KR102415181B1 - Preparation of photo-crosslinkable biodegradable tissue adhesive using copolymer - Google Patents
Preparation of photo-crosslinkable biodegradable tissue adhesive using copolymer Download PDFInfo
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- 239000003106 tissue adhesive Substances 0.000 title claims abstract description 18
- 229920001577 copolymer Polymers 0.000 title abstract description 21
- 238000002360 preparation method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 238000004132 cross linking Methods 0.000 claims description 14
- 239000000017 hydrogel Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 5
- 229920002674 hyaluronan Polymers 0.000 abstract description 22
- 229960003160 hyaluronic acid Drugs 0.000 abstract description 22
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 abstract description 21
- 230000001070 adhesive effect Effects 0.000 abstract description 11
- 230000000704 physical effect Effects 0.000 abstract description 5
- 229940075469 tissue adhesives Drugs 0.000 abstract description 4
- 208000031737 Tissue Adhesions Diseases 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000853 adhesive Substances 0.000 description 9
- 238000002156 mixing Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 206010052428 Wound Diseases 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- XLBDEMIFDOANPN-UHFFFAOYSA-N 9-benzyl-3h-purine-6-thione Chemical compound C1=NC=2C(=S)N=CNC=2N1CC1=CC=CC=C1 XLBDEMIFDOANPN-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 229940030225 antihemorrhagics Drugs 0.000 description 4
- 239000002874 hemostatic agent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- -1 hyaluronic acid compound Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000009864 tensile test Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000007334 copolymerization reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- ULDDEWDFUNBUCM-UHFFFAOYSA-N pentyl prop-2-enoate Chemical compound CCCCCOC(=O)C=C ULDDEWDFUNBUCM-UHFFFAOYSA-N 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
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- 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
-
- 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
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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
- A61L15/42—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
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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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
- 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
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Abstract
본 발명은 공중합체를 이용한 광가교형 생분해성 조직접착제 제조에 관한 것으로, 연신율, 기계적 물성 및 조직 접착력이 우수한 히알루론산 공중합체 화합물을 제공하고, 이는 근본적으로 상분리가 되지 않으며, 원하는 접착 특성 및 물성을 가진 조직 접착제를 제조할 수 있는 특징이 있다.The present invention relates to the production of a photocrosslinkable biodegradable tissue adhesive using a copolymer, and provides a hyaluronic acid copolymer compound having excellent elongation, mechanical properties and tissue adhesion, which does not fundamentally phase-separate, and desired adhesive properties and physical properties It has the characteristics of being able to manufacture tissue adhesives with
Description
본 발명은 공중합체를 이용한 광가교형 생분해성 조직접착제 제조에 관한 것이다.The present invention relates to the manufacture of a photocrosslinkable biodegradable tissue adhesive using a copolymer.
의료용 조직 접착제는 상처부위의 지혈이나 접합 또는 치료부위를 보호하여 상처회복을 목적으로 사용된다. Medical tissue adhesives are used for the purpose of wound healing by protecting the hemostasis or bonding or treatment area of the wound.
종래 시아노아크릴레이트 (cyanoacrylate) 계열의 조직 접착제는 빠른 접착성능을 보이지만, 젖은 표면에서 접착성과 유연성이 떨어지고 분해과정에서 포름알데히드와 같은 독성 부산물이 생성되어 생체적합성이 낮다. 또한, 형성된 접착층이 불투명하고 고르지 못하여, 안구 표면과 같이 높은 광투과성이 요구되는 표면에는 적용이 어려운 한계가 있어왔다.Conventional cyanoacrylate-based tissue adhesives show fast adhesive performance, but have poor adhesion and flexibility on wet surfaces, and toxic by-products such as formaldehyde are generated in the decomposition process, resulting in low biocompatibility. In addition, since the formed adhesive layer is opaque and uneven, there has been a limitation in that it is difficult to apply to a surface requiring high light transmittance, such as the surface of the eyeball.
또한, 체내 혈액의 응고과정을 이용한 피브린 (fibrin) 계열의 조직 접착제는 생체적합성은 높은 편이지만 점막과 젖은 조직에 접착력이 낮다는 단점이 있었다. In addition, although the fibrin-based tissue adhesive using the blood coagulation process in the body has high biocompatibility, it has a disadvantage in that it has low adhesion to mucous membranes and wet tissues.
최근에 UV와 같은 빛에 의해 즉석에서 하이드로젤을 형성하여 조직과 높은 접착력을 유지할 수 있는 광가교형 조직접착제가 주목을 받고 있다. 이는 일반적으로 수용성 고분자에 광가교 그룹을 도입하여 광가교형 고분자를 제조하고 이를 녹인 용액에 빛을 조사하여 하이드로젤을 형성함으로써 원하는 조직에 높은 접착력을 달성할 수 있다.Recently, a photo-crosslinking type tissue adhesive capable of maintaining high adhesion with a tissue by forming a hydrogel on the fly by light such as UV is attracting attention. In general, it is possible to achieve high adhesion to a desired tissue by introducing a photocrosslinking group to a water-soluble polymer to prepare a photocrosslinkable polymer, and irradiating light to a solution in which it is dissolved to form a hydrogel.
특히, 인체 내 다양한 조직의 구성성분인 히알루론산 (Hyaluronic acid, HA)은 상처회복에 도움을 줄 수 있어 광가교 그룹을 도입함에 따라 상처 봉합뿐만 아니라 조직 재생에도 도움을 줄 수 있다. In particular, hyaluronic acid (HA), which is a component of various tissues in the human body, can help wound healing, so that by introducing a photo-crosslinking group, it can help not only wound closure but also tissue regeneration.
하지만, 기존의 광가교형 HA는 유연성이 떨어지고 물성 조절이 어려워 제한적인 분야에서만 활용될 수 있는 문제점이 있어왔다.However, the conventional light-crosslinking type HA has a problem in that it can be used only in limited fields due to poor flexibility and difficult to control physical properties.
따라서 유연하면서도 기계적 물성이 향상됨과 동시에 접착력 또한 향상될 수 있는 공중합체를 이용한 광가교형 히알루론산 화합물 및 이를 이용한 조직접착제에 대한 연구가 필요한 실정이다.Therefore, there is a need for research on a light-crosslinked hyaluronic acid compound using a copolymer that is flexible and capable of improving mechanical properties and improving adhesion at the same time, and a tissue adhesive using the same.
본 발명의 목적은 우수한 연신율과 기계적 물성 및 피부, 점막조직에서도 우수한 접착력 특성을 나타내기 위해 광가교 길이가 상이한 히알루론산 화합물을 공중합한 히알루론산 공중합체 화합물을 제공하는 데에 있다.An object of the present invention is to provide a hyaluronic acid copolymer compound obtained by copolymerizing hyaluronic acid compounds having different optical crosslinking lengths in order to exhibit excellent elongation, mechanical properties, and excellent adhesion properties even in skin and mucosal tissues.
또한, 본 발명의 다른 목적은 상기 히알루론산 공중합체 화합물을 이용한 생분해성 조직 접착제를 제공하는 데에 있다.In addition, another object of the present invention is to provide a biodegradable tissue adhesive using the hyaluronic acid copolymer compound.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물을 제공한다.In order to achieve the above object, the present invention provides a compound represented by the following formula (1).
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
m 또는 n은 각각 1 내지 10,000의 정수이고, m or n are each an integer from 1 to 10,000,
X1~X8은 각각 동일하거나 다를 수 있으며, OH 또는 화학식 1-1의 치환기 이며,X 1 to X 8 may each be the same or different, and is OH or a substituent of Formula 1-1,
[화학식 1-1][Formula 1-1]
상기 화학식 1-1에서, p 또는 q는 각각 0 내지 10의 정수임.In Formula 1-1, p or q is an integer of 0 to 10, respectively.
또한, 본 발명은 상기 화학식 1 내지 화학식 3으로 표시되는 화합물을 포함하며, 광 가교 반응을 통해 형성되는 것을 특징으로 하는 하이드로젤을 제공한다. In addition, the present invention provides a hydrogel comprising the compound represented by Chemical Formulas 1 to 3, characterized in that it is formed through a photocrosslinking reaction.
또한, 본 발명은 상기 화학식 1의 화합물을 포함하는 생분해성 조직 접착제를 제공한다.In addition, the present invention provides a biodegradable tissue adhesive comprising the compound of
본 발명에 따라 제조된 히알루론산 공중합체 화합물은 단일 성분으로써 근본적으로 상분리가 되지 않으며, 우수한 연신율 및 기계적 특성을 가질 뿐만 아니라 피부, 점막조직에서도 우수한 접착력을 갖는 효과가 있다.The hyaluronic acid copolymer compound prepared according to the present invention does not fundamentally phase-separate as a single component, and has excellent elongation and mechanical properties, as well as excellent adhesion to skin and mucosal tissues.
또한, 광가교 길이가 상이한 히알루론산 화합물을 공중합함으로써 접착제의 물성을 조절할 수 있어, 신체의 여러 부위에 사용할 수 있는 의료용 접착제로 이용될 수 있으며, 의료용 지혈제, 창상피복제, 유착방지제로도 유용하게 활용 가능하다.In addition, the physical properties of the adhesive can be controlled by copolymerizing a hyaluronic acid compound having a different optical crosslinking length, so it can be used as a medical adhesive that can be used in various parts of the body, and is useful as a medical hemostatic agent, wound dressing agent, and anti-adhesion agent. can be used
도 1은 HAMA와 HAPA의 혼합비율에 따른 인장강도의 변화를 나타낸 도면이다.
도 2는 HAMA-co-HAPA 공중합체 내 성분비에 따른 기계적 성질 변화를 나타낸 도면으로, (a) 인장 강도, (b) 인장 탄성계수, (c) 인성, (d) 연신율의 분석 결과를 나타낸 것이다.
도 3은 HAMA-co-HAPA 공중합체의 접착력 시험 결과를 나타낸 것이다.
도 4는 HAMA-co-HAPA 공중합체의 NMR 이미지이다.
도 5 및 도 6은 HAMA 및 HAPA의 각 NMR 이미지이다.1 is a view showing the change in tensile strength according to the mixing ratio of HAMA and HAPA.
2 is a diagram showing the change in mechanical properties according to the component ratio in the HAMA-co-HAPA copolymer, and shows the analysis results of (a) tensile strength, (b) tensile modulus of elasticity, (c) toughness, and (d) elongation. .
3 shows the results of the adhesion test of the HAMA-co-HAPA copolymer.
4 is an NMR image of a HAMA-co-HAPA copolymer.
5 and 6 are NMR images of HAMA and HAPA respectively.
이하에서는 본 발명을 구체적으로 설명한다.Hereinafter, the present invention will be described in detail.
본 발명자들은 연신율, 기계적 강도 및 조직 접착력이 우수한 특성을 갖는 광가교 길이가 상이한 히알루론산 화합물을 공중합한 히알루론산 공중합체 화합물을 합성하였으며, 이는 근본적으로 상분리가 되지 않으며, 원하는 접착 특성 및 물성을 가진 조직 접착제를 제조할 수 있어, 신체의 여러 부위에 사용할 수 있는 의료용 접착제, 의료용 지혈제, 창상피복제, 유착방지제로 유용하게 이용될 수 있음을 밝혀내어 본 발명을 완성하였다.The present inventors synthesized a hyaluronic acid copolymer compound copolymerized with a hyaluronic acid compound having different optical crosslinking lengths having excellent properties such as elongation, mechanical strength and tissue adhesion, which does not fundamentally phase-separate, and has desired adhesive properties and physical properties The present invention was completed by discovering that tissue adhesives can be prepared and can be usefully used as medical adhesives, medical hemostatic agents, wound dressings, and anti-adhesion agents that can be used in various parts of the body.
본 발명은 하기 화학식 1로 표시되는 화합물을 제공한다.The present invention provides a compound represented by the following formula (1).
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
m 또는 n은 각각 1 내지 10,000의 정수이고, m or n are each an integer from 1 to 10,000,
X1~X8은 각각 동일하거나 다를 수 있으며, OH 또는 화학식 1-1의 치환기 이며,X 1 to X 8 may each be the same or different, and is OH or a substituent of Formula 1-1,
[화학식 1-1][Formula 1-1]
상기 화학식 1-1에서, p 또는 q는 각각 0 내지 10의 정수임.In Formula 1-1, p or q is an integer of 0 to 10, respectively.
이때, X1~X4 및 X5~X8은 각각 적어도 하나 이상의 화학식 1-1의 치환기를 필수적으로 포함하며, 나머지는 하이드록시기일 수 있고, 화학식 1-1의 치환기의 치환율은 1~400%가 될 수 있다.In this case, each of X 1 to X 4 and X 5 to X 8 essentially includes at least one substituent of Formula 1-1, and the remainder may be a hydroxyl group, and the substitution ratio of the substituent of Formula 1-1 is 1 to 400 % can be
특히, 상기 화학식 1에서 m 또는 n은 각각 1 내지 10000의 정수이고, X1~X4는 적어도 하나 이상의 화학식 1-1의 치환기를 포함하고, X5~X8도 적어도 하나 이상의 화학식 1-1의 치환기를 포함하되 X1~X4의 치환기와 다른 치환기를 포함하며, p 또는 q는 각각 0 내지 10의 정수인 것이 바람직하다.In particular, in
상기와 같이, 화학식 1의 화합물은 생체적합성이 우수한 히알루론산 반복단위에 에틸렌성 불포화기를 갖는 것을 특징으로 한다.As described above, the compound of Formula 1 is characterized in that it has an ethylenically unsaturated group in the repeating unit of hyaluronic acid having excellent biocompatibility.
또한, 상기 화학식 1로 표시되는 화합물은 하기 화학식 2 또는 화학식 3으로 표시되는 화합물일 수 있다.In addition, the compound represented by Formula 1 may be a compound represented by Formula 2 or Formula 3 below.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
상기 화학식 2 또는 화학식 3에서,In Formula 2 or Formula 3,
m 또는 n은 각각 1 내지 10,000의 정수임.m or n is an integer from 1 to 10,000, respectively.
이때, 상기 화학식 1로 표시되는 화합물은 m과 n이 9:1 내지 7:3 의 비율로 랜덤 공중합할 수 있으며, 바람직하게는 7:3의 비율로 랜덤 공중합하여 형성할 수 있으나, 이에 제한되는 것은 아니다.In this case, the compound represented by Formula 1 may be randomly copolymerized with m and n in a ratio of 9:1 to 7:3, and preferably may be formed by random copolymerization in a ratio of 7:3, but limited thereto it is not
상기 화학식 1 내지 화학식 3의 화합물은 광가교 길이가 상이한 히알루론산 화합물을 랜덤 공중합한 히알루론산 공중합체 화합물로써 둘 이상의 고분자를 단순히 혼합하여 생길 수 있는 상분리 및 제품의 상품성 저하의 문제점을 해결할 수 있다.The compounds of
본 발명의 일 실시예에 따르면, HAMA와 HAPA가 랜덤 공중합하여 제조된 화학식 2의 화합물은 단순 HAMA와 HAPA의 혼합물보다 기계적 강도가 향상되는 것을 확인하였으며, 연신율 및 접착력 또한 우수함을 확인하였다. 즉, 본 발명에 따르면, 공중합체 하이드로젤 내부에 다중망상구조가 생겨서 유연성도 높아지면서 동시에 기계적 강도도 높아지는 반면, 일반적으로 혼합물의 경우에는 강도가 높은 단일 물질(HAMA)보다 혼합물의 강도가 높기 힘들어서 통상 평균값의 강도를 나타낼 뿐이다.According to an embodiment of the present invention, it was confirmed that the compound of
또한, 본 발명은 상기 화학식 1 내지 화학식 3으로 표시되는 화합물을 포함하며, 광 가교 반응을 통해 형성되는 것을 특징으로 하는 하이드로젤을 제공한다. 상기 하이드로젤은 생리활성물질 또는 약물 전달체용 담체나, 조직재생 및 충진용 임플란트 소재 등으로 활용 가능하지만, 이에 한정되는 것은 아니다.In addition, the present invention provides a hydrogel comprising the compound represented by Chemical Formulas 1 to 3, characterized in that it is formed through a photocrosslinking reaction. The hydrogel can be used as a carrier for a physiologically active material or drug delivery, or an implant material for tissue regeneration and filling, but is not limited thereto.
또한, 본 발명은 상기 화학식 1 내지 화학식 3으로 표시되는 화합물 중 어느 한 화합물을 포함하는 생분해성 조직 접착제를 제공한다.In addition, the present invention provides a biodegradable tissue adhesive comprising any one of the compounds represented by
이때, 상기 화합물은 광에 의해 가교 반응이 일어나 하이드로젤(hydrogel)을 형성하여 조직과 높은 접착력을 유지할 수 있는 광가교형 생분해성 조직 접착제이다. 이때, 광 가교 반응은 UV에 의한 가교 반응 뿐 아니라, 흡수파장이 다른 광개시제를 사용하면 가시광선을 비롯한 다른 파장의 빛에서도 광 가교 반응에 따른 하이드로젤 형성이 가능할 수 있다. In this case, the compound is a photo-cross-linkable biodegradable tissue adhesive capable of maintaining high adhesion with the tissue by forming a hydrogel through a cross-linking reaction by light. In this case, in the photocrosslinking reaction, in addition to 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 photocrosslinking reaction in light of other wavelengths including visible light.
또한, 상기 생분해성 조직 접착제는 의료용 접착제, 의료용 지혈제, 창상피복제, 유착방지제, 세포배양 지지체, 3D 프린터 바이오잉크(printer bioink) 및 바이오코팅 재료로 이루어진 군에서 어느 하나 이상 선택되는 용도로 이용될 수 있지만, 이에 한정되는 것은 아니다.In addition, the biodegradable tissue adhesive is a medical adhesive, a medical hemostatic agent, a wound coating agent, an anti-adhesion agent, a cell culture support, a 3D printer bioink (printer bioink) and any one or more selected from the group consisting of a bio-coating material It will be used for may, but is not limited thereto.
종래의 광가교형 히알루론산 메타크릴레이트(Hyaluronic acid methacrylate; HAMA)는 광가교시 유연성이 부족하여 제한적인 분야에 활용되어 왔다. 이를 개선하기 위해 연신율이 우수한 히알루론산 부틸아크릴레이트(Hyaluronic acid butylacrylate; HABA) 또는 히알루론산 펜틸아크릴레이트(Hyaluronic acid Pentylacrylate; HAPA)를 혼합하여 하이드로겔 조직접착제의 기계적 물성을 조절함으로써 움직임이 있는 부분에 사용범위를 넓힐 수 있고, 이를 통해 조직의 접착력 증대도 기대할 수 있다.Conventional light-crosslinking type hyaluronic acid methacrylate (HAMA) has been utilized in limited fields due to lack of flexibility during light crosslinking. In order to improve this, hyaluronic acid butylacrylate (HABA) or hyaluronic acid pentylacrylate (HAPA) having excellent elongation is mixed to adjust the mechanical properties of the hydrogel tissue adhesive to the moving parts. The scope of use can be broadened, and through this, an increase in tissue adhesion can be expected.
하지만 두 개 이상의 고분자를 단순히 섞는 것은 내외부적인 요인으로 상분리가 생길 수 있으며, 이는 제품의 상품성 저하로 이어진다. However, simply mixing two or more polymers may cause phase separation due to internal and external factors, which leads to a decrease in the commercial value of the product.
본 발명에서는 이를 해결하기 위해 히알루론산에 두 개 이상의 길이가 서로 상이한 광가교 기능기를 동시에 도입하여 유연하면서도 기계적 물성이 우수한 새로운 광가교형 공중합체를 합성하였다.In the present invention, in order to solve this problem, two or more photocrosslinkable functional groups having different lengths were simultaneously introduced into hyaluronic acid to synthesize a new photocrosslinkable copolymer with excellent mechanical properties while being flexible.
공중합체는 단일 성분으로써 근본적으로 상분리가 될 수 있는 위험요소를 가지지 않는다. 또한, 상기 합성된 새로운 광가교형 공중합체는 유연하면서 기계적 강도가 우수할 뿐만 아니라 접착제의 물성을 자유로이 조절할 수 있으므로 신체의 여러 부위에 사용할 수 있는 의료용 접착제의 개발이 가능하다. As a single component, the copolymer essentially does not have a risk of phase separation. In addition, the synthesized new photocrosslinkable copolymer is flexible and has excellent mechanical strength, and the physical properties of the adhesive can be freely adjusted, so it is possible to develop a medical adhesive that can be used in various parts of the body.
또한, 본 발명에 따른 공중합체 화합물은 의료용 지혈제, 창상피복제, 유착방지제, 세포배양 지지체, 3D 프린터 바이오잉크(printer bioink) 및 바이오코팅 재료로의 응용이 가능하나, 이에 제한 없이 생체 접착제로 사용될 수 있으면 모두 응용 가능하다.In addition, the copolymer compound according to the present invention can be used as a medical hemostatic agent, wound dressing agent, anti-adhesion agent, cell culture support, 3D printer bioink and biocoating material, but without limitation, it can be used as a bioadhesive All possible applications are possible.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it is to those of ordinary skill in the art to which the present invention pertains that the scope of the present invention is not limited by these examples according to the gist of the present invention. it will be self-evident
<합성예 1> HAMA-co-HAPA 공중합체 합성<Synthesis Example 1> Synthesis of HAMA-co-HAPA copolymer
[반응식 1][Scheme 1]
상기 반응식 1에서와 같이, 정제수 100ml에 히알루론산 10g(26mmol)을 녹이고 0-5℃로 냉각시켰다. 여기에 메타크릴 무수물(methacrylic anhydride) 36.4mmol, 4-펜테노익 무수물(4-pentenoic anhydride) 15.6mmol과 3M NaOH 100ml 용액을 첨가한 후 2일간 교반하였다. 이 반응물을 에탄올에 침전하여 정제하고, 진공건조하여 HAMA-HAPA 랜덤공중합체를 제조하였다(이하 'HAMA-co-HAPA'라 칭함). As in
수율: 82%, 1H-NMR (300 MHz, D2O):δ(ppm)= 6.5, 6.1, 5.6(CH=CH2), 4.5-4.3 (CH2), 3.8-3.0(CH), 2.5-2.35(CH2CH2), 1.8(CH3), 1.7(CH3). (도 4 참조)Yield: 82%, 1 H-NMR (300 MHz, D 2 O): δ (ppm) = 6.5, 6.1, 5.6 (CH=CH 2 ), 4.5-4.3 (CH 2 ), 3.8-3.0 (CH), 2.5-2.35 (CH 2 CH 2 ), 1.8 (CH 3 ), 1.7 (CH 3 ). (See Fig. 4)
상기 합성된 HAMA-co-HAPA에서 m과 n의 비율은 7:3이었으며, 첨가되는 메타크릴 무수물(methacrylic anhydride) 및 4-펜테노익 무수물(4-pentenoic anhydride)의 비율을 10:0, 9:1로 달리한 HAMA-co-HAPA 공중합체를 제조하여 하기 실시예의 샘플로 이용하였다.The ratio of m and n in the synthesized HAMA-co-HAPA was 7:3, and the ratio of methacrylic anhydride and 4-pentenoic anhydride to be added was 10: 0, 9: A HAMA-co-HAPA copolymer different from 1 was prepared and used as a sample in Examples below.
<비교예 1> HAMA 및 HAPA 간 혼합물 제조<Comparative Example 1> Preparation of mixture between HAMA and HAPA
정제수 100ml에 히알루론산 10g(26mmol)을 녹이고 0-5℃로 냉각시켰다. 여기에 메타크릴 무수물(methacrylic anhydride) 104mmol 과 3M NaOH 100ml 용액을 첨가한 후 2일간 교반하였다. 이 반응물을 에탄올에 침전하여 정제하고, 진공건조하여 히알루론산 메타크릴레이트(Hyaluronic acid methacrylate; HAMA)를 제조하였다(도 5 참조).10 g (26 mmol) of hyaluronic acid was dissolved in 100 ml of purified water and cooled to 0-5 °C. Here, 104 mmol of methacrylic anhydride and 100 ml of 3M NaOH were added and stirred for 2 days. The reaction product was purified by precipitation in ethanol, and vacuum dried to prepare hyaluronic acid methacrylate (HAMA) (see FIG. 5 ).
정제수 100ml에 히알루론산 10g(26mmol)을 녹이고 0-5℃로 냉각시켰다. 여기에 4-펜테노익 무수물(4-pentenoic anhydride) 156mmol 과 3M NaOH 100ml 용액을 첨가한 후 2일간 교반하였다. 이 반응물을 에탄올에 침전하여 정제하고, 진공건조하여 히알루론산 펜타크릴레이트(Hyaluronic acid Pentacrylate; HAPA)를 제조하였다(도 6 참조).10 g (26 mmol) of hyaluronic acid was dissolved in 100 ml of purified water and cooled to 0-5 °C. Here, 156 mmol of 4-pentenoic anhydride and 100 ml of 3M NaOH were added, followed by stirring for 2 days. The reaction product was purified by precipitation in ethanol, and vacuum dried to prepare hyaluronic acid pentaacrylate (HAPA) (see FIG. 6 ).
상기 제조된 HAMA와 HAPA의 혼합비율을 10:0, 9:1, 8:2, 7:3, 6:4 및 5:5로 달리하여 단순 혼합함으로써 HAMA 및 HAPA 간의 혼합물을 각각 제조하였다.Mixtures between HAMA and HAPA were prepared by simply mixing the prepared HAMA and HAPA mixing ratios of 10:0, 9:1, 8:2, 7:3, 6:4 and 5:5, respectively.
<실시예 1> HAMA-co-HAPA의 기계적 강도 및 유연성 분석<Example 1> Analysis of mechanical strength and flexibility of HAMA-co-HAPA
상기 <합성예 1>에서 첨가되는 메타크릴 무수물(methacrylic anhydride) 및 4-펜테노익 무수물(4-pentenoic anhydride)의 비율을 달리하여 HAMA와 HAPA의 비율이 10:0, 9:1 및 7:3로 합성된 공중합체 HAMA-co-HAPA의 인장강도 (Tensile strength), 인장 탄성계수(Tensile modulus), 인성(Toughness) 및 연신율(Elongation)을 인장실험을 통해 측정하였다.By varying the ratio of methacrylic anhydride and 4-pentenoic anhydride added in <Synthesis Example 1>, the ratio of HAMA and HAPA is 10:0, 9:1 and 7:3 Tensile strength, tensile modulus, toughness, and elongation of the copolymer HAMA-co-HAPA synthesized with HAMA-co-HAPA were measured through a tensile test.
인장실험은 AND사의 만능재료시험기 (Universal testing machine)를 사용하여 ASTM 방법에 따라 도그본(Dogbone) 형태로 성형된 시험편을 1 mm/min의 속도로 측정하였다.Tensile test was measured using AND's universal testing machine (Universal testing machine), a test piece molded in a dogbone (Dogbone) shape according to the ASTM method at a speed of 1 mm / min.
인장 강도는 응력-변형도 선도(Strain-stress curve)에서 최대 응력을 측정하였고, 인장 탄성계수는 응력과 변형률간의 기울기를 측정하였다. 인성은 시편이 파단되는 지점(Fracture)까지의 전체 면적을 적분하여 분석을 수행하였고, 연신율은 파단점에서의 변형율을 측정하여 분석을 수행하였다.For tensile strength, the maximum stress was measured in a strain-stress curve, and for tensile modulus, the slope between stress and strain was measured. Toughness was analyzed by integrating the total area up to the fracture point of the specimen, and elongation was analyzed by measuring the strain rate at the fracture point.
그 결과, 도 1과 같이 HAMA와 HAPA의 단순 혼합에 의해 형성된 혼합물은 가교 길이가 긴 HAPA의 비율이 높아짐에 따라 형성된 하이드로젤의 인장 강도가 낮아짐을 확인하였다.As a result, as shown in FIG. 1 , in the mixture formed by simple mixing of HAMA and HAPA, it was confirmed that the tensile strength of the formed hydrogel decreased as the ratio of HAPA with a long cross-linking length increased.
그러나 상기 <합성예 1>에 따른 HAMA-co-HAPA 공중합체를 제조한 경우, 인장실험에서 오히려 가교 길이가 긴 HAPA의 비율이 높아짐에 따라 형성된 하이드로젤의 인장 강도와 인장 탄성계수가 높아지는 결과를 보였다(도 2a 및 도 2b 참조). However, in the case of preparing the HAMA-co-HAPA copolymer according to <Synthesis Example 1>, the tensile strength and tensile modulus of the hydrogel formed as the ratio of HAPA with a rather long crosslinking length increased in the tensile test. was seen (see FIGS. 2A and 2B).
또한, 변형에 대한 저항성을 나타내는 인성 실험에서 HAMA-co-HAPA 공중합체가 HAMA 화합물 보다 2배 이상 높은 결과를 보였으며(도 2c), 연신율도 기존의 광가교형 단일고분자 (HAMA, MA:PA=10:0) 보다 월등히 향상된 결과를 보였다(도 2d).In addition, in the toughness test showing resistance to deformation, the HAMA-co-HAPA copolymer showed a result that was more than two times higher than that of the HAMA compound (Fig. 2c), and the elongation was also higher than that of the conventional light-crosslinked single polymer (HAMA, MA:PA). =10:0) showed a significantly improved result (FIG. 2d).
따라서, HAMA와 HAPA를 단순 혼합하는 것이 아닌 공중합체를 합성함에 따라, 기계적 강도의 향상뿐만 아니라 유연성도 향상됨을 확인하였다.Therefore, it was confirmed that by synthesizing a copolymer rather than simply mixing HAMA and HAPA, not only mechanical strength but also flexibility was improved.
<실시예 2> HAMA-co-HAPA의 접착 성능 분석<Example 2> Analysis of adhesion performance of HAMA-co-HAPA
상기 <합성예 1>에서 제조된 HAMA-co-HAPA 공중합체의 접착성능을 평가하기 위해, 첨가되는 메타크릴 무수물(methacrylic anhydride) 및 4-펜테노익 무수물(4-pentenoic anhydride)의 혼합비율을 10:0 및 9:1로 달리하여 합성된 공중합체 HAMA-co-HAPA의 Lap shear test를 진행하였다. In order to evaluate the adhesive performance of the HAMA-co-HAPA copolymer prepared in <Synthesis Example 1>, a mixing ratio of methacrylic anhydride and 4-pentenoic anhydride to be added was 10. Lap shear test of the synthesized copolymer HAMA-co-HAPA was performed by varying the ratios of :0 and 9:1.
젤라틴으로 만들어진 인공피부의 사이에 HAMA-co-HAPA 용액을 도포한 후, UV를 5초 동안 조사하고, 양 끝단을 당겨서 접착력을 평가하였다. After applying the HAMA-co-HAPA solution between the artificial skin made of gelatin, UV was irradiated for 5 seconds, and the adhesive strength was evaluated by pulling both ends.
그 결과, 도 3과 같이, HAMA-co-HAPA 공중합체가 HAMA 단일고분자보다 높은 접착력을 보였고, 이는 기계적 물성의 향상에 의한 것으로 판단된다.As a result, as shown in FIG. 3 , the HAMA-co-HAPA copolymer showed higher adhesion than the HAMA single polymer, which is judged to be due to the improvement of mechanical properties.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the content of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (7)
[화학식 1]
상기 화학식 1에서,
m 또는 n은 각각 1 내지 10,000의 정수이고,
상기 m과 n은 9~7:1~3의 비율을 갖고,
X1~X4는 각각 동일하거나 다를 수 있으며, OH 또는 화학식 1-1의 치환기이며,
X5~X8은 각각 동일하거나 다를 수 있으며, OH 또는 화학식 1-2의 치환기이며,
X1~X4 중 적어도 하나 이상은 화학식 1-1의 치환기이고,
X5~X8 중 적어도 하나 이상은 화학식 1-2의 치환기이고,
[화학식 1-1]
상기 화학식 1-1에서, p1는 0 내지 1의 정수이고, q1는0 또는 1이고,
[화학식 1-2]
상기 화학식 1-2에서, p2는 2 내지 10의 정수이고, q2는 0 또는 1임.A compound represented by the following formula (1):
[Formula 1]
In Formula 1,
m or n are each an integer from 1 to 10,000,
The m and n have a ratio of 9-7:1-3,
X 1 to X 4 may each be the same or different, and is OH or a substituent of Formula 1-1,
X 5 ~ X 8 Each may be the same or different, OH or a substituent of Formula 1-2,
At least one of X 1 to X 4 is a substituent of Formula 1-1,
At least one of X 5 to X 8 is a substituent of Formula 1-2,
[Formula 1-1]
In Formula 1-1, p 1 is an integer of 0 to 1, q 1 is 0 or 1,
[Formula 1-2]
In Formula 1-2, p 2 is an integer of 2 to 10, and q 2 is 0 or 1.
상기 화학식 1로 표시되는 화합물은,
하기 화학식 2로 표시되는 화합물인 것을 특징으로 하는 화합물:
[화학식 2]
상기 화학식 2에서,
m 또는 n은 1 내지 10,000의 정수임.The method of claim 1,
The compound represented by Formula 1 is,
A compound characterized in that it is a compound represented by the following formula 2:
[Formula 2]
In Formula 2,
m or n is an integer from 1 to 10,000.
[화학식 3]
상기 화학식 3에서,
m 또는 n은 1 내지 10,000의 정수이고,
상기 m과 n은 9~7:1~3의 비율을 가짐.A compound represented by the following formula (3):
[Formula 3]
In Formula 3,
m or n is an integer from 1 to 10,000,
The m and n have a ratio of 9-7:1-3.
상기 화합물은 광에 의해 가교 반응이 일어나 하이드로젤(hydrogel)을 형성하는 것을 특징으로 하는 생분해성 조직 접착제.7. The method of claim 6,
The compound is a biodegradable tissue adhesive, characterized in that the crosslinking reaction occurs by light to form a hydrogel (hydrogel).
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| US17/772,530 US20220387664A1 (en) | 2019-10-31 | 2020-10-31 | Manufacture of photo-crosslinkable biodegradable tissue adhesive using copolymer |
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