Adhesive, wound dressing material, and adhesion prevention material

Abstract

This adhesive comprises: a first agent containing gelatin, a gelatin derivative in which a hydrophobic group is bonded to the gelatin via an imino group and that is represented by formula 1: GltnNH-R1, and cyclodextrin, the gelatin having a molecular weight smaller than 50,000; and a second agent containing a crosslinking agent for at least one substance selected from the group consisting of the above gelatin and the above gelatin derivative. The adhesive has an excellent tissue adhesion even when a gelatin derivative having a high introduction rate is used. In formula 1, Gltn represents a gelatin residue, R1 represents the hydrophobic group, and NH represents the imino group bonded to the gelatin residue and the hydrophobic group.

Description

Technical Field

[0001] The present invention relates to an adhesive, a wound dressing, and an anti-adhesion material.

Background Art

[0002] A tissue adhesive using a gelatin derivative obtained by introducing a hydrophobic group into gelatin is known. Patent Document 1 describes "a tissue adhesive obtained by mixing an adhesive component containing an aqueous solution of fish-derived gelatin and a curing component containing an aqueous solution of a water-soluble crosslinking molecule and applying it to a tissue, wherein the molecular main chain of the water-soluble crosslinking molecule has an amide bond or an ethylene glycol unit or a sugar chain and has two or more active ester groups or acid anhydrides or aldehyde groups."

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The properties of a gelatin derivative into which a hydrophobic group has been introduced change according to the amount of the introduced hydrophobic group. In particular, a highly hydrophobic gelatin (hereinafter also referred to as "high-introduction-rate hydrophobic gelatin") has excellent self-assembling ability (the function of aggregating and gelling) and is expected to be applied to particulate members. On the other hand, as a gelatin derivative used for a tissue adhesive for adhesion to living tissues, a gelatin derivative with a high introduction rate has a strong self-assembling ability, so there is room for improvement in adhesion when used alone.

[0005] If a gelatin derivative with a high introduction rate can be applied not only to members with a particulate shape but also to tissue adhesives, it is convenient because the applications will expand even if the types of gelatin derivatives produced are limited. Therefore, an object of the present invention is to provide an adhesive having excellent tissue adhesion even when using a gelatin derivative with a high introduction rate. Another object of the present invention is to provide a wound dressing material and an anti-adhesion material.

Means for Solving the Problems

[0006] As a result of intensive studies to achieve the above problems, the present inventors have found that the above problems can be achieved by the following configuration.

[0007] [1] An adhesive comprising a first agent containing gelatin, a gelatin derivative in which a hydrophobic group is bonded to the gelatin via an imino group and represented by the following formula 1, and cyclodextrin, wherein the molecular weight of the gelatin is less than 50,000, and a second agent containing at least one crosslinking agent selected from the group consisting of the gelatin and the gelatin derivative. [2] The adhesive according to [1], wherein the introduction rate of the hydrophobic group in the gelatin derivative is 0.40 to 0.80. [3] The adhesive according to [1] or [2], further containing polyethylene glycol. [4] R in the above formula 1 1 is a linear or branched alkyl group having 1 to 20 carbon atoms, and the adhesive according to any one of [1] to [3]. [5] The adhesive according to [4], wherein the above R 1 is a linear alkyl group having 7 to 12 carbon atoms. [6] The adhesive according to any one of [1] to [5], wherein the cyclodextrin is α-cyclodextrin or a derivative thereof. [7] The adhesive according to any one of [1] to [6], wherein the average introduction rate of the hydrophobic group in the first agent is 0.01 to 0.50. [8] The adhesive according to any one of [1] to [7], wherein the molar ratio of the cyclodextrin content to the hydrophobic group content in the first agent is 0.1 to 2.5. [9] The adhesive according to [7], wherein the average introduction rate is 0.01 or more and less than 0.40.

[10] The adhesive according to [7], wherein the average introduction rate is less than 0.30.

[11] The adhesive according to [7], wherein the average introduction rate is less than 0.15.

[12] The adhesive according to any one of [1] to

[11] , wherein the crosslinking agent is a compound having at least two active ester groups.

[13] The adhesive according to [3], wherein the number average molecular weight of the polyethylene glycol is 400 to 3500.

[14] The adhesive according to any one of [1] to

[13] , wherein the gelatin is cold water fish gelatin.

[15] A wound dressing material containing the adhesive according to any one of [1] to

[14] .

[16] An adhesion prevention material containing the adhesive according to any one of [1] to

[14] . [Effect of the Invention]

[0008] According to the present invention, an adhesive having excellent tissue adhesion can be provided even when a gelatin derivative with a high introduction rate is used. Further, according to the present invention, a wound dressing material and an adhesion prevention material can also be provided. [Embodiments for Carrying Out the Invention]

[0009] Hereinafter, the present invention will be described in detail. The description of the constituent elements described below may be made based on representative embodiments of the present invention, but the present invention is not limited to such embodiments. In this specification, a numerical range represented by "~" means a range including the numerical values described before and after "~" as the lower limit value and the upper limit value.

[0010] In the notation of groups (atomic groups) in this specification, notations that do not indicate substitution or non-substitution include those having no substituents and those having substituents as long as the effects of the present invention are not impaired. For example, the term "alkyl group" includes not only an alkyl group having no substituents (unsubstituted alkyl group) but also an alkyl group having substituents (substituted alkyl group). This also applies to each compound.

[0011] [Adhesive] The adhesive according to an embodiment of the present invention includes gelatin, a gelatin derivative in which a hydrophobic group is bonded to the gelatin via an imino group and which is represented by Formula 1 described later (hereinafter, also simply referred to as "gelatin derivative"), and cyclodextrin, and has a first agent in which the molecular weight of the gelatin is less than 50,000, and a second agent including gelatin and at least one crosslinking agent selected from the group consisting of the gelatin derivative.

[0012] The mechanism by which the problems of the present invention are solved by the above adhesive is not necessarily clear, but the present inventor speculates as follows. Note that the following mechanism is a speculation, and even if the problems of the present invention are solved by a mechanism other than the following mechanism, it is included in the scope of the present invention.

[0013] When synthesizing a gelatin derivative with a high introduction rate from raw gelatin and applying it to a tissue adhesive, the present inventor considered the application to humans and restricted the molecular weight of the raw gelatin used to less than 50,000 from the viewpoint of being less likely to cause an allergic reaction, and proceeded with the study.

[0014] The present inventor synthesized a gelatin derivative from such raw gelatin and thought that the self-assembling power of the hydrophobized gelatin with a high introduction rate could be adjusted by mixing this with the raw gelatin, and conducted an experiment.

[0015] In this specification, "high introduction rate" means that the molar ratio of the content of imino groups to the total content of amino groups and imino groups in the gelatin derivative (imino group / (amino group + imino group)) is 0.10 or more, preferably 0.30 or more, more preferably 0.40 or more, still more preferably 0.50 or more, particularly preferably 0.60 or more, and preferably 0.80 or less. Typically, for a gelatin derivative with a "high introduction rate", the introduction rate of the hydrophobic group is preferably 0.40 to 0.80.

[0016] However, the desired results were not obtained in the above experiments. When the raw material gelatin, gelatin derivative, and solvent (water) were mixed, the raw material gelatin and the gelatin derivative separated. Since the separation of the raw material gelatin and the gelatin derivative in water was a phenomenon that could not be predicted from previous experiments, the inventor of the present invention intensively studied the above reasons.

[0017] As a result, it was presumed that the separation of the raw material gelatin and the gelatin derivative was due to the fact that the molecular weight of the raw material gelatin was less than 50,000 and small, and that many hydrophobic groups were introduced into the gelatin derivative with a high introduction rate, resulting in high hydrophobicity and making hydrophobic interaction more likely to occur.

[0018] Therefore, the inventor of the present invention added cyclodextrin thereto to adjust the compatibility between the gelatin derivative and the raw material gelatin, and obtained an adhesive having uniform and excellent tissue adhesion, thereby completing the present invention. Hereinafter, the components included in the adhesive according to the present embodiment (hereinafter, also referred to as "the present adhesive") will be described in detail.

[0019] <Agent 1> Agent 1 according to the present embodiment contains gelatin, a gelatin derivative, and cyclodextrin. Agent 1 is crosslinked by Agent 2 described later to form the skeleton of the cured product. The curing reaction is typically a reaction between the primary amino groups of gelatin and / or hydrophobized gelatin and the crosslinkable groups (typically active ester groups, etc.) of Agent 2.

[0020] In this regard, the content of the first agent in this adhesive is preferably adjusted so that it is 0.1 to 3.0 equivalents of the crosslinkable group in the second agent with respect to 1 equivalent of the amino group in the first agent, more preferably adjusted so that it is 0.2 to 2.0 equivalents, still more preferably adjusted so that it is 0.3 to 1.5 equivalents, and particularly preferably adjusted so that it is 0.3 to 0.8 equivalents, in relation to the content of the crosslinkable group of the second agent described later. Also, the content of gelatin and gelatin derivatives in the first agent, and their ratio are not particularly limited, and may be adjusted so that the amino group and the curable group are within the above numerical ranges in relation to the curable group of the second agent and the average introduction rate described later.

[0021] (Gelatin) The first agent contains gelatin (hereinafter also referred to as "ORG gelatin"). ORG gelatin is gelatin into which no hydrophobic group has been introduced (not derivatized), and is the gelatin that is the raw material of the gelatin derivative described later.

[0022] The molecular weight of ORG gelatin is less than 50,000 in terms of weight average molecular weight. When the adhesive is applied to a living tissue (especially a human), if the molecular weight of gelatin is less than 50,000, an allergic reaction is less likely to occur. In this regard, the molecular weight of gelatin is preferably 45,000 or less, more preferably 40,000 or less. The lower limit is not particularly limited, but in terms of the cured product of the adhesive having more excellent mechanical strength, it is preferably 10,000 or more.

[0023] ORG gelatin can be used without particular limitation regardless of whether it is gelatin obtained by natural origin, chemical synthesis, fermentation method, genetic recombination, etc. Among them, natural origin gelatin is preferred. Examples of natural origin gelatin include those derived from mammals such as cows and pigs, and those derived from fish such as Thai, sharks, salmon, and cod.

[0024] When this adhesive is used as a liquid, from the viewpoint of handleability, it preferably has excellent fluidity at the use temperature (for example, body temperature). In this regard, ORG gelatin is preferably fish-derived gelatin, and among them, gelatin derived from cold-water fish such as salmon and walleye pollock is particularly preferred. Note that "used as a liquid" means that either one or both of the first agent and the second agent are liquids containing a solvent, and there are cases where both the first agent and the second agent are solids and are used by mixing with a solvent during use.

[0025] Fish-derived gelatin, particularly cold-water fish gelatin, preferably has 80 or fewer units derived from hydroxyproline and / or 110 or fewer units derived from proline per 1000 amino acids as constituent units. Gelatin having such conditions has better fluidity at room temperature, so when used in the first agent, an adhesive with excellent handleability can be obtained.

[0026] ORG gelatin may be either acid-treated gelatin or alkali-treated gelatin. The first agent may contain two or more different types of gelatin as ORG gelatin. Two or more different types mean those having differences in origin, molecular weight, treatment method, etc., either singly or in combination. Note that the first agent may contain one type of ORG gelatin alone or two or more types. When the first agent contains two or more types of ORG gelatin, it is preferable that the total content is within the above numerical range.

[0027] (Gelatin derivative) The first agent is a gelatin derivative in which a hydrophobic group is bonded to the above gelatin via an imino group (that is, -NH-), and includes those represented by Formula 1. Formula 1: GltnNH-R 1

[0028] In formula 1, Gltn represents a gelatin residue. The above is the residue of gelatin described as ORG gelatin. Further, NH represents an imino group bonded to a gelatin residue and a hydrophobic group.

[0029] In formula 1, R 1 represents a hydrophobic group. Although not particularly limited as the hydrophobic group, a group having a hydrocarbon group with 1 to 20 carbon atoms is preferable. Here, the group having a hydrocarbon group with 1 to 20 carbon atoms means the hydrocarbon group itself with 1 to 20 carbon atoms, and a group including a linking group and a hydrocarbon group with 1 to 20 carbon atoms, etc.

[0030] That is, when L is a single bond or a divalent linking group, and R 21 is a hydrocarbon group with 1 to 20 carbon atoms, the hydrophobic group is preferably a group represented by *-L-R 21 where * represents the bonding position.

[0031] Further, as the divalent linking group of L, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -N(R)- (R represents a hydrogen atom or a monovalent organic group (preferably a hydrocarbon group with 1 to 20 carbon atoms)), an alkylene group (preferably an alkylene group with 2 to 10 carbon atoms), an alkenylene group (preferably an alkenylene group with 2 to 10 carbon atoms), and combinations thereof, etc. can be mentioned. Among them, -O-, -C(O)-, and -C(O)O- are preferable. When L contains a carbon atom, it is preferable that the total number of carbon atoms of L and R 21 is 1 to 20, more preferably 4 to 18, still more preferably 6 to 14, and particularly preferably 7 to 12.

[0032] Examples of the hydrocarbon group with 1 to 20 carbon atoms include a linear hydrocarbon group with 1 to 20 carbon atoms, an alicyclic hydrocarbon group with 3 to 20 carbon atoms, an aromatic hydrocarbon group with 6 to 14 carbon atoms, and groups combining these.

[0033] Examples of the chain hydrocarbon group having 1 to 20 carbon atoms include linear or branched alkyl groups, with linear hydrocarbon groups being preferred. Examples of the linear or branched alkyl group include a methyl group having 1 carbon atom; an ethyl group having 2 carbon atoms; a propyl group or isopropyl group having 3 carbon atoms; a butyl group, isobutyl group, tert-butyl group, or sec-butyl group having 4 carbon atoms; a pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, or 1-ethylpropyl group having 5 carbon atoms; a hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1,4-dimethylbutyl group, 2,3-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-ethyl-2-methyl-propyl group, or 1,1,2-trimethylpropyl group having 6 carbon atoms; a heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 4,4-dimethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,4-dimethylpentyl group, 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 1,2,2-trimethylbutyl group, 1,1,2-trimethylbutyl group, 1,3,3-trimethylbutyl group, 1,1,3-trimethylbutyl group, 2,2,3-trimethylbutyl group, or 2,3,3-trimethylbutyl group having 7 carbon atoms; Octyl groups with 8 carbon atoms, 1-methylheptyl groups, 2-methylheptyl groups, 3-methylheptyl groups, 4-methylheptyl groups, 5-methylheptyl groups, 6-methylheptyl groups, 1-ethylhexyl groups, 2-ethylhexyl groups, 3-ethylhexyl groups, 4-ethylhexyl groups, 1-propylpentyl groups, 2-propylpentyl groups, 1,1-dimethylhexyl groups, 2,2-dimethylhexyl groups, 3,3-dimethylhexyl groups, 4,4-dimethylhexyl groups, 5,5-dimethylhexyl groups, 3-ethyl-3-methylpentyl groups, 1,1-diethylbutyl groups, 2,2-diethylbutyl groups, 1,1,2,2-tetramethylbutyl groups, 1,1,3,3-tetramethylbutyl groups, 2,2,3,3-tetramethylbutyl groups, 1,1-dimethyl-2-ethylbutyl groups; Nonyl groups with 9 carbon atoms, 2-methyloctyl groups, 3-methyloctyl groups, 4-methyloctyl groups, 2,2-dimethylheptyl groups, 2,3-dimethylheptyl groups, 2,4 dimethylheptyl groups, 2,6 dimethylheptyl groups, 3,3 dimethylheptyl groups, 3,4 dimethylheptyl groups, 3,5 dimethylheptyl groups, 4,4 dimethylheptyl groups, 3-ethylheptyl groups, 4-ethylheptyl groups, 2,2,3-trimethylhexyl groups, 2,2,4-trimethylhexyl groups, 2,2,5-trimethylhexyl groups, 2,3,3-trimethylhexyl groups, 2,3,4-trimethylhexyl groups, 2,3,5-trimethylhexyl groups, 2,4,4-trimethylhexyl groups, 3,3,4-trimethylhexyl groups, 2 methyl-3-ethylhexyl groups, 3-methyl-3-ethylhexyl groups, 3-ethyl-4-methylhexyl groups, 3-ethyl-5-methylhexyl groups, 2,2,3,3-tetramethylpentyl groups, 2,2,3,4-tetramethylpentyl groups, 2,2,4,4-tetramethylpentyl groups, 2,3,3,4-tetramethylpentyl groups, 2,2-dimethyl-3-ethylpentyl groups, 2,3-dimethyl-3-ethylpentyl groups, 2,4-dimethyl-3-ethylpentyl groups, 3,3-diethylpentyl groups; Decyl groups with 10 carbon atoms, 2-methylnonyl groups, 2-ethyloctyl groups, 2-propylheptyl groups, and 2-butylhexyl groups; etc. can be mentioned.

[0034] In addition to the above, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, and icosyl group, etc. can be mentioned.

[0035] Examples of the alicyclic hydrocarbon group having 3 to 20 carbon atoms include cyclopropyl group, cyclopentyl group, cyclohexyl group, adamantyl group, and norbornyl group, etc.

[0036] The aromatic hydrocarbon group having 6 to 14 carbon atoms is not particularly limited, and examples include phenyl group, tolyl group, and naphthyl group, etc.

[0037] The group formed by combining the above is not particularly limited, and examples include aralkyl groups having 6 to 12 carbon atoms such as benzyl group, phenethyl group, naphthylmethyl group, and naphthylethyl group, etc.

[0038] Also, R 1 may be a group represented by the following formula. In the following formula, * represents the bonding position.

[0039]

Chemical formula

[0040] In Formula 1, the nitrogen atom (N) directly bonded to the residue of gelatin is mainly derived from the ε-amino group of lysine (Lys) in gelatin. The NH structure of Formula (1) can be detected by a band around 3300 cm -1 in, for example, the FT-IR spectrum.

[0041] In terms of obtaining an adhesive having better effects of the present invention, the gelatin derivative is preferably a gelatin derivative represented by Formula (11). Formula 11: GlnNH-CHR 2 R 3 In the above Formulas 11 and 12, R 2represents a hydrocarbon group having 1 to 19 carbon atoms. Specific examples thereof include R 1 Among the hydrocarbon groups of 1 , the same groups as the hydrocarbon groups having 1 to 19 carbon atoms can be mentioned, and the preferred forms are also the same. R 3 represents a hydrocarbon group having 1 to 19 carbon atoms or a hydrogen atom, and a hydrogen atom is preferred. Note that R 2 , and R 3 The total number of carbon atoms of is not particularly limited, but 2 to 19 are preferred, 3 to 17 are more preferred, 5 to 13 are still more preferred, and 6 to 11 are particularly preferred.

[0042] The introduction rate (molar basis) of the hydrophobic group in the gelatin derivative is not particularly limited, but 0.10 (10 mol%) or more is preferred, 0.30 (30 mol%) or more is more preferred, 0.40 (40 mol%) or more is still more preferred, 0.50 (50 mol%) or more is particularly preferred, and 0.60 (60 mol%) or more is most preferred. The upper limit is not particularly limited, but 0.80 (80 mol%) or less is preferred. Note that the introduction rate of the hydrophobic group is a value defined as the content of imino groups / (content of imino groups + content of amino groups) in the gelatin derivative, and the amount of amino groups in the raw material gelatin and the amount of amino groups after bonding the hydrophobic group can be determined by quantifying by the 2,4,6-trinitrobenzenesulfonic acid method.

[0043] (Cyclodextrin) The first agent contains cyclodextrin. Cyclodextrin is a cyclic compound in which D-glucose units are cyclically bonded by α-1,4-glucoside bonds, and can be produced by allowing an enzyme such as cyclodextrin glucanotransferase to act on starch and / or a hydrolyzate of starch.

[0044] As cyclodextrin, cyclodextrins having 6 (α-type), 7 (β-type), 8 (γ-type), etc. glucose units can be used, and derivatives thereof can also be used. Among them, α-cyclodextrin or its derivatives are preferable in that the size of its inner cavity is more suitable for inclusion of hydrophobic groups.

[0045] Examples of the derivative of α-cyclodextrin include methyl α-cyclodextrin, butyl α-cyclodextrin, 2-hydroxypropyl α-cyclodextrin, acetyl α-cyclodextrin, succinyl α-cyclodextrin, glucosyl α-cyclodextrin, maltosyl α-cyclodextrin, α-cyclodextrin carboxymethyl ether, phosphate ester α-cyclodextrin, and carboxymethyl α-cyclodextrin, etc.

[0046] Examples of the derivative of β-cyclodextrin include methyl-β-cyclodextrin (MBCD), (2-hydroxypropyl)-β-cyclodextrin (HPBCD), carboxymethyl-β-cyclodextrin, carboxymethyl-ethyl-β-cyclodextrin, diethyl-β-cyclodextrin, dimethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, hydroxybutenyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, maltosyl-β-cyclodextrin, random methyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, 2-selenium crosslinked-β-cyclodextrin, and 2-tellurium crosslinked-β-cyclodextrin, etc.

[0047] Examples of derivatives of γ-cyclodextrin include 2-hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, butyl-γ-cyclodextrin, 3A-amino-3A-deoxy-(2AS,3AS)-γ-cyclodextrin, mono-2-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-6-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-6-O-mesitylenesulfonyl-γ-cyclodextrin, octakis(2,3,6-tri-O-methyl)-γ-cyclodextrin, octakis(2,6-di-O-phenyl)-γ-cyclodextrin, octakis(6-O-t-butyldimethylsilyl)-γ-cyclodextrin, and octakis(2,3,6-tri-O-acetyl)-γ-cyclodextrin, etc.

[0048] The content of cyclodextrin in the first agent is not particularly limited, but in terms of obtaining an adhesive having more excellent effects of the present invention, when the total mass of the solid content of the first agent is 100% by mass, 0.1 to 25% by mass is preferable, 1.0 to 20% by mass is more preferable, 1.0 to 10% by mass is further preferable, 1.0 to 8.0% by mass is particularly preferable, and 1.0 to 3.0% by mass is most preferable. Cyclodextrin may be used alone or in combination of two or more. When cyclodextrin is used in combination of two or more, it is preferable that the total content is within the above numerical range.

[0049] In addition, cyclodextrin has a function of enhancing the compatibility between ORG gelatin and the gelatin derivative. It is presumed that it forms an inclusion compound by including the hydrophobic group of the gelatin derivative. From the viewpoint of easily obtaining more excellent compatibility between ORG gelatin and the gelatin derivative, the molar ratio of the content of cyclodextrin to the content of the hydrophobic group in the first agent (cyclodextrin / hydrophobic group) is preferably 0.1 to 2.5, more preferably 0.1 to 1.5, further preferably 0.5 to 1.3, and particularly preferably 0.8 to 1.2. When two or more cyclodextrins are used in combination, it is preferable that their total content is within the above numerical range.

[0050] (Average introduction rate) The first agent contains gelatin and a gelatin derivative, and includes an amino group derived from gelatin, an amino group derived from the gelatin derivative, and a hydrophobic group bonded via an imino group. The average introduction rate is a value that reflects the content ratio (molar basis) of the content of the imino group to the total content of the amino group and the imino group in the whole of the first agent (that is, in the whole including gelatin and the gelatin derivative). The average introduction rate is a value calculated by the following formula A.

[0051] Formula A: Average introduction rate = Introduction rate of the hydrophobic group in the gelatin derivative × (Content of the gelatin derivative in the first agent based on mass) / (Content of gelatin in the first agent based on mass + Content of the gelatin derivative in the first agent based on mass)

[0052] As the average introduction rate, 0.01 to 0.50 is preferable in terms of obtaining an adhesive having a more excellent effect of the present invention. Also, from the viewpoint that the adhesive has a more excellent adhesive force, 0.01 or more is preferable, more preferably more than 0.10, preferably less than 0.40, and preferably less than 0.25.

[0053] Also, from the viewpoint that gelatin and the gelatin derivative have better compatibility and the cured product of the adhesive becomes more uniform, and as a result, the variation in tissue adhesive force is more likely to be smaller, the average introduction rate is preferably 0.01 or more and less than 0.15.

[0054] Also, when the first agent is mixed with a solvent, from the viewpoint of being less likely to foam, the average introduction rate is preferably less than 0.40, preferably 0.35 or less, more preferably less than 0.30, still more preferably 0.25 or less, particularly preferably less than 0.15, and most preferably 0.10 or less. In addition, when it is less likely to foam when mixed with a solvent, it is less likely for air bubbles to be mixed into the cured product obtained with the adhesive, and it is easier to obtain a more uniform cured product.

[0055] Further, when the first agent is solid (including powder, xerogel, etc.), from the viewpoint of being more easily dissolved in a solvent quickly, the average introduction rate is preferably less than 0.40, more preferably less than 0.35, still more preferably less than 0.30, further more preferably less than 0.25, particularly preferably less than 0.15, and most preferably less than 0.10.

[0056] (Polyethylene glycol) The first agent preferably contains polyethylene glycol. When the first agent is solid, when the first agent contains polyethylene glycol, when the solvent and the first agent are mixed, it is easy to prepare a uniform solution in a shorter time.

[0057] The content of polyethylene glycol in the first agent is not particularly limited, but from the viewpoint of exhibiting the above-mentioned excellent effects, when the solid content of the first agent is 100% by mass, 0.1 to 10% by mass is preferable, 0.3 to 9% by mass is more preferable, and 0.5 to 3% by mass is still more preferable. Polyethylene glycol may be used alone or in combination of two or more. When two or more polyethylene glycols are used, the content thereof is preferably within the above numerical range.

[0058] The number average molecular weight of polyethylene glycol is not particularly limited, but in terms of having the above-mentioned excellent effects, it is preferably 200 or more, more preferably 400 or more, preferably 20000 or less, still more preferably 9000 or less, and particularly preferably 3500 or less.

[0059] (Solvent) The first agent may further contain a solvent. Examples of the solvent include aqueous solutions. Examples of the aqueous solvent include ultrapure water; physiological saline; various inorganic salt buffers such as boric acid, phosphoric acid, and carbonic acid; mixtures thereof; and the like. The aqueous solvent is preferably a boric acid buffer with a pH of 8 to 13, more preferably a boric acid buffer with a pH of 9 to 12. The aqueous solvent is preferably used in an amount such that the solid content of the first agent is 10 to 80 mass / volume%.

[0060] (Second agent) The second agent contains at least one crosslinking agent selected from the group consisting of gelatin and gelatin derivatives. The second agent may also contain a solvent.

[0061] <Crosslinking agent> Typically, the crosslinking agent is a compound having at least two substituents (crosslinkable groups) capable of reacting with the primary amino groups of gelatin and gelatin derivatives in one molecule.

[0062] The crosslinkable groups of the crosslinking agent are not particularly limited, but from the viewpoint of being selectively reactive under mild conditions with respect to the primary amino groups of gelatin and gelatin derivatives, an active ester group (activated ester group) is preferred. That is, as the crosslinking agent, a compound having at least two active ester groups in one molecule is preferred. Examples of such crosslinking agents include polybasic acids activated with N-hydroxysuccinimide or N-hydroxysulfosuccinimide.

[0063] In addition to the above, as the crosslinking agent, genipin, aldehyde compounds, acid anhydrides, dithiocarbonates, and diisothiocyanates can be used.

[0064] Examples of the polybasic acid include tartaric acid, citric acid, malic acid, glutaric acid, glutamic acid, aspartic acid, oxaloacetic acid, cis-aconitic acid, 2-ketoglutaric acid, poly(tartaric acid), poly(citric acid), poly(malic acid), poly(glutamic acid), poly(aspartic acid), carboxymethylated dextrin, carboxymethylated dextran, carboxymethylated starch, carboxymethylated cellulose, carboxymethylated chitosan, and carboxymethylated pullulan, etc.

[0065] Examples of the crosslinking agent that can also be used include disuccinimidyl glutarate (DSG), disuccinimidyl suberate (DSS), disuccinimidyl tartrate (DST), etc.

[0066] In addition, a polybasic acid ester of polyethylene glycol or polyethylene glycol ether, in which at least one of the carboxyl groups that has not reacted with polyethylene glycol in the polybasic acid is activated and esterified, such as di(N-succinimidyl) 4,7,10,13,16-pentaoxanonadecanedioate, and polyethylene glycol di(succinimidyl succinate) (SS-PEG-SS) represented by the following formula:

[0067]

Chemical formula

[0068] (n is a number such that the number average molecular weight is about 20,000); Furthermore, pentaerythritol-polyethylene glycol ether tetrasuccinimidyl glutarate (4S-PEG) represented by the following formula:

[0069]

Chemical formula

[0070] (n is a number such that Mw is about 3,000 to 30,000, preferably 5,000 to 27,000, more preferably 15,000 to 25,000); is preferred.

[0071] Examples of the aldehyde compound include formyl group-introduced polysaccharides in which two or more formyl groups are introduced into one molecule, such as formyl group-introduced starch, formyl group-introduced dextran, formyl group-introduced dextrin, and formyl group-introduced hyaluronic acid.

[0072] Examples of the acid anhydride include glutaric anhydride, maleic anhydride, and succinic anhydride. Examples of the diisothiocyanate include hexamethylene diisothiocyanate. As the crosslinking agent, activated polyethylene glycol polybasic acid ester and formyl group-introduced polysaccharides are preferred, and activated polyethylene glycol polybasic acid ester is more preferred.

[0073] The content of the crosslinking agent in the second agent and the content of the second agent in the adhesive may be appropriately adjusted according to the content of the amino group in gelatin and the gelatin derivative.

[0074] For example, with respect to 1 equivalent of the total amount of amino groups in gelatin and the gelatin derivative (that is, the amount of amino groups in the adhesive), the crosslinkable group in the crosslinking agent, such as an ester group activated with N-hydroxysuccinimide, is preferably 0.1 to 3 equivalents, more preferably 0.2 to 2 equivalents, still more preferably 0.3 to 1.5 equivalents, and most preferably 0.3 to 0.8. Note that the second agent may contain one type of crosslinking agent alone or may contain two or more types. When the second agent contains two or more types of crosslinking agents, it is preferable that the total content is within the above numerical range.

[0075] (Solvent) The second agent may contain a solvent. An aqueous solvent is preferred as the solvent. Note that as the aqueous solution, the ones already described as the aqueous solution that the first agent may contain can be used.

[0076] Among them, a phosphate buffer solution with a pH of 3 to 8 is preferred, and a phosphate buffer solution with a pH of 4 to 6 is more preferred. When the first agent containing a solvent and the second agent containing a solvent are mixed in the same volume, it is preferable that the ionic strengths of both aqueous solvents are adjusted so that the pH becomes about 8 to about 10. For example, by setting the first agent as a borate buffer solution with a pH of 9 and an ionic strength of 0.05 to 0.1, and the second agent as a phosphate buffer solution with a pH of 4 and an ionic strength of 0.01 to 0.03, the pH within the above range can be achieved when mixed in the same volume. Alternatively, the first agent may be a borate buffer solution with a pH of 10 and an ionic strength of 0.05 to 0.1, and the second agent may be a phosphate buffer solution with a pH of 4 and an ionic strength of 0.01 to 0.07.

[0077] <Additive> The above-mentioned first agent and / or second agent may further contain various additives in an amount that does not inhibit the object of the present invention. Examples of the additives include coloring agents, pH adjusters, viscosity adjusters, preservatives, and the like. For example, a coloring agent (such as brilliant blue) may be added to the first agent and / or second agent so that the application location of the adhesive is easily distinguishable. The addition amount may be, for example, 10 to 100 μg / mL.

[0078] This adhesive contains gelatin and a gelatin derivative in which a hydrophobic group is introduced into the gelatin. However, as long as the combination of the above gelatin / gelatin derivative is included, "other" gelatin and / or "other" gelatin derivatives may also be included. That is, when the first agent contains skate gelatin and its derivative, the first agent and / or second agent may contain, for example, pig gelatin and / or pig gelatin derivative, etc. From the viewpoint that more excellent uniformity is easily obtained when the first agent is dissolved in a solvent, it is preferable that this adhesive does not contain the above-mentioned "other" gelatin and gelatin derivative.

[0079] [Method for manufacturing an adhesive] This adhesive can be obtained by separately preparing a first agent and a second agent. Hereinafter, the preparation methods of the first agent and the second agent will be described respectively.

[0080] <Preparation method of the first agent> The first agent can be produced by mixing gelatin, a gelatin derivative, cyclodextrin, and other components such as polyethylene glycol. At this time, it preferably has a step of inclusion of at least a part of the hydrophobic group of the gelatin derivative by cyclodextrin (forming an inclusion compound).

[0081] The method for including the hydrophobic group of the gelatin derivative with cyclodextrin is not particularly limited, and methods such as adding the gelatin derivative to a slurry prepared by adding water to cyclodextrin and kneading, and dissolving cyclodextrin and the gelatin derivative in a solvent and drying this can be used.

[0082] The production method of the gelatin derivative used in the production of the first agent is not particularly limited, and known methods can be used. For example, a method of reacting an aldehyde or a ketone with the ε-amino group of the gelatin derivative to bond a hydrophobic group via a Schiff base and reducing the Schiff base to obtain a gelatin derivative can be mentioned. This method is described, for example, in paragraphs 0029 to 0031 of JP-A-2019-216755.

[0083] According to the above method, a gelatin derivative in which a hydrophobic group is directly bonded to a gelatin residue via an imino group (formula: GltnNH-R 1 ) is obtained. This hydrophobic group is derived from an aldehyde or a ketone.

[0084] As another method, a method of reacting an acid halide or a chloroformate compound or the like with the ε-amino group of gelatin in the presence of a base such as triethylamine to obtain an amide can be mentioned. This method is described, for example, in paragraphs 0072 to 0080 of WO 2014 / 112208.

[0085] According to the above method, a gelatin derivative in which a hydrophobic group is bonded to a gelatin residue via an amide bond (including an imino group) can be obtained. This hydrophobic group is derived from an acid halide or a chloroformate compound.

[0086] When a large excess of a poor solvent, such as cold ethanol, is added to the reaction solution obtained above, the gelatin derivative precipitates. By filtering this, a gelatin derivative can be obtained. Note that this gelatin derivative may be washed with ethanol or the like.

[0087] By the above method, a solid (powdered) first agent can be obtained. When a liquid first agent is used, the above solid may be dissolved in an aqueous solvent such as a borate buffer. Additives may be added at this point if necessary. The obtained first agent can be filled in a predetermined container such as a plastic dispenser made of, for example, polypropylene. When used as a tissue adhesive, it is preferable to fill an aqueous solution of the first agent in one of a double syringe type dispenser or the like capable of mixing the two agents at the tip.

[0088] <Method for preparing the second agent> The second agent contains a cross-linking agent. The cross-linking agent may be synthesized by a known method or a commercially available one may be used. When the second agent is a liquid, the cross-linking agent and an aqueous solvent such as a phosphate buffer for dissolving it may be mixed.

[0089] <Method of application to tissue> This adhesive can be applied to incisions and skin wounds in various surgical operations such as thoracic surgery, gastrointestinal surgery, cardiovascular surgery, neurosurgery, and oral surgery. As a method of applying the adhesive to tissue, a solid second agent is mixed with a solvent immediately before use to form a solution, which is filled into the empty syringe of a double syringe type dispenser already filled with the first agent (liquid), and the plunger is pressed, or it is applied to the target part by spraying with an air-assisted spray equipped with a double syringe.

[0090] When the two agents are mixed, a curing reaction immediately occurs and a cured product is formed. The temperature during the curing reaction is not particularly limited, but generally 15 to 45 °C is preferred, and 20 to 42 °C is more preferred. The curing time is not particularly limited, but sufficient adhesive strength can be obtained within 1 to 60 minutes.

Examples

[0091] Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto.

[0092] (1) Preparation of gelatin derivative 10 g of alkali-treated gelatin (Mw = 37000, "BeaMatrix Fish Gelatin TA (trade name)", manufactured by Nitta Gelatin, hereinafter referred to as "Org gelatin") derived from Alaska pollock was added to 50 mL of an ultrapure water-ethanol mixed solvent in an eggplant-shaped flask immersed in an oil bath at 50 °C, and dissolved with stirring for about 2 hours to prepare a 20% by mass aqueous solution. Next, 1.5 times the equivalent amount of picoline borane (manufactured by Junsei Chemical) of decanal was added to the obtained aqueous solution, and then decanal (manufactured by Tokyo Chemical Industry) was added in an amount of 2 times the equivalent amount with respect to the amino group of gelatin (molar ratio of decanal to 1 mol of the amino group of gelatin).

[0093] Next, a reflux condenser was attached to the eggplant-shaped flask, and the reaction was carried out at 50 °C for 17 hours with stirring. Next, the reaction solution was dropped into 1 L of ethanol for reprecipitation. After stirring for 1 hour, it was allowed to stand in a freezer for 1 hour and then filtered through a glass filter. The filter residue was put into 1 L of ethanol in a beaker again for reprecipitation, stirred for 1 hour, and allowed to stand in a freezer for 1 hour. After filtering again through a glass filter, the filter residue was dried in a vacuum dryer overnight or more to obtain a gelatin derivative in which a decyl group (C10), which is a hydrophobic group, was introduced into the gelatin residue via an imino group in a yield of 85%.

[0094] The introduction rate of the decyl group in the obtained gelatin derivative was determined by the following method. First, Org gelatin and the gelatin derivative were each 0.1 mass / volume% It was dissolved in a water·DMSO (dimethyl sulfoxide) mixed solvent (volume ratio 1:1, the same hereinafter), and 100 μL was dispensed into a 48-well plate. To this, 100 μL of 0.1 volume / volume% triethylamine (TEA, manufactured by Nacalai Tesque) dissolved in a water·DMSO mixed solvent was added, and it was stirred at 400 rpm for 1 minute with a plate shaker. Further, 100 μL of 0.1 mass / volume% trinitrobenzenesulfonic acid (TNBS, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in a water·DMSO mixed solvent was added, and it was stirred at 400 rpm for 1 minute with a plate shaker. It was shielded from light with aluminum foil, allowed to stand in an incubator at 37 °C for 2 hours, then taken out from the incubator, 50 μL of HCl (6 mol / L) was added to stop the reaction, and it was stirred at 400 rpm for 1 minute with a plate shaker. Next, after shielding from light and allowing to stand for 10 minutes, the absorbance (Abs) at 340 nm was measured with an absorptiometer (manufactured by TECAN, Spark 10M-NMST). From the measured absorbance, the absorbance of the blank sample that differed only in that it did not contain gelatin was subtracted, and it was determined that the decyl group introduction rate of the gelatin derivative was 67 mol% (0.67) by the following calculation formula. Introduction rate (mol%) = [Abs(raw gelatin) - Abs(gelatin derivative) / [Abs(Org gelatin)] × 100

[0095] The gelatin derivative obtained by the above method was designated as "67C10".

[0096] (2) Preparation of the first agent 67C10 and Org gelatin were weighed, ultrapure water (containing 50 μg / mL of acid blue) was added, and it was dissolved in a water bath at 50 °C. Next, polyethylene glycol ("Macrogol 1500", represented by HOCH2(CH2OCH2)nCH2OH, an equimolar mixture of n being 5 to 6 and 28 to 36, and a number average molecular weight of about 550) was weighed and a predetermined amount was added. Further, α-cyclodextrin (manufactured by Fujifilm Wako Pure Chemical) was weighed and a predetermined amount was added, and they were mixed.

[0097] 1 mol / L sodium hydroxide aqueous solution was added to this solution to adjust the pH to 7, and the volume was made up with ultrapure water. Next, 11 mL of the solution was dispensed into a 20 mL vial, frozen at -80 °C, and then lyophilized to obtain the first agent (solid).

[0098] To the obtained first agent (solid), 0.075 mol / L boric acid buffer (pH 9.5) was added and adjusted to 15 - 18 mass(g) / volume(mL)% to obtain a liquid first agent.

[0099] Each component is contained in 1 mL of this first agent in the amounts described in Table 1. That is, in the case of Example 1, 67C10 is 11.2 mg, Org gelatin is 138.8 mg, α - cyclodextrin is 2.4 mg, and polyethylene glycol is 10 mg, and it was prepared so that the average introduction rate would be 0.05. In addition to the above, preparations were made so that the average introduction rates would be 0.10, 0.15, 0.20, 0.25, 0.30, and 0.35, which were designated as Examples 2 - 7, respectively.

[0100] (3) Preparation of the second agent As a cross - linking agent, pentaerythritol - polyethylene glycol ether tetrasuccinimidyl glutarate (“4S - PEG”, weight - average molecular weight 20,000, manufactured by NOF Corporation) was prepared. This was dissolved in 0.01 mol / L phosphate buffer (pH 4.0) to obtain the second agent.

[0101] (4) Preparation of the adhesive The first agent and the second agent were filled into a W syringe manufactured by ADY so that (NHS ester of the cross - linking agent) / (total primary amino groups of gelatin and gelatin derivatives) would be 0.5 (50 mol%) on a molar basis. This was extruded and mixed at the time of use.

[0102] <Evaluation> (Foaming property of the first agent) The first agent (solid) was dissolved in a boric acid buffer solution, and the foaming property when obtaining a liquid first agent was evaluated. A lower foaming property is preferable in that less foam transfers to the cured product obtained by mixing with the second agent.

[0103] A predetermined amount (as described above) of boric acid buffer solution was added to the first agent (solid) weighed in a vial, and the foaming state when dissolving the solid content of the first agent was visually inspected and evaluated according to the following criteria. The results are shown in Table 1.

[0104] · Criteria A There was little foaming, and when the inside of the vial was brought to normal pressure, almost no foam remained. B Foaming occurred, but when the inside of the vial was brought to normal pressure, some foam disappeared. C Considerable foaming occurred, and the foam did not disappear even when the inside of the vial was brought to normal pressure.

[0105] (Time required for dissolving the first agent) The dissolution time (minutes) when dissolving the first agent (solid) in a boric acid buffer solution was evaluated. The shorter the dissolution time, the more preferable in that it can be used more quickly.

[0106] A predetermined amount (as described above) of boric acid buffer solution was added to the first agent (solid) weighed in a vial, and the time required to dissolve the solid content of the first agent was measured. Note that for each sample, the evaluation was made after standing still after adding the boric acid buffer solution to the vial. The measurement results were evaluated according to the following criteria, and the evaluation results are shown in Table 1.

[0107] · Criteria A The dissolution time was within 5 minutes. B The dissolution time exceeded 5 minutes and was within 10 minutes. C The dissolution time exceeded 10 minutes.

[0108] (Adhesiveness to biological tissue) In accordance with ASTM-F2392-04R, adhesion evaluation using a collagen casing was conducted as a model tissue for evaluating tissue adhesion. A pinhole with a diameter of 3 mm was made in a collagen casing with a diameter of 35 mm, and 200 μL of an adhesive was added. This was allowed to stand at 37 °C for 10 minutes, and the pressure resistance strength was measured. The test was conducted 3 times, and the pressure resistance strength and its standard deviation were determined. The results are shown in Table 1.

[0109]

Table 1

[0110]

Table 2

[0111] Table 1 is divided into two tables, "Table 1 (Part 1)" and "Table 1 (Part 2)". Each example is described row by row across the two tables. That is, for Example 1, in 1 mL of the first agent, it contains 11.2 mg of 67C10, 138.8 mg of Org gelatin, 2.4 mg of α-cyclodextrin (α-CD), and 10 mg of polyethylene glycol (PEG), with an average introduction rate of 0.05. The molar ratio of the content of α-cyclodextrin to the content of hydrophobic groups in the first agent (αCD / C10) is 1.1. The average value of the pressure resistance strength (n = 3) is 98.9 cmH2O, the standard deviation is 6.1, the foaming property is "A", and the dissolution time is "A".

[0112] From the results in Table 1, it was found that the adhesive composed of the first agent containing gelatin, gelatin derivative, and cyclodextrin, and the second agent containing its cross-linking agent has excellent tissue adhesion.

[0113] Also, it was found that the adhesive of Example 1 containing a gelatin derivative with a high introduction rate (67C10) in the range of 0.40 to 0.80 for the introduction rate of hydrophobic groups has more excellent tissue adhesion.

[0114] In addition, it was found that the adhesive of Example 1 containing a gelatin derivative (67C10: decyl group) in which the hydrophobic group contains a linear alkyl group having 7 to 12 carbon atoms has more excellent tissue adhesiveness.

[0115] In addition, it was found that the adhesive of Example 1 having an average introduction rate of 0.01 to 0.50 has more excellent tissue adhesive strength. In addition, it was found that the adhesive of Example 1 having an average introduction rate of 0.01 or more and less than 0.40 has more excellent tissue adhesive strength. In addition, it was found that the adhesive of Example 1 having an average introduction rate of less than 0.30 has more excellent foaming property (less likely to foam) and a shorter dissolution time compared to the adhesive of Example 6.

[0116] In addition, it was found that the adhesive of Example 1 having an average introduction rate of less than 0.15 has more excellent foaming property (less likely to foam) and a shorter dissolution time compared to the adhesive of Example 3, and furthermore, the variation in tissue adhesive strength is smaller.

[0117] On the other hand, it was found that the adhesive of Example 3 having an average introduction rate exceeding 0.10 and less than 0.25 has more excellent tissue adhesive strength compared to the adhesives of Example 5 and Example 2.

Industrial Applicability

[0118] Since the adhesive of the present invention exhibits excellent tissue adhesive strength even when using a gelatin derivative with a high introduction rate and strong cohesive force, it can be used as a tissue adhesive used in surgical operations and the like. In addition, the adhesive of the present invention can also be used as a wound covering material that covers the wound part caused by surgical operations and the like and promotes wound recovery. Further, by applying this adhesive to the damaged part after tissue resection, it functions as a physical barrier to prevent adhesion between surrounding tissues generated during the repair process and can also be used as an adhesion prevention material.

Claims

1. A first agent comprising gelatin, a gelatin derivative in which a hydrophobic group is bonded to the gelatin via an imino group and represented by the following formula 1, and cyclodextrin, wherein the molecular weight of the gelatin is less than 50,000, and a second agent comprising at least one cross-linking agent selected from the group consisting of the gelatin and the gelatin derivative, wherein the introduction rate (molar basis) of the hydrophobic group in the gelatin derivative is 0.30 to 0.80, the cyclodextrin is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and derivatives thereof, the derivative of α-cyclodextrin is selected from the group consisting of methyl α-cyclodextrin, butyl α-cyclodextrin, 2-hydroxypropyl α-cyclodextrin, acetyl α-cyclodextrin, succinyl α-cyclodextrin, glucosyl α-cyclodextrin, maltosyl α-cyclodextrin, α-cyclodextrin carboxymethyl ether, phosphate ester α-cyclodextrin, and carboxymethyl α-cyclodextrin, the derivative of β-cyclodextrin is selected from the group consisting of methyl-β-cyclodextrin (MBCD), (2-hydroxypropyl)-β-cyclodextrin (HPBCD), carboxymethyl-β-cyclodextrin, carboxymethyl-ethyl-β-cyclodextrin, diethyl-β-cyclodextrin, dimethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, hydroxybutenyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, maltosyl-β-cyclodextrin, random methyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, 2-selenium cross-linked-β-cyclodextrin, and 2-tellurium cross-linked-β-cyclodextrin, The derivative of the γ-cyclodextrin is an adhesive selected from the group consisting of 2-hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, butyl-γ-cyclodextrin, 3A-amino-3A-deoxy-(2AS,3AS)-γ-cyclodextrin, mono-2-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-6-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-6-O-mesitylenesulfonyl-γ-cyclodextrin, octakis(2,3,6-tri-O-methyl)-γ-cyclodextrin, octakis(2,6-di-O-phenyl)-γ-cyclodextrin, octakis(6-O-t-butyldimethylsilyl)-γ-cyclodextrin, and octakis(2,3,6-tri-O-acetyl)-γ-cyclodextrin. Formula 1: GltnNH-R １ (In Formula 1, Gltn represents a residue of the gelatin, R １ represents the hydrophobic group, NH represents the imino group bonded to the residue and the hydrophobic group, and the hydrophobic group is represented by the following Formula 2.) Formula 2: *-L-R21 (In Formula 2, L is a divalent linking group selected from the group consisting of -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -N(R)-(R is a hydrogen atom or a monovalent organic group), an alkylene group, an alkenylene group, and combinations thereof, or a single bond; R21 is a hydrocarbon group having 1 to 20 carbon atoms; * is a bonding position; The total number of carbon atoms of L and R21 is 1 to 20.) **Claim 2** The adhesive according to Claim 1, wherein the introduction rate of the hydrophobic group in the gelatin derivative is 0.40 to 0.

80. **Claim 3** The adhesive according to Claim 1, wherein the first agent further contains polyethylene glycol. **Claim 4** R in the formula (1) above １ The adhesive according to any one of claims 1 to 3, wherein is a linear or branched alkyl group having 1 to 20 carbon atoms. **Claim 5** The aforementioned R １ The adhesive according to claim 4, wherein R is a linear alkyl group having 7 to 12 carbon atoms. **Claim 6** The adhesive according to any one of Claims 1 to 3, wherein L in Formula 2 is -C(O)-. **Claim 7** The adhesive according to any one of Claims 1 to 6, wherein the cyclodextrin is the α-cyclodextrin or a derivative thereof. **Claim 8** The adhesive according to any one of Claims 1 to 6, wherein the cyclodextrin is at least one selected from the group consisting of the α-cyclodextrin, the β-cyclodextrin, and the γ-cyclodextrin. **Claim 9** The adhesive according to any one of Claims 1 to 8, wherein the average introduction rate of the hydrophobic group in the first agent is 0.01 to 0.

50. **Claim 10** The adhesive according to any one of claims 1 to 9, wherein the molar ratio of the content of cyclodextrin to the content of the hydrophobic group in the first agent is 0.1 to 2.

5.

11. The adhesive according to claim 9, wherein the average introduction rate is 0.01 or more and less than 0.

40.

12. The adhesive according to claim 9, wherein the average introduction rate is less than 0.

30.

13. The adhesive according to claim 9, wherein the average introduction rate is less than 0.

15.

14. The adhesive according to any one of claims 1 to 13, wherein the crosslinking agent is a compound having at least two active ester groups.

15. The adhesive according to claim 3, wherein the number average molecular weight of the polyethylene glycol is 400 to 3500.

16. The adhesive according to any one of claims 1 to 15, wherein the gelatin is cold water fish gelatin.

17. A wound dressing material comprising the adhesive according to any one of claims 1 to 16.

18. An anti-adhesion material comprising the adhesive according to any one of claims 1 to 16.

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