WO2021086081A1 - Fabrication d'adhésif tissulaire biodégradable photo-réticulable - Google Patents

Fabrication d'adhésif tissulaire biodégradable photo-réticulable Download PDF

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Publication number
WO2021086081A1
WO2021086081A1 PCT/KR2020/014955 KR2020014955W WO2021086081A1 WO 2021086081 A1 WO2021086081 A1 WO 2021086081A1 KR 2020014955 W KR2020014955 W KR 2020014955W WO 2021086081 A1 WO2021086081 A1 WO 2021086081A1
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WO
WIPO (PCT)
Prior art keywords
formula
adhesive
hama
photo
integer
Prior art date
Application number
PCT/KR2020/014955
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English (en)
Korean (ko)
Inventor
양승윤
박삼대
이혜선
Original Assignee
부산대학교 산학협력단
주식회사 에스엔비아
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Priority claimed from KR1020200142804A external-priority patent/KR102515178B1/ko
Application filed by 부산대학교 산학협력단, 주식회사 에스엔비아 filed Critical 부산대학교 산학협력단
Publication of WO2021086081A1 publication Critical patent/WO2021086081A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/58—Adhesives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the present invention relates to a photo-crosslinkable biodegradable tissue adhesive and a method of manufacturing the same.
  • Medical tissue adhesives are used for the purpose of healing wounds by protecting the hemostasis, bonding, or treatment area of the wound.
  • fibrin-based tissue adhesives using the blood coagulation process in the body have high biocompatibility, but have a disadvantage of low adhesion to mucous membranes and wet tissues.
  • a photo-crosslinked tissue adhesive capable of maintaining high adhesion to the tissue by forming a hydrogel on the fly by light such as UV is attracting attention.
  • hyaluronic acid which is a constituent of various tissues in the human body, can help in wound recovery, and thus can help not only wound closure but also tissue regeneration with the introduction of the optical crosslinking group.
  • HAMA hyaluronic acid methacrylate
  • An object of the present invention is to provide a hyaluronic acid compound having excellent elongation and excellent adhesion to skin and mucous membranes.
  • Another object of the present invention is to provide a hydrogel or biodegradable tissue adhesive formed through a photocrosslinking reaction using the hyaluronic acid compound.
  • another object of the present invention is to provide a biodegradable tissue adhesive in which the hyaluronic acid compound and the hyaluronic acid compound having a different photocrosslink length are introduced in order to control the physical properties of the biodegradable tissue adhesive.
  • the present invention provides a compound represented by the following formula (1).
  • n is an integer of 1 to 10,000, and X 1 to X 4 may be the same or different, respectively, and are OH or a substituent of Formula 1-1.
  • p or q are each an integer of 0 to 10.
  • the present invention provides a hydrogel comprising the compound of Formula 1 and formed through a photocrosslinking reaction.
  • the present invention provides a biodegradable tissue adhesive comprising the compound of Formula 1 above.
  • the present invention provides a composition comprising further mixing a hyaluronic acid methacrylate (HAMA) compound with the compound of Formula 1 above.
  • HAMA hyaluronic acid methacrylate
  • the present invention provides a hydrogel comprising the composition, characterized in that formed through a photo-crosslinking reaction.
  • the present invention provides a biodegradable tissue adhesive comprising the composition.
  • Hyaluronic acid butylacrylate (HABA) prepared according to the present invention has excellent elongation and excellent adhesion to skin and mucous membrane tissues.
  • HAMA hyaluronic acid methacrylate
  • HA hyaluronic acid methacrylate
  • It can be used as a medical hemostatic agent, wound coating agent, anti-adhesion agent, cell culture support, 3D printer bioink, and bio-coating material.
  • HAMA is a diagram showing the elongation of HAMA, HABA, and HAPA.
  • FIG. 4 is a view showing the change in tensile strength according to the mixing ratio of HAMA and HABA.
  • FIG. 5 is a view showing the change in tensile strength according to the mixing ratio of HAMA and HAPA.
  • FIG. 6 is a diagram showing the results of a skin adhesion test of an adhesive in which HAMA, HAMA and HAPA are mixed.
  • FIG. 7 is a diagram showing the results of a test result of adhesion of an adhesive mixed with HAMA and HAPA to the ocular mucosa.
  • the present inventors synthesized a material of hyaluronic acid butylacrylate (HABA), which is excellent in elongation and tissue adhesion, and is a light cross-linking type HA such as hyaluronic acid methacrylate (HAMA) and the HABA. It is possible to prepare tissue adhesives with desired adhesive properties and physical properties by mixing HAs with different crosslinking lengths, so that medical adhesives that can be used on various parts of the body, medical hemostatic agents, wound coating agents, anti-adhesion agents, cell culture supports, 3D printers The present invention was completed by finding that it can be usefully used as a bio-ink and a bio-coating material.
  • HABA hyaluronic acid butylacrylate
  • HAMA hyaluronic acid methacrylate
  • the present invention provides a compound represented by the following formula (1).
  • n is an integer of 1 to 10,000, and X 1 to X 4 may be the same or different, respectively, and are OH or a substituent of Formula 1-1.
  • p or q are each an integer of 0 to 10.
  • X 1 to X 4 may include at least one or more substituents of Formula 1-1, the rest may be hydroxy groups, and the substitution rate of the substituents of Formula 1-1 may be 1 to 400%.
  • n is an integer of 1 to 10,000
  • X 1 to X 4 includes at least one substituent of Formula 1-1
  • p or q in Formula 1-1 is an integer of 0 to 10, respectively. It is desirable.
  • Chemical Formula 1 is characterized by having an ethylenically unsaturated group in the hyaluronic acid repeating unit excellent in biocompatibility.
  • the compound represented by Formula 1 may be a compound represented by Formula 2 below.
  • n is an integer of 1 to 10,000.
  • the present invention provides a hydrogel comprising any one of the compounds represented by Chemical Formulas 1 to 2, and is formed through a photocrosslinking reaction.
  • the hydrogel may be used as a physiologically active material or a carrier for a drug delivery system, or as an implant material for tissue regeneration and filling, but is not limited thereto.
  • the present invention provides a biodegradable tissue adhesive comprising any one of the compounds represented by Chemical Formulas 1 to 2.
  • the compound is a photo-crosslinkable biodegradable tissue adhesive capable of maintaining a high adhesion to the tissue by forming a hydrogel through a crosslinking reaction by light.
  • the photo-crosslinking reaction as well as the crosslinking reaction by UV, if a photoinitiator having a different absorption wavelength is used, it may be possible to form a hydrogel according to the photo-crosslinking reaction in light of other wavelengths including visible light.
  • biodegradable tissue adhesive is made of medical adhesive, medical hemostatic agent, wound coating agent, anti-adhesion agent, medical hemostatic agent, wound coating agent, anti-adhesion agent, cell culture support, 3D printer bioink, and bio-coating material. It may be used for any one or more selected purposes from the group, but is not limited thereto.
  • hyaluronic acid methacrylate Conventional photo-crosslinked hyaluronic acid methacrylate (HAMA) has been used in limited fields due to lack of flexibility during photocrosslinking.
  • HABA hyaluronic acid butylacrylate
  • HAPA hyaluronic acid pentacrylate
  • the range of use can be broadened, and through this, it is expected to increase the adhesion of the tissue.
  • the present invention provides a composition characterized in that the hyaluronic acid methacrylate (HAMA) compound is further mixed with the compound represented by the following formula (1).
  • HAMA hyaluronic acid methacrylate
  • n is an integer of 1 to 10,000, and X 1 to X 4 may be the same or different, respectively, and are OH or a substituent of Formula 1-1.
  • p or q are each an integer of 0 to 10.
  • X 1 to X 4 may include at least one or more substituents of Formula 1-1, the rest may be hydroxy groups, and the substitution rate of the substituents of Formula 1-1 may be 1 to 400%.
  • n is an integer of 1 to 10,000
  • X 1 to X 4 includes at least one substituent of Formula 1-1
  • p or q in Formula 1-1 is an integer of 0 to 10, respectively. It is desirable.
  • Chemical Formula 1 is characterized by having an ethylenically unsaturated group in the hyaluronic acid repeating unit excellent in biocompatibility.
  • the compound represented by Formula 1 may be a composition represented by Formula 2 or Formula 3.
  • n is an integer of 1 to 10,000.
  • n is an integer of 1 to 10,000.
  • the HAMA and the compound represented by Chemical Formula 1 may be mixed in a weight ratio of 10:0 to 5:5, and preferably in a weight ratio of 7:3, but are not limited thereto.
  • the mechanical properties can be adjusted according to the mixing ratio of each compound of HAMA and HABA or HAMA and HAPA, and the flexibility can be increased than that of conventional HAMA, so that the range of use can be expanded to a moving part. I can.
  • the mixed composition of HAMA and HAPA can have excellent adhesion to not only skin but also mucosal tissues than simple HAMA.
  • the present invention provides a hydrogel comprising the composition, characterized in that formed through a photo-crosslinking reaction.
  • the methacrylate, butyl acrylate, and pentaacrylate are photo-crosslinking agents and react with the hyaluronic acid to obtain a photo-crosslinkable hydrogel.
  • the "photocrosslinking agent” refers to a compound capable of inducing a radical reaction in a reaction system by forming a radical by light irradiation, and a compound that is generally used as a photocrosslinker or a photoinitiator may be used as a photocrosslinker of the present invention, but , It is more preferable to use a photocrosslinking agent or a photoinitiator that is not toxic or weak in vivo.
  • the hydrogel may be used as a physiologically active material or a carrier for a drug delivery system, or as an implant material for tissue regeneration and filling, but is not limited thereto.
  • the present invention provides a biodegradable tissue adhesive comprising the composition.
  • the composition is a photo-crosslinkable biodegradable tissue adhesive capable of maintaining high adhesion to the tissue by forming a hydrogel by crosslinking reaction by light.
  • the photo-crosslinking reaction as well as the crosslinking reaction by UV, if a photoinitiator having a different absorption wavelength is used, it may be possible to form a hydrogel according to the photo-crosslinking reaction in light of other wavelengths including visible light.
  • biodegradable tissue adhesive is made of medical adhesive, medical hemostatic agent, wound coating agent, anti-adhesion agent, medical hemostatic agent, wound coating agent, anti-adhesion agent, cell culture support, 3D printer bioink, and bio-coating material. It may be used for any one or more selected purposes from the group, but is not limited thereto.
  • HA which is a component of various tissues in the human body, and which promotes tissue regeneration while being transparent, to develop a flexible and transparent tissue adhesive that has excellent adhesion to not only skin but also mucosal tissues.
  • HABA HA-Butylaacrylate
  • HABA hyaluronic acid methacrylate
  • HAMA hyaluronic acid methacrylate
  • the physical properties of the adhesive can be freely adjusted as described above, it is possible to develop a medical adhesive that can be used on various parts of the body.
  • the above technology can be applied to medical hemostatic agents, wound coating agents, anti-adhesion agents, cell culture supports, 3D printer bioinks, and biocoating materials, but any application is possible as long as it can be used as a bio-adhesive without limitation. Do.
  • HAPA hyaluronic acid pentacrylate
  • Tensile tests were performed on a test piece molded in a dogbone shape according to the ASTM method at a rate of 1 mm/min using a universal testing machine of AND Corporation. The elongation was analyzed by measuring the strain at the fracture point of the specimen.
  • the elongation tends to increase as the length of the optical crosslinking increases. It was confirmed that HABA can increase three times or more from 7.5 mm before stretching to 25.5 mm after stretching, and compared with HAMA, HABA and HAPA showed excellent elongation.
  • HAMA or HAMA and HAPA are mixed at 7:3, and the photoinitiator, lithium phenyl-2,4,6-triethylbenzoyl phosphinate (Lithium phenyl-2,4,6-trimethylbenzoyl phosphinate; LAP)
  • UV was irradiated for 5 seconds, and the adhesive strength was confirmed in a dynamic environment by bending.

Abstract

La présente invention concerne la fabrication d'un adhésif tissulaire biodégradable photo-réticulable, et fournit un nouveau composé acide hyaluronique affichant un excellent allongement et une excellente force d'adhérence même à la peau et à des tissus muqueux, les propriétés physiques de l'adhésif pouvant être ajustées par mélange de HAMA avec un HA photo-réticulable ayant une longueur photo-réticulable différente, et l'adhésif pouvant ainsi être utilisé comme adhésif médical pouvant être appliqué sur divers sites d'un corps.
PCT/KR2020/014955 2019-10-31 2020-10-31 Fabrication d'adhésif tissulaire biodégradable photo-réticulable WO2021086081A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2019-0137871 2019-10-31
KR20190137871 2019-10-31
KR1020200142804A KR102515178B1 (ko) 2019-10-31 2020-10-30 광가교형 생분해성 조직접착제 제조
KR10-2020-0142804 2020-10-30

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Publication Number Publication Date
WO2021086081A1 true WO2021086081A1 (fr) 2021-05-06

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130231474A1 (en) * 2010-11-18 2013-09-05 Universite Joseph Fourier - Grenoble 1 Polysaccharide derivatives including an alkene unit and thiol-click chemical coupling reaction
CN103724455A (zh) * 2013-12-11 2014-04-16 四川大学 一种透明质酸衍生物及其水凝胶的制备方法
WO2014072330A1 (fr) * 2012-11-06 2014-05-15 Centre National De La Recherche Scientifique (Cnrs) Hydrogel réagissant au glucose comprenant l'acide hyaluronique (ha) sur lequel est greffé pba

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130231474A1 (en) * 2010-11-18 2013-09-05 Universite Joseph Fourier - Grenoble 1 Polysaccharide derivatives including an alkene unit and thiol-click chemical coupling reaction
WO2014072330A1 (fr) * 2012-11-06 2014-05-15 Centre National De La Recherche Scientifique (Cnrs) Hydrogel réagissant au glucose comprenant l'acide hyaluronique (ha) sur lequel est greffé pba
CN103724455A (zh) * 2013-12-11 2014-04-16 四川大学 一种透明质酸衍生物及其水凝胶的制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHANDRASEKHARAN AJEESH, SEONG KEUM-YONG, YIM SANG-GU, KIM SODAM, SEO SUNGBAEK, YOON JINHWAN, YANG SEUNG YUN: "In situ photocrosslinkable hyaluronic acid-based surgical glue with tunable mechanical properties and high adhesive strength", JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY, JOHN WILEY & SONS, INC., US, vol. 57, no. 4, 7 December 2018 (2018-12-07), US, pages 522 - 530, XP055807154, ISSN: 0887-624X, DOI: 10.1002/pola.29290 *
SHIRZAEI SANI EHSAN, PORTILLO-LARA ROBERTO, SPENCER ANDREW, YU WENDY, GEILICH BENJAMIN M., NOSHADI IMAN, WEBSTER THOMAS J., ANNABI: "Engineering Adhesive and Antimicrobial Hyaluronic Acid/Elastin-like Polypeptide Hybrid Hydrogels for Tissue Engineering Applications", ACS BIOMATERIALS SCIENCE & ENGINEERING, AMERICAN CHEMICAL SOCIETY, US, vol. 4, no. 7, 27 April 2018 (2018-04-27), US, pages 2528 - 2540, XP055807162, ISSN: 2373-9878, DOI: 10.1021/acsbiomaterials.8b00408 *
VAN NIEUWENHOVE INE; VAN VLIERBERGHE SANDRA; SALAMON ACHIM; PETERS KIRSTEN; THIENPONT HUGO; DUBRUEL PETER: "Photo-crosslinkable biopolymers targeting stem cell adhesion and proliferation: the case study of gelatin and starch-based IPNs", JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE, SPRINGER NEW YORK LLC, UNITED STATES, vol. 26, no. 2, 6 February 2015 (2015-02-06), United States, pages 1 - 8, XP035443088, ISSN: 0957-4530, DOI: 10.1007/s10856-015-5424-4 *

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