WO1998055140A1 - Concentre de fibrinogene provenant de plasma humain - Google Patents
Concentre de fibrinogene provenant de plasma humain Download PDFInfo
- Publication number
- WO1998055140A1 WO1998055140A1 PCT/EP1998/003364 EP9803364W WO9855140A1 WO 1998055140 A1 WO1998055140 A1 WO 1998055140A1 EP 9803364 W EP9803364 W EP 9803364W WO 9855140 A1 WO9855140 A1 WO 9855140A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fibrinogen
- fibrinogen concentrate
- concentrate according
- proteins
- factor
- Prior art date
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Classifications
-
- 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
- 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
- A61K38/363—Fibrinogen
Definitions
- fibrin sealants produced from naturally occurring components of human blood plasma and is the subject of many patents and applications, such as WO 86/01814, EP 0 305 243 (Immuno), and US 5,605,887. These fibrin sealants are composed of the combination of a fibrinogen containing concentrate with an activating thrombin component .
- fibrinogen containing preparations contain a limited number of plasma proteins that are separately purified and then recombined into a final product, as described in (Immuno Patent), containing primarily fibrinogen and factor XIII.
- Others rely on the fact that factor XIII copurifies with the fibrinogen to result in a product containing primarily fibrinogen, with trace amounts of factor XIII and fibronectin, as is described in EP 0 305 243 and in US 5,605,887.
- These fibrinogen concentrates as described contain 90 to 95% of the total protein present as fibrinogen.
- the present invention describes a fibrinogen concentrate that contains multiple proteins in high concentrations that give a surprisingly beneficial effect to the resulting fibrin glue that is produced.
- the fibrinogen concentrate of the invention is virus inactivated to reduce the risk of transmission of pathogenic viruses.
- the fibrinogen concentrate of this invention provides for the production of a fibrin glue that has superior' qualities compared to other products in terms of hemostatic effect and reduction ensuing tissue adhesions following application of the glue.
- the superior effect of the glue is also evidenced in the reduction of the amount of glue required to achieve the hemostatic effects.
- the fibrinogen concentrate is prepared from human plasma, preferably by the use of a cryoprecipitation step, wherein a multitude of proteins are concentrated, virus inactivated, and presented in a final form allowing the combination with a thrombin component for the formation of a fibrin glue.
- the resulting fibrinogen concentrate contains a total protein concentration of at least 30 mg/ml up to 120 mg/ml , preferably in the range of 50 to 100 mg/ml. This represents the protein concentration of the product either in the final form for a liquid product, or after reconstitution for a lyophilized product.
- the fibrinogen concentrate of this invention contains multiple proteins in addition of fibrinogen, fibronectin, and factor XIII, specifically included are von WiUebrand factor, factor VIII, and vitronectin, in addition to other naturally occurring plasma proteins with molecular weights greater than 30,000 kD, and which may include in particular certain growth factors.
- These other natuarlly occurring plasma porteins have been unexpectedly found to provide the superior qualities of the resulting fibrin glue when the total content is found to exceed 20% of the total content of proteins. That is, the superior results have been found when the concentration of fibrinogen in the fibrinogen concentrate is less than 80% of the total content of proteins, and the difference is made up of other naturally occurring plasma proteins.
- This fibrinogen concentrate may be virus inactivated, preferably using the solvent detergent inactivation technique, and the most preferred presentation the concentrate is doubly inactivated by the combination of the solvent detergent method with a second virus inactivation method, for example, with pasteurization or inactivation with UVC light.
- the resulting concentrate may be combined with a thrombin product for the production of a fibrin glue and for use in surgical applications.
- This invention provides for a fibrinogen concentrate from human blood plasma that, when utilized in combination with a thrombin component, is highly effective as a hemostatic agent, a tissue sealant, and a tissue adhesive for use in local surgical applications.
- the concentrate is produced from pooled human blood plasma, is treated by one or several virus inactivation techniques, and is suitable for routine manufacture .
- the method of production of said concentrate allows the retention of most major protein components of human plasma above the molecular weight of 30,000 kD.
- the surprising result of this invention is that the fibrinogen concentrate produced by this method, when combined with a thrombin component, yields a superior fibrin glue product. It is the fact that these other protein components are maintained in relatively high concentrations and in biologically active forms that results in the superior qualities of the resulting glue product.
- the novel composition of the fibrinogen concentrate containing less than 80% of total proteins as fibrinogen and the rest as other proteins, has resulted in the surprising qualities of this product.
- the fibrinogen product is produced from human blood plasma.
- the fibrinogen is precipitated from the pooled plasma by one of the standard precipitation techniques, such as cryoprecipitation, alcohol precipitation, and PEG precipitation.
- the fibrinogen is concentrated by a cryoprecipitation step, which also concentrates a multiple of other plasma proteins in the precipitate.
- the resulting precipitate is resuspended in a buffer solution and treated with aluminum hydroxide for the removal of vitamin K dependant proteins.
- the resulting solution is then virus inactivated by the solvent detergent inactivation technique, and the virucidal agents are removed.
- the resulting solution may then be concentrated on an ultra- filtration membrane, stabilized, and then formulated into a final product.
- This fibrinogen concentrate may be stored as a liquid, either in a frozen form or at refrigerated temperatures, or may be lyophilized.
- the solution following the SD inactivation step is treated with a second virus inactivation process which could be pasteurization in solution in the presence of stabilizers, or by irradiation with UVC light.
- the product is then concentrated on an ultra- filtration membrane, stabilized, and then formulated into a final product.
- This fibrinogen concentrate may be stored as a liquid, either in a frozen form or at refrigerated temperatures, or may be lyophilized.
- the resulting fibrinogen concentrate from this process has a final protein concentration of 30 to 120 mg/ml.
- the total protein concentration is between 50 to 100 mg/ml, and more preferred the protein concentration is about 60 to 80 mg/ml.
- the fibrinogen concentration is approximately 40 to 60 mg/ml, or about 50 to 80% of the total protein concentration of the final product
- fibronectin concentration of the preferred presentation is 5 to 15 mg/ml
- von WiUebrand concentration is 40 to 60 IU/ml
- factor XIII concentration is 2 to 10 IU/ml
- factor VIII concentration is 10 to 25 IU/ml
- vitronectin concentration is 0.03 to 0.07 mg/ml.
- This fibrinogen concentrate may be stabilized with a variety of amino acid combinations, preferably utilizing amino acids other than ⁇ -amino acids, such as tranexamic acid and e- aminocaproic acid. These stabilizers may be used in combination with other amino acids as stabilizers, preferably basic amino acids such as lysine and arginine . In the most preferred presentation, tranexamic acid and arginine are used as stabilizers.
- the fibrinogen concentrate of this invention When the fibrinogen concentrate of this invention is combined with a thrombin concentrate, a superior fibrin glue results. This is demonstrated by the use of a rabbit model for a surgical resection of a liver lobe. After excision of lateral lobe of the liver, the cut surface is treated with a fibrin glue product and the amount of time to achieve hemostasis is recorded. The amount of glue required is also measured. In direct comparison with other commercially available glue products, that have the fibrinogen component containing > 80% of the total protein as fibrinogen, the fibrin glue of this invention was found to have dramatically reduced bleeding times of 45 seconds vs. > 195 seconds, and dramatically reduced quantities of glue required to achieve this effect of 3.6 ml vs. 4.5 to 10 ml. The competitor products evaluated were Tissucol (Immuno AG) , Beriplast (Centeon) , and Biocol (LFB, France) .
- a further unexpected benefit of the present invention is the reduction of adhesion of other tissues to the application site of the glue following the surgical operation performed above in comparison to the competitor products. Seven days following the treatment of the animals with the glue products, a necropsy was performed to evaluate the adherence of other surrounding tissues to the glue application site. The competitor products had on average at least six adhesions, while the product of this invention had less than one .
- the unexpected results of the fibrinogen concentrate clearly demonstrate the superiority of this product to other commercially available products in terms of hemostatic effect, ability to adhere to the cut surface, reduction in quantity of glue required, and ability to reduce adhesions to surrounding tissues.
- These beneficial qualities of the product show it to be useful for use in any surgical applications related to hemostasis, tissue adhesion, and tissue sealing.
- the fibrinogen concentrate had the following composition due to biochemical analysis.
- the fibrinogen concentrate of this invention indicated as Quixil below, was compared in the rabbit model for liver resection against commercially available products. The results are as follows:
- Fig. la depicts the SDS PAGE of the fibrinogen concentrate samples.
- the 3 strongest bands at 88, 75 and 68 kD correspond to the fibrinogen 4,22 ⁇ -A, B ⁇ and ⁇ chains, respectively. The same is true for the high molecular weight bands, corresponding to von WiUebrand and fibronectin.
- the Fig. 1 shows SDS-PAGE Analysis of Fibrinogen Concentrate Proteins.
- Bands denoted A correspond to high molecular weight von WiUebrand and fibronectin proteins
- B correspond to fibrinogen ⁇ -A, B ⁇ and ⁇ chains
- C+D correspond to low molecular weight proteins.
- (B) Densitometric scans of bands from SDS-PAGE - Densitometry was carried out as described in Materials and Methods .
- Graphs 1,2,3,5,7 and 8 correspond to the scans of bands from the corresponding lanes in (A) .
- the letters denoting the bands in (B) are used to denote their corresponding peaks in (B) .
- Table 1 summarizes the molecular weights of all the bands in each sample calculated from the linear regression curve made according to the distance of migration of the LMW marker bands.
- Fig. lb depicts the superimposed results of the densitometric scanning of the bands from each lane .
- the peak areas show that the relative amounts of von WiUebrand and fibronectin (15-20 % of total protein) , fibrinogen (75-80 % of total protein) , and low molecular weight proteins (5 % of total protein) are the same in all batches of fibrinogen concentrate.
- Table 1 Molecular weights of fibrinogen concentrate proteins analyzed by SDS-PAGE. The molecular weight of each protein band was derived by interpolation from a linear regression of Log MW vs. Distance from the bands corresponding to the LMW marker.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU83360/98A AU8336098A (en) | 1997-06-05 | 1998-06-05 | Fibrinogen concentrate from human plasma |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4866597P | 1997-06-05 | 1997-06-05 | |
US60/048,665 | 1997-06-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998055140A1 true WO1998055140A1 (fr) | 1998-12-10 |
Family
ID=21955775
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1998/003364 WO1998055140A1 (fr) | 1997-06-05 | 1998-06-05 | Concentre de fibrinogene provenant de plasma humain |
Country Status (2)
Country | Link |
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AU (1) | AU8336098A (fr) |
WO (1) | WO1998055140A1 (fr) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1057490A2 (fr) * | 1999-05-31 | 2000-12-06 | Grupo Grifols, S.A. | Utilisation de l'acide tranexemique dans la préparation d'une composition de fibrinogène humain |
EP1091735A1 (fr) * | 1998-06-22 | 2001-04-18 | Autologous Wound Therapy, Inc. | Cicatrisant pour blessures ameliore a l'aide de plaquettes enrichies |
JP2003507091A (ja) * | 1999-08-13 | 2003-02-25 | オムリックス・バイオファーマシューティカルズ・エス.アー. | フィブリノゲン多量体の使用 |
NL1020426C2 (nl) * | 2002-04-18 | 2003-10-21 | Tno | Modificatie van de eigenschappen van een fibrinematrix met betrekking tot groei en ingroei van cellen. |
US7112342B2 (en) | 1998-06-22 | 2006-09-26 | Cytomedix, Inc. | Enriched platelet wound healant |
EP2034010A1 (fr) * | 2007-08-30 | 2009-03-11 | Omrix Biopharmaceuticals Ltd. | Compositions convenables pour la réparation et/ou le traitement de tissu spinal endommagé |
US20150238529A1 (en) * | 2014-02-27 | 2015-08-27 | Omrix Biopharmaceuticals Ltd. | Plasma-supplemented formulation |
WO2020121289A1 (fr) | 2018-12-12 | 2020-06-18 | Omrix Biopharmaceuticals Ltd. | Compositions de protéines faiblement concentrées destinées à prévenir l'adhérence tissulaire |
CN113194974A (zh) * | 2018-12-12 | 2021-07-30 | 奥姆里克斯生物药品有限公司 | 用于防止组织粘连的低浓缩蛋白质组合物 |
WO2023119277A1 (fr) | 2021-12-21 | 2023-06-29 | Omrix Biopharmaceuticals Ltd. | Compositions de fibrinogène hautement solubles |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0305243A1 (fr) * | 1987-07-30 | 1989-03-01 | Centre Regional De Transfusion Sanguine De Lille | Concentré de protéines coagulables par la thrombine, son procédé d'obtention et son utilisation thérapeutique |
EP0534178A2 (fr) * | 1991-09-27 | 1993-03-31 | Opperbas Holding B.V. | Colle améliorée pour tissus préparée à partir de cryoprécipité |
US5420250A (en) * | 1990-08-06 | 1995-05-30 | Fibrin Corporation | Phase transfer process for producing native plasma protein concentrates |
US5605887A (en) * | 1993-03-01 | 1997-02-25 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
-
1998
- 1998-06-05 WO PCT/EP1998/003364 patent/WO1998055140A1/fr active Application Filing
- 1998-06-05 AU AU83360/98A patent/AU8336098A/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0305243A1 (fr) * | 1987-07-30 | 1989-03-01 | Centre Regional De Transfusion Sanguine De Lille | Concentré de protéines coagulables par la thrombine, son procédé d'obtention et son utilisation thérapeutique |
US5420250A (en) * | 1990-08-06 | 1995-05-30 | Fibrin Corporation | Phase transfer process for producing native plasma protein concentrates |
EP0534178A2 (fr) * | 1991-09-27 | 1993-03-31 | Opperbas Holding B.V. | Colle améliorée pour tissus préparée à partir de cryoprécipité |
US5605887A (en) * | 1993-03-01 | 1997-02-25 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1091735A4 (fr) * | 1998-06-22 | 2004-05-06 | Cytomedix Inc | Cicatrisant pour blessures ameliore a l'aide de plaquettes enrichies |
EP1091735A1 (fr) * | 1998-06-22 | 2001-04-18 | Autologous Wound Therapy, Inc. | Cicatrisant pour blessures ameliore a l'aide de plaquettes enrichies |
US7112342B2 (en) | 1998-06-22 | 2006-09-26 | Cytomedix, Inc. | Enriched platelet wound healant |
EP1057490A3 (fr) * | 1999-05-31 | 2002-04-03 | Probitas Pharma, S.A. | Utilisation de l'acide tranexemique dans la préparation d'une composition de fibrinogène humain |
EP1057490A2 (fr) * | 1999-05-31 | 2000-12-06 | Grupo Grifols, S.A. | Utilisation de l'acide tranexemique dans la préparation d'une composition de fibrinogène humain |
JP2003507091A (ja) * | 1999-08-13 | 2003-02-25 | オムリックス・バイオファーマシューティカルズ・エス.アー. | フィブリノゲン多量体の使用 |
WO2003087160A1 (fr) * | 2002-04-18 | 2003-10-23 | Nederlandse Organisatie Voor Toegepast- Natuurwetenschappeijk Onderzoek Tno | Modification des proprietes d'une matrice de fibrine par rapport a la croissance et a l'interposition des cellules |
NL1020426C2 (nl) * | 2002-04-18 | 2003-10-21 | Tno | Modificatie van de eigenschappen van een fibrinematrix met betrekking tot groei en ingroei van cellen. |
US7867519B2 (en) | 2002-04-18 | 2011-01-11 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno | Method for the acceleration or deceleration of angiogenesis using fibrin matrix formed from increased or decreased HMW/LMW fibrinogen ratio |
EP2034010A1 (fr) * | 2007-08-30 | 2009-03-11 | Omrix Biopharmaceuticals Ltd. | Compositions convenables pour la réparation et/ou le traitement de tissu spinal endommagé |
EP2602316A1 (fr) * | 2007-08-30 | 2013-06-12 | Omrix Biopharmaceuticals Ltd. | Compositions appropriées pour le traitement de la maladie, un trouble ou un état de la moelle épinière |
US8968724B2 (en) | 2007-08-30 | 2015-03-03 | Omrix Biopharmaceuticals Ltd. | Compositions suitable for treatment of spinal disease, disorder or condition |
US9326998B2 (en) | 2007-08-30 | 2016-05-03 | Omrix Biopharmaceuticals Ltd. | Compositions suitable for treatment of spinal disease, disorder or condition |
US20150238529A1 (en) * | 2014-02-27 | 2015-08-27 | Omrix Biopharmaceuticals Ltd. | Plasma-supplemented formulation |
WO2015128858A1 (fr) * | 2014-02-27 | 2015-09-03 | Omrix Biopharmaceuticals Ltd. | Formulation enrichie de plasma |
CN106061519A (zh) * | 2014-02-27 | 2016-10-26 | 奥姆里克斯生物药品有限公司 | 血浆补充的制剂 |
AU2015221786B2 (en) * | 2014-02-27 | 2019-05-02 | Omrix Biopharmaceuticals Ltd. | Plasma-supplemented formulation |
US10806755B2 (en) * | 2014-02-27 | 2020-10-20 | Omrix Biopharmaceuticals, Ltd. | Plasma-supplemented formulation |
AU2019208251B2 (en) * | 2014-02-27 | 2020-10-22 | Omrix Biopharmaceuticals Ltd. | Plasma-supplemented formulation |
WO2020121289A1 (fr) | 2018-12-12 | 2020-06-18 | Omrix Biopharmaceuticals Ltd. | Compositions de protéines faiblement concentrées destinées à prévenir l'adhérence tissulaire |
WO2020121290A1 (fr) | 2018-12-12 | 2020-06-18 | Omrix Biopharmaceuticals Ltd. | Compositions de protéine à concentration élevée pour prévenir l'adhésion tissulaire |
CN113194974A (zh) * | 2018-12-12 | 2021-07-30 | 奥姆里克斯生物药品有限公司 | 用于防止组织粘连的低浓缩蛋白质组合物 |
US11583573B2 (en) | 2018-12-12 | 2023-02-21 | Omrix Biopharmaceuticals Ltd. | High concentrated protein compositions for preventing tissue adhesion |
US11918629B2 (en) | 2018-12-12 | 2024-03-05 | Omrix Biopharmaceuticals Ltd. | Low concentrated protein compositions for preventing tissue adhesion |
WO2023119277A1 (fr) | 2021-12-21 | 2023-06-29 | Omrix Biopharmaceuticals Ltd. | Compositions de fibrinogène hautement solubles |
Also Published As
Publication number | Publication date |
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AU8336098A (en) | 1998-12-21 |
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