JPH02167234A - Adhesive for bio-tissue - Google Patents
Adhesive for bio-tissueInfo
- Publication number
- JPH02167234A JPH02167234A JP63173977A JP17397788A JPH02167234A JP H02167234 A JPH02167234 A JP H02167234A JP 63173977 A JP63173977 A JP 63173977A JP 17397788 A JP17397788 A JP 17397788A JP H02167234 A JPH02167234 A JP H02167234A
- Authority
- JP
- Japan
- Prior art keywords
- blood
- coagulation factor
- factor
- blood coagulation
- coagulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000853 adhesive Substances 0.000 title abstract description 4
- 230000001070 adhesive effect Effects 0.000 title abstract description 4
- 108010014173 Factor X Proteins 0.000 claims abstract description 13
- 239000003106 tissue adhesive Substances 0.000 claims abstract description 11
- 108010049003 Fibrinogen Proteins 0.000 claims abstract description 8
- 102000008946 Fibrinogen Human genes 0.000 claims abstract description 8
- 229940012952 fibrinogen Drugs 0.000 claims abstract description 8
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims abstract description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910001424 calcium ion Inorganic materials 0.000 claims abstract description 4
- 108010076282 Factor IX Proteins 0.000 claims abstract 7
- 108010023321 Factor VII Proteins 0.000 claims abstract 4
- -1 prothrompin Proteins 0.000 claims description 5
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 4
- 108010071289 Factor XIII Proteins 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 108090000190 Thrombin Proteins 0.000 abstract description 12
- 229960004072 thrombin Drugs 0.000 abstract description 12
- 230000015271 coagulation Effects 0.000 abstract description 10
- 238000005345 coagulation Methods 0.000 abstract description 10
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 abstract description 7
- 108010039627 Aprotinin Proteins 0.000 abstract description 6
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 abstract description 6
- 229960004405 aprotinin Drugs 0.000 abstract description 6
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 abstract description 6
- 102000009123 Fibrin Human genes 0.000 abstract description 5
- 108010073385 Fibrin Proteins 0.000 abstract description 5
- 239000001110 calcium chloride Substances 0.000 abstract description 5
- 229910001628 calcium chloride Inorganic materials 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 229950003499 fibrin Drugs 0.000 abstract description 5
- 238000002156 mixing Methods 0.000 abstract description 3
- 108010054265 Factor VIIa Proteins 0.000 abstract description 2
- 108010094028 Prothrombin Proteins 0.000 abstract 3
- 102100027378 Prothrombin Human genes 0.000 abstract 3
- 229940039716 prothrombin Drugs 0.000 abstract 3
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical class CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 abstract 1
- 102100022641 Coagulation factor IX Human genes 0.000 abstract 1
- 108010054218 Factor VIII Proteins 0.000 abstract 1
- 102000001690 Factor VIII Human genes 0.000 abstract 1
- 239000004019 antithrombin Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 229960004222 factor ix Drugs 0.000 abstract 1
- 229940012414 factor viia Drugs 0.000 abstract 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 10
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 10
- 239000003114 blood coagulation factor Substances 0.000 description 10
- 229940019700 blood coagulation factors Drugs 0.000 description 8
- 206010052428 Wound Diseases 0.000 description 7
- 208000027418 Wounds and injury Diseases 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 230000023555 blood coagulation Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229940075469 tissue adhesives Drugs 0.000 description 3
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 229940073490 sodium glutamate Drugs 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- KWTQSFXGGICVPE-UHFFFAOYSA-N 2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical compound Cl.OC(=O)C(N)CCCN=C(N)N KWTQSFXGGICVPE-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102100029117 Coagulation factor X Human genes 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 108010018823 anti-inhibitor coagulant complex Proteins 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960003589 arginine hydrochloride Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940105756 coagulation factor x Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 229940105776 factor viii inhibitor bypassing activity Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- DNTNDFLIKUKKOC-UHFFFAOYSA-N gabexate methanesulfonate Chemical compound CS([O-])(=O)=O.CCOC(=O)C1=CC=C(OC(=O)CCCCCN=C(N)[NH3+])C=C1 DNTNDFLIKUKKOC-UHFFFAOYSA-N 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 229940106780 human fibrinogen Drugs 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000003356 suture material Substances 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229950008558 ulinastatin Drugs 0.000 description 1
- ODVKSTFPQDVPJZ-UHFFFAOYSA-N urinastatin Chemical compound C1C=CCCC11COC(C=2OC=CC=2)OC1 ODVKSTFPQDVPJZ-UHFFFAOYSA-N 0.000 description 1
- 108010088854 urinastatin Proteins 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は生体組織及び生体創傷部位の接着、創傷被覆、
固定、止血、創傷治癒促進等に用いられる生体組織接着
剤に関するちのである。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to adhesion of biological tissue and biological wound sites, wound covering,
This article relates to biological tissue adhesives used for fixation, hemostasis, promotion of wound healing, etc.
（従来技術）
従来、損傷した生体組織の修復にあたっては、組織の接
着・固定の手段として古くから縫合が行われている。縫
合材料の改良や縫合技術の研究に幾多の努力が払われて
きたが、外科的縫合の場合はその縫合という基本操作に
よる組織損傷は避けられず、また縫合操作に時間がかか
るばかりでなく、縫合の困難な部位や縫合のみでは修復
し得ない部位も多い。(Prior Art) In repairing damaged biological tissues, suturing has been used for a long time as a means of adhering and fixing tissues. Many efforts have been made to improve suture materials and research suturing techniques, but in the case of surgical suturing, tissue damage due to the basic operation of suturing is unavoidable, and the suturing operation not only takes time; There are many areas that are difficult to suture or cannot be repaired with sutures alone.
このような縫合法の問題点を解決するちのとして、血液
凝固反応を応用した生体組織接着剤が近年用いられてい
る。In order to solve these problems with suturing methods, biological tissue adhesives that utilize blood coagulation reactions have been used in recent years.
（発明が解決しようとする問題点）
しかし従来の生体組織接着剤は、血液凝固第Ｘ ＩＩＩ
因子含有フィブリノゲン凍結乾燥粉末、アプロチニン液
、トロンビン凍結乾燥粉末、塩化カルシウム液の４種類
のバイアルから構成されていて、用時にフィブリノゲン
末をアプロチニン液で、またトロンビン宋を塩化カルシ
ウム液でそれぞれ別に調製して、接着部位で各液を重層
あるいは混合して反応させなければならないちのであり
、取扱いが面倒であった。このため使用時に混合して用
いるこのような２液タイプよりも、そのまま使用できる
１液タイプの生体組織接着剤が望まれていた。(Problem to be solved by the invention) However, conventional biological tissue adhesives
It consists of four types of vials: factor-containing fibrinogen lyophilized powder, aprotinin solution, thrombin lyophilized powder, and calcium chloride solution.When using, fibrinogen powder is prepared separately with aprotinin solution, and thrombin song is prepared separately with calcium chloride solution. Therefore, each liquid must be layered or mixed to react at the bonding site, which is cumbersome to handle. For this reason, a one-liquid type biological tissue adhesive that can be used as is has been desired, rather than a two-liquid type that is mixed before use.
（発明の目的）
本発明はこのような不都合に鑑みなされたものであり、
用時調製や混合操作などの必要がなく取扱いの簡便な１
液タイプの生体組織接着剤を提供することを目的とする
。(Object of the invention) The present invention has been made in view of these disadvantages,
Easy to handle as there is no need for preparation or mixing at the time of use.
The purpose of the present invention is to provide a liquid type biological tissue adhesive.
（発明の構成）
本発明のこの目的は、フィブリノゲンと、プロトロンピ
ンと、血液凝固第Ｘ因子と血液凝固第Ｘ因子と、血液凝
固第Ｘ因子と、血液凝固第Ｘ ＩＩＩ因子と、アンチト
ロンピンと、蛋白質分解酵素阻害剤と、カルシウムイオ
ンとを含有することを特徴とする生体組織接着剤より達
成される。(Structure of the Invention) This object of the present invention is to synthesize fibrinogen, prothrompin, blood coagulation factor X, blood coagulation factor X, blood coagulation factor X, blood coagulation factor This is achieved by a biological tissue adhesive characterized by containing a protease inhibitor and calcium ions.
本発明の原理を第１図を基に説明する。The principle of the present invention will be explained based on FIG.
血液凝固系には、血液が異物表面（血管壁のコラーゲン
など）に接触して開始される血液単独の過程である内因
性凝血機序と、組織液が血液に混入して開始される外因
性（組織由来性）凝血機序とがある。いずれちリン脂質
層内でプロトロンピンからトロンビンを形成した後、以
降カスケード状に進行する血液凝固反応により不溶性フ
ィブリンポリマーゲルが作られる。従来の接着剤はこの
凝血機序内のトロンビン以降の反応のみを利用したもの
で、トロンビン、フィブリノゲン、血液凝固第Ｘ ＩＩ
Ｉ因子、Ｃａ”＋を用いたちのである。従って使用前の
凝固反応を防止するためこれらは用時に混合して用いて
いた。The blood coagulation system consists of an intrinsic coagulation mechanism, which is a blood-only process that is initiated when blood comes into contact with a foreign surface (such as collagen in a blood vessel wall), and an extrinsic coagulation mechanism, which is initiated when tissue fluid mixes with the blood. (tissue-derived) coagulation mechanism. After thrombin is formed from prothrompin within the phospholipid layer, an insoluble fibrin polymer gel is created by a blood coagulation reaction that proceeds in a cascade. Conventional adhesives utilize only reactions after thrombin within the coagulation mechanism, and include thrombin, fibrinogen, and blood coagulation factor XII.
Factor I and Ca''+ were used. Therefore, in order to prevent a coagulation reaction before use, these were mixed before use.
これに対し本発明は、トロンビンの代りにプロトロンピ
ン、第■因子、第■因子および第Ｘ因子を用いることに
より、外因系の凝血機序により反応するようにしたもの
である。すなわち創傷部より出る組織トロンボプラスチ
ンおよび第１Ｘａ因子にまり同第■因子および同第Ｘ因
子を活性化しく図中、添字ａは活性型を示す）、活性型
第Ｘａ因子によりプロトロンピンからトロンビンを生じ
させて以降の反応を進めるようにした。このため必要な
試薬、第■因子、第■因子、第Ｘ因子、プロトロンピン
、フィブリノゲン、第Ｘ ＩＩＩ因子及びＣａ”を混合
しておいても、創傷部の組織液に触れない限りフィブリ
ン塩は生じない。従って、全試薬を予め混合しておくこ
とができ、用時にわざわざ各試薬を混合する必要がない
１液タイプの生体組織接着剤として使用できる。In contrast, the present invention uses prothrompin, factor ①, factor ②, and factor X in place of thrombin, so that the reaction is caused by the extrinsic coagulation mechanism. In other words, tissue thromboplastin and factor 1 released from the wound activate factor Ⅰ and factor I decided to do this and proceed with the subsequent reactions. Therefore, even if the necessary reagents, factor ①, factor ②, factor X, prothrompin, fibrinogen, factor Therefore, all the reagents can be mixed in advance, and it can be used as a one-liquid type biological tissue adhesive without the need to take the trouble to mix each reagent before use.
本発明で併せて用いるアンチトロンピンＩＩＩは、活性
型箔ＶＩＩ ａ因子、活性型第１Ｘａ因子、活性型第Ｘ
ａ因子、トロンビンなどの凝固反応の過程で生成される
活性型セリンプロテアーゼ凝固因子を中和ないし不活化
するインヒビターであり、血液凝固反応を制御調節する
因子として最も重要なインヒビターとして知られている
。その作用機作は不明であるが、トロンビン以降の反応
のみを利用してアンチトロンピンＩＩＩの調節制御を必
要としていなかった従来技術のものとは異なり、より生
体反応に近い反応機序を利用した本発明ではアンチトロ
ンピンによる制御が必要と考えられる。Antithrompin III used in conjunction with the present invention includes activated factor VII a, activated factor 1 Xa, activated factor X
It is an inhibitor that neutralizes or inactivates active serine protease coagulation factors such as factor A and thrombin that are produced during the coagulation reaction process, and is known as the most important inhibitor as a factor that controls and regulates the blood coagulation reaction. Although its mechanism of action is unknown, it uses a reaction mechanism that is closer to biological reactions, unlike conventional technology that only uses reactions after thrombin and does not require regulation of antithrompin III. In the present invention, control by antithrompin is considered necessary.
本発明で用いられる蛋白分解酵素阻害剤はブラスミノー
ゲンアクチベーター及びプラスミンの阻害剤であり、凝
固反応により形成された不溶性フィブリンポリマーゲル
が接着後直ちに線溶（ｆｉｂｒｉｎｏｌｙｓｉｓ）され
るのを防止する。すなわち、接着部位への繊維芽細胞（
ｆｉｂｒｏｂｌａｓｔ）の侵潤により結合組織が再生さ
れるまでフィブリン塩が緩やかに線溶されるようにして
、組織再生までに接着部位が外れたりすることがないよ
うにする。The protease inhibitor used in the present invention is an inhibitor of blasminogen activator and plasmin, and prevents fibrinolysis of the insoluble fibrin polymer gel formed by the coagulation reaction immediately after adhesion. That is, fibroblasts (
The fibrin salt is slowly fibrinolyzed until the connective tissue is regenerated by infiltration with a fibroblast, thereby preventing the attachment site from becoming dislodged until the tissue regenerates.
本発明を構成する各成分、フィブリノゲン、プロトロン
ピン、血液凝固第１Ｘ因子、血液凝固第１Ｘ因子、同第
Ｘ因子及び同第Ｘ ＩＨ因子、アンチトロンピン等は、
何れも公知のものを用いることができるが、ヒトの治療
などに用いる場合には、抗原性のないヒト由来のものを
用いるのが好ましい。Each component constituting the present invention, fibrinogen, prothrompin, blood coagulation factor 1X, blood coagulation factor 1X, coagulation factor X, prothrompin, antithrompin, etc.
Any of the known ones can be used, but when used for human treatment, it is preferable to use a non-antigenic one derived from humans.
これらの配合量・配合比は、接着部位の組織の種類や、
接着面積、出血の有無、単なる傷口の縫合か皮膚移植か
の用途等の条件に応じて適宜法められる。特にアンチト
ロンピンは血液凝固反応を制御する因子であるから、そ
の量はトロンビンや他の凝固因子の量に応じて決められ
る。カルシウムイオンＣａ ２ ＊源は特に限定されな
いが、塩化カルシウムは硫酸カルシウムなどの形で添加
されることが好ましく、特に塩化カルシウムが好ましい
。The amount and ratio of these ingredients depends on the type of tissue at the adhesion site,
Laws are determined as appropriate depending on conditions such as the adhesion area, the presence or absence of bleeding, and whether the wound is simply sutured or a skin graft. In particular, since antithrompin is a factor that controls blood coagulation reactions, its amount is determined depending on the amount of thrombin and other coagulation factors. Although the calcium ion Ca 2 * source is not particularly limited, calcium chloride is preferably added in the form of calcium sulfate or the like, and calcium chloride is particularly preferred.
なおプロトロンピン、血液凝固第■■因子、血液凝固第
■因子及び同第Ｘ因子はそれぞれ精製品を用いてちよい
が、これら各因子を含有している乾燥ヒト血液凝固第■
因子複合体（「基礎と臨床」Ｖｏｌ、 １６． Ｎｏ、
８ 昭和５７年６月号 松本研二著ｒＦＥＩＢＡに
関する研究 第３報 −ＦＥＩＢＡ活性成分の単離とそ
の性質について−」参照）をこれらの代わりに用いても
よい。Although purified products of prothrompin, blood coagulation factor ■■, blood coagulation factor ■, and factor X may be used, dried human blood coagulation factor
Factor complex (“Basic and Clinical” Vol. 16. No.
8, June 1981, Kenji Matsumoto, Research on rFEIBA, Report 3 - Isolation of FEIBA active ingredient and its properties -'' may be used in place of these.
蛋白分解酵素阻害剤は、接着後から生体組織再生までの
間だけ線溶系を阻害するものであればよく特に限定され
ないが、アプロチニン、ウリナスタチン、ＦＯＹ （小
野製薬）などのセリンプロテアーゼなどを用いることが
できる。この中ではアプロチニンが好ましい。The protease inhibitor is not particularly limited as long as it inhibits the fibrinolytic system only during the period from adhesion to biological tissue regeneration, but serine proteases such as aprotinin, ulinastatin, and FOY (Ono Pharmaceutical) can be used. can. Among these, aprotinin is preferred.
好ましい各構成成分の配合比の一例を下記に示す。An example of a preferable blending ratio of each component is shown below.
フィブリンゲル ６（１〜１２０ ｍｇ／ｍ
ｌ血液凝固第Ｘ ＩＩＩ因子 ４０〜８０ 単位
／ｍｌ血液凝固第■因子複合体１６〜２８ 単位／ｍ
ｌ（プロトロンピン活性単位で換算）
アンチ、トロンビンＩＩＩ Ｏ１１〜０．３単位／
ｍ１アプロチニン ８００〜１２００ ＫＩＵ
／ｍ１（ＫＩＵ ：カリクレイン国際単位）
塩化カルシウム ０．０３〜０．１１ ｍｇ／ｍ
１本発明の生体組織接着剤には、必要に応じて、各種蛋
白やアミノ酸、有機酸塩、無機塩等を安定剤や等張化剤
とし、て含有させてもよい。例えば上記配合例に対して
は、
ヒト血清アルブミン ３〜２０ ｍｇ／ｍ１Ｌ
−塩酸アルギニン ５〜１６ ｍｇ／ｍ１Ｌ−
イソロイシン １０〜１６ ｍｇ／ｍ１Ｌ−
グルタミン酸ナトリウム３〜８ ｍｇ／ｍｌクエン酸ナ
トリウム ２〜８ ｍｇ／ｍｌ塩化ナトリウ
ム １．０〜２０ ｍｇ／ｍｌを併せて含有
させるのが好ましい。Fibrin gel 6 (1-120 mg/m
l Blood coagulation factor X, factor III 40-80 units/ml blood coagulation factor
l (converted to prothrompin activity units) Anti, thrombin III O11~0.3 units/
m1 aprotinin 800-1200 KIU
/m1 (KIU: kallikrein international unit) Calcium chloride 0.03-0.11 mg/m
1. The biological tissue adhesive of the present invention may contain various proteins, amino acids, organic acid salts, inorganic salts, etc. as stabilizers and tonicity agents, if necessary. For example, for the above formulation example, human serum albumin 3-20 mg/ml
-Arginine hydrochloride 5-16 mg/ml-
Isoleucine 10-16 mg/ml-
It is preferable to contain 3 to 8 mg/ml of sodium glutamate, 2 to 8 mg/ml of sodium citrate, and 1.0 to 20 mg/ml of sodium chloride.
（実施例）
家兎（Ａｌｂｉｎｏ Ｒａｂｂｉｔ：１０週令メス）の
背部な刺毛、消毒した後、局所麻酔下で皮膚片（直径３
ｃｍ、円形）を剥離した。この皮膚片を用いて再度同部
位に以下のように接着した。(Example) After disinfecting the stinging hair on the back of a domestic rabbit (10-week-old female), a piece of skin (diameter 3
cm, circular) was peeled off. This skin piece was used to adhere to the same site again as follows.
下記の各成分、
ヒトフィブリノゲン ８０ｍｇ（ＫＡＢＩ社
製）
ヒト血液凝固第Ｘ Ｉ１１因子 ６００単位（ＢＥ
ＨｒｌＩＮＧ社製）
ヒト血液凝固第■因子複合体 ２０単位（ＩＭＭＵＮ
Ｏ社製）
（プロトロンピン単位で換算）
ヒ１−アンチトロンピンＩＩＩ Ｏ，３単位（Ｂ
ＥＨＲＩＮＧ社製）
ウシアプロチニン １００ＯＫＩＵ（ＢＥＩｆ
ＲＩＮＧ社製）
塩化カルシウム ０．５ｍｇヒト血清アル
ブミン １０ｍｇＬ−塩酸アルギニン
１０ｍｇＬ−インロイシン １０
ｍ ｇＬ−グルタミン酸ナトリウム ５ｍｇクエン
酸ナトリウム ５ｍｇの凍結乾燥粉末（滅
菌済み）を１ｍｌの０８０５ＭＣａＣ１□水溶液に溶解
し、ゆっくり振盪しながら５分間、室温（２５℃）にお
いた。Each of the following components: Human fibrinogen 80 mg (manufactured by KABI) Human blood coagulation factor X I11 600 units (BE
Human blood coagulation factor complex 20 units (IMMUN)
(manufactured by Company O) (converted in prothrompin units) Hi-1-antithrompin III O,3 units (B
(Manufactured by EHRING) Bovine Protinin 100OKIU (BEIf
(manufactured by RING) Calcium chloride 0.5 mg Human serum albumin 10 mg L-arginine hydrochloride
10mgL-inleucine 10
m gL-Sodium glutamate 5 mg Sodium citrate 5 mg of lyophilized powder (sterilized) was dissolved in 1 ml of 0805MCaC1□ aqueous solution and kept at room temperature (25°C) for 5 minutes with slow shaking.
この溶解液を注射器に吸引して、家兎背部の創傷部に０
．５ｍ１滴下し創傷郡全体に拡散させた。その後直ちに
先の剥離皮膚片を元と同じ位置に載せた。約５分後には
皮膚片は創傷部から剥れなくなり接着・固定が確認でき
た。１〜２週間後には繊維芽細胞が侵潤してフィブリン
ゲルも消失しており、組織の再生が確認できた。Aspirate this solution into a syringe and apply it to the wound on the rabbit's back.
．． A drop of 5 ml was applied and spread over the entire wound area. Immediately thereafter, the previously exfoliated skin piece was placed in the same position as before. After about 5 minutes, the skin piece no longer peeled off from the wound area, and adhesion and fixation could be confirmed. After 1 to 2 weeks, fibroblasts had invaded and the fibrin gel had disappeared, confirming tissue regeneration.
（発明の効果）
以上のように本発明は、外因系の凝血機序を利用して接
着部位の組織液により凝固するようにしたので、反応各
試薬を予め混合した１液タイプの生体組織接着剤とする
ことができる。従って用時の度に試薬を調製したり混合
する必要がなく、極めて簡便に使用することができる。(Effects of the Invention) As described above, the present invention utilizes an extrinsic coagulation mechanism to coagulate with the interstitial fluid at the adhesion site. It can be done. Therefore, there is no need to prepare or mix reagents each time they are used, making them extremely easy to use.
第１図は本発明の原理説明図である。 FIG. 1 is a diagram explaining the principle of the present invention.
Claims (2)
第VII因子、血液凝固第IX因子と、血液凝固第Ｘ因子と
、血液凝固第ＸIII因子と、アンチトロンピンと、蛋白
質分解酵素阻害剤と、カルシウムイオンとを含有するこ
とを特徴とする生体組織接着剤。(1) Fibrinogen, prothrompin, blood coagulation factor VII, blood coagulation factor IX, blood coagulation factor X, blood coagulation factor XIII, antithrompin, protease inhibitor, calcium ion A biological tissue adhesive characterized by containing.
第IX因子と血液凝固第Ｘ因子とが血液凝固第IX因子複合
体として含有されていることを特徴とする請求項第１項
記載の生体組織接着剤。(2) The living organism according to claim 1, wherein prothrompin, blood coagulation factor VII, blood coagulation factor IX, and blood coagulation factor X are contained as a blood coagulation factor IX complex. Tissue adhesive.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63173977A JPH02167234A (en) | 1988-07-14 | 1988-07-14 | Adhesive for bio-tissue |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63173977A JPH02167234A (en) | 1988-07-14 | 1988-07-14 | Adhesive for bio-tissue |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02167234A true JPH02167234A (en) | 1990-06-27 |
Family
ID=15970522
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63173977A Pending JPH02167234A (en) | 1988-07-14 | 1988-07-14 | Adhesive for bio-tissue |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02167234A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997029792A1 (en) * | 1996-02-20 | 1997-08-21 | Cohesion Corporation | Tissue sealant compositions and methods of use thereof |
| WO2003039590A1 (en) * | 2001-11-09 | 2003-05-15 | Novo Nordisk Health Care Ag | Pharmaceutical composition comprising factor vii polypeptides and aprotinin polypeptides |
| WO2005034990A1 (en) * | 2003-10-09 | 2005-04-21 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Hemostatic composition containing antithrombin iii |
| JP2005239613A (en) * | 2004-02-25 | 2005-09-08 | Asahi Kasei Medical Co Ltd | Fibrinogen composition liquid and method for producing the same |
| USRE39192E1 (en) | 1990-11-27 | 2006-07-18 | American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| USRE39298E1 (en) | 1990-11-27 | 2006-09-19 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| USRE39321E1 (en) | 1990-11-27 | 2006-10-03 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US7196054B1 (en) | 1990-11-27 | 2007-03-27 | The American National Red Cross | Methods for treating wound tissue and forming a supplemented fibrin matrix |
| FR2894831A1 (en) * | 2005-12-16 | 2007-06-22 | Lab Francais Du Fractionnement | Thrombin-free biological adhesive, useful as bandage or gel for hemostasia and/or cicatrization of injured biological tissue like cartilage, collagen and bones, comprises fibrinogen, factor VII and a calcium ion source |
-
1988
- 1988-07-14 JP JP63173977A patent/JPH02167234A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE39192E1 (en) | 1990-11-27 | 2006-07-18 | American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| USRE39298E1 (en) | 1990-11-27 | 2006-09-19 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| USRE39321E1 (en) | 1990-11-27 | 2006-10-03 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US7196054B1 (en) | 1990-11-27 | 2007-03-27 | The American National Red Cross | Methods for treating wound tissue and forming a supplemented fibrin matrix |
| US7208179B1 (en) | 1990-11-27 | 2007-04-24 | The American National Red Cross | Methods for treating disease and forming a supplemented fibrin matrix |
| WO1997029792A1 (en) * | 1996-02-20 | 1997-08-21 | Cohesion Corporation | Tissue sealant compositions and methods of use thereof |
| WO2003039590A1 (en) * | 2001-11-09 | 2003-05-15 | Novo Nordisk Health Care Ag | Pharmaceutical composition comprising factor vii polypeptides and aprotinin polypeptides |
| JPWO2005034990A1 (en) * | 2003-10-09 | 2007-11-22 | 財団法人化学及血清療法研究所 | Anti-thrombin III-containing hemostatic composition |
| WO2005034990A1 (en) * | 2003-10-09 | 2005-04-21 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Hemostatic composition containing antithrombin iii |
| JP4613133B2 (en) * | 2003-10-09 | 2011-01-12 | 一般財団法人化学及血清療法研究所 | Anti-thrombin III-containing hemostatic composition |
| JP2005239613A (en) * | 2004-02-25 | 2005-09-08 | Asahi Kasei Medical Co Ltd | Fibrinogen composition liquid and method for producing the same |
| WO2007080276A1 (en) * | 2005-12-16 | 2007-07-19 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies Societe Anonyme | Thrombin-free biological adhesive and use thereof as a medicament |
| FR2894831A1 (en) * | 2005-12-16 | 2007-06-22 | Lab Francais Du Fractionnement | Thrombin-free biological adhesive, useful as bandage or gel for hemostasia and/or cicatrization of injured biological tissue like cartilage, collagen and bones, comprises fibrinogen, factor VII and a calcium ion source |
| US8383104B2 (en) | 2005-12-16 | 2013-02-26 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies S.A. | Thrombin-free biological adhesive and use thereof as a medicament |
| JP2013075906A (en) * | 2005-12-16 | 2013-04-25 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies Sa | Thrombin-free biological adhesive, and use thereof as medicament |
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