Polymer composition and medical adhesive containing same

Abstract

The present invention addresses the problem of providing a medical adhesive which has higher adhesive strength to a material that is in a wet state.　The problem can be solved by: a polymer composition containing an alcohol-based solvent and a copolymer that contains, as constituent components, a monomer (A) which is represented by chemical formula (1-A), a monomer B which is a compound that is not represented by formula (1-A) and has a Hansen solubility parameter (HSP value) within a first specific range, and a monomer C which is a compound that is not represented by formula (1-A) and has a Hansen solubility parameter (HSP value) within a second specific range; and a medical adhesive containing the same. (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 adhesive containing same

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

[0002] Medical adhesives require adhesiveness in wet conditions, so fibrin glue and cyanoacrylate adhesives are the mainstream, and there are few materials that can be used. 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] However, while the adhesive described in Non-Patent Document 1 can adhere to adherends in a wet state, it requires the use of a large amount of a crosslinker composed of hydrogen peroxide and horseradish peroxidase to achieve sufficient adhesive strength. 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, Patent Document 2 does not mention adhesive performance to substrates or biological tissues in a wet environment. Patent Document 3 does not mention the use of catechol groups in the examples, nor does it confirm adhesive performance to biological tissues. Patent Document 4 only evaluates bone bonding, and does not provide data on adhesive performance to soft tissues, leaving it unclear. Thus, it is difficult to achieve sufficient adhesive strength in a wet state simply by introducing catechol groups. Therefore, the present invention aims to provide a medical adhesive with high adhesive strength to materials in a wet state.

[0014] As a result of extensive research into the present invention, the inventors have found that the above-mentioned problems can be solved by a polymer composition containing, as constituent components, a copolymerized polymer including: a monomer (A) represented by chemical formula (1-A); a monomer B which is a compound other than formula (1-A) and has a Hansen solubility parameter (HSP value) within a first specific range; and a monomer C which is a compound other than formula (1-A) and has a Hansen solubility parameter (HSP value) within a second specific range; and an alcohol-based solvent, and a medical adhesive containing the same, thereby completing the present invention.

[0015] That is, the present invention comprises the following: Item 1. A copolymer (P) containing, as constituent components, a group derived from a monomer (A) represented by the following formula (1-A), a group derived from a monomer (B), and a group derived from a monomer (C), and an alcohol-based solvent (S), wherein the monomer (B) is a compound not corresponding to formula (1-A) and has a Hansen solubility parameter (HSP value) in which the dispersion term (δd1) is 15.5≦δd1≦17.0, the polar term (δp1) is 2.8≦δp1≦13.5, and the hydrogen bond term (δh1) is 7.6≦δh1≦13.5, and the monomer (C) is a compound not corresponding to formula (1-A) and has a Hansen solubility parameter (HSP value) in which the dispersion term (δd2) is 14.4≦δd2≦19.0, the polar term (δp 2 ) is 1.8≦δp2 ≦9.6, and the hydrogen bonding term (δh2) is 2.4≦δh2 ≦7.5. [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, wherein the constituent ratios of the monomer (A), the monomer (B), and the monomer (C) are, relative to the entire copolymer (P), 0.01 to 30 mol % for the monomer (A), 20 to 99.98 mol % for the monomer (B), and 0.01 to 50 mol % for the monomer (C). Item 4. The polymer composition according to any one of Items 1 to 3, wherein the molar ratio (B / A) of the monomer (B) to the monomer (A) constituting the copolymer (P) is 2.0 to 40. Item 5. The polymer composition according to any one of Items 1 to 4, wherein the molar ratio (C / A) of the monomer (C) to the monomer (A) constituting the copolymer (P) is 0.1 to 20. Item 6. Item 5. The polymer composition according to any one of Items 1 to 5, wherein the copolymer (P) has a weight average molecular weight of 50,000 or more and 500,000 or less. Item 7. The polymer composition according to any one of Items 1 to 6, wherein the alcohol-based solvent (S) is ethanol, isopropanol, or a mixed solvent containing one or more of these. Item 8. The polymer composition according to any one of Items 1 to 7, wherein the concentration of the copolymer (P) is 1 to 40 mass%. Item 9. The polymer composition according to any one of Items 1 to 8, 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 10. The polymer composition according to any one of Items 1 to 9, wherein the monomer (B) has at least one group selected from the group consisting of a hydroxy group, a carboxyl group, and an amino group in its structure. Item 11. The polymer composition according to any one of Items 1 to 10, wherein the monomer (C) has at least one group selected from the group consisting of an alkyl group, a cycloalkyl group, and a skeleton having a heteroatom not containing hydrogen-bonding hydrogen in its structure. Item 12. A medical adhesive comprising the polymer composition according to any one of Items 1 to 11. Item 13. The medical adhesive according to Item 12, which is an adhesive that can be used to prevent inflammation, bleeding, and stenosis inside the digestive tract, prevent colorectal anastomotic failure, prevent pancreatic fistula, prevent bleeding from dialysis shunts, prevent venous occlusion in varicose veins of the lower limbs, or prevent vascular stenosis. Item 14. Item 14. A method for applying an adhesive containing the polymer composition according to any one of Items 1 to 13 to biological tissue to coat the surface of biological tissue, join biological tissues together, or join biological tissue to a medical device. Item 15. A method for applying an adhesive containing the polymer composition according to any one of Items 1 to 13 to biological tissue to prevent inflammation, bleeding, or stenosis inside the digestive tract, prevent colonic anastomotic failure, prevent pancreatic fistula, prevent bleeding from a dialysis shunt, occlude veins in varicose veins of the lower limbs, or prevent vascular stenosis. Item 16. Use of the polymer composition according to any one of Items 1 to 13 to produce an adhesive used for coating the surface of biological tissue, joining biological tissues together, or joining biological tissue to a medical device. Item 17. Item 14. Use of the polymer composition according to any one of Items 1 to 13 for producing an adhesive used to prevent inflammation, bleeding, or stenosis inside the digestive tract, prevent colonic anastomotic failure, prevent pancreatic fistula, prevent bleeding from dialysis shunts, prevent venous obstruction in varicose veins of the lower extremities, or prevent vascular stenosis.

[0016] According to the present invention, it is possible to provide a medical polymer composition having high adhesiveness to wet biological tissues and a medical adhesive containing the same.

[0017] 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.

[0018] The medical polymer composition of the present invention comprises a group derived from a monomer (A) represented by the following formula (1-A), a group derived from a monomer (B) having Hansen solubility parameters (HSP values) within the ranges of a dispersion term (δd1) of 15.5≦δd1≦17.0, a polar term (δp1) of 2.8≦δp1≦13.5, and a hydrogen bond term (δh1) of 7.6≦δh1≦13.5, but not falling under the formula (1-A), and a group derived from a monomer (B) having Hansen solubility parameters (HSP values) within the ranges of a dispersion term (δd2) of 14.4≦δd2≦19.0, a polar term (δp 2 The copolymer (P) contains as a constituent a group derived from a monomer (C) whose molecular weight (ρ) is 1.8≦δp2≦9.6 and whose hydrogen bond term (δh2) is 2.4≦δh2≦7.5, but which does not fall under the following formula (1-A): and an alcohol-based solvent (S). By including the monomer (C) as a constituent of the copolymer (P) in addition to the monomer (A), hydrophobic interactions are expressed, thereby enabling the copolymer (P) to have excellent adhesive properties to wet biological tissues, and by including the monomer (B) as a constituent of the copolymer (P), hydrogen bonds can be formed, allowing the affinity with the alcohol-based solvent to be adjusted.

[0019] In the formula (1-A), R represents a hydrogen atom or a methyl group, and is particularly preferably a methyl group.

[0020] In the formula (1-A), L represents an amide bond, an ester bond, or a direct bond. Among these, an amide bond or an ester bond is preferred, and an ester bond is more preferred from the viewpoint of further increasing the solubility in alcoholic solvents.

[0021] 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.

[0022] 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.

[0023] 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.]

[0024] 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.

[0025] 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.]

[0026] 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.

[0027] 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 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.

[0028] 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.

[0029] Among these, N-[2-(3,4-dihydroxyphenyl)ethyl]methacrylamide (formula (3)) and / or 2-(3,4-dihydroxyphenyl)ethyl methacrylate (formula (4)) are preferred due to their 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 raw material for supplements and can be produced by plant extraction or biosynthesis.

[0030]

[0031]

[0032] The monomer (A) constituting the copolymer (P) may be one type or two or more types.

[0033] HSP (Hansen Solubility Parameter) is a value used to predict the solubility of a substance and is expressed by three parameters: London dispersion force, dipole-dipole force, and hydrogen bonding force. In the present invention, the component corresponding to London dispersion force is referred to as the dispersion term (hereinafter also referred to as "δd"), the component corresponding to dipole-dipole force is referred to as the polar term (hereinafter also referred to as "δp"), and the component corresponding to hydrogen bonding force is referred to as the hydrogen bonding term (hereinafter also referred to as "δh"). These three parameters can be regarded as coordinates in a three-dimensional space (Hansen space). When the HSPs of two substances are plotted in Hansen space, the closer the distance between the two plotted points, the higher the affinity of the two substances and the easier they are to dissolve in each other.

[0034] A database has been constructed for the HSPs of commonly used substances, and by referring to this database, the HSP value of a desired substance can be obtained.

[0035] Even for substances whose HSP values ​​are not registered in the database, the HSP value can be calculated from their chemical structure using computer software such as Hansen Solubility Parameters in Practice (HSPiP). Alternatively, the HSP value can be determined by conducting a dissolution test using multiple solvents with known HSP values ​​and inputting the resulting solubilities into HSPiP. Furthermore, in the case of a mixture of multiple substances, the HSP value can be calculated as the sum of the values ​​obtained by multiplying the HSP values ​​of each substance by the volume ratio of each substance. In the present invention, the HSP value of a monomer is determined by HSPiP.

[0036] As the monomer (B), from the viewpoint of solubility in alcohol and adhesiveness, those having a Hansen solubility parameter (HSP value) dispersion term (δd1) within the range of 15.5≦δd1≦17.0, a polar term (δp1) within the range of 2.8≦δp1≦13.5, and a hydrogen bond term (δh1) within the range of 7.6≦δh1≦13.5 are preferred, and those having a dispersion term (δd1) within the range of 16.0≦δd1≦17.0, a polar term (δp1) within the range of 5.0≦δp1≦10.0, and a hydrogen bond term (δh1) within the range of 8.0≦δh1≦11.5 are more preferred, and those having a dispersion term (δd1) within the range of 16.0≦δd1≦17.0, a polar term (δp1) within the range of 5.5≦δp1≦ More preferably, the hydrogen bond term (δh1) is in the range of 10.0≦δh1≦11.5.

[0037] Monomer (B) is preferably a monomer copolymerizable with monomer (A) and having a polymerizable unsaturated group. Examples of the polymerizable unsaturated group include a vinyl group and a (meth)acryloyl group. Of these, a (meth)acryloyl group is preferred, and a methacryloyl group is more preferred from the viewpoints of controlling the degree of polymerization and durability (e.g., acid resistance and enzyme resistance). The number of polymerizable unsaturated groups per molecule of monomer (B) is preferably 1 to 4, more preferably 1.

[0038] Furthermore, the monomer (B) is preferably a monomer having a hydrophilic group, and examples of the hydrophilic group include a carboxy group, a hydroxy group, an amino group, a sulfonate ion group, and an ammonium ion group. Among these, at least one selected from a carboxy group, a hydroxy group, and an amino group is preferred, a hydroxy group and / or a carboxy group is more preferred, and it is even more preferred that the monomer (B) has at least a hydroxy group. The number of hydrophilic groups per molecule of the monomer (B) is preferably 1 to 4, and more preferably 1.

[0039] As the monomer (B), it is preferable to use at least one monomer having a hydrophilic group and a (meth)acryloyl group (particularly, a (meth)acrylate monomer having a hydrophilic group), and more specifically, it is preferable to use at least one monomer having at least one hydrophilic group selected from a carboxy group, a hydroxy group, an amino group, a sulfonic acid ion group, and an ammonium ion group, and a (meth)acryloyl group (particularly, a (meth)acrylate monomer having a carboxy group, a hydroxy group, an amino group, a sulfonic acid ion group, and / or an ammonium ion group), it is more preferable to use at least one monomer having at least one hydrophilic group selected from a carboxy group, a hydroxy group, an amino group, a sulfonic acid ion group, and an ammonium ion group, and a methacryloyl group, and it is even more preferable to use at least one monomer having at least one hydrophilic group selected from a carboxy group, a hydroxy group, an amino group, a sulfonic acid ion group, and an ammonium ion group, and a methacryloyl group. Among these, it is preferable to use at least one (meth)acrylate monomer having a hydroxy group, and it is more preferable to use at least one methacrylate monomer having a hydroxy group, since the solubility in water can be adjusted to prevent the polymer from dissolving due to water in the body.

[0040] Examples of the (meth)acrylate monomer having a hydroxy group include hydroxyalkyl (meth)acrylates such as 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 (meth)acrylate; polyalkylene glycol mono(meth)acrylates such as polyethylene glycol mono(meth)acrylate; and N-methylol (meth)acrylamide. Among these, hydroxyalkyl (meth)acrylates are preferred, and hydroxyalkyl (meth)acrylates are more preferred, as they allow for easy adjustment of the solubility in ethanol and water. 1-12 Alkyl (meth)acrylate, more preferably hydroxy C 2-4 Alkyl (meth)acrylates are preferred, with 2-hydroxyethyl (meth)acrylate and 2-hydroxypropyl (meth)acrylate being particularly preferred.

[0041] In 100 mol % of groups derived from the monomer (B) constituting the copolymer (P), the amount of groups derived from the (meth)acrylate monomer having a hydroxy group is preferably 30 mol % or more, more preferably 60 mol % or more, even more preferably 80 mol % or more, still more preferably 90 mol % or more, and may even be 100 mol %.

[0042] The monomer having a carboxy group includes (meth)acrylic acid. Among them, a monomer having a carboxy group and a (meth)acryloyl group is preferred, (meth)acrylic acid is more preferred, and methacrylic acid is even more preferred.

[0043] The monomer (B) constituting the copolymer (P) may be one type or two or more types.

[0044] From the viewpoint of solubility in alcohol and adhesiveness, the monomer (C) is selected from the group consisting of a dispersion term (δd2) of the Hansen solubility parameter (HSP value) of 14.4 ≦ δd2 ≦ 19.0, a polar term (δp 2 ) is preferably in the range of 1.8≦δp2≦9.6, the hydrogen bond term (δh2) is preferably in the range of 2.4≦δh2≦7.5, the dispersion term (δd2) is preferably in the range of 15.0≦δd2≦19.0, and the polar term (δp 2 It is more preferable that the dispersion term (δd2) is in the range of 15.5 ≦ δd2 ≦ 16.5, the polar term (δp 2 It is more preferable that the hydrogen bond term (δh) is in the range of 1.8≦δp2≦3.5 and the hydrogen bond term (δh2) is in the range of 2.4≦δh2≦4.5.

[0045] Monomer (C) is preferably a monomer copolymerizable with monomer (A) and having a polymerizable unsaturated group. Examples of the polymerizable unsaturated group include a vinyl group and a (meth)acryloyl group. Of these, a (meth)acryloyl group is preferred, and a methacryloyl group is more preferred from the viewpoint of controlling the degree of polymerization. The number of polymerizable unsaturated groups per molecule of monomer (C) is preferably 1 to 4, and more preferably 1.

[0046] As the monomer (C), it is preferable to use a monomer having, in addition to the above polymerizable unsaturated group, at least one of a hydrophobic alkyl group, a cycloalkyl group, and a skeleton having a heteroatom that does not contain hydrogen-bonding hydrogen.

[0047] 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.

[0048] Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group, and among these, a cycloalkyl group having 4 to 8 carbon atoms is preferred.

[0049] 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.

[0050] 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.

[0051] In particular, in order to suppress water absorption into the polymer, it is preferable to use at least one (meth)acrylate monomer having an alkyl group and / or a cycloalkyl group as the monomer (C), and it is more preferable to use at least one (meth)acrylate monomer having an alkyl group.

[0052] Examples of (meth)acrylate monomers having an alkyl or cycloalkyl group 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; and polyalkylene glycol monoalkyl ether (meth)acrylates such as polyethylene glycol monomethyl ether (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.

[0053] The monomer having a skeleton containing a heteroatom that does not contain hydrogen-bonding hydrogen is preferably a (meth)acrylate monomer, and specific examples thereof include tetrahydrofurfuryl (meth)acrylate and N-succinimidyl (meth)acrylate.

[0054] The monomer (C) constituting the copolymer (P) may be one type or two or more types.

[0055] The copolymer (P) may have a group derived from a monomer other than the above monomers (A) to (C) (hereinafter referred to as monomer (D)). Monomer (D) is not particularly limited as long as it is a monomer other than (A) to (C) and is copolymerizable with monomer (A). Examples of monomer (D) include 2-(trifluoromethyl)(meth)acrylic acid, mono(2-(meth)acryloyloxyethyl) succinate, 4-[[6-((meth)acryloyloxy)hexyl]oxy]benzoic acid, 2,2,6,6-tetramethyl-4-piperidyl (meth)acrylate, (2-oxo-1,3-dioxolan-4-yl)methyl (meth)acrylate, 4-benzoylphenyl (meth)acrylate, and 9-anthrylmethyl methacrylate. The monomer (D) constituting the copolymer (P) may be one type or two or more types.

[0056] 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, particularly preferably 5 mol% or more, and may be 8 mol% or more or 10 mol% or more, from the viewpoint of further improving adhesiveness to wet tissues. Furthermore, from the viewpoint of further improving solubility in alcoholic solvents, it is preferably 30 mol% or less, more preferably 25 mol% or less, even more preferably 20 mol% or less, and particularly preferably 12 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 25 mol%, even more preferably 1 to 20 mol%, even more preferably 5 to 12 mol%, and may be 8 to 30 mol% or 10 to 30 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 alcohol-based solvents 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.

[0057] 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 alcohol solvents. Furthermore, from the viewpoint of suppressing the polymer's 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%. Furthermore, the molar ratio (B / A) of monomer (B) to monomer (A) constituting copolymer (P) is, for example, 1.5 to 100, preferably 1.5 to 50, more preferably 2 to 35, and even more preferably 3 to 15.

[0058] The ratio of monomer (C) 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 even more preferably 5 mol% or more, from the viewpoint of suppressing the water absorption of the polymer and further strengthening adhesive strength. Furthermore, from the viewpoint of further enhancing solubility in alcohol solvents, it is preferably 50 mol% or less, more preferably 30 mol% or less, even more preferably 15 mol% or less, and even more preferably 10 mol% or less. That is, the ratio of monomer (C) to all monomers constituting copolymer (P) is preferably 0.01 to 50 mol%, more preferably 0.1 to 30 mol%, even more preferably 1 to 15 mol%, and even more preferably 5 to 10 mol%. Furthermore, the molar ratio (C / A) of monomer (C) to monomer (A) constituting copolymer (P) is, for example, 0.01 to 100, preferably 0.1 to 20, more preferably 0.1 to 15, and even more preferably 0.5 to 10.

[0059] The total proportion of the monomers (A) to (C) relative to all the monomers constituting the copolymer (P) is preferably 50 mol% or more, more preferably 80 mol% or more, even more preferably 90 mol% or more, still more preferably 95 mol% or more, and may be 100 mol%.

[0060] 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.

[0061] 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 alcohol-based 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. By adjusting the weight-average molecular weight to the above-mentioned lower limit or more, the mechanical strength of the copolymer (P) is increased, and adhesive strength tends to be further improved. Furthermore, by adjusting the weight average molecular weight to the above upper limit or less, the solubility in alcohol-based solvents can be further increased, and the concentration of copolymer (P) in the adhesive can be increased, which tends to make it easier for the adhesive performance to be exhibited.

[0062] 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 monomers (A), (B), (C) and, if necessary, another monomer (D) in an organic solvent, adding a polymerization initiator, and then heating or irradiating the resulting mixture with light.

[0063] Examples of organic solvents used in the polymerization of the copolymer (P) include, but are not limited to, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 1,4-dioxane, toluene, xylene, hexane, heptane, ethyl acetate, ethanol, and the like, which can be used alone or in combination of two or more. Since the solvent is intended for medical use, dimethyl sulfoxide and ethanol, which have a proven track record of use in pharmaceuticals, are preferred.

[0064] 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), but the polymerization initiator is not limited to these.

[0065] The polymer composition of the present invention may contain one or more copolymers (P).

[0066] Examples of the alcohol-based solvent (S) of the present invention include alkyl alcohols such as methanol, ethanol, propanol, isopropanol, and butanol; glycols such as ethylene glycol and propylene glycol; and the like. 1-4 The alcohol-based solvent (S) preferably 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.

[0067] From the viewpoint of curing time, the solid content concentration of the copolymer (P) 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 alcohol-based solvents, it is preferably 40% by mass or less, more preferably 35% by mass or less. That is, the solid content concentration of the copolymer (P) is preferably 1 to 40% by mass, more preferably 5 to 35% by mass, even more preferably 10 to 35% by mass, or may be 20 to 40% by mass or 25 to 40% by mass. Adjusting the solid content concentration 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 solid content concentration to the above-mentioned upper limit or below further enhances solubility in alcohol-based solvents, and tends to facilitate the exertion of adhesive performance. The "solid content concentration of the copolymer (P)" refers to the concentration of the copolymer (P) (in terms of solid content) in the polymer composition.

[0068] The content of the copolymer (P) relative to 100 parts by mass of the alcohol-based 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, and still more preferably 15 to 55 parts by mass, and may be 30 to 100 parts by mass or 40 to 100 parts by mass.

[0069] The total content of the copolymer (P) and the alcohol-based 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.

[0070] 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.

[0071] 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.

[0072] The polymer composition of the present invention can be used for medical applications. Specifically, because it exhibits excellent adhesion 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 tissue to coat the biological tissue surface, join biological tissues together, or join biological tissue to a medical device. 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 anastomosis 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 serve as adherends include catheters, sutures, endoscopes, syringes, injectors, pumps, filters, artificial joints, artificial blood vessels, and artificial organs.

[0073] The polymer composition and medical adhesive can adhere (cure) at temperatures close to human body temperature (e.g., about 30 to 45°C), and do not require treatment at high temperatures (e.g., 50°C or higher). There are no particular limitations on how they are used; they can be applied to the biological tissue to be adhered and cured (dried) to form a coating. Alternatively, they can be applied to the site of anastomosis using sutures or the like and cured (dried). Furthermore, they can be injected intravenously and cured within the blood vessel. They can be used in a variety of ways depending on the application.

[0074] The method for delivering the polymer composition and medical adhesive of the present invention to the vicinity of the adherend is not particularly limited, as long as they reach the vicinity of the adherend while maintaining their adhesive strength. Specific examples include a method in which the polymer composition or medical adhesive reaches the vicinity of the adherend via a tube using a driving force such as a pump, a syringe, gravity, or a combination of these. It is also possible to deliver the polymer composition or medical adhesive to the vicinity of the adherend using a spatula or the like while it is still in a liquid state, or using tweezers or the like after gelling it in advance.

[0075] Methods for coating or bonding with the polymer composition and medical adhesive of the present invention that have reached the vicinity of the area to be adhered include direct application in a liquid state, or pressing a gelled product against the area to be adhered.

[0076] The thickness of the adhesive layer is not particularly limited and may be determined appropriately depending on the application.

[0077] As described above, the polymer composition and medical adhesive of the present invention have high adhesive strength to materials in a wet state. When the adhesive strength is measured using the polymer composition and medical adhesive 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 25 kPa or more, and particularly preferably 28 kPa or more.

[0078] This application claims the benefit of priority based on Japanese Patent Application No. 2024-057358, filed on March 29, 2024. The entire contents of the specification of Japanese Patent Application No. 2024-057358, filed on March 29, 2024, are incorporated herein by reference.

[0079] 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.

[0080] (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. 1H-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 analysis: 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. 13 C 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

[0081] (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.

[0082] (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 1The 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.

[0083] (Synthesis of Copolymer) Example 1 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / EHMA=10 / 80 / 10. The weight average molecular weight (Mw) of the obtained polymer was 326,200. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0084] 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), 0.34 g (2.0 mmol) of ethyl methacrylate (ELMA), 16.25 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. 1It was confirmed by H-NMR that the monomer had been consumed, and furthermore, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / ELMA=10 / 80 / 10. The weight average molecular weight (Mw) of the obtained polymer was 397,900. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0085] 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 allowed to react 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / SLMA=10 / 80 / 10. The weight average molecular weight (Mw) of the obtained polymer was 182,400. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0086] Example 4 Under a nitrogen atmosphere, 0.44 g (2.0 mmol) of MMA-HT, 1.30 g (10.0 mmol) of 2-hydroxyethyl methacrylate (HEMA), 1.59 g (8.0 mmol) of 2-ethylhexyl methacrylate (EHMA), 18.86 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / EHMA=10 / 50 / 40. The weight average molecular weight (Mw) of the obtained polymer was 234,600. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0087] Example 5 Using the polymer polymerized in Example 1, the solubility in isopropanol and adhesive strength were measured.

[0088] Example 6 Under a nitrogen atmosphere, 0.44 g (2.0 mmol) of MMA-HT, 2.29 g (17.6 mmol) of 2-hydroxyethyl methacrylate (HEMA), 0.08 g (0.4 mmol) of 2-ethylhexyl methacrylate (EHMA), 15.95 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / EHMA=10 / 88 / 2. The weight average molecular weight (Mw) of the obtained polymer was 355,300. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0089] Example 7 Under a nitrogen atmosphere, 0.13 g (0.6 mmol) of MMA-HT, 2.26 g (17.4 mmol) of 2-hydroxyethyl methacrylate (HEMA), 0.40 g (2.0 mmol) of 2-ethylhexyl methacrylate (EHMA), 15.83 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / EHMA=3 / 87 / 10. The weight average molecular weight (Mw) of the obtained polymer was 341,600. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0090] Example 8 Under a nitrogen atmosphere, 0.17 g (0.15 mmol) of MMA-HT, 1.66 g (12.8 mmol) of 2-hydroxyethyl methacrylate (HEMA), 0.30 g (1.51 mmol) of 2-ethylhexyl methacrylate (EHMA), 11.37 g of DMSO, and 0.02 g (0.01 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. 1It was confirmed by H-NMR that the monomer had been consumed, and furthermore, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / EHMA=5 / 85 / 10. The weight average molecular weight (Mw) of the obtained polymer was 284,300. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0091] Example 9 Under a nitrogen atmosphere, 0.62 g (2.8 mmol) of MMA-HT, 1.98 g (15.2 mmol) of 2-hydroxyethyl methacrylate (HEMA), 0.40 g (2.0 mmol) of 2-ethylhexyl methacrylate (EHMA), 16.98 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / EHMA=14 / 76 / 10. The weight average molecular weight (Mw) of the obtained polymer was 296,300. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0092] Example 10 Under a nitrogen atmosphere, 0.44 g (2.0 mmol) of MMA-HT, 2.31 g (16.0 mmol) of hydroxypropyl methacrylate (HPMA), 0.40 g (2.0 mmol) of 2-ethylhexyl methacrylate (EHMA), 17.84 g of DMSO, and 0.03 g (0.2 mmol) of AIBN were placed in a 30 ml recovery flask, and the mixture was allowed to react 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HPMA / EHMA=10 / 80 / 10. The weight average molecular weight (Mw) of the obtained polymer was 325,100. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0093] Example 11 Under a nitrogen atmosphere, 0.44 g (2.0 mmol) of MMA-HT, 1.48 g (11.4 mmol) of 2-hydroxyethyl methacrylate (HEMA), 0.52 g (6.0 mmol) of methacrylic acid (MAA), 0.11 g (0.6 mmol) of N-succinimide methacrylate (NSMA), 14.47 g of DMSO, and 0.03 g (0.2 mmol) of AIBN were placed in a 30 ml recovery flask, and the mixture was allowed to react 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, NMR analysis confirmed that the polymer composition (molar ratio) was MMA-HT / HEMA / MAA / NSMA=10 / 57 / 30 / 3. The weight average molecular weight (Mw) of the obtained polymer was 264,300. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0094] Comparative 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 placed in a 30 ml recovery flask and 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 to be 10 / 90 (molar ratio). The weight average molecular weight (Mw) was 356,700. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0095] Comparative Example 2 Under a nitrogen atmosphere, 3.32 g (25.5 mmol) of HEMA, 0.89 g (4.5 mmol) of 2-ethylhexyl methacrylate (EHMA), 23.86 g of DMSO, and 0.04 g (0.2 mmol) of AIBN were added to a 100 ml recovery flask, and the mixture was reacted at 65° C. for 13 hours to produce a polymer. 1 The ratio of hydroxyethyl groups to 2-ethylhexyl groups was determined by H-NMR to be 85 / 15 (molar ratio). The weight average molecular weight (Mw) was 265,300. The solubility in ethanol and adhesive strength of the obtained polymer were measured.

[0096] (Solubility Test) The solubility in ethanol or isopropanol of each polymer polymerized in Examples 1 to 11 and Comparative Examples 1 and 2 was confirmed. The test method involved adding 100 mg of each polymer obtained in the Examples and Comparative Examples and 213 mg of ethanol or isopropanol to a screw tube, capping it, and dissolving it in an ultrasonic cleaner (AS ONE, triple-frequency ultrasonic cleaner) at a frequency of 28 Hz for 10 hours while maintaining the temperature at 20°C or higher and 40°C or lower. The state of dissolution of the polymer was then visually confirmed. The solubility was evaluated as follows: no residual residue was left undissolved, evaluated as ◯; and residual residue was observed, evaluated as ×. The results obtained using each polymer are shown in Table 2.

[0097] (Tensile Adhesion Test) - Preparation of Polymer Composition - 79 mg of each polymer obtained in the Examples and Comparative Examples and 500 mg of ethanol or isopropanol were added to a screw tube, and the polymer was dissolved under the same conditions as in the solubility test to prepare a polymer composition. - Tensile 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, with the backside of a 15 mm square piece of pig skin approximately 5 mm thick attached to the edge using 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 the polymer composition (7.5 mg of polymer) to the pig skin surface, and the two samples were left to stand at 37°C for 10 minutes before being bonded together. The samples were fixed with clips and dried at 37°C for 1 hour to prepare test specimens. A tensile adhesion test was carried out using a tensile testing machine (Orientec Co., Ltd., RTA-100) under the 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 carried out five times for each polymer composition, and the average value was taken as the adhesive strength. The results are shown in Table 2.

[0098] The HSP values ​​of the monomers used are shown in Table 1.

[0099]

[0100]

[0101] The polymer composition of the present invention exhibits excellent adhesive properties to wet biological tissues, and is therefore excellent in tissue-coating properties and tissue joining properties, and is expected to make a significant contribution to various medical applications as a medical adhesive.

Claims

1. A copolymer (P) containing, as constituent components, a group derived from a monomer (A) represented by the following formula (1-A), a group derived from a monomer (B), and a group derived from a monomer (C), and an alcohol-based solvent (S), wherein the monomer (B) is a compound not corresponding to formula (1-A) and has a Hansen solubility parameter (HSP value) in which the dispersion term (δd1) is 15.5 ≦ δd1 ≦ 17.0, the polar term (δp1) is 2.8 ≦ δp1 ≦ 13.5, and the hydrogen bond term (δh1) is 7.6 ≦ δh1 ≦ 13.5, and the monomer (C) is a compound not corresponding to formula (1-A) and has a Hansen solubility parameter (HSP value) in which the dispersion term (δd2) is 14.4 ≦ δd2 ≦ 19.0, the polar term (δp 2 ) is 1.8≦δp2 ≦9.6, and the hydrogen bonding term (δh2) is 2.4≦δh2 ≦7.

5. [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, wherein the constituent ratios of the monomer (A), the monomer (B), and the monomer (C) are, relative to the entire copolymer (P), 0.01 to 30 mol % for the monomer (A), 20 to 99.98 mol % for the monomer (B), and 0.01 to 50 mol % for the monomer (C), respectively.

4. The polymer composition according to claim 1, wherein the molar ratio (B / A) of the monomer (B) to the monomer (A) constituting the copolymer (P) is 2.0 to 40.

5. The polymer composition according to claim 1, wherein the molar ratio (C / A) of the monomer (C) to the monomer (A) constituting the copolymer (P) is 0.1 to 20.

6. 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.

7. The polymer composition according to claim 1, wherein the alcohol-based solvent (S) is ethanol, isopropanol, or a mixed solvent containing at least one of these.

8. The polymer composition according to claim 1, wherein the concentration of the copolymer (P) is 1 to 40% by mass.

9. 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.) 10. The polymer composition according to claim 1, wherein the monomer (B) has at least one group selected from the group consisting of a hydroxy group, a carboxyl group, and an amino group in its structure.

11. The polymer composition according to claim 1, wherein the monomer (C) has, in its structure, a polymerizable unsaturated group and at least one of an alkyl group, a cycloalkyl group, and a skeleton having a heteroatom that does not contain hydrogen-bonding hydrogen.

12. A medical adhesive comprising the polymer composition according to any one of claims 1 to 11.

13. The medical adhesive according to claim 12, which is an adhesive that can be used to prevent inflammation, bleeding, and stenosis inside the digestive tract, prevent colonic anastomotic failure, prevent pancreatic fistula, prevent bleeding from dialysis shunts, prevent venous blockage in varicose veins of the lower limbs, or prevent vascular stenosis.

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