WO2022183750A1 - 一种医用组织粘合胶及其制备方法 - Google Patents

一种医用组织粘合胶及其制备方法 Download PDF

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WO2022183750A1
WO2022183750A1 PCT/CN2021/126764 CN2021126764W WO2022183750A1 WO 2022183750 A1 WO2022183750 A1 WO 2022183750A1 CN 2021126764 W CN2021126764 W CN 2021126764W WO 2022183750 A1 WO2022183750 A1 WO 2022183750A1
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group
bond
acid
carbonate
groups
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PCT/CN2021/126764
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English (en)
French (fr)
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邱凌啸
陈晓杰
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海宁侏罗纪生物科技有限公司
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Priority to KR1020237028265A priority Critical patent/KR20230133361A/ko
Priority to AU2021431616A priority patent/AU2021431616A1/en
Priority to EP21928824.8A priority patent/EP4282443A1/en
Priority to US18/275,214 priority patent/US20240115759A1/en
Priority to JP2023548326A priority patent/JP2024507337A/ja
Publication of WO2022183750A1 publication Critical patent/WO2022183750A1/zh

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    • 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
    • C09J177/00—Adhesives based on polyamides obtained by reactions forming a carboxylic amide link in the main chain; Adhesives based on derivatives of such polymers
    • C09J177/04—Polyamides derived from alpha-amino carboxylic acids
    • 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
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • 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
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained 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
    • 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
    • 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
    • A61L24/104—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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—Polysaccharides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment
    • 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
    • C09J171/00—Adhesives based on polyethers obtained by reactions forming an ether link in the main chain; Adhesives based on derivatives of such polymers
    • C09J171/02—Polyalkylene oxides
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624—Nanocapsules
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions

Definitions

  • the invention relates to the technical field of adhesives, in particular to a medical tissue adhesive and a preparation method thereof.
  • Tissue adhesive can be broadly defined as any substance with in situ polymerizing properties that allows tissue to tissue or tissue to non-tissue surfaces to adhere, control bleeding (hemostatic agents), and act as a barrier to gas and fluid leakage (Sealants).
  • An ideal biomedical adhesive needs to meet the requirements of biocompatibility, biodegradability, mechanical compliance with underlying tissue, acceptable swelling index, and storage stability.
  • the degradation time is suitable, and the degradation products are non-toxic.
  • the commonly used medical adhesives on the market are generally divided into active ingredients and cross-linking agents. When using, they are first dissolved to form a solution, and then the active ingredients and cross-linking agents are mixed through the blending injection head and injected into the bleeding. part.
  • active ingredients and cross-linking agents are mixed through the blending injection head and injected into the bleeding. part.
  • this will lead to inconvenient clinical use and uncontrollable gel formation speed (too fast or too slow gel formation), which is easily washed away by a large amount of blood on the surface of the tissue, resulting in an unsatisfactory hemostasis effect, which is only suitable for hemostasis with a small amount of bleeding. .
  • Patent CN201910049714.4 uses a hydrophobic organic solvent such as castor oil that is immiscible with water as a dispersant to disperse the active ingredient and the auxiliary cross-linking agent, and increases the probability of the active ingredient in contact with the tissue surface through the action of the hydrophobic dispersion to expel blood, so as to achieve energy efficiency. Adhesion to tissue surfaces with a large amount of blood. However, since the active ingredients and auxiliary cross-linking agents are encapsulated by a large amount of hydrophobic dispersants, it is difficult to contact enough water for dissolution and subsequent cross-linking, resulting in slow gel formation speed and poor gel strength. The purpose of rapid hemostasis and strong tissue adhesion in massive bleeding.
  • a hydrophobic organic solvent such as castor oil that is immiscible with water as a dispersant to disperse the active ingredient and the auxiliary cross-linking agent, and increases the probability of the active ingredient in contact with the tissue surface through the action of the hydrophobic dispersion
  • the present invention is made to solve the above problems, and aims to provide a medical tissue adhesive and a preparation method thereof.
  • the present invention provides a medical tissue adhesive for adhering biological tissues, which has the characteristics of comprising: an active ingredient, an auxiliary cross-linking agent and a dispersing agent, wherein the active ingredient is modified by tissue adhesive groups Micro-nano particles modified by polymer chains or tissue adhesive groups, the auxiliary cross-linking agent is a compound that undergoes a cross-linking reaction with the tissue-adhesive group or a compound that stimulates the tissue-adhesive group to cross-link itself , a dispersant is a compound that brings the active ingredient into contact with the surface of biological tissue when in contact with an aqueous liquid.
  • the tissue adhesive provided by the present invention, it also has the following characteristics: wherein, the tissue adhesive groups include: o-nitrobenzyl phototrigger group, active ester group, isocyanate group, Isothiocyanate group, epoxy group, cyclic carbonate group, thiocyclic carbonate group, active carbonyl group or active double bond group, o-nitrobenzyl
  • the tissue adhesive groups include: o-nitrobenzyl phototrigger group, active ester group, isocyanate group, Isothiocyanate group, epoxy group, cyclic carbonate group, thiocyclic carbonate group, active carbonyl group or active double bond group, o-nitrobenzyl
  • the structure of the light-based trigger group is shown in formula I or formula II:
  • LG is halogen atom, O-R', S-R' or NH-R';
  • R' is hydrogen, alkyl, ether, thioether, ketone, ester, sulfur Any one of an ester group, an amide group, a sulfate group, a sulfate group, a sulfonic acid group, a sulfonic acid ester group, a phosphonic acid group or a phosphonic acid ester group;
  • R 1 is hydrogen, halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, aldehyde group, ketone group, ester group, amide group, thioester group, sulfuric acid group, sulfate ester group, sulfonic acid group, sulfonic acid ester any one of a group, a phosphonic acid group, a phosphonate group, a sulfone group, a sulfoxide group, an aryl group, an alkyl group or a modified alkyl group;
  • R 2 , R 3 , R 4 , and R 5 are bonded with polymer chains or micro-nano particles,
  • R 2 , R 3 , R 4 , and R 5 is bonded to the polymer chain or micro-nano particles, it is a terminal amino group, a hydroxyl group, a mercapto group, a halogen atom, an acid halide group, an acid anhydride group, a carboxyl group, a carboxyl group Acid group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, thio Any one of aryl, alkyl or modified alkyl groups modified by cyclic carbonate groups, active carbonyl groups or active double bond groups,
  • R 2 , R 3 , R 4 , and R 5 that are not connected to the polymer chain or micro-nano particles are independently selected from hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, aldehyde , ketone group, carboxyl group, ester group, thioester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group , amide group, sulfate group, sulfate group, sulfonic acid group, sulfonic acid ester group, phosphonic acid group, phosphonic acid ester group, sulfone group, sulfoxide group, aryl group, alkyl group or any one of modified alkyl groups kind;
  • the active ester group is a succinimide type active ester group as shown in formula III or a triazole type active ester group as shown in formula IV:
  • the active ester group of succinimide is bonded to the polymer chain or micro-nano particles represented by P through R 6 ,
  • R 6 is directly bonded with polymer chains or micro-nano particles, or through terminal-modified ether bonds, thioether bonds, ketone bonds, ester bonds, thioester bonds, amide bonds, sulfate bonds, sulfate bonds Bond, sulfonic acid bond, sulfonate bond, phosphonic acid bond, phosphate bond, sulfone bond, sulfoxide bond, aryl bond, alkyl bond or modified alkyl bond and any one of the polymer chain or micro nanoparticle bonding,
  • R 7 and R 8 are independently selected from hydrogen, halogen atom, hydroxyl group, mercapto group, amine group, nitro group, cyano group, aldehyde group, ketone group, ester group, thioester group, isocyanate group, isothiocyanate group , epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfate group, sulfate group, sulfonic acid group, sulfonic acid ester group, phosphonic acid group, phosphonate group, sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group or the bond between R 7 and R 8 forms a ring,
  • the triazole-based active ester group is bonded to the polymer chain or micro-nano particles represented by P through R 9 ,
  • R 9 is directly bonded with polymer chains or micro-nano particles, or through terminal-modified ether bonds, thioether bonds, ketone bonds, ester bonds, thioester bonds, amide bonds, sulfate bonds, sulfate bonds Bond, sulfonic acid bond, sulfonic acid ester bond, phosphonic acid bond, phosphate ester bond, sulfone bond, sulfoxide bond, aryl group, alkyl group or modified alkyl group and polymer chain or micro-nano particle bond Knot,
  • R 10 and R 11 are independently selected from hydrogen, halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, aldehyde group, ketone group, ester group, thioester group, isocyanate group, isothiocyanate group, Epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfate group, sulfate group, sulfonic acid group, sulfonic acid ester group, phosphonic acid group , any one of phosphonate group, sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group, or R 10 and R 11 are bonded to form a ring;
  • R 12 is bonded to a polymer chain or micro-nano particles, and R 12 is a terminal amino group, hydroxyl group, mercapto group, halogen group, acid halide group, acid anhydride group, carboxyl group before being bonded to the polymer chain or micro-nano particle group , carboxylate group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, Any one of aryl, heteroaryl, alkyl or modified alkyl groups modified by thiocyclic carbonate groups, active carbonyl groups or active double bond groups;
  • the isothiocyanate group is shown in formula VI:
  • R 13 is bonded to a polymer chain or micro-nano particles, and R 13 is a terminal amino group, hydroxyl group, mercapto group, halogen group, acid halide group, acid anhydride group, carboxyl group before being bonded to the polymer chain or micro-nano particle group , carboxylate group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, Any one of aryl, heteroaryl, alkyl or modified alkyl groups modified by thiocyclic carbonate groups, active carbonyl groups or active double bond groups;
  • Epoxy groups are shown in formula VII:
  • R 14 is bonded with a polymer chain or micro-nano particles, and before R 14 is bonded with a polymer chain or micro-nano particles, it is a terminal amino group, a hydroxyl group, a mercapto group, a halogen, an acid halide group, an acid anhydride group, a carboxyl group, Carboxylate group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, sulfur Any one of aryl, heteroaryl, alkyl or modified alkyl groups modified by cyclic carbonate-based groups, active carbonyl-based groups or active double-bond-based groups,
  • R 15 is hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonic acid Ester group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfuric acid group, sulfate group, sulfonic acid group, sulfonic acid ester group, phosphonic acid group, phosphonic acid ester group , any one of sulfone group, sulfoxide group, aryl group, alkyl group, modified alkyl group, or bonded with R 14 to form a ring;
  • R 16 is bonded to a polymer chain or micro-nano particles, and R 16 is a terminal amino group, hydroxyl group, mercapto group, halogen, acid halide group, acid anhydride group, carboxyl group before being bonded to the polymer chain or micro-nano particle , carboxylate group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, Any one of aryl, heteroaryl, alkyl, or modified alkyl groups modified by thiocyclic carbonate groups, active carbonyl groups or active double bond groups,
  • R 17 is hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonic acid Ester group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfuric acid group, sulfate group, sulfonic acid group, sulfonic acid ester group, phosphonic acid group, phosphonic acid ester group , any one of sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group or bond with R 16 to form a ring;
  • the thiocyclic carbonate group is any one of the seven compounds shown in formula IX:
  • the active carbonyl group is shown in formula X:
  • R 18 is bonded with polymer chains or micro-nano particles, and R 18 is a terminal amino group, hydroxyl group, mercapto group, halogen group, acid halide group, acid anhydride group, carboxyl group before being bonded to the polymer chain or micro-nano particles , carboxylate group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, Any one of aryl, heteroaryl, alkyl or modified alkyl groups modified by thiocyclic carbonate groups, active carbonyl groups or active double bond groups,
  • R 19 is hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonic acid Ester group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfuric acid group, sulfate group, sulfonic acid group, sulfonic acid ester group, phosphonic acid group, phosphonic acid ester group , any one of sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group or bond with R 18 to form a ring;
  • R 20 is bonded to a polymer chain or micro-nano particles, and R 20 is a terminal amino group, hydroxyl group, mercapto group, halogen group, acid halide group, acid anhydride group, carboxyl group before being bonded to the polymer chain or micro-nano particle group , carboxylate group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, Any one of aryl, heteroaryl, alkyl or modified alkyl groups modified by thiocyclic carbonate groups, active carbonyl groups or active double bond groups,
  • R 21 is hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonic acid Ester group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfuric acid group, sulfate group, sulfonic acid group, sulfonic acid ester group, phosphonic acid group, phosphonic acid ester group , any one of sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group or bond with R 20 to form a ring.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the dispersing agent is a liquid dispersing agent, and the liquid dispersing agent includes one of polyol compounds or liquid polyethylene glycol and derivatives thereof or Various mixtures.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the polymer chain is a natural carbohydrate compound or a hydrophilic or water-soluble synthetic polymer, and the micro-nano particles are nanoparticles formed by the polymer chain. Or micro-particles, and the polymer chain is a natural sugar compound or a hydrophilic or water-soluble synthetic polymer.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the natural carbohydrate compounds are hyaluronic acid, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose Alginate, alginic acid, dextran, agarose, heparin, chondroitin sulfate, ethylene glycol chitosan, propylene glycol chitosan, chitosan lactate, carboxymethyl chitosan or chitosan quaternary ammonium salt any of the .
  • the natural carbohydrate compounds are hyaluronic acid, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose Alginate, alginic acid, dextran, agarose, heparin, chondroitin sulfate, ethylene glycol chitosan, propylene glycol chitosan, chitosan
  • the hydrophilic or water-soluble synthetic polymer is two-arm polyethylene glycol, multi-arm polyethylene glycol, polyethyleneimine, dendrimer body, synthetic peptides, polyurethane, polylysine, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, polyvinyl alcohol, poly Any one or more of vinylpyrrolidone.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein the auxiliary cross-linking agent is an amino group-containing compound, a nanoparticle formed from an amino group-containing compound, or a microparticle formed from an amino group-containing compound. any one or more of them.
  • the compound containing amino group is hydrophilic or water-soluble animal and vegetable protein, collagen, serum protein, silk fibroin, elastin, protein Degradants, polyethyleneimine, dendrimers, synthetic polypeptides, polylysine, polyarginine, polyhistidine, amino-terminated two-arm polyethylene glycol, amino-terminated multi-arm polyethylene glycol, or amino Any one or more of the end-capped polyurethanes.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the general formula of the polyol compound is C n H 2n-m+2 (OH) m , n is a positive integer greater than or equal to 2, m It is a positive integer less than or equal to n, and polyethylene glycol and its derivatives are straight-chain polyethylene glycol, branched polyethylene glycol, multi-arm polyethylene glycol homopolymer, copolymer and its end group modification or Any one or more of the salt-forming products.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein the auxiliary cross-linking agent is an amino group-containing compound, a nanoparticle formed from an amino group-containing compound, or a microparticle formed from an amino group-containing compound. any one or more of them.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein the dispersing agent is a solid dispersing agent, and the solid dispersing agent is melted into a liquid that uniformly disperses the active ingredient and the auxiliary cross-linking agent under heating conditions and does not mix with The active ingredient reacts with the auxiliary cross-linking agent, and the dispersing agent is any one or more of polyethylene glycol and its derivatives or saccharide compounds.
  • the medical tissue adhesive provided by the present invention, it also has the following characteristics: wherein the polyethylene glycol and its derivatives are straight-chain polyethylene glycol, branched polyethylene glycol, and multi-arm polyethylene glycol. Any one or more of polymers, copolymers and their end-group modifications or salt-forming products.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the auxiliary cross-linking agent is a compound that undergoes a cross-linking reaction with tissue adhesive groups, and the auxiliary cross-linking agent is an amino group, a carboxyl group, a thiol group or any one or more of hydroxy compounds.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the compound containing amino groups is polyethyleneimine, polylysine, polyarginine, polyhistidine, gelatin, collagen, Any one or more of elastin, silk fibroin, chitosan and its derivatives or copolymers, the compound containing carboxyl group is hyaluronic acid, carboxymethyl chitosan, carboxymethyl cellulose, carboxymethyl Any one of base starch, alginic acid, chondroitin sulfate, heparin, polysaccharide uronic acid, polyglutamic acid, polyaspartic acid, gelatin, collagen, silk fibroin, polylactic acid and its derivatives or copolymers One or more; the compound containing sulfhydryl group is any one or more of polycysteine, gelatin, collagen and its derivatives, and the compound containing hydroxyl group is hyaluronic acid, chitosan, agarose,
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the auxiliary cross-linking agent is a compound that stimulates the cross-linking of the tissue adhesive group itself, and the auxiliary cross-linking agent is a peroxide or a reducing agent .
  • the peroxide is an alkyl peroxide (ROOH), a dialkyl peroxide (ROOR'), a diacyl peroxide ( Any one or more of RCOOOOCR'), peroxyester (RCOOOR'), peroxycarbonate (ROCOOOOCOR') and ketone peroxide [R 2 C(OOH) 2 ], preferably benzoyl peroxide, Tert-butyl peroxide, cyclohexanone peroxide, methyl ethyl ketone peroxide, hydrogen peroxide, persulfate, hydrogen persulfate, potassium persulfate, ammonium persulfate.
  • ROOH alkyl peroxide
  • ROOR' dialkyl peroxide
  • a diacyl peroxide Any one or more of RCOOOOCR'), peroxyester (RCOOOR'), peroxycarbonate (ROCOOOOCOR') and ketone peroxide [R 2 C(OOH) 2 ]
  • the medical tissue adhesive provided by the present invention, it also has the following characteristics: wherein the reducing agent is sulfite, hydrogen sulfite, ferrous salt, naphthenate, tertiary amine compound, mercaptan in Any one or more, preferably sodium sulfite, sodium bisulfite, ferrous chloride, ferrous sulfate, cobalt naphthenate, N,N-dimethylaniline, tetraethylethylenediamine.
  • the reducing agent is sulfite, hydrogen sulfite, ferrous salt, naphthenate, tertiary amine compound, mercaptan in Any one or more, preferably sodium sulfite, sodium bisulfite, ferrous chloride, ferrous sulfate, cobalt naphthenate, N,N-dimethylaniline, tetraethylethylenediamine.
  • the medical tissue adhesive provided by the present invention also has the following characteristics: wherein, the mass ratio of the active ingredient, the auxiliary crosslinking agent and the dispersing agent is 1:(0.01-10):(0.1-30).
  • the present invention provides a method for preparing a medical tissue adhesive, which is used for preparing any one of the above-mentioned medical tissue adhesive. , add dispersant, mix evenly, and get it.
  • the mechanism of action of the medical tissue adhesive provided by the invention is as follows:
  • the dispersant in the medical tissue adhesive absorbs water and dissolves, and the dissolved dispersant displaces the tissue fluid or blood on the tissue surface, allowing the active ingredients and auxiliary
  • the cross-linking agent has sufficient contact with the tissue surface.
  • the adhesive molecular fragments in the active ingredient quickly generate chemical bonds with the amino, carboxyl or hydroxyl groups on the tissue surface to form strong tissue adhesion.
  • the medical tissue adhesive further absorbs water in tissue fluid and blood, and the absorbed water is gradually mixed with the dispersing agent, and gradually infiltrates the active ingredient and auxiliary cross-linking agent, so that the active ingredient and auxiliary cross-linking agent are fully dissolved.
  • the medical tissue adhesive of the present invention because of the active ingredients, auxiliary cross-linking agents and dispersing agents of the adhesive molecular fragments, the medical tissue adhesive provided by the present invention can not only utilize The dispersing agent displaces the tissue fluid or blood on the tissue surface, so that the adhesive molecular fragments in the active ingredient quickly form chemical bonds with the amino groups on the tissue surface to form strong tissue adhesion, and can also trigger the adhesive in the active ingredient.
  • the molecular fragment reacts with the amino group on the auxiliary cross-linking agent, so that the whole medical tissue adhesive is quickly gelled and solidified, so that it has good blood drainage performance, hemostasis performance, tissue adhesion performance and wound sealing performance.
  • Fig. 1 is embodiment one TCM tissue adhesive glue diagram
  • Fig. 2 is the use effect diagram of the medical tissue adhesive of embodiment two in the blood drainage performance test
  • Fig. 3 is the use effect diagram of the medical tissue adhesive of embodiment 2 in the performance test of water absorption and gel formation;
  • Fig. 4 is the use effect diagram of the medical tissue adhesive of embodiment 7 in the performance test of water absorption and gel formation;
  • Figure 5 is a diagram of a rabbit liver hemorrhage model in Test Example 4.
  • Fig. 6 is the use effect diagram of TCM tissue adhesive in Test Example 4.
  • FIG. 7 is a diagram of a rabbit abdominal aortic hemorrhage model in Test Example 2;
  • Fig. 8 is the use effect diagram of TCM tissue adhesive in Test Example 2;
  • Fig. 9 is the use effect diagram of the medical tissue adhesive of Test Example 7.
  • Figure 10 is the effect diagram of the use of TCM tissue adhesive in Test Example 6;
  • Fig. 11 is the medical tissue adhesive glue figure in the embodiment eight of the present invention.
  • Fig. 12 is the medical tissue adhesive glue figure in the embodiment nine of the present invention.
  • Fig. 13 is the medical tissue adhesive glue diagram in the tenth embodiment of the present invention.
  • Fig. 14 is the use effect diagram of the medical tissue adhesive in Embodiment 11 of the present invention in the performance test of water absorption and gel formation;
  • Fig. 15 is another use effect diagram of the medical tissue adhesive in the embodiment 8 of the present invention in the performance test of water absorption and gel formation;
  • Fig. 16 is the effect diagram of the performance test of the medical tissue adhesive in test example four of the present invention.
  • Fig. 17 is the effect diagram of the medical tissue adhesive in Test Example 4 of the present invention to absorb water into gel and swell performance test;
  • Fig. 18 is the water-absorbing effect diagram of TCM tissue adhesive in Test Example 5 of the present invention.
  • Fig. 19 is the initial effect diagram of the use of the TCM tissue adhesive in Test Example 6 of the present invention.
  • Figure 20 is the effect diagram after the use of the TCM tissue adhesive in Test Example 6 of the present invention.
  • Figure 21 is a diagram of a rabbit abdominal aorta hemorrhage model in Test Example 7 of the present invention.
  • Figure 22 is the effect diagram after rabbit abdominal aorta hemostasis in Test Example 7 of the present invention.
  • Figure 23 is a diagram of a rabbit femoral artery hemorrhage model in Test Example 7 of the present invention.
  • Fig. 24 is the contrast effect diagram of using common medical gauze in test example seven of the present invention.
  • Fig. 25 is the after-use effect diagram of test example seven traditional Chinese medicine gauze of the present invention.
  • Fig. 26 is the effect diagram of test example seven Chinese medical tissue adhesives of the present invention.
  • Figure 27 is the after-use effect diagram of test example seven Chinese medical tissue adhesives of the present invention.
  • FIG. 28 is a graph showing the effect of testing the adhesive strength of the medical tissue adhesive in Test Example 8 of the present invention.
  • the medical tissue adhesive prepared by the dispersing agent being a liquid dispersing agent or a solid dispersing agent.
  • N-hydroxysuccinimide is replaced by its abbreviation "NHS”
  • ortho-nitrobenzyl light trigger is replaced by its abbreviation "NB”
  • 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride replaced by its abbreviation "EDC”
  • 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine salt The acid salt is replaced by its abbreviation DMTMM.
  • Polyglutamic acid the molecular weight is 700,000 to 1,000,000;
  • Polyethyleneimine the molecular weight is 70,000;
  • Hyaluronic acid molecular weight is 1 million
  • Polylysine molecular weight is 1500;
  • Carboxyl-terminated four-arm polyethylene glycol molecular weight is 2000;
  • Amino-terminated four-arm polyethylene glycol molecular weight 2000.
  • the dispersing agent is the relevant examples and test examples of the medical tissue adhesive prepared by the liquid dispersing agent.
  • the medical tissue adhesive provided in this example is prepared from 1 part by weight of NB-modified polyglutamic acid with a graft ratio of 10%, 0.01 part of polyethyleneimine and 1 part of 1,2-propanediol .
  • the preparation method of NB-modified polyglutamic acid is to dissolve aminated NB: polyglutamic acid: EDC: NHS in water according to a mass ratio of 1:15:1:1, and adjust the pH to 5.5, Heating to 35° C., stirring and reacting for 3 hours, dialysis and freeze-drying to obtain NB-modified polyglutamic acid with a grafting rate of 10%.
  • the preparation method of the medical tissue adhesive provided in this example is as follows: NB-modified polyglutamic acid with a graft ratio of 10%, polyethyleneimine and 1,2-propanediol are in a mass ratio of 1:0.01:1 It is obtained after mixing uniformly, and the final product is shown in Figure 1.
  • the medical tissue adhesive provided in this example is prepared from 1 part of NHS-modified hyaluronic acid (HANHS) with a graft ratio of 10%, 0.5 part of polylysine and 2 parts of glycerol by weight.
  • HANHS NHS-modified hyaluronic acid
  • the preparation method of NHS-modified hyaluronic acid is to dissolve hyaluronic acid:EDC:NHS in water according to a mass ratio of 10:1:1, adjust the pH to 5.5, heat to 35°C, and stir for 1 hour. , dialyzed and freeze-dried to obtain NHS-modified hyaluronic acid with a grafting rate of 10%.
  • the preparation method of the medical tissue adhesive provided in this example is as follows: the NHS-modified hyaluronic acid, polylysine and glycerol with a graft ratio of 10% are mixed uniformly in a mass ratio of 1:0.5:2 to obtain .
  • the medical tissue adhesive provided in this example is prepared from 1 part by weight of aldehyde group-modified dextran (ODEX) with an aldehyde group graft ratio of 30%, 0.2 parts of gelatin and 1.5 parts of ethylene glycol .
  • ODEX aldehyde group-modified dextran
  • the preparation method of aldehyde group-modified glucan is as follows: glucan:sodium periodate are dissolved in water according to the molar ratio of 1:1, the pH is adjusted to 4.5, the reaction is stirred for 1.5 hours, followed by dialysis and freeze-drying, An aldehyde group-modified glucan with an aldehyde group graft ratio of 30% was obtained.
  • the preparation method of the medical tissue adhesive provided in this example is as follows: the aldehyde group-modified dextran with an aldehyde group graft ratio of 30%, gelatin and ethylene glycol are mixed uniformly in a mass ratio of 1:0.1:30. That's it.
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of active ester-modified four-arm polyethylene glycol (4a-PEG-NHS) with a graft ratio of 100%, 0.2 parts of amino-terminated four-arm Prepared from polyethylene glycol (4a-PEG- NH2 ) and 1.5 parts of glycerol.
  • the preparation method of the amino-terminated four-arm polyethylene glycol is as follows: the carboxyl-terminated four-arm polyethylene glycol (4a-PEG-COOH):EDC:NHS is dissolved in water according to the mass ratio of 1:0.1:0.1, The pH was adjusted to 5.5, heated to 35° C., stirred and reacted for 0.5 hour, followed by dialysis and freeze-drying to obtain an active ester-modified four-arm polyethylene glycol with a graft ratio of 100%.
  • the preparation method of the medical tissue adhesive provided in this example is as follows: the NHS-modified hyaluronic acid, polylysine and glycerol with a graft ratio of 10% are mixed uniformly in a mass ratio of 1:0.5:2 to obtain .
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of microparticles (mHA-NHS, the diameter of the microsphere is 5 microns) modified by tissue adhesive groups with a graft ratio of 100%, 0.5 parts by weight Made with chitosan and 2 parts glycerol.
  • the preparation method of microparticles modified by tissue adhesive groups is as follows: dissolving hyaluronic acid:EDC:NHS in water according to a mass ratio of 1:0.1:0.1, adjusting the pH to 5.5, heating to 35°C, and stirring the reaction After 0.5 hours, followed by centrifugation and washing for 3 times, microparticles modified with tissue adhesive groups (mHA-NHS) with a grafting rate of 100% were obtained.
  • the preparation method of the medical tissue adhesive provided in this embodiment is as follows: the microparticles modified with tissue adhesive groups with a graft ratio of 100%, chitosan and glycerol are mixed uniformly according to the mass ratio of 1:0.5:2 Get it later.
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of hyaluronic acid (HANB) modified with NB-modified macromolecular backbone with a graft ratio of 4% tissue adhesive groups, 0.5 part by weight Chitosan nanoparticles (nCS, nanoparticle diameter of 50 nm) and 1.5 parts of glycerol were prepared.
  • HANB hyaluronic acid
  • nCS Chitosan nanoparticles
  • glycerol glycerol
  • the preparation method of the macromolecular main chain modified by the tissue adhesive group is NB-modified hyaluronic acid is: dissolving NB:hyaluronic acid:EDC:NHS into water according to the mass ratio of 1:20:1:1 , adjusted pH to 5.5, heated to 35°C, stirred for 2 hours, dialyzed and freeze-dried to obtain hyaluronic acid whose main chain of macromolecular main chain modified by tissue adhesive group was NB-modified with grafting rate of 4%.
  • the preparation method of the medical tissue adhesive provided in this embodiment is as follows: the macromolecular backbone modified by tissue adhesive groups with a graft ratio of 4% is NB-modified hyaluronic acid, chitosan nanoparticles and glycerol According to the mass ratio of 1:0.5:1.5, it can be obtained after mixing evenly.
  • the medical tissue adhesive provided in this example is prepared from 1 part of NHS-modified hyaluronic acid (HANHS) with a graft ratio of 10%, 0.5 part of polylysine and 2 parts of silicone oil by weight.
  • HANHS NHS-modified hyaluronic acid
  • the preparation method of the medical tissue adhesive provided in this example is as follows: the NHS-modified hyaluronic acid with a graft ratio of 10%, polylysine and silicone oil are mixed uniformly in a mass ratio of 1:0.5:2 to obtain .
  • the method for testing blood drainage performance is as follows: drop 2 ml of blood on a glass slide, and then drop 2 ml of the medical tissue adhesive provided in Example 2 or Example 7 on the blood.
  • the medical tissue adhesive provided in Example 2 uses the hydrophilic dispersant glycerol, so it can quickly drain the blood and contact the bottom of the slide, and then absorb the water in the blood and solidify into a glue, which proves that The tissue adhesive has good blood-draining properties and water-absorbing gel-forming properties. Since the medical tissue adhesive provided in Example 7 uses the hydrophobic dispersant silicone oil, it can also quickly drain the blood and make contact with the bottom of the glass slide.
  • test method for water absorption and gel formation is as follows: add 5 ml of deionized water to a petri dish, and then dropwise add 0.2 ml of the medical tissue adhesive provided in Example 2 or Example 7 to the water.
  • the hydrophilic dispersant glycerol used in the medical tissue adhesive in Example 2 can dissolve in water, it will quickly absorb water, dissolve the active ingredient and the auxiliary cross-linking agent to form a gel, and the color gradually changes from milky white from outside to inside. It becomes colorless and transparent, and completely becomes colorless and transparent after 2 minutes, forming a complete glue.
  • the medical tissue adhesive provided in Example 7 uses a hydrophobic dispersant silicone oil that is immiscible with water, which will cause the active ingredient and auxiliary cross-linking agent to be wrapped in a large amount of silicone oil, making it difficult for water to contact and prevent water. Dissolving the active ingredient and auxiliary cross-linking agent, with the increase of soaking time, the emulsion glue will be gradually dispersed by water from the outside to the inside to form milky white particles, which eventually leads to the failure to form a complete agglomerate glue.
  • the first test method is: first, as shown in Figure 4, a liver injury model is made on the rabbit liver with a needle with a diameter of 2 mm, and it can be observed that a large amount of blood is left; then, the medical tissue provided in Example 4 is immediately glued. The glue is squeezed onto the gauze and pressed to the lesion for 10 seconds, after which the gauze is removed.
  • the medical tissue adhesive can firmly adhere to the surface of the liver and has absorbed the water in the blood to form a gel, and there is no blood flow out at the same time, which proves the good tissue adhesion performance of the tissue adhesive, Wound sealing properties and hemostatic properties.
  • the second test method is as follows: First, as shown in Figure 7, a large hemorrhage model of abdominal aortic injury was created on the rabbit abdominal aorta with a needle with a diameter of 2 mm, and a large amount of blood columns could be observed; The medical tissue adhesive provided in Example 7 was extruded onto the gauze and pressed to the injury for 10 seconds, and then the gauze was removed.
  • the medical tissue adhesive provided in Example 2 can firmly adhere to the surface of the abdominal aorta and has absorbed the water in the blood to form a glue, and at the same time, no blood flows out, and the abdominal aorta can be clearly seen.
  • the arteries and the glue adhered to the defect proved that the tissue adhesive had good tissue adhesion properties, wound sealing properties and hemostatic properties.
  • Example 7 the medical tissue adhesive provided in Example 7 could not stop the massive hemorrhage of abdominal aorta injury, and a large amount of blood was still ejected rapidly, and a large amount of blood submerged the abdominal cavity, which proved that the medical treatment using the hydrophobic dispersant Tissue adhesive cannot effectively seal the wound and stop bleeding.
  • test method is as follows: apply the medical tissue adhesives of Examples 1 to 7 between two pieces of pigskin at a smearing amount of 0.1 mL/cm 2 , then soak the pigskin coated with the tissue adhesives in water, and record Bonding time.
  • the tissue adhesives provided in Examples 1 to 6 can be cured within 60s, and the two pieces of pigskin can be bonded together.
  • the bonding rate is very high and can be widely used in Various medical environments.
  • the dispersing agent is the relevant examples and test examples of the medical tissue adhesive prepared by the solid dispersing agent.
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of active ester-modified four-arm polyethylene glycol (4a-PEG-NHS) with a graft ratio of 100%, 0.12 parts of polyethyleneimine ( PEI) and 3 parts of polyethylene glycol 1000 (PEG-1000).
  • the preparation method of active ester-modified four-arm polyethylene glycol (4a-PEG-NHS) is as follows: carboxyl-terminated four-arm polyethylene glycol (4a-PEG-COOH):EDC:NHS according to the mass ratio of 1 :0.1:0.1 was dissolved in water, adjusted to pH 5.5, heated to 35°C, stirred for 0.5 hours, then dialyzed and freeze-dried to obtain active ester-modified four-arm polyethylene glycol with a graft ratio of 100%.
  • the preparation method of the medical tissue adhesive provided in this embodiment is as follows: four-arm polyethylene glycol modified with active ester, amino-terminated four-arm polyethylene glycol and polyethylene glycol 1000 are prepared according to the graft ratio of 100%. The mass ratio is 1:0.12:3. After melting polyethylene glycol 1000 under drying and heating conditions at 50°C, add active ester-modified four-arm polyethylene glycol and amino-terminated four-arm polyethylene glycol to mix evenly, and then pour the mold to cool. The final product is shown in Figure 11.
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of microparticles (mHA-NHS, the diameter of the microsphere is 5 microns) modified by tissue adhesive groups with a graft ratio of 100%, 0.5 parts by weight Chitosan and 2 parts of polyethylene glycol 1000 are prepared.
  • the preparation method of microparticles modified by tissue adhesive groups is as follows: dissolving hyaluronic acid:EDC:NHS in water according to a mass ratio of 1:0.1:0.1, adjusting the pH to 5.5, heating to 35°C, and stirring the reaction After 0.5 hours, followed by centrifugation and washing for 3 times, microparticles modified with tissue adhesive groups (mHA-NHS) with a grafting rate of 100% were obtained.
  • the preparation method of the medical tissue adhesive provided in this example is as follows: after melting polyethylene glycol 1000 at 50° C., microparticles, chitosan and microparticles modified with tissue adhesive groups with a grafting rate of 100% According to the mass ratio of 2:1:0.5, it can be obtained after mixing evenly, and the final product is shown in Figure 12.
  • the medical tissue adhesive provided in this example is composed of 1 part of acrylate-terminated four-arm polyethylene glycol (4a-PEG-AA), 1 part of ammonium persulfate, 1 part of chlorite Iron and 2 parts polyethylene glycol 1000 (PEG-1000).
  • the preparation method of the medical tissue adhesive provided in this embodiment is as follows: the acrylate-terminated four-arm polyethylene glycol, ammonium persulfate, ferrous chloride and polyethylene glycol 1000 are in a molar ratio of 1:1:1 : 2 Under the condition of drying and heating at 50°C, the mixture is evenly mixed and then poured and cooled. The final product is shown in Figure 13.
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of polyglutamic acid (PGAMA) modified with methacrylic anhydride with a graft ratio of 10%, 0.1 part of sodium periodate, 0.1 part of vitamin C And 3 parts of polyethylene glycol 1500 (PEG-1500) prepared.
  • PGAMA polyglutamic acid
  • PEG-1500 polyethylene glycol 1500
  • the preparation method of polyglutamic acid (PGAMA) modified by methacrylic anhydride is to completely dissolve 1 part of polyglutamic acid by weight in deionized water, and according to the carboxyl content of polyglutamic acid: methacrylic acid
  • the methacrylic anhydride with an anhydride molar ratio of 10:1 was added to the polyglutamic acid solution, the pH was adjusted to 8-9, the reaction was stirred for 4 hours, dialyzed, and freeze-dried to obtain a methacrylic anhydride modified with a graft ratio of 10%.
  • Polyglutamic acid Polyglutamic acid.
  • the preparation method of the medical tissue adhesive provided in this embodiment is as follows: polyglutamic acid modified with methacrylic anhydride with a graft ratio of 10%, sodium periodate, vitamin C and polyethylene glycol 1500 are prepared according to the mass ratio Mix evenly at 1:0.1:0.1:3 under drying and heating conditions at 50 °C, and grind the sample into powder after cooling, and the final product is shown in Figure 14.
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of active ester-modified four-arm polyethylene glycol (4a-PEG-NHS) with a graft ratio of 100%, 0.2 parts of amino-terminated four-arm It was prepared from polyethylene glycol (4a-PEG-NH 2 ) and 1.5 parts of polyethylene glycol 1000 (PEG-1000).
  • the preparation method of active ester-terminated four-arm polyethylene glycol (4a-PEG-NHS) is as follows: carboxyl-terminated four-arm polyethylene glycol (4a-PEG-COOH):EDC:NHS according to the mass ratio of 1 :0.1:0.1 was dissolved in water, adjusted to pH 5.5, heated to 35°C, stirred for 0.5 hours, then dialyzed and freeze-dried to obtain active ester-modified four-arm polyethylene glycol with a graft ratio of 100%.
  • the preparation method of the medical tissue adhesive provided in this embodiment is as follows: four-arm polyethylene glycol modified with active ester, amino-terminated four-arm polyethylene glycol and polyethylene glycol 1000 are prepared according to the graft ratio of 100%.
  • the mass ratio is 1:0.2:1.5, and the mixture is uniformly mixed under the condition of drying and heating at 50°C, and then poured and cooled.
  • the medical tissue adhesive provided in this example is composed of 1 part of sodium periodate, 1 part of vitamin C and 2 parts of acrylate-terminated four-arm polyethylene glycol 1000 (4a-PEG- AA-1000).
  • the preparation method of the medical tissue adhesive provided in this example is as follows: sodium periodate, vitamin C and acrylate-terminated four-arm polyethylene glycol 1000 are dried and heated at 50°C according to a mass ratio of 1:1:2 After mixing evenly, pour it into the mold and cool it down.
  • the medical tissue adhesive provided in this example is composed of 1 part by weight of active ester-modified four-arm polyethylene glycol (4a-PEG-NHS) with a graft ratio of 100%, 0.12 parts of polyethyleneimine ( PEI) and 2 parts maltose.
  • 4a-PEG-NHS active ester-modified four-arm polyethylene glycol
  • PEI polyethyleneimine
  • the preparation method of active ester-modified four-arm polyethylene glycol is as follows: carboxyl-terminated four-arm polyethylene glycol (4a-PEG-COOH):EDC:NHS is dissolved in water according to the mass ratio of 1:0.1:0.1 , adjusted pH to 5.5, heated to 35° C., stirred and reacted for 0.5 hour, followed by dialysis and freeze-drying to obtain active ester-modified four-arm polyethylene glycol with a grafting rate of 100%.
  • the preparation method of the medical tissue adhesive provided in this example is as follows: the maltose is melted under drying and heating conditions at 150° C., mixed with 100% active ester-modified four-arm polyethylene glycol (4a-PEG-NHS) and polyethylene
  • the imine (PEI) was mixed uniformly according to the weight ratio of 2:1:0.12, and then poured into the mold and cooled.
  • the medical tissue adhesive provided in this example is used as a comparative example by molar parts of 1 part of sodium periodate and 1 part of acrylate-terminated four-arm polyethylene glycol 1000 (4a-PEG-AA-1000 ) are prepared.
  • the preparation method of the medical tissue adhesive provided in this embodiment is as follows: the sodium periodate and the acrylate-terminated four-arm polyethylene glycol 1000 are mixed uniformly under the condition of drying and heating at 50°C according to the mass ratio of 1:1, and then poured. The mold is cooled.
  • the medical tissue adhesive provided in this example is composed of 1 part of sodium periodate, 0.5 part of vitamin C and 1 part of acrylate-terminated four-arm polyethylene glycol 1000 (4a-PEG- AA-1000).
  • the preparation method of the medical tissue adhesive provided in this example is as follows: sodium periodate, vitamin C and acrylate-terminated four-arm polyethylene glycol 1000 are dried and heated at 50°C according to the mass ratio of 1:0.5:1 After mixing evenly, pour it into the mold and cool it down.
  • the medical tissue adhesive provided in this example is prepared from 1 part of vitamin C and 1 part of acrylate-terminated four-arm polyethylene glycol 1000 (4a-PEG-AA-1000) in molar parts.
  • the preparation method of the medical tissue adhesive provided in this example is as follows: vitamin C and acrylate-terminated four-arm polyethylene glycol 1000 are mixed uniformly under the condition of drying and heating at 50°C according to the mass ratio of 1:1, and then poured and cooled. That's it.
  • the first test method for water absorption and gel formation is: add 2 ml of deionized water to a petri dish, and then place a 10 mm*1 mm cylindrical medical tissue adhesive provided in Example 8 in the water.
  • the medical tissue adhesive provided in Example 8 uses polyethylene glycol as a solid dispersant, it can drain liquids such as water by gravity and contact the bottom of the petri dish, and then absorb water and solidify into a glue. It is proved that the tissue adhesive has good drainage performance and water absorption and gelling performance.
  • the hydrophilic dispersing agent polyethylene glycol used in the medical tissue adhesive provided in Example 8 can be dissolved in water.
  • the color gradually becomes colorless and transparent from milky white from outside to inside, and completely becomes colorless and transparent after 5 minutes, forming a complete glue.
  • the second test method for water absorption and gel formation is as follows: add 2 ml of deionized water to the petri dish, and then place the medical tissue adhesive provided in Example 9 with a diameter of 10 mm in the water.
  • the medical adhesive provided in Example 9 uses the hydrophilic solid dispersant polyethylene glycol, during the process of water dissolving, the micro-particles dispersed in it can react with the auxiliary cross-linking agent to form a Glue, the adhesive glue changes from white to colorless and transparent, forming a finished glue in the form of interconnected micron particles, and hardly swells.
  • test method for water absorption performance is as follows: add 1 mL of deionized water to the centrifuge tube, and then add 100 mg of four-arm polyethylene glycol by weight of 1000 to the water in Example 13, Example 15, Example 16, and Example 10 Seven medical tissue adhesives are provided.
  • the medical tissue adhesive provided in Example 13 can form a complete form of water due to the auxiliary cross-linking agent with redox properties and the active ingredient four-arm polyethylene glycol as a solid dispersant at the same time. gel.
  • Example 16 Because the content of the auxiliary crosslinking agent is not optimal, only a partial hydrogel can be formed. However, Example 15 and Example 17 cannot form auxiliary cross-linking because they only contain a single oxidant or reducing agent component, so they cannot form a gel after being dispersed in water. The necessity of auxiliary cross-linking agents for the active ingredient to function is demonstrated.
  • test method is as follows: first, immerse the fresh tissue in the blood, as shown in Figure 19, take 200 mg of the medical tissue adhesive in Example 14 and press it on the surface of the bloody tissue for 15s, and let it stand in the blood for 3 minutes. .
  • the medical tissue adhesive provided in Example 14 can firmly adhere to the surface of the bloody tissue and form a gel, and the colloid on the tissue can be clearly seen, which proves that the tissue adhesive Adhesive properties in blood.
  • the first test method is: first, as shown in Figure 21, a large hemorrhage model of abdominal aortic injury was created on the abdominal aorta of the rabbit with a needle with a diameter of 2 mm, and a large amount of blood columns could be observed; Press the medical tissue adhesive to the injury for 15 seconds, then release the pressure.
  • the medical tissue adhesive provided in Example 8 can be firmly adhered to the surface of the abdominal aorta and has absorbed the water in the blood to form a glue, and at the same time no blood flows out, and the abdominal aorta can be clearly seen.
  • the arteries and the glue adhered to the defect proved that the tissue adhesive had good tissue adhesion properties, wound sealing properties and hemostatic properties.
  • the second test method is: first, as shown in Figure 23, the femoral artery of the rabbit is directly cut with a scalpel, and a large amount of blood can be observed; then, immediately press the wound with ordinary medical gauze, and it can be seen that the gauze is quickly stained with blood. Red, after pressing for 3 minutes, it can be seen that a large amount of blood still seeps through the gauze, as shown in Figure 24. After the gauze was removed, a large amount of blood was still gushing out, and the bleeding did not decrease, as shown in Figure 25.
  • Example 10 As shown in Figure 26, in the case of severe bleeding from the same femoral artery cut, the medical tissue adhesive provided in Example 10 was spread on the gauze and pressed to the injury site for 10 seconds, and then the pressure was released. It can be seen that the gauze was not continued with blood Red, that is, the bleeding has stopped. Continuing to observe for 3 minutes, no blood continued to stain the gauze, and no blood continued to ooze out, proving that the medical tissue adhesive provided in Example 10 has good tissue adhesion, wound closure and hemostatic properties.
  • the test method is: sandwich the medical tissue adhesive of Example 12 between two pieces of pigskin, and the usage amount is 0.1cm*0.1cm*0.01cm, and then soak the pigskin coated with the tissue adhesive in water , and after 5 minutes, the two pieces of pig skin were pulled by a universal test machine.
  • the medical tissue adhesive of Example 12 can bond two pieces of pigskin together, and after pulling, there is still glue remaining between the two pieces of pigskin, which proves that the medical tissue of Example 5 is adhesive Adhesive has strong adhesive strength.
  • the dispersant used is a liquid dispersant
  • the hydrophilic liquid dispersant will squeeze the blood away at the moment when it comes into contact with the blood , so that the adhesive group on the active ingredient can fully contact and react with the amino group on the tissue surface, without being affected by the amino group reaction on the protein in the blood and tissue fluid, and then the hydrophilic liquid dispersant will absorb the blood It dissolves rapidly with the water in the tissue fluid, further dissolves the active ingredients, and triggers the reaction between the adhesive molecular fragments in the active ingredients and the amino groups on the auxiliary cross-linking agent, so that the whole medical tissue adhesive is quickly gelled and cured. Therefore, The medical tissue adhesives prepared in Examples 1 to 6 can quickly cross-link into a glue while having good blood drainage performance, thereby realizing rapid tissue adhesion and wound closure.
  • the dispersant used is a solid hydrophilic dispersant
  • the solid dispersant contacts blood
  • the adhesive group on the active ingredient can fully contact and react with the amino group on the tissue surface, and will not be affected by the reaction of the amino group on the protein in the blood and tissue fluid.
  • the solid hydrophilic dispersant will absorb the water in the blood and tissue fluid, further dissolve the active ingredient, and trigger the reaction between the adhesive molecular fragments in the active ingredient and the amino groups on the auxiliary cross-linking agent, so that the medical tissue adheres
  • the whole glue is quickly gelled and cured. Therefore, the medical tissue adhesives prepared in Examples 8 to 17 can also be quickly cross-linked into gels while having good blood drainage performance, thereby realizing rapid bonding. Tissue and seal wounds.

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Abstract

一种医用组织粘合胶及其制备方法，属于粘合胶领域。所述医用组织粘合胶包括：活性成分、辅助交联剂以及分散剂，其中，活性成分为组织粘附性基团修饰的高分子链或组织粘附性基团修饰的微纳颗粒，组织粘附性基团包括：邻硝基苄基光扳机型基团、活性酯类基团或羰基型基团。所述医用组织粘合胶不仅能够利用分散剂排挤掉组织表面的组织液或血液使得活性成分中具有粘附性的分子片段快速与组织表面的氨基产生化学键形成较强的组织粘附力，而且还能触发活性成分中具有粘附性的分子片段与辅助交联剂上的氨基发生反应，使得医用组织粘合胶整体快速成胶固化，从而具有良好的排血性能、止血性能以及组织粘附性能。

Description

一种医用组织粘合胶及其制备方法 技术领域
本发明涉及粘合胶技术领域，具体涉及一种医用组织粘合胶及其制备方法。
背景技术
医用粘合剂主要包括组织粘合剂、止血剂、组织密封剂，在临床手术中得到了广泛的应用。组织粘合剂可以广义地定义为任何具有原位聚合特性的物质，它可以使组织与组织或组织与非组织表面产生粘附，控制出血(止血剂)，以及作为气体和液体渗漏的屏障(密封剂)。理想的生物医用粘合剂需要满足生物相容性、生物降解性、与下层组织的机械顺应性、可接受的溶胀指数和保存稳定等要求。具体来说应该具有以下特征：安全无毒，容易灭菌和制备；具有流体的性质，在伤口部位容易使用；在生理环境下能快速固化，减少流血和手术时间；具有优秀的组织粘连性能，在特定的时间内保持稳定；在愈合过程中保持原有的机械性能；降解时间合适，降解产物无毒。
目前市面上常用的医用粘合剂一般都是将活性成分和交联剂分装，在使用时先分别溶解配成溶液，再通过共混注射头将活性成分和交联剂混合后注射到出血部位。但是这会导致临床使用不方便和成胶速度不可控(过快或过慢成胶)，容易被组织表面大量的血液冲走，造成止血效果不理想，只能适用于少量渗血情况的止血。
专利CN201910049714.4用与水不互溶的蓖麻油等疏水有机溶剂作为分散剂来分散活性成分和辅助交联剂，通过疏水分散的排挤血液的作用增加活性成分与组织表面接触的概率，从而达到能在有大量血液的组织表面粘附的目的。然而，由于活性成分和辅助交联剂被大量的疏水分散剂包裹，难以接触足够的水发生溶解以及后续的交联，带来成胶速度缓慢和成胶强度差的问题，也无法达到对较大出血快速止血和强力组织粘合的目的。
发明内容
本发明是为了解决上述问题而进行的，目的在于提供一种医用组织粘合胶及其制备方法。
本发明提供了一种医用组织粘合胶，用于粘合生物组织，具有这样的特征，包括：活性成分、辅助交联剂以及分散剂，其中，活性成分为组织粘附性基团修饰的高分子链或组织粘附性基团修饰的微纳颗粒，辅助交联剂为与组织粘附性基团发生交联反应的化合物或激发所述组织粘附性基团自身发生交联的化合物，分散剂为在接触含水液体时让活性成分接触生物组织表面的化合物。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，组织粘附性基团包括：邻硝基苄基光扳机类基团、活性酯类基团、异氰酸酯类基团、异硫氰酸酯类基团、环氧类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团，邻硝基苄基光扳机类基团的结构如式I或式II所示：
Figure PCTCN2021126764-appb-000001
在式I和式II中，LG为卤原子、O-R’、S-R’或NH-R’；R’为氢、烷基、醚基、硫醚基、酮基、酯基、硫酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基或膦酸酯基中的任意一种；
R 1为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、酯基、酰胺基、硫酯基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种；
R 2、R 3，R 4，R 5中的任意一个或多个与高分子链或微纳颗粒键结，
R 2、R 3，R 4，R 5中的任意一个或多个与高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤原子、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、烷基或改性烷基中的任意一种，
R 2、R 3，R 4，R 5中与未与高分子链或微纳颗粒相连的取代基分别独立地选自氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种；
活性酯类基团为如式III所示的丁二酰亚胺类活性酯基或如式IV所示三氮唑类活性酯基：
Figure PCTCN2021126764-appb-000002
丁二酰亚胺类活性酯基通过R 6与P表示的高分子链或微纳颗粒键结，
在式III中，R 6直接与高分子链或微纳颗粒键结，或通过末端改性的醚键、硫醚键、酮键、酯键、硫酯键、酰胺键、硫酸键、硫酸酯键、磺酸键、磺酸酯键、膦酸键、磷酸酯键、砜键、亚砜键、芳基键、烷基键或改性烷基键中的任意一种与高分子链或微纳颗粒键结，
R 7、R 8分别独立地选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基或R 7与R 8之间键结成环，
三氮唑类活性酯基通过R 9与P表示的高分子链或微纳颗粒键结，
在式IV中，R 9直接与高分子链或微纳颗粒键结，或通过末端改性的醚键、硫醚键、酮键、酯键、硫酯键、酰胺键、硫酸键、硫酸酯键、磺酸键、磺酸酯键、膦酸键、磷酸酯键、砜键、亚砜键、芳基、烷基或改性烷基中的任意一种与高分子链或微纳颗粒键结，
R 10、R 11分别独立地选自氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或R 10与R 11之间键结成环；
异氰酸酯类基团的结构式如式V所示：
O＝C＝N-R 12
式V
在式V中，R 12与高分子链或微纳颗粒键结，R 12在与高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性 烷基中的任意一种；
异硫氰酸酯类基团如式VI所示：
S＝C＝N-R 13
式VI
在式VI中，R 13与高分子链或微纳颗粒键结，R 13在与高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种；
环氧类基团如式VII所示：
Figure PCTCN2021126764-appb-000003
在式VII中，R 14与高分子链或微纳颗粒键结，R 14与高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种，
R 15为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基、改性烷基、中的任意一种或与R 14键结成环；
环状碳酸酯类基团如式VIII所示：
Figure PCTCN2021126764-appb-000004
在式VIII中，R 16与高分子链或微纳颗粒键结，R 16在与高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基、或改性烷基中的任意一种，
R 17为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或与R 16键结成环；
硫代环状碳酸酯类基团为式IX所示的七种化合物中的任意一种：
Figure PCTCN2021126764-appb-000005
活性羰基类基团如式X所示：
Figure PCTCN2021126764-appb-000006
在式X中，R 18与高分子链或微纳颗粒键结，R 18在与高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种，
R 19为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或与R 18键结成环；
活性双键类基团如式XI所示：
Figure PCTCN2021126764-appb-000007
在式XI中，R 20与高分子链或微纳颗粒键结，R 20在与高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种，
R 21为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或与R 20键结成环。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，分散剂为液体分散剂，液体分散剂包括多元醇类化合物或液态聚乙二醇及其衍生物中的一种或多种的混合物。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，高分子链为天然糖类化合物或亲水性或水溶性合成聚合物，微纳颗粒为高分子链形成的纳米颗粒或微米颗粒，高分子链为天然糖类化合物或亲水性或水溶性合成聚合物。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，天然糖类化合物为透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐中的任意一种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，亲水性或水溶性合成聚合物为两臂聚乙二醇、多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚氨酯、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，辅助交联剂为含有氨基的化合物、由含有氨基的化合物形成的纳米颗粒或由含有氨基的化合物形成的微米颗粒中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，含有氨基的化合物为亲 水性或水溶性的动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白、蛋白降解物、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚精氨酸、聚组氨酸、氨基封端的两臂聚乙二醇、氨基封端的多臂聚乙二醇或氨基封端的聚氨酯中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，多元醇类化合物的通式为C nH 2n-m+2(OH) m，n为大于等于2正整数，m为小于等于n的正整数，聚乙二醇及其衍生物为直链聚乙二醇、支化聚乙二醇、多臂聚乙二醇均聚物、共聚物及其端基改性或成盐产物中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，辅助交联剂为含有氨基的化合物、由含有氨基的化合物形成的纳米颗粒或由含有氨基的化合物形成的微米颗粒中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，分散剂为固体分散剂，固体分散剂在加热条件下融化成均匀分散活性成分和辅助交联剂的液体且不与活性成分和辅助交联剂发生反应，分散剂为聚乙二醇及其衍生物或者糖类化合物中任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，聚乙二醇及其衍生物为直链聚乙二醇、支化聚乙二醇、多臂聚乙二醇均聚物、共聚物及其端基改性或成盐产物中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，辅助交联剂为与组织粘附性基团发生交联反应的化合物，辅助交联剂为含有氨基、羧基、巯基或羟基的化合物中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，含有氨基的化合物为聚乙烯亚胺、聚赖氨酸、聚精氨酸、聚组氨酸、明胶、胶原蛋白、弹性蛋白、丝素蛋白、壳聚糖及其衍生物或共聚物中的任意一种或多种，含有羧基的化合物为透明质酸、羧甲基壳聚糖、羧甲基纤维素、羧甲基淀粉、海藻酸、硫酸软骨素、肝素、多聚糖醛酸、聚谷氨酸、聚天冬氨酸、明胶、胶原、丝素蛋白、聚乳酸及其衍生物或共聚物中的任意一种或多种；含有巯基的化合物为聚半胱氨酸、明胶、胶原及其衍生物中的任意一种或多种，含有羟基的化合物为透明质酸、壳聚糖、琼脂糖、纤维素、淀粉、海藻酸、硫酸软骨素、肝素、多聚糖醛酸、环糊精、聚丝氨酸、明胶、胶原、丝素蛋白、聚乙烯醇及其衍生物或共聚物中的任意一种或多种。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，辅助交联剂为激发组织粘附性基团自身发生交联的化合物，辅助交联剂为过氧化物或还原剂。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，过氧化物为烷基过氧化物(ROOH)、二烷基过氧化物(ROOR’)、二酰基过氧化物(RCOOOOCR’)、过氧酯(RCOOOR’)、过氧化碳酸酯(ROCOOOOCOR’)及酮过氧化物[R 2C(OOH) 2]中的任意一种或多种，优选过氧化苯甲酰、过氧化叔丁基、过氧化环己酮、过氧化甲乙酮、过氧化氢、过硫酸盐、过硫酸氢盐、过硫酸钾、过硫酸铵。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，还原剂为亚硫酸盐、亚硫酸氢盐、亚铁盐、环烷酸盐、叔胺类化合物、硫醇中的任意一种或多种，优选亚硫酸钠、亚硫酸氢钠、氯化亚铁、硫酸亚铁、环烷酸钴、N，N-二甲基苯胺、四乙基乙二胺。
在本发明提供的医用组织粘合胶中，还具有这样的特征：其中，活性成分、辅助交联剂以及分散剂的质量比为1：(0.01～10)：(0.1～30)。
本发明提供了一种医用组织粘合胶的制备方法，用于制备上述任意一项的医用组织粘合胶，具有这样的特征，包括如下步骤：将活性成分以及辅助交联剂磨成粉末状，加入分散剂，混合均匀，即得。
本发明提供的医用组织粘合胶的作用机理如下：
当本医用组织粘合胶接触到含组织液或血液的湿的组织表面时，医用组织粘合胶中的分散剂吸水溶解，溶解的分散剂排挤掉组织表面的组织液或血液，让活性成分和辅助交联剂能充分接触到组织表面。随后，活性成分中具有粘附性的分子片段快速与组织表面的氨基、羧基或羟基产生化学键形成较强的组织粘附力。与此同时，医用组织粘合胶进一步吸收组织液和血液中的水，吸收的水与分散剂逐渐混合，并逐渐浸润活性成分和辅助交联剂，使活性成分和辅助交联剂充分溶解，从而触发活性成分中具有粘附性的分子片段与辅助交联剂上的氨基发生反应或激发粘附性的分子自身发生交联，使得医用组织粘合胶整体成胶固化，最终达到创面封闭和组织渗血渗液的效果。
发明的作用与效果
根据本发明所涉及的医用组织粘合胶及其制备方法，因为具有粘附性的分子片段的活性成分、辅助交联剂以及分散剂，所以，本发明提供的医用组织粘合胶不仅能够利用分散剂排挤掉组织表面的组织液或血液使得活性成分中具有粘附性的分子片段快速与组织表面的氨基产生化学键形成较强的组织粘附力，而且还能触发活性成分中具有粘附性的分子片段与辅助交联剂上的氨基发生反应，使得医用组织粘合胶整体快速成胶固化，从而具有良好的排血性能、止血性能、组织粘附性能以及创面封闭性能。
附图说明
图1是实施例一中医用组织粘合胶图；
图2是实施例二的医用组织粘合胶的在排血性能测试中的使用效果图；
图3是实施例二的医用组织粘合胶在吸水成胶性能测试中的使用效果图；
图4是实施例七的医用组织粘合胶在吸水成胶性能测试中的使用效果图；
图5是测试例四中兔子肝脏出血模型图；
图6是测试例四中医用组织粘合胶的使用效果图；
图7是测试例二中兔子腹主动脉出血模型图；
图8是测试例二中医用组织粘合胶的使用效果图；
图9是测试例七的医用组织粘合胶的使用效果图；
图10是测试例六中医用组织粘合胶的使用效果图；
图11是本发明的实施例八中的医用组织粘合胶图；
图12是本发明的实施例九中的医用组织粘合胶图；
图13是本发明的实施例十中的医用组织粘合胶图；
图14是本发明的实施例十一中的医用组织粘合胶在吸水成胶性能测试中的使用效果图；
图15是本发明的实施例八中的医用组织粘合胶在吸水成胶性能测试中的另一使用效果图；
图16是本发明的测试例四中的医用组织粘合胶吸水成胶性能测试的效果图；
图17是本发明的测试例四中的医用组织粘合胶吸水成胶和溶胀性能测试的效果图；
图18是本发明的测试例五中医用组织粘合胶的吸水成胶效果图；
图19是本发明的测试例六中医用组织粘合胶的使用初期效果图；
图20是本发明的测试例六中医用组织粘合胶的使用粘合后效果图；
图21是本发明的测试例七中兔子腹主动脉出血模型图；
图22是本发明的测试例七中兔子腹主动脉止血后的效果图；
图23是本发明的测试例七中兔子股动脉出血模型图；
图24是本发明的测试例七中用普通医用纱布的对照效果图；
图25是本发明的测试例七中医普通纱布的使用后效果图；
图26是本发明的测试例七中医用组织粘合胶的用效果图；
图27是本发明的测试例七中医用组织粘合胶的使用后效果图；以及
图28是本发明的测试例八中医用组织粘合胶的粘合强度测试效果图。
具体实施方式
以下对分散剂为液体分散剂或固体分散剂制得的医用组织粘合胶分别进行详细描述。
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，以下结合实施例及附图对本发明一种医用组织粘合胶及其制备方法作具体阐述。
下述实施例中，为简化说明文字，将N-羟基琥珀酰亚胺用其缩写“NHS”代替，邻硝基苄基类光扳机用其缩写“NB”代替，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐用其缩写“EDC”代替，4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐用其缩写DMTMM代替。
下述实施例中使用的部分原料的分子量分布如下：
聚谷氨酸：分子量为70～100万；
聚乙烯亚胺：分子量为7万；
透明质酸：分子量为100万；
聚赖氨酸：分子量为1500；
葡聚糖：分子量为10万；
羧基封端的四臂聚乙二醇：分子量为2000；
氨基封端的四臂聚乙二醇：分子量为2000。
下述实施例一至实施例七、测试例一至测试例三中，分散剂为液体分散剂制得的医用组织粘合胶的相关实施例与测试例。
<实施例一>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为10％的NB修饰的聚谷氨酸、0.01份聚乙烯亚胺以及1份1,2-丙二醇制备而成。
其中，NB修饰的聚谷氨酸(PGNAB)的制备方法为将氨基化的NB:聚谷氨酸:EDC:NHS按照质量比为1:15:1:1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应3小时，透析、冻干，得到接枝率为10％的NB修饰的聚谷氨酸。
氨基化的NB结构式如下所示：
Figure PCTCN2021126764-appb-000008
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为10％的NB修饰的聚谷氨酸、聚乙烯亚胺以及1,2-丙二醇按照质量比为1：0.01：1混合均匀后即得，最终产品如图1所示。
<实施例二>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为10％的NHS修饰的透明质酸(HANHS)、0.5份聚赖氨酸以及2份甘油制备而成。
其中，NHS修饰的透明质酸(HANHS)的制备方法为将透明质酸:EDC:NHS按照质量比为10：1:1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应1小时，透析、冻干， 得到接枝率为10％的NHS修饰的透明质酸。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为10％的NHS修饰的透明质酸、聚赖氨酸以及甘油按照质量比为1：0.5：2混合均匀后即得。
<实施例三>
本实施例提供的医用组织粘合胶由按重量份计的1份醛基接枝率为30％的醛基修饰的葡聚糖(ODEX)、0.2份明胶以及1.5份乙二醇制备而成。
其中，醛基修饰的葡聚糖的制备方法为：将葡聚糖:高碘酸钠按照摩尔比为1：1溶解到水中，调节pH为4.5，搅拌反应1.5小时，随后透析、冻干，得到醛基接枝率为30％的醛基修饰的葡聚糖。
本实施例提供的医用组织粘合胶的制备方法为：将醛基接枝率为30％的醛基修饰的葡聚糖、明胶以及乙二醇按照质量比为1：0.1：30混合均匀后即得。
<实施例四>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为100％的活性酯修饰的四臂聚乙二醇(4a-PEG-NHS)、0.2份氨基封端的四臂聚乙二醇(4a-PEG-NH 2)以及1.5份甘油制备而成。
其中，氨基封端的四臂聚乙二醇的制备方法为：将羧基封端的四臂聚乙二醇(4a-PEG-COOH):EDC:NHS按照质量比为1:0.1:0.1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应0.5小时，随后透析、冻干，得到接枝率为100％的活性酯修饰的四臂聚乙二醇。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为10％的NHS修饰的透明质酸、聚赖氨酸以及甘油按照质量比为1：0.5：2混合均匀后即得。
<实施例五>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为100％的组织粘附性基团修饰的微米颗粒(mHA-NHS，微米球直径为5微米)、0.5份壳聚糖以及2份甘油制备而成。
其中，组织粘附性基团修饰的微米颗粒的制备方法为：将透明质酸:EDC:NHS按照质量比为1:0.1:0.1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应0.5小时，随后离心洗涤3次后，得到接枝率为100％的组织粘附性基团修饰的微米颗粒(mHA-NHS)。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为100％的组织粘附性基团修饰的微米颗粒、壳聚糖以及甘油按照质量比为1：0.5：2混合均匀后即得。
<实施例六>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为4％的组织粘附性基团修饰的大分子主链为NB修饰的透明质酸(HANB)、0.5份壳聚糖纳米颗粒(nCS，纳米颗粒直径为50纳米)以及1.5份甘油制备而成。
其中，组织粘附性基团修饰的大分子主链为NB修饰的透明质酸的制备方法为：将NB:透明质酸:EDC:NHS按照质量比为1:20:1:1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应2小时，透析、冻干，得到接枝率为4％的组织粘附性基团修饰的大分子主链为NB修饰的透明质酸。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为4％的组织粘附性基团修饰的大分子主链为NB修饰的透明质酸、壳聚糖纳米颗粒以及甘油按照质量比为1：0.5：1.5混合均匀后即得。
<实施例七>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为10％的NHS修饰的透明质酸(HANHS)、0.5份聚赖氨酸以及2份硅油制备而成。
其中，NHS修饰的透明质酸(HANHS)的制备方法同实施例二。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为10％的NHS修饰的透明质酸、聚赖氨酸以及硅油按照质量比为1：0.5：2混合均匀后即得。
<测试例一>
排血性能以及吸水成胶性能测试
排血性能的测试方法为：在载玻片上滴加2ml的血液，随后在血液上滴加2ml的实施例二或实施例七提供的医用组织粘合胶。
排血性能的测试结果如图2所示。
如图2所示，实施例二提供的医用组织粘合胶由于使用了亲水分散剂甘油，因此可以迅速排开血液并与载玻片底部接触，随后吸收血液中的水固化成胶，证明了该组织粘合胶良好的排血性能和吸水成胶性能。实施例七提供的医用组织粘合胶由于使用了疏水分散剂硅油，因此也可以迅速排开血液并与载玻片底部接触。
吸水成胶性能测试方法为：在培养皿中加入5ml去离子水，随后在水中滴加0.2ml的实施例二或实施例七提供的医用组织粘合胶。
吸水成胶性能的测试结果如图3-4所示。
如图3所示，由于实施例二医用组织粘合胶使用的亲水分散剂甘油能与水互溶会快速吸收水，溶解活性成分和辅助交联剂从而成胶，颜色从乳白色由外向内逐渐变成无色透明，2分钟后完全变成无色透明，形成一块完整的胶。
然而，如图4所示，实施例七提供的医用组织粘合胶由于使用了不能与水互溶的疏水分散剂硅油，这会导致活性成分和辅助交联剂被大量硅油包裹，水难以接触并溶解活性成分和辅助交联剂，随着浸泡时间的增加，乳态胶会由外向内逐渐被水分散形成乳白色颗粒状，最终导致无法形成完整的团块胶。
<测试例二>
组织粘附性能、创面封闭性能和止血性能测试
测试方法一为：首先，如图4所示，在兔子肝上用直径为2mm的针造一个肝脏损伤模型，可以观察到血液大量留出；随后，立刻将实施例四提供的医用组织粘合胶挤到纱布上并压至损伤处10秒，随后移除纱布。
测试结果如图5所示。
如图5所示，医用组织粘合胶能够牢固地粘附在肝脏表面并已经吸收血液中的水成胶，同时不再有血液流出，证明了该组织粘合胶良好的组织粘附性能、创面封闭性能和止血性能。
测试方法二为：首先，如图7所示，在兔子腹主动脉上用直径为2mm的针造腹主动脉损伤大出血模型，可以观察到血柱大量喷出；随后，立刻将实施例二或实施例七提供的医用组织粘合胶挤到纱布上并压至损伤处10秒，随后移除纱布。
测试结果如图8-9所示。
如图8所示，实施例二提供的医用组织粘合胶能够牢固地粘附在腹主动脉表面并已经吸收血液中的水成胶，同时不再有血液流出，能够清晰的看到腹主动脉及粘附在缺损上面的胶，证明了该组织粘合胶良好的组织粘附性能、创面封闭性能和止血性能。
然而，如图9所示，实施例七提供的医用组织粘合胶无法止住腹主动脉损伤大出血，仍 然有大量的血液快速喷出，大量血液淹没了腹腔，证明了采用疏水分散剂的医用组织粘合胶无法有效的创面封闭性能和止血。
<测试例三>
粘合速率测试
测试方法为：将实施例一到七的医用组织粘合胶涂抹到两块猪皮之间，涂抹量为0.1mL/cm 2，随后将涂有组织粘合胶的猪皮浸泡到水中，记录粘合时间。
测试结果如表1及图10所示。
表1粘合速率测试测果
Figure PCTCN2021126764-appb-000009
如图10所示，实施例一到实施例六提供的组织粘合胶均可在60s内即可成胶固化并将两块猪皮粘合到一起，粘合速率非常高，可以广泛适用于各种医用环境。
下述实施例八至实施例十七、测试例四至测试例八中，分散剂为固体分散剂制得的医用组织粘合胶的相关实施例与测试例。
<实施例八>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为100％的活性酯修饰的四臂聚乙二醇(4a-PEG-NHS)、0.12份聚乙烯亚胺(PEI)以及3份聚乙二醇1000(PEG-1000)制备而成。
其中，活性酯修饰的四臂聚乙二醇(4a-PEG-NHS)的制备方法为：将羧基封端的四臂聚乙二醇(4a-PEG-COOH):EDC:NHS按照质量比为1:0.1:0.1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应0.5小时，随后透析、冻干，得到接枝率为100％的活性酯修饰的四臂聚乙二醇。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为100％的活性酯修饰的四臂聚乙二醇、氨基封端的四臂聚乙二醇及聚乙二醇1000按照质量比为1：0.12：3，在50℃干燥加热条件融化聚乙二醇1000后，加入活性酯修饰的四臂聚乙二醇和氨基封端的四臂聚乙二醇混合均匀后倒模冷却即得，最终产品如图11所示。
<实施例九>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为100％的组织粘附性基团修饰的微米颗粒(mHA-NHS，微米球直径为5微米)、0.5份壳聚糖以及2份聚乙二醇1000制备而成。
其中，组织粘附性基团修饰的微米颗粒的制备方法为：将透明质酸:EDC:NHS按照质量比为1:0.1:0.1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应0.5小时，随后离心洗涤3次后，得到接枝率为100％的组织粘附性基团修饰的微米颗粒(mHA-NHS)。
本实施例提供的医用组织粘合胶的制备方法为：将聚乙二醇1000在50℃融化后，与接枝率为100％的组织粘附性基团修饰的微米颗粒、壳聚糖以按照质量比为2：1：0.5混合均 匀后即得，最终产品如图12所示。
<实施例十>
本实施例提供的医用组织粘合胶由按摩尔量份计的1份丙烯酸酯封端的四臂聚乙二醇(4a-PEG-AA)、1份的过硫酸铵、1份的氯化亚铁以及2份的聚乙二醇1000(PEG-1000)。
本实施例提供的医用组织粘合胶的制备方法为：将丙烯酸酯封端的四臂聚乙二醇、过硫酸铵、氯化亚铁以及聚乙二醇1000按照摩尔比为1：1：1：2在50℃干燥加热条件下混合均匀后倒模冷却即得，最终产品如图13所示。
<实施例十一>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为10％的甲基丙烯酸酐修饰的聚谷氨酸(PGAMA)、0.1份高碘酸钠、0.1份维生素C以及3份聚乙二醇1500(PEG-1500)制备而成。
其中，甲基丙烯酸酐修饰的聚谷氨酸(PGAMA)的制备方法为将按重量份计的1份聚谷氨酸完全溶解于去离子水中，将按照聚谷氨酸羧基含量：甲基丙烯酸酐摩尔比10：1的甲基丙烯酸酐加入聚谷氨酸溶液中，调节pH为8-9，搅拌反应4小时，透析、冻干，得到接枝率为10％的甲基丙烯酸酐修饰的聚谷氨酸。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为10％的甲基丙烯酸酐修饰的聚谷氨酸、高碘酸钠、维生素C以及聚乙二醇1500按照质量比为1：0.1：0.1：3在50℃干燥加热条件下混合均匀，冷却后将样品研磨成粉状，最终产品如图14所示。
<实施例十二>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为100％的活性酯修饰的四臂聚乙二醇(4a-PEG-NHS)、0.2份氨基封端的四臂聚乙二醇(4a-PEG-NH 2)以及1.5份聚乙二醇1000(PEG-1000)制备而成。
其中，活性酯封端的四臂聚乙二醇(4a-PEG-NHS)的制备方法为：将羧基封端的四臂聚乙二醇(4a-PEG-COOH):EDC:NHS按照质量比为1:0.1:0.1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应0.5小时，随后透析、冻干，得到接枝率为100％的活性酯修饰的四臂聚乙二醇。
本实施例提供的医用组织粘合胶的制备方法为：将接枝率为100％的活性酯修饰的四臂聚乙二醇、氨基封端的四臂聚乙二醇及聚乙二醇1000按照质量比为1：0.2：1.5在50℃干燥加热条件下混合均匀后倒模冷却即得。
<实施例十三>
本实施例提供的医用组织粘合胶由按摩尔量份计的1份的高碘酸钠、1份的维生素C以及2份的丙烯酸酯封端的四臂聚乙二醇1000(4a-PEG-AA-1000)制备而成。
本实施例提供的医用组织粘合胶的制备方法为：将高碘酸钠、维生素C以及丙烯酸酯封端的四臂聚乙二醇1000按照质量比为1：1：2在50℃干燥加热条件下混合均匀后倒模冷却即得。
<实施例十四>
本实施例提供的医用组织粘合胶由按重量份计的1份接枝率为100％的活性酯修饰的四臂聚乙二醇(4a-PEG-NHS)、0.12份聚乙烯亚胺(PEI)以及2份麦芽糖制备而成。
其中，活性酯修饰的四臂聚乙二醇的制备方法为：将羧基封端的四臂聚乙二醇 (4a-PEG-COOH):EDC:NHS按照质量比为1:0.1:0.1溶解到水中，调节pH为5.5，加热到35℃，搅拌反应0.5小时，随后透析、冻干，得到接枝率为100％的活性酯修饰的四臂聚乙二醇。
本实施例提供的医用组织粘合胶的制备方法为：将麦芽糖在150℃干燥加热条件下融化，与100％的活性酯修饰的四臂聚乙二醇(4a-PEG-NHS)和聚乙烯亚胺(PEI)按照重量比2：1：0.12混合均匀后倒模冷却即得。
<实施例十五>
本实施例提供的医用组织粘合胶作为对比例由按摩尔量份计的1份的高碘酸钠以及1份的丙烯酸酯封端的四臂聚乙二醇1000(4a-PEG-AA-1000)制备而成。
本实施例提供的医用组织粘合胶的制备方法为：将高碘酸钠以及丙烯酸酯封端的四臂聚乙二醇1000按照质量比为1:1在50℃干燥加热条件下混合均匀后倒模冷却即得。
<实施例十六>
本实施例提供的医用组织粘合胶由按摩尔量份计的1份的高碘酸钠、0.5份的维生素C以及1份的丙烯酸酯封端的四臂聚乙二醇1000(4a-PEG-AA-1000)制备而成。
本实施例提供的医用组织粘合胶的制备方法为：将高碘酸钠、维生素C以及丙烯酸酯封端的四臂聚乙二醇1000按照质量比为1：0.5：1在50℃干燥加热条件下混合均匀后倒模冷却即得。
<实施例十七>
本实施例提供的医用组织粘合胶由按摩尔量份计的1份的维生素C以及1份的丙烯酸酯封端的四臂聚乙二醇1000(4a-PEG-AA-1000)制备而成。
本实施例提供的医用组织粘合胶的制备方法为：将维生素C以及丙烯酸酯封端的四臂聚乙二醇1000按照质量比为1：1在50℃干燥加热条件下混合均匀后倒模冷却即得。
<测试例四>
吸水成胶性能测试
吸水成胶性能测试方法一为：在培养皿中加入2ml去离子水，随后在水中放置10mm*1mm圆柱状的实施例八提供的医用组织粘合胶。
吸水成胶性能的测试结果如图15与图16所示。
如图15所示，实施例八提供的医用组织粘合胶由于使用了固体分散剂聚乙二醇，因此可以通过重力作用排开水等液体并与培养皿底部接触，随后吸收水固化成胶，证明了该组织粘合胶良好的排水性能和吸水成胶性能。
如图16所示，实施例八提供的医用组织粘合胶使用的亲水分散剂聚乙二醇能与溶于水，水溶解分散剂后快速溶解活性成分和辅助交联剂从而成胶，颜色从乳白色由外向内逐渐变成无色透明，5分钟后完全变成无色透明，形成一块完整的胶。
吸水成胶性能测试方法二为：在培养皿中加入2ml去离子水，随后在水中放置直径为10mm圆盘状的实施例九提供的医用组织粘合胶。
吸水成胶性能的测试结果如图17所示。
如图17所示，实施例九提供的医用粘合胶由于使用了亲水的固体分散剂聚乙二醇，水溶解的过程中，分散于其中的微米颗粒能够与辅助交联剂反应从而成胶，粘合胶从白色变成无色透明，形成由微米颗粒互相连接形式的完成的胶，且几乎不会溶胀。
<测试例五>
吸水成胶性能测试
吸水性能测试方法为：在离心管中加入1mL去离子水，随后在水中加入按四臂聚乙二醇1000重量计100mg的实施例十三、实施例十五、实施例十六、实施例十七提供的医用组织粘合胶。
吸水成胶测试结果如图18所示。
如图18所示，实施例十三提供的医用组织粘合胶由于同时具氧化还原性质的辅助交联剂和作为固体分散剂的活性成分四臂聚乙二醇，因此可以形成完整形态的水凝胶。实施例十六由于辅助交联剂的含量不是最优，只能形成部分水凝胶。而实施例十五和实施例十七由于只含有单一的氧化剂或者还原剂成分而不能形成辅助交联的作用，因而在水中散掉无法成胶。证明了辅助交联剂对活性成分发挥作用的必要性。
<测试例六>
血液中粘附性能测试
测试方法为：首先，将新鲜的组织浸没于血液中，如图19所示取200mg实施例十四中的医用组织粘合胶按压于带血的组织表面15s，在血液中静置3分钟后。
测试结果如图20所示。
如图20所示，实施例十四提供的医用组织粘合胶能够牢固的黏附在带血的组织表面并形成凝胶，能够清晰的看到组织上的胶体，证明了该组织粘合胶在血液中的黏附性能。
<测试例七>
组织粘附性能、创面封闭性能及止血性能测试
测试方法一为：首先，如图21所示，在兔子腹主动脉上用直径为2mm的针造腹主动脉损伤大出血模型，可以观察到血柱大量喷出；随后，立刻将实施例八提供的医用组织粘合胶压至损伤处15秒，随后松开按压。
测试结果如图22所示。
如图22所示，实施例八提供的医用组织粘合胶能够牢固地粘附在腹主动脉表面并已经吸收血液中的水成胶，同时不再有血液流出，能够清晰的看到腹主动脉及粘附在缺损上面的胶，证明了该组织粘合胶良好的组织粘附性能、创面封闭性能和止血性能。
测试方法二为：首先，如图23所示，将兔子股动脉用手术刀直接切断，可以观察到大量血液喷涌出；随后，立即用普通医用纱布按压到伤口出血处，可见纱布迅速被血液染红，按压3分钟后，可见仍然有大量血液透过纱布渗出，如图24所示。将纱布移除后，可见仍然有大量血液喷涌出，出血未见减小，如图25所示。
测试结果如图26与图27所示。
如图26所示，在同等股动脉切断的大出血情况下，将实施例十提供的医用组织粘合胶铺展在纱布上并压至损伤处10秒，随后松开按压，可见纱布未被血继续染红，即已经停止出血。继续观察3分钟，未见纱布被血继续染红，无血液继续渗出，证明了实施例十提供的医用组织粘合胶具有良好的组织粘附性能、创面封闭性能及止血性能。
如图27所示，将纱布移除后，可见在伤口处被一层胶覆封闭，未见血液继续流出，证明了该医用组织粘合胶具有较强的封闭和止血能力。
<测试例八>
粘合强度测试
测试方法为：将实施例十二的医用组织粘合胶夹到两块猪皮之间，使用量为0.1cm*0.1 cm*0.01cm，随后将涂有组织粘合胶的猪皮浸泡到水中，待5min之后，将两块猪皮用万能力学测试机进行牵拉。
测试结果如图28所示。
如图28所示，实施例十二的医用组织粘合胶能够将两块猪皮粘合在一起，拉扯过后，依然有胶体存留在两块猪皮之间，证明实施例五的医用组织粘合胶具有很强的粘合强度。
实施例的作用与效果
根据实施例一至实施例六所涉及的医用组织粘合胶及其制备方法，因为使用的分散剂为液体分散剂，而亲水性液体分散剂在接触到血液的瞬间，会先将血液挤开，使活性成分上的粘附性基团能够充分与组织表面的氨基接触反应，而不会受到血液和组织液中蛋白上的氨基反应而影响粘附性，随后亲水性液体分散剂会吸收血液和组织液中的水并快速互溶，进一步溶解活性成分，触发活性成分中具有粘附性的分子片段与辅助交联剂上的氨基发生反应，使得医用组织粘合胶整体快速成胶固化，所以，实施例一到实施例六中制得的医用组织粘合胶能够在拥有良好的排血性能的同时还能快速交联成胶，从而实现快速粘合组织及封闭创面。
根据实施例八至实施例十七所涉及的医用组织粘合胶及其制备方法，因为使用的分散剂为固体亲水性分散剂，而固体分散剂在接触到血液的瞬间，由于重力作用和密度作用会先接触到组织表面，随着吸水溶解，活性成分上的粘附性基团能够充分与组织表面的氨基接触反应，而不会受到血液和组织液中蛋白上的氨基反应而影响粘附性，随后固体亲水性分散剂会吸收血液和组织液中的水，进一步溶解活性成分，触发活性成分中具有粘附性的分子片段与辅助交联剂上的氨基发生反应，使得医用组织粘合胶整体快速成胶固化，所以，实施例八至实施例十七中制得的医用组织粘合胶同样能够在拥有良好的排血性能的同时还能快速交联成胶，从而实现快速粘合组织及封闭创面。
上述实施方式为本发明的优选案例，并不用来限制本发明的保护范围。

Claims (16)

  1. 一种医用组织粘合胶，用于粘合生物组织，其特征在于，包括：
    活性成分、辅助交联剂以及分散剂，
    其中，所述活性成分为组织粘附性基团修饰的高分子链或组织粘附性基团修饰的微纳颗粒，
    所述辅助交联剂为与所述组织粘附性基团发生交联反应的化合物或激发所述组织粘附性基团自身发生交联的化合物，
    所述分散剂为能在接触含水液体时，让所述活性成分接触所述生物组织表面的化合物。
  2. 根据权利要求1所述的医用组织粘合胶，其特征在于：
    其中，所述组织粘附性基团包括：邻硝基苄基光扳机类基团、活性酯类基团、异氰酸酯类基团、异硫氰酸酯类基团、环氧类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团，
    所述邻硝基苄基光扳机类基团的结构如式I或式II所示：
    Figure PCTCN2021126764-appb-100001
    在式I和式II中，LG为卤原子、O-R’、S-R’或NH-R’；R’为氢、烷基、醚基、硫醚基、酮基、酯基、硫酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基或膦酸酯基中的任意一种；
    R 1为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、酯基、酰胺基、硫酯基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种；
    R 2、R 3，R 4，R 5中的任意一个或多个与所述高分子链或所述微纳颗粒键结，
    R 2、R 3，R 4，R 5中的任意一个或多个与所述高分子链或所述微纳颗粒键结前为末端氨基、羟基、巯基、卤原子、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、烷基或改性烷基中的任意一种，
    R 2、R 3，R 4，R 5中与未与所述高分子链或所述微纳颗粒相连的取代基分别独立地选自氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种；
    所述活性酯类基团为如式III所示的丁二酰亚胺类活性酯基或如式IV所示三氮唑类活性酯基：
    Figure PCTCN2021126764-appb-100002
    所述丁二酰亚胺类活性酯基通过R 6与P表示的所述高分子链或所述微纳颗粒键结，
    在式III中，R 6直接与所述高分子链或所述微纳颗粒键结，或通过末端改性的醚键、硫醚键、酮键、酯键、硫酯键、酰胺键、硫酸键、硫酸酯键、磺酸键、磺酸酯键、膦酸键、磷酸酯键、砜键、亚砜键、芳基键、烷基键或改性烷基键中的任意一种与所述高分子链或微纳颗粒键结，
    R 7、R 8分别独立地选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基或R 7与R 8之间键结成环，
    所述三氮唑类活性酯基通过R 9与P表示的所述高分子链或所述微纳颗粒键结，
    在式IV中，R 9直接与所述高分子链或所述微纳颗粒键结，或通过末端改性的醚键、硫醚键、酮键、酯键、硫酯键、酰胺键、硫酸键、硫酸酯键、磺酸键、磺酸酯键、膦酸键、磷酸酯键、砜键、亚砜键、芳基、烷基或改性烷基中的任意一种与所述高分子链或微纳颗粒键结，
    R 10、R 11分别独立地选自氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或R 10与R 11之间键结成环；
    所述异氰酸酯类基团的结构式如式V所示：
    O＝C＝N-R 12
    式V
    在式V中，R 12与所述高分子链或微纳颗粒键结，R 12在与所述高分子链或所述微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种；
    所述异硫氰酸酯类基团如式VI所示：
    S＝C＝N-R 13
    式VI
    在式VI中，R 13与所述高分子链或微纳颗粒键结，R 13在与所述高分子链或所述微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种；
    所述环氧类基团如式VII所示：
    Figure PCTCN2021126764-appb-100003
    在式VII中，R 14与所述高分子链或微纳颗粒键结，R 14与所述高分子链或所述微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种，
    R 15为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基、改性烷基、中的任意一种或与R 14键结成环；
    所述环状碳酸酯类基团如式VIII所示：
    Figure PCTCN2021126764-appb-100004
    在式VIII中，R 16与所述高分子链或所述微纳颗粒键结，R 16在与所述高分子链或所述微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基、或改性烷基中的任意一种，
    R 17为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或与R 16键结成环；
    所述硫代环状碳酸酯类基团为式IX所示的七种化合物中的任意一种：
    Figure PCTCN2021126764-appb-100005
    所述活性羰基类基团如式X所示：
    Figure PCTCN2021126764-appb-100006
    在式X中，R 18与所述高分子链或所述微纳颗粒键结，R 18在与所述高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种，
    R 19为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或与R 18键结成环；
    所述活性双键类基团如式XI所示：
    Figure PCTCN2021126764-appb-100007
    在式XI中，R 20与所述高分子链或所述微纳颗粒键结，R 20在与所述高分子链或微纳颗粒键结前为末端氨基、羟基、巯基、卤素、酰卤基、酸酐基、羧基、羧酸盐基、活性酯类基 团、异氰酸酯基类基团、异硫氰酸酯基类基团、环氧基类基团、碳酸酯基类基团、环状碳酸酯类基团、硫代环状碳酸酯类基团、活性羰基类基团或活性双键类基团改性的芳基、杂芳基、烷基或改性烷基中的任意一种，
    R 21为氢、卤原子、羟基、巯基、氨基、硝基、氰基、醛基、酮基、羧基、酯基、硫酯基、异氰酸酯基、异硫氰酸酯基、环氧基、碳酸酯基、硫代碳酸酯基、环状碳酸酯基、硫代环状碳酸酯基、酰胺基、硫酸基、硫酸酯基、磺酸基、磺酸酯基、膦酸基、膦酸酯基、砜基、亚砜基、芳基、烷基或改性烷基中的任意一种或与R 20键结成环。
  3. 根据权利要求1所述的医用组织粘合胶，其特征在于：
    其中，所述分散剂为液体分散剂，所述液体分散剂包括多元醇类化合物或液态聚乙二醇及其衍生物中的一种或多种的混合物。
  4. 根据权利要求3所述的医用组织粘合胶，其特征在于：
    其中，所述多元醇类化合物的通式为C nH 2n-m+2(OH) m，n为大于等于2正整数，m为小于等于n的正整数，
    所述聚乙二醇及其衍生物为直链聚乙二醇、支化聚乙二醇、多臂聚乙二醇均聚物、共聚物及其端基改性或成盐产物中的任意一种或多种。
  5. 根据权利要求1所述的医用组织粘合胶，其特征在于：
    其中，所述分散剂为固体分散剂，所述固体分散剂在加热条件下融化成均匀分散所述活性成分和所述辅助交联剂的液体且不与所述活性成分和所述辅助交联剂发生反应，
    所述分散剂为固态聚乙二醇及其衍生物或者糖类化合物中任意一种或多种。
  6. 根据权利要求5所述的医用组织粘合胶，其特征在于：
    其中，所述固态聚乙二醇及其衍生物为直链聚乙二醇、支化聚乙二醇、多臂聚乙二醇均聚物、共聚物及其端基改性或成盐产物中的任意一种或多种，
    其中，所述糖类化合物为葡萄糖、果糖、麦芽糖、木糖醇或山梨糖醇中的任意一种或多种。
  7. 根据权利要求1所述的医用组织粘合胶，其特征在于：
    其中，所述辅助交联剂为与所述组织粘附性基团发生交联反应的化合物，所述辅助交联剂为含有氨基、羧基、巯基或羟基的化合物中的任意一种或多种。
  8. 根据权利要求7所述的医用组织粘合胶，其特征在于：
    其中，所述含有氨基的化合物为聚乙烯亚胺、聚赖氨酸、聚精氨酸、聚组氨酸、明胶、胶原蛋白、弹性蛋白、丝素蛋白、壳聚糖及其衍生物或共聚物、氨基封端的两臂聚乙二醇、氨基封端的多臂聚乙二醇或氨基封端的聚氨酯中的任意一种或多种，
    所述含有羧基的化合物为透明质酸、羧甲基壳聚糖、羧甲基纤维素、羧甲基淀粉、海藻酸、硫酸软骨素、肝素、多聚糖醛酸、聚谷氨酸、聚天冬氨酸、明胶、胶原、丝素蛋白、聚乳酸及其衍生物或共聚物中的任意一种或多种，
    所述含有巯基的化合物为聚半胱氨酸、明胶、胶原及其衍生物中的任意一种或多种，
    所述含有羟基的化合物为透明质酸、壳聚糖、琼脂糖、纤维素、淀粉、海藻酸、硫酸软骨素、肝素、多聚糖醛酸、环糊精、聚丝氨酸、明胶、胶原、丝素蛋白、聚乙烯醇及其衍生物或共聚物中的任意一种或多种。
  9. 根据权利要求1所述的医用组织粘合胶，其特征在于：
    其中，所述辅助交联剂为激发所述组织粘附性基团自身发生交联的化合物，
    所述辅助交联剂为过氧化物或还原剂。
  10. 根据权利要求9所述的医用组织粘合胶，其特征在于：
    其中，所述过氧化物为烷基过氧化物、二烷基过氧化物、二酰基过氧化物、过氧酯、过氧化碳酸酯或酮过氧化物中的任意一种或多种，
    所述还原剂为亚硫酸盐、亚硫酸氢盐、亚铁盐、环烷酸盐、叔胺类化合物或硫醇中的任意一种或多种。
  11. 根据权利要求1所述的医用粘合胶，其特征在于：
    其中，所述高分子链为天然糖类化合物或亲水性或水溶性合成聚合物。
  12. 根据权利要求1所述的医用粘合胶，其特征在于：
    其中，所述微纳颗粒为所述高分子链形成的纳米颗粒或微米颗粒，
    所述高分子链为天然糖类化合物或亲水性或水溶性合成聚合物。
  13. 根据权利要求11或12所述的医用粘合胶，其特征在于：
    其中，所述天然糖类化合物为透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐中的任意一种。
  14. 根据权利要求11或12所述的医用粘合胶，其特征在于：
    其中，所述亲水性或水溶性合成聚合物为两臂聚乙二醇、多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚氨酯、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮中的任意一种或多种。
  15. 根据权利要求1所述的医用组织粘合胶，其特征在于：
    其中，所述活性成分、所述辅助交联剂以及所述分散剂的质量比为1：(0.01～10)：(0.1～30)。
  16. 一种医用组织粘合胶的制备方法，用于制备权利要求1-15任意一项所述的医用组织粘合胶，其特征在于，包括如下步骤：
    将活性成分以及辅助交联剂磨成粉末状，加入液体分散剂，混合均匀，即得，
    或将活性成分以及辅助交联剂磨成粉末状，加入融化后的固体分散剂，分散均匀，即得。
PCT/CN2021/126764 2021-03-04 2021-10-27 一种医用组织粘合胶及其制备方法 WO2022183750A1 (zh)

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