Polymer composition, and medical material and adhesive each containing same

Abstract

The present invention addresses the problem of providing a material such as an adhesive which exhibits high adhesiveness to a material in a wet state, has a low viscosity in a high shear environment such as a liquid fed in a long thin tube, is extremely low in fluidity and is not likely to move in a low shear environment after coating or in a non-shear environment, and is suitable for medical use or the like.　The problem can be solved by a polymer composition which contains: a copolymer (P) that contains, as constituent components, a monomer (A) represented by chemical formula (1-A) and a monomer (B) that has a polymerizable unsaturated bond and is different from the monomer (A); a filler (F); and water and / or an alcohol solvent (S). (In the formula, R represents a hydrogen atom or a methyl group, L represents an amide bond, an ester bond, or a direct bond, Z represents a direct bond or an alkylene group having 1 to 10 carbon atoms, and y represents an integer of 1 to 5.)

Description

Polymer composition, and medical materials and adhesives containing the same

[0001] The present invention relates to a polymer composition containing a polymer made from a monomer having two or more types of unsaturated bonds, water and / or an alcohol-based solvent, and a filler, and to a medical material and adhesive containing the same.

[0002] Adhesives used in medical applications are often required to adhere well in wet conditions. Fibrin glue and cyanoacrylate adhesives are the mainstream of such adhesives, and only a few materials are available. However, fibrin glue has problems, such as the need to properly mix fibrinogen and thrombin, low adhesive strength, and concerns about viral infection. Cyanoacrylate adhesives also have problems, such as generating toxic formaldehyde upon hydrolysis, exhibiting brittleness in the cured product, and poor flexibility that prevents them from conforming to soft tissue. As a result, their applications are limited, and new medical adhesives are desired.

[0003] In recent years, mimicking the marine organism Mytilus galloprovincialis has attracted attention due to its high adhesive properties to wet substrates. Mytilus galloprovincialis attaches to rocks and reefs using adhesive proteins called byssus threads. It has been revealed that the catechol structure contributes to the adhesion to wet substrates. Therefore, the development of materials with this or similar structures in their skeletons is progressing.

[0004] For example, Non-Patent Document 1 shows that modifying hyaluronic acid with a catechol group improves adhesive strength compared to unmodified hyaluronic acid.

[0005] Furthermore, Non-Patent Document 2 shows that by introducing a catechol group into hydroxybutylchitosan, the adhesive strength is improved to eight times that of chitosan.

[0006] Patent Documents 1 to 4 disclose copolymers having catechol groups in the side chains of acrylic polymers.

[0007] In the examples of Patent Document 1, the copolymer is dissolved in methyl ethyl ketone, and the adhesive performance to glass, acrylic, or polycarbonate is evaluated.

[0008] In Patent Document 2, in the examples, adhesive performance to inorganic materials and synthetic polymers is evaluated.

[0009] In the examples of Patent Document 3, a polymer into which boronic acid has been introduced is used, and its adhesive performance to glass in water is evaluated.

[0010] Patent Document 4 discloses a bioabsorbable adhesive in which a catechol group is introduced into the side chain of an aliphatic polycarbonate.

[0011] European Polymer Journal, 2020, 134, 109763-109772ACS Biomater. Sci. Eng. , 2020, 6, 3619-3629

[0012] International Publication No. 2019 / 194047 International Publication No. 2019 / 221135 International Publication No. 2021 / 020451 Japanese Patent Application Laid-Open No. 2021-142049

[0013] A typical use of medical adhesives is through endoscopy. Because the adhesive must be delivered through a long, thin tube, the adhesive's viscosity must be kept low to maintain appropriate delivery resistance. However, although this was previously overlooked, it has been discovered that when adhesive viscosity is kept low, the adhesive can migrate from the application site before losing its fluidity. While increasing the adhesive's viscosity can somewhat prevent the adhesive from migrating from the application site, it is not sufficient, and delivery resistance becomes excessive, making endoscopy impractical.

[0014] The adhesive described in Non-Patent Document 1 can adhere to adherends in a wet state, but to achieve sufficient adhesive strength, a large amount of a crosslinker composed of hydrogen peroxide and horseradish peroxidase is required. Furthermore, there is no mention of fluid delivery resistance or fluidity after application. The adhesive described in Non-Patent Document 2 can also adhere to adherends in a wet state, but its adhesive strength is less than half that of Non-Patent Document 1, resulting in insufficient adhesive strength. Furthermore, the methyl ethyl ketone used in Patent Document 1 is a highly toxic solvent and cannot be used in living organisms. Furthermore, there is no mention of adhesive performance to substrates or biological tissues in a wet environment, nor of fluid delivery resistance or fluidity after application. Patent Document 2 also does not mention adhesive performance to substrates or biological tissues in a wet environment, nor of fluid delivery resistance or fluidity after application. Patent Document 3 does not mention the use of catechol groups in the examples, and does not confirm adhesive performance to biological tissues, fluid delivery resistance, or fluidity after application. Patent Document 4 only evaluates bone bonding, and does not provide data on adhesive performance to soft tissue, making it unclear.

[0015] Therefore, the present invention aims to provide a material that exhibits high adhesion to wet materials, has low viscosity in a high-shear environment such as when the liquid is pumped through a long, thin tube, and has extremely low fluidity and is difficult to move in a low-shear or no-shear environment after application.

[0016] As a result of extensive research into the present invention, it has been found that the above-mentioned problems can be solved by a polymer composition and a material (e.g., a medical adhesive) containing the polymer composition, the polymer composition comprising a copolymer (P) containing, as constituent components, a monomer (A) represented by formula (1-A) and a monomer (B) having a polymerizable unsaturated bond different from that of the monomer (A), a filler (F), and water and / or an alcohol solvent (S), and the polymer composition has been completed.

[0017] That is, the present invention comprises the following: Item 1. A polymer composition comprising: a copolymer (P) containing, as constituent components, a monomer (A) represented by the following formula (1-A) and a monomer (B) having a polymerizable unsaturated bond different from that of the monomer (A); a filler (F); and water and / or an alcohol solvent (S). [In the formula, R represents a hydrogen atom or a methyl group, L represents an amide bond, an ester bond, or a direct bond, Z represents a direct bond or an alkylene group having 1 to 10 carbon atoms, and y represents an integer of 1 to 5.] Item 2. The polymer composition according to Item 1, wherein the monomer (A) is a monomer represented by the following formula (1): [In the formula, R represents a hydrogen atom or a methyl group, L represents an amide bond, an ester bond, or a direct bond, x represents 0 or an integer of 1 to 10, and y represents an integer of 1 to 5.] Item 3. The polymer composition according to Item 1 or 2, containing the copolymer (P) in an amount of 1 to 40% by mass, the filler (F) in an amount of 0.1 to 50% by mass, and the solvent (S) in an amount of 10 to 98% by mass, based on the total amount of the polymer composition. Item 4. The polymer composition according to any one of Items 1 to 3, having a loss tangent of 2.50 or less when measured using a rheometer at a measurement temperature of 20°C and an angular frequency of 10 rad / s. Item 5. The polymer composition according to Item 1, wherein the loss tangent is measured using a rheometer at a measurement temperature of 20°C and an angular frequency of 10 rad / s, based on the total amount of the polymer composition. -1 Item 6. The polymer composition according to any one of Items 1 to 4, wherein the viscosity measured using a rheometer at 200 Pa s or less. Item 7. The polymer composition according to any one of Items 1 to 5, wherein the monomer (A) accounts for 0.01 to 30 mol % of the total copolymer (P). Item 8. The polymer composition according to any one of Items 1 to 6, wherein the filler (F) is fibrous or particulate. Item 9. The polymer composition according to Item 7, wherein the fibrous filler (F) has an average fiber diameter of 0.5 nm or more and 10 μm or less. Item 10. The polymer composition according to Item 7 or 8, wherein the particulate filler (F) has an average particle diameter (by number) or d50 particle diameter (by number) of 0.1 μm or more and 300 μm or less. Item 11. The polymer composition according to Item 10, wherein the specific gravity of the filler (F) is 5 g / cm 3Item 11. The polymer composition according to any one of Items 1 to 9, wherein the filler (F) is constituted by a polysaccharide. Item 12. The polymer composition according to any one of Items 1 to 11, wherein the copolymer (P) has a weight average molecular weight of 50,000 or more and 500,000 or less. Item 13. The polymer composition according to any one of Items 1 to 12, wherein the monomer (A) is represented by the following formula (1a): [In the formula, R represents a hydrogen atom or a methyl group, L represents an amide bond, an ester bond, or a direct bond, and x represents 0 or an integer of 1 to 10.] Item 14. The polymer composition according to any one of Items 1 to 13, wherein the monomer (B) is an acrylic compound and / or a methacrylic compound. Item 15. The polymer composition according to any one of Items 1 to 14, wherein the monomer (A) is an acrylic compound and / or a methacrylic compound. Item 16. The polymer composition according to any one of Items 1 to 15, wherein the monomer (B) includes a monomer represented by the following formula (2): [In the formula, R 1 represents a hydrogen atom or a methyl group. 1 is -O-, or any C-H is C-R 2 -O-(CH2) optionally substituted with y -O-, -(O-CH2-CH2) y -O- or -(O-CH-CH-CH) y represents —O—, and R 2represents an alkyl group having 1 to 6 carbon atoms, and y represents an integer of 1 to 10.] Item 17. A medical material comprising the polymer composition according to any one of Items 1 to 16. Item 18. A medical adhesive comprising the polymer composition according to any one of Items 1 to 16. Item 19. An adhesive comprising the polymer composition according to any one of Items 1 to 16. Item 20. A method for applying a material comprising the polymer composition according to any one of Items 1 to 16 to biological tissue. Item 21. Use of the polymer composition according to any one of Items 1 to 16 for producing a material to be applied to biological tissue. Item 22. A method for coating the surface of biological tissue, joining biological tissues together, or joining biological tissue to a medical device by applying an adhesive comprising the polymer composition according to any one of Items 1 to 16 to biological tissue. Item 23. Use of the polymer composition according to any one of Items 1 to 16 for producing an adhesive used for coating the surface of biological tissue, joining biological tissues together, or joining biological tissue to a medical device.

[0018] The present invention can provide a polymer composition that has high adhesiveness to wet biological tissue, can be delivered using a long, thin tube, and does not drip after application, as well as a material containing the same, such as a medical adhesive.

[0019] The present invention will be described in detail below. Note that the present invention is not limited to the embodiments described below. Furthermore, (meth)acrylate refers to methacrylate and acrylate, and (meth)acrylic refers to methacrylic and acrylic. Note that in this application, tissue coverage refers to a property suitable for covering the surface of biological tissue, and tissue bonding refers to a property suitable for bonding biological tissues together or bonding biological tissue to a medical device. Furthermore, adhesiveness includes both tissue coverage and / or tissue bonding.

[0020] The polymer composition of the present invention is a polymer composition comprising a copolymer (P) containing, as constituent components, a monomer (A) represented by the following formula (1-A) and a monomer (B) having a polymerizable unsaturated bond different from that of the monomer (A), a filler (F), and water and / or an alcohol solvent (S). By including the monomer (A) as a constituent component of the copolymer (P), it is possible to impart excellent adhesiveness to wet biological tissue, and by incorporating the filler (F), it is possible to suppress dripping after application. Furthermore, by incorporating the filler (F), the polymer composition exhibits thixotropy, and the viscosity of the polymer composition temporarily decreases due to shear during delivery, facilitating delivery of the liquid to the coating.

[0021] In the formula (1-A), R represents a hydrogen atom or a methyl group, and is particularly preferably a methyl group.

[0022] In the formula (1-A), L represents an amide bond, an ester bond, or a direct bond, and among these, an amide bond or an ester bond is preferred, and an ester bond is more preferred particularly from the viewpoint of dispersibility of the filler. When L is an ester bond, the monomer (A) represented by the formula (1-A) is preferably an acrylic compound and / or a methacrylic compound.

[0023] In the formula (1-A), Z represents a direct bond or an alkylene group having 1 to 10 carbon atoms. The alkylene group having 1 to 10 carbon atoms may be linear or branched, but is preferably linear. The number of carbon atoms in the alkylene group is preferably 1 to 5, more preferably 1 to 3, and even more preferably 2. Z is preferably a direct bond or a linear alkylene group having 1 to 5 carbon atoms, more preferably a direct bond or a linear alkylene group having 1 to 3 carbon atoms, even more preferably a linear alkylene group having 1 to 3 carbon atoms, and particularly preferably an ethylene group.

[0024] In the formula (1-A), y represents an integer of 1 to 5, preferably an integer of 1 to 3, more preferably 2 or 3, and even more preferably 2. When y is an integer of 2 or more, it is preferable that multiple OH groups are bonded to adjacent carbon atoms.

[0025] The monomer (A) is preferably a monomer represented by formula (1). [In formula (1), x represents 0 or an integer of 1 to 10, and R, L, and x, including their preferred embodiments, are the same as those defined above.]

[0026] In formula (1), x is preferably 0 or an integer of 1 to 5, more preferably 0 or an integer of 1 to 3, even more preferably an integer of 1 to 3, and particularly preferably 2.

[0027] In particular, from the viewpoint of further enhancing adhesiveness, the monomer (A) is preferably a monomer represented by formula (1-A) or formula (1) in which y is 2 or 3 and a plurality of OH groups are bonded to adjacent carbon atoms, more preferably a monomer represented by formula (1a) or formula (1b), and even more preferably a monomer represented by formula (1a). [In formula (1a) and formula (1b), R, L, and x, including preferred embodiments thereof, are the same as defined above.]

[0028] The amide bond represented by L is preferably a group represented by *-CO-NH- (* indicates a bond to the carbon atom to which R is bonded), that is, when L is an amide bond, the compounds represented by the formulae (1-A), (1), (1a) and (1b) are preferably (meth)acrylamide compounds. Examples thereof include N-[(3,4-dihydroxyphenyl)](meth)acrylamide; N-[(3,4-dihydroxyphenyl)methyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)ethyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)propyl](meth)acrylamide, N-[3-(3,4-dihydroxyphenyl)propyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)butyl](meth)acrylamide, N-[4-(3,4-dihydroxyphenyl)butyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)pentyl](meth)acrylamide, N-[5-(3,4-dihydroxyphenyl)pentyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)hexyl](meth)acrylamide, N-[6-(3,4-dihydroxyphenyl) N-[(3,4-dihydroxyphenyl)alkyl](meth)acrylamides such as N-[2-(3,4-dihydroxyphenyl)heptyl](meth)acrylamide, N-[7-(3,4-dihydroxyphenyl)heptyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)octyl](meth)acrylamide, N-[8-(3,4-dihydroxyphenyl)octyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)nonyl](meth)acrylamide, N-[9-(3,4-dihydroxyphenyl)nonyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)decyl](meth)acrylamide, and N-[10-(3,4-dihydroxyphenyl)decyl](meth)acrylamide; N-[(3,4,5-trihydroxyphenyl)](meth)acrylamide;N-[(3,4,5-trihydroxyphenyl)methyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)ethyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)propyl](meth)acrylamide, N-[3-(3,4,5-trihydroxyphenyl)propyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)butyl](meth)acrylamide, N-[4-(3,4,5-trihydroxyphenyl)butyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)pentyl](meth)acrylamide, N-[5-(3,4,5-trihydroxyphenyl)pentyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)hexyl](meth)acrylamide, N-[6-(3,4,5-trihydroxyphenyl)hexyl](meth)acrylamide N-[(3,4,5-trihydroxyphenyl)alkyl](meth)acrylamides such as N-[2-(3,4,5-trihydroxyphenyl)heptyl](meth)acrylamide, N-[7-(3,4,5-trihydroxyphenyl)heptyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)octyl](meth)acrylamide, N-[8-(3,4,5-trihydroxyphenyl)octyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)nonyl](meth)acrylamide, N-[9-(3,4,5-trihydroxyphenyl)nonyl](meth)acrylamide, N-[2-(3,4,5-trihydroxyphenyl)decyl](meth)acrylamide, and N-[10-(3,4,5-trihydroxyphenyl)decyl](meth)acrylamide; and the like.

[0029] Furthermore, the ester bond represented by L is preferably a group represented by *-CO-O- (* indicates a bond to the carbon atom to which R is bonded). In other words, when L is an ester bond, the compounds represented by the formulae (1-A), (1), (1a) and (1b) are preferably (meth)acrylic compounds, more preferably (meth)acrylic acid esters. Examples thereof include (meth)acrylic acid-(3,4-dihydroxyphenyl) ester; (meth)acrylic acid-(3,4-dihydroxyphenyl)methyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)ethyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)propyl ester, (meth)acrylic acid-3-(3,4-dihydroxyphenyl)propyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)butyl ester, (meth)acrylic acid-4-(3,4-dihydroxyphenyl)butyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)pentyl ester, (meth)acrylic acid-5-(3,4-dihydroxyphenyl)pentyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)hexyl ester, (meth)acrylic acid-6-(3,4- (meth)acrylic acid-(3,4-dihydroxyphenyl)alkyl esters such as (meth)acrylic acid-2-(3,4-dihydroxyphenyl)hexyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)heptyl ester, (meth)acrylic acid-7-(3,4-dihydroxyphenyl)heptyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)octyl ester, (meth)acrylic acid-8-(3,4-dihydroxyphenyl)octyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)nonyl ester, (meth)acrylic acid-9-(3,4-dihydroxyphenyl)nonyl ester, (meth)acrylic acid-2-(3,4-dihydroxyphenyl)decyl ester, and (meth)acrylic acid-10-(3,4-dihydroxyphenyl)decyl ester; (meth)acrylic acid-(3,4,5-trihydroxyphenyl) esters;(Meth)acrylic acid-(3,4,5-trihydroxyphenyl)methyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)ethyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)propyl ester, (meth)acrylic acid-3-(3,4,5-trihydroxyphenyl)propyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)butyl ester, (meth)acrylic acid-4-(3,4,5-trihydroxyphenyl)butyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)pentyl ester, (meth)acrylic acid-5-(3,4,5-trihydroxyphenyl)pentyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)hexyl ester, (meth)acrylic acid-6-(3,4,5-trihydroxyphenyl) (meth)acrylic acid-(3,4,5-trihydroxyphenyl)alkyl esters such as (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)hexyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)heptyl ester, (meth)acrylic acid-7-(3,4,5-trihydroxyphenyl)heptyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)octyl ester, (meth)acrylic acid-8-(3,4,5-trihydroxyphenyl)octyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)nonyl ester, (meth)acrylic acid-9-(3,4,5-trihydroxyphenyl)nonyl ester, (meth)acrylic acid-2-(3,4,5-trihydroxyphenyl)decyl ester, and (meth)acrylic acid-10-(3,4,5-trihydroxyphenyl)decyl ester; and the like.

[0030] Furthermore, when L is a direct bond, examples of the hydroxyl group include 3,4-dihydroxystyrene, 3-(3,4-dihydroxyphenyl)-1-propene, 4-(3,4-dihydroxyphenyl)-1-butene, 5-(3,4-dihydroxyphenyl)-1-pentene, 6-(3,4-dihydroxyphenyl)-1-hexene, 7-(3,4-dihydroxyphenyl)-1-heptene, 8-(3,4-dihydroxyphenyl)-1-octene, 9-(3,4-dihydroxyphenyl)-1-nonene, 10-(3,4-dihydroxyphenyl)-1-decene ... (3,4-dihydroxyphenyl)-2-methyl-1-propene, 4-(3,4-dihydroxyphenyl)-2-methyl-1-butene, 5-(3,4-dihydroxyphenyl)-2-methyl-1-pentene, 6-(3,4-dihydroxyphenyl)-2-methyl-1-hexene, 7-(3,4-dihydroxyphenyl)-2-methyl-1-heptene, 8-(3,4-dihydroxyphenyl)-2-methyl-1-octene, 9-(3,4-dihydroxyphenyl)-2-methyl-1-nonene, 10-(3,4-dihydroxyphenyl)-2-methyl-1-decene, 3,4,5 -trihydroxystyrene, 3-(3,4,5-trihydroxyphenyl)-1-propene, 4-(3,4,5-trihydroxyphenyl)-1-butene, 5-(3,4,5-trihydroxyphenyl)-1-pentene, 6-(3,4,5-trihydroxyphenyl)-1-hexene, 7-(3,4,5-trihydroxyphenyl)-1-heptene, 8-(3,4,5-trihydroxyphenyl)-1-octene, 9-(3,4,5-trihydroxyphenyl)-1-nonene, 10-(3,4,5-trihydroxyphenyl)-1-decene, 3-(3 ,4,5-trihydroxyphenyl)-2-methyl-1-propene, 4-(3,4,5-trihydroxyphenyl)-2-methyl-1-butene, 5-(3,4,5-trihydroxyphenyl)-2-methyl-1-pentene, 6-(3,4,5-trihydroxyphenyl)-2-methyl-1-hexene, 7-(3,4,5-trihydroxyphenyl)-2-methyl-1-heptene, 8-(3,4,5-trihydroxyphenyl)-2-methyl-1-octene, 9-(3,4,5-trihydroxyphenyl)-2-methyl-1-nonene, 10-(3,4,5-trihydroxyphenyl)-2-methyl-1-decene, etc.

[0031] Among these, N-[2-(3,4-dihydroxyphenyl)ethyl]methacrylamide (formula (3)) or 2-(3,4-dihydroxyphenyl)ethyl methacrylate (formula (4)) is preferred due to its ease of availability. Furthermore, 2-(3,4-dihydroxyphenyl)ethyl methacrylate is more preferred. Hydroxytyrosol, the raw material for 2-(3,4-dihydroxyphenyl)ethyl methacrylate, is a substance used as a supplement raw material and can be produced by plant extraction or biosynthesis.

[0032]

[0033]

[0034] The monomer (A) constituting the copolymer (P) may be one type or two or more types.

[0035] Monomer (B) is preferably a monomer different from monomer (A) and having a polymerizable unsaturated bond. The number of polymerizable unsaturated bonds per molecule of monomer (B) is preferably 1 to 4, more preferably 1. The polymerizable unsaturated bond is not particularly limited, and examples thereof include a vinyl group, a (meth)acrylic group, an acetylene group, an allene group, and a cumulene group. Among these, from the viewpoint of polymerizability, a compound having a (meth)acrylic group (i.e., an acrylic compound and / or a methacrylic compound) is preferred, and a monomer having one (meth)acrylic group per molecule is more preferred. Furthermore, from the viewpoint of polymerizability, monomer (B) is preferably a monomer having a methacrylic group as the polymerizable unsaturated bond.

[0036] The monomer (B) preferably contains, in addition to the polymerizable unsaturated bond, a monomer having a functional group at its molecular terminal (hereinafter, sometimes referred to as monomer (B1)). By using the monomer (B1), the adhesiveness can be further improved and the solubility in the solvent (S) can be increased. Examples of the terminal functional group possessed by the monomer (B1) include a carboxy group, a hydroxy group, an amino group, and an alkoxy group. Among these, a carboxy group and a hydroxy group are preferred, and a hydroxy group is more preferred.

[0037] The monomer (B1) is preferably a monomer having a (meth)acrylic group as a polymerizable unsaturated bond. Examples of the monomer (B1) include (meth)acrylic monomers (B1-1) in which the carbon chain length between the ester group or amide group containing a (meth)acrylic group-derived C(═O) and the terminal functional group is 0 to 15, and (meth)acrylic monomers (B1-2) in which the structure between the ester group containing a (meth)acrylic group-derived C(═O) and the terminal functional group is polyether.

[0038] The carbon chain length in the monomer (B1-1) is preferably 1 to 15, more preferably 1 to 10, and even more preferably 2 to 4. The carbon chain length refers to the total number of carbon atoms constituting the group linking the terminal functional group to an ester group or amide group containing a C(═O) derived from a (meth)acrylic group. In the monomer (B1-1), the group linking the terminal functional group to an ester group or amide group is preferably a hydrocarbon group. The hydrocarbon group may be a saturated hydrocarbon group, an unsaturated hydrocarbon group, or an aromatic hydrocarbon group, but is preferably a saturated hydrocarbon group. Examples of saturated hydrocarbon groups include linear or branched alkylene groups, cycloalkylene groups, and combinations thereof. Among these, an alkylene group is preferred, and a linear alkylene group is more preferred.

[0039] The polyether constituting the monomer (B1-2) has a structure having a plurality of ether structures in the skeleton, and preferably has a structure having repeating ether bonds in the skeleton. Specifically, the polyether structure is preferably a polyalkylene glycol structure such as polyethylene glycol or polypropylene glycol. The number of repeating units in the polyether structure is preferably 2 to 10.

[0040] The monomer (B1) is particularly preferably represented by the following formula (2):

[0041] [In formula (2), R 1 represents a hydrogen atom or a methyl group. 1 is -O-, or any C-H is C-R 2 -O-(CH2) optionally substituted with y -O-, -(O-CH2-CH2) y -O- or -(O-CH-CH-CH) y represents —O—, and R 2 represents an alkyl group having 1 to 6 carbon atoms, and y represents an integer of 1 to 10.

[0042] R 1 As the alkyl group, a methyl group is preferred.

[0043] L 1 As for C-H, any C-R 2 -O-(CH2) optionally substituted with y -O-, or any C-H is C-R 2 -(O-CH-CH) y -O- is preferred, and -(O-CH-CH) y -O-, -(O-CH2-CH(CH3)) y -O-, or any C-H is C-R 2 -O-(CH2) optionally substituted with y More preferably, it is —O—, and more preferably —O—(CH2) y It is more preferably —O—.

[0044] R 2The alkyl group represented by the formula (I) may be linear or branched, and among these, linear alkyl groups are preferred, and linear alkyl groups having 1 to 3 carbon atoms such as a methyl group, an ethyl group, or an n-propyl group are more preferred.

[0045] Preferably, y is an integer of 2 to 10.

[0046] Specific examples of the monomer (B1) include monomers (B1-1) such as (meth)acrylic acid, hydroxyalkyl (meth)acrylates (for example, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, 8-hydroxyoctyl (meth)acrylate, 10-hydroxydecyl (meth)acrylate, and 12-hydroxylauryl (meth)acrylate), (4-hydroxymethylcyclohexyl)methyl acrylate, and N-methylol (meth)acrylamide; and monomers (B1-2) such as polyethylene glycol mono(meth)acrylate, polypropylene glycol mono(meth)acrylate, and polyethylene glycol monomethyl ether (meth)acrylate. Among these, monomer (B1-1) is preferred because it allows for easy adjustment of the solubility in alcohol solvents and water, and hydroxyalkyl (meth)acrylate is more preferred, and hydroxyalkyl (meth)acrylate is even more preferred. 1-12 Alkyl (meth)acrylate, even more preferably hydroxy C 2-4 Alkyl (meth)acrylates are preferred, with 2-hydroxyethyl (meth)acrylate and 2-hydroxypropyl (meth)acrylate being particularly preferred.

[0047] The monomer (B) preferably contains, in addition to the polymerizable unsaturated bond, a monomer having at least one hydrophobic group selected from the group consisting of an alkyl group, a cycloalkyl group, and a skeleton having a heteroatom that does not contain hydrogen-bonding hydrogen (hereinafter, sometimes referred to as monomer (B2)). When the copolymer (P) contains a group derived from monomer (B2) in addition to a group derived from monomer (A), the adhesiveness is further improved. It is preferable that the monomer (B2) is a monomer that does not contain a carboxy group, a hydroxy group, an amino group, or an alkoxy group.

[0048] Examples of the alkyl group include linear alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, lauryl, and stearyl; and branched alkyl groups such as isopropyl, isobutyl, t-butyl, and 2-ethylhexyl. Of these, alkyl groups having 2 to 20 carbon atoms are preferred, more preferably alkyl groups having 4 to 20 carbon atoms, and even more preferably alkyl groups having 6 to 20 carbon atoms. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl groups, and of these, cycloalkyl groups having 4 to 8 carbon atoms are preferred. Examples of the skeleton having a heteroatom that does not contain hydrogen-bonding hydrogen include a group obtained by removing one hydrogen atom from tetrahydrofuran, a group obtained by removing a hydrogen atom bonded to a nitrogen atom from succinimide, a group obtained by removing one hydrogen atom from furan, a group obtained by removing a hydrogen atom bonded to a nitrogen atom from morpholine, a group obtained by removing a hydrogen atom from dioxane, a group obtained by removing a hydrogen atom from epoxy, and a group obtained by removing a hydrogen atom from oxetane.

[0049] The hydrophobic group is preferably an alkyl group having 2 to 20 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, or a group obtained by removing a hydrogen atom bonded to a nitrogen atom from succinimide, more preferably an alkyl group having 4 to 20 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, or a group obtained by removing a hydrogen atom bonded to a nitrogen atom from succinimide, and even more preferably an alkyl group having 6 to 20 carbon atoms, or a group obtained by removing a hydrogen atom bonded to a nitrogen atom from succinimide.

[0050] Specific examples of the monomer (B2) include alkyl (meth)acrylates such as methyl (meth)acrylate, ethyl (meth)acrylate, isopropyl (meth)acrylate, t-butyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, hexyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, lauryl (meth)acrylate, and stearyl (meth)acrylate; cycloalkyl (meth)acrylates such as cyclohexyl (meth)acrylate; tetrahydrofurfuryl (meth)acrylate; and N-succinimidyl (meth)acrylate. Among these, alkyl (meth)acrylates are preferred, and from the viewpoint of suppressing water absorption into the polymer, C 1-20 Alkyl (meth)acrylate is more preferred, C 4-20 Alkyl (meth)acrylate is more preferred, and C 6-20 Alkyl (meth)acrylates are even more preferred, with 2-ethylhexyl (meth)acrylate, lauryl (meth)acrylate, and stearyl (meth)acrylate being particularly preferred.

[0051] The monomer (B) preferably contains the monomer (B1), and more preferably contains the monomer (B1) and the monomer (B2).

[0052] The monomer (B) constituting the copolymer (P) may be one type or two or more types.

[0053] The ratio of monomer (A) to all monomers constituting copolymer (P) is preferably 0.01 mol% or more, more preferably 0.1 mol% or more, even more preferably 1 mol% or more, and particularly preferably 5 mol% or more, from the viewpoint of further improving adhesiveness to wet tissues. Furthermore, from the viewpoint of further improving solubility in solvent (S) (especially alcohol solvents), it is preferably 30 mol% or less, more preferably 20 mol% or less, even more preferably 12 mol% or less, and particularly preferably 10 mol% or less. That is, the ratio of monomer (A) to all monomers constituting copolymer (P) is preferably 0.01 to 30 mol%, more preferably 0.1 to 20 mol%, even more preferably 1 to 12 mol%, and particularly preferably 5 to 10 mol%. Adjusting the constituent ratio of monomer (A) to the above-mentioned lower limit or more tends to further improve adhesiveness to wet tissues. Furthermore, by adjusting the constituent ratio of the monomer (A) to be equal to or less than the above upper limit, the solubility in the solvent (S) (particularly an alcohol solvent) can be further increased, and the concentration of the copolymer (P) in the adhesive can be increased, which tends to make it easier for the adhesive performance to be exhibited.

[0054] The ratio of monomer (B) to all monomers constituting copolymer (P) is preferably 40 mol% or more, more preferably 50 mol% or more, and even more preferably 60 mol% or more, from the viewpoint of further increasing solubility in solvent (S) (particularly alcohol solvents). Furthermore, from the viewpoint of reducing solubility in water, it is preferably 99.98 mol% or less, more preferably 95 mol% or less, and even more preferably 90 mol% or less. That is, the ratio of monomer (B) to all monomers constituting copolymer (P) is preferably 40 to 99.98 mol%, more preferably 50 to 95 mol%, and even more preferably 60 to 90 mol%.

[0055] The proportion of the monomer (B1) in 100 mol% of the monomer (B) constituting the copolymer (P) is preferably 30 to 100 mol%, more preferably 50 to 98 mol%, and even more preferably 70 to 95 mol%. The total proportion of the monomer (B1) and the monomer (B2) in 100 mol% of the monomer (B) constituting the copolymer (P) is preferably 50 mol% or more, more preferably 80 mol% or more, even more preferably 90 mol% or more, particularly preferably 95 mol% or more, and may even be 100 mol%.

[0056] The composition ratio of the copolymer (P) is suitably determined by a nuclear magnetic resonance (NMR) method. 1 The composition ratio may be determined solely by H-NMR analysis, 13 C-NMR analysis alone, or 1 H-NMR analysis and 13 The composition ratio may be determined by combining this with C-NMR analysis. Two-dimensional NMR analysis is also an effective method.

[0057] From the viewpoint of further enhancing adhesiveness, the weight-average molecular weight of the copolymer (P) is preferably 50,000 or more, more preferably 100,000 or more, and even more preferably 150,000 or more. Furthermore, from the viewpoint of further enhancing solubility in the solvent (S) (particularly, alcohol solvents), it is preferably 500,000 or less, more preferably 400,000 or less, and even more preferably 300,000 or less. That is, the weight-average molecular weight of the copolymer (P) is preferably 50,000 to 500,000, more preferably 100,000 to 400,000, and even more preferably 150,000 to 300,000. When the weight-average molecular weight is 50,000 (preferably the above-mentioned lower limit) or more, the mechanical strength of the copolymer (P) is sufficiently maintained, and better adhesive performance is exhibited. Furthermore, if the weight average molecular weight is 500,000 (preferably the above upper limit) or less, the solubility in the solvent (S) (particularly alcohol solvents) can be further increased.

[0058] The polymerization method for the copolymer (P) is not particularly limited, and various known methods can be used for polymerization. For example, the copolymer (P) can be polymerized by dissolving the monomer (A), the monomer (B), and other monomers used as needed in an organic solvent, adding a polymerization initiator, and then heating or irradiating the resulting mixture with light.

[0059] Examples of organic solvents that can be used in the polymerization of the copolymer (P) include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), 1,4-dioxane, toluene, xylene, hexane, heptane, ethyl acetate, ethanol, etc. For medical use, dimethyl sulfoxide and ethanol, which have a proven track record of use in pharmaceuticals, are preferred.

[0060] As the polymerization initiator, it is preferable to use, for example, an azo compound such as 2,2'-azobisbutyronitrile (AIBN) or a peroxide such as benzoyl peroxide (BPO).

[0061] The polymer composition of the present invention may contain one or more copolymers (P).

[0062] From the viewpoint of curing time, the concentration of the copolymer (P) in the polymer composition is preferably 1% by mass or more, more preferably 5% by mass or more, and even more preferably 10% by mass or more. It may also be 20% by mass or more, or even 25% by mass or more. From the viewpoint of solubility in the solvent (S) (particularly alcohol solvents), it is preferably 40% by mass or less, more preferably 35% by mass or less. That is, the concentration of the copolymer (P) in the polymer composition is preferably 1 to 40% by mass, more preferably 5 to 35% by mass, even more preferably 10 to 35% by mass, and may be 20 to 40% by mass or 25 to 40% by mass. Adjusting the concentration of the copolymer (P) to the above-mentioned lower limit or above enables curing in a short time, and thus tends to facilitate the exertion of adhesive performance in a short time. Adjusting the concentration of the copolymer (P) to the above-mentioned upper limit or below further enhances solubility in the solvent (S) (particularly alcohol solvents), and tends to facilitate the exertion of adhesive performance.

[0063] The filler (F) contained in the polymer composition of the present invention is preferably fibrous or particulate in shape. In this specification, fillers having a ratio of the average fiber length to the average fiber diameter (average fiber length / average fiber diameter) described below of 100 or more are defined as fibrous, and other fillers are defined as particulate. From the viewpoint of thixotropy, the filler (F) is preferably bent, and more preferably bent fibrous.

[0064] The fiber length indicates the length of the fibrous filler, and the fiber diameter indicates the diameter of the fibrous filler.

[0065] When the filler (F) is fibrous, the fiber diameter is measured by measuring the diameters of any five fibers in an image taken with a scanning electron microscope (SEM image) and calculating the average fiber diameter from the arithmetic mean value. The average fiber length is calculated by measuring the lengths of any five fibers in an SEM image and calculating the arithmetic mean value. From the viewpoint of thixotropy, a larger aspect ratio (fiber length / fiber diameter) is preferable. Therefore, the average fiber diameter is preferably 10 μm or less, more preferably 5 μm or less, and even more preferably 1 μm or less. From the viewpoint of adhesive strength, it is also preferable that the average fiber diameter is not too small. Specifically, the average fiber diameter is preferably 0.5 nm to 10 μm, more preferably 1 nm to 5 μm, and even more preferably 1 nm to 1 μm. From the viewpoint of thixotropy, the ratio of the average fiber length to the average fiber diameter (average fiber length / average fiber diameter) is preferably 100 or more, and may be 1,000 or more. The upper limit of the ratio of the average fiber length to the average fiber diameter is not particularly limited, but is, for example, 100,000 or less.

[0066] When the filler (F) is particulate, the shape of the particles is not particularly limited, but from the viewpoint of further improving drip prevention, it is preferable to use at least one type of spherical, polyhedral, plate-like, rod-like, needle-like, etc. Among these, it is more preferable to use at least one type of plate-like, rod-like, or needle-like particle.

[0067] When the filler (F) is particulate, the particle diameters of any five particles can be measured from an SEM image, and the arithmetic average value can be used as the average particle diameter. From the viewpoint of thixotropy, a larger surface area of ​​the filler (F) is preferable. Therefore, its average particle diameter (number basis) or d50 particle diameter (number basis) is preferably 300 μm or less, more preferably 200 μm or less, and even more preferably 100 μm or less. Furthermore, from the viewpoint of dispersibility, it is also preferable that the particle diameter of the filler (F) is not too small. Specifically, the average particle diameter or d50 particle diameter of the filler (F) is preferably 0.1 to 300 μm, more preferably 0.3 to 200 μm, and even more preferably 0.5 to 100 μm.

[0068] If the specific gravity of the filler (F) is large, the filler may be more likely to settle. Therefore, from the viewpoint of dispersion stability of the filler, the specific gravity of the filler (F) is set to 5 g / cm or less. 3 or less than 5.0 g / cm 3 Preferably, it is 4.5 g / cm or less. 3 More preferably, it is 3.5 g / cm or less. 3 Although there is no particular lower limit, from the viewpoint of dispersibility during blending, the specific gravity of the polymer (about 1.2 g / cm 3 Dispersion is easier when the density is close to 0.5 g / cm 3 It is preferable that the density is 0.8 g / cm or more. 3 More preferably, the specific gravity of the filler (F) is 0.5 to 5 g / cm. 3 or 0.5 to 5.0 g / cm 3 is preferably 0.8 to 4.5 g / cm 3 , more preferably 0.8 to 3.5 g / cm 3 In particular, in the case of a particulate filler, it is preferable to adjust the specific gravity to fall within the above range.

[0069] Examples of components of the filler (F) include alkaline earth metal salts (particularly Ba salts and Ca salts) such as barium sulfate, calcium octaphosphate, and hydroxyapatite (calcium hydroxide phosphate); proteins such as silk fibroin; carbon; and polysaccharides such as cellulose, chitin, and paramylon.

[0070] The filler (F) may be carbon fiber, cellulose fiber, chitin fiber, paramylon fiber, or the like.

[0071] The filler (F) is not particularly limited, but from the viewpoint of biocompatibility, it is preferable to use a filler containing a polysaccharide as a constituent component, and more preferable examples include cellulose fibers (cellulose nanofibers, cellulose microfibers, etc.), chitin nanofibers, paramylon nanofibers, etc. In particular, when the filler (F) is fibrous, the above embodiment is preferable.

[0072] The cellulose (e.g., cellulose nanofiber, cellulose microfiber) constituting the filler (F) may be chemically modified, and examples of the chemical modification include TEMPO oxidation, carboxymethylation, esterification, phosphate esterification, deacetylation, etc. Here, TEMPO refers to 2,2,6,6-tetramethylpiperidine-1-oxyl radical.

[0073] When the filler (F) is particulate (particularly plate-like, rod-like, or needle-like), preferred examples of its constituent components include barium sulfate, calcium octaphosphate, hydroxyapatite, silk fibroin, carbon, and carboxymethyl cellulose.

[0074] In particular, from the viewpoint of extremely reducing fluidity in a low shear or no shear environment, a filler composed of hydroxyapatite or cellulose fiber having a ratio of average fiber length to average fiber diameter (average fiber length / average fiber diameter) of 100 or more is preferred.

[0075] The content of the filler (F) in the polymer composition is preferably 0.1 to 60% by mass, more preferably 0.5 to 50% by mass, and even more preferably 1 to 40% by mass, and may be 5 to 50% by mass, 10 to 40% by mass, 0.1 to 20% by mass, 0.5 to 10% by mass, or 1 to 5% by mass, etc. By adjusting the content of the filler (F) to be equal to or greater than the above lower limit, dripping can be further suppressed, and by adjusting the content to be equal to or less than the above upper limit, fluidity during delivery can be further improved.

[0076] When the filler (F) is fibrous, the content of the filler (F) in the polymer composition is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1% by mass or more, from the viewpoint of further suppressing dripping. Furthermore, from the viewpoint of further improving fluidity during delivery, the content is preferably 20% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less. That is, the content of the filler (F) in the polymer composition is preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and even more preferably 1 to 5% by mass.

[0077] Furthermore, when the filler (F) is particulate, the content of the filler (F) in the polymer composition is preferably 1% by mass or more, more preferably 5% by mass or more, and even more preferably 10% by mass or more, from the viewpoint of further suppressing dripping. Furthermore, from the viewpoint of further improving fluidity during delivery, the content is preferably 60% by mass or less, more preferably 50% by mass or less, and even more preferably 40% by mass or less. That is, the content of the filler (F) in the polymer composition is preferably 1 to 60% by mass, more preferably 5 to 50% by mass, and even more preferably 10 to 40% by mass. When the filler (F) is rod-shaped or needle-shaped, or is carbon fiber, cellulose fiber, chitin fiber, paramylon fiber, or the like, the content of the filler (F) in the polymer composition is preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and even more preferably 1 to 8% by mass, from the viewpoint of further improving fluidity and adhesiveness during delivery.

[0078] Furthermore, the content of the filler (F) per 100 parts by mass of the copolymer (P) is preferably 0.1 to 500 parts by mass, more preferably 1 to 350 parts by mass, even more preferably 10 to 250 parts by mass, and may be 10 to 200 parts by mass, 10 to 80 parts by mass, 10 to 30 parts by mass, 40 to 350 parts by mass, or 60 to 250 parts by mass. In particular, when the filler (F) is fibrous, the content of the filler (F) per 100 parts by mass of the copolymer (P) is preferably 0.1 to 200 parts by mass, more preferably 1 to 80 parts by mass, even more preferably 10 to 30 parts by mass. When the filler (F) is particulate, the content of the filler (F) per 100 parts by mass of the copolymer (P) is preferably 10 to 500 parts by mass, more preferably 40 to 350 parts by mass, even more preferably 60 to 250 parts by mass. When the filler (F) is rod-shaped or needle-shaped, or is carbon fiber, cellulose fiber, chitin fiber, paramylon fiber, or the like, the content of the filler (F) relative to 100 parts by mass of the copolymer (P) is preferably 0.1 to 200 parts by mass, more preferably 1 to 80 parts by mass, and even more preferably 10 to 30 parts by mass, from the viewpoint of further improving the fluidity and adhesiveness during liquid delivery.

[0079] The solvent (S) of the present invention is composed of water and / or an alcohol solvent. From the viewpoint of polymer solubility, the solvent (S) preferably contains an alcohol solvent. The proportion of the alcohol solvent in the solvent (S) is, for example, 20% by mass or more, preferably 50% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and may be 100% by mass.

[0080] Examples of the alcohol solvent include alkyl alcohols such as methanol, ethanol, propanol, isopropanol, and butanol; glycols such as ethylene glycol and propylene glycol; and the like. 1-4Preferably, the solvent contains an alkyl alcohol, more preferably ethanol, isopropanol, or a mixed solvent containing at least one of these, and even more preferably ethanol, isopropanol, or a mixed solvent thereof. In consideration of biocompatibility, volatility, and polymer solubility, ethanol is particularly preferred. 1-4 The content of alkyl alcohol (particularly ethanol and isopropanol) is preferably 50% by mass or more, more preferably 80% by mass or more, and even more preferably 90% by mass or more, and may be 100% by mass.

[0081] The content of the solvent (S) in the polymer composition is preferably 10 to 98% by mass, more preferably 25 to 90% by mass, and even more preferably 35 to 85% by mass. The content of the copolymer (P) per 100 parts by mass of the solvent (S) is preferably 1 to 100 parts by mass, more preferably 5 to 80 parts by mass, even more preferably 10 to 70 parts by mass, still more preferably 20 to 60 parts by mass, particularly preferably 30 to 60 parts by mass, and may even be 40 to 60 parts by mass.

[0082] The total content of the copolymer (P), the filler (F), and the solvent (S) is preferably 80% by mass or more, more preferably 90% by mass or more, even more preferably 95% by mass or more, particularly preferably 98% by mass or more, based on 100% by mass of the polymer composition, and may be 100% by mass.

[0083] The polymer composition of the present invention may or may not contain a curing agent such as a polyisocyanate-based curing agent, a melamine-based curing agent, a diamine-based curing agent, an epoxy-based curing agent, a urea-based curing agent, or a metal chelate-based curing agent, or a crosslinking agent (for example, a crosslinking agent composed of hydrogen peroxide and horseradish peroxidase), but can exhibit adhesive performance even without these agents. The total content of the curing agent and crosslinking agent may be about 0.05 to 1 part by mass per 100 parts by mass of the copolymer (P), but is preferably less than 0.05 part by mass, and it is more preferable that the polymer composition is substantially free of curing agents and / or crosslinking agents.

[0084] The polymer composition of the present invention may or may not contain a monomer having at least two polymerizable functional groups per molecule (hereinafter referred to as a crosslinking monomer), but adhesive performance can be achieved even without the crosslinking monomer. Examples of the crosslinking monomer include polyfunctional (meth)acrylamides having two or more (meth)acryloyl groups, polyfunctional (meth)acrylates having two or more (meth)acryloyl groups, polyfunctional isocyanates having two or more isocyanate groups, polyfunctional amines having two or more polymerizable carbon-carbon double bonds, and aromatic compounds having two or more polymerizable carbon-carbon double bonds. The content of the crosslinking monomer may be about 0.1 to 20 parts by mass per 100 parts by mass of the copolymer (P), but is preferably less than 0.1 part by mass. It is more preferable that the polymer composition is substantially free of crosslinking monomers.

[0085] The polymer composition of the present invention can be prepared by mixing the copolymer (P), the filler (F), the alcohol-based solvent (S), and other components used as needed.

[0086] The loss tangent tan δ is expressed as the ratio of the storage modulus G' to the loss modulus G" (tan δ=G" / G'), and the smaller the loss tangent value, the lower the fluidity of the polymer composition.

[0087] The polymer composition preferably has a loss tangent tanδ of 2.5 or less or 2.50 or less, more preferably 2.0 or less, even more preferably 1.5 or less, and particularly preferably 1.0 or less, when measured in a low shear environment at a vibration mode, a measurement temperature of 20°C, a strain of 0.5%, and an angular frequency of 10 rad / s. By adjusting the loss tangent of the polymer composition to fall within the above range, dripping after application can be suppressed.

[0088] If the viscosity of the polymer composition is too high, it becomes difficult to send the liquid through a tube, etc. Therefore, the viscosity of the polymer composition is adjusted to a rotational mode at a shear rate of 25 s -1The viscosity when measured under a high shear environment is preferably 200 Pa s or less, more preferably 180 Pa s or less, even more preferably 150 Pa s or less, even more preferably 100 Pa s or less, and particularly preferably 80 Pa s or less or 60 Pa s or less.

[0089] The loss tangent and viscosity of the polymer composition can be measured using a rheometer.

[0090] The polymer composition of the present invention exhibits excellent adhesive properties to wet materials and can therefore be suitably used as various adhesives. Furthermore, the polymer composition of the present invention can be used for medical applications. Specifically, because it exhibits excellent adhesive properties to wet biological tissues, it can be used as a medical adhesive for coating biological tissue surfaces, joining biological tissues together, and joining biological tissues to medical devices. For example, the polymer composition or medical adhesive of the present invention can be applied to biological tissues to coat the biological tissue surface, join biological tissues together, or join biological tissues to medical devices. More specifically, the polymer composition of the present invention can be used as an adhesive for preventing inflammation, bleeding, or stenosis caused by resection of the inside of the digestive tract, preventing colonic anastomotic failure, preventing pancreatic fistula, preventing bleeding after dialysis shunt formation, injecting into varicose veins of the lower limbs to block the veins, and preventing vascular stenosis. Examples of biological tissues that can be used as adherends include the skin, organs, and blood vessels of fish, amphibians, reptiles, birds, humans, and non-human mammals (e.g., cows, sheep, horses, pigs, mice, rats, guinea pigs, hamsters, dogs, cats, rabbits, etc.). Examples of medical devices that can be used as adherends include catheters, sutures, endoscopes, syringes, injectors, pumps, filters, artificial joints, artificial blood vessels, and artificial organs.

[0091] This polymer composition (e.g., a medical adhesive) can adhere (cure) at temperatures close to human body temperature (e.g., about 30 to 45°C), and does not require treatment at high temperatures (e.g., 50°C or higher). There are no particular limitations on how it can be used; it can be applied to an adherend (e.g., biological tissue) and cured (dried) to form a coating. Alternatively, it can be applied to an anastomotic site using sutures or the like and cured (dried). Furthermore, it can be injected intravenously and cured within the blood vessel. It can be used in a variety of ways depending on the application.

[0092] The method for delivering the polymer composition to the application site is not particularly limited, but may be delivered through a tube, as long as the adhesive strength is maintained while the composition is delivered to the adherend. When the polymer composition is used as a medical adhesive, the method for delivering the polymer composition to the application site is also not particularly limited, but may be delivered through a tube using an endoscope, as long as the adhesive strength is maintained while the composition is delivered to the biological tissue that will become the adherend. Specifically, examples include methods in which the polymer composition or medical adhesive is delivered to the vicinity of the application site through a tube using a driving force such as a pump, a syringe, gravity, or a combination thereof.

[0093] Examples of methods for coating or bonding with the present polymer composition (for example, a medical adhesive) include a method in which the composition is delivered in solution form through a tube and then coated and bonded.

[0094] The thickness of the adhesive layer is not particularly limited and may be determined appropriately depending on the application.

[0095] As described above, the polymer composition of the present invention has high adhesive strength to materials in a wet state. When the adhesive strength is measured using the polymer composition of the present invention according to the method described in the Examples below, the adhesive strength can be preferably 14 kPa or more, more preferably 18 kPa or more, even more preferably 20 kPa or more, and particularly preferably 25 kPa or more.

[0096] This application claims the benefit of priority based on Japanese Patent Application Nos. 2024-057359 and 2024-057360, filed on March 29, 2024. The entire contents of the specifications of Japanese Patent Application Nos. 2024-057359 and 2024-057360, filed on March 29, 2024, are incorporated herein by reference.

[0097] The present invention will be explained in more detail below with reference to examples. The present invention is not limited to the following examples, and modifications can of course be made within the scope of the above and below-described aims, and all such modifications are included within the technical scope of the present invention. Analysis or evaluation in the examples and comparative examples was carried out as follows.

[0098] (Determination of Polymer Composition) 1 H-NMR analysis, 13 C-NMR analysis and two-dimensional NMR analysis were appropriately selected and carried out as necessary to determine the polymer composition. 1 H-NMR, 13 Typical conditions for C-NMR analysis are shown below. The measurement and analysis software used was Topspin 4.0.3 from Bruker BioSpin. 1 H-NMR measurement: Apparatus: Fourier transform nuclear magnetic resonance spectrometer (AVANCE NEO 600 model, Bruker Biospin Corporation) Measurement solution: 7 to 15 mg of sample was dissolved in 0.6 ml of deuterated dimethyl sulfoxide. Trifluoroacetic acid (4 to 5% by volume relative to the deuterated dimethyl sulfoxide) was added as necessary. 1 H resonance frequency: 600.13 MHz Flip angle of detection pulse: 30° Data acquisition time: 4.0 seconds Delay time: 1.0 seconds Number of integrations: 64 Measurement temperature: 90°C 13 C-NMR measurement: Equipment: 1 The same equipment as used for H-NMR measurement was used. 1 The same solution as that used for the H-NMR measurement was used. 13C resonance frequency: 150.92 MHz Flip angle of detection pulse: 30° Data acquisition time: 2.0 seconds Delay time: 0.5 seconds Proton decoupling: Full decoupling Number of accumulations: 51,200 Measurement temperature: 50°C

[0099] (Method for measuring weight-average molecular weight) Measurement was carried out using a gel permeation chromatograph (TOSOH HLC-8420GPC). A sample solution was prepared using 30 mM LiBr / DMAc to a concentration of 0.2% by mass, and filtered through a membrane filter before use. Measurement was carried out using two columns (TOSOH TSKgel SuperAWM-H) under conditions of a temperature of 40°C, a flow rate of 0.3 mL / min, and an injection volume of 10 μL. Detection was carried out using a differential refractometer (RI), and the molecular weight was calculated in terms of standard polystyrene.

[0100] (Synthesis of Monomer) <Synthesis Example 1> In a nitrogen atmosphere, 7.75 g (50 mmol) of hydroxytyrosol (HT), 0.985 g (5 mmol) of p-toluenesulfonic acid monohydrate, and 55 ml (500 mmol) of methyl methacrylate (MMA) were placed in a 150 ml recovery flask, and the mixture was heated and stirred at 100° C. The reaction was analyzed by thin layer chromatography (developing solvent: 100% ethyl acetate) and 1 The reaction mixture was monitored by H-NMR. After 6 hours, the reaction solution was returned to room temperature and the reaction was stopped using a saturated aqueous solution of sodium bicarbonate. The reaction solution was extracted three times with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over magnesium sulfate, and the solvent was then distilled off. The obtained crude product was dissolved in methanol and washed three times with hexane, and the solvent was then distilled off. The product was then purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 30 / 70 (volume ratio)), and 9.9 g of methacrylic acid-2-(3,4-dihydroxyphenyl)ethyl ester (MMA-HT) was obtained (yield 89%). The compound was identified by 1 H-NMR was performed.

[0101] (Polymerization of Copolymer) <Polymerization Example 1> Under a nitrogen atmosphere, 0.81 g (3.6 mmol) of MMA-HT, 4.22 g (32.4 mmol) of 2-hydroxyethyl methacrylate (HEMA), 28.43 g of DMSO, and 0.05 g (0.3 mmol) of AIBN were added to a 30 ml recovery flask, and the mixture was reacted at 65°C for 28 hours to produce a copolymer. 1 The ratio of 3,4-dihydroxyphenyl groups to hydroxyethyl groups was determined by H-NMR, and it was confirmed that the molar ratio was 10 / 90, resulting in Polymer 1. The weight average molecular weight (Mw) was 387,800.

[0102] <Polymerization Example 2> Under a nitrogen atmosphere, 0.44 g (2.0 mmol) of MMA-HT, 2.08 g (16.0 mmol) of 2-hydroxyethyl methacrylate (HEMA), 0.40 g (2.0 mmol) of 2-ethylhexyl methacrylate (EHMA), 16.57 g of DMSO, and 0.03 g (0.2 mmol) of AIBN were added to a 30 ml recovery flask, and the mixture was reacted at 65°C for 28 hours to produce a copolymer. 1 It was confirmed by H-NMR that the monomer had been consumed, and furthermore, it was confirmed by NMR analysis that Polymer 2 was obtained, which had the same polymer composition as the charged ratio (MMA-HT / HEMA / EHMA=10 / 80 / 10). The weight average molecular weight (Mw) of the obtained polymer was 326,200.

[0103] <Polymerization Example 3> Under a nitrogen atmosphere, 0.44 g (2.0 mmol) of MMA-HT, 2.08 g (16.0 mmol) of 2-hydroxyethyl methacrylate (HEMA), 0.68 g (2.0 mmol) of stearyl methacrylate (SLMA), 18.16 g of ethanol, and 0.03 g (0.2 mmol) of AIBN were placed in a 30 ml recovery flask, and the mixture was reacted at 65°C for 28 hours to produce a copolymer. 1 It was confirmed by H-NMR that the monomer had been consumed, and furthermore, it was confirmed by NMR analysis that Polymer 3 was obtained, which had the same polymer composition as the charged ratio (MMA-HT / HEMA / SLMA=10 / 80 / 10). The weight average molecular weight (Mw) of the obtained polymer was 182,400.

[0104] (Preparation of Polymer Composition) Example A1 300 mg of Polymer 1 was dissolved in 650 mg of ethanol, the resulting polymer solution was placed in an ointment container, and 50 mg of CNF: cellulose nanofiber (Leocrysta standard grade, fibrous, manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.) was added thereto, followed by dispersion by the following method: For dispersion, a planetary centrifugal mixer (ARE-310, manufactured by Thinky Corporation) was used, and stirring and mixing were carried out at room temperature (25°C) at a rotation speed of 2000 rpm for 20 minutes.

[0105] Examples A2 to A7, Comparative Examples A1 to A3 Polymer compositions of Examples A2 to A7 and Comparative Examples A1 to A3 were prepared in the same manner as in Example A1, except that the types and proportions of polymer, solvent, and filler were changed according to Table 1. The CMF: cellulose microfiber was BiNFi-s CMF manufactured by Sugino Machine Ltd., and was in the form of a fiber.

[0106] Example B1 260 mg of Polymer 1 was dissolved in 540 mg of ethanol, and the resulting polymer solution was placed in an ointment container, to which 200 mg of BAX-A (Japanese Pharmacopoeia barium sulfate (for manufacturing purposes only), manufactured by Sakai Chemical Industry Co., Ltd.) was added, followed by dispersion by the following method: For dispersion, a planetary centrifugal mixer (ARE-310, manufactured by Thinky Corporation) was used, and the mixture was stirred and mixed at room temperature (25°C) at 2000 rpm for 20 minutes.

[0107] Examples B2 to B12 and Comparative Examples B1 to B4 Using the same method as in Example B1, the types and proportions of polymer, solvent, and filler were changed according to Table 2 to prepare polymer compositions of Examples B2 to B12 and Comparative Examples B1 to B4, and their properties were evaluated. Note that BAX-A and BAX-40 are Japanese Pharmacopoeia barium sulfate (for manufacturing purposes only) manufactured by Sakai Chemical Industry Co., Ltd., and CNT is a product name "reinforcing carbon nanofiber" manufactured by Almedio Co., Ltd. CMT is a product name "reinforcing carbon microfiber" manufactured by Almedio Co., Ltd. Cellenpia is manufactured by Nippon Paper Industries Co., Ltd. HAP-100 is hydroxyapatite manufactured by Taihei Chemical Industry Co., Ltd. Note that when the particle shapes were observed using a scanning electron microscope, BAX-A and Cellenpia were amorphous, with average particle sizes of 0.5 μm and 122.3 μm, respectively. BAX-40 was polyhedral and had an average particle size of 3.1 μm. CNT, CMT, and HAP-100 were rod-shaped and had average particle sizes of 9.3 μm, 23.3 μm, and 73 μm, respectively.

[0108] (Evaluation of Dispersibility) The prepared polymer composition was left standing overnight at 25° C. and visually observed. When no sediment was observed, it was rated as ◯, and when sediment was observed, it was rated as ×.

[0109] (Adhesion Test) The test was performed according to the following procedure. The substrate was a PET film (Toyobo Co., Ltd., Model No. A4381) cut to a width of 15 mm and a length of 60 mm, and the backside of a 15 mm square piece of pig skin approximately 5 mm thick was adhered and fixed to the edge with Aron Alpha (Toa Gosei Co., Ltd., Model No. 201). The pig skin surface was wetted with pure water, and excess water was wiped off. Two samples were prepared by applying a polymer composition (polymer amount 7.5 mg) to the pig skin surface. The samples were left to stand at 37°C for 10 minutes, and then bonded together. The samples were fixed with clips and dried at 37°C for 1 hour to prepare test pieces. A tensile adhesion test was performed using a tensile tester (Orientec Co., Ltd., RTA-100) under conditions of a chuck distance of 35 mm, a temperature of 23°C, a relative humidity of 25%, and a pulling rate of 10 mm / min. The above measurement was performed three times using each polymer composition, and the average value was taken as the adhesive strength. The results obtained are shown in Tables 1-2.

[0110] (Method for measuring loss tangent) The loss tangent was measured using a rheometer (MCR-302, manufactured by Anton Paar). For the measurement, a CP-50 (cone-plate, diameter: 49.9 mm, angle: 0.988°) was used, and the measurement was performed by vibration measurement under the measurement conditions of a temperature of 20°C, a strain of 0.5%, and an angular frequency of 10 rad / s. The results obtained using each polymer composition are shown in Tables 1 and 2.

[0111] (Viscosity Measurement Method) The viscosity was measured using a rheometer (MCR-302, manufactured by Anton Paar). For the measurement, a CP-50 (cone-plate, diameter: 49.9 mm, angle: 0.988°) was used, and the measurement was performed by rotational measurement under the measurement conditions of a temperature of 20°C, a shear rate of 25 s -1 The results obtained with each polymer composition are shown in Tables 1-2.

[0112]

[0113]

[0114] The polymer composition of the present invention exhibits excellent adhesive properties to wet biological tissues, and is therefore expected to make a significant contribution to various medical applications such as medical adhesives, etc. Furthermore, due to its properties of low viscosity in a high shear environment and extremely reduced fluidity in a non-shear or low shear environment, it can be used, in particular, as a medical adhesive that can be used via an endoscope, as well as in various applications other than medical use, such as adhesives and coating agents.

Claims

1. A polymer composition comprising: a copolymer (P) containing, as constituent components, a monomer (A) represented by the following formula (1-A) and a monomer (B) having a polymerizable unsaturated bond different from that of the monomer (A); a filler (F); and water and / or an alcohol solvent (S). [In the formula, R represents a hydrogen atom or a methyl group, L represents an amide bond, an ester bond, or a direct bond, Z represents a direct bond or an alkylene group having 1 to 10 carbon atoms, and y represents an integer of 1 to 5.] 2. The polymer composition according to claim 1, wherein the monomer (A) is a monomer represented by the following formula (1): [In the formula, R represents a hydrogen atom or a methyl group, L represents an amide bond, an ester bond, or a direct bond, x represents 0 or an integer of 1 to 10, and y represents an integer of 1 to 5.] 3. The polymer composition according to claim 1, comprising, relative to the total amount of the polymer composition, 1 to 40 mass% of the copolymer (P), 0.1 to 50 mass% of the filler (F), and 10 to 98 mass% of the solvent (S).

4. The polymer composition according to claim 1, which has a loss tangent of 2.50 or less when measured using a rheometer at a measurement temperature of 20°C and an angular frequency of 10 rad / s.

5. Measurement temperature: 20°C and shear rate: 25 s -1 2. The polymer composition according to claim 1, wherein the viscosity of the polymer composition is 200 Pa·s or less when measured at room temperature using a rheometer.

6. The polymer composition according to claim 1, wherein the content of said monomer (A) is 0.01 to 30 mol % based on the total amount of said copolymer (P).

7. The polymer composition according to claim 1, wherein the filler (F) is fibrous or particulate.

8. The polymer composition according to claim 7, wherein the average fiber diameter of the fibrous filler (F) is 0.5 nm or more and 10 μm or less.

9. The polymer composition according to claim 7, wherein the particulate filler (F) has an average particle size (by number) or a d50 particle size (by number) of 0.1 μm or more and 300 μm or less.

10. The specific gravity of the filler (F) is 5 g / cm 3 2. The polymer composition of claim 1, wherein:

11. Polymer composition according to claim 1, characterized in that the filler (F) is constituted by a polysaccharide.

12. The polymer composition according to claim 1, wherein the copolymer (P) has a weight average molecular weight of 50,000 or more and 500,000 or less.

13. The polymer composition according to claim 1, wherein the monomer (A) is represented by the following formula (1a): [In the formula, R represents a hydrogen atom or a methyl group, L represents an amide bond, an ester bond, or a direct bond, and x represents 0 or an integer of 1 to 10.] 14. The polymer composition of claim 1, wherein the monomer (B) is an acrylic and / or methacrylic compound.

15. The polymer composition of claim 1, wherein the monomer (A) is an acrylic and / or methacrylic compound.

16. The polymer composition according to claim 1, wherein the monomer (B) comprises a monomer represented by the following formula (2): [In the formula, R 1 represents a hydrogen atom or a methyl group. 1 is -O-, or any C-H is C-R 2 -O-(CH2) optionally substituted with y -O-, -(O-CH2-CH2) y -O- or -(O-CH-CH-CH) y represents —O—, and R 2 represents an alkyl group having 1 to 6 carbon atoms, and y represents an integer of 1 to 10.

17. A medical material comprising the polymer composition according to any one of claims 1 to 16.

18. A medical adhesive comprising the polymer composition of any one of claims 1 to 16.

19. An adhesive comprising the polymer composition of any one of claims 1 to 16.

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