WO2008056516A1

WO2008056516A1 - 2-cyanoacrylate-based adhesive for living organism

Info

Publication number: WO2008056516A1
Application number: PCT/JP2007/070287
Authority: WO
Inventors: Yoshihiko Abe; Kazuyoshi Tani; Muneaki Kano
Original assignee: Terumo Kabushiki Kaisha; Toagosei Co., Ltd.
Priority date: 2006-11-07
Filing date: 2007-10-17
Publication date: 2008-05-15
Also published as: JPWO2008056516A1; KR20090077759A

Abstract

Disclosed is a 2-cyanoacrylate-based adhesive for living organisms, which has a certain hardness, adequate flexibility and high safety, while exhibiting sufficient degradability. Specifically disclosed is a 2-cyanoacrylate-based adhesive for living organisms, whose cured product has a Shore A hardness of 15-90. This 2-cyanoacrylate-based adhesive for living organism has a formaldehyde emission of not more than 500 ppm in a hydrolysis test, and contains at least one ether bond in a molecule.

Description

Specification

2-cyanacrylate biomedical adhesive

Technical field

[0001] 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.

Background art

[0002] Various 2-cyanacrylate compounds are known, and it is also known that this 2-cyanacrylate compound is useful as an adhesive in medical applications! For example, 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. However, for internal use, there are problems such as hardened products and slow degradation. For example, when 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. However, decomposition is slow.

[0003] In order to impart flexibility to a cured product of a cyanoacrylate adhesive having a problem that the cured product is hard as described above, 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. Various methods such as Patent Document 6 and Patent Document 7 are known. It is also known that a biodegradable polymer is blended in order to impart flexibility to the cured product and accelerate decomposition (see, for example, Patent Document 8).

[0004] Furthermore, 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

Disclosure of the invention

Problems to be solved by the invention

[0006] However, in the method of adding a plasticizer or the like as described above, the initial stage of adhesion can be imparted to the cured product, but the plasticizer gradually bleeds and becomes harder after implantation in the body. There is a problem that there is. In addition, in order to reduce the flame retardant properties, it is necessary to be an adhesive that can further reduce the amount of formaldehyde released and obtain a cured product having more sufficient degradability!

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.

Means for solving the problem

The present invention is as follows.

1. It contains a 2-cyanacrylate compound having at least one ether bond in one molecule, the Shore A hardness of the cured product is 15 to 90, and the amount of formaldehyde released in the hydrolysis test is 500 ppm or less An adhesive for 2-cyanacrylate-based organisms.

2. The 2-cyanacrylate biomedical adhesive according to 1. above, wherein the stiffness parameter of the cured product is 10 to 65 when the coating thickness force is OO to 150 m.

3. The 2-cyanacrylate-based biomedical adhesive according to the above 1 or 2, containing at least one of a compound represented by the following formula (1) and a compound represented by the following formula (2): Agent.

[Chemical 1]

CN

H ₂ C = C

C-one O-Rr〇ichi R-piece (1)

II '

o

[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

When 2 1 is 3 or 4, R is a linear or side chain alkyl group having 4 to 8 carbon atoms.

2

]

[Chemical 2]

CN

H ₂ C = C

C-0-R ₃ -0-R ₄ -0-R ₅ (2)

O

[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,

Five

When 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.

3 4 5

Is an alkyl group of ˜8. ]

4. The 2-cylinder according to 3 above, wherein R, R and R have 2 or 3 carbon atoms.

1 3 4

Anoacrylate biomedical adhesive.

5. containing a compound represented by the above formula (1), wherein R has 2 carbon atoms, and R

12. The 2-cyanacrylate bioadhesive according to the above 3 or 4, wherein the carbon number of 2 is 6-8.

6. containing a compound represented by the above formula (1), wherein R has 3 carbon atoms, and R

12. The 2-cyanacrylate biomaterial adhesive according to 3. or 4 above, wherein the carbon number of 2 is 4-8.

7. Contains a compound represented by the above formula (2), wherein R and R have 3 carbon atoms

3 4

The R according to any one of 3. to 6. above, wherein the carbon number of R is 3-5.

Five

2-Cyanoacrylate biomedical adhesive.

8. The 2-cyanacrylate biomedical adhesive according to the above 1 or 2, comprising a compound represented by the following formula (1) and a compound represented by the following formula (2).

[Chemical 3

CN

H ₂ C = C

C-one O— RrO— R (1)

II

o

[In the above formula (1), R represents an ethylene group or a propylene group, and R represents a straight chain or a side chain.

1 2

It is an alkyl group having 3 to 8 carbon atoms. ]

[Chemical 4

CN

H ₂ C = C

C-0-R ₃ -0-R ₄ -0-R ₅ (2)

O

[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. ]

9. The above R, wherein R is a propylene group, and R and R have 3 to 5 carbon atoms.

1 2 5

A 2-cyanacrylate bioadhesive as described in.

10. The method according to any one of 1 to 9 above, which has been subjected to at least one sterilization treatment among an electron beam sterilization method, a gamma ray sterilization method, a filtration sterilization method, and a dry heat sterilization method. —Cyanoacrylate biological adhesive.

11. The 2-cyanacrylate biomedical adhesive according to any one of 1 to 10 above, which is used for bonding between living tissues or between a living tissue and an artificial prosthesis, or for assisting in bonding.

12. The 2-cyanacrylate biomedical adhesive according to the above 11, wherein the living tissue is at least one of skin, myocardium, luminal organ and parenchymal organ.

13. The 2-cyanacrylate biomedical adhesive according to the above 11 or 12, wherein the artificial prosthesis is at least one of an artificial blood vessel, a hemostatic material, a bone pin and a suture.

14. The 2-cyanacrylate biomedical adhesive according to any one of the above 1 to 13, which is used by being filled in an aneurysm.

15. The 2-cyanacrylate biomedical adhesive according to 14. above, wherein the blood vessel in which the aneurysm has occurred is a cerebral blood vessel.

16. The 2-cyanacrylate biomedical adhesive according to any one of the above 1 to 13, used for embolization of blood vessels.

17. The 2-cyanacrylate bioadhesive according to 16. above, wherein the blood vessel is a hepatic blood vessel.

18. The 2-cyanacrylate biomedical adhesive according to any one of 1 to 13 above, which is used as a bone filling material.

The invention's effect

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. In addition, when the coating thickness is 100 to 150 m, and 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.

Further, when it contains at least one of the compound represented by the formula (1) and the compound represented by the formula (2), it is easily decomposed with sufficient flexibility and high safety. Thus, a bioadhesive that is absorbed by a living body and forms a cured product having a predetermined stiffness parameter can be obtained.

In addition, when R, R, and R have 2 or 3 carbon atoms, the cured product is more easily flexible.

1 3 4

Therefore, it is possible to provide a bioadhesive that is highly safe and is sufficiently decomposed and absorbed.

Furthermore, it contains a compound represented by the formula (1), R has 2 carbon atoms, and R has carbon atoms

1 2

If it is 6 to 8 and contains the compound represented by the formula (1), the carbon number of R is 3, and the carbon number of R is ˜8, the amount of formaldehyde released is less than safety

2

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.

Further, it contains a compound represented by the formula (2), R and R have 3 carbon atoms,

3 4 5 When the prime number is 3 to 5, it is possible to provide a biomedical adhesive in which a softer cured product having a lower Shore A hardness is formed.

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.

In addition, if at least one of the sterilization methods of electron beam sterilization method, γ-ray sterilization method, filtration sterilization method, and dry heat sterilization method is applied, it will be more safe! be able to. Furthermore, when used for joining of living tissues or between living tissues and an artificial prosthesis, or for joining assistance, these can be joined by a cured product having sufficient flexibility, and safety is also high.

Further, the living tissue is at least one of skin, myocardium, luminal organ and parenchymal organ. If 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.

In addition, 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.

Furthermore, when used for embolization of 2-cyanacrylate-based bioadhesive strength S, blood vessels, especially hepatic blood vessels, it functions well as a blood vessel embolizing agent and is highly safe.

In addition, when used as a 2-cyanacrylate bioadhesive strength S and a bone filler, it functions well for this application!

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

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.

[0010] 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

Yes

The Shore A hardness, Shore D hardness, and formaldehyde emission can be measured by the methods described in detail in the following examples.

[0011] 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.

[0012] As described above, there are no particular limitations on 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)”. And a compound represented by the above formula (2) [hereinafter referred to as “compound of the above formula (2)”. ], A 2-cyanacrylate biomedical adhesive containing at least one of the above. 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.

In the above formula (1), 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

2 In the case of 1 or 4, R is preferably a linear or side chain alkyl group having 4 to 8 carbon atoms.

2

Good. If 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. In addition, R and R in the above formula (2)

3 4 is an alkylene group having 2 to 4 carbon atoms. When 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

3 4

R is preferably a C 3-8 alkyl group having a straight chain or a side chain. R

5 3

If R, R is within the above range, the amount of formaldehyde released with low hardness is appropriate.

4 5

In addition, a cured product having a predetermined rigidity parameter is formed, and a bioadhesive having both flexibility, safety, and sufficient degradability can be obtained.

Further, R in the formula (1) and R and R 1 in the formula (2) are both 2 or 3

1 3 4

It is more preferable that When 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.

[0014] 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

When the number of carbon atoms is 2, the amount of formaldehyde released is appropriate, and a bioadhesive having excellent safety and sufficient degradability can be obtained. In this case, the amount of formaldehyde released is 500 ppm or less, 300 to 300 ppm, and 150 ppm or less (usually 40 ppm or more).

[0015] 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. Thus, R and R are specific carbon

2 1 2

When it is a number, the amount of formaldehyde released is appropriate, and a bioadhesive having excellent safety and sufficient degradability can be obtained. In this case, 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).

[0016] Furthermore, the bioadhesive of the present invention contains the compound of the formula (2), and R and R carbon numbers.

It is more preferable that the carbon number of R is 3-5. In this way, R, R, and R are special

5 3 4 5 When the carbon number is constant, 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. Furthermore, the stiffness parameter should be 15 or less.

[0017] With this bioadhesive, it is possible to include the compound of the formula (1) and the compound of the formula (2) together. As described above, when the compound of the formula (1) and the compound of the formula (2) are included, the hardness of the cured product and the amount of formaldehyde released are determined by changing the mass ratio of each. Can be adjusted to the range. Furthermore, the stiffness parameter can be easily reduced. In the bioadhesive containing the compound of the formula (1) and the compound of the formula (2), each of the compound of the formula (1) and the compound of the formula (2) is There is no particular limitation, and any combination is possible! /.

[0018] When the compound of the formula (1) and the compound of the formula (2) are contained, R

1, R and R 3 4 preferably have the same number of carbon atoms. In addition, each carbon number of R and R

twenty five

Are more preferably the same. Thus, if the number of carbon atoms of the alkylene group of each of the compound of the formula (1) and the compound of the formula (2), and the number of carbon atoms of the alkylene group and the alkyl group are the same, Therefore, it is possible to obtain a more homogeneous bioadhesive that can be easily mixed, and it is also easy to adjust the hardness of the cured product and the amount of formaldehyde released, and the rigidity parameters can be adjusted.

[0019] Further, when the compound of the formula (1) and the compound of the formula (2) are contained, R is an ethylene group or propylene group, R and R are propylene groups, and each of R and R

3 4 2 5

More preferably, it has 3 to 8 carbon atoms. In this case, it is particularly preferable that R is a propylene group and R and R have 3 to 5 carbon atoms. Thus, the equation (1)

twenty five

When the compound and the compound of the formula (2) have a specific number of carbon atoms, 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. In this case, 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;

[0020] When 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.

[0021] 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! / When the biomedical adhesive contains other components except the compound of the formula (1) and the compound of the formula (2), 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. When these other components are contained, 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.

[0022] 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;! -200 mass ppm, especially 10-100 mass ppm. Further, in the case of “Radiocanole Polymerization Inhibition I”, it can be used by blending ί, 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.

[0023] Examples of the thickener 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.

[0024] 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.

[0025] 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 γ-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. For example, when 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. If 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.

[0026] 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.

[0027] 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. Examples of 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.

[0028] 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. Depending on the method of embolization, it can be used as a vascular embolization agent. This blood vessel is not particularly limited, but hepatic blood vessels are typical. Furthermore, 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.

[0029] The method for producing the 2-cyanacrylate biomedical adhesive of the present invention is not particularly limited.

For example, in the case of a bioadhesive containing the above-mentioned specific 2-cyanoacrylate compound, first, 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. To condense. As the catalyst, an amine or a base group can be used. Examples of the amine include piperidine, jetylamine, dibutylamine, morpholine, etc., and 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.

[0030] Thereafter, 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. Add 5 to 3% by mass and depolymerize by heating to 140 to 250 ° C. 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.

Example

[0031] Hereinafter, the present invention will be specifically described by way of examples.

[1] Manufacture of bioadhesives containing stabilizers in cyanoacrylate

(1) Examples;! ~ 8

Example 1

Sanoacetic acid (manufactured by Tateyama Kasei Co., Ltd.) 3 mol of ethylene glycol monohexyl ether (hexyl glycol, HeG by Nippon Emulsifier Co., Ltd.) 3.15 monole, toluene 2.4 monole, and 0.12 mol of sulfuric acid were added The mixture was refluxed and reacted for 12 hours with azeotropic dehydration to esterify. Thereafter, unreacted cyanoacetic acid and sulfuric acid were neutralized with sodium hydroxide, the organic layer was dehydrated with magnesium sulfate, then desolvated and distilled to give 2-hexoxychetyl with a boiling point of 114 ° C / 0.18 mmHg. —Siano acetate was obtained. The yield was 80%.

[0032] Subsequently, paraformaldehyde 0 · 84 monole, tonolein 200 mL, and piperidine 0.3 mL were added to 0.8 mol of 2-hexoxychetyl 2-cyanoacetate obtained as described above, and refluxed. The mixture was allowed to react for 12 hours with azeotropic dehydration for condensation. Next, the condensed solution was washed with a 1% by mass paratoluenesulfonic acid aqueous solution and saturated brine, the organic layer was dehydrated with magnesium sulfate, and then the solvent was distilled off. Next, 1% by mass of diphosphorus pentoxide and hydroquinone were added, pressure 0.;! ~ 3. OmmHg, temperature 150 ~; depolymerized at 190 ° C, distilled, boiling point 115 ° C / 0.53mmHg Of 2-hexoxychetinoyl 2-cyanoacrylate (abbreviated as “EGH” in Table 1). The yield was 17%. Thereafter, 20 mass ppm of sulfur dioxide and 1000 mass ppm of noduloquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.

[0033] Example 2

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%. Thereafter, condensation and depolymerization were conducted in the same manner as in Example 1, and 2- (2-ethylhexoxy) ethyl-2-cyanoacrylate having a boiling point of 114 ° C / 0.19 mmHg (“EGEH” in Tables 1 and 5). For short). The yield was 28%. 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.

[0034] Example 3

Except for using ethylene glycol-monomonohexenore etherol instead of diethylene glycol-monomonobutinole ether (Nippon Emulsifier Co., Ltd., Ptyl Diglycol, BDG), the esterification reaction was carried out in the same manner as in Example 1, A 2- (2-butoxyethoxy) ethyl 2-cyanoacetate having a boiling point of 136 ° C / 1.88 mmHg was obtained. The yield was 80%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1, and 2- (2-butoxyethoxy) ethyl-2-cyanoacrylate having a boiling point of 133 ° C / 0.38 mmHg (referred to as “DEGB” in Table 1). Abbreviated.) The yield was 20%. Next, 20 mass ppm of sulfur dioxide and 1000 ppm of idroquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.

[0035] Example 4

Except for using propylene glycol monobutyl ether (butyl emulsifier butyl propylene glycol, BFG) instead of ethylene glycol monohexyl ether, an esterification reaction was conducted in the same manner as in Example 1 to obtain a boiling point of 103 ° C. / 0. 38 mmHg of 2-butoxyisopropyl-2-cyanoacetate was obtained. The yield was 76%. Thereafter, condensation and depolymerization are carried out in the same manner as in Example 1 and abbreviated as 2-butoxyisopropyl-2-cyanoacrylate (08 in Tables 1 and 5) having a boiling point of 95 ° C / 0.053 mmHg. ) The yield was 38%. Subsequently, 20 mass ppm of sulfur dioxide and 1000 mass ppm of nodroquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.

[0036] Example 5

Other than using ethylene glycol monohexyl ether, propylene glycol monohexyl ether (Hexyl Propylene Glycol, HeFG) Was subjected to an esterification reaction and the like in the same manner as in Example 1 to obtain 2-hexoxyisopropyl-2-cyanoacetate having a boiling point of 125 ° C./0.90 mmHg. The yield was 78%. Thereafter, condensation and depolymerization are carried out in the same manner as in Example 1, and 2-hexoxyisopropyl-2-cyanoacrylate having a boiling point of 114 ° C./0.22 mmHg (abbreviated as “PGH” in Table 1). ) Was obtained. The yield was 19%. Subsequently, 20 mass ppm of sulfur dioxide and 1000 mass ppm of neuroquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.

[0037] Example 6

Esterification reaction in the same manner as in Example 1 except that propylene glycol mono 2-ethylhexyl ether (2-Ethylhexyl propylene glycol, E HFG manufactured by Nippon Emulsifier Co., Ltd.) was used instead of ethylene glycol monohexyl ether. Thus, 2- (2-ethylhexoxy) isopropyl-2-sianoacetate having a boiling point of 124 ° C./0.53 mmHg was obtained. The yield was 76%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1, and 2- (2-ethylhexoxy) isopropyl-2-cyanate acrylate having a boiling point of 120 ° C / 0.22 mmHg (in Table 1, “PGEH”) Abbreviated.) The yield was 13%. 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.

[0038] Example 7

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. As a result, 2- (2-propoxyisopropoxy) isopropyl-2-cyanoacetate having a boiling point of 143 ° C / 3.OOmmHg was obtained. The yield was 72%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1, and 2- (2-propoxyisopropoxy) isopropynoleate 2-cyananoate (both in Table 1 and Table 5) having a boiling point of 125 ° C / 0.22 mmHg. Abbreviated as “DPGP”). The yield was 24%. 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.

[0039] Example 8

Dipropylene glycolenomonobutylate instead of ethylene glycolenohexenoreethenore Except for using ruether (Butyl Propylene Diglycol, BFDG, manufactured by Nippon Emulsifier Co., Ltd.), the esterification reaction was carried out in the same manner as in Example 1, and the boiling point was 132 ° C / 2.25 mmHg. ) Isopropyl-2 cyanoacetate was obtained. The yield was 75%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1 to obtain 2- (2-butoxyisopropoxy) isopropyl-2-cyanoacrylate having a boiling point of 124 ° C / 0.22 mmHg (in Table 1, ¾ 08). Abbreviated.) The yield was 20%. 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.

[0040] Examples 9-; 13

2-propoxyisopropyl-2-cyanoacrylate (PGP) obtained in Comparative Example 9 described later and 2- (2propoxyisopropoxy) isopropyl 2-cyanoacrylate (DPGP) obtained in Example 7, A bioadhesive composed of a mixture mixed at the mass ratio shown in Table 1 was subjected to a performance evaluation test (Example 9). Further, a bioadhesive comprising a mixture obtained by mixing 2-butoxyisopropyl 2-cianoacrylate (PGB) obtained in Example 4 and DPGP obtained in Example 7 at a mass ratio shown in Table 1. Was subjected to a performance evaluation test (Example 10). Further, the PGB obtained in Example 4 and 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).

[0041] As described above, the number of carbon atoms of the alkylene group and the alkyl group of each of the two cyanoacrylate compounds in Examples 1 to 8, and the compounds of Formula (1) in Examples 9 to 13 and Formula (2) above. Table 1 shows the types and mass ratios of the respective 2-cyanacrylate compounds when the compounds are contained together.

[0042] [Table 1] table 1

[0043] (2) Comparative Example;! ~ 13

Comparative Example 1

2 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.

[0044] Comparative Example 2

Except for using ethylene glycol monoisopropyl ether (Nippon Emulsifier Co., Ltd., isopropyldaricol, iPG) instead of ethylene glycol monohexyl ether, an esterification reaction was conducted in the same manner as in Example 1 to obtain a boiling point of 109 ° C. / 2. 25 mmHg of 2 isopropoxy shecillate 2 cyanoacetate was obtained. The yield was 92%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1 to obtain 2 isoprene having a boiling point of 92 ° C / 0.075 mmHg. 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.

[0045] Comparative Example 3

Esterification reaction, etc. in the same manner as in Example 1 except that instead of ethyleneglycolenohexenoreethenore, ethyleneglycololemonobutinoleet tel (Nippon Emulsifier Co., Ltd. butyldalicol, BG) was used. To give 2-butoxetyl-2-cyanoacetate having a boiling point of 106 ° C / 2.25 mmHg. The yield was 89%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1 to obtain 2-butoxetyl-2-cyanoacrylate (abbreviated as “EGB” in Table 2) having a boiling point of 95 ° C./0.075 mmHg. The yield was 32%. 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.

[0046] Comparative Example 4

Except for using ethylene glycol-monohexenoreethenore instead of diethylene glycol-monomonomethylol ether (Methyl Diglycol, MDG manufactured by Nippon Emulsifier Co., Ltd.), the esterification reaction, etc. was carried out in the same manner as in Example 1. A 2- (2 methoxy) ethoxyxyl-2-cyanoacetate having a boiling point of 146 ° C / 2.78 mmHg was obtained. The yield was 83%. Thereafter, condensation and depolymerization are carried out in the same manner as in Example 1, and 2- (2-methoxy) ethoxyethyl-2-cyanacrylate having a boiling point of 93 ° C./0.075 mmHg (abbreviated as “DEGM” in Table 2). ) Was obtained. The yield was 46%. Subsequently, 20 mass ppm of sulfur dioxide and 1000 mass ppm of neuroquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.

[0047] Comparative Example 5

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.

[0048] Comparative Example 6

An esterification reaction, etc. was carried out in the same manner as in Example 1 except that diethylene glycolenomonomonoisopropylene ether (isopropyl diglycol, iPDG manufactured by Nippon Emulsifier Co., Ltd.) was used instead of ethyleneglycolenohexenoyletherenore. Thus, 2- (2-isopropoxyethoxy) ethyl-2-cyanoacetate having a boiling point of 140 ° C./2.03 mmHg was obtained. The yield was 72%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1, and 2- (2-isopropoxyethoxy) ethyl-2-cyanoacrylate having a boiling point of 113 ° C / 0.45 mmHg (in Table 2, “DEGiP” Abbreviated.) The yield was 23%. Subsequently, 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.

[0049] Comparative Example 7

Except for using ethylene glycol monohexyl ether in place of propylene glycol monomethyl ether (Methyl Propylene Glycol, MFG manufactured by Nippon Emulsifier Co., Ltd.), the esterification reaction was carried out in the same manner as in Example 1 to obtain a boiling point of 90 ° C / 2. 33 mmHg of 2-methoxyisopropyl-2-sianoacetate was obtained. The yield was 85%. Thereafter, condensation and depolymerization are carried out in the same manner as in Example 1 to obtain 2-methoxyisopropyl-2-cyanoacrylate (abbreviated as “PGM” in Table 2) having a boiling point of 73 ° C./0.68 mmHg. It was. The yield was 31%. Subsequently, 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.

[0050] Comparative Example 8

Except for using propylene glycol monoethyl ether (manufactured by Wako Pure Chemical Industries, Ltd.) instead of ethylene glycol monohexyl ether, an esterification reaction or the like was performed in the same manner as in Example 1 to obtain a boiling point of 94 ° C / 2. lOmmHg of 2-ethoxyisopropyl 1-cyanoacetate was obtained. The yield was 89%. Thereafter, condensation and depolymerization are carried out in the same manner as in Example 1 to obtain 2-ethoxyisopropyl-2-cyanoacrylate (abbreviated as “PGE” in Table 2) having a boiling point of 74 ° C./0.064 mmHg. It was. The yield was 27%. Then with the stabilizer Then, 20 mass ppm of sulfur dioxide and 1000 mass ppm of hydroquinone were added, and this bioadhesive was subjected to a performance evaluation test.

[0051] Comparative Example 9

Except for using propylene glycolenomonopropyl ether (propylene glycol, PFG manufactured by Nippon Emulsifier Co., Ltd.) instead of ethylene glycolenohexenoreethenole, the esterification reaction was carried out in the same manner as in Example 1 to obtain a boiling point. 107 ° C / 2. 33-mmHg 2-poxy isopropyl-2-cyanoacetate was obtained. The yield was 85%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1, and 2-propoxyisopropyl 2-cyanoacrylate having a boiling point of 87 ° C./0.038 mmHg (abbreviated as “PGP” in Tables 1 and 2). Got. The yield was 11%. Next, 20 mass ppm of sulfur dioxide and 1000 ppm of idroquinone were added as stabilizers, and this bioadhesive was subjected to a performance evaluation test.

Yes

[0052] Comparative Example 10

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%. Thereafter, condensation and depolymerization were carried out in the same manner as in Example 1, and 2- (2 methoxypropoxy) isopropyl-2-cyanacrylate having a boiling point of 84 ° C./0.038 mmHg (abbreviated as “DPGM” in Table 2). .) The yield was 44%. 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.

[0053] Comparative Example 11

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.

[0054] Comparative Example 12

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)

[0055] Comparative Example 13

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%. Thereafter, 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%. Subsequently, 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.

[0056] The carbon number of the alkylene group and the alkyl group of each 2-cyanacrylate compound in Comparative Examples 1 to 13 is shown in Table 2.

[0057] [Table 2]

Table 2

[2] Performance evaluation

The performance was evaluated using the biomedical adhesive produced in [1] above.

(1) Hardness

(a) Sample preparation

About 3 g of the biomedical adhesive produced in [1] above was poured into a petri dish made of tetrafluoroethylene having an inner diameter of 30 mm and allowed to stand for 1 hour in an N, N'-dimethylaniline atmosphere to be cured. This casting and curing of cyanoacrylate was repeated until the thickness of the cured product reached 7 mm. When the thickness of the cured product reached 7 mm, the force and further under the N, N'-dimethylaniline atmosphere. Then, the disc-shaped cured product was taken out from the petri dish and used for hardness measurement.

(b) Measurement method

In accordance with JIS K 6251, Shore A hardness and Shore D hardness were measured using an A-type hardness meter and a D-type hardness meter (manufactured by Kobunshi Keiki Co., Ltd.). [0059] (2) Formaldehyde emission

(a) Sample preparation

Pour about 1 lg of the biomedical adhesive produced in [1] above into a tetrafluoroethylene petri dish with an inner diameter of 30 mm, and let stand for 24 hours in an N, N'-dimethylaniline atmosphere to harden. A disk-shaped cured product having a diameter of about 30 mm and a thickness of about 1 mm was obtained.

(b) Hydrolysis

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.

(c) Preparation of specimens

After 7 days, remove from the thermostat, leave at room temperature (20-30 ° C) for about 1 hour, cool to near room temperature, open and remove 2 mL of physiological saline. A specimen (colored solution) was prepared according to the instruction manual of Wako Pure Chemical Industries, Ltd. A formaldehyde standard solution and a blind test (blank solution) were also prepared in the same manner. The formaldehyde content of the formaldehyde diluted stock solution used for preparing the formaldehyde standard solution was quantified according to the above instruction manual. In the blind preparation, physiological saline was used instead of distilled water.

(d) Measurement method

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.

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.

[0060] (3) Flammability

(a) Sample preparation

For biomedical products manufactured in [1] above on a tetrafluoroethylene petri dish with an inner diameter of 10 mm About 0.4 g of the adhesive was poured, and allowed to stand for 24 hours in an N, N′-dimethylaniline atmosphere to be cured to obtain a disk-shaped cured product having a diameter of about 10 mm and a thickness of about 1 mm.

(b) Measurement method

Take out the cured product from the petri dish, and implant the cured product and high-density polyethylene (made by Food and Drug Safety Center), which is a negative target, under the skin of Usagi. After 14 days, the site of implantation is removed and immediately removed. Fixation was performed with a 10% strength by weight buffered formalin aqueous solution. Next, paraffin sections having a thickness of 3 m were prepared according to a conventional method, stained with hematoxylin and eosin, and microscopically examined using an optical microscope. As a result of histopathological observation by this microscopic examination, if the inflammation reaction is significantly stronger than that of a negative subject, the inflammation is considered positive, and no obvious tissue necrosis or degeneration occurs. The flammability was negative.

(4) Storage modulus

(a) Meaning of storage modulus

Apart from the above-mentioned “hardness”, storage elastic modulus (G ′) can be mentioned as an index of the hardness of the cured product. By measuring the shear viscoelasticity of the cured product, a temperature dispersion curve of G ′ can be obtained, and the temperature dependence of G ′ can be confirmed. When comparing G 'at a given temperature, 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. In addition, when assuming the state of the cured product in the body, the G 'value at 37 ° C should be compared in large / small. For flexibility at 25 ° C., G ′ at 25 ° C. is preferably 0.01-50 MPa S, more preferably 0.05-45 MPa. In terms of flexibility at 37 ° C, it is preferable that G at 37 ° C is 0 · 0;! ~ 20MPa, more preferably 0.05 ~; 15MPa.

(b) Sample preparation

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 δ were constant.

(c) Measurement method Using the above rheometer and 6mmφ parallel plate, shear viscoelasticity was measured while increasing the temperature at a rate of 2 ° C / min at a frequency of 1Ηζ and a strain of 0.1%, and the storage elasticity at 25 ° C and 37 ° C. The rate G 'was determined.

[0062] (5) Rigidity parameter

(a) Meaning of stiffness parameter

When biomedical adhesives are used in living tissues, especially blood vessels, if the cured product can follow changes in the outer dimensions of the tissues, especially changes in the outer diameter of the blood vessels due to the pulsation of the heart, the adhesive properties of this bioadhesive can be reduced. High reliability! /. An index for evaluating this reliability is the stiffness parameter (Matsuda Γ, et al: A novel elastomeric surgical adhesive: design, properties an a in vivo performances. Trans Am Soc Artif Intern Organs 33: 151-156, 1986. reference)

Yes

(b) Sample preparation

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.

(c) Measurement method

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. Then, the reference internal pressure was lOOmmHg, the value derived from the following equation (1) was taken on the vertical axis of the graph, the value derived from the following equation (2) was taken on the horizontal axis of the graph, and measurements were made in the range of 60 mmHg to 160 mmHg. The results of each measurement point were plotted on a graph, and the slope when approximated by a straight line was taken as the stiffness parameter (/ 3 value). Formula (1) LnP / Ps [P: Internal pressure at each measurement point? 3: Reference internal pressure (100111111 ^ ¾)] Equation (2) R / Rs-1 (R: Outer diameter at each measurement point, Rs: Outer diameter at internal pressure lOOmmHg)

[0063] (6) Beat test

(a) Sample preparation Samples were prepared in the same manner as in the above (5) and (b).

(b) Measurement method

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.

[0064] (7) Change weight

(a) Sample preparation

Pour approximately 0.2 g of bioadhesive into a tetrafluoroethylene petri dish with an inner diameter of 10 mm, and let stand for 24 hours in an N, N'-dimethylaniline atmosphere to cure. Diameter about 10 mm, thickness A disk-shaped cured product having a thickness of about 0.5 mm was obtained.

(b) Hydrolysis

Place the sample prepared as above in the extraction thimble, then place it in a sterile glass vial and pour 21 ml of Dulbecco's phosphate buffered saline containing antibiotics and antiepileptics, then Sterile glass vials were placed in a water bath adjusted to 39 ° C. Phosphate buffered saline was changed after 7 days.

(c) Measurement method

After 7 days and 14 days have passed since the sterilized glass vial was placed in the water bath, remove the sample from the sterilized glass vial, wash it with sterilized water three times, and then vacuum dry for 24 hours to reduce the weight of the sample. Weighing and calculating the change weight (weight reduction) according to the following formula was used as an index for evaluation of degradability.

Change weight (%) = [(Sample weight before hydrolysis Sample weight after hydrolysis) / Sample weight before hydrolysis] X I 00

Of the above evaluation results (excluding change weight), the results of Examples are shown in Table 3, and the results of Comparative Examples are shown in Table 4, respectively. In addition, the evaluation results of the weight change are shown in Table 5.

In Tables 3 and 4, “Storage modulus” is abbreviated as “”, stiffness parameter is “β value”, and “formaldehyde release amount” is abbreviated as “FA release amount”.

Table 3

“One” in the column of Shore hardness D means less than the measurement limit value.

0066

Table 4

Table 5

[0069] According to the results in Table 3, R 2, R 2, 2-cyano-acryl of formula (1) having a specific carbon number

1 2

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. In particular, the bioadhesives of Examples 2, 5, and 6 have superior safety with a very small amount of formaldehyde released, and are sufficiently degradable. In addition, R, R and R

Example 7 in which 3 4 contains a 2-cyanacrylate compound of formula (2) having a specific carbon number

Five

The bioadhesives of 8 have superior flexibility with extremely low hardness.

[0070] Also, 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 In the bioadhesive of Example 10 formed by mixing equal amounts of the same, and the bioadhesive of Example 12 prepared by mixing equal amounts of the bioadhesives of Examples 4 and 8, respectively, formaldehyde release It can be seen that the amount is appropriate and has both excellent safety with low hardness and sufficient decomposability and flexibility. In addition, according to 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.

Yes

Furthermore, 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.

[0071] On the other hand, according to the results in Table 4, the biomedical adhesives containing no 2-cyanacrylate compound having the chemical structure of the formula (1) in Comparative Examples;! -3, 7-9 and 11 However, although safety and degradability are high, flexibility is inferior. Particularly in Comparative Examples;! To 3, 7 to 9 and 11, after the pulsation test, fractures such as cracks were also observed in the cured product centering on the edge of the bonded portion. In addition, the bioadhesives of Comparative Examples 4 to 6 and 10 that do not contain the 2-cyanacrylate compound having the chemical structure of the formula (2) have sufficient flexibility, but the formaldehyde emission amount is extremely high. It is very inferior in safety. Further, it can be seen that the biomedical adhesives containing the 2-cyanacrylate compounds of Comparative Examples 12 and 13 that have been used conventionally have high safety but are inferior in flexibility. In particular, in 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.

[0072] Further, according to the results in Table 5, 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. On the other hand, the bioadhesive of Comparative Example 13 has a weight change of less than 1% even after 14 days and is inferior in degradability.

Claims

The scope of the claims

[1] It contains a 2-cyanacrylate compound having at least one ether bond in one molecule, 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. A 2-cyanacrylate biomedical adhesive characterized by

[2] The 2-cyanacrylate biomedical adhesive according to claim 1, wherein when the coating thickness is 100 to 150 m, the stiffness parameter of the cured product is 10 to 65.

[3] The 2-cyanacrylate-based biological material according to claim 1 or 2, comprising at least one of a compound represented by the following formula (1) and a compound represented by the following formula (2): adhesive.

[Chemical 1

CN

H ₂ C = C

C-one O— RrO— R (1)

II

o

In the case of 2 1 or 3, R is a linear or side chain alkyl group having 4 to 8 carbon atoms.

2

]

[Chemical 2]

CN

H ₂ C = C

C-O-R3-O- R4-O-R5 (2)

O

[R and R in the above formula (2) are alkylene groups having 2 to 4 carbon atoms;

When 3 4 3 4 has 2 carbon atoms, R is a linear or side chain alkyl group having 4 to 8 carbon atoms,

Five

3 4 5

Is an alkyl group of ˜8. ]

[4] The 2-cyano group according to claim 3, wherein R, R, and R have 2 or 3 carbon atoms. Atallate-based biomedical adhesive.

[5] containing a compound represented by the above formula (1), wherein R has 2 carbon atoms,

1. The 2-cyanacrylate biomedical adhesive according to claim 3, wherein the carbon number is 6 8.

[6] containing a compound represented by the above formula (1), wherein R has 3 carbon atoms,

1 2 The 2-cyanacrylate biomedical adhesive according to claim 3 or 4, wherein the number of carbon atoms is 48.

[7] containing a compound represented by the above formula (2), wherein R and R have 3 carbon atoms

3 4

The force according to any one of claims 3 to 6, wherein the carbon number of R is 35.

Five

Cyanacrylate bioadhesive.

[8] The 2-cyanacrylate biomedical adhesive according to claim 1 or 2, comprising a compound represented by the following formula (1) and a compound represented by the following formula (2).

[Chemical 3

CN

H ₂ C = C

C One O— R _r O— R (1)

II

o

1 2

It is an alkyl group having 38 carbon atoms. ]

[Chemical 4

CN

H ₂ C = C

C-0-R ₃ -0-R ^ -0-R _s (2)

II

o

[R and R in the above formula (2) are propylene groups, R has a straight chain or a side chain

3 4 5

It is an alkyl group having 38 carbon atoms. ]

[9] The R is a propylene group, and the carbon number of the R and the R is 35.

1 2 5

A 2-cyanacrylate biomedical adhesive described in 1.

[10] Deletion of at least one of electron beam sterilization method, gamma ray sterilization method, filtration sterilization method, and dry heat sterilization method 10. The 2-cyanoacrylate biomedical adhesive according to any one of claims 1 to 9, which has been subjected to a fungus treatment.

[11] The force of any one of claims 1 to 10, which is used for joining biological tissues to each other or between a biological tissue and an artificial prosthesis, or for joining assistance; Agent.

12. The 2-cyanacrylate biomedical adhesive according to claim 11, wherein the biological tissue is at least one of skin, myocardium, luminal organ and parenchymal organ.

13. The 2-cyanacrylate biomedical adhesive according to claim 11 or 12, wherein the artificial prosthesis is at least one of an artificial blood vessel, a hemostatic material, a bone pin, and a suture.

[14] The 2-cyanacrylate biomedical adhesive according to any one of [1] to [13] used by being filled in an aneurysm.

15. The 2-cyanacrylate biomedical adhesive according to claim 14, wherein the blood vessel in which the aneurysm has occurred is a cerebral blood vessel.

[16] The 2-cyanate acrylate biomedical adhesive according to any one of claims 1 to 13, which is used for embolization of blood vessels.

17. The 2-cyanacrylate biomedical adhesive according to claim 16, wherein the blood vessel is a hepatic blood vessel.

[18] The 2-cyanacrylate biomedical adhesive according to any one of claims 1 to 13, which is used as a bone filling material.