One component fibrin glue comprising zymogens
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/48
A61K-038/36
A61K-031/194
A61K-031/198
A61K-038/17
A61K-033/14
A61L-024/00
A61L-024/10
출원번호
US-0560089
(2014-12-04)
등록번호
US-9814765
(2017-11-14)
우선권정보
IL-230150 (2013-12-24)
발명자
/ 주소
Pilpel, Yair
Deanglis, Ashley
Zherdev, Yuri
Doron, Sivan
Gorman, Anne
Nur, Israel
출원인 / 주소
Ethicon, Inc.
대리인 / 주소
Crichton, David R.
인용정보
피인용 횟수 :
0인용 특허 :
11
초록
Provided herein is a single component sealant formulation (e.g. in a liquid form), methods for its preparation, and use. The formulation includes fibrinogen; vitamin K-dependent clotting zymogens comprising at least Factor II (FII) and Factor X (FX).
대표청구항▼
1. A storage stable liquid sealant formulation comprising about 1-100 mg/ml fibrinogen; vitamin K-dependent clotting zymogens comprising at least Factor II and Factor X and having a ratio of about 0.01-1.0 IU/mg relative to fibrinogen; and at least one reversible inhibitor of at least one of the vit
1. A storage stable liquid sealant formulation comprising about 1-100 mg/ml fibrinogen; vitamin K-dependent clotting zymogens comprising at least Factor II and Factor X and having a ratio of about 0.01-1.0 IU/mg relative to fibrinogen; and at least one reversible inhibitor of at least one of the vitamin K-dependent clotting zymogens, wherein the sealant formulation is free of an added irreversible thrombin inhibitor; wherein the added reversible inhibitor is selected from the group consisting of 0.125 IU/ml heparin, a about 1-50 mM calcium chelator, about 0.1-5% serine protease active site inhibitor and a combination thereof. 2. The formulation of claim 1, wherein the formulation comprises a pharmaceutically acceptable carrier. 3. The formulation of claim 2, wherein the liquid formulation remains stable at least 7 days at an ambient temperature of about 2° C. and up to room temperature. 4. The formulation of claim 3, wherein the liquid formulation is stable for about 30 days at room temperature. 5. The formulation of claim 1, wherein the formulation further comprises Factor V. 6. The formulation of claim 1, wherein the vitamin K-dependent clotting zymogens further comprise Factor VII. 7. The formulation of claim 6, wherein the vitamin K-dependent clotting zymogens further comprise Factor IX. 8. The formulation of claim 7, wherein Factor X, Factor VII, and/or Factor IX are, at least partially, in their active form. 9. The formulation of claim 1, wherein the formulation is in liquid form and is stable for at least 14 days at an ambient temperature of about 2° C. to 8° C. 10. The formulation of claim 1, being free of added thrombin. 11. The formulation of claim 1, wherein the irreversible thrombin inhibitor is hirudin. 12. The formulation of claim 1, wherein the irreversible thrombin inhibitor is anti-thrombin III. 13. The formulation of claim 1, wherein the vitamin K-dependent clotting zymogens is provided as a concentrate, concentrated by about 2- to 50-fold compared to their concentration in plasma, as normalized to Factor II. 14. The formulation of claim 13, wherein the vitamin K-dependent clotting zymogen concentrate is Prothrombin Complex Concentrate (PCC). 15. The formulation of claim 1, wherein the ratio of the vitamin K-dependent clotting zymogens to fibrinogen is about 0.01 U/mg clottable protein to about 1.0 U/mg clottable protein, as normalized to Factor II. 16. The formulation of claim 1, wherein the reversible inhibitor is a calcium chelator. 17. The formulation of claim 16, wherein the calcium chelator is selected from the group consisting of a citrate ion, oxalate, EDTA, EGTA and a combination of such calcium chelators. 18. The formulation of claim 17, wherein the calcium chelator is a citrate ion. 19. The formulation of claim 18, wherein the citrate ion is provided by sodium citrate. 20. The formulation of claim 19, comprising from about 1 mM to about 50 mM sodium citrate. 21. The formulation of claim 20, comprising from about 5 mM to about 25 mM sodium citrate. 22. The formulation of claim 17, comprising from about 0.1 mM to about 2.5 mM EDTA and/or EGTA. 23. The formulation of claim 1, wherein the reversible inhibitor is a serine protease active site inhibitor. 24. The formulation of claim 23, wherein the reversible inhibitor is arginine. 25. The formulation of claim 24, comprising from about 0.1% to about 5% (w/v) arginine. 26. The formulation of claim 1, for use in hemostasis, healing and/or surgery. 27. A container comprising the formulation of claim 1. 28. A kit comprising the container of claim 27, and optionally instructions for use. 29. A storage stable liquid sealant formulation comprising about 1-100 mg/ml fibrinogen; vitamin K-dependent clotting zymogens comprising at least Factor II, Factor IX and Factor X and having a ratio of about 0.01-1.0 IU/mg relative to fibrinogen; and at least one reversible inhibitor of at least one of the vitamin K-dependent clotting zymogens, wherein the formulation is free of added irreversible thrombin inhibitor; wherein the added reversible inhibitor is selected from the group consisting of 0.125 IU/ml heparin, about 1-50 mM calcium chelator, about 0.1-5% serine protease active site inhibitor and a combination thereof. 30. A storage stable liquid calcium-free sealant formulation comprising about 1-100 mg/ml fibrinogen and vitamin K-dependent clotting zymogens comprising at least Factor II and Factor X and having a ratio of about 0.01-1.0 IU/mg relative to fibrinogen, and at least one reversible inhibitor of at least one of the vitamin K-dependent clotting zymogens selected from the group consisting of 0.125 IU/ml heparin, about 1-50 mM calcium chelator, about 0.1-5% serine protease active site inhibitor and a combination thereof. 31. A container comprising the formulation of claim 29 or 30. 32. A kit comprising the container of claim 31; and optionally instructions for use.
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