JP2009268894A - Adhesive for extensible ptfe - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a means which can quickly prevent bleeding of blood or cerebrospinal fluid by solving the problem that no practically usable adhesive developed so far having excellent adhesive property to a medical material made of extensible PTFE (Polytetrafluoroethylene) is unknown, thereby providing an adhesive for extensible PTFE that is excellent in adhesive property to a medical material made of extensible PTFE and has practical reaction property (curing rate). <P>SOLUTION: The adhesive for extensible PTFE includes a urethane polymer (UP) obtained by reacting a fluorine containing polyisocyanate component (A) with a polyol component (B) containing hydrophilic polyol (B1) as an indispensable component, and is a medical material in which one of matters to be adhered is made of the extensible PTFE. The polyol component (B) preferably includes a random coaddition compound of ethylene oxide and propylene oxide to diol, and polypropylene glycol. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an expanded PTFE adhesive having excellent adhesion to a medical material made of expanded PTFE. More specifically, the present invention relates to an expanded PTFE adhesive having excellent adhesion to artificial blood vessels, artificial dura mater, and artificial medical materials made of expanded PTFE, such as patch materials for repairing the heart or blood vessels.

  In surgical operations, artificial medical materials are frequently used as patch materials for repairing artificial blood vessels, artificial dura mater, and biological tissues such as the heart or blood vessels. As a raw material for artificial medical materials, expanded PTFE (polytetrafluoroethylene) is one of the most frequently used materials because it has the property of hardly adhering to a living body.

Treatment for patients with chronic renal failure is generally performed by artificial dialysis, but blood can be taken in and out by performing an internal shunt operation by arteriovenous anastomosis prior to artificial dialysis therapy. Further, in many cases, an artificial blood vessel made of expanded PTFE or the like is transplanted and used for a patient who is unable to perform an internal shunt operation due to an aging of the patient or a primary disease such as diabetes.
However, if such an artificial blood vessel is used in a site where frequent punctures are performed, such as artificial dialysis, blood leaks from the artificial blood vessel, hindering the treatment performed on average three times a week, formation of aneurysm or hematoma, The risk of causing infections has been pointed out. In addition, since blood easily leaks, it may take a long time after hemodialysis to stop bleeding, and in some cases, rebleed after returning home or cause a serious situation. Furthermore, bleeding from the needle hole at the time of vascular suturing is also a problem, which may prolong the operation time and cause postoperative complications.

Further, in the case of neurosurgery, the dura mater may have to be excised, resulting in dura deficiency, or primary suturing may be difficult due to the natural contraction of the dura mater itself. Closing with the dura mater open may cause cerebrospinal fluid leakage, causing intracranial infections, causing adhesions between the brain parenchyma and bone or subcutaneous tissue, resulting in local neurological symptoms, and epileptic seizures. It may cause serious complications such as focusing. Therefore, strict suturing is required so that there is no gap in the dura when closing. For this reason, when a deficiency arises in the dura mater or primary suturing becomes difficult, it is necessary to completely sew so as not to generate a gap by using any supplementary material.
Autologous fascia has been most widely used from the beginning to the present day, but there are many problems such as fascia defects at the excision site and easy adhesion to the brain. Dried human dura mater is a dural supplement material obtained by performing radiation treatment etc. on the dura mater collected from the cadaver, and it has been the most excellent material to date, but is considered to cause Creutzfeldt-Jakob disease There is a possibility that prions may be present in the dura mater, and a case of Creutzfeldt-Jakob disease infection via human dry dura mater was reported, and its use was completely banned in 1998. It was.
Currently, the only material that can be used as a dural replacement material other than self-fascia is expanded PTFE approved by the Ministry of Health and Welfare. Since expanded PTFE is a polymer material, it has no adhesiveness to the living body. This property is excellent in that it does not cause adhesions with the brain. On the other hand, since cerebrospinal fluid leaks from the needle hole due to poor contractility, it is necessary to perform suturing using a special suture. In addition, since there is no bioadhesiveness, there is a high possibility of cerebrospinal fluid leakage from the gap between the stitched surfaces. At the same time, since there is no adhesiveness with the surrounding tissue, there is a high possibility that it becomes a simple skeleton material. Many attempts have been made so far on how to use expanded PTFE, but all use expanded PTFE as a skeletal material and wait for a fibrous tissue coating to form around it. It was.

  In order to fix the medical material using the expanded PTFE shown in the above example as a raw material to the tissue for treatment, a method of fixing these material and the living body by anastomosis is employed. However, when these medical materials are anastomosed with a surgical thread, blood or cerebrospinal fluid leaks from the material portion through which the needle passes. Therefore, normally, as a method other than inducing blood coagulation by pressing the affected part, leakage of these is prevented by using a biological tissue adhesive called fibrin glue. However, since the fibrin glue has poor adhesion of expanded PTFE, a sufficient leakage prevention effect cannot be obtained. Therefore, as shown in Patent Document 1, the surface of expanded PTFE is modified to increase the adhesion to the fibrin glue, or an artificial blood vessel as shown in Patent Document 2 is made into a multiple structure. Methods for suppressing blood leakage have been studied.

Therefore, an adhesive that can reliably stop the leakage of blood, spinal fluid, etc. from in-vivo implants such as artificial blood vessels or artificial dura mater made of expanded PTFE whose surface is not specially processed. It has not been found so far.
On the other hand, as a medical adhesive, a medical adhesive composed of a fluorine-containing hydrophilic urethane prepolymer having an isocyanate group terminal obtained by a reaction between a fluorine-containing polyisocyanate and a polyether polyol has been developed (Patent Documents 3 and 3). 4). However, in the examples of these publications, the PTFE sheet is used as a sheet having good releasability with respect to the medical adhesive, and these medical adhesives are known to have no adhesiveness with PTFE. . From this, it is expected that these medical adhesives do not have adhesiveness with expanded PTFE.

JP 2004-89361 A JP 2005-152178 A Japanese Patent Laid-Open No. 1-227762 (corresponding patent application: US4994542A, etc.) International publication WO03 / 051952 pamphlet (corresponding patent application: US4994542A etc.)

None of the adhesives that have been developed so far is excellent in adhesiveness with medical materials made from expanded PTFE and can be put to practical use.
The present invention provides an expanded PTFE adhesive that has excellent adhesiveness with medical materials made of expanded PTFE and has practical reactivity (curing speed), thereby quickly leaking blood or cerebrospinal fluid. It is an object of the present invention to provide a means that can prevent the above.

  The inventors of the present invention have arrived at the present invention as a result of intensive studies to solve the above problems. That is, the present invention comprises a urethane prepolymer (UP) obtained by reacting a fluorine-containing polyisocyanate component (A) with a polyol component (B) having a hydrophilic polyol (B1) as an essential component. At least one of the adhesives is an expanded PTFE adhesive that is a medical material made of expanded PTFE.

The expanded PTFE adhesive of the present invention has the following effects.
(1) Excellent adhesion to medical materials made from expanded PTFE.
(2) Good has reactivity (curing speed).
(3) It can be applied regardless of whether or not a blood anticoagulant is administered.

It is a schematic diagram of a suture model blood vessel for conducting a pulse pressure load test of an expanded PTFE adhesive. It is the apparatus connection schematic of a pulse pressure load test.

  In the present invention, the fluorine-containing polyisocyanate component (A) is essentially a fluorine-containing polyisocyanate (A1).

  The fluorine-containing polyisocyanate (A1) includes a fluorine-containing aliphatic diisocyanate (A11) having 1 to 22 carbon atoms (not including the number of carbon atoms of the isocyanate group; the same shall apply hereinafter), and a fluorine-containing alicyclic diisocyanate having 6 to 19 carbon atoms. (A12), fluorine-containing poly (3- to 6-valent) isocyanate (A13) having 15 to 66 carbon atoms, fluorine-containing aromatic polyisocyanate (A14) and the like can be used.

The fluorinated aliphatic diisocyanates having 1 to 22 carbon atoms (A11), include such those represented by OCN-Rf-NCO with those represented and _{OCN-CH 2 -Rf-CH 2} -NCO. However, Rf in both formulas represents a C1-C20 perfluoroalkylene group which may contain an ether bond.
Examples of OCN-Rf-NCO include difluoromethylene diisocyanate, perfluorodimethylene diisocyanate, perfluorotrimethylene diisocyanate, perfluoroeicosadiisocyanate, bis (isocyanatoperfluoroethyl) ether and bis (isocyanatoper Fluoroisopropyl) ether and the like.

OCN—CH ₂ —Rf—CH ₂ —NCO includes bis (isocyanatomethyl) difluoromethane, bis (isocyanatomethyl) perfluoroethane, bis (isocyanatomethyl) perfluoropropane, bis ( Isocyanatomethyl) perfluorobutane, bis (isocyanatomethyl) perfluoropentane, bis (isocyanatomethyl) perfluorohexane, bis (isocyanatomethyl) perfluoroeicosane, bis (isocyanatomethylperfluoroethyl) ether, etc. Is mentioned.

  Examples of the fluorine-containing alicyclic diisocyanate having 6 to 19 carbon atoms (A12) include diisocyanatoperfluorocyclohexane, bis (isocyanatomethyl) perfluorocyclohexane, bis (isocyanatomethyl) perfluorodimethylcyclohexane, and bis (isocyanato). Perfluorocyclohexyl), bis (isocyanatoperfluorocyclohexyl) perfluoropropane, and bis (isocyanatomethylperfluorocyclohexyl) perfluoropropane.

  Examples of the fluorine-containing poly (3- to 6-valent) isocyanate (A13) having 15 to 66 carbon atoms include the diisocyanate nurate, tris (isocyanatoperfluorophenyl) methane and tris (isocyanatotetrafluorocyclohexyl) methane. Can be mentioned.

  Examples of the fluorinated aromatic polyisocyanate (A14) include aromatics not containing fluorine atoms having 6 to 19 carbon atoms (for example, 1,3- or 1,4-phenylene diisocyanate (PDI), 2,4- or 2, 6-tolylene diisocyanate (TDI), 2,4′- or 4,4′-diphenylmethane diisocyanate (MDI), crude MDI, etc.), part or all of the hydrogen atoms of the aromatic ring are fluorine atoms or fluoroalkyl groups Substituted fluorine-containing aromatic polyisocyanate (A15), fluorine-containing aromatic polyisocyanate (A16) in which part or all of hydrogen atoms other than aromatic rings are substituted with fluorine atoms or fluoroalkyl groups, and aromatic rings A part or all of the hydrogen atoms and a part or all of the hydrogen atoms other than the aromatic ring are fluorine atoms or fluoro Fluorinated aromatic substituted with alkyl group polyisocyanate (A17) or the like is used.

  As the fluorine-containing aromatic polyisocyanate (A15), 1,3- or 1,4-perfluorophenylene diisocyanate, 2,4- or 2,6-perfluorotolylene diisocyanate, 1,3,5,6- or 1,3,4,5-tetrafluoro-2,4- or 2,6-tolylene diisocyanate and 2,4'- or 4,4'-perfluorodiphenylmethane diisocyanate and tetrafluoro-2,4'- or 4,4′-diphenylmethane diisocyanate and the like.

  Examples of the fluorinated aromatic polyisocyanate (A16) include 2,4'- or 4,4'-diphenyldifluoromethane diisocyanate.

  Examples of the fluorinated aromatic polyisocyanate (A17) include trifluoromethylphenylene-1,3- or 1,4-perfluorodiisocyanate.

In addition, the position of the isocyanate group in the fluorine-containing polyisocyanate (A1) is preferably a position with little steric hindrance from the viewpoint of reactivity with the polyol component (B) and reactivity with blood, body fluids, and the like. Is a terminal position with little steric hindrance.
Moreover, 1 type or 2 or more types of mixtures may be sufficient as fluorine-containing polyisocyanate (A1).
Of the fluorine-containing polyisocyanates (A1), those having two isocyanate groups are preferred from the viewpoint of suppressing side reactions such as crosslinking reactions.

Of the fluorine-containing polyisocyanate (A1), fluorine-containing aliphatic diisocyanate (A11) and fluorine-containing alicyclic diisocyanate (A12) are preferable from the viewpoint of safety such as mutagenicity, and more preferably OCN-CH _2. Fluorine-containing aliphatic diisocyanate represented by —Rf—CH ₂ —NCO, particularly preferably bis (isocyanatomethyl) perfluoropropane, bis (isocyanatomethyl) perfluorobutane, bis (isocyanatomethyl) perfluoropentane and Bis (isocyanatomethyl) perfluorohexane.

  In addition, from the viewpoint of adhesiveness with expanded PTFE and the availability of isocyanate, the proportion (% by weight) of fluorine atoms in the fluorinated polyisocyanate (A1) is based on the weight of (A1). 35-70 are preferable, More preferably, it is 38-70, Most preferably, it is 40-56.

  In the present invention, the fluorine-containing polyisocyanate component (A) may contain a polyisocyanate (A2) that does not contain a fluorine atom. As polyisocyanate (A2) not containing a fluorine atom, aliphatic polyisocyanate (A21) not containing a fluorine atom having 1 to 22 carbon atoms, alicyclic polyisocyanate not containing a fluorine atom having 6 to 19 carbon atoms (A22) ), An aromatic aliphatic polyisocyanate having 8 to 16 carbon atoms not containing fluorine atoms (A23), an aromatic polyisocyanate not containing fluorine atoms having 6 to 19 carbon atoms (A24), and their modified products (A25). Used.

  Examples of the aliphatic polyisocyanate (A21) containing no fluorine atom include tetramethylene diisocyanate, hexamethylene diisocyanate (HDI), 2,2,4-trimethylhexamethylene diisocyanate, and lysine diisocyanate.

  Examples of the alicyclic polyisocyanate containing no fluorine atom (A22) include isophorone diisocyanate (IPDI), dicyclohexylmethane-4,4′-diisocyanate (hydrogenated MDI), cyclohexylene diisocyanate and methylcyclohexylene diisocyanate (hydrogenated TDI). Etc.

  Examples of the araliphatic polyisocyanate (A23) containing no fluorine atom include m- or p-xylylene diisocyanate (XDI) and α, α, α ′, α′-tetramethylxylylene diisocyanate (TMXDI). .

  Examples of the aromatic polyisocyanate (A24) containing no fluorine atom 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.

  These modified products (A25) include modified HDI (urethane modified HDI, carbodiimide modified HDI, trihydrocarbyl phosphate modified HDI, etc.), modified MDI (urethane modified MDI, carbodiimide modified MDI, etc.) and modified TDI (urethane modified TDI). Carbodiimide-modified TDI, etc.).

In addition, the polyisocyanate (A2) which does not contain a fluorine atom may be one type or a mixture of two or more types.
Of these polyisocyanates (A2) not containing fluorine atoms, aromatic polyisocyanates (A24) not containing fluorine atoms are preferred from the viewpoint of reactivity, and more preferably MDI and TDI.
In the case of using a polyisocyanate (A2) that does not contain a fluorine atom, from the viewpoint of adhesion to expanded PTFE, the content (% by weight) of (A2) is 20 based on the weight of the fluorine-containing polyisocyanate (A1). The following is preferable, more preferably 10 or less, and particularly preferably 5 or less.

  The fluorine-containing polyisocyanate component (A) has a fluorine atom content (% by weight) in the fluorine-containing polyisocyanate component (A) from the viewpoint of adhesion to expanded PTFE and easy availability of isocyanate. ) Based on weight, it is preferably 28 or more, more preferably 35 to 70, and particularly preferably 40 to 56.

As the polyol component (B), the hydrophilic polyol (B1) is essential, but another polyol (B2) having low hydrophilicity may be included.
The hydrophilic polyol (B1) includes a polyol containing an oxyethylene group and having an oxyethylene group content of at least 30% by weight based on the weight of the oxyalkylene group. The polyester polyol (B1-2) etc. which have an ether polyol (B1-1) and the polyether polyol (B1-1) containing an oxyethylene group as an essential structural unit can be used.
Examples of the oxyalkylene group include oxyalkylene groups having 2 to 8 carbon atoms (oxyethylene, oxypropylene, oxybutylene, oxyphenylethylene, and the like).

The polyether polyol (B1-1) containing an oxyethylene group is an adduct of ethylene oxide (hereinafter abbreviated as EO) to a compound having at least two active hydrogens, or EO and alkylene having 3 to 8 carbon atoms. Oxide (1,2- or 1,3-propylene oxide (hereinafter abbreviated as PO), 1,2-, 1,3-, 2,3- or 1,4-butylene oxide, styrene oxide, etc.) Coadducts and the like can be used. In the case of a co-adduct, the addition form may be random, block, or a combination thereof, but is preferably random.
Further, 1,2-PO is preferable as the alkylene oxide having 3 to 8 carbon atoms.

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 hydrophilic polyol is obtained when a compound having two active hydrogens is used, and a trivalent or higher hydrophilic 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, dodecane. Diol, tetradecanediol, neopentyl glycol and 2,2-diethyl-1,3-propanediol, etc.); C6-C24 alicyclic diol (1,4-cyclohexanedimethanol, hydrogenated bisphenol A, etc.); Bisphenol having 12 to 30 carbon atoms (such as bisphenol A, bisphenol F, and bisphenol S); dihydroxybenzene (such as catechol and hydroquinone) and the like are used.

  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 (succinic acid, adipic acid, sebacic acid, dodecenyl succinic acid, azelaic acid, sebacic acid, dodecanedicarboxylic acid, octadecanedicarboxylic acid, dodecyl succinic acid, octadecyl succinic acid, etc.) Alkene dicarboxylic acid having 4 to 32 carbon atoms (maleic acid, fumaric acid, citraconic acid, mesaconic acid, dimer acid, dodecenyl succinic acid and pentadecenyl succinic acid); aromatic dicarboxylic acid having 8 to 20 carbon atoms (phthalic acid) Acid, isophthalic acid, terephthalic acid, naphthalenedicarboxylic acid and the like). In addition to these, acid anhydrides of dicarboxylic acids (maleic anhydride, phthalic anhydride, etc.) and the like can also be used.
As the trivalent to tetravalent polycarboxylic acid, aromatic polycarboxylic acid having 9 to 20 carbon atoms (trimellitic acid, pyromellitic acid, etc.) and the like are used. In addition to these, acid anhydrides of polycarboxylic acid (such as trimellitic anhydride and pyromellitic anhydride) can also be used.

Monoamines include ammonia and aliphatic primary amines having 1 to 20 carbon atoms {1 to 1 carbon atoms.
20 alkylamines (such as methylamine, ethylamine, propylamine, hexylamine, dodecylamine and eicosylamine)}, alicyclic amines having 4 to 15 carbon atoms (piperidine, aminocyclohexane, isophorone monoamine and 4-methylenediamine) Cyclohexane monoamine etc.); C6-C15 aromatic ring-containing aliphatic amine (aniline etc.) etc. are used.

  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 (2-6 carbon atoms) polyamines (diethylenetriamine, dipropylenetriamine, triethylenetetramine, pentaethylenehexamine, etc.), alicyclic polyamines having 4-15 carbon atoms (1,3-diaminocyclohexane, isophoronediamine and 4) , 4′-methylenedicyclohexanediamine); heterocyclic polyamines having 4 to 15 carbon atoms (piperazine, N-aminoethylpiperazine, 1,4-diaminoethylpiperazine, N-aminoethylpyridine, etc.) It is needed.

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.] are used.
As compounds having at least two active hydrogens, amino acids, oxycarboxylic acids, amino alcohols, and the like can be used in addition to those listed above.

These compounds having at least two active hydrogens may be one kind or a mixture of two or more kinds.
Of these compounds having at least two active hydrogens, water and diol are preferable, water and alkylene glycol are more preferable, and water and alkylene glycol having 2 to 4 carbon atoms are particularly preferable.

Preferred examples of the polyether polyol (B1-1) containing an oxyethylene group include EO adducts to diols (such as EO adducts to ethylene glycol and EO adducts to propylene glycol), and diols. Of EO and alkylene oxides having 3 to 8 carbon atoms (random or block coadducts of EO and PO with ethylene glycol, and random or block coaddition of EO and butylene oxide with ethylene glycol) Body etc.).
Of these, EO adducts to diols and co-adducts of EO and PO to diols are preferred, particularly preferably from the viewpoint of faster reactivity with water and better adhesion strength and the like. It is a co-adduct of EO and PO to a diol.
These polyether polyols (B1-1) may be one kind or a mixture of two or more kinds.

The hydroxyl group equivalent (number average molecular weight per hydroxyl group) of the polyether polyol (B1-1) is preferably 50 to 5,000, more preferably 100 to 4,000, particularly preferably 200 to 3,000. It is. Within this range, the adhesive strength and the like are further improved.
The hydroxyl group equivalent is calculated by dividing 56100 by the hydroxyl value measured according to JIS K1557-1: 2007 [weight of hydroxyl group and equivalent potassium hydroxide in 1 g of sample (mg)]. .

As the polyester polyol (B1-2) having the polyether polyol (B1-1) as an essential constituent unit, the polyether polyol (B1-1) and the above dicarboxylic acid, dicarboxylic acid anhydride and / or dicarboxylic acid lower Polyester with an alkyl ester is used. The end of these polyesters is a hydroxyl group.
In addition, as a part of dicarboxylic acid, dicarboxylic acid anhydride and / or dicarboxylic acid lower alkyl ester, polycarboxylic acid, polycarboxylic acid anhydride, polycarboxylic acid lower alkyl ester and the like can be used, and when these are used, The amount used (mol%) is preferably 0.1 to 10, more preferably 0.1 to 5, based on the total number of moles of all carboxylic acids, carboxylic anhydrides and carboxylic acid lower alkyl esters. Most preferably, it is 0.1-2. Within this range, the adhesive strength and the like are further improved.

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

  The hydroxyl group equivalent of the polyester polyol (B1-2) is preferably from 50 to 5,000, more preferably from 100 to 4,000, particularly preferably from 200 to 3,000, from the viewpoints of viscosity and adhesive strength. Within this range, the adhesive strength and the like are further improved. In addition, the viscosity becomes optimum, and the hardness is such that the expanded PTFE adhesive is easily spread in a surgical operation.

  The content (% by weight) of the oxyethylene group in the hydrophilic polyol (B1) is 30 to 100, preferably 40 to 40, based on the total weight of the oxyethylene group and the oxyalkylene group having 3 to 8 carbon atoms. 95, more preferably 50-90. Within this range, the adhesive strength and the like are further improved.

  The hydroxyl group equivalent of the hydrophilic polyol (B1) is preferably from 50 to 5,000, more preferably from 100 to 4,000, particularly preferably from 200 to 3,000, from the viewpoint of viscosity and adhesive strength. Within this range, the adhesive strength and the like are further improved. In addition, the viscosity becomes optimum, and the hardness is such that the expanded PTFE adhesive is easily spread in a surgical operation.

As the hydrophilic polyether (B1), a random coadduct of EO and PO to water, ethylene glycol and / or propylene glycol having a number average molecular weight (Mn) of 2,000 to 6,000 is preferably used.
In the present invention, the number average molecular weight (Mn) is measured by gel permeation chromatography (GPC) by preparing a calibration curve using polystyrene as a standard substance.

  As other polyol (B2) having low hydrophilicity, an oxyalkylene group is contained in addition to the diol and the trivalent to hexavalent polyol, and the content of the oxyethylene group is 30% based on the weight of the oxyalkylene group. %, A polyether polyol (B2-1), a polyester polyol (B2-2) having the polyether polyol (B2-1) as an essential constituent unit, and an oxyethylene group and a carbon number of 3 to 3%. Polyester polyol (B2-3) etc. which do not contain 8 oxyalkylene groups can be used.

As the polyether polyol (B2-1), a (co) adduct of a C3-C8 alkylene oxide to a compound having at least two active hydrogens, and EO and a C3-C8 alkylene oxide Coadducts and the like can be used. However, the content of oxyethylene groups is less than 30% by weight based on the total weight of oxyethylene groups and oxyalkylene groups.
As suitable examples of the polyether polyol (B2-1), polypropylene glycol (1,2- or 1,3-PO adduct of propylene glycol), EO adduct to polyalkylene glycol (to ethylene glycol or propylene glycol) EO and PO block adducts having an EO content of 5 to 45% by weight, etc., and random copolymers of PO and EO (EO and PO random adducts to ethylene glycol or propylene glycol) And EO content of 10 to 25% by weight), polytetramethylene glycol (1,4-butylene glycol 1,2-, 1,3-, 2,3- or 1,4- Butylene oxide adduct) and 1,4-butylene oxide and EO copolymer (ethylene glycol or butylene glycol) A 75 to 90 wt% EO10～25 weight of 1,4-butylene oxide block or random adducts, EO content are those, etc.) or the like of 10 to 25 wt%.
Among these, from the viewpoint of hydrophilicity, an EO adduct to polypropylene glycol (EO content of less than 5 to 30% by weight) is preferable, and an EO adduct to polypropylene glycol (EO content of 15 to 15%) is more preferable. Less than 30% by weight).
These polyether polyols (B2-1) may be one kind or a mixture of two or more kinds.

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

  As polyester polyol (B2-2) which has polyether polyol (B2-1) as an essential structural unit, from polyether polyol (B2-1) and dicarboxylic acid, dicarboxylic acid anhydride, or dicarboxylic acid lower alkyl ester. Polyester polyols that can be derived can be used.

Preferable examples of the polyester polyol (B2-2) include polypropylene glycol (1,2- or 1,3-PO adduct to propylene glycol), EO adduct to polyalkylene glycol (to ethylene glycol or propylene glycol). EO and PO block adducts having an EO content of 5 to 45% by weight, etc., and random copolymers of PO and EO (EO and PO random adducts to ethylene glycol or propylene glycol) And EO content of 10 to 25% by weight), polytetramethylene glycol (1,4-butylene glycol 1,2-, 1,3-, 2,3- or 1,4- Butylene oxide adduct) and / or a copolymer of 1,4-butylene oxide and EO (ethylene glycol or butylene) A block or random adduct of 10 to 25 weight percent of EO and 75 to 90 weight percent of 1,4-butylene oxide with a EO content of 10 to 25 weight percent, and a dicarboxylic acid (adipic acid, And polyester polyols that can be derived from dicarboxylic acid anhydrides and / or lower alkyl esters of dicarboxylic acids (such as methyl and ethyl esters of dicarboxylic acids).
These polyester polyols (B2-2) may be one kind or a mixture of two or more kinds.

  The hydroxyl group equivalent of the polyester polyol (B2-2) is the same as that of the polyester polyol (B1-2), and the preferred range is also the same.

As the polyester polyol (B2-3) not containing an oxyethylene group and an oxyalkylene group having 3 to 8 carbon atoms, a diol and / or a tri- to hexavalent polyol, the above dicarboxylic acid, dicarboxylic acid anhydride, and / or Alternatively, a polyester that can be derived from a lower alkyl ester of a dicarboxylic acid, a polyester that is derived from ring-opening polymerization of caprotactic, 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 Polyester diols derived from ethylene glycol, butane diol and adipic acid; polyester diols derived from ethylene glycol and sebacic acid; polyester diols derived from cyclohexane diol and phthalic acid; and derived from ring-opening polymerization of caprotactone Examples include polycaprotactone.
These polyester polyols (B2-3) may be one kind or a mixture of two or more kinds.

  The number average molecular weight (hydroxyl group equivalent) per hydroxyl group of the polyester polyol (B2-3) is the same as that of the polyester polyol (B1-2), and the preferred range is also the same.

  Among these other polyols (B2) having low hydrophilicity, polyether polyols (B2-1) having an oxyethylene group content of less than 30% by weight are preferable, and polypropylene glycol is more preferable from the viewpoint of adhesive strength. And an adduct of 5 to 15% by weight of EO to polypropylene glycol, particularly preferably polypropylene glycol.

  The hydroxyl group equivalent of the other polyol (B2) having low hydrophilicity is preferably 50 to 5,000, more preferably 75 to 3,000, and particularly preferably 100 to 2, from the viewpoint of viscosity and adhesive strength. 000. Within this range, the adhesive strength and the like are further improved. In addition, the viscosity becomes optimum, and the hardness is such that the expanded PTFE adhesive is easily spread in a surgical operation.

When other polyol (B2) having low hydrophilicity is used, the content (% by weight) of the hydrophilic polyol (B1) is the weight of the polyol component (B) from the viewpoint of reactivity (curing speed) and adhesive strength. Is preferably 30 to 99, more preferably 50 to 98, and particularly preferably 80 to 95.
When the polyol (B2) having low hydrophilicity is used, the content (% by weight) of the polyol (B2) is based on the weight of the polyol component (B) from the viewpoint of adhesive strength and reactivity (curing speed). 1-70 are preferable, More preferably, it is 2-50, Most preferably, it is 5-20.

  Moreover, when using other polyol (B2) with low hydrophilicity, content (weight%) of the oxyethylene group in the polyol component (B) whole is from a viewpoint of reactivity (curing speed) and adhesive strength ( Based on the weight of the oxyalkylene group in B), it is preferably 30 to 100, more preferably 35 to 98, particularly preferably 40 to 95, and most preferably 50 to 90.

  Further, the average hydroxyl group equivalent of the entire polyol component (B) is preferably 50 to 5,000, more preferably 100 to 4,000, particularly preferably 200 to 3,000, from the viewpoint of viscosity and adhesive strength. Most preferably, it is 500-2,000. Within this range, the adhesive strength and the like are further improved. In addition, the viscosity becomes optimum, and the hardness is such that the expanded PTFE adhesive is easily spread in a surgical operation.

  When other polyol (B2) having low hydrophilicity is used in combination, as the hydrophilic polyol (B1), an EO adduct to diol (EO adduct to ethylene glycol, EO adduct to propylene glycol, etc.), and Co-adducts of EO and alkylene oxides of 3 to 8 carbon atoms to diols (random or block co-adducts of EO and PO to ethylene glycol, and random or block of EO and butylene oxide to ethylene glycol) A co-adduct, etc.) is preferred, more preferably a co-adduct of EO and PO to a diol, and particularly preferably a random co-adduct of EO and PO to a diol.

  When other polyol (B2) having low hydrophilicity is used in combination, the other polyol (B2) having low hydrophilicity is a polysiloxane having a content of oxyethylene groups of less than 30% by weight based on the weight of oxyalkylene groups. Ether polyols are preferred, more preferably polyether polyols containing oxypropylene groups and having an oxyethylene group content of less than 30% by weight based on the total weight of oxyethylene groups and oxypropylene groups, particularly preferably polypropylene. Glycol.

The content (mmol / kg) of alkali metal and alkaline earth metal in the polyol component (B) is preferably 0 or less than 0.07, more preferably 0 or 0.04, based on the weight of (B). Less than, particularly preferably 0 or less than 0.02, most preferably 0 or less than 0.01. Within this range, it is easy to prevent abnormal reactions in the reaction between the fluorine-containing polyisocyanate component (A) and the polyol component (B).
In addition, the content of alkali metal and alkaline earth metal in the polyol component (B) is 30% by weight methanol solution of (B) or (B) 10 g of heat in a platinum dish and dissolved in 10 g of water. It is determined by a method of analyzing the aqueous solution by ion chromatography, a method of titrating a solution obtained by dissolving 30 g of the polyol component (B) in 100 ml of methanol with a 1/100 normal hydrochloric acid aqueous solution, or the like.

  Alkali metals and alkaline earth metals are mainly mixed as catalysts in the synthesis of polyether polyols. Such catalysts include hydroxides (potassium hydroxide, sodium hydroxide, cesium hydroxide, beryllium hydroxide and magnesium hydroxide), alcoholates (lithium methylate, sodium ethylate, potassium butyrate and magnesium hexalate). Etc.) and simple metals (potassium, sodium, lithium, magnesium, calcium, etc.) and the like. In (B), 0.1 to 0.3 mmol / kg of these catalysts often remain. In order to make the content of the alkali metal and alkaline earth metal in (B) within the above range, a polyether polyol having a low content of alkali metal and alkaline earth metal may be used.

  A polyether polyol having a low content of alkali metal and alkaline earth metal is obtained by adding an alkylene oxide to a compound having active hydrogen in the presence of a catalyst as described above to obtain a crude polyether polyol. And a method for removing alkaline earth metal, and a composite metal cyanide complex (complex catalyst of zinc hexacyanocobaltate and polyether) disclosed in JP-A-8-104741 (corresponding patent application: US5482908A, US5533683A, etc.) Etc.), organoboron compounds [trifluoroboron and tris (pentafluorophenyl) borane, etc.], and a method of addition polymerization of alkylene oxide in the presence of a catalyst containing no alkali metal or alkaline earth metal such as a transition metal complex catalyst Obtained by etc. Examples of the method for removing alkali metal and alkaline earth metal from the crude polyether polyol include a method of treating with an adsorbent and a method of treating with an ion exchanger.

Adsorbents include silicates (magnesium silicate, talc, soapstone, stearite, calcium silicate, magnesium aluminosilicate, sodium aluminosilicate, etc.), clay (active clay, acidic clay, etc.), hydrotalcite, silica gel , Diatomaceous earth, activated alumina and the like. Of these adsorbents, silicate is preferred from the viewpoint of ease of adsorbent removal, and magnesium silicate is more preferred.
Examples of the ion exchange agent include strong cation exchange resins, weak cation exchange resins, and chelate resins. As a method of treating with an ion exchange agent, a crude polyether polyol added with water is mixed and stirred with an ion exchange agent, and then filtered to remove the ion exchange agent or passed through a column filled with the ion exchange agent. And the like. For filtration, a filtration device such as filter paper, filter cloth, or glass filter is used.

The urethane prepolymer (UP) is obtained by reacting the fluorine-containing polyisocyanate component (A) and the polyol component (B) (prepolymer reaction).
The amount ratio of the fluorine-containing polyisocyanate component (A) to the polyol component (B) is such that the equivalent ratio of the isocyanate group of (A) to the hydroxyl group of (B) (NCO group / OH group) is 1. The usage ratio is preferably 5 to 3, more preferably 1.8 to 2.3, and particularly preferably 1.9 to 2.1. Within this range, the viscosity is relatively low, and it is easier to handle as an adhesive, and the adhesive strength is further improved.

The urethane prepolymer (UP) preferably has a structure having at least one (preferably two) isocyanate groups in the molecule and no active hydrogen.
The position of the isocyanate group in the urethane prepolymer (UP) is preferably a position with less steric hindrance, more preferably a terminal position with less steric hindrance, from the viewpoint of reactivity with blood or body fluid.

  Further, the isocyanate group content (% by weight) in the expanded PTFE adhesive {weight ratio of isocyanate groups to the total weight of the expanded PTFE adhesive} is preferably 1 to 10, more preferably 1.2 to 8. Especially preferably, it is 1.5-6. Within this range, the adhesive strength is further improved.

  The isocyanate group content in the expanded PTFE adhesive is 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, it is measured according to JIS K7301-1995, 6.3 isocyanate group content.

  The content (% by weight) of the oxyethylene group in the urethane prepolymer (UP) is preferably 30 to 100, more preferably 50 to 98, particularly preferably based on the weight of the oxyalkylene group in (UP). 60-95, most preferably 70-90. Within this range, the adhesive strength (particularly the initial adhesive strength) is further increased.

  The number average molecular weight (Mn) of the urethane prepolymer (UP) is preferably 500 to 30,000, more preferably 800 to 20,000, and particularly preferably 1,000 to 10,000, from the viewpoints of viscosity and adhesive strength. Most preferably, it is 1,200 to 8,000. Within this range, the adhesive strength is further improved. In addition, the viscosity becomes optimum, and the hardness is such that the expanded PTFE adhesive is easily spread in a surgical operation.

As a method for producing this urethane prepolymer (UP), a conventionally known method {International Publication WO03 / 051952 pamphlet (the disclosure of US patent application 10 / 499,331 is incorporated into this application by reference), etc.} Examples thereof include a method of reacting the fluorine-containing polyisocyanate component (A) and the polyol component (B) at 50 to 100 ° C. for 1 to 10 hours. In this case, the method of adding the fluorine-containing polyisocyanate component (A) and the polyol component (B) may be a method of adding from the beginning or a method of gradually decreasing.
Since the fluorine-containing polyisocyanate (A) is very easy to react with moisture, it is necessary to remove moisture in the reaction apparatus and raw materials as much as possible. In particular, the polyol component (B) that easily contains moisture is preferably subjected to dehydration treatment. As the dehydration treatment, a method of dehydrating for 0.5 to 10 hours at 50 to 150 ° C. and 0.001 hPa to atmospheric pressure while supplying an inert gas (nitrogen gas or the like) as necessary can be applied.
As a mixing method of the fluorine-containing polyisocyanate component (A) and the polyol component (B), (1) a method of mixing at once, (2) a method of gradually reducing (B) to (A), (3 ) Method of gradually dropping into (A) and (B), (4) After mixing and reacting part of (A) and (B), the remaining (B) is dropped or mixed at once Any of the methods may be used. Of these, the method (1) and the method (2) are preferable, and the method (1) is more preferable, from the viewpoint of simplicity of the reaction operation.
The reaction may be performed in the presence of a catalyst (an organic metal compound such as dibutyltin oxide or dibutyltin dilaurate, or an organic acid metal salt such as zirconium acetate).

  The expanded PTFE adhesive of the present invention may further contain a phenol-containing radical scavenger (PRS). When a phenol-containing radical scavenger (PRS) is included, it suppresses degradation over time of a sheet-like or sponge-like water-reacted cured product produced by the reaction of urethane prepolymer (UP) and moisture, and has an adhesive strength. This is preferable because it is possible to prevent a decrease in the thickness.

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

  Examples of the monophenol-containing 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 Co., Ltd. 50} and the like.

  As the bisphenol-containing radical scavenger, 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, ANTAGE 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 {for example, ADK STAB AO-80 manufactured by Asahi Denka) .

  As the polymer type phenol-containing 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 ′ Di -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 phenol-containing radical scavenger (PRS) preferably has a molecular weight of 500 to 1,200, more preferably 600 to 1,100, and particularly preferably 700 to 1,000. Within this range, the water-reacted cured product becomes more difficult to be degraded and decomposed over time, that is, the adhesion durability is further improved.

  The phenol-containing radical scavenger (PRS) preferably has at least two hydroxyl groups, more preferably 2 to 5, and particularly preferably 3 to 4. Within this range, the water-reacted cured product becomes more difficult to be degraded and decomposed over time, that is, the adhesion durability is further improved.

  Among these phenol-containing radical scavengers, bisphenol-containing radical scavengers and polymer-type phenol-containing radical scavengers are preferable, and tetrakis- [methylene 3- (3 ′, 5′-di-tert-butyl 4′-hydroxyphenyl) propionate] methane, 1,1,3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, , 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 It is a t- butyl-4-hydroxyphenyl) propionate].

The content (% by weight) of these phenol-containing radical scavengers (PRS) is preferably 0.01 to 3, more preferably 0.02 to 1, particularly preferably based on the weight of the urethane prepolymer (UP). Is 0.05 to 0.5. Within this range, deterioration with time of the water reaction cured product can be suppressed, and a decrease in adhesive strength can be prevented.
The phenol-containing radical scavenger (PRS) may be added to the urethane prepolymer (UP), or added in advance to the fluorine-containing polyisocyanate component (A) and / or the polyol component (B) before the urethane prepolymer. (UP) may be obtained.

The expanded PTFE adhesive of the present invention may contain other components as required in addition to the urethane prepolymer (UP) and the phenol-containing radical scavenger (PRS).
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, etc.), and plasticizers (DBP, DOP, TCP, tributoxy) Ethyl phosphate and other various esters). When other components are included, the content thereof is appropriately determined depending on the application. Other components may be premixed with the fluorine-containing polyisocyanate component (A), the polyol component (B) and / or the phenol-containing radical scavenger (PRS) in advance, and after the reaction. The urethane prepolymer (UP) and / or the phenol-containing radical scavenger (PRS) may be mixed.

The adhesive of the present invention comprises (1) a fluorine-containing polyisocyanate component (A) and / or a polyol component (B), a phenol-containing radical scavenger (PRS) and, if necessary, other components, and then (A ) And (B), and (2) a urethane polymer (UP), a phenol-containing radical scavenger (PRS) and, if necessary, a method of mixing other components.
As a mixing method, there is no limitation on conditions and apparatuses as long as uniform dissolution or uniform dispersion is possible. However, since the urethane prepolymer (UP) tends to be easily polymerized by moisture, the phenol-containing radical scavenger (PRS) and other components need not contain moisture. The mixing is preferably performed in an atmosphere of a dry gas {inert gas (such as nitrogen gas and argon gas) and air can be used, but inert gas is preferred} so that the mixture does not come into contact with moisture. Moreover, 0-60 degreeC is preferable for mixing temperature, More preferably, it is 5-40 degreeC, Most preferably, it is 10-30 degreeC.

  The adhesive of the present invention is preferably stored from the viewpoint of reaction with moisture and the like so as not to be exposed to moisture (for example, filled in an ampoule container or syringe with air shut off).

  Expanded PTFE (polytetrafluoroethylene) is a material obtained by stretching PTFE and having a fine continuous porous structure. In addition to the properties of PTFE such as chemical stability, thermal stability, and low friction properties, it has biocompatibility and antithrombotic properties and is used as a material for medical materials.

  The expanded PTFE may be any one having a fine continuous porous structure, and is not limited to a specific production method. Expanded PTFE can be produced by a method described in, for example, Japanese Patent Publication No. 42-13560 and Japanese Patent Publication No. 57-30059.

  The medical material made of expanded PTFE may contain materials other than expanded PTFE. However, from the viewpoint of adhesiveness, the surface to which the expanded PTFE adhesive is applied (that is, the adhesion site of the medical material) needs to be expanded PTFE.

  As a medical material using expanded PTFE as a raw material, pre-crotting treatment may be performed.

  The expanded PTFE has a fine continuous porous structure obtained by stretching PTFE. The expression of the degree of porosity is expressed by the length of fibers called thin fibrils that connect the nodules caused by cracks, in other words, the distance between individual nodules. As materials for medical materials, products with a length of 30 microns are mainly used. In this gap, blood does not leak because there are countless fibrils between the nodules. However, even if the blood cell component of the blood does not leak, a so-called “sweat” phenomenon occurs in which the serum component oozes out. For this reason, a “ceroma” in which transparent serum is stored around an artificial blood vessel made of expanded PTFE is formed, which may cause inconvenience of pressing the artificial blood vessel from the periphery. When using an artificial blood vessel having such a fine continuous porous structure, the artificial blood vessel is brought into contact with blood immediately before implantation, and a blood clot is artificially created in the fiber gap. The operation of clogging, that is, so-called pre-clotting is performed. Examples of the material used for pre-clotting include gelatin and collagen that are decomposed and absorbed in vivo.

  Examples of medical materials made of expanded PTFE include artificial blood vessels, artificial dura mater, and patch materials for repairing the heart or blood vessels.

  An artificial blood vessel made of expanded PTFE is used to replace a damaged blood vessel with an abdominal aorta, an artery or vein of a lower limb, or the like. During these replacements, blood often leaks from the needle holes when the biological blood vessels are stitched together with surgical sutures.

  Artificial dura mater made of expanded PTFE is used at the time of craniotomy to compensate for defects caused by brain tumors, subarachnoid hemorrhage, or traffic accidents. Also during this operation, cerebrospinal fluid leaks from the needle hole as in the case of the artificial blood vessel.

  A patch material for repairing a heart or blood vessel made of expanded PTFE is used for repairing a defect site when a lesion of the heart or blood vessel is removed. Similarly, when this repair material is sewn to a blood vessel, heart, etc., blood and tissue fluid leak from the needle hole.

  The expanded PTFE adhesive of the present invention is used to stop tissue fluid such as blood and cerebrospinal fluid that leaks from medical materials made from these expanded PTFE.

When the expanded PTFE adhesive of the present invention is used, the urethane prepolymer (UP) reacts with moisture (water in body fluids such as blood and lymph) to produce amine and carbon dioxide. Furthermore, it reacts with the urethane prepolymer (UP) to increase the molecular weight (polymerization). A foamed (sponge-like) water reaction cured product is generated by the carbon dioxide generated at this time.
Therefore, when the adhesive for expanded PTFE of the present invention is applied to a medical practice such as surgery, the polymerization site is rapidly brought into contact with a body fluid such as blood, and the application site is adhered. Moreover, the initial adhesive force, the hemostatic effect, etc. can be heightened by spraying, for example, physiological saline or the like as needed to replenish water.

  In the operation, the adhesive of the present invention is used to join the sutured part or the anastomosis part. The direct application method in which the adhesive of the present invention is directly applied to the incised part; For example, a transfer coating method in which an adhesive is applied to a high film, the incision is covered with the film, and the film is removed after the reaction is performed.

  The expanded PTFE adhesive of the present invention exhibits a strong adhesive effect and hemostatic effect on living tissues such as viscera, skin, mucous membranes and blood vessels in addition to medical materials made of expanded PTFE. Accordingly, it is sufficient that at least one of the adherends is a medical material made of expanded PTFE, the bonding between the living tissue and the medical material made of expanded PTFE, and the medical materials made of expanded PTFE. It is suitable for joining and sealing of an incision part and a needle hole of a medical material made of expanded PTFE.

The expanded PTFE adhesive of the present invention is suitable for surgical operations on internal organs, skin, mucous membranes, blood vessels, etc., and in places such as blood vessels such as heart, arteries, respiratory organs, digestive organs, etc. where blood and body fluids are likely to leak. Significantly exerts hemostatic effect. In addition, since eruptive bleeding can be stopped in a short time, it is particularly suitable for surgery on blood vessels.
The expanded PTFE adhesive of the present invention can also be used for surgical operations on animals other than humans (pets and livestock).

  A blood anticoagulant such as heparin is always administered in a heart or aorta surgery using a heart-lung machine. While this blood anticoagulant is acting, the bleeding blood does not clot, so a large amount of bleeding during surgery can be a fatal obstacle for the patient. However, even in such a case, the expanded PTFE adhesive of the present invention can be applied regardless of whether or not a blood anticoagulant is administered, and can stop hemostasis in a short time.

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 addition, a part shows a weight part and% shows weight%.
<Production Example 1>
The 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 vacuum dehydrated at 120 ° C. for 60 minutes.
Next, after injecting a mixture of 784.5 parts of EO and 200 parts of PO at 100 to 130 ° C. for about 10 hours, the reaction is continued at 130 ° C. for 3 hours, and a liquid crude polyether having an oxyethylene group content of 80% Got.
Place 1000 parts of this liquid crude polyether in an autoclave, perform nitrogen substitution (oxygen concentration of 450 ppm in the gas phase part), add 30 parts of ion exchange water, and then synthetic magnesium silicate (sodium content 0.2%) 10 parts were added, and the atmosphere was purged with nitrogen again, and then stirred at 90 ° C. for 45 minutes at a stirring speed of 300 rpm. Subsequently, filtration was performed under nitrogen using a glass filter (GF-75: manufactured by Toyo Roshi) to obtain an EO / PO random co-adduct (b1). This (b1) had a number average molecular weight of 4000, an oxyethylene group content of 80%, and an alkali metal and / or alkaline earth metal content of 0.02 mmol / kg.

<Production Example 2>
The autoclave was charged with 362 parts of prolene glycol and 3.8 parts of potassium hydroxide, purged with nitrogen (oxygen concentration in the gas phase part 450 ppm), and vacuum dehydrated at 120 ° C. for 60 minutes.
Then, 632 parts of PO632 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 was 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 PO adduct (b2). This (b2) had a number average molecular weight of 210, an oxyethylene group content of 0%, and an alkali metal and / or alkaline earth metal content of 0.04 mmol / kg.

<Production Example 3>
In an autoclave, 180 parts of prolene glycol and 3.8 parts of potassium hydroxide were charged, and after nitrogen substitution (oxygen concentration in the gas phase part 450 ppm), vacuum dehydration was performed at 120 ° C. for 60 minutes.
Subsequently, 820 parts of PO at 100 to 130 ° C. was injected in about 10 hours, and then the reaction was continued at 130 ° C. until the volatile content was 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 PO adduct (b3). This (b3) had a number average molecular weight of 420, an oxyethylene group content of 0%, and an alkali metal and / or alkaline earth metal content of 0.03 mmol / kg.

<Production Example 4>
The autoclave was charged with 42.2 parts of prolene glycol and 3.8 parts of potassium hydroxide, purged with nitrogen (oxygen concentration in the gas phase part: 450 ppm), and vacuum dehydrated at 120 ° C. for 60 minutes.
Next, after injecting a mixture of 800.0 parts of EO and 157.8 parts of PO at 100 to 130 ° C. in about 10 hours, the reaction is continued at 130 ° C. until the volatile content is 0.1% or less, and the liquid crude polyether is obtained. Obtained.
This liquid crude polyether was treated with synthetic magnesium silicate in the same manner as in Production Example 1 to obtain a PO adduct (b4). This (b4) had a number average molecular weight of 1800, an oxyethylene group content of 80%, and an alkali metal and / or alkaline earth metal content of 0.03 mmol / kg.

<Example 1>
As the polyol component (B), 100 parts of the EO / PO random co-adduct (b1) obtained in Production Example 1 was used, and after dehydrating this (b1) under reduced pressure at 100 ° C. for 2 hours in a nitrogen atmosphere, 50 After cooling to 0 ° C., 0.5 parts of tetrakis- [methylene-3- (3 ′, 5′-di-t-butyl4′-hydroxyphenyl) propionate] methane (Irganox) as a phenolic radical scavenger (PRS) 1010, manufactured by Ciba Specialty Chemicals Co., Ltd.) and stirred uniformly for 30 minutes. After further cooling to 40 ° C., 15.6 parts of bis (isocyanatomethyl) perfluorobutane {OCN—CH ₂ — (CF ₂ ) ₄ —CH ₂ —NCO} as the fluorine-containing polyisocyanate component (A) (NCO group) / OH group ratio = 2/1) was added and stirred uniformly, and then the temperature was raised to 80 ° C and reacted at 80 ° C for 6 hours to obtain an expanded PTFE adhesive (P1) of the present invention. The isocyanate group content of this (P1) was 1.8%. The oxyethylene group content in the polyol component (B) is 80%, the oxyethylene group content in (UP) is 69%, and the fluorine content in (A) is 49%.

<Example 2>
As a polyol component (B), a mixture of 90 parts of the EO / PO random coadduct (b1) obtained in Production Example 1 and 10 parts of the PO adduct (b2) obtained in Production Example 2 was used, and a fluorine-containing polyisocyanate component The adhesive for expanded PTFE of the present invention is the same as in Example 1 except that 45.6 parts of bis (isocyanatomethyl) perfluorobutane (NCO group / OH group ratio = 2/1) is used as (A). (P2) was obtained. The isocyanate group content of (P2) was 4.0%. The oxyethylene group content in the polyol component (B) is 72%, the oxyethylene group content in (UP) is 49%, and the fluorine content in (A) is 49%.

<Example 3>
Mixture of 70 parts of EO / PO random coadduct (b1) obtained in Production Example 1 and 30 parts of PO adduct (b3) obtained in Production Example 3 as a polyol component (B), fluorine-containing polyisocyanate component (A) As in Example 1 except that 61.0 parts of bis (isocyanatomethyl) perfluorobutane (NCO group / OH group ratio = 2.2 / 1) was used as the adhesive for expanded PTFE of the present invention ( P3) was obtained. The isocyanate group content of (P3) was 5.6%. The oxyethylene group content in the polyol component (B) is 56%, the oxyethylene group content in (UP) is 34%, and the fluorine content in (A) is 49%.

<Example 4>
As a polyol component (B), a mixture of 90 parts of the EO / PO random coadduct (b1) obtained in Production Example 1 and 10 parts of the PO adduct (b2) obtained in Production Example 2 was used, and a fluorine-containing polyisocyanate component This is the same as in Example 1 except that 33.9 parts of perfluorotrimethylene diisocyanate {OCN- (CF ₂ ) ₃ —NCO} (NCO group / OH group ratio = 2/1) is used as (A). An expanded PTFE adhesive (P4) of the invention was obtained. The isocyanate group content of this (P4) was 4.6%. The oxyethylene group content in the polyol component (B) is 72%, the oxyethylene group content in (UP) is 54%, and the fluorine content in (A) is 49%.

<Example 5>
As a polyol component (B), a mixture of 90 parts of the EO / PO random coadduct (b1) obtained in Production Example 1 and 10 parts of the PO adduct (b2) obtained in Production Example 2 was used, and a fluorine-containing polyisocyanate component (A) 28.4 parts of bis (isocyanatomethyl) perfluoropropane {OCN—CH ₂ — (CF ₂ ) ₃ —CH ₂ —NCO} and 7.0 parts of 2,4-tolylene diisocyanate (TDI) ( An expanded PTFE adhesive (P5) of the present invention was obtained in the same manner as in Example 1 except that the NCO group / OH group ratio = 2.1 / 1) was used. The isocyanate group content of (P5) was 4.6%. The oxyethylene group content in the polyol component (B) is 72%, the oxyethylene group content in (UP) is 56%, and the fluorine content in (A) is 35%.

<Example 6>
As a polyol component (B), a mixture of 90 parts of the EO / PO random co-adduct (b4) obtained in Production Example 4 and 10 parts of the PO adduct (b2) obtained in Production Example 2 was used. The adhesive for expanded PTFE of the present invention is the same as in Example 1 except that 61.2 parts of bis (isocyanatomethyl) perfluorobutane (NCO group / OH group ratio = 2/1) is used as (A). (P6) was obtained. The isocyanate group content of this (P6) was 5.1%. The oxyethylene group content in the polyol component (B) is 72%, the oxyethylene group content in (UP) is 45%, and the fluorine content in (A) is 49%.

<Comparative Example 1>
As a polyol component (B), a mixture of 90 parts of the EO / PO random coadduct (b1) obtained in Production Example 1 and 10 parts of the PO adduct (b2) obtained in Production Example 2 was used, and a fluorine-containing polyisocyanate component For expanded PTFE for comparison in the same manner as in Example 1 except that 25.2 parts of 2,4-tolylene diisocyanate (TDI) (NCO group / OH group ratio = 2/1) is used instead of (A) An adhesive (C1) was obtained. The isocyanate group content of (C1) was 4.8%. The oxyethylene group content in the polyol component (B) is 72%, the oxyethylene group content in (UP) is 58%, and the fluorine content in (A) is 0%.

<Comparative example 2>
Fibrin glue (product name: Veriplast P, manufactured by ZLB Behring Co., Ltd.) was used as a comparative adhesive for expanded PTFE (C2).

<Evaluation 1: Adhesive strength>
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 of about 0.02 g of adhesive for evaluation Was applied using.
A test piece was prepared by applying an adhesive for evaluation and adhering the end portion 1 cm × 1 cm of the other ePTFE tape. The test piece was covered with a fully moistened Kimwipe, and a 100 g weight was placed on the bonded part of the ePTFE tape so that a load of 100 g / cm ² was applied. The sample was left for 5 minutes, and then the weight was removed to obtain a test piece. .
Subsequently, the tensile strength of the test piece was measured according to JIS K6850-1999 under an environment of 25 ± 5 ° C. and humidity of 65 ± 5 RH%, and the load at break was defined as the adhesive strength.
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.

  From the results in Table 1, it was found that the expanded PTFE adhesives of the present invention (Examples 1 to 6) were more strongly bonded to expanded PTFE than Comparative Examples 1 and 2.

<Evaluation 2: Pulse pressure test>
<Production of suture model blood vessel>
An expanded PTFE artificial blood vessel (product name: Maxiflow Standard Wall, distributor: Nippon Lifeline Co., Ltd.) is incised 5 mm in the lateral direction, and 6-0 suture (product name: Proleen, manufactured by Johnson & Johnson Co., Ltd.) A suture model blood vessel was prepared by suturing at intervals of 1 mm.
<Hemostasis determination>
Both ends of this suture model blood vessel were connected to a pressure load test device (manufactured by Anhiko Co., Ltd.) line (see FIG. 1 for the suture model blood vessel, and FIG. 2 for the device connection outline of the pressure load test device) and heparinized. Horse blood was filled. The downstream side of the pressure load testing device line was blocked, and a pulse pressure of 120/60 mmHg (16000 Pa / 8000 Pa) was applied at a cycle of 1 second, and it was confirmed that there was bleeding from the sutured part. Once the blood in the suture model blood vessel was removed, the blood adhering to and around the sutured part was wiped off.
An adhesive for evaluation was applied to the stitched portion, and physiological saline was applied, and a silicone sheet was placed on the top and pressed for 3 minutes to be cured. The adhesive for evaluation of Comparative Example 2 was allowed to stand for 3 minutes after the main agent and the curing agent were sequentially applied to the stitched portion. However, for the evaluation adhesive of Comparative Example 2, the mechanism of the curing reaction is different from the other evaluation adhesives (Examples 1 to 6 and Comparative Example 1), so the operation of applying physiological saline and silicone No pressing operation was performed on the made sheet.
Again, heparinized horse blood was filled into the suture model blood vessel, the downstream side of the pressure load test device line was blocked, and a pulse pressure of 120/60 mmHg (16000 Pa / 8000 Pa) was applied in a cycle of 1 second. After applying the pulse pressure, it was observed for 5 minutes, and during that time, no hemorrhage was regarded as “hemostasis”, and any slight hemorrhage was termed “bleeding”.

  From the results in Table 2, the expanded PTFE adhesives of the present invention (Examples 1 to 6) were able to stop bleeding at the incised portion of the expanded PTFE artificial blood vessel. Moreover, Comparative Examples 1 and 2 could not stop bleeding at the incision portion of the expanded PTFE artificial blood vessel.

The expanded PTFE adhesive of the present invention is excellent in adhesiveness with medical materials made from expanded PTFE and provides an expanded PTFE adhesive having practical reactivity (curing speed), thereby quickly The leakage of blood or cerebrospinal fluid can be prevented.
In addition, the expanded PTFE adhesive of the present invention can be applied regardless of the presence or absence of administration of a blood anticoagulant such as heparin, and can stop hemostasis in a short time. It can also be used for aortic surgery.

DESCRIPTION OF SYMBOLS 1 Expanded PTFE artificial blood vessel 2 Suture part 3 Hose band 4 Tube connector 5 Rubber stopper with a hole that can be inserted into the tube connector 6 Compressor 7 Low pressure regulator 8 High pressure regulator 9 Tank 10 Timer 11 Electromagnetic valve 12 Throttle valve 13 Manometer 14 Compliance tank 15 Horse blood 16 Pressure load test equipment line (upstream side)
17 Pressure load test device body 18 Blood inlet 19 Sutured blood vessel model 20 in FIG. 1 Roller clamp 21 Pressure load test device line (downstream side)

Claims (5)

It comprises a urethane prepolymer (UP) obtained by reacting a fluorine-containing polyisocyanate component (A) with a polyol component (B) having a hydrophilic polyol (B1) as an essential component, and at least one of the adherends Is an expanded PTFE (polytetrafluoroethylene) adhesive, which is a medical material made from expanded PTFE. 2. The expanded PTFE adhesive according to claim 1, wherein the fluorine content in the expanded PTFE adhesive is 28 to 70% by weight based on the weight of the fluorine-containing polyisocyanate component (A). The expanded PTFE adhesive according to claim 1 or 2, wherein the isocyanate group content in the expanded PTFE adhesive is 1 to 10% by weight based on the weight of the urethane prepolymer (UP). The adhesive for expanded PTFE according to any one of claims 1 to 3, wherein the content of oxyethylene group in the polyol component (B) is 30 to 100% by weight based on the weight of the oxyalkylene group in the polyol component (B). Agent. The expanded PTFE adhesive according to any one of claims 1 to 4, wherein the polyol component (B) comprises a random coadduct of ethylene oxide and propylene oxide to diol and polypropylene glycol.