WO2023026586A1 - Adhésif, pansement et matériau anti-adhérence - Google Patents

Adhésif, pansement et matériau anti-adhérence Download PDF

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Publication number
WO2023026586A1
WO2023026586A1 PCT/JP2022/018106 JP2022018106W WO2023026586A1 WO 2023026586 A1 WO2023026586 A1 WO 2023026586A1 JP 2022018106 W JP2022018106 W JP 2022018106W WO 2023026586 A1 WO2023026586 A1 WO 2023026586A1
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Prior art keywords
group
gelatin
agent
cyclodextrin
adhesive according
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PCT/JP2022/018106
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English (en)
Japanese (ja)
Inventor
哲志 田口
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国立研究開発法人物質・材料研究機構
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Priority to JP2023543683A priority Critical patent/JPWO2023026586A1/ja
Publication of WO2023026586A1 publication Critical patent/WO2023026586A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/58—Adhesives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J11/00—Features of adhesives not provided for in group C09J9/00, e.g. additives
    • C09J11/02—Non-macromolecular additives
    • C09J11/06—Non-macromolecular additives organic
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J11/00—Features of adhesives not provided for in group C09J9/00, e.g. additives
    • C09J11/08—Macromolecular additives
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J189/00—Adhesives based on proteins; Adhesives based on derivatives thereof

Definitions

  • the present invention relates to adhesives, wound dressings, and anti-adhesion materials.
  • Patent Document 1 describes "A tissue adhesive that is applied to a tissue 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 cross-linking molecule, wherein the water-soluble cross-linking molecule is added to the tissue.
  • a tissue adhesive whose molecular main chain has an amide bond, ethylene glycol unit or sugar chain and two or more active ester groups, acid anhydride groups or aldehyde groups.
  • a gelatin derivative into which a hydrophobic group has been introduced changes its properties according to the amount of the introduced hydrophobic group.
  • hydrophobized gelatin which has a large amount of hydrophobic groups introduced (hereinafter also referred to as "high introduction rate"), has excellent self-organizing ability (function to aggregate and gel), and can be applied to particle-shaped members.
  • high introduction rate hydrophobized gelatin
  • a gelatin derivative used as a tissue adhesive for adhesion to living tissue a gelatin derivative with a high introduction rate has a strong self-organizing ability, so there is room for improvement in adhesive strength when it is used alone. rice field.
  • an object of the present invention is to provide an adhesive that exhibits excellent tissue adhesion even when a gelatin derivative with a high introduction rate is used.
  • Another object of the present invention is to provide a wound dressing and an anti-adhesion material.
  • Gelatin a gelatin derivative in which a hydrophobic group is bound to the gelatin via an imino group and represented by formula 1 described below, and cyclodextrin, wherein the gelatin has a molecular weight of 50, 000, and a second agent containing at least one cross-linking agent selected from the group consisting of gelatin and gelatin derivatives.
  • the adhesive according to [1] wherein the introduction rate of the hydrophobic group in the gelatin derivative is 0.40 to 0.80.
  • cross-linking agent is a compound having at least two active ester groups.
  • an adhesive having excellent tissue adhesion can be provided even when a gelatin derivative with a high introduction rate is used.
  • the present invention also provides wound dressings and anti-adhesion materials.
  • an "alkyl group” includes not only an alkyl group having no substituent (unsubstituted alkyl group) but also an alkyl group having a substituent (substituted alkyl group). This is also the same for each compound.
  • the adhesive according to the embodiment of the present invention includes gelatin and a gelatin derivative obtained by bonding a hydrophobic group to the gelatin via an imino group, which is represented by Formula 1 described later (hereinafter simply referred to as "gelatin and cyclodextrin, wherein the molecular weight of the gelatin is less than 50,000, at least one selected from the group consisting of the first agent, gelatin, and the gelatin derivative. and a second agent containing the agent.
  • the inventor thought that by synthesizing a gelatin derivative from such raw material gelatin and mixing it with the raw material gelatin, it would be possible to adjust the self-organizing power of hydrophobized gelatin with a high introduction rate, and conducted an experiment.
  • the term “high introduction rate” refers to the molar ratio of the imino group content to the sum of the amino group content and the imino group content 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 0 0.80 or less is preferred.
  • a gelatin derivative with a “high introduction rate” preferably has a hydrophobic group introduction rate of 0.40 to 0.80.
  • the starting gelatin and the gelatin derivative are separated because the molecular weight of the starting gelatin is as small as less than 50,000, and many hydrophobic groups are introduced into the gelatin derivative with a high introduction rate. It was presumed that the hydrophobic interaction was more likely to work due to the high hydrophobicity.
  • the present inventors have further added cyclodextrin to these to adjust the compatibility between the gelatin derivative and the starting material gelatin to obtain an adhesive having uniform and excellent tissue adhesive strength, thereby completing the present invention. completed.
  • Components contained in the adhesive according to the present embodiment hereinafter also referred to as "the present adhesive" will be described in detail below.
  • the first agent according to this embodiment contains gelatin, a gelatin derivative, and cyclodextrin.
  • the first agent is crosslinked by the second agent, which will be described later, to form the skeleton of the cured product.
  • the hardening reaction is typically a reaction between a primary amino group possessed by gelatin and/or hydrophobized gelatin and a crosslinkable group possessed by the second agent (typically an active ester group or the like).
  • the content of the first agent in the present adhesive is related to the content of the crosslinkable groups of the second agent, which will be described later, with respect to 1 equivalent of the amino group in the first agent, It is preferably adjusted to 0.1 to 3.0 equivalents, more preferably 0.2 to 2.0 equivalents, more preferably 0.3 to 1.0 equivalents of the crosslinkable groups in the agent. It is more preferable to prepare 5 equivalents, and particularly preferably 0.3 to 0.8 equivalents.
  • the content and ratio of gelatin and gelatin derivatives in the first agent are not particularly limited. and the curable group may be adjusted so as to fall within the above numerical range.
  • the first agent contains gelatin (hereinafter also referred to as "ORG gelatin”).
  • ORG gelatin is gelatin to which no hydrophobic group has been introduced (non-derivatized), and is a raw material for gelatin derivatives described later.
  • the weight average molecular weight of ORG gelatin is less than 50,000.
  • the molecular weight of gelatin is preferably 45,000 or less, more preferably 40,000 or less.
  • the lower limit is not particularly limited, it is preferably 10,000 or more because the cured product of the adhesive has superior mechanical strength.
  • ORG gelatin can be used without any particular limitation, regardless of whether it is naturally derived, chemically synthesized, fermented, or obtained by genetic recombination. Among them, naturally derived gelatin is preferable.
  • Naturally derived gelatins include, for example, those derived from mammals such as bovine and porcine, and those derived from fish such as sea bream, sturgeon, salmon and cod.
  • ORG gelatin is preferably fish-derived gelatin, and particularly preferably cold-water fish-derived gelatin such as salmon and Alaska pollock.
  • used as a liquid means that either one or both of the first agent or the second agent is a liquid containing a solvent, and that both the first agent and the second agent are solid and may be used by mixing with a solvent at the time of use.
  • Fish-derived gelatin especially cold-water fish gelatin, has 80 or less hydroxyproline-derived units and/or 110 or less proline-derived units per 1000 amino acids that are constituent units. is preferred.
  • Gelatin having such conditions has excellent fluidity at room temperature, and therefore, when used as the first agent, an adhesive having excellent handleability can be obtained.
  • ORG gelatin may be either acid-processed gelatin or alkali-processed gelatin.
  • the first agent may contain two or more different types of gelatin as ORG gelatin. Two or more different kinds means those different in one or more of the origin, molecular weight, treatment method, and the like.
  • the first agent may contain one type of ORG gelatin alone, or may contain two or more types. When the first agent contains two or more types of ORG gelatin, the total content is preferably within the above numerical range.
  • the first agent includes gelatin derivatives represented by Formula 1, which are obtained by bonding a hydrophobic group to the above gelatin via an imino group (that is, --NH--).
  • Formula 1 GltnNH- R1
  • Gltn represents a gelatin residue. Above are the residues of gelatin described as ORG gelatin. NH represents an imino group bound to a gelatin residue and a hydrophobic group.
  • R 1 represents a hydrophobic group.
  • the hydrophobic group is not particularly limited, a group having a hydrocarbon group with 1 to 20 carbon atoms is preferred.
  • the group having a hydrocarbon group with 1 to 20 carbon atoms means the hydrocarbon group itself with 1 to 20 carbon atoms, and the linking group and the hydrocarbon group with 1 to 20 carbon atoms. means a group including
  • the divalent linking group for L includes -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 having 1 to 20 carbon atoms), an alkylene group (preferably an alkylene group having 2 to 10 carbon atoms), an alkenylene group (preferably carbon 2 to 10 alkenylene groups), and combinations thereof, among which -O-, -C(O)- and -C(O)O- are preferred.
  • L contains carbon atoms
  • the total number of carbon atoms of L and R 21 is preferably 1 to 20, more preferably 4 to 18, and further preferably 6 to 14.
  • 7 to 12 are particularly preferred.
  • hydrocarbon groups having 1 to 20 carbon atoms include chain hydrocarbon groups having 1 to 20 carbon atoms, alicyclic hydrocarbon groups having 3 to 20 carbon atoms, and aromatic hydrocarbon groups having 6 to 14 carbon atoms. group hydrocarbon groups, and groups that are combinations thereof.
  • chain hydrocarbon groups having 1 to 20 carbon atoms include linear or branched alkyl groups, with linear hydrocarbon groups being preferred.
  • a linear or branched alkyl group a methyl group having one carbon atom; an ethyl group having two carbon atoms; a propyl group having 3 carbon atoms, an isopropyl group; a butyl group having 4 carbon atoms, an isobutyl group, a tert-butyl group, a sec-butyl group; Pentyl group having 5 carbon atoms, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group; hexyl group having 6 carbon atoms, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-
  • undecyl, dodecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl groups are also included.
  • Examples of the alicyclic hydrocarbon group having 3 to 20 carbon atoms include cyclopropyl group, cyclopentyl group, cyclohexyl group, adamantyl group, and norbornyl group.
  • the aromatic hydrocarbon group having 6 to 14 carbon atoms is not particularly limited, but includes a phenyl group, a tolyl group, a naphthyl group, and the like.
  • Groups in which the above are combined are not particularly limited, but examples thereof include aralkyl groups having 6 to 12 carbon atoms such as benzyl group, phenethyl group, naphthylmethyl group, and naphthylethyl group.
  • R 1 may be a group represented by the following formula.
  • * represents a bonding position.
  • the nitrogen atoms (N) directly attached to the gelatin residues are mainly derived from the ⁇ -amino group of lysine (Lys) in gelatin.
  • the NH structure of formula (1) can be detected, for example, by a band around 3300 cm ⁇ 1 in the FT-IR spectrum.
  • the gelatin derivative is preferably a gelatin derivative represented by formula (11) in that an adhesive having the superior effects of the present invention can be obtained.
  • R 2 represents a hydrocarbon group having 1 to 19 carbon atoms, and specific examples thereof are the same as the hydrocarbon groups having 1 to 19 carbon atoms among the hydrocarbon groups for R 1 and preferred forms are also the same.
  • R 3 represents a hydrocarbon group having 1 to 19 carbon atoms or a hydrogen atom, preferably a hydrogen atom.
  • the total number of carbon atoms in R 2 and R 3 is not particularly limited, but is preferably 2 to 19, more preferably 3 to 17, even more preferably 5 to 13, and particularly 6 to 11. preferable.
  • the introduction rate (molar basis) of the hydrophobic group in the gelatin derivative is not particularly limited, but is preferably 0.10 (10 mol %) or more, more preferably 0.30 (30 mol %) or more, and more preferably 0.40. (40 mol %) or more is more preferable, 0.50 (50 mol %) or more is particularly preferable, and 0.60 (60 mol %) or more is most preferable. Although the upper limit is not particularly limited, 0.80 (80 mol %) or less is preferable.
  • the introduction rate of the hydrophobic group is a value defined as the imino group content/(imino group content + amino group content) in the gelatin derivative. It can be determined by quantifying the amount of amino groups after bonding the functional groups by the 2,4,6-trinitrobenzenesulfonic acid method.
  • the first agent contains cyclodextrin.
  • Cyclodextrin is a cyclic compound in which D-glucose units are cyclically linked by ⁇ -1,4-glucosidic bonds. can be manufactured by
  • cyclodextrins having 6 ( ⁇ -type), 7 ( ⁇ -type), 8 ( ⁇ -type), and the like constituent glucose can be used, and derivatives thereof can also be used. can be done. Among them, ⁇ -cyclodextrin or a derivative thereof is preferred because the size of its lumen is more suitable for encapsulating a hydrophobic group.
  • ⁇ -cyclodextrin Derivatives of ⁇ -cyclodextrin include, for example, methyl ⁇ -cyclodextrin, butyl ⁇ -cyclodextrin, 2-hydroxypropyl ⁇ -cyclodextrin, acetyl ⁇ -cyclodextrin, succinyl ⁇ -cyclodextrin, glucosyl ⁇ -cyclodextrin, maltosyl ⁇ -cyclodextrin, ⁇ -cyclodextrin carboxymethyl ether, phosphate ester ⁇ -cyclodextrin, carboxymethyl ⁇ -cyclodextrin and the like.
  • ⁇ -cyclodextrin examples include, for example, methyl- ⁇ -cyclodextrin (MBCD), (2-hydroxypropyl)- ⁇ -cyclodextrin (HPBCD), carboxymethyl- ⁇ -cyclodextrin, carboxymethyl-ethyl- ⁇ - cyclodextrin, diethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, hydroxybutenyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, random Examples include methyl- ⁇ -cyclodextrin, sulfobutyl ether- ⁇ -cyclodextrin, 2-selenium bridged- ⁇ -cyclodextrin, and 2-tellurium bridged- ⁇ -cyclodextrin.
  • MCD methyl- ⁇ -cyclodextr
  • ⁇ -cyclodextrin examples include, for example, 2-hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, butyl- ⁇ -cyclodextrin, 3A-amino-3A-deoxy-(2AS, 3AS )- ⁇ -cyclodextrin, mono-2-O-(p-toluenesulfonyl)- ⁇ -cyclodextrin, mono-6-O-(p-toluenesulfonyl)- ⁇ -cyclodextrin, mono-6-O-mesitylene sulfonyl- ⁇ -cyclodextrin, octakis(2,3,6-tri-O-methyl)- ⁇ -cyclodextrin, octakis(2,6-di-O-phenyl)- ⁇ -cyclodextrin, octakis(6-O -t-butyldimethyls
  • the content of cyclodextrin in the first agent is not particularly limited, but in terms of obtaining an adhesive having a more excellent effect of the present invention, when the total mass of the solid content of the first agent is 100% by mass , preferably 0.1 to 25% by mass, more preferably 1.0 to 20% by mass, still more preferably 1.0 to 10% by mass, particularly preferably 1.0 to 8.0% by mass, 1.0 to 3.0% by weight is most preferred.
  • a cyclodextrin may be used individually by 1 type, and may use 2 or more types together. When two or more cyclodextrins are used in combination, the total content is preferably within the above numerical range.
  • cyclodextrin has a function of enhancing compatibility between ORG gelatin and gelatin derivatives. It is presumed that this is due to inclusion of the hydrophobic group of the gelatin derivative to form an inclusion compound.
  • the molar ratio of the cyclodextrin content to the hydrophobic group content in the first agent (cyclodextrin/hydrophobic group) is preferably 0.1 to 2.5, more preferably 0.1 to 1.5, still more preferably 0.5 to 1.3, and 0.8 to 1.5. 2 is particularly preferred.
  • the total content is preferably within the above numerical range.
  • the first agent contains gelatin and a gelatin derivative, and contains 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 ratio is the content ratio (on a molar basis) of the content of imino groups to the total content of amino groups and imino groups in the entire first agent (that is, in the entirety including gelatin and gelatin derivatives). It is a reflected value.
  • the average introduction rate is a value calculated by Equation A below.
  • the average introduction rate is preferably from 0.01 to 0.50 from the viewpoint of obtaining an adhesive having superior effects of the present invention. 01 or more is preferable, more than 0.10 is more preferable, less than 0.40 is preferable, and less than 0.25 is preferable.
  • the cured product of the adhesive becomes more uniform, and as a result, the variation in tissue adhesive strength tends to be smaller, the average introduction rate is 0.01 or more and less than 0.15 is preferable.
  • the average introduction rate is preferably less than 0.40, preferably 0.35 or less, more preferably less than 0.30, and 0.25 or less. is more preferred, less than 0.15 is particularly preferred, and 0.10 or less is most preferred.
  • the adhesive is less likely to foam when mixed with a solvent, air bubbles are less likely to be mixed into the cured product obtained from the adhesive, and a more uniform cured product is more likely to be obtained.
  • the average introduction rate is preferably less than 0.40, preferably 0.35 or less, from the viewpoint of being easily dissolved in the solvent more quickly. , is more preferably less than 0.30, more preferably less than 0.25, particularly preferably less than 0.15, and most preferably less than 0.10.
  • the first agent preferably contains polyethylene glycol.
  • the first agent is solid, if the first agent contains polyethylene glycol, it is easier to prepare a uniform solution in a shorter time when the solvent and the first agent are mixed.
  • the content of polyethylene glycol in the first agent is not particularly limited, but from the viewpoint of exhibiting a more excellent effect, when the solid content of the first agent is 100% by mass, 0.1 to 10% by mass It is preferably 0.3 to 9% by mass, and even more preferably 0.5 to 3% by mass.
  • One type of polyethylene glycol may be used alone, or two or more types may be used in combination. When two or more types of polyethylene glycol are used, the content is preferably within the above numerical range.
  • the number average molecular weight of polyethylene glycol is not particularly limited, it is preferably 200 or more, more preferably 400 or more, preferably 20000 or less, further preferably 9000 or less, and particularly 3500 or less in terms of having the above-mentioned excellent effects. preferable.
  • the first agent may further contain a solvent.
  • solvents include aqueous solutions, and examples of aqueous solvents that can be used include ultrapure water; physiological saline; various inorganic salt buffers such as boric acid, phosphoric acid, and carbonic acid; mixtures thereof;
  • the aqueous solvent is preferably a borate buffer of pH 8-13, more preferably a borate buffer of pH 9-12.
  • the aqueous solvent is preferably used in such an amount that the solid content of the first agent is 10 to 80 mass/volume %.
  • the second agent contains at least one cross-linking agent selected from the group consisting of gelatin and gelatin derivatives. Moreover, the second agent may contain a solvent.
  • the cross-linking agent is typically a compound having at least two substituents (cross-linking groups) capable of reacting with the primary amino groups of gelatin and gelatin derivatives in one molecule.
  • the crosslinkable group possessed by the crosslinker is not particularly limited, but an active ester group (activated ester groups) are preferred. That is, the cross-linking agent is preferably a compound having at least two active ester groups in one molecule.
  • Such cross-linking agents include polyacids activated with N-hydroxysuccinimide or N-hydroxysulfosuccinimide.
  • genipin aldehyde compounds, acid anhydrides, dithiocarbonates, diisothiocyanates, and the like can be used as cross-linking agents.
  • Polybasic acids include tartaric acid, citric acid, malic acid, glutaric acid, glutamic acid, aspartic acid, oxaloacetic acid, cis-aconitic acid, 2-ketoglutaric acid, polytartaric acid, polycitric acid, polymalic acid, polyglutamic acid, polyaspartic acid. , carboxymethylated dextrin, carboxymethylated dextran, carboxymethylated starch, carboxymethylated cellulose, carboxymethylated chitosan, and carboxymethylated pullulan.
  • DSG disuccinimidyl glutarate
  • DSS disuccinimidyl suberate
  • DST disuccinimidyl tartrate
  • a polybasic acid ester of polyethylene glycol or polyethylene glycol ether in which at least one of the carboxyl groups of the polybasic acid that has not reacted with polyethylene glycol is active-esterified such as 4, 7, 10, 13 , 16-pentaoxanonadecanedioic acid di(N-succinimidyl), and polyethylene glycol di(succinimidyl succinate) represented by the following formula (SS-PEG-SS):
  • 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.
  • aldehyde compounds include formyl group-introduced polysaccharides in which two or more formyl groups are introduced in one molecule, such as formyl group-introduced starch, formyl group-introduced dextran, formyl group-introduced dextrin, and formyl group-introduced hyaluronic acid. mentioned.
  • Acid anhydrides include glutaric anhydride, maleic anhydride, and succinic anhydride. Moreover, hexamethylene diisothiocyanate etc. are mentioned as a diisothiocyanate.
  • an activated polyethylene glycol polybasic acid ester, a formyl group-introduced polysaccharide, and the like are preferable, and an activated polyethylene glycol polybasic acid ester is more preferable.
  • the content of the cross-linking agent in the second agent and the content of the second agent in the adhesive may be appropriately adjusted according to the content of amino groups in gelatin and gelatin derivatives.
  • one equivalent of the total amino groups of gelatin and gelatin derivatives i.e., the amount of amino groups in the adhesive
  • a crosslinkable group in the crosslinker such as N-hydroxysuccinimide.
  • the ester group is preferably 0.1 to 3 equivalents, more preferably 0.2 to 2 equivalents, even more preferably 0.3 to 1.5 equivalents, and most preferably 0.3 to 0.8 equivalents.
  • the 2nd agent may contain 1 type of a crosslinking agent independently, and may contain 2 or more types. When the second agent contains two or more cross-linking agents, the total content is preferably within the above numerical range.
  • the second agent may contain a solvent.
  • An aqueous solvent is preferred as the solvent.
  • the aqueous solution those already described as the aqueous solution that the first agent may contain can be used.
  • Phosphate buffers with a pH of 3-8 are preferred, and phosphate buffers with a pH of 4-6 are more preferred.
  • the ionic strength of both aqueous solvents is preferably adjusted so that the pH becomes about 8 to about 10 when the same volume of the first agent containing the solvent and the second agent containing the solvent are mixed.
  • the first agent is a borate buffer with pH 9 and an ionic strength of 0.05 to 0.1
  • the second agent is a phosphate buffer with a pH of 4 and an ionic strength of 0.01 to 0.03.
  • the first agent may be a borate buffer solution of pH 10 and an ionic strength of 0.05 to 0.1
  • the second agent may be a phosphate buffer solution of pH 4 and an ionic strength of 0.01 to 0.07.
  • the first agent and/or the second agent may further contain various additives in amounts that do not hinder the object of the present invention.
  • Additives include colorants, pH adjusters, viscosity adjusters, preservatives, and the like.
  • a coloring agent for example, brilliant blue
  • the amount added may be, for example, 10-100 ⁇ g/mL.
  • the present adhesive contains gelatin and a gelatin derivative in which a hydrophobic group is introduced into the gelatin.
  • the present adhesive can be obtained by separately preparing the first agent and the second agent. Below, the preparation method of the 1st agent and the 2nd agent is each demonstrated.
  • the first agent can be produced by mixing gelatin, gelatin derivatives, cyclodextrin, and other ingredients such as polyethylene glycol. At this time, it is preferable to include a step of including at least part of the hydrophobic groups of the gelatin derivative with cyclodextrin (forming an inclusion compound).
  • the method of including the hydrophobic group of the gelatin derivative with the cyclodextrin is not particularly limited, and a method of adding the gelatin derivative to a slurry prepared by adding water to the cyclodextrin and kneading, and a method of kneading the cyclodextrin and the gelatin derivative. is dissolved in a solvent and dried.
  • the method for producing the gelatin derivative used for producing the first agent is not particularly limited, and known methods can be used.
  • a gelatin derivative can be obtained by reacting an ⁇ -amino group of a gelatin derivative with an aldehyde or a ketone to bind a hydrophobic group via a Schiff base and reducing the Schiff base. This method is described, for example, in paragraphs 0029 to 0031 of JP-A-2019-216755.
  • a gelatin derivative (formula: GltnNH--R 1 ) in which a hydrophobic group is directly bonded to a gelatin residue via an imino group is obtained.
  • This hydrophobic group is derived from an aldehyde or ketone.
  • Another method is to obtain an amide by reacting an ⁇ -amino group of gelatin with an acid halide, a chloroformate compound, or the like in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • a gelatin derivative in which a hydrophobic group is bound to a gelatin residue via an amide bond (including an imino group).
  • This hydrophobic group is derived from an acid halide or chloroformate compound.
  • a gelatin derivative is precipitated, which can be filtered off to obtain a gelatin derivative.
  • This gelatin derivative may be washed with ethanol or the like.
  • a solid (powder) first agent is obtained by the above method.
  • the liquid first agent When the liquid first agent is used, the above solid may be dissolved in an aqueous solvent such as a borate buffer. In addition, you may add an additive at this time as needed.
  • the obtained first agent can be filled in a predetermined container such as a dispenser made of plastic such as polypropylene.
  • a tissue adhesive When used as a tissue adhesive, it is preferable to fill one side of a double syringe type dispenser or the like capable of mixing the two agents at the tip with the aqueous solution of the first agent.
  • the second agent contains a cross-linking agent.
  • a cross-linking agent may be synthesized by a known method, or a commercially available one may be used.
  • the cross-linking agent may be mixed with an aqueous solvent such as a phosphate buffer for dissolving the cross-linking agent.
  • the adhesive can be applied to incisions, skin wounds, etc. in various surgical procedures such as respiratory surgery, gastrointestinal surgery, cardiovascular surgery, neurosurgery, and oral surgery.
  • the solid second agent is mixed with a solvent immediately before use to form a solution, which is then added to the empty space of a double syringe type dispenser already filled with the first agent (liquid). It may be applied to the target area by filling the syringe and depressing the plunger, or by spraying with an air-assisted sprayer with a double syringe.
  • a curing reaction immediately occurs and a cured product is formed.
  • the temperature during the curing reaction is not particularly limited, it is generally preferably 15 to 45°C, more preferably 20 to 42°C.
  • the curing time is not particularly limited, but sufficient adhesion can be obtained in 1 to 60 minutes.
  • decanal manufactured by Tokyo Kasei Kogyo Co., Ltd.
  • molar ratio of decanal to 1 mole of group was added.
  • a reflux condenser was attached to the eggplant-shaped flask, and the mixture was reacted at 50°C for 17 hours while stirring.
  • the reaction solution was added dropwise to 1 L of ethanol for reprecipitation. After stirring for 1 hour, the mixture was allowed to stand in a freezer for 1 hour, and then filtered through a glass filter. The filtration residue was again placed in 1 L of ethanol in the beaker for reprecipitation, stirred for 1 hour, and then allowed to stand in a freezer for 1 hour.
  • the introduction rate of decyl groups in the obtained gelatin derivative was determined by the following method. First, 0.1% by mass/volume of each of Org gelatin and a gelatin derivative was dissolved in a mixed solvent of water and DMSO (dimethyl sulfoxide) (volume ratio 1:1, the same applies hereinafter), and 100 ⁇ L was dispensed into a 48-well plate. 100 ⁇ L of 0.1 volume/volume % triethylamine (TEA, manufactured by Nacalai Tesque) dissolved in a mixed solvent of water and DMSO was added thereto, and the mixture was stirred at 400 rpm for 1 minute on a plate shaker.
  • TSA triethylamine
  • TNBS trinitrobenzenesulfonic acid
  • a mixed solvent of water and DMSO 100 ⁇ L was added, and the mixture was stirred at 400 rpm for 1 minute on a plate shaker. After shielding from light with aluminum foil and allowing to stand in a 37° C. incubator for 2 hours, the mixture was taken out of the incubator, 50 ⁇ L of HCl (6 mol/L) was added to stop the reaction, and the plate shaker was stirred at 400 rpm for 1 minute.
  • the gelatin derivative obtained by the above method was named "67C10".
  • a 1 mol/L sodium hydroxide aqueous solution was added to this solution to adjust the pH to 7, and the volume was adjusted with ultrapure water.
  • 11 mL of the solution was dispensed into a 20-mL vial, frozen at -80°C, and then lyophilized to obtain a first agent (solid).
  • each component is contained in the amount shown in Table 1. That is, in Example 1, 67C10 is 11.2 mg, Org gelatin is 138.8 mg, ⁇ -cyclodextrin is 2.4 mg, polyethylene glycol is 10 mg, and the average introduction rate is 0.05. was done. In addition to the above, preparations were made so that the average introduction rate was 0.10, 0.15, 0.20, 0.25, 0.30, and 0.35, and these were designated as Examples 2 to 7, respectively.
  • Pentaerythritol-polyethylene glycol ether tetrasuccinimidyl glutarate (“4S-PEG”, weight average molecular weight 20,000, manufactured by NOF Corporation) was prepared as a cross-linking agent. This was dissolved in 0.01 mol/L phosphate buffer (pH 4.0) to obtain the second agent.
  • a predetermined amount of borate buffer (as described above) is added to the first agent (solid) weighed in a vial, and the state of foaming when the solid content of the first agent is dissolved is visually inspected. was evaluated according to The results are listed in Table 1.
  • Criterion A Little foaming occurred, and when the inside of the vial bottle was brought to normal pressure, the foam almost disappeared.
  • B Bubbles were generated, but the bubbles disappeared to some extent when the inside of the vial was brought to normal pressure.
  • C It foamed considerably, and the foam did not disappear even if the inside of the vial was kept under normal pressure.
  • the dissolution time (minutes) when dissolving the first agent (solid) in the borate buffer was evaluated. A shorter dissolution time is preferable because it can be used more quickly.
  • a predetermined amount (as described above) of borate buffer 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.
  • each sample was dissolved after adding a borate buffer solution to the vial and allowing the vial to stand.
  • the measurement results were evaluated according to the following criteria, and the evaluation results are shown in Table 1.
  • adhesion to biological tissue In accordance with ASTM-F2392-04R, adhesion evaluation was performed using a collagen casing as a model tissue for evaluating tissue adhesion. A 3 mm diameter pinhole was made in a 35 mm diameter collagen casing and 200 ⁇ L of adhesive was added. This was allowed to stand at 37° C. for 10 minutes, and the compressive strength was measured. The test was performed 3 times, and the compressive strength and its standard deviation were obtained. The results are listed in Table 1.
  • Example 1 which contains a gelatin derivative (67C10) with a high introduction rate, in which the introduction rate of the hydrophobic group is in the range of 0.40 to 0.80, has superior tissue adhesion. I found out.
  • 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 superior tissue adhesiveness.
  • Example 1 which had an average introduction rate of 0.01 to 0.50, had superior tissue adhesive strength. Moreover, it was found that the adhesive of Example 1, which had an average introduction rate of 0.01 or more and less than 0.40, had superior tissue adhesive strength. In addition, the adhesive of Example 1, which has an average introduction rate of less than 0.30, has better foaming properties (less foaming) and more than the adhesive of Example 6. It was found to have a short dissolution time.
  • the adhesive of Example 1 which has an average introduction rate of less than 0.15, has better foaming properties (less foaming) and more than the adhesive of Example 3. It was found to have a short dissolution time and, moreover, less variability in tissue adhesion.
  • the adhesive of Example 3 which has an average introduction rate of more than 0.10 and less than 0.25, exhibits superior tissue adhesive strength compared to the adhesives of Examples 5 and 2. found to have.
  • the adhesive of the present invention can be used as a tissue adhesive used in surgical operations, etc., because it exhibits excellent tissue adhesion even when a gelatin derivative with a high cohesive force and a high introduction rate is used.
  • the adhesive of the present invention can also be used as a wound dressing to cover wounds caused by surgical operations or the like to promote wound recovery.
  • the adhesive when applied to an injured area after tissue excision, the adhesive acts as a physical barrier to prevent adhesion between surrounding tissues during the repair process, and can also be used as an anti-adhesion material.

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Abstract

L'adhésif de la présente invention comprend : un premier agent contenant de la gélatine, un dérivé de gélatine dans lequel un groupe hydrophobe est lié à la gélatine par l'intermédiaire d'un groupe imino et qui est représenté par la formule 1 : GltnNH-R1, ainsi que de la cyclodextrine, la gélatine ayant un poids moléculaire inférieur à 50 000 ; et un second agent contenant un agent de réticulation pour au moins une substance choisie dans le groupe constitué par la gélatine ci-dessus et le dérivé de gélatine ci-dessus. L'adhésif a une excellente adhérence tissulaire même lorsqu'un dérivé de gélatine ayant un taux d'introduction élevé est utilisé. Dans la formule 1, Gltn représente un résidu de gélatine, R1 représente le groupe hydrophobe et NH représente le groupe imino lié au résidu de gélatine et au groupe hydrophobe.
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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2012046717A1 (fr) * 2010-10-05 2012-04-12 独立行政法人物質・材料研究機構 Adhésif tissulaire à deux composants et procédé de production de celui-ci
WO2014112208A1 (fr) * 2013-01-18 2014-07-24 独立行政法人物質・材料研究機構 Tissu adhésif et procédé de production associé
CN105664245A (zh) * 2016-02-18 2016-06-15 深圳市第二人民医院 一种可注射型超分子水凝胶及其制备方法
JP2021112234A (ja) * 2020-01-16 2021-08-05 国立研究開発法人物質・材料研究機構 内視鏡用粘膜下注入材

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WO2012046717A1 (fr) * 2010-10-05 2012-04-12 独立行政法人物質・材料研究機構 Adhésif tissulaire à deux composants et procédé de production de celui-ci
WO2014112208A1 (fr) * 2013-01-18 2014-07-24 独立行政法人物質・材料研究機構 Tissu adhésif et procédé de production associé
CN105664245A (zh) * 2016-02-18 2016-06-15 深圳市第二人民医院 一种可注射型超分子水凝胶及其制备方法
JP2021112234A (ja) * 2020-01-16 2021-08-05 国立研究開発法人物質・材料研究機構 内視鏡用粘膜下注入材

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FENG QIAN; WEI KONGCHANG; LIN SIEN; XU ZHEN; SUN YUXIN; SHI PENG; LI GANG; BIAN LIMING: "Mechanically resilient, injectable, and bioadhesive supramolecular gelatin hydrogels crosslinked by weak host-guest interactions assist cell infiltration and in situ tissue regeneration", BIOMATERIALS, ELSEVIER, AMSTERDAM, NL, vol. 101, 2 June 2016 (2016-06-02), AMSTERDAM, NL , pages 217 - 228, XP029621560, ISSN: 0142-9612, DOI: 10.1016/j.biomaterials.2016.05.043 *
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