WO2015076252A1 - Film poreux adhésif tissulaire, son procédé de fabrication, et bande de film poreux adhésif tissulaire - Google Patents

Film poreux adhésif tissulaire, son procédé de fabrication, et bande de film poreux adhésif tissulaire Download PDF

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WO2015076252A1
WO2015076252A1 PCT/JP2014/080477 JP2014080477W WO2015076252A1 WO 2015076252 A1 WO2015076252 A1 WO 2015076252A1 JP 2014080477 W JP2014080477 W JP 2014080477W WO 2015076252 A1 WO2015076252 A1 WO 2015076252A1
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group
tissue
gelatin
porous membrane
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PCT/JP2014/080477
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English (en)
Japanese (ja)
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田口　哲志
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独立行政法人物質・材料研究機構
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Priority to JP2015549152A priority Critical patent/JP6120392B2/ja
Publication of WO2015076252A1 publication Critical patent/WO2015076252A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • 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

Definitions

  • a tissue adhesive film prepared from a medical material (Patent Document 1) prepared by cross-linking gelatin, which is a non-blood preparation, with succinimidated poly-L-glutamic acid (Patent Document 1) and gelatin or Collagen (Patent Document 2) ),
  • a tissue adhesive composition (Patent Document 3) in which a polymerizable and / or crosslinkable material in the form of particles and a particulate material are mixed, and gelatin having an alkyl group introduced in the side chain have been reported.
  • a tissue adhesive composition (Patent Document 3) in which a polymerizable and / or crosslinkable material in the form of particles and a particulate material are mixed, and gelatin having an alkyl group introduced in the side chain have been reported.
  • all of these have a problem that the adhesive force to the wet tissue is not sufficient.
  • Non-Patent Document 2 Non-Patent Document 2
  • An object of the present invention is to provide a tissue adhesive film having a high adhesive strength to a wet tissue and an appropriate strength, and a method for producing the same.
  • the inventors of the present invention have prepared a porous tissue-adhesive porous membrane containing a hydrophobicized gelatin in which a hydrophobic group is introduced into the amino group of gelatin, thereby sufficiently absorbing moisture from the wet tissue, On the other hand, it was discovered that a tissue adhesive film having high adhesive strength and appropriate strength and a method for producing the same can be provided, and the present invention has been completed.
  • the present invention has the following configuration.
  • the tissue-adhesive porous membrane according to (1) wherein the porous structure is composed of pores between a plurality of hydrophobic gelatins provided in the crosslinked structure of the hydrophobic gelatin.
  • the porous structure includes voids between a plurality of hydrophobic gelatins provided in the crosslinked structure of the hydrophobic gelatin, and porogen holes provided in the crosslinked structure using a porogen as a template.
  • the tissue-adhesive porous membrane according to (1) The tissue-adhesive porous membrane according to (3), wherein the porogen pores are provided using a porogen having a particle size of 50 to 100 ⁇ m as a template.
  • tissue adhesive porous material according to (1), wherein the gelatin is one or a combination of two or more of gelatin derived from human, pig, cow, tilapia, cod or genetically modified gelatin
  • the membrane (10) The tissue adhesive porous membrane according to any one of (1) to (9), wherein the tissue adhesive porous membrane contains a drug.
  • the agent is a cell differentiation inducer, anticancer agent, immunosuppressant, cell growth factor, cytokine, thrombin inhibitor, antithrombotic agent, thrombolytic agent, fibrinolytic agent, vasospasm inhibitor, calcium channel Blocking agents, vasodilators, antihypertensive agents, antibacterial agents, antibiotics, surface glycoprotein receptor inhibitors, antiplatelet agents, cytostatics, microtubule inhibitors, antisecretory agents, actin inhibitors, remodeling inhibitors Drugs, antisense nucleotides, antimetabolites, antiproliferative substances, anticancer chemotherapeutic drugs, anti-inflammatory steroids or non-steroidal anti-inflammatory drugs, immunosuppressants, growth hormone antagonists, dopamine agonists, radiotherapy drugs, Peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavengers, chelators, antioxidants, antipolymers , Antiviral agents, photodynamic therapy agents, and one or a combination of
  • a method for producing a tissue-adhesive porous membrane comprising the steps of:
  • a step of dissolving hydrophobized gelatin in a water-soluble organic solvent to prepare a hydrophobized gelatin-containing solution, and dispersing a porogen in the hydrophobized gelatin-containing solution to prepare a porogen-dispersed hydrophobized gelatin-containing solution A step of adding a cross-linking agent or a condensing agent to the porogen-dispersed hydrophobized gelatin-containing solution to cross-link the hydrophobized gelatin to form a hydrophobized gelatin cross-linked body containing a water-soluble organic solvent and a porogen; Water-containing hydrophobized gelatin in which porogen pores are formed by placing a hydrophobized gelatin cross-linker containing a water-soluble organic solvent and a porogen into water, replacing the water-soluble organic solvent with water, and dissolving and removing the porogen A step of forming a crosslinked body, and a step of lyophilizing the water-containing hydrophobized gelatin crosslinked body in which the porogen
  • tissue-adhesive porous membrane according to (13) wherein the porogen is particles made of any material of NaCl, KCl, MgCl, ice, and polyethylene glycol.
  • the method for producing a tissue-adhesive porous membrane of the present invention comprises a step of dissolving a hydrophobic gelatin in a water-soluble organic solvent to prepare a hydrophobic gelatin-containing solution, and dispersing a porogen in the hydrophobic gelatin-containing solution.
  • a step of forming a gelatin cross-linked product, and the hydrophobized gelatin cross-linked product containing the water-soluble organic solvent and porogen is placed in water, the water-soluble organic solvent is replaced with water, and the porogen is dissolved and removed.
  • tissue-adhesive porous membrane tape of the present invention has a structure in which the tissue-adhesive porous membrane described above is formed in a strip shape, the cut portion of the intestine can be easily wound, and the tissue adhesive can be obtained by leaving it as it is. Can be made.
  • tissue adhesive porous membrane which is the 1st Embodiment of this invention It is the schematic which shows adhesion
  • tissue adhesive porous membrane which is the 2nd Embodiment of this invention. It is the schematic of the adhesion test of a tissue adhesive porous membrane and porcine large intestine epidermis.
  • 2 is an electron micrograph of a cross section of the tissue adhesive porous membrane of Example 1.
  • FIG. 4 is an electron micrograph of the surface of the tissue adhesive porous membrane of Example 2.
  • FIG. 4 is an electron micrograph of the surface of the tissue adhesive porous membrane of Example 3.
  • FIG. 4 is an electron micrograph of the surface of the tissue-adhesive porous membrane of Example 4.
  • 6 is an electron micrograph of the surface of a tissue adhesive porous membrane of Example 5.
  • FIG. 4 is an electron micrograph of the surface of the tissue adhesive porous membrane of Example 6.
  • FIG. 4 is an electron micrograph of a cross section of a porous film of Comparative Example 1.
  • 4 is an electron micrograph of the surface of a porous film of Comparative Example 2.
  • 4 is an electron micrograph of the surface of a porous film in Comparative Example 3.
  • 4 is an electron micrograph of the surface of a porous film in Comparative Example 4.
  • 6 is an electron micrograph of the surface of a porous membrane of Comparative Example 5.
  • 6 is an electron micrograph of the surface of a porous membrane in Comparative Example 6.
  • 2 is an electron micrograph of a cross section of a tissue adhesive porous membrane of Examples 13 to 17.
  • 6 is a graph showing the results of water absorption rate tests of the tissue adhesive porous membranes of Examples 13 to 17 and the porous membranes of Comparative Examples 7 to 11.
  • 6 is a graph showing the results of L929 cell culture tests of the tissue adhesive porous membranes of Examples 1 to 6 and the porous membranes of Comparative Examples 1 to 6.
  • 2 is a photomicrograph showing the extension of L929 cells on the tissue adhesive porous membranes of Examples 1 to 6 and the porous membranes of Comparative Examples 1 to 6. It is a graph which shows the result of angiogenesis evaluation using the tissue adhesive porous membrane of Examples 2 and 5 and the porous membrane of Comparative Examples 2 and 5.
  • FIG. 1 is a schematic view showing a tissue-adhesive porous membrane according to the first embodiment of the present invention.
  • the tissue adhesive porous membrane 1 is a membrane having a porous structure in which a hydrophobic gelatin 10 is cross-linked and is composed of a plurality of holes 10c1.
  • the tissue adhesive porous membrane 1 is formed by integrating only the hydrophobic gelatin 10 into a film shape.
  • the shape of the tissue adhesive porous membrane 1 is, for example, a substantially rectangular shape in plan view. One side and the other side of the film are each flat.
  • the hydrophobized gelatin 10 has a main chain 13 made of gelatin, an amino group 12 and a hydrophobic functional group 11 on its side chain. By using the gelatin skeleton, it can be easily decomposed by an enzyme in the wound healing process, and the biocompatibility of the porous membrane can be increased.
  • the hydrophobized gelatin 10 is gelatin in which a part of the amino group 12 of Lys contained as an amino acid is substituted with a hydrophobic functional group 11.
  • gelatin to be the main chain 13 examples include human, porcine, bovine, tilapia, cod-derived gelatin and genetically modified gelatin. One or a combination of two or more of these gelatins may be used.
  • the hydrophobized gelatin 10 is preferably cross-linked by thermal cross-linking 14.
  • the hydrophobized gelatin 10 is thermally cross-linked, peptide bonds that link the linear polymers are formed in the hydrophobized gelatin 10.
  • it can be insolubilized in water, the strength of the membrane is increased, and a tissue-adhesive porous membrane having high adhesive strength and appropriate strength even in a wet environment can be obtained.
  • the hydrophobic functional group 11 introduced into the hydrophobic gelatin 10 anchors to the hydrophobic domain of the extracellular matrix and the lipid bilayer of the cell contained in the tissue.
  • the tissue adhesive porous membrane 1 is firmly fixed to the tissue.
  • the tissue adhesive porous membrane 1 has a porous structure, it can absorb moisture in the living tissue. Thereby, the water
  • the hydrophobicity of the hydrophobic gelatin 10 is low, so that the anchoring effect of the hydrophobic functional group 11 cannot be sufficiently obtained, and the tissue adhesive porous The membrane 1 cannot be firmly fixed to the tissue.
  • FIG. 2 is a schematic view showing adhesion of the tissue adhesive porous membrane when the tissue adhesive porous membrane according to the first embodiment of the present invention is applied to a living tissue.
  • the hydrophobic functional group 11 having a certain molecular weight and size pierces the tissue 21 due to hydrophobic interaction (this is called anchoring).
  • anchoring the tissue adhesive porous membrane 1 is firmly fixed to the tissue 21.
  • FIG. 3 is a process diagram for explaining an example of a method for producing a tissue-adhesive porous membrane according to the first embodiment of the present invention.
  • the method for producing a tissue adhesive porous membrane according to the first embodiment of the present invention includes a hydrophobized gelatin-containing solution preparation step S1, a water-soluble organic solvent-containing hydrophobized gelatin crosslinked body forming step S2, and a water-containing hydrophobizing step. It has gelatin crosslinked body formation process S3 and structure
  • the hydrophobized gelatin is preferably prepared by the following hydrophobized gelatin synthesis step S21.
  • hydrophobized gelatin synthesis step S21 an organic molecule having a hydrophobic functional group is added to a solution in which gelatin is dissolved in the presence of triethylamine, and a part of the amino group of the side chain of the gelatin is substituted with the hydrophobic functional group. This is the step of synthesizing hydrophobic gelatin.
  • a gelatin having a molecular weight of hydrophobized gelatin of more than 50,000 and not more than 100,000 is selected.
  • an organic molecule having a hydrophobic functional group having reactivity with an amino group is mixed with gelatin dissolved in an organic solvent in the presence of triethylamine to prepare a mixed solution in a container.
  • a mixed solution for example, dimethyl sulfoxide (DMSO) is used as the organic solvent.
  • DMSO dimethyl sulfoxide
  • Examples of the organic molecule having a hydrophobic functional group having reactivity with an amino group include hexanoyl chloride represented by the following chemical formula (1).
  • Hydrophobized gelatin-containing solution preparation step S1 The hydrophobized gelatin is dissolved in a water-soluble organic solvent to prepare a hydrophobized gelatin-containing solution 51 in a container 50 as shown in FIG.
  • a water-soluble organic solvent examples include dimethyl sulfoxide (DMSO).
  • tissue-adhesive porous film forming step S4 The water-containing hydrophobized gelatin crosslinked body 58 is lyophilized. As a result, as shown in FIG. 3 (d), water molecules are removed, and a porous structure is formed which includes pores 10c1 between the plurality of hydrophobic gelatins 10 provided in the crosslinked structure of the hydrophobic gelatin 10. A tissue adhesive porous membrane 1 is formed.
  • FIG. 4 is a schematic view showing a tissue adhesive porous membrane according to a second embodiment of the present invention.
  • the tissue adhesive porous membrane 2 according to the second embodiment of the present invention is the tissue adhesive property according to the first embodiment of the present invention except that the porogen hole 10c2 is provided in addition to the void hole 10c1.
  • the configuration is the same as that of the porous membrane 1.
  • a porogen is a particle that serves as a template for a pore, and examples of the porogen material include NaCl, KCl, MgCl, ice, and polyethylene glycol.
  • a porogen hole is a hole provided in a crosslinked structure using porogen as a template. Since the porogen materials exemplified above are water-soluble, for example, when these porogen materials are used, in the production method described later, the water-soluble organic solvent of the hydrophobized gelatin crosslinked product containing the water-soluble organic solvent and the porogen is used. When replacing with water, the porogen dissolves in water, so that the porogen is easily removed from the hydrophobized gelatin crosslinked product. Thereby, the porogen hole 10c2 is formed in the tissue adhesive porous membrane 2.
  • the porogen hole 10c2 is a hole provided using porogen as a template, the porogen hole 10c2 is defined to have substantially the same shape and size as the porogen used. Further, by making the shape and size of each porogen the same, the shape and size of the porogen hole can be made the same.
  • FIG. 4 illustrates a spherical porogen hole.
  • the size of the porogen can be appropriately set according to the shape and size of the tissue-adhesive porous membrane to be produced, the type of gelatin serving as the main chain of the hydrophobized gelatin, the type of hydrophobic functional group, and the like. For example, a porogen having a particle size of 50 to 100 ⁇ m can be used.
  • FIG. 5 is a schematic view showing adhesion of the tissue adhesive porous membrane when the tissue adhesive porous membrane according to the second embodiment of the present invention is applied to a living tissue.
  • the tissue adhesive porous membrane 2 has the same configuration as that of the tissue adhesive porous membrane 1 according to the first embodiment of the present invention except that the porogen hole 10c2 is provided.
  • the tissue-adhesive porous membrane 2 absorbs moisture in the living tissue more effectively than the tissue-adhesive porous membrane 1 by providing the porogen hole 10c2, and the tissue-adhesive porous membrane 2 The moisture at the bonding site between the membrane 2 and the tissue 21 can be removed more effectively, and the tissue-adhesive porous membrane 2 can be physically and firmly bonded to the tissue 21.
  • Porogen-dispersed hydrophobized gelatin-containing solution preparation step S12 Porogen 62 is dispersed in the hydrophobized gelatin-containing solution 51 to prepare a porogen-dispersed hydrophobized gelatin-containing solution 60 in the container 50 as shown in FIG.
  • the porogen dispersed hydrophobized gelatin-containing solution 60 is cross-linked by adding a cross-linking agent or a condensing agent. Thereby, as shown in FIG.6 (c), the hydrophobized gelatin crosslinked body 63 containing a water-soluble organic solvent and a porogen is formed.
  • the hydrophobized gelatin cross-linked body 63 containing a water-soluble organic solvent and a porogen is formed by networking the hydrophobized gelatin 10 in the form of a network, and contains the water-soluble organic solvent 55 and the porogen 62.
  • the hydrophobized gelatin 10 is a hydrophobized gelatin molecular chain, and has a main chain made of gelatin and an amino group and a hydrophobic functional group in its side chain.
  • a hydrophobized gelatin cross-linked body 63 containing a water-soluble organic solvent and a porogen is immersed in a large excess of water. For example, put it in water. Thereby, as shown in FIG.6 (d), the water-soluble organic solvent 55 can be substituted by the water 20, and the unreacted crosslinking agent, the bridge
  • the porogen hole 10c2 is physically provided by dissolving and removing the porogen 62. Thereby, the water-containing hydrophobized gelatin crosslinked body 68 in which the porogen hole 10c2 is formed is formed.
  • tissue-adhesive porous film forming step S15 The water-containing hydrophobized gelatin crosslinked product 68 is lyophilized. Thereby, water is removed from the pores of the crosslinked structure, and the tissue adhesiveness having a porous structure composed of the void holes 10c1 and the porogen holes 10c2 between the plurality of hydrophobic gelatins 10 provided in the crosslinked structure of the hydrophobic gelatin 10 The porous membrane 2 can be obtained.
  • the tissue adhesive porous membranes 1 and 2 that are embodiments of the present invention may further contain a drug.
  • the porous membrane when used for tissue adhesion, not only firmly adheres to the tissue, but also can be treated with a drug.
  • Examples of the drug include cell differentiation inducer, anticancer agent, immunosuppressive agent, cell growth factor, cytokine, thrombin inhibitor, antithrombotic agent, thrombolytic agent, fibrinolytic agent, vasospasm inhibitor, calcium channel blocker , Vasodilator, antihypertensive, antibacterial, antibiotic, surface glycoprotein receptor inhibitor, antiplatelet agent, cytostatic, microtubule inhibitor, antisecretory, actin inhibitor, remodeling inhibitor, Antisense nucleotide, antimetabolite, antiproliferative substance, anticancer chemotherapeutic agent, anti-inflammatory steroid or non-steroidal anti-inflammatory agent, immunosuppressant, growth hormone antagonist, dopamine agonist, radiotherapy agent, peptide, Protein, enzyme, extracellular matrix component, inhibitor, free radical scavenger, chelating agent, antioxidant, antipolymer , Antiviral agents, mention may be made of photodynamic therapy, and one or more combinations selected from the gene therapy. By using these drugs, it is
  • tissue-adhesive porous membrane tape is formed by forming the tissue-adhesive porous membranes 1 and 2 into a strip shape. Thereby, according to the magnitude
  • Tissue-adhesive porous membranes 1 and 2 are membranes in which hydrophobic gelatin 10 is crosslinked and has a porous structure, and hydrophobic gelatin 10 is a part of amino group 12 of Lys. Is the gelatin 13 substituted with the hydrophobic functional group 11, so that the hydrophobic functional group 11 introduced into the gelatin simultaneously with the absorption of moisture contained in the tissue is driven (anchored) into the physical structure Strong bond can be formed, and the adhesive strength can be increased even in a wet environment. Moreover, since the tissue adhesive porous membrane 2 has a physical porous structure provided using porogen as a template, the adhesive strength can be increased by more effectively absorbing moisture contained in the tissue.
  • tissue-adhesive porous membranes 1 and 2 are characterized in that the porous structure becomes a scaffold for tissue regeneration after application to a living tissue. Moreover, since gelatin 13 is easily decomposed by an enzyme (collagenase) in the wound healing process, the biocompatibility of the tissue adhesive porous membranes 1 and 2 can be increased.
  • collagenase an enzyme
  • the tissue-adhesive porous membrane 1 has a structure in which the porous structure is composed of gap holes 10c1 between a plurality of hydrophobic gelatins 10 provided in a crosslinked structure of the hydrophobic gelatin 10.
  • the holes 10c1 can absorb water contained in the tissue, have high adhesive strength even in a moist environment and have an appropriate strength, and can easily enter the tissue and can be used as a scaffold excellent in tissue regeneration.
  • the porous structure is composed of a void hole 10c1 and a porogen hole 10c2 provided with a porogen as a template in the cross-linked structure.
  • the porogen hole 10c2 the water contained in the tissue can be absorbed more effectively, and can be used as a film having a high adhesive strength and an appropriate strength even in a wet environment, making the invasion of the tissue easier, It can be used as an excellent scaffold for tissue regeneration.
  • tissue-adhesive porous membranes 1 and 2 have a configuration in which the hydrophobic gelatin 10 is crosslinked by a crosslinking agent or a condensing agent, it can be insolubilized in water and the strength of the membrane can be increased.
  • a tissue-adhesive porous membrane having high adhesive strength and moderate strength even in a moist environment can be obtained.
  • the crosslinking agent or condensing agent is triscinimimidyl citrate, disuccinimidyl tartrate, disuccinimidyl malate, disuccinimidyls. Since it is composed of one or more of succinate, glutaraldehyde, formaldehyde, polyethylene glycol diglycidyl ether, genipin, and water-soluble carbodiimide, it can be insolubilized in water, increasing the strength of the film, and in a humid environment However, a tissue adhesive porous membrane having high adhesive strength and appropriate strength can be obtained.
  • tissue-adhesive porous membranes 1 and 2 have a structure in which the hydrophobic gelatin 10 is crosslinked by thermal crosslinking 14, so that it can be insolubilized in water, the strength of the membrane is increased, and the wetness is increased.
  • a tissue-adhesive porous membrane having high adhesive strength and moderate strength even in an environment can be obtained.
  • the hydrophobic functional group 11 is an ethyl group (carbon number 2), propyl group (carbon number 3), butyl group (carbon number) which is a saturated fatty acid.
  • the gelatin 13 is one or a combination of two or more of gelatin derived from human, pig, cow, tilapia and cod or genetically modified gelatin. Because of the structure, the strength of the film can be increased.
  • tissue-adhesive porous membranes 1 and 2 include a drug, the therapeutic effect on the tissue can be enhanced.
  • the drug is a cell differentiation inducer, anticancer agent, immunosuppressant, cell growth factor, cytokine, thrombin inhibitor, antithrombotic agent, thrombus Solubilizer, fibrinolytic agent, vasospasm inhibitor, calcium channel blocker, vasodilator, antihypertensive agent, antibacterial agent, antibiotic, surface glycoprotein receptor inhibitor, antiplatelet agent, cytostatic agent, micro Vascular inhibitor, antisecretory drug, actin inhibitor, remodeling inhibitor, antisense nucleotide, antimetabolite, antiproliferative substance, anticancer chemotherapeutic agent, anti-inflammatory steroid or non-steroidal anti-inflammatory drug, immunosuppression Drugs, growth hormone antagonists, dopamine agonists, radiation therapy drugs, peptides, proteins, enzymes, extracellular matrix components, inhibitors, free radical scavenges Since the composition is one or a combination of two or more selected from
  • the method for producing a tissue-adhesive porous membrane 1 includes a step of preparing hydrophobized gelatin-containing solution 51 by dissolving hydrophobized gelatin in a water-soluble organic solvent, and hydrophobized gelatin-containing solution 51.
  • the method for producing a tissue adhesive porous membrane 2 includes a step of preparing a hydrophobized gelatin-containing solution 51 by dissolving hydrophobized gelatin in a water-soluble organic solvent, and a hydrophobized gelatin-containing solution 51.
  • a step of forming a hydrophobized gelatin cross-linked body 63 containing water and a porogen, and the hydrophobized gelatin cross-linked body 63 containing a water-soluble organic solvent and a porogen is placed in water, and the water-soluble organic solvent is replaced with water.
  • the porogen is a particle made of any material of NaCl, KCl, MgCl, ice, and polyethylene glycol.
  • a porogen hole provided as a mold can be easily formed.
  • the method for producing tissue-adhesive porous membranes 1 and 2 according to an embodiment of the present invention has a structure in which the water-soluble organic solvent is dimethyl sulfoxide, so that a stable crosslinked structure can be formed and water can be easily replaced. .
  • tissue adhesive tape according to the embodiment of the present invention has a band-shaped configuration of the tissue adhesive porous membranes 1 and 2 described above, the cut portion of the intestine can be easily wound and left as it is. Thus, tissue adhesion can be achieved.
  • Example 1 (Production of tissue adhesive porous membrane) ⁇ Synthesis of hydrophobized AlGltn and confirmation of introduction rate>
  • AlGltn alkali-treated gelatin
  • the alkali-treated gelatin is gelatin obtained by converting asparagine and glutamine present in gelatin into aspartic acid and glutamic acid by deamidation.
  • Non-patent Document 1 hydrophobized AlGltn (Hx: C 6 ) was introduced by hydrophobizing alkali-treated gelatin (AlGltn) using Hexanoyl chloride. HxAlGltn) was prepared.
  • the 27HxAlGltn was mixed with AlGltn to prepare a relatively 25HxAlGltn (hereinafter referred to as 25 ′ (27) HxAlGltn).
  • 25 ′ (27) HxAlGltn was dissolved in a 10% lactic acid-DMSO mixed solvent at a content ratio of 25 w / v%, it had fluidity suitable for film formation. Therefore, a porous membrane was prepared using 25 w / v% 25 ′ (27) HxAlGltn / 10% lactic acid-DMSO.
  • TSC trisuccinimidyl citrate
  • 25 w / v% 25 ′ is used so that the molar ratio of the amino group of HxAlGltn to the succinimidyl group contained in TSC is 1: 1.
  • HxAlGltn / 10% lactic acid-DMSO 8 mL and TSC / 10% lactic acid-DMSO 2 mL were sufficiently mixed and stirred with a hand stirrer to obtain a 20 w / w% HxAlGltn solution.
  • Example 2 A tissue-adhesive porous membrane was prepared in the same manner as in Example 1 except that the weight ratio of the HxAlGltn solution and NaCl (particle size 250 to 500 ⁇ m: average particle size 375 ⁇ m) was 1: 1.
  • Example 3 A tissue-adhesive porous membrane was prepared in the same manner as in Example 1 except that the weight ratio of the HxAlGltn solution and NaCl (particle size 250 to 500 ⁇ m: average particle size 375 ⁇ m) was 1: 2.
  • Example 4 A tissue-adhesive porous membrane was prepared in the same manner as in Example 1 except that the weight ratio of the HxAlGltn solution and NaCl (particle size 250 to 500 ⁇ m: average particle size 375 ⁇ m) was 1: 3.
  • Example 5 A tissue-adhesive porous membrane was prepared in the same manner as in Example 1 except that the weight ratio of the HxAlGltn solution and NaCl (particle size 250 to 500 ⁇ m: average particle size 375 ⁇ m) was 1: 4.
  • FIG. 8 to 13 are electron micrographs of the tissue adhesive porous membranes of Examples 1 to 6.
  • FIG. 8 to 13 From these electron micrographs, it can be seen that a porous structure is formed and that more pores are present as the amount of NaCl mixed at the time of production increases.
  • the obtained gel-like DMSO / NaCl-containing AlGltn cross-linked product is released in ultrapure water cooled to 4 ° C. and immersed for 3 days while exchanging the ultrapure water in a large excess amount.
  • NaCl, lactic acid, DMSO, and N-hydroxysuccinimide, which is a cross-linking byproduct, were removed.
  • the obtained water-containing AlGltn crosslinked product was frozen at ⁇ 80 ° C. and dried under reduced pressure to obtain a porous membrane made of non-hydrophobized alkali-treated gelatin.
  • ⁇ Porosity and moisture content measurement> The porosity and moisture content were determined by punching a porous membrane swollen by immersing in water for a predetermined time to ⁇ 1 cm, W 2 : weight of moisture in the pores (the porous membrane after swelling), W 1 : in the pores Weight when not containing water (porous film before swelling), W 0 : Measured as weight when dried (porous film dried under vacuum after swelling), and calculated using the following equations (1) and (2) did.
  • FIG. 7 is a schematic diagram of an adhesion test between a tissue-adhesive porous membrane and porcine large intestine epidermis. As shown in FIG. 7, first, the tissue-adhesive porous membranes of Examples 1 to 6 punched to a diameter of 7 mm or the porous membranes of Comparative Examples 1 to 6 were placed on a plate set at 37 ° C. It was fixed with cello tape (registered trademark) punched to 4 mm.
  • cello tape registered trademark
  • the surface of the porcine large intestine epidermis fixed to the probe is brought into contact with the tissue adhesive porous membrane (or porous membrane) fixed on the plate, pressurized at 40 g / mm 2 for 3 minutes, and then at 10 mm / min.
  • a tensile test was performed. The experiment was performed three times, and the average value was taken as the measured value. The results are shown in FIG.
  • tissue adhesive porous membrane by immunostaining of CD34, ⁇ -SMA After the tissue adhesive porous membranes of Examples 2 and 5 and the porous membranes of Comparative Examples 2 and 5 were implanted subcutaneously in rats for 7 days, the tissue sections containing each porous membrane were subjected to CD34 and ⁇ -SMA. Immunostaining was performed using ( ⁇ smooth muscle actin), and evaluation was performed using Image J. In the evaluation, the total area of the portion immunostained in brown was defined as “Vessel-Area” and the field of view was defined as “Area”. The results are shown in FIG.
  • water-containing hydrophobized gelatin cross-linked product 60 ... porogen-dispersed hydrophobized gelatin-containing solution, 62 ... porogen, 63 ... water-soluble organic solvent And a hydrophobized gelatin cross-linked product containing porogen, 68... Water-containing hydrophobized gelatin cross-linked product in which porogen pores are formed.

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Abstract

La présente invention concerne un film poreux adhésif tissulaire (1) présentant une structure poreuse dans laquelle de la gélatine rendue hydrophobe (10) est réticulée, ladite gélatine rendue hydrophobe (10) étant de la gélatine (13) dans laquelle une partie d'un groupement aminé (12) de L-lysine est substituée à un groupe fonctionnel hydrophobe (11). Ce film poreux adhésif tissulaire (1) permet de fournir un film adhésif tissulaire présentant une force d'adhésion élevée au tissu humide et une résistance adéquate, ainsi que son procédé de fabrication.
PCT/JP2014/080477 2013-11-22 2014-11-18 Film poreux adhésif tissulaire, son procédé de fabrication, et bande de film poreux adhésif tissulaire WO2015076252A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016117569A1 (fr) * 2015-01-20 2016-07-28 国立研究開発法人物質・材料研究機構 Agent d'étanchéité chirurgical
JP2019076070A (ja) * 2017-10-27 2019-05-23 株式会社豊田中央研究所 多孔質細胞足場及びその利用
WO2020071429A1 (fr) * 2018-10-04 2020-04-09 国立研究開発法人物質・材料研究機構 Promoteur d'angiogenèse et procédé thérapeutique
CN111298192A (zh) * 2020-03-06 2020-06-19 华中科技大学同济医学院附属协和医院 一种用于皮肤和黏膜破损部位的防护性修复水凝胶及其制备方法
CN112512602A (zh) * 2018-09-05 2021-03-16 国立研究开发法人物质·材料研究机构 防粘连材料
US11679177B2 (en) 2017-08-08 2023-06-20 Baxter International Inc. Polymeric compositions, delivery devices, and methods
WO2024053602A1 (fr) * 2022-09-06 2024-03-14 国立研究開発法人物質・材料研究機構 Feuille poreuse, film adhésif tissulaire, leur utilisation en tant qu'agent hémostatique ou matériau anti-adhérence, et leurs procédés de production

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007503881A (ja) * 2003-08-29 2007-03-01 メイヨ フオンデーシヨン フオー メデイカル エジユケーシヨン アンド リサーチ 生分解性スカフォールド類製造用ヒドロゲルポロゲン類
WO2012046759A1 (fr) * 2010-10-05 2012-04-12 独立行政法人物質・材料研究機構 Film d'adhésif tissulaire et procédé de production de celui-ci
JP2014100420A (ja) * 2012-11-22 2014-06-05 National Institute For Materials Science 組織接着膜及びその製造方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014005211A (ja) * 2012-06-21 2014-01-16 Kagoshima Univ ゼラチンゲルの作製法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007503881A (ja) * 2003-08-29 2007-03-01 メイヨ フオンデーシヨン フオー メデイカル エジユケーシヨン アンド リサーチ 生分解性スカフォールド類製造用ヒドロゲルポロゲン類
WO2012046759A1 (fr) * 2010-10-05 2012-04-12 独立行政法人物質・材料研究機構 Film d'adhésif tissulaire et procédé de production de celui-ci
JP2014100420A (ja) * 2012-11-22 2014-06-05 National Institute For Materials Science 組織接着膜及びその製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MATSUDA ET AL.: "Enhanced tissue penetration- induced high bonding strength of a novel tissue adhesive composed of cholesteryl group-modified gelatin and disuccinimidyl tartarate", COLLOIDS AND SURFACES B: BIOINTERFACES, vol. 91, 1 March 2012 (2012-03-01), pages 48 - 56, XP028347786, DOI: doi:10.1016/j.colsurfb.2011.10.030 *
MATSUDA ET AL.: "In vitro evaluation of tissue adhesives composed of hydrophobically modified gelatins and disuccinimidyl tartrate", SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS, vol. 13, 2012 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016117569A1 (fr) * 2015-01-20 2016-07-28 国立研究開発法人物質・材料研究機構 Agent d'étanchéité chirurgical
EP3248622A4 (fr) * 2015-01-20 2018-11-14 National Institute for Materials Science Agent d'étanchéité chirurgical
US10420855B2 (en) 2015-01-20 2019-09-24 National Institute For Materials Science Surgical sealant
US11679177B2 (en) 2017-08-08 2023-06-20 Baxter International Inc. Polymeric compositions, delivery devices, and methods
JP2019076070A (ja) * 2017-10-27 2019-05-23 株式会社豊田中央研究所 多孔質細胞足場及びその利用
CN112512602A (zh) * 2018-09-05 2021-03-16 国立研究开发法人物质·材料研究机构 防粘连材料
WO2020071429A1 (fr) * 2018-10-04 2020-04-09 国立研究開発法人物質・材料研究機構 Promoteur d'angiogenèse et procédé thérapeutique
JPWO2020071429A1 (ja) * 2018-10-04 2021-09-02 国立研究開発法人物質・材料研究機構 血管新生促進剤、及び治療方法
JP7132465B2 (ja) 2018-10-04 2022-09-07 国立研究開発法人物質・材料研究機構 血管新生促進剤、及び治療方法
CN111298192A (zh) * 2020-03-06 2020-06-19 华中科技大学同济医学院附属协和医院 一种用于皮肤和黏膜破损部位的防护性修复水凝胶及其制备方法
CN111298192B (zh) * 2020-03-06 2021-11-16 华中科技大学同济医学院附属协和医院 一种用于皮肤和黏膜破损部位的防护性修复水凝胶及其制备方法
WO2024053602A1 (fr) * 2022-09-06 2024-03-14 国立研究開発法人物質・材料研究機構 Feuille poreuse, film adhésif tissulaire, leur utilisation en tant qu'agent hémostatique ou matériau anti-adhérence, et leurs procédés de production

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