JP2004261590A - Adhesive for medical treatment - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an adhesive for medical treatment useful as a surgical adhesive which works effectively as an adhesive within the living body only during a surgical operation but has such characteristics that decomposes rapidly when restoration of the living body is completed. <P>SOLUTION: The adhesive for medical treatment comprises a urethan prepolymer containing isocyanate groups which is an adduct of a polyol (A) and a polyisocyanate (B). The polyol (A) has an oxyethylene group (a), an organic group (b) of formula (1), an organic group (c) of formula (2) and/or an organic group (d) of formula (3). <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention relates to medical adhesives. More specifically, the present invention relates to an adhesive suitable for medical use such as surgery, which is easily decomposed after a certain period of time in a living body.

Medical adhesives used for surgical operations for joining blood vessels and solid organs and for stopping bleeding are foreign substances to living organisms. Therefore, it is desirable to use an adhesive that functions as an adhesive in a living body only for a necessary period of time and that is decomposed and lost when the repair of the living body is completed.
Conventionally, as a medical adhesive having such degradability, a urethane prepolymer obtained by a reaction between a polyester polyol obtained by ring-opening polymerization of ε-caprolactone or lactide and an aromatic polyisocyanate is known. (Patent Document 1).
U.S. Pat. No. 4,804,691

  However, there is a problem that the adhesive has a low hydrolyzability of an ester bond in a living body, and the adhesive remains in an affected part for a long period of time even after repair of a living body. That is, an object of the present invention is to provide a medical adhesive which can be rapidly decomposed and lost with the repair of a living body.

  The present inventors have conducted intensive studies to achieve the above object, and as a result, have reached the present invention. That is, the medical adhesive of the present invention is characterized in that, in the medical adhesive comprising an isocyanate group-containing urethane prepolymer which is an adduct of the polyol (A) and the polyisocyanate (B), the polyol (A) is oxyethylene A group (a) and an organic group (b) represented by the chemical formula (1) and an organic group (c) represented by the chemical formula (2) and / or an organic group (d) represented by the chemical formula (3) The point is to have.

The conventional urethane prepolymer-based medical adhesive (for example, the adhesive of Comparative Example 2), which is said to have degradability, remains at the site of use for several years because of its slow degradation in vivo. This is the actual situation, and the existence of such a shape as it is when used for a long period of time may cause adverse effects on living organisms such as carcinogenesis.
On the other hand, the medical adhesive of the present invention has an effect of quickly decomposing and disappearing without remaining in the affected part over a long period of time after repairing the affected part of the living body, and is also excellent in safety. . Furthermore, the medical adhesive of the present invention, in addition to the above-mentioned characteristic of degradability, satisfies three basic characteristics of curing speed, bondability with living tissue, and flexibility that can follow movement of living tissue. It has the effect of greatly increasing the safety and certainty of medical procedures such as surgery.

As the polyol (A), a polyol (A1) having an oxyethylene group (a), an organic group (b), and an organic group (c), an oxyethylene group (a), an organic group (b), and an organic Polyol (A2) having a group (d) and polyol (A3) having an oxyethylene group (a), an organic group (b), an organic group (c) and an organic group (d) Is included.
An oxyethylene group (a) and an organic group (b) represented by the chemical formula (1) and an organic group (c) represented by the chemical formula (2) and / or an organic group (d) represented by the chemical formula (3) Examples of the polyol (A) having the formula (I) include ring-opening polymerization of a polyether polyol (aa) having an oxyethylene group with ε-caprolactone (bb) and trimethylene carbonate (cc) and / or L-lactide (dd). Can be obtained.
The oxyethylene group (a) is formed of ethylene oxide, the organic group (b) of formula (1) is formed of ε-caprolactone (bb), and the organic group (c) of formula (2) is trimethylene. The organic group (d) represented by the chemical formula (3) may be formed by L-lactide (dd).
That is, the polyol (A1) can be produced by ring-opening polymerization of a polyether polyol (aa) having an oxyethylene group, ε-caprolactone (bb), and trimethylene carbonate (cc). Further, the polyol (A2) can be produced by ring-opening polymerization of a polyether polyol (aa) having an oxyethylene group, ε-caprolactone (bb), and L-lactide (dd). The polyol (A3) is produced by ring-opening polymerization of a polyether polyol having an oxyethylene group (aa), ε-caprolactone (bb), trimethylene carbonate (cc), and L-lactide (dd). obtain.

As the polyether polyol (aa) having an oxyethylene group (a), an alkylene oxide (co) adduct of a compound having at least two active hydrogens and the like can be used. Examples of the alkylene oxide include alkylene oxides having 2 to 8 carbon atoms (ethylene oxide, 1,2- or 1,3-propylene oxide, 1,2-, 1,3-, 2,3- or 1,4-butylene oxide, Tetrafluorofuran and styrene oxide, etc.) and C2-8 fluoroalkylene oxide (1,1-difluoroethylene oxide, tetrafluoroethylene oxide, 3,3,3-trifluoropropylene oxide, perfluoropropylene oxide, perfluorobutylene oxide, Perfluorotetrahydrofuran and perfluorostyrene oxide). As the alkylene oxide, ethylene oxide and 1,2-propylene oxide are preferable, and ethylene oxide alone and a mixture of ethylene oxide and 1,2-propylene oxide are more preferable.
In the case of a co-adduct, the addition form may be random, block, or a combination thereof, but is preferably random.

  In the case of a co-adduct, the content (% by weight) of the oxyethylene group is preferably 30 or more, more preferably 50 or more, and particularly preferably 60 or more, based on the weight of the co-adduct {polyether polyol (aa)}. The above is most preferably 70 or more, and preferably 99 or less, more preferably 98 or less, particularly preferably 95 or less, and most preferably 90 or less. When it is in this range, the water absorption of the adhesive is further increased, and the adhesive strength (particularly the initial adhesive strength), the curing speed, and the decomposability of the adhesive are more likely to be further increased.

  Compounds having at least two active hydrogens include water, diols, tri- to hexa-valent polyols, dicarboxylic acids, tri- to tetra-valent polycarboxylic acids, monoamines, polyamines, polythiols, hydroxycarboxylic acids, hydroxyamines, aminocarboxylic acids And saccharides. When a compound having two active hydrogens is used, a divalent polyether polyol is obtained, and when a compound having three or more active hydrogens is used, a trivalent or more polyether polyol is obtained.

  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, octadecanediol, eicosandiol, trichosandiol, etc.); alicyclic diols having 6 to 24 carbon atoms (1,4 -Cyclohexanedimethanol and hydrogenated bisphenol A {2,2-bis (4-hydroxyphenyl) propane} etc.); bisphenols having 15 to 30 carbon atoms (such as bisphenol A, bisphenol F and bisphenol S); dihydroxybenzene (category) Lumpur and hydroquinone) and the like.

  Examples of the trivalent to hexavalent polyol include aliphatic polyhydric (trivalent to hexavalent) alcohols having 3 to 20 carbon atoms (glycerin, diglycerin, triglycerin, tetraglycerin, trimethylolethane, trimethylolpropane, pentaerythritol, Pentaerythritol, sorbitan, sorbitol and the like).

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

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

  Examples of the monoamine include aliphatic amines having 1 to 20 carbon atoms such as alkylamines having 1 to 20 carbon atoms (such as methylamine, ethylamine, propylamine, hexylamine, dodecylamine, and eicosylamine); Alicyclic amines (e.g., cyclohexylamine); C4-C15 heterocyclic amines (e.g., 2-benzofuranamine and 4-quinolylamine); C6-C15 aromatic ring-containing aliphatic amines (benzylamine and naphthyl) Ethylamine and the like); aromatic amines having 6 to 15 carbon atoms (aniline, naphthylamine and the like) and the like are used.

  Examples of the polyamine include aliphatic polyamines having 2 to 18 carbon atoms ｛alkylene diamines having 2 to 12 carbon atoms (such as ethylenediamine, propylenediamine, trimethylenediamine, hexamethylenediamine, and undecylenediamine) and polyalkylenes (having 2 to 6 carbon atoms). Polyamines (such as diethylenetriamine, dipropylenetriamine, dihexylenetriamine, triethylenetetramine and pentaethylenehexamine), etc., and alicyclic polyamines having 4 to 15 carbon atoms (1,3-cyclohexanediamine, isophoronediamine and bis (4-amino Cyclohexyl) methane); a heterocyclic polyamine having 4 to 15 carbon atoms (imidazolidine, pyrazolidine, piperazine, N-aminoethylpiperazine, 1,4-diaminoethylpiperazine, etc.); Aromatic ring-containing aliphatic amines (such as bis (aminomethyl) benzene and 1,4-bis (aminomethyl) tetrachlorobenzene); aromatic polyamines having 6 to 20 carbon atoms (phenylenediamine, naphthylenediamine, bis (aminophenyl)) Methane, 4-aminophenyl-2-chloroaniline, 1-methyl-2-methylamino-4-aminobenzene, etc.) are used.

  As the polythiol, a polythiol having 1 to 24 carbon atoms (methanedithiol, ethanedithiol, 1,4-butanedithiol, 1,6-hexanedithiol, 1,2,3-propanetrithiol, or the like) is used.

  Examples of the hydroxycarboxylic acids include aliphatic hydroxycarboxylic acids having 2 to 12 carbon atoms (glycolic acid, lactic acid, ω-oxycaproic acid, ω-oxyenanthic acid, ω-oxycaprylic acid, ω-oxypelargonic acid, ω-oxy Capric acid, 11-oxyundecanoic acid, 12-oxidedecanoic acid, and the like).

  Examples of the hydroxyamine include hydroxyamines having 2 to 12 carbon atoms (2-aminoethanol, 3-aminopropanol, 1-amino-2-propanol, 4-aminobutanol, 5-aminopentanol, 6-aminohexanol and Aminomethyl-3,5,5-trimethylcyclohexanol and the like are used.

Examples of the aminocarboxylic acid include aminocarboxylic acids having 2 to 12 carbon atoms (amino acids such as glycine, alanine, valine, leucine, isoleucine, phenylalanine, ω-aminocaproic acid, ω-aminoenanthic acid, ω-aminocaprylic acid, ω- Aminopelargonic acid, ω-aminocapric acid, 11-aminoundecanoic acid, 12-aminododecanoic acid and the like are used.
As saccharides, glucose, fructose, sucrose and the like are used.
In addition to these compounds, hydrogen sulfide, ammonia, and the like can be used as the compound having at least two active hydrogens.

  Of these compounds having at least two active hydrogens, diols are preferred, alkylene glycols are more preferred, alkylene glycols having 2 to 30 carbon atoms are particularly preferred, and alkylene glycols having 2 to 4 carbon atoms are most preferred (ethylene glycol). , 1,2-propylene glycol, 1,3-propylene glycol, 1,4-butanediol, etc.).

The number average molecular weight (Mn) of the polyether polyol (aa) is preferably 200 or more, more preferably 300 or more, particularly preferably 400 or more, and preferably 10,000 or less, more preferably 8,000 or less. And particularly preferably 6,000 or less. When it is within this range, the adhesive strength tends to be further increased.
Mn can be determined by gel permeation chromatography (GPC) using polyethylene glycol or polystyrene as a standard substance.
The polyether polyol (aa) can be produced by a usual alkylene oxide addition reaction.

  The content (% by weight) of the oxyethylene group in the polyol (A) is preferably 20 or more, more preferably 30 or more, particularly preferably 40, and 95 or less based on the weight of the polyol (A). It is preferably 90 or less, more preferably 80 or less. Within this range, a medical adhesive having better adhesiveness and degradability can be easily obtained.

  The content (% by weight) of the organic group (b) represented by the chemical formula (1) in the polyol (A) is preferably 2 or more, more preferably 5 or more, and particularly preferably, based on the weight of the polyol (A). Is 10, preferably 70 or less, more preferably 50 or less, particularly preferably 40 or less. When it is in this range, a medical adhesive having good workability and decomposability is easily obtained.

The content (% by weight) of the organic group (c) represented by the chemical formula (2) and / or the organic group (d) represented by the chemical formula (3) in the polyol (A) is based on the weight of the polyol (A). Based on this, it is preferably 2 or more, more preferably 5 or more, particularly preferably 10, and preferably 70 or less, more preferably 50 or less, and particularly preferably 40 or less. When it is in this range, a medical adhesive having good workability and decomposability is easily obtained.
When both the organic group (c) and the organic group (d) are present, the ratio is not particularly limited, and any ratio can be used.

  Mn of the polyol (A) is preferably 250 or more, more preferably 350 or more, particularly preferably 450 or more, and preferably 20,000 or less, more preferably 16,000 or less, and particularly preferably 12,000 or less. It is as follows. Within this range, it is easy to obtain a medical adhesive having flexibility that can easily follow the movement of a living body and that has good workability.

  The method of ring-opening polymerization of the polyether polyol (aa) with ε-caprolactone (bb) and trimethylene carbonate (cc) and / or L-lactide (dd) is not particularly limited, and may be performed by a known method. For example, (aa), (bb) and (cc) and / or (dd) can be obtained at preferably 120 to 200 ° C., preferably 3 to 10 hours, in the presence of a catalyst such as tin 2-ethylhexanoate. The polyol (A) can be obtained by ring-opening polymerization below.

  As the polyisocyanate (B), an aromatic polyisocyanate having 6 to 19 carbon atoms (excluding carbon in the isocyanate group, the same applies hereinafter), an aliphatic polyisocyanate having 1 to 22 carbon atoms, and an alicyclic ring having 6 to 19 carbon atoms Aromatic polyisocyanates, araliphatic polyisocyanates having 8 to 16 carbon atoms, modified products thereof, and mixtures of two or more thereof are used.

  Examples of the aromatic polyisocyanate include 1,3- or 1,4-phenylene diisocyanate (PDI), 2,4- or 2,6-tolylene diisocyanate (TDI), crude TDI, 2,4′- or 4,4 '-Diphenylmethane diisocyanate (MDI), crude MDI, 1,5-naphthalene diisocyanate, 4,4', 4 "-triphenylmethane triisocyanate, m- or p-isocyanatophenylsulfonyl isocyanate, and mixtures thereof. Can be

  As the aliphatic polyisocyanate, an aliphatic polyisocyanate containing no fluorine, a fluorinated aliphatic polyisocyanate and the like are used. Examples of the aliphatic polyisocyanate containing no fluorine include methylene diisocyanate, ethylene diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate (HDI), dodecamethylene diisocyanate, 1,6,11-undecane triisocyanate, 2,2,4-trimethyl hexaisocyanate. Methylene diisocyanate, lysine diisocyanate, 2,6-diisocyanatomethylcaproate, bis (2-isocyanatoethyl) fumarate, bis (2-isocyanatoethyl) carbonate, 2-isocyanatoethyl-2,6-diisocyanate Hexanoate and mixtures thereof, and the like.

The fluorinated aliphatic polyisocyanates, those represented by OCN-R _f -NCO, those represented by _{OCN-CH 2 -R f -CH 2} -NCO, OCN-CF 2 -R-CF 2 -NCO in those represented, those represented by _{OCN-CH 2 -CF 2 -R-} CF 2 -CH 2 -NCO, represented by _{OCN-CH (CF 3) -R} -CH (CF 3) -NCO And mixtures thereof are used. However, in the formula, R _f represents a perfluoroalkylene group having 1 to 20 carbon atoms which may contain an ether bond, and R represents an alkylene group having 1 to 18 carbon atoms which may contain an ether bond. .

Examples of OCN- _Rf- NCO include difluoromethylene diisocyanate, perfluorodimethylene diisocyanate, perfluorotrimethylene diisocyanate, perfluoroeicosa diisocyanate, bis (isocyanato perfluoroethyl) ether and bis (diisocyanate). (Naperfluoroisopropyl) ether and the like.

Bis (isocyanatomethyl) difluoromethane, bis (isocyanatomethyl) perfluoroethane, bis (isocyanatomethyl) perfluoropropane, bis (isocyanatomethyl) perfluoropropane, and bis (isocyanatomethyl) difluoromethane are represented by OCN—CH ₂ —R _f —CH ₂ —NCO. (Isocyanatomethyl) perfluorobutane (FHMDI), bis (isocyanatomethyl) perfluoropentane, bis (isocyanatomethyl) perfluorohexane, bis (isocyanatomethyl) perfluoroeicosane and bis (isocyanatomethylperfluoro) Ethyl) ether and the like.

As those represented by _{OCN-CF 2 -R-CF 2} -NCO, bis (isocyanatomethyl difluoromethyl) methane, bis (isocyanatomethyl difluoromethyl) propane, bis (isocyanatomethyl difluoromethyl) octadecane and 2,2 ' -Bis (isocyanatodifluoromethylethyl) ether and the like.

As represented by _{OCN-CH 2 -CF 2 -R-} CF 2 -CH 2 -NCO are bis (2-isocyanato-1,1-difluoroethyl) methane, bis (2-isocyanato-1,1 Difluoroethyl) propane, bis (2-isocyanato-1,1-difluoroethyl) hexadecane and bis (2-isocyanato-1,1-difluoroethylethyl) ether.

Examples of OCN—CH (CF ₃ ) —R—CH (CF ₃ ) —NCO include diisocyanato-1,1,1,4,4,4-hexafluoropentane and bis (isocyanato-3,3 , 3-trifluoropropyl) ether and the like.

As the alicyclic polyisocyanate, an alicyclic polyisocyanate containing no fluorine, a fluorinated alicyclic polyisocyanate, or the like is used.
Examples of the alicyclic polyisocyanate containing no fluorine include isophorone diisocyanate (IPDI), dicyclohexylmethane-4,4′-diisocyanate (hydrogenated MDI), cyclohexylene diisocyanate, methylcyclohexylene diisocyanate (hydrogenated TDI), 4,4 ', 4''-tricyclohexylmethane triisocyanate, bis (2-isocyanatoethyl) -4-cyclohexene-1,2-dicarboxylate, 2,5- or 2,6-norbornane diisocyanate and mixtures thereof No.

  As the fluorinated alicyclic polyisocyanate, diisocyanato perfluorocyclohexane, diisocyanatotetrafluorocyclohexane, bis (isocyanatomethyl) perfluorocyclohexane, bis (isocyanatomethyl) tetrafluorocyclohexane, bis (isocyanatomethyl) Perfluorodimethylcyclohexane, bis (isocyanatomethyl) dimethyltetrafluorocyclohexane, bis (isocyanatodifluoromethyl) cyclohexane, bis (isocyanatoperfluorocyclohexyl), bis (isocyanatotetrafluorocyclohexyl), bis (isocyanatoperfluorocyclohexyl) ) Perfluoropropane, bis (isocyanatotetrafluorocyclohexyl) perfluoropropane, bis (isocyanate Tomethyl perfluorocyclohexyl) perfluoropropane, bis (isocyanatomethyltetrafluorocyclohexyl) perfluoropropane, bis (2-isocyanato-1,1-difluoroethyl) cyclohexane, bis (2-isocyanato-1,1-difluoroethyl) ) Cyclohexane and mixtures thereof.

As the araliphatic polyisocyanate, an araliphatic polyisocyanate containing no fluorine, a fluorinated araliphatic polyisocyanate and the like are used.
Examples of the fluorinated araliphatic polyisocyanate include m- or p-xylylene diisocyanate (XDI), α, α, α ′, α′-tetramethylxylylene diisocyanate (TMXDI), α, α, α ′, α'-tetraethylxylylene diisocyanate (TMXDI) and mixtures thereof.

  Examples of the fluorinated aromatic aliphatic polyisocyanate include bis (isocyanatomethyl) perfluorobenzene, bis (isocyanatomethyl) dimethylperfluorobenzene, bis (isocyanatoperfluorophenyl) perfluoropropane, and bis (isocyanatomethylperfluoro) Phenyl) perfluoropropane, bis (2-isocyanato-2,2-difluoroethyl) benzene, bis (2-isocyanato-1,1-difluoroethyl) benzene, and mixtures thereof.

  These modified products include modified HDI (such as urethane-modified HDI, carbodiimide-modified HDI and trihydrocarbyl phosphate-modified HDI), modified FHMDI (such as urethane-modified FHMDI, carbodiimide-modified FHMDI and trihydrocarbyl phosphate-modified FHMDI), and modified MDI (urethane-modified). MDI, carbodiimide-modified MDI and trihydrocarbyl phosphate-modified MDI, etc., modified TDI (urethane-modified TDI, carbodiimide-modified TDI and trihydrocarbyl phosphate-modified TDI, etc.), and mixtures thereof.

  Other polyisocyanates other than those described above include tertiary amino group-containing polyisocyanates such as N, N-bis (isocyanatoethyl) methylamine and N, N-bis (4-isocyanatocyclohexyl) methylamine and the like. Polyammonio group-containing polyisocyanates [N, N-bis (isocyanatoethyl) dimethylammonium chloride, N, N-bis (4-isocyanatocyclohexyl) dimethylammonium chloride, etc.] can also be preferably used. By using these polyisocyanates, the curing reactivity is further increased.

Among these polyisocyanates (B), aliphatic polyisocyanates, alicyclic polyisocyanates, tertiary amino group-containing polyisocyanates and quaternary ammonium group-containing polyisocyanates are preferred from the viewpoint of safety and the like. From the viewpoints of fluorinated aliphatic polyisocyanate, fluorinated alicyclic polyisocyanate, tertiary amino group-containing polyisocyanate and quaternary ammonium group-containing polyisocyanate, more preferably fluorinated aliphatic polyisocyanate and fluorinated aromatic polyisocyanates, most preferably those represented by _{OCN-CH 2 -R f -CH 2} -NCO.

The isocyanate group-containing urethane prepolymer has a structure obtained by reacting a polyol (A) with a polyisocyanate (B).
The content ratio between the polyol (A) unit and the polyisocyanate (B) unit is preferably 1.5 or more as the equivalent ratio (NCO / OH equivalent ratio) between the isocyanate group of (B) and the hydroxyl group of (A). , More preferably 1.7 or more, particularly preferably 1.8, most preferably 1.9, preferably 2.5 or less, more preferably 2.3 or less, particularly preferably 2.1, Most preferred is 2.0. When it is within this range, the adhesive strength tends to be further increased.

  The NCO content (% by weight) of the isocyanate group-containing urethane prepolymer is preferably 1 or more, more preferably 1.1 or more, particularly preferably 1.2 or more, still more preferably 1.3 or more, and most preferably. Is preferably 1.4 or more and 10 or less, more preferably 8 or less, particularly preferably 5 or less, still more preferably 3 or less, and most preferably 2.5 or less. Within this range, the curability of the obtained adhesive and the followability to the movement of a living body are likely to be further improved.

  The isocyanate group-containing urethane prepolymer can be obtained by reacting the polyol (A) with the polyisocyanate (B) by a known method. For example, (A) and (B) are preferably reacted at 50 to 130 ° C. The reaction is preferably performed for 1 to 10 hours to obtain an isocyanate group-terminated urethane prepolymer. This reaction may be carried out in the presence of a catalyst [for example, an organic compound of tin or lead (such as dibutyltin dilaurate) and a tertiary amine (such as tributylamine)].

The adhesive of the present invention can rapidly polymerize due to the presence of a very small amount of moisture, for example, moisture in the air, form a tough film, and firmly adhere the adherend.
The material of the adherend is not limited, but proteins such as collagen and keratin are suitable.
Further, the properties of the adherend may be a rigid structure or a flexible structure, but a flexible structure is required to effectively utilize the flexibility of the adhesive of the present invention after bonding. More suitable.
Such an adherend is not limited, but is preferably an animal, particularly preferably a mammal, and most preferably a human. That is, the adhesive of the present invention is suitable as a medical adhesive for surgical operations on internal organs, blood vessels, skeletons, nerves, skin, and the like.
The adhesive of the present invention can be used for bonding blood vessels, hearts, trachea, lungs, esophagus, stomach, duodenum, small intestine, large intestine, rectum, kidney, spleen, pancreas, nerves, etc. It is useful as a surgical adhesive for fixing, reinforcing an affected part, or avoiding an accident of stenosis of the smallest blood vessel. In addition, the medical adhesive of the present invention is useful not only in surgery but also in all kinds of medical treatment such as bonding of wounds and incisions, adhesion treatment in dentistry, and treatment by gradually releasing a drug in combination with a bioactive drug. It provides high reliability and high performance.

  The medical adhesive of the present invention may contain other known components, if necessary. For example, when used as a medical adhesive, if necessary, as a component other than the isocyanate group-containing urethane prepolymer, a drug having a physiological activity (a drug for central nervous system, a drug for allergy, a drug for circulatory organ, a drug for respiratory organ) , Drugs for digestive organs, hormonal agents, metabolic drugs, antineoplastic agents, antibiotics and chemotherapeutic agents, etc., fillers (carbon black, red iron oxide, calcium silicate, sodium silicate, titanium oxide, acrylic resin) Powders and various ceramic powders), softeners (DBP, DOP, TCP, tributoxyethyl phosphate and other various esters, etc.) and stabilizers (trimethyldihydroquinone, phenyl-β-naphthylamine, P-isopropoxydiphenylamine and diphenyl-). P-phenylenediamine etc.) . When these are compounded, the amounts of these are preferably 0.1 to 20% by weight, more preferably 0.5 to 5% by weight, based on the adhesive of the present invention.

  The isocyanate group-containing urethane prepolymer rapidly undergoes polymerization due to the presence of a very small amount of moisture, for example, moisture in the air, and forms a tough film. Accordingly, it is necessary to use anhydrous components for each component to be blended in the medical adhesive of the present invention. It is preferable to shut off air even when an adhesive is produced by blending each component. The obtained adhesive can be stored for a long period of time by filling it in a container such as an ampoule or the like in which air is blocked.

The medical adhesive of the present invention can be applied to an adherend by a known method. For example, when used as a surgical adhesive, in a surgical procedure, when joining a living tissue with the medical adhesive of the present invention, a method of applying the adhesive of the present invention directly to an incision is a direct bonding method. Method: Apply a thin cloth piece or cotton-like material such as dacron, oxidized cellulose, collagen, chitin, polyurethane, polyester or PVA or a biological tissue piece such as vein, fascia or muscle to an affected area and apply the adhesive of the present invention. Coating adhesion method: a suture fixing method of applying the adhesive of the present invention so as to partially apply a suture and seal the remaining joint. Examples of the application method include a method using a brush, tweezers, a special spatula, and a method using a spray using Freon or nitrogen gas. In addition, the medical adhesive of the present invention not only adheres to living tissues, but also uses a flexibility and a bonding property with living tissues to provide a coating agent for an aneurysm or the like, or a sealing agent for a plugging substance, a cerebrospinal fluid leak, etc. It can be used by a method such as application to the skin or injection using a catheter or the like.
When the medical adhesive of the present invention is used for a living body, the decomposition proceeds within a few weeks at an early stage and within a few months at a later stage.

Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited thereto. Hereinafter, unless otherwise specified, parts indicate parts by weight and% indicates% by weight.
<Example 1>
60 parts of polyether diol (random copolymer of ethylene oxide and propylene oxide starting from propylene glycol, Mn: 3,000, oxyethylene content: 80%) 60 parts, ε-caprolactone 20 parts, trimethylene 20 parts of carbonate and 90 μL of a 0.33 M tin 2-ethylhexanoate toluene solution were charged and reacted at 180 ° C. for 8 hours under a nitrogen atmosphere. After cooling, unreacted monomers were removed at 110 ° C. under a reduced pressure of 0.1 mmHg to obtain Mn4,980 polyol (1).
11. 100 parts of polyol (1) is charged into a reaction vessel, dehydrated at 90 ° C. under reduced pressure, and then bis (isocyanatomethyl) perfluorobutane (FHMDI, OCN—CH ₂ (CF ₂ ) ₄ CH ₂ —NCO). 5 parts (NCO / OH equivalent ratio = 2.0) was added and reacted at 80 ° C. for 8 hours to obtain an isocyanate group-containing urethane prepolymer (1) having an NCO content of 1.5%. This (1) was used as it was as a medical adhesive (X1).

<Example 2>
70 parts of polyether diol (random copolymer of ethylene oxide and propylene oxide starting from propylene glycol, Mn: 2,000, oxyethylene content: 60%) 70 parts, ε-caprolactone 20 parts, trimethylene 10 parts of carbonate and 90 μL of a 0.33 M tin 2-ethylhexanoate toluene solution were charged and reacted at 180 ° C. for 8 hours under a nitrogen atmosphere. After cooling, unreacted monomers were removed at 110 ° C. under a reduced pressure of 0.1 mmHg to obtain a polyol (2) having Mn of 5,780.
After 100 parts of polyol (2) was charged into a reaction vessel and dehydrated at 90 ° C. under reduced pressure, bis (isocyanatomethyl) perfluorohexane (OCN—CH ₂ (CF ₂ ) ₆ CH ₂ —NCO) 61.1 parts (NCO / OH equivalent ratio = 2.3) and reacted at 80 ° C. for 8 hours to obtain an isocyanate group-containing urethane prepolymer (2) having an NCO content of 2.4%. This (2) was used as a medical adhesive (X2) as it was.

<Example 3>
In a reaction vessel, 60 parts of polyether diol (random copolymer of ethylene oxide and propylene oxide starting from propylene glycol, Mn: 3,000, oxyethylene content: 80%), 20 parts of ε-caprolactone, L- 20 parts of lactide and 90 μL of a 0.33 M tin 2-ethylhexanoate toluene solution were charged and reacted at 180 ° C. for 8 hours under a nitrogen atmosphere. After cooling, unreacted monomers were removed at 110 ° C. under reduced pressure of 0.1 mmHg to obtain Mn4,980 polyol (3).
A reaction vessel was charged with 100 parts of polyol (3), dehydrated at 90 ° C. under reduced pressure, and 12.5 parts of FHMDI (NCO / OH equivalent ratio = 2.0) was added. The mixture was reacted at 80 ° C. for 8 hours to contain NCO. A 1.5% isocyanate group-containing urethane prepolymer (3) was obtained. This (3) was used as it was as a medical adhesive (X3).

<Example 4>
70 parts of polyether diol (random copolymer of ethylene oxide and propylene oxide starting from propylene glycol, Mn: 4,000, oxyethylene content: 90%) 70 parts, ε-caprolactone 10 parts, trimethylene 10 parts of carbonate, 10 parts of L-lactide and 90 μL of a 0.33 M tin 2-ethylhexanoate toluene solution were charged and reacted at 180 ° C. for 8 hours in a nitrogen atmosphere. After cooling, unreacted monomers were removed at 110 ° C. under a reduced pressure of 0.1 mmHg to obtain Mn5,720 polyol (4).
A reaction vessel was charged with 100 parts of polyol (4), dehydrated at 90 ° C. under reduced pressure, 12.6 parts of FHMDI (NCO / OH equivalent ratio = 2.3) was added, and the mixture was reacted at 80 ° C. for 8 hours to contain NCO. An isocyanate group-containing urethane prepolymer (4) having an amount of 1.7% was obtained. This (4) was used as it was as a medical adhesive (X4).

<Example 5>
70 parts of polyether diol (random copolymer of ethylene oxide and propylene oxide starting from propylene glycol, Mn: 3,000, oxyethylene content: 80%) 70 parts, ε-caprolactone 10 parts, trimethylene 10 parts of carbonate, 10 parts of L-lactide and 90 μL of a 0.33 M tin 2-ethylhexanoate toluene solution were charged and reacted at 180 ° C. for 8 hours in a nitrogen atmosphere. After cooling, unreacted monomers were removed at 110 ° C. under a reduced pressure of 0.1 mmHg to obtain Mn3,870 polyol (5).
A reaction vessel was charged with 100 parts of polyol (5), dehydrated at 90 ° C. under reduced pressure, 13.1 parts of FHMDI (NCO / OH equivalent ratio = 1.8) was added, and the mixture was reacted at 80 ° C. for 8 hours to contain NCO. An isocyanate group-containing urethane prepolymer (5) having an amount of 1.4% was obtained. This (5) was used as it was as a medical adhesive (X5).

<Comparative Example 1>
In a reaction vessel, 90 parts of a polyether polyol (random copolymer of ethylene oxide and propylene oxide with propylene glycol as a starting material, Mn 3,000, oxyethylene content 80%) and polycaprolactone diol with ethylene glycol as a starting material ( (Mn: 520), and after dehydrating at 90 ° C. under reduced pressure, adding 17.1 parts of TDI (NCO / OH equivalent ratio = 2.0) and reacting at 80 ° C. for 8 hours to obtain an NCO content of 3. A 5% isocyanate group-containing urethane prepolymer (6) was obtained. This (6) was used as it is as a comparative medical adhesive (R1).

<Comparative Example 2>
A reaction vessel was charged with 100 parts of polylactic acid (Mn: 2,900), dehydrated at 90 ° C. under reduced pressure, and then 12.0 parts of TDI (NCO / OH equivalent ratio = 2.0) was added, followed by 8 hours at 80 ° C. This was reacted to obtain an isocyanate group-containing urethane prepolymer (7) having an NCO content of 2.6%. This (7) was used as it is as a comparative medical adhesive (R2).

<Comparative Example 3>
60 parts of polyether polyol (random copolymer of ethylene oxide and propylene oxide starting from propylene glycol, Mn 2,000, oxyethylene content 80%) 60 parts, trimethylene carbonate 20 parts, L-lactide 30 parts in a reaction vessel And 90 μL of a 0.33 M tin 2-ethylhexanoate toluene solution were charged and reacted at 180 ° C. for 8 hours in a nitrogen atmosphere. After cooling, unreacted monomers were removed at 110 ° C. under a reduced pressure of 0.1 mmHg to obtain Mn3,000 polyol (6).
A reaction vessel was charged with 100 parts of polyol (6), dehydrated under reduced pressure at 90 ° C., and then added with 8.7 parts of TDI (NCO / OH equivalent ratio = 2.0), and reacted at 80 ° C. for 8 hours to obtain an NCO content. 1.9% of an isocyanate group-containing urethane prepolymer (8) was obtained. This (8) was used as it is as a comparative medical adhesive (R3).

<Adhesion test in vivo>
The liver parenchyma of the adult mongrel dog (using 4 dogs) was subjected to forceps according to an assumed incision line over a length of about 2 cm, and then the liver parenchyma was excised along the inside of the forceps. The entire surface of the cut surface is coated with the medical adhesives (X1) to (X5) of the present invention or the medical adhesives (R1) to (R3) for comparison, and then pressed with a fluororesin film 15 from above. After a minute, the film was peeled off and the affected part was observed.
The medical adhesives (R1) to (R3) for comparison had high viscosity and were partially waxy, so that workability was poor, and the adhesiveness to living tissue was poor, and blood leakage from the application surface was observed. There was also a problem with hemostasis. In addition, there was also a problem that the resin after bonding was hard and could not follow the flexible movement of the living body. On the other hand, all of the medical adhesives (X1) to (X5) of the present invention have good workability, and are well bonded to tissue, so that there is no leakage of blood from the application surface and hemostatic properties. Was good. In addition, the resin after bonding was soft and well followed the movement of the living tissue.

<Degradation test in vivo>
After applying a small amount of the medical adhesives (X1) to (X5) of the present invention or the medical adhesives (R1) to (R3) for comparison on the liver surface of mice (using four mice), the affected area was closed. Six months later, these mice were dissected and visually examined for degradability.
The medical adhesives (X1) to (X5) of the present invention were considerably degraded and did not maintain the initial shape. The comparative medical adhesives (R1) and (R2) showed almost no decomposition and remained in the initial shape.

Claims (2)

In a medical adhesive comprising an isocyanate group-containing urethane prepolymer which is an adduct of a polyol (A) and a polyisocyanate (B), the polyol (A) is represented by an oxyethylene group (a) and a chemical formula (1). Characterized in that it has an organic group (b) and an organic group (c) represented by the chemical formula (2) and / or an organic group (d) represented by the chemical formula (3). Agent.

The medical adhesive according to claim 1, wherein the oxyethylene group content in the polyol (A) is 20 to 95% by weight based on the weight of (A).