WO2008056516A1 - Adhésif à base de 2-cyanoacrylate destiné à des organismes vivants - Google Patents

Adhésif à base de 2-cyanoacrylate destiné à des organismes vivants Download PDF

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Publication number
WO2008056516A1
WO2008056516A1 PCT/JP2007/070287 JP2007070287W WO2008056516A1 WO 2008056516 A1 WO2008056516 A1 WO 2008056516A1 JP 2007070287 W JP2007070287 W JP 2007070287W WO 2008056516 A1 WO2008056516 A1 WO 2008056516A1
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WIPO (PCT)
Prior art keywords
cyanacrylate
carbon atoms
biomedical adhesive
bioadhesive
adhesive according
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PCT/JP2007/070287
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English (en)
Japanese (ja)
Inventor
Yoshihiko Abe
Kazuyoshi Tani
Muneaki Kano
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Terumo Kabushiki Kaisha
Toagosei Co., Ltd.
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Application filed by Terumo Kabushiki Kaisha, Toagosei Co., Ltd. filed Critical Terumo Kabushiki Kaisha
Priority to JP2008543021A priority Critical patent/JPWO2008056516A1/ja
Publication of WO2008056516A1 publication Critical patent/WO2008056516A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Definitions

  • the present invention relates to a 2-cyanacrylate biomedical adhesive. More specifically, in the present invention, the cured product has a predetermined hardness, is moderately flexible, has an appropriate amount of formaldehyde released by hydrolysis, has high safety, and has sufficient degradability.
  • the present invention relates to a 2-cyanacrylate biomedical adhesive having at least one ether bond in one molecule. Furthermore, it has a predetermined stiffness parameter, and is a 2-cyanose particularly useful in applications such as joints between living blood vessels or between living blood vessels and human blood vessels, and aneurysm fillers, vascular embolization agents, and bone filling agents.
  • the present invention relates to an acrylate biomedical adhesive.
  • 2-cyanacrylate compounds are known, and it is also known that this 2-cyanacrylate compound is useful as an adhesive in medical applications!
  • alkyl cyanoacrylates such as ethyl-2-cyanoacrylate, butyl-2-cyanoacrylate, 2-octanoleno-2-cyanoacrylate and the like are used as adhesives for skin for external use.
  • problems such as hardened products and slow degradation.
  • ethyl 2-cyanoacrylate and butyl 2-cyanoacrylate are used, the cured product is hard, whereas when 2-octyl-2-cyanoacrylate is used, the cured product is relatively soft.
  • decomposition is slow.
  • a plasticizer is blended (see, for example, Patent Document 1 and Patent Document 2).
  • a specific flexible polymer is blended (for example, see Patent Document 3), a polyfunctional compound is blended (for example, see Patent Document 4 and Patent Document 5), and an alkoxyalkylcyano acrylate is blended.
  • Patent Document 6 and Patent Document 7 are known.
  • a biodegradable polymer is blended in order to impart flexibility to the cured product and accelerate decomposition (see, for example, Patent Document 8).
  • an adhesive containing an ethoxyethyl cyanoacrylate compound is used for surgical use. It is also known (for example, see Non-Patent Document 1), and various types of alkoxycyanoacrylates contained in adhesives used for surgical applications (for example, see Patent Document 2 and Patent Document 9). And alkyl ester cyanoacrylates (see, for example, Patent Document 10) are also known. Patent Document 10 also describes the promotion of decomposition by the combined use of 2-cyanacrylate compounds. ! /
  • Patent Document 1 Japanese Patent Laid-Open No. 2-34678
  • Patent Document 2 International Publication WO2002 / 053666 Noriyuki
  • Patent Document 3 European Patent Publication No. 0530626
  • Patent Document 4 International Publication WO 1994/01 1454
  • Patent Document 5 JP-A-6-145606
  • Patent Document 6 US Pat. No. 4,321,180 specification
  • Patent Document 7 US Patent No. 4364876
  • Patent Document 8 US Patent No. 6103778
  • Non-Patent Document 1 Artificial organs, 1989, 18, 409-413
  • Patent Document 9 International Publication WO2002 / 009785
  • Patent Document 10 U.S. Pat.No. 3995641
  • the present invention has been made in view of the above-described conventional situation, and a cured product has a predetermined hardness, is moderately flexible, has an appropriate amount of formaldehyde released by hydrolysis, and is safe.
  • the object is to provide a 2-cyanacrylate biomedical adhesive that is sufficiently degradable and has sufficient degradability. Furthermore, it has a predetermined stiffness parameter, It is interesting to provide 2-cyanacrylate-based bioadhesives that are useful in joints between tubes or between living blood vessels and artificial blood vessels, and in body use such as aneurysm fillers, vascular embolizers, and bone fillers. Say it.
  • the present invention is as follows.
  • R in the above formula (1) is an alkylene group having 2 to 4 carbon atoms, and when R has 2 carbon atoms, R is a linear or side chain alkyl group having 5 to 8 carbon atoms, Carbon number of R
  • R is a linear or side chain alkyl group having 4 to 8 carbon atoms.
  • R and R in the above formula (2) are alkylene groups having 2 to 4 carbon atoms; When the number of carbon atoms is 2, R is a linear or side chain alkyl group having 4 to 8 carbon atoms,
  • R and the carbon number of R are 3 or 4
  • the R has 3 carbon atoms having a straight chain or a side chain.
  • R represents an ethylene group or a propylene group, and R represents a straight chain or a side chain.
  • R and R in the above formula (2) are propylene groups, R has a straight chain or a side chain It is an alkyl group having 3 to 8 carbon atoms. ]
  • R wherein R is a propylene group, and R and R have 3 to 5 carbon atoms.
  • the 2-cyanacrylate biomedical adhesive of the present invention has a cured product having a specific Shore hardness and a small amount of formaldehyde released, so that the cured product is moderately flexible and highly safe. It is fully absorbed by the living body due to decomposition of, and is useful as a bioadhesive.
  • the coating thickness is 100 to 150 m
  • the stiffness parameter of the cured product is 10 to 65, it is particularly useful for adhesion between living blood vessels or between blood vessels and artificial blood vessels. It can be used as an agent.
  • R, R, and R have 2 or 3 carbon atoms, the cured product is more easily flexible.
  • R has 2 carbon atoms, and R has carbon atoms
  • the carbon number of R is 3, and the carbon number of R is ⁇ 8, the amount of formaldehyde released is less than safety
  • a force S is used to make a bioadhesive that has high properties and forms a cured product that is sufficiently decomposed and absorbed by the living body.
  • R and R have 3 carbon atoms
  • the 2-cyanacrylate biomedical adhesive according to another embodiment of the present invention can easily adjust the Shore A hardness, formaldehyde emission amount, and stiffness parameter of the cured product, and can provide a predetermined flexibility and safety. And a bioadhesive that forms a cured product that is sufficiently decomposed and absorbed by the living body.
  • the living tissue is at least one of skin, myocardium, luminal organ and parenchymal organ.
  • the prosthesis is at least one of an artificial blood vessel, a hemostatic material, a bone pin, and a suture, a hardened material having sufficient flexibility for the living tissue and the prosthesis. Can be joined together, and safety is high.
  • aneurysm when used in a 2-cyanacrylate-based bioadhesive force S, aneurysm, especially an aneurysm generated in the cerebral blood vessel, it functions sufficiently as an aneurysm filler and is also safe. high.
  • the 2-cyanacrylate biomedical adhesive of the present invention is characterized in that the cured product has a Shore A hardness of 15 to 90, and the amount of formaldehyde released in the hydrolysis test is 500 ppm or less.
  • This bioadhesive has excellent flexibility because the hardness of the cured product is low, and has an appropriate amount of formaldehyde released when the cured product is hydrolyzed, so it has excellent safety and sufficient Decomposes and is absorbed by the body.
  • the Shore A hardness of the hard article can be 15-90, in particular 50-90, more preferably 50-70. Further, it is preferable that the Shore A hardness is 15 to 90 and the Shore D hardness is 40 or less, particularly 30 or less. Furthermore, the amount of formaldehyde released may be 500 ppm or less, particularly 300 ppm or less, and even 200 ppm or less, and may be 150 ppm or less, particularly lOOppm or less, and further 50 ppm or less (usually 40 ppm or more). That is, the amount of formaldehyde released can be set to 40 to 500 ppm, and can be from 40 ppm to each of the above upper limit values.
  • Formaldehyde is released by decomposition of the cured product, and if this release amount is large, force that is problematic in terms of safety, such as positive flame resistance, the cured product decomposes and is absorbed by the living body. It is advantageous as an adhesive for internal use. Therefore, the amount of formaldehyde released is small. In terms of the fact that the cured product is degraded and absorbed by the living body, formaldehyde is released to the extent that it is non-toxic to the living body or at least extremely toxic, that is, it is preferable that the cured product decomposes. .
  • the lower limit in this sense is the above 40ppm
  • the Shore A hardness, Shore D hardness, and formaldehyde emission can be measured by the methods described in detail in the following examples.
  • the bioadhesive of the present invention has a predetermined Shore A hardness and formaldehyde emission amount, and a cured product has a stiffness parameter of 10 to 65 when the coating thickness is 100 to 150 111. It is preferable that This stiffness parameter is preferably 10 to 60, in particular 10 to 40, more preferably 10 to 30, more preferably force S, 10 to 20, in particular 10 to 15; With this stiffness parameter force S 10 to 65, it has both excellent flexibility and safety, and when used in tissues whose dimensions change due to the pulsation of the heart such as blood vessels, the cured product It can sufficiently follow the dimensional change, and can prevent or at least suppress the destruction of the cured product (cracking, etc.) at the edge of the bonded part.
  • the stiffness parameter can be measured by the method described in detail in the examples below.
  • the 2-cyanacrylate biomedical adhesive that provides a cured product having a specific Shore A hardness and formaldehyde emission, and further a cured product having a specific stiffness parameter.
  • a compound represented by the formula (1) [hereinafter referred to as “the compound of the formula (1)”.
  • a compound represented by the above formula (2) [hereinafter referred to as “compound of the above formula (2)”.
  • the bioadhesive may contain only one type of the compound of the formula (1) and the compound of the formula (2), or two or more types of each.
  • R is an alkylene group having 2 to 4 carbon atoms, and when R has 2 carbon atoms, R is a linear or side chain alkyl group having 5 to 8 carbon atoms. Yes, R has 3 carbon atoms
  • R is preferably a linear or side chain alkyl group having 4 to 8 carbon atoms.
  • R and R are within the above ranges, the hardness (meaning Shore A hardness and Shore D hardness) This is the taste, and so on. ) Has a low formaldehyde emission amount, and a cured product having a predetermined rigidity parameter is formed, and a bioadhesive having both flexibility, safety and sufficient degradability can be obtained.
  • R 3 4 is an alkylene group having 2 to 4 carbon atoms.
  • R and R have 2 carbon atoms, R is linear or
  • 3 45 is an alkyl group having 4 to 8 carbon atoms having a side chain, and when R and R have 3 or 4 carbon atoms
  • R is preferably a C 3-8 alkyl group having a straight chain or a side chain.
  • R is within the above range, the amount of formaldehyde released with low hardness is appropriate.
  • a cured product having a predetermined rigidity parameter is formed, and a bioadhesive having both flexibility, safety, and sufficient degradability can be obtained.
  • R in the formula (1) and R and R 1 in the formula (2) are both 2 or 3
  • the number of carbon atoms of the alkylene group is 2 or 3, it can be a bioadhesive agent having both superior flexibility, safety and sufficient decomposability.
  • the bioadhesive of the present invention contains the compound of the formula (1), wherein R has 2 carbon atoms, and R has 6 to 8 carbon atoms, particularly 7 to 8 carbon atoms. preferable. In this way, R and R are specific
  • the amount of formaldehyde released is appropriate, and a bioadhesive having excellent safety and sufficient degradability can be obtained.
  • the amount of formaldehyde released is 500 ppm or less, 300 to 300 ppm, and 150 ppm or less (usually 40 ppm or more).
  • the bioadhesive agent of the present invention preferably contains the compound of the formula (1), R has 3 carbon atoms, and R has a carbon number power of -8.
  • R and R are specific carbon
  • the amount of formaldehyde released is appropriate, and a bioadhesive having excellent safety and sufficient degradability can be obtained.
  • the amount of formaldehyde released should be 500 ppm or less, especially 300 ppm or less, and 250 ppm or less (usually 40 ppm or more).
  • bioadhesive of the present invention contains the compound of the formula (2), and R and R carbon numbers.
  • R is more preferable that the carbon number of R is 3-5.
  • R, R, and R are special
  • the hardness is lower and the stiffness parameter is smaller. It can be used as a bioadhesive having high flexibility.
  • the Shore A hardness in this case can be 20-70, in particular 30-70, and even 40-70.
  • the stiffness parameter should be 15 or less.
  • R and R 3 4 preferably have the same number of carbon atoms. In addition, each carbon number of R and R
  • R is an ethylene group or propylene group
  • R and R are propylene groups
  • the hardness of the cured product and the amount of formaldehyde released can be easily set within a predetermined range, and the stiffness parameter can be set within a predetermined range. Therefore, the biomedical adhesive having excellent flexibility, safety, and sufficient decomposability can be obtained.
  • the Shore A hardness can be 30 to 70, especially 40 to 70, the amount of honolemaldehyde released is 40 to 350 ppm, particularly 100 to 250 ppm, and the Oka ij tensei parameter is 12 to 16;
  • the biomedical adhesive contains the compound of the formula (1) and the compound of the formula (2)
  • Content of each compound is not specifically limited, It can be set as arbitrary mass ratios. In order to sufficiently obtain the action and effect of the inclusion of both compounds, it is preferable that the content of each compound is 5 to 95% by mass when the total content is 100% by mass. It is more preferable that the mass ratios are 10 to 90 mass%, particularly 15 to 85 mass%, and further 20 to 80 mass%, respectively.
  • the mass ratio of the compound of the formula (1) and the compound of the formula (2) is set in consideration of the hardness of the cured product, the amount of formaldehyde released, and the stiffness parameter when only each compound is contained. It is preferable to do.
  • This bioadhesive contains a compound of the above formula (1) and other components excluding the compound of the above formula (2) within a range where the predetermined performance is not impaired! Yo! /
  • the other component includes a stabilizer for improving storage stability. Examples thereof include a thickener for improving medical usefulness and a curing accelerator for promoting curing. Further, if necessary, a plasticizer, a thixotropic agent, a dye and the like can be blended.
  • the total content of the other components is preferably 20% by mass or less, more preferably 10% by mass or less, and further 5% when the bioadhesive is 100% by mass. It is to be determined that the mass% or less.
  • Stabilizers include sulfur dioxide, p-toluenesulfonic acid, methanesulfonic acid, propane sanoleton, boron trifluoride complex and other anionic polymerization inhibitors, and noduloquinone, catechol, pyrogallol, butylated hydroxyaniline. Sole, a radical polymerization inhibitor such as 2,2-methylenebis (4-methyl 6-t-butylphenol) can be used. Stabilizers are prohibited from anionic polymerization when the content of each of the compound of formula (1) and the compound of formula (2) or the total content when both compounds are contained is 100 parts by mass. In the case of an agent, it can be used by mixing;!
  • Radiocanole Polymerization Inhibition I it can be used by blending ⁇ , 100 to 10000 ppm by mass, and 500 to 5,000 ppm by mass. These stabilizers may be used alone or in combination of two or more.
  • thickener examples include acrylic polymers or copolymers such as poly (meth) acrylate, cellulose derivatives such as acetylcellulose, and acrylic rubber.
  • Thickener is , Each content of the compound of the formula (1) and the compound of the formula (2), or when both compounds are contained, when the total content is 100 parts by mass; In particular, 2 to 10 parts by mass can be used. These thickeners may be used alone or in combination of two or more.
  • Examples of the curing accelerator include polyethylene glycol derivatives, crown ether derivatives, calixarene, and the like. These curing accelerators can be blended and used at a mass ratio within a range that does not affect storage stability. These curing accelerators may be used alone or in combination of two or more.
  • the biomedical adhesive of the present invention is sterilized by various methods and then used for various applications.
  • the sterilization method is not particularly limited, and examples thereof include an electron beam sterilization method, a ⁇ -ray sterilization method, a filtration sterilization method, and a dry heat sterilization method. Sterilization may be performed by one of these various methods, and may be performed by two or more methods as necessary.
  • this bioadhesive container is a glass ampule
  • the adhesive enclosed in the glass ampule is sterilized by dry heat or sterilized by filtration and aseptically filled.
  • this bioadhesive container is made of polyolefin, it should be aseptically filled by filtration.
  • the outside of these containers can be sterilized with ethylene oxide gas sterilization. Further, this ethylene oxide gas sterilization can be replaced by electron beam sterilization or gamma ray sterilization.
  • This living body adhesive is used for bonding between living tissues or between a living tissue and an artificial prosthesis, or for assisting bonding.
  • This joining aid means to enhance the sealing property of the sutured portion using the needle thread or to reinforce the anastomosis.
  • the biological tissue is not particularly limited, and examples thereof include skin, myocardium, luminal organ, and parenchymal organ.
  • Luminal organs include blood vessels, respiratory organs [air passages from the upper respiratory tract (nasal cavity, paranasal sinuses, pharynx, larynx) to the lower respiratory tract (trachea, bronchi)], digestive tract (a series of organs from the oral cavity to the anus) Etc.), urinary tract system (renal pelvis, ureter, bladder, urethra) and the like.
  • the real organ include bone, kidney, digestive organ (liver, spleen), immune organ (thymus, lymph node) and the like.
  • the artificial prosthesis is not particularly limited, and examples thereof include an artificial blood vessel, a hemostatic material, a bone pin, and a suture thread.
  • the bioadhesive having a predetermined stiffness parameter of the present invention can be used for parts that are repeatedly operated such as assisting anastomosis between living blood vessels, or between a living blood vessel and an artificial blood vessel, and further assisting anastomosis at a cardiac incision. It is particularly useful in joining or joining assistance.
  • This bioadhesive is useful as a 2-cyanacrylate bioadhesive for filling an aneurysm, which is highly safe.
  • the 2-cyanacrylate bioadhesive is used as an aneurysm. It can be used as a vascular aneurysm filler by the usage method of filling the vascular vessel.
  • the blood vessel is not particularly limited, but a typical example is a cerebral blood vessel in which an aneurysm is frequently observed.
  • This bioadhesive is also useful as a 2-cyanacrylate bioadhesive for vascular embolization, and the 2-cyanacrylate bioadhesive is placed in a diseased part in a blood vessel.
  • this bioadhesive is also useful as a 2-cyanacrylate bioadhesive for bone repair, and the 2-cyanacrylate bioadhesive is implanted in a diseased part to produce new bone. It can be used as a bone filling material depending on the method of use to form the bone.
  • the method for producing the 2-cyanacrylate biomedical adhesive of the present invention is not particularly limited.
  • a cyanoacetic acid ester produced by an esterification reaction of cyanoacetic acid and an alcohol, etc. in a solvent in the presence of a catalyst.
  • a catalyst an amine or a base group can be used.
  • the amine include piperidine, jetylamine, dibutylamine, morpholine, etc.
  • examples of the base include potassium hydroxide, sodium hydroxide, sodium alkoxide, secondary amine. Examples include salts.
  • the catalyst is used in the range of 0.001 to 10 moles, preferably 0.01 to;
  • As the solvent toluene, ethyl acetate or the like is used.
  • the reaction temperature is the temperature at which the solvent can be refluxed, and is divided by the force S.
  • the solvent is distilled off from the condensate, and then phosphorus pentoxide, phosphoric acid, condensed phosphoric acid and the like are added in an amount of 0.01 to 10% by mass, particularly 0%, based on the condensate obtained by distilling off the solvent. 5.
  • the crude 2-cyanacrylate compound produced by this depolymerization is distilled to increase the purity, and the 2-cyanacrylate compound is used in bioadhesives. Get power S to get.
  • the above-mentioned stabilizer and the like can be blended with the 2-cyanacrylate compound thus obtained to obtain a 2-cyanacrylate biomedical adhesive.
  • the esterification reaction was carried out in the same manner as in Example 1 except that ethylene glycol mono-2-ethylhexyl ether (2-ethyl hexyl glycol, EHG manufactured by Nippon Emulsifier Co., Ltd.) was used instead of ethylene glycol monohexyl ether. Boiling point li C / 0.11 mm Hg 2- (2-ethynolehexoxy) ethenole 2-cianoacetate was obtained. The yield was 80%.
  • the esterification reaction, etc. was carried out in the same manner as in Example 1, except that dipropylene glycolenomonopropyl ether (propylene diglycol, PFDG manufactured by Nippon Emulsifier Co., Ltd.) was used instead of ethylene glycolenohexenoreethenole.
  • dipropylene glycolenomonopropyl ether propylene diglycol, PFDG manufactured by Nippon Emulsifier Co., Ltd.
  • 2- (2-propoxyisopropoxy) isopropyl-2-cyanoacetate having a boiling point of 143 ° C / 3.OOmmHg was obtained.
  • the yield was 72%.
  • Example 4 2- (2 butoxyisopropoxy) isopropyl-2-cyanoacrylate (DPGB) obtained in Example 8 were mixed at the mass ratio shown in Table 1.
  • a bioadhesive composed of the mixed mixture was subjected to a performance evaluation test (Examples 11 to 13).
  • Ethoxyethyl 2-cyanoacetate was used in the same manner as in Example 1, except that condensation and depolymerization were carried out in the same manner as in Example 1 to obtain a 2-ethyloxetyl-2-cyanoacrylate having a boiling point of 102 ° C / 3. Abbreviated as “EGE”). The yield was 70%. Next, 20 mass ppm of sulfur dioxide and 1000 mass ppm of hydroquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.
  • Lopochichetil 2-cyanoacrylate (abbreviated as “EGiP” in Table 2) was obtained. The yield was 36%. Next, sulfur dioxide 20 mass ppm and hydroquinone 1000 mass ppm were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.
  • Example 2 In the same manner as in Example 1 except that diethylene glycolenomonoethylenole ether (manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of ethylene glycolenohexenoreethenole, a boiling point of 128 ° C / 2. 78 mmHg of 2- (2 ethoxyethoxy) ethyl-2-cyanoacetate was obtained. The yield was 80%. Thereafter, condensation and depolymerization were performed in the same manner as in Example 1, and 2- (2 ethoxyethoxy) ethyl-2-cyanoacrylate having a boiling point of 93 ° C / 0.068 mmHg (abbreviated as “DEGE” in Table 2). .) The yield was 54%. Next As a stabilizer, sulfur dioxide 20 mass ppm and hydroquinone 1000 mass ppm were added, and this bioadhesive was subjected to a performance evaluation test.
  • DEGE 2- (2 e
  • the esterification reaction was carried out in the same manner as in Example 1 except that dipropylene glycolenomonomethyl ether (methyl emulsifier diglycol, MFDG manufactured by Nippon Emulsifier Co., Ltd.) was used instead of ethylene glycolenohexenoreethenole.
  • a 2- (2-methoxyisopropoxy) isopropyl-2-cyanoacetate having a boiling point of 116 ° C./2.18 mmHg was obtained. The yield was 76%.
  • the esterification reaction was carried out in the same manner as in Example 1 except that 3-methoxy-1-butanol monoure (manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of ethylene glycol monohexenoreethenore, and the boiling point was 90. C./0.6 mmHg of 3 methoxy 1-3 methylpropyl 1-2 cyanoacetate was obtained. The yield was 83%. Thereafter, condensation and depolymerization were performed in the same manner as in Example 1 to obtain 3 methoxy 1-3 methyl propyl 1-2 cyanoacrylate having a boiling point of 70 ° C / 0.15 mmHg. The rate (abbreviated as “BGM” in Table 2) was obtained. The yield was 36%. Next, 20 mass ppm of sulfur dioxide and 1000 mass ppm of hydroquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.
  • 3-methoxy-1-butanol monoure
  • E-2-CA Commercially available industrial instant adhesive (Ethyl 2-ciano acrylate, trade name “Alon Alpha 201” manufactured by Toagosei Co., Ltd.) (abbreviated as “E-2-CA” in Table 2)
  • Ethyleneglycolenomono 2-Ethinolehexenoreethenole was replaced with 2-year-old kuta nore in the same manner as in Example 1 except that an esterification reaction was performed, and a boiling point of 88 ° C / 0.15 mmHg 2 —Octyl-2-sianoacetate was obtained.
  • the yield was 80%.
  • condensation and depolymerization were carried out in the same manner as in Example 1, and 2-octyl-2-cyanoacrylate having a boiling point of 75 ° C / 0.075 mmHg (“2-0-0-2-CA” in Tables 2 and 5). For short).
  • the yield was 39%.
  • 20 mass ppm of sulfur dioxide and 1000 mass ppm of hydrated quinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.
  • the cured product was taken out from the petri dish, and the cured product was put into a sealable glass container, and 40 mL of physiological saline was added and sealed. After that, it was placed in a thermostatic chamber adjusted to 50 ° C. and left to stand for 7 days for hydrolysis.
  • Formaldehyde was quantified using a spectrophotometer (manufactured by Shimadzu Corporation, model “UV-2400PC”). Specifically, the absorbance of the sample and formaldehyde standard solution at a wavelength of 550 nm was measured using a blind test as a control, while a calibration curve was created using the absorbance of the formaldehyde standard solution, and the sample was measured using this calibration curve. Based on the value, the formaldehyde released from the cured product was calculated.
  • a spectrophotometer manufactured by Shimadzu Corporation, model “UV-2400PC”. Specifically, the absorbance of the sample and formaldehyde standard solution at a wavelength of 550 nm was measured using a blind test as a control, while a calibration curve was created using the absorbance of the formaldehyde standard solution, and the sample was measured using this calibration curve. Based on the value, the formaldehyde released from the cured product was calculated.
  • the amount of formaldehyde produced in Tables 1 and 2 is the value obtained by dividing the measured value by the weight of the cured product, that is, the amount of formaldehyde produced per gram of cured product.
  • G ′ storage elastic modulus
  • G ′ storage elastic modulus
  • a temperature dispersion curve of G ′ can be obtained, and the temperature dependence of G ′ can be confirmed.
  • the G' is higher at this given temperature, the harder the hardened product, the lower the G '! Measured at room temperature (25 ° C)! /
  • the above-mentioned “hardness” large (hard! /) / Small (soft), and 25 ° C G 'large (hard! / )) / Small (soft! /,) Has a good correlation.
  • G ′ at 25 ° C. is preferably 0.01-50 MPa S, more preferably 0.05-45 MPa.
  • G at 37 ° C is 0 ⁇ 0;! ⁇ 20MPa, more preferably 0.05 ⁇ ; 15MPa.
  • step 1 Apply amine (dimethylaniline) to the geometry and stage of the rheometer (Reologica, model “VAR-50”), and then adjust the geometry to the specified gap (0.3 mm).
  • the bioadhesive produced in step 1 was injected and cured until G ′, G ′′ and tan ⁇ were constant.
  • a bio-adhesive is applied to the entire circumference of a pseudo blood vessel (latex sleeve, manufactured by Imamura Co., Ltd., outer diameter 6 mm, wall thickness 20 m) with a stiffness parameter of about 10, and a coating film with a width of 5 mm and a thickness of about 100 m. And allowed to stand for 24 hours in an N, N′-dimethylaniline atmosphere and cured.
  • a pseudo blood vessel latex sleeve, manufactured by Imamura Co., Ltd., outer diameter 6 mm, wall thickness 20 m
  • the sample blood vessel prepared in (b) above was immersed in warm water at 37 ° C, one end was sealed, 37 ° C warm water was injected from the other end, and the sample was further pressurized to an internal pressure of 60 mmHg. .
  • the external diameter of the sample blood vessel at the time of pressurization was measured with a laser outer diameter measuring device (manufactured by Keyence Corporation, model “LS-5040T”). Thereafter, the internal pressure of the sample was gradually increased to 160 mmHg, and the outer diameter of the sample blood vessel at each internal pressure was measured.
  • the sample blood vessel prepared in (a) above is immersed in warm water at 37 ° C, one end is sealed, and the other end is repeatedly pressurized with air and returned to normal pressure at intervals of 0.2 seconds.
  • the pulsating pressure was applied to the inside of the sample blood vessel so that the internal pressure during pressurization was 160 mmHg. After continuing the pulsation test for one week in this way, the sample blood vessel was removed and the state of adhesion was observed under a magnifying glass.
  • the biological adhesives of Examples 1, 2, and 4 to 6 containing the compound, and the biological adhesives of Examples 3, 7, and 8 containing the 2-cyanoacrylate compound of the formula (2) It also has the specified physical properties, etc., and has sufficient flexibility and high strength, safety and sufficient decomposability.
  • the bioadhesives of Examples 2, 5, and 6 have superior safety with a very small amount of formaldehyde released, and are sufficiently degradable.
  • R, R and R
  • the bioadhesives of 8 have superior flexibility with extremely low hardness.
  • the biological adhesive of Example 9 obtained by mixing equal amounts of the biological adhesives of Comparative Example 9 and Example 7, and the biological adhesives of Examples 4 and 7
  • formaldehyde release It can be seen that the amount is appropriate and has both excellent safety with low hardness and sufficient decomposability and flexibility.
  • Examples 11 to 13 in which the mass ratios of the bioadhesives in Examples 4 and 8 were changed it can be seen that the hardness and the amount of formaldehyde released can be easily adjusted.
  • each of the bioadhesives of each example is soft enough to have low hardness and storage elastic modulus and small stiffness parameter, so it is sufficient for deformation due to pulsatile pressure in pulsation test. No abnormality was observed in the cured product after the test.
  • Comparative Example 12 where the hardness and storage elastic modulus were high and the rigidity parameter was larger, after the pulsation test, the cured product was broken, such as cracks, around the edge of the bonded part.
  • the bioadhesives of Examples 2, 4, and 7, in particular, the 2-cyanoacrylate compound using dipropylene glycol-based ether of Example 7 It can be seen that the bioadhesive has sufficient degradability.
  • the bioadhesive of Comparative Example 13 has a weight change of less than 1% even after 14 days and is inferior in degradability.

Abstract

La présente invention concerne un adhésif à base de 2-cyanoacrylate destiné à des organismes vivants, qui présente une certaine dureté, une souplesse adéquate et une sécurité élevée tout en offrant des propriétés de dégradation suffisantes. L'invention porte plus particulièrement sur un adhésif à base de 2-cyanoacrylate destiné à des organismes vivants dont le produit durci possède une dureté Shore A comprise entre 15 et 90. Cet adhésif à base de 2-cyanoacrylate destiné à des organismes vivants possède une émission de formaldéhyde ne dépassant pas 500 ppm dans un test d'hydrolyse et contient au moins un lien éther dans une molécule.
PCT/JP2007/070287 2006-11-07 2007-10-17 Adhésif à base de 2-cyanoacrylate destiné à des organismes vivants WO2008056516A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11013824B2 (en) 2017-03-30 2021-05-25 Chiba Institute Of Technology Adhesive for hard tissue bonding, adhesive kit for hard tissue bonding, and bone cement
CN113679876A (zh) * 2021-08-13 2021-11-23 上海恩盛医疗科技有限公司 一种医用软组织粘合剂及其制备方法
CN114269716A (zh) * 2019-08-08 2022-04-01 东亚合成株式会社 2-氰基丙烯酸酯化合物、及粘接剂组合物
WO2022080429A1 (fr) * 2020-10-14 2022-04-21 東亞合成株式会社 Composition durcissable
WO2022092090A1 (fr) * 2020-10-29 2022-05-05 日東電工株式会社 Résine pour feuille adhésive et feuille adhésive
CN115006584A (zh) * 2022-06-28 2022-09-06 杭州储泰生物科技有限公司 一种皮肤创面修复粘合剂
WO2023286709A1 (fr) * 2021-07-12 2023-01-19 東亞合成株式会社 Composition d'adhésif à base de 2-cyanoacrylate
WO2023286710A1 (fr) * 2021-07-12 2023-01-19 東亞合成株式会社 Composition d'adhésif à base de 2-cyanoacrylate

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KR101286624B1 (ko) * 2011-03-10 2013-07-15 (주)인튜이티브메디코프 생체 접착제 조성물을 내장한 스프레이 장치
KR20180057931A (ko) * 2016-11-23 2018-05-31 한서대학교 산학협력단 접착제의 제조방법
KR102164819B1 (ko) 2020-03-02 2020-10-13 주식회사 이노테라피 지혈용 기구 및 이의 제조방법

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JPH06145606A (ja) * 1992-11-11 1994-05-27 Toagosei Chem Ind Co Ltd シアノアクリレート系接着剤組成物
JPH07236687A (ja) * 1993-03-31 1995-09-12 Tri Point Medical Lp 生物学的適合性単量体組成物および重合体組成物
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11013824B2 (en) 2017-03-30 2021-05-25 Chiba Institute Of Technology Adhesive for hard tissue bonding, adhesive kit for hard tissue bonding, and bone cement
CN114269716A (zh) * 2019-08-08 2022-04-01 东亚合成株式会社 2-氰基丙烯酸酯化合物、及粘接剂组合物
WO2022080429A1 (fr) * 2020-10-14 2022-04-21 東亞合成株式会社 Composition durcissable
WO2022092090A1 (fr) * 2020-10-29 2022-05-05 日東電工株式会社 Résine pour feuille adhésive et feuille adhésive
WO2023286709A1 (fr) * 2021-07-12 2023-01-19 東亞合成株式会社 Composition d'adhésif à base de 2-cyanoacrylate
WO2023286710A1 (fr) * 2021-07-12 2023-01-19 東亞合成株式会社 Composition d'adhésif à base de 2-cyanoacrylate
CN113679876A (zh) * 2021-08-13 2021-11-23 上海恩盛医疗科技有限公司 一种医用软组织粘合剂及其制备方法
CN115006584A (zh) * 2022-06-28 2022-09-06 杭州储泰生物科技有限公司 一种皮肤创面修复粘合剂
CN115006584B (zh) * 2022-06-28 2023-11-17 浙江伽奈维医疗科技有限公司 一种皮肤创面修复粘合剂

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