shinko Kagaku Kogyo Co., Ltd.} and stearyl-β- (3,5-di-t-butyl-4-) Hydroxyphenyl) propionate {for example, Adecastab AO-50 manufactured by ADEKA Co., Ltd.} and the like can be mentioned.

Examples of the bisphenol radical trapping agent include 2,2'-methylenebis (4-methyl-6-t-butylphenol) {for example, Antage W-400 manufactured by Kawaguchi Chemical Industry Co., Ltd.} and 2,2'-methylenebis (4-ethyl). -6-t-Butylphenol) {for example, Antage W-500 manufactured by Kawaguchi Chemical Industry Co., Ltd.}, 4,4'-butylidenebis (3-methyl-6-t-butylphenol) {For example, Antage manufactured by Kawaguchi Chemical Industry Co., Ltd. Crystal}, 4,4'-thiobis (3-methyl-6-t-butylphenol) {for example, Antage W-300 manufactured by Kawaguchi Chemical Industry Co., Ltd.}, 1,6-hexanediol-bis [3- (3,5) -Di-t-butyl-4-hydroxyphenyl) propionate] {for example, irganox 259 manufactured by BASF] 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 {for example, Adecastab AO-80 manufactured by ADEKA Co., Ltd.} and the like can be mentioned.

Examples of the high molecular weight phenolic radical trapping agent include tetrakis- [methylene-3- (3', 5'-di-t-butyl-4'-hydroxyphenyl) propionate] methane {for example, Irganox 1010 manufactured by BASF). 1,3,5-trimethyl-2,4,6-tris (3,5-di-t-butyl-4-hydroxybenzyl) benzene {for example, Adecastab AO-330 manufactured by ADEKA Co., Ltd.}, 1,1,3 -Tris (2-methyl-4-hydroxy-5-t-butylphenyl) butane {for example, Adecastab AO-30 manufactured by ADEKA Co., Ltd.}, bis [3,3'-bis- (4'-hydroxy-3'-) t-Butylphenyl) Butylic Acid] Glycolester and 1,3,5-tris (3', 5'-di-t-butyl-4'-hydroxybenzyl) -sec-triazine-2,4,6-( 1H, 3H, 5H) Trion {for example, Adecastab AO-20 manufactured by ADEKA Co., Ltd.} and the like can be mentioned.

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

The phenolic radical scavenger (PRS) preferably has at least 2 hydroxyl groups, more preferably 2 to 5, and particularly preferably 3 to 4. Within this range, the cured product is less likely to be deteriorated and decomposed over time.

Among these phenol-based radical trapping agents, bisphenol-based radical trapping agents and polymer-type phenol-based radical trapping agents are preferable, and tetrakis- [methylene-3] is more preferable, from the viewpoint of suppressing deterioration and decomposition of the cured product over time. -(3', 5'-di-t-butyl 4'-hydroxyphenyl) propionate] methane, 1,1,3-tris (2-methyl-4-hydroxy-5-t-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-4) -Hydroxyphenyl) propionate].

Even with the same radical scavenger, non-phenolic radical scavengers [for example, aromatic amine scavengers {octylated diphenylamine, Nn-butyl-p-aminophenol, phenothiazine, etc.}, sulfur scavengers, etc. {Dilauryl-3,3'-thiodipropionate, distearyl-3,3'-thiodipropionate, pentaerythritol tetrakis (3-laurylthiopropionate), etc.} and phosphorus radical scavenger {trisnonylphenyl Phenolic radical scavengers (PRS) are preferred over phosphite, tris (2,4-di-t-butylphenyl) phosphite, distearylpentaerythritol diphosphite, etc.}]. When the phenolic radical scavenger (PRS) is used, it is possible to suppress the deterioration and decomposition of the cured product of the urethane prepolymer (UP) having an isocyanate group over time, and to exhibit excellent adhesive durability.
A phenolic radical scavenger (PRS) and a radical scavenger other than (PRS) may be used in combination.

The content (% by weight) of these phenolic radical scavengers (PRS) is preferably 0.01 to 3 and more preferably 0.02 to 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 product over time can be suppressed, and the human body is not adversely affected.
The phenolic radical trapping agent (PRS) may be added to the urethane prepolymer (UP) having an isocyanate group, or may be added to the polyisocyanate component (B) and / or the polyol component (A) in advance and then isocyanate. A urethane prepolymer (UP) having a group may be obtained.

The medical adhesive of the present invention may contain other components, if necessary, in addition to the urethane prepolymer (UP) having an isocyanate group and the phenolic radical scavenger (PRS).
Other ingredients include bioactive drugs (central nervous system drugs, allergic drugs, circulatory organ drugs, respiratory organ drugs, digestive organ drugs, hormonal agents, metabolic drugs, antineoplastic agents, antibiotics). Preparations and chemotherapeutic agents, etc.), fillers (carbon black, red iron oxide, calcium silicate, sodium silicate, titanium oxide, acrylic resin powder, various ceramic powders, etc.) and plasticizers (DBP, DOP, TCP, tributoxyethyl, etc.) Phosphate and other various esters, etc.) are included. When other components are contained, their contents are appropriately determined depending on the intended use and the like.

The viscosity (mPa · s) of the medical adhesive at 25 ° C. is 5,000 to 30,000.
If the viscosity is less than 5,000, the medical adhesive may flow from the bonding target portion before the reaction with water proceeds and the medical adhesive is cured.
Further, if it exceeds 30,000, it becomes difficult to inject the medical adhesive with an instrument having a small injection diameter.
The viscosity (mPa · s) of the medical adhesive at 25 ° C. is preferably 7,000 to 20,000 from the viewpoint of facilitating injection into an instrument having a small injection diameter.

In the urethane prepolymer (UP) having an isocyanate group contained in the adhesive of the present invention, the isocyanate group reacts with water (water in a body fluid such as blood or lymph) to generate an amino group and carbon dioxide. Then, this amino group further reacts with the isocyanate group to promote high molecular weight (polymerization). Carbon dioxide generated during the reaction causes foaming (sponge-like), and a film containing a foam having wet adhesive strength and flexibility is formed.
Therefore, when the adhesive of the present invention comes into contact with a body fluid such as blood in a medical practice such as surgery, the moisture rapidly polymerizes and the adhesive strength is developed. Further, if necessary, the initial adhesive strength can be increased by, for example, spraying physiological saline or the like to replenish the water.

In surgery, as a joining method when joining the biological tissue with the adhesive of the present invention, a direct bonding method in which the adhesive of the present invention is directly applied to the incision; to a film having high peelability such as a silicone film and a fluorine film. Examples thereof include a transfer bonding method in which the incision is covered with a film after applying an adhesive and the film is removed after the reaction.

Among endoscopic surgery, endoscopic surgery involves making several small holes of about 0.5 cm in the abdominal cavity, thoracotomy, retroperitoneal cavity, etc., and inserting a video camera and special surgical instruments through them to monitor. It is a surgical procedure that is minimally invasive and reduces the burden on the patient as compared with conventional open chest and abdominal surgery. In addition to the fields of digestive organs and general surgery, it is also applied to operations such as chest (thoracic cavity) such as lung and heart, neck such as 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 trocars, cannulas, catheters and the like having a small injection diameter. In addition, the medical adhesive of the present invention may be used for endoscopic surgery that does not require an incision (surgery in which a video camera and a special surgical instrument are inserted through the nose, mouth, etc.).

The medical adhesive of the present invention is preferably used for adhering living tissue from the viewpoint of safety to the living body and adhesive strength to the living body, and the biological tissue is preferably used for blood vessels, nerves, heart, and respiratory organs. And digestive organs, more preferably lungs, arteries, hearts, veins, trachea, esophagus, stomach, duodenum, small intestine, large intestine, rectum, liver, spleen, kidneys, pancreas and nerves.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. In the following, unless otherwise specified,% indicates a weight% and a part indicates a weight part.

Mn in Examples was measured by gel permeation chromatography (GPC) under the following conditions.
Equipment: Gel Permeation Chromatograph Solvent: Tetrahydrofuran Reference Material: Polyoxyethylene Glycol Sample Concentration: 0.25% by Weight
Column stationary phase: TSKgelSuperH4000
Column temperature: 40 ° C

<Production Example 1: Production of ethylene oxide / propylene oxide random co-adduct (A1-1)>
15.5 parts of ethylene glycol and 3.8 parts of potassium hydroxide were charged in an autoclave, and after nitrogen substitution (oxygen concentration in the gas phase part was 450 ppm), dehydration was performed at 120 ° C. for 60 minutes under reduced pressure (100 kPa). Then, a mixture of 784.5 parts of ethylene oxide and 200 parts of propylene oxide was press-fitted at 100 to 130 ° C. for about 10 hours, and then the reaction was continued at 130 ° C. for 3 hours to obtain a liquid crude polyether. 1,000 parts of this liquid crude polyether is charged into an autoclave, subjected to nitrogen substitution (oxygen concentration in the gas phase part is 450 ppm), 30 parts of ion-exchanged water is added, and then synthetic magnesium silicate (sodium content 0.2%). ) Was added and the mixture was replaced with nitrogen again, and then the mixture was stirred at 90 ° C. for 45 minutes at a stirring speed of 300 rpm. Then, using a glass filter (GF-75: manufactured by Toyo Filter Paper Co., Ltd.), filtration was performed under nitrogen, and the oxy with respect to the weight of the ethylene oxide / propylene oxide random co-adduct (A1-1) [(A1-1)). Weight ratio of ethylene group: 80% by weight] was obtained. The Mn of this ethylene oxide / propylene oxide random co-addition (A1-1) was 4,000.

<Production Example 2: Production of ethylene oxide / propylene oxide random co-adduct (A1-2)>
In Production Example 1, in the same manner except that the input amount of ethylene glycol was changed to 20.7 parts and the input amount of ethylene oxide was changed to 779.3 parts, the ethylene oxide / propylene oxide random co-additive (A1-2) [ Weight ratio of oxyethylene group to weight of (A1-2): 80% by weight] was obtained. The Mn of this ethylene oxide / propylene oxide random co-addition (A1-2) was 3,000.

<Production Example 3: Production of ethylene oxide / propylene oxide random co-adduct (A1-3)>
In Production Example 1, the ethylene oxide / propylene oxide random co-adduct (A1-3) [A1-3] is the same except that the ethylene glycol input amount is changed to 41.3 parts and the ethylene oxide input amount is changed to 758.7 parts. Weight ratio of oxyethylene group to weight of (A1-3): 80% by weight] was obtained. The Mn of this ethylene oxide / propylene oxide random co-adduct (A1-3) was 1,500.

<Comparative Production Example 1: Production of Ethylene Oxide / Propylene Oxide Random Co-Addition (a1-1)>
In Production Example 1, the ethylene oxide / propylene oxide random co-adduct (a1-1) [a1-1] was carried out in the same manner except that the input amount of ethylene glycol was changed to 10.3 parts and the input amount of ethylene oxide was changed to 789.7 parts. Weight ratio of oxyethylene group to weight of (a1-1): 80% by weight] was obtained. The Mn of this ethylene oxide / propylene oxide random co-adduct (a1-1) was 6,000.

<Comparative Production Example 2: Production of Ethylene Oxide / Propylene Oxide Random Co-Adduct (a1-2)>
In Production Example 1, the ethylene oxide / propylene oxide random co-adduct (a1-2) [(a1-2) was obtained in the same manner except that the input amount of ethylene glycol was changed to 124 parts and the input amount of ethylene oxide was changed to 676 parts. ) To the weight of the oxyethylene group: 80% by weight] was obtained. The Mn of this ethylene oxide / propylene oxide random co-adduct (a1-2) was 500.

<Production Example 4: Production of Propylene Oxide Adduct (A2-1)>
362 parts of propylene glycol and 3.8 parts of potassium hydroxide were charged in an autoclave, and after nitrogen substitution (oxygen concentration in the gas phase part was 450 ppm), dehydration was performed at 120 ° C. for 60 minutes under reduced pressure (100 kPa). Then, 632 parts of propylene oxide was press-fitted at 100 to 130 ° C. for about 10 hours, and then the reaction was continued at 130 ° C. for 3 hours 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 (A2-1). The Mn of this propylene oxide adduct (A2-1) was 210.

<Production Example 5: Production of Propylene Oxide Adduct (A2-2)>
A propylene oxide adduct (A2-2) was obtained in the same manner except that the amount of propylene glycol added was changed to 190 parts and the amount of propylene oxide added was changed to 810 parts in Production Example 4. The Mn of this propylene oxide adduct (A2-2) was 400.

<Production Example 6: Production of Propylene Oxide Adduct (A2-3)>
A propylene oxide adduct (A2-3) was obtained in the same manner except that the amount of propylene glycol added was changed to 126.7 parts and the amount of propylene oxide added was changed to 873.3 parts in Production Example 4. The Mn of this propylene oxide adduct (A2-3) was 600.

<Production Example 7: Production of Propylene Oxide Adduct (A2-4)>
A propylene oxide adduct (A2-4) was obtained in the same manner except that the amount of propylene glycol added was changed to 76 parts and the amount of propylene oxide added was changed to 924 parts in Production Example 4. The Mn of this propylene oxide adduct (A2-4) was 1,000.

<Production Example 8: Production of Propylene Oxide Adduct (a2-1)>
A propylene oxide adduct (a2-1) was obtained in the same manner except that the amount of propylene glycol added was changed to 38 parts and the amount of propylene oxide added was changed to 962 parts in Production Example 4. The Mn of this propylene oxide adduct (a2-1) was 2,000.

<Example 1>
As the polyol component (A), a mixture of 90 parts of the ethylene oxide / propylene oxide random co-additive (A1-1) obtained in Production Example 1 and 10 parts of the propylene oxide adduct (A2-2) obtained in Production Example 5 was prepared. After dehydration under reduced pressure at 100 ° C. for 2 hours in a nitrogen atmosphere, the mixture was cooled to 50 ° C. and 0.5 part of tetrakis- [methylene-3- (3', 5)) was used as a phenolic hydroxyl group-containing radical scavenger (PRS). '-Di-t-butyl-4'-hydroxyphenyl) propionate] Methane (Irganox 1010, manufactured by BASF) was added and stirred uniformly for 30 minutes. After further cooling to 40 ° C., 45.6 parts of bis (isocyanatomethyl) perfluorobutane (B-1), which is a fluorine-containing non-aromatic polyisocyanate as a polyisocyanate component (B) (isocyanate group / hydroxyl group equivalent ratio =) After adding 2/1) and stirring uniformly, the temperature was raised to 80 ° C. and reacted at 80 ° C. for 6 hours to produce a urethane prepolymer to produce a medical adhesive.

<Examples 2 to 10 and Comparative Examples 1 to 6>
Except that in Example 1, the type and the number of parts by weight of the polyol component (A) were changed to the contents shown in Table 1, and the type and the number of parts by weight of the polyisocyanate component (B) were changed to the contents shown in Table 1. , A urethane prepolymer was produced in the same manner as in Example 1 to obtain the medical adhesives described in Examples 2 to 10 and Comparative Examples 1 to 6.
The viscosity, curing time and adhesiveness of the prepared medical adhesive were measured or evaluated by the methods described below. The results are shown in Table 1.

<Evaluation 1: Viscosity>
The viscosity at 25 ° C. was measured using an E-type viscometer [model TVE-22H manufactured by Toki Sangyo Co., Ltd.].
Generally, when the viscosity is 30,000 mPa · s or less, it can be suitably used for endoscopic surgery.

<Evaluation 2: Curing time>
In an environment of 25 ± 5 ° C., 1.0 g of a medical adhesive was weighed in a polyethylene cup, 1.0 mL of ion-exchanged water was added thereto, and the time of addition was defined as the measurement time start time. The medical adhesive and ion-exchanged water were quickly stirred with a glass rod so that they were uniform. When the glass rod is pulled up from the mixture, the mixture continues to pull the thread between the mixture and the glass rod, but if it is recognized that the mixture is in a state where it can be cut without pulling the thread as the curing progresses, it is judged that the curing is completed. The time from the start of stirring to this point was defined as the curing time. Those having a curing time of 5 minutes or less were evaluated as ◯, and those having a curing time of more than 5 minutes were evaluated as x.

<Evaluation 3: Adhesiveness evaluation>
<Preparation of test piece>
Both sides of a strong double-sided tape (Nystack super strong type, manufactured by Nichiban Co., Ltd.) were covered with a collagen film (collagen casing, manufactured by Nippi Co., Ltd.) to form an adherend.
Approximately 0.02 g of a medical adhesive was applied to an area of 1 cm × 1 cm on one side of both ends (short side) of the adherend cut into 1 cm × 7 cm using a spatula.
After attaching one end (short side side) of two other adherends cut into 1 cm x 4 cm to the part (2 places) to which the medical adhesive was applied so as to overlap each other by 1 cm x 1 cm (total). (Attach the three adherends so that the long sides are horizontal), cover with a sufficiently moistened cloth, place a 100 g weight on the adhered part, and leave it for 5 minutes to adhere. After that, I removed the weight.
This was immersed in 0.9 wt% physiological saline for 3 hours and water-absorbed and swollen to prepare a test piece.
<Measurement>
Then, in an environment of 25 ± 5 ° C. and a humidity of 65 ± 5 RH%, both ends of the test piece (the ends of the adherend cut into 1 cm × 4 cm) were periodically pulled in the opposite direction (the direction in which the sheet stretched), and the test piece was continuously pulled. Adhesion was evaluated by measuring the number of tensions until the test piece peeled off. In addition, three test pieces were prepared for each of the medical adhesives, the measured values were taken as the average value, and a three-stage evaluation was performed according to the following criteria.
The tensile tester used was a measuring stand MX-500N manufactured by Imada Co., Ltd. The continuous cycle mode was set, the tensile distance was set to 25 mm, and the tensile speed was set to 300 mm / min. In addition, the part to be fixed with the gripper is the part of the adherend cut into 1 cm x 4 cm with the non-adhesive end 1 cm and the other end of the adherend cut into 1 cm x 4 cm with the non-adhesive end 1 cm. It was used as a part and fixed so that it would not loosen.
[Evaluation criteria]
⊚: 10 times or more ○: 3 times or more and less than 10 times ×: less than 3 times

From the results in Table 1, it can be seen that the medical adhesives of Examples 1 to 10 have a low viscosity and are excellent in adhesiveness.

Since the medical adhesive of the present invention has excellent adhesive strength, it can be particularly effectively used for adhering moving biological tissues. For example, arteries, veins, lungs, hearts, trachea, esophagus, stomach, duodenum, small intestine, and pancreas. It is extremely effective as a medical adhesive used for adhesion of the small intestine, liver, spleen, kidney, pancreas, nerves, etc., prevention of bleeding, prevention of enzyme leakage from the digestive organs, temporary fixation prior to suturing, and reinforcement of the affected area. In addition, it exhibits high reliability and high performance for joining wound surfaces and incisions, and for 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 a trocar, a cannula and a catheter, and is particularly useful for endoscopic surgery using these.

Claims (5)

A medical adhesive containing a urethane prepolymer (UP) having an isocyanate group.
The medical adhesive has a viscosity of 5,000 to 30,000 mPa · s at 25 ° C.
The urethane prepolymer (UP) having an isocyanate group is a reaction product of the polyol component (A) and the polyisocyanate component (B).
The polyol component (A) contains a polyoxyalkylene glycol (A1) containing an oxyethylene group and an oxypropylene group as essential constituent units.
The weight ratio of the oxyethylene group contained in the polyoxyalkylene glycol (A1) is 30% by weight or more based on the weight of the polyoxyalkylene glycol (A1).
The polyoxyalkylene glycol (A1) has a number average molecular weight of 800 to 5,000.
A medical adhesive having the polyisocyanate component (B) at least one selected from the group consisting of an aromatic ring and a fluorine atom. The medical adhesive according to claim 1, wherein the polyol component (A) further contains polypropylene glycol (A2), and the number average molecular weight of the polypropylene glycol (A2) is 100 to 1200. The medical adhesive according to claim 1 or 2, wherein the urethane prepolymer (UP) having an isocyanate group has an isocyanate group content of 1 to 10% by weight based on the weight of the (UP). The medical adhesive according to any one of claims 1 to 3, which is used for adhering living tissue. The medical adhesive according to claim 4, wherein the living tissue is at least one tissue selected from the group consisting of blood vessels, nerves, heart, respiratory organs and digestive organs.