JP5746041B2 - フィブリノーゲンと硫酸化多糖類に基づく製剤 - Google Patents
フィブリノーゲンと硫酸化多糖類に基づく製剤 Download PDFInfo
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- JP5746041B2 JP5746041B2 JP2011540116A JP2011540116A JP5746041B2 JP 5746041 B2 JP5746041 B2 JP 5746041B2 JP 2011540116 A JP2011540116 A JP 2011540116A JP 2011540116 A JP2011540116 A JP 2011540116A JP 5746041 B2 JP5746041 B2 JP 5746041B2
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- Prior art keywords
- fibrinogen
- thrombin
- sulfated
- fibrin
- solution
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- VZORGPCQYCYZLZ-UHFFFAOYSA-E nonasodium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O VZORGPCQYCYZLZ-UHFFFAOYSA-E 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000000276 potassium ferrocyanide Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000003805 procoagulant Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- KZVLNAGYSAKYMG-UHFFFAOYSA-N pyridine-2-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=N1 KZVLNAGYSAKYMG-UHFFFAOYSA-N 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N pyridinedicarboxylic acid Natural products OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000002278 reconstructive surgery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000027140 splenic disease Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 108010034963 tachocomb Proteins 0.000 description 1
- 229940030990 tachosil Drugs 0.000 description 1
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- DJJCXFVJDGTHFX-XVFCMESISA-N uridine 5'-monophosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-XVFCMESISA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000011912 vitamin B7 Nutrition 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
- UBORTCNDUKBEOP-UUOKFMHZSA-N xanthosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UUOKFMHZSA-N 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
-
- 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
- A61L24/106—Fibrin; Fibrinogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- 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
- A61L15/44—Medicaments
-
- 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
- A61L24/043—Mixtures of macromolecular materials
-
- 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
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/08—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Surgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(a)本発明の製剤を溶液として提供する工程、
(b)陽イオン含有溶液を、トロンビンを場合によっては含む別個の成分として、又はトロンビンを場合によっては含む本発明の硫酸化多糖類成分と一緒の溶液として、提供する工程、
(c)場合によってはトロンビン溶液を提供する工程、及び
(d)フィブリン凝塊様構造物が得られるように(a)と(b)と場合によっては(c)とを同時に又は続いて任意の順で混合する工程
を含む方法(process)によって得ることができるフィブリン凝塊様構造物を提供する。
(1)キャリア、及び
(2)硫酸化多糖類である少なくとも1種類の止血剤
を含み、
該キャリアが硫酸化多糖類である場合、該キャリアは該止血剤と同じ硫酸化多糖類ではない、
止血パッチを提供する。
(a)第1の注射器外筒中の請求項1に記載の1成分組成物、及び
(b)第2の注射器外筒中の、場合によってはトロンビンと一緒の、陽イオン含有製剤
又は
(a’)第1の注射器外筒中の、場合によってはトロンビンと一緒の、請求項1に記載の別々の硫酸化多糖類と陽イオン含有製剤、及び
(b’)第2の注射器外筒中のフィブリノーゲン製剤
を含む、2成分注射器(two−component syringe)システムを提供する。
例えば、本発明は以下の項目を提供する。
(項目1)
フィブリノーゲンと硫酸化多糖類を、1成分組成物として、又はフィブリノーゲンと硫酸化多糖類を別々の成分として含む部品からなるキットとして、含む、製剤。
(項目2)
(a)項目1に記載の製剤を溶液として提供する工程、
(b)陽イオン含有溶液を、トロンビンを場合によっては含む別個の成分として、又は陽イオン含有溶液を、トロンビンを場合によっては含む項目1に記載の硫酸化多糖類成分と一緒の溶液として、提供する工程、
(c)場合によってはトロンビン溶液を提供する工程、及び
(d)フィブリン凝塊様構造物が得られるように(a)と(b)と場合によっては(c)とを同時に又は続いて任意の順で混合する工程
を含む方法によって得ることができる、フィブリン凝塊様構造物。
(項目3)
(1)キャリア、及び
(2)硫酸化多糖類である少なくとも1種類の止血剤
を含み、
該キャリアが硫酸化多糖類である場合、該キャリアは該止血剤と同じ硫酸化多糖類ではない、
止血パッチ。
(項目4)
前記キャリアが、コラーゲン、ゼラチン、フィブリノーゲン、フィブリン及び多糖類又はその誘導体若しくは混合物からなる群から選択される生体適合性材料である、項目3に記載の止血パッチ。
(項目5)
2成分注射器システムであって、
(a)該第1の注射器外筒中の項目1に記載の1成分組成物、及び
(b)該第2の注射器外筒中の、場合によってはトロンビンと一緒の、陽イオン含有製剤
又は
(a’)該第1の注射器外筒中の、場合によってはトロンビンと一緒の、項目1に記載の別々の硫酸化多糖類と陽イオンを含有する製剤、及び
(b’)該第2の注射器外筒中のフィブリノーゲン製剤
を含む、2成分注射器システム。
(項目6)
止血を促進するための、項目1に記載の製剤、項目2に記載のフィブリン凝塊様構造物、又は項目3に記載のパッチの使用。
(項目7)
創傷治癒のための、項目1に記載の製剤の製剤、項目2に記載のフィブリン凝塊様構造物、又は項目3に記載のパッチの使用。
(項目8)
項目1に記載の製剤、項目2に記載のフィブリン凝塊様構造物、又は項目3に記載のパッチの薬物送達システムとしての使用。
(項目9)
項目1に記載の製剤、項目2に記載のフィブリン凝塊様構造物、又は項目3に記載のパッチを創面に適用することを含む、組織密封又は組織接着の方法。
(a)本発明の製剤を溶液として提供する工程、
(b)陽イオン含有溶液を、トロンビンを場合によっては含む別個の成分として、又はトロンビンを場合によっては含む本発明の硫酸化多糖類成分と一緒の溶液として、提供する工程、
(c)場合によってはトロンビン溶液を提供する工程、及び
(d)フィブリン凝塊様構造物が得られるように(a)と(b)と場合によっては(c)とを同時に又は続いて任意の順で混合する工程
を含む方法によって得ることができるフィブリン凝塊様構造物を提供する。
(1)キャリア、及び
(2)硫酸化多糖類である少なくとも1種類の止血剤
を含み、
該キャリアが硫酸化多糖類である場合、該キャリアは該止血剤と同じ硫酸化多糖類ではない、
止血パッチを提供する。
(a)第1の注射器外筒中の請求項1に記載の1成分組成物、及び
(b)第2の注射器外筒中の、場合によってはトロンビンと一緒の、陽イオン含有製剤
又は
(a’)第1の注射器外筒中の、場合によってはトロンビンと一緒の、請求項1に記載の別々の硫酸化多糖類と陽イオン含有製剤、及び
(b’)第2の注射器外筒中のフィブリノーゲン製剤
を含む、2成分注射器システムを提供する。
− 本発明による止血パッチを創面に適用することを含む組織密封又は組織接着方法、
− 本発明の止血パッチを血液漏出域に適用することを含む、止血を得る方法、
− キャリアを硫酸化多糖類で被覆すること、及び/又は硫酸化多糖類をキャリア内に分布させることを含む、本発明の止血パッチを製造する方法、
− 止血パッチ、例えば、本発明のパッチにおいて止血機能をもたらす硫酸化多糖類の使用
も提供する。
驚くべきことに、本発明者らは、高フィブリノーゲン濃度において、フコイダン及びCa2+イオンの存在下で、巨視的にゲル様の凝集体が急速に形成されるのを観察した。すべてのこれら3種類の化合物は、これらの自己集合性凝集体を得るのに必要である。フィブリノーゲン濃度50mg/mlで得られた材料の粘ちゅう性は、フコイダン及びCa2+イオン濃度の増加とともに明るい乳光から凝塊様外観に変化する(図1)。実験では、指定濃度のフコイダンを含むTisseel VH S/D密封タンパク質溶液0.5mlをまず24ウェル細胞培養プレートのウェルに入れる。CaCl2溶液0.5mlを添加して、図1に示す最終濃度にし、フィブリノーゲン溶液と迅速に混合する。得られた混合物の濁度及び粘ちゅう性を評価する。一定フィブリノーゲン濃度50mg/mlにおいて、混合物の濁度は、フコイダン又はペントサンポリスルファート濃度の増加とともに増加する。しかしこの増加は、Ca2+イオンに大きく依存する。それは1mMCa2+濃度では低いが、20mMCa2+濃度では顕著である。フコイダン/ペントサンポリホスファート及びCa2+の高濃度で得られた混合物は、ゲル様であり、細胞培養プレート壁に付着するが、低濃度で得られた混合物は、粘性流体の粘ちゅう性を有する。どちらも、ゲル様材料を得るために、より高濃度のフコイダン/ペントサンポリスルファート及びCa2+イオンが必要である。フコイダン/ペントサンポリスルファート及びCa2+イオンのより高濃度で得られる混合物の均一性の欠如は、自己集合による速すぎる硬化、及び気泡含有のために混合が不十分であることによって説明することができる。
実施例1においてフコイダン/ペントサンポリスルファート及びCa2+イオンの最高濃度で得られるゲル様材料の構造物(図1A、B及びCの右上)を走査型電子顕微鏡(SEM)によって分析する。37℃で1.5時間の凝塊形成時間後、凝塊は、0.1カコジラート緩衝剤pH7.3中の2.5%グルタルアルデヒドからなる固定溶液に移される。凝塊と固定溶液の重量比は1:10である。4℃で12時間後、凝塊を前と同じ重量比で0.1Mカコジラート緩衝剤pH7.3を用いて3回洗浄する。後固定を1%フェロシアン化カリウムを含む0.5%四酸化オスミウム中で2時間実施する。凝塊を蒸留水で洗浄し、2.2ジメトキシプロパンを用いて脱水する。試料をアセトンに移し、液体窒素中で破壊する。試料をヘキサメチルジシラザンを用いて化学的に脱水し、スタブに配置し、パラジウム−金アロイで被覆する。
フィブリノーゲンと一緒にゲル様材料を形成する、Ca2+イオンと組み合わせたフコイダンの観察された諸性質のために、コラーゲンに基づく止血パッドが調製される。その背後にある考えは、コラーゲンパッドに含まれるこれらの添加剤が、血中フィブリノーゲンと相互作用して、コラーゲンパッドの止血性を増強できることである。厚さ2mmのコラーゲンスポンジ(Matristypt(登録商標)、Dr.Suwelack、Germany)をA.nodosum LMWフコイダン及びCaCl2を含有する溶液で湿らせ、凍結乾燥させる。浸漬溶液は、凍結乾燥後に0.3mg/cm2 A.nodosum LMWフコイダン及び0.9mg/cm2 CaCl2の濃度がパッド中で得られるような濃度の成分を含む。パッドをウサギ止血モデルに適用して、その止血性を評価する。ウサギを1000IU/kg体重でヘパリン処置する。研磨回転ツールを用いて、肝被膜の擦過によって環状出血させる(直径1.8cm)。この傷を上記パッドで処置する。乾燥パッドを出血した傷にあてる。食塩水に浸漬したガーゼを用いてパッドを傷に2分間押しつける。対照として、Matristypt(登録商標)を同じ動物の別の肝葉に同様に適用する。実験を第2の動物を用いて2回実施する。結果は、両方の動物で同じであり、図3に一方の動物の結果を例示する。図3から認められるように、フコイダン及びCaCl2を含むコラーゲンパッドに浸漬された血液は、対照よりも濃く見える。これは、成分の作用に起因したパッド中でのより速い凝固によって説明することができる。
濁度の動力学に対するフコイダンの影響は、トロンビンによって触媒されたフィブリン凝塊形成中に増加する。得られた凝塊の最終濁度を、希釈フィブリンシーラントTisseel VH S/D(Baxter)をフィブリノーゲン基質として使用してさらに確認する。Tisseel VH S/D密封タンパク質溶液を(フィブリノーゲン濃度5mg/mlに対応して)1/20希釈し、フコイダン濃度を20μM(ペントサンポリスルファート、Ascophyllum nodosum LMW)、2μM(Fucus vesiculosus)、及び0.2μM(Ascophyllum nodosum HMW、Laminaria japonica)に調節する。(フィブリノーゲン、フィブロネクチン及び第XIII因子を含む)これらの希釈Tisseel VH S/D溶液100μlを96ウェルマイクロプレートのウェル中で、40mM CaCl2を含む0.25IU/mlトロンビン溶液(Baxter)100μlと混合する。37℃での血塊形成中の濁度増加の測定を混合後1.5時間にわたり630nmで記録する。結果を図4に示す。一部のフコイダン、さらにはペントサンポリスルファートも、トロンビンによって触媒された血塊形成反応を加速し、濁度の増加したフィブリン凝塊の形成に影響を及ぼし得ることが認められる。
フィブリン凝塊の濁度増加は、「粗い」凝塊、すなわち、線維直径の増加したフィブリン凝塊に関連する(Oenick MD Studies on fibrin polymerization and fibrin structure−a retrospective.Biophys Chem.2004 Dec 20;112(2−3):187−92)。
トロンビンによって媒介されるフィブリン形成、及びこの方法に対する硫酸化多糖類の効果を試験するアッセイを開発した。手短に述べると、血塊形成は、フィブリノーゲンを含有する溶液中でトロンビンの添加によって開始され、分光光度的に追跡される。405nmにおける吸光度は、フィブリン凝塊の量及び/又は質に依存する凝塊不透明性を示す。
トロンビンによって媒介されるフィブリン凝塊形成に対する異なる濃度の6種類の硫酸化多糖類の各々の影響を実施例6に記載の方法によって調べる。硫酸化多糖類の詳細を下表2に示す。
硫酸化多糖類は、トロンビンに依存したフィブリン生成を改善するために、フィブリンシーラントに含有させることができる。硫酸化多糖類の含有によって改変することができる適切なフィブリンシーラントは、Baxter Healthcare Corporation(CA、USA)製Tisseel(登録商標)フィブリンシーラントである。これは、本発明の最も好ましい実施形態である。
硫酸化多糖類は、トロンビンに依存したフィブリン生成を改善するために、止血パッチに含有させることができる。
Claims (7)
- フィブリノーゲン、硫酸化多糖類および陽イオンを含む、止血を促進するためのフィブリン凝塊様構造物であって、該構造物がトロンビンを含まず、該構造物は、フィブリノーゲンと、陽イオン含有溶液とを、硫酸化多糖類の存在下で混合する工程、を含む方法によって得ることができ、該混合物はトロンビンを含まない、フィブリン凝塊様構造物。
- 接着小胞の3次元構造物として得られる、請求項1に記載のフィブリン凝塊様構造物。
- 薬物送達のためのシステムであって、請求項1に記載のフィブリン凝塊様構造物を含むシステム。
- 組織密封又は組織接着のためのシステムであって、請求項1に記載のフィブリン凝塊様構造物を含み、該フィブリン凝塊様構造物は、創面に適用される、システム。
- 前記硫酸化多糖類は、グリコサミノグリカン(GAG)、ヘパリン様分子、スルファトイド、ポリ硫酸化オリゴ糖、コンドロイチン硫酸、デルマタン硫酸、フコイダン、ペントサンポリスルファート(PPS)、フコピラノンスルファート、スルファトイド、ヘパリノイド、過ヨウ素酸塩−酸化型ヘパリン(POH)、硫酸化されたラミナリン(SL)、硫酸化されたアルギン酸(SAA)、硫酸化されたペクチン(SP)、デキストラン硫酸(DXS)、並びにヘパリン由来のオリゴ糖(HDO)からなる群から選択される、請求項1に記載のフィブリン凝塊様構造物。
- 前記ヘパリン様分子が、N−アセチルヘパリン及びN−脱硫酸化ヘパリンから選択される、請求項5に記載のフィブリン凝塊様構造物。
- 前記スルファイドがGM1474及びSR80258Aから選択される、請求項5に記載のフィブリン凝塊様構造物。
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US10022410B2 (en) | 2010-12-22 | 2018-07-17 | Ethicon, Inc. | Hemostatic preparation containing an extract of golden moss |
US9446166B2 (en) * | 2013-01-24 | 2016-09-20 | Ethicon, Inc. | Fibrin sealant compositions with chemical crosslinking |
IL230151A0 (en) | 2013-12-24 | 2014-09-30 | Omrix Biopharmaceuticals Ltd | One-component fibrin glue containing a polymerization inhibitor |
IL231792A0 (en) | 2014-03-27 | 2014-08-31 | Omrix Biopharmaceuticals Ltd | Device and method for the preparation and administration of one-component fibrin glue |
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