WO1993005822A1 - Colle tissulaire preparee a l'aide d'un cryoprecipite - Google Patents

Colle tissulaire preparee a l'aide d'un cryoprecipite Download PDF

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Publication number
WO1993005822A1
WO1993005822A1 PCT/EP1991/001850 EP9101850W WO9305822A1 WO 1993005822 A1 WO1993005822 A1 WO 1993005822A1 EP 9101850 W EP9101850 W EP 9101850W WO 9305822 A1 WO9305822 A1 WO 9305822A1
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WO
WIPO (PCT)
Prior art keywords
tissue glue
component
glue
tissue
thrombin
Prior art date
Application number
PCT/EP1991/001850
Other languages
English (en)
Inventor
Uri Martinowitz
Frederic Bal
Original Assignee
Octapharma Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
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Priority to CS922942A priority Critical patent/CZ280540B6/cs
Priority to PCT/EP1991/001850 priority patent/WO1993005822A1/fr
Priority to SK2942-92A priority patent/SK294292A3/sk
Application filed by Octapharma Ag filed Critical Octapharma Ag
Priority to DE69231791T priority patent/DE69231791T2/de
Priority to ES92114942T priority patent/ES2155437T3/es
Priority to EP92114942A priority patent/EP0534178B1/fr
Priority to AT92114942T priority patent/ATE200631T1/de
Priority to IL10311892A priority patent/IL103118A/en
Priority to AU25288/92A priority patent/AU648198B2/en
Priority to CA002079077A priority patent/CA2079077C/fr
Priority to NO19923737A priority patent/NO316155B1/no
Priority to BR929203763A priority patent/BR9203763A/pt
Priority to ZA927360A priority patent/ZA927360B/xx
Priority to HU9203070A priority patent/HUT67051A/hu
Priority to FI924306A priority patent/FI924306A/fi
Priority to JP28112592A priority patent/JP2668762B2/ja
Publication of WO1993005822A1 publication Critical patent/WO1993005822A1/fr
Priority to HU95P/P00739P priority patent/HU211631A9/hu

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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
    • A61L24/0005—Ingredients of undetermined constitution or reaction products thereof
    • 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
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0088—Liquid substances
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • This invention relates to a tissue glue comprising two components A and B, a process for preparing the tissue glue and the use of cryoprecipitate of whole blood for preparing a tissue glue, the use of a high amount of aprotinin and the use of a snake venom proteolytic enzyme for preparing a tissue glue.
  • This concentrate also contains ⁇ fibronectin and factor XIII which are important for clot stabilization and strength.
  • the second component is thrombin, an active enzyme that converts fibrinogen, the last component of the normal coagulation system into a fibrin clot. This process bypasses most of the steps of normal coagulation and mimicks its last phase.
  • Some manufacturers add plasminogen which is an enzyme that will .- induce clot lysis after some time whereas others add aprotinin which is an inhibitor of proteases for preventing .clot lysis.
  • these products give satisfactory results in patients although with mild bleeding disorders, but patients suffering severe bleeding disorders such as hemophilia A or B, still have a very high risk of post ⁇ operative bleeding. Sometimes a delayed bleeding com ⁇ plications after . an average of days from the surgery occur. Also patients who are treated with anticoagulation factors cannot be treated with the tissue glue of the prior art. Another severe disadvantage of the commerical concentrates are the high producing costs.
  • One object of the invention is to provide a tissue glue which can be prepared in an easier and cheaper way.
  • Another object of the present invention is to provide a tissue glue which is also suitable for patients with severe blood coagulation disorders like hemophilia A ' or B.
  • a further object of the present invention is to pro ⁇ vide a tissue glue which can also be used for patients which have already developed antibodies against bovine thrombin which is the active factor of the component B.
  • Still another object of the present invention is to provide a tissue glue for patients who are treated with anticoagulation factors like heparin. Because of the risk of transferring viral diseases with the components of the tissue glue it must be ensured that fractions of the tissue glue are virus inactivated.
  • the tissue glue according to the invention comprises a component A which comprises cryoprecipitate of whole blood and a component B which comprises a proteolytic enzyme capable of cleaving specifically fibrinogen and causing the formation of fibrin by clotting of the activated fibrinogen.
  • cryoprecipitate can be used for preparation of the tissue glue of the invention. However, it can be advantageous to concentrate the cyroprecipitate between a factor 2 and 5, preferably factor 3.
  • the addition of a protease inhibitor in sufficient con ⁇ centration to the cryoprecipitate makes the tissue glue of the invention suitable for use in patients with severe bleeding disorders.
  • the protease inhibitor aprotinin is used in amounts of 3,000 bis 5,000 KIU.
  • Aprotinin is commerically available under the trademark Trasylol or Antagosan .
  • the cryoprecipitate can be obtained from the patient himself by donating an auto- logous blood unit prior to the operation. This approach prevents the risk of transmission of viral infections by blood derivatives.
  • the cryoprecipitate has to become virus-inactivated. A procedure for virus-inactivation is described in PCT/EP 91/00503.
  • the basic principle is treatment• of the cryoprecipitate with special detergents and removing the detergent lateron from the cryopre ⁇ cipitate.
  • the second component, component B, of the tissue glue of the present invention is prepared by a solution of a pro ⁇ teolytic enzyme being capable of cleaving specifically fibrinogen.
  • a pro ⁇ teolytic enzyme being capable of cleaving specifically fibrinogen.
  • thrombin has been used which was isolated from plasma of human beings or mamals such as bovine. This thrombin can be delivered in a lyophilized form. The reconstitution of thrombin occurs with a 40 mmol solution of calcium chloride. The preferred concen ⁇ tration of thrombin is 50 to 200 u/ml.
  • the thrombin solution of roughly 100 u/ml of calcium chloride will be prepared.
  • a slow glue ⁇ for example by filing of cavities, i. e. tooth extraction or sealing the cavity of transphenoided hypophisectomy the thrombin will be further dissolved to a concentration of 25 u/ml with the appropiate calcium chloride solution.
  • tissue glue comprises as component B a proteolytic enzyme which is isolated from snake venom.
  • component B a proteolytic enzyme which is isolated from snake venom.
  • This embodiment is advantageous because also patients having developed antibodies against thrombin can be treated.
  • patients which are pretreated with heparin can be treated with the tissue glue according to the invention, because heparin does not influence the reaction of the snake venom enzyme.
  • the snake venom enzyme batroxobin which can be isolated from the South American pit viper Bothrpos mou eni.
  • component B contains 0.5 to 10 u/ml of the respective proteolytic enzyme of snake venom.
  • tissue glues comprising purified fibrinogen, fibronectin and factor XIII can be used as component A. The risk of after-bleeding is then dramatically reduced.
  • proteolytic proteases from snake venom .are used for the preparation of component B also "conventional" com ⁇ ponents A having fibrinogen, fibronectin and factor XIII can be used.
  • the use of high amounts of aprotinin according to the invention is preferred.
  • a very preferred embodiment is the combination of the component A of the invention derived from cryoprecipitate with or without high amounts of aprotinin- and the component B of the invention having the proteolytic enzyme isolated from snake venom.
  • the process for preparing the fibrin glue of the invention comprises the ⁇ steps of manufacturing component A com ⁇ prising the steps of preparing a cryosolution from cryo ⁇ precipitate,
  • a cryopaste is prethawed over night at 4 to 10 °C.
  • the cryopaste is dissolved in a buffer containing sodiumchlorid trisodiumcitrate and glycin and having a pH of 7.0 to 7.2 and than heated to 30 to 35°C.
  • the cryopaste should dissolve readily otherwise it is not suitable for the preparation.
  • the dissolution can be speeded up by cutting. ' the cryopaste in small pieces after thawing.
  • After cooling the solution to almost room temperature and adjusting the pH to a value of 7..0 to 7.2 aluminium- hydroxid is added under stirring.
  • the precipitate- is centrifuged and discarded.
  • a filtration step is carried out.
  • Than calcium chloride is added up to the desired final concentration of calcium chloride.
  • the solution is heated up to 30 e C. Than the detergents are added. Other stirring for some time the solution is transferred into a virus free container -and left at slightly elevated temperatures for several hours without stirring.
  • the virucidal agents are removed by adding an amount of ricine oil and gently stirring for several ' inutes.
  • the solution is cooled to room temperature.
  • the aqueous layer is withdrawn in a virussafe container and the oillayer is discarded.
  • the aqueous layer is clarified by filtration.
  • the pH must be checked to be 7.0 to 7.2. Then the protein solution is pumped through a reversed phase column at ambient tem ⁇ perature.
  • the eluate is concentrated by diafiltration to a protein content of 60 to 100 g/ml and dialysed against a buffer which is identical to the buffer mentioned above but having additionally a relatively high concentration of calcium chloride. Then the protease in ⁇ hibitor is added. A sterile filtration is carried out and the sample is filled and deep frozen in suitable con ⁇ tainers.
  • Component B is preferably a freeze dried protease.
  • Parti ⁇ cularly preferred is lyophilized thrombin or lyophilized fraction of the South American pip viper Bothrpos moujeni.
  • the proteolyic enzyme is known under the tradename Repti- lase and is the enzyme batroxobin.
  • the proteolytic enzymes are dissolved in a calcium chloride buffer.
  • the application of the two components A and B is performed using a double syringe technique for example through a plastic connector. Upon mixing of the two components a clot will be formed. The application can occur via a canula or may be sprayed to a three lumen catheter. Each one of the two components is injected into a separate lumen and an air pressure source in the range of some atmospheres is connected to the third lumen in order to spray the mixture.
  • the tissue glue of the invention is advantageous because it can be used with patients having severe blood coagu- lation disorders and being still cheaper than the known tissue glues.
  • Patients with severe hemophilia can sub-, sequently, for example undergo tooth extractions without preventive infusions of factor VIII concentrates with a success rate of over 80%. This means only about one fifth of the patients need infusions due to post extraction bleeding.
  • such patients who are pretreated with heparin can be treated with the tissue glue of the in ⁇ vention.
  • tissue glue which is substituted by a protease from snake venom especially Defibrase which is the ⁇ erine protease batroxobin isolated from the venum of the South American pit viper Bothrpos moujeni.
  • Bovine thrombin was from commercial sources (Merz-Dade or
  • ReptilaseR was normalized to that of thrombin by com ⁇ paring their rates of prpteolysis of a non-specific chromogenic- substrate BAPNA (0.25 mM) at 37'C, in Tris/saline, pH 8.0, monitored at 405 nm for 15 minutes. On the basis of their esterolytic activity, the unit- activity of the reptilase was normalized to that of thrombin.
  • Fibrin glue was essentially generated by a dual syringe method with pure or cryoprecipitate fibrinogen substrate in one syringe, and reptilase (20 U/ml) or thrombin with CaClthrough (20 mM) in the other.
  • Clotting time was determined with a Research Model 300-R ACL Coagulation Analyzer (IL, Milan) .
  • Viscoelasti- city was determined on a 3-channel Häer Thrombo- elastograph at 37°C.
  • Breaking strength (BS) of glues was determined by mixing the glue components between two pieces of coarse weaved, synthetic fiber (0.5 x 1 cm) , allowing the formation of gel totally interweaved between the two pieces of coarse mesh and after 2 hours at 2 °C the ensemble of mesh-glue-mesh pulled apart using an Accuforce Cadet Ten ⁇ ionometer (AMATEK, Mansfield & Greene, USA) .
  • AMATEK Accuforce Cadet Ten ⁇ ionometer
  • Sterile cryoprecipitate (cryo) was prepared from frozen (-30 ⁇ C) human plasma which was thawed at ⁇ C and the supernatant plasma removed. Five such units were pooled to determine protein and fibrinogen concentrations was determined by.the Buiret method before and after clotting the cryoprecipitate (diluted 1 : 5) with 2 U/mL thrombin. Factor XIII was determined by measuring [ 3H]-putrescine incorporation into dimethylated casein after activation of the samples with 4 U/mL bovine thrombin, 10 min, 22 ⁇ C.
  • a notable f ature of the CT-fibrinogen curve is. that it is biphasic for a fixed level of thrombin or reptilase (i.e. 1 U/ml, figure 1A) and reaches a minimum in the 1 - 8 mM fibrinogen range. This differs somewhat from the maximal turbidity (after 10 min) which peaks in the range 20 to 40 mM fibrinogen.
  • a converse experiment shows the dependency of CT on either thrombin or reptilase levels. This curve shows a near linear inverse dependency of gelling rate at low enzyme levels (les ⁇ than 2 U/mL) , which plateaus above at higher levels..
  • CT clotting time
  • cryo glues prepared with exces ⁇ of CaCl, and either thrombin or reptilase achieve equivalent TEG values in roughly the same, time frame. It seems that after the initial onset of gelation, factor Xllla-induced cross-linking bolsters the gel fiber structure, so that the TEG values for both glues converge within 1 hour. Similarly with the final BS of both cryo glues formed with an excess of CaCl,. Both cryo glues break at 50 to 60g.
  • cryo-solution Preparation of a cryo-solution.
  • Commerically cryopaste is prethawed over night at 4 to 10°C.
  • One kilo of the cryo is dissolved in two liters of buffer A (120 mM/1 NaCl, 10. mM/1 trisodiumcitrate, 120 mM/1 glycin and pH 7.0 to 7.2) and preheated to 30 to 35*C.
  • the cryopaste should dissolve readily otherwise it is not suitable for the preparation.
  • cut the cryopaste in small pieces after thawing.
  • the solution is cooled to 20"C to 22 ⁇ C and the pH is checked.
  • it must be adjusted to pH 7.0 to 7.2 by adding diluted sodiumhydroxid or acidic acid.
  • the solution is heated up to 30°C. 1% w/v TNBP and 1% w/v Triton X 100 i ⁇ added. The mixture i ⁇ gently stirred for 1/2 hour. The- solution is than transferred into a- virus- free container and left at 30 ⁇ C for 3 1/2 hours without stirring.
  • the eluate is concentrated by diafiltration to a protein content of 70 to 80 mg/ml and ' dialyse again ⁇ t ⁇ ufficient amount of a buffer B (same ingredients as buffer A but additionally 1 mM/1 calcium chloride) . Then 4 io. KIU aprotinin per liter solution is added. Afterwards a sterile filtration carried out using a 0.45 ⁇ m + 0.2 ⁇ m cascade. The solution is than filled and deep .frozen in plastic bags, optionally lyophilized.
  • Lyophilized thrombin is di ⁇ solved in a solution of 40 mM/L calcium chloride.
  • The.amount of thrombin is 100 U/ml in the glue.
  • a thrombin solution of 100 U/ml in calcium chloride will be suffi ⁇ cient.
  • a slow glue for example filling of cavities during a tooth extraction or sealing the cavity of trans ⁇ phenoided hypophisectomy the thrombin will be further dissolved to a final concentration of 25 U/ml by adding great amounts of CaCl 2 .
  • reptilase The preparation of reptilase is similar to that of thrombin. However, the amount of reptilase is roughly 2 U/ml.
  • MY a 21 year old male
  • No background disease i.e. tumor, or autoimmune disea ⁇ e
  • Laboratory test confirmed by two outside laboratories indicated that MY had high levels of anti-thrombin IgG anitbody.
  • Elective lithotripsy by ultrasound was planned. Based on the technique that IgG bind ⁇ to protein-A affinity columns, the patient was placed on ' immuno- suppressive therapy combined with extra-corporal immuno-adsorption.
  • the inhibitor titer decreased by 98%. This was determined by measuring the thrombin time (TT) of normal pooled plasma, with pre- and post-affinity purified MJ plasma. Nevertheless, the TT as well as PT and APTT values were prolonged. At this time, the kidney stone moved to the urethra, causing complete blockage of the kidney accompanied by hydronephrosis. The patient received 10 more immuno-adsorption treatments (roughly 80 liter plasma) followed by intensive plasmapheresi ⁇ (roughly 50 liter) and high doese immunoglobulin infusion (2 g/kg) .

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Abstract

Colle tissulaire comportant un constituant A comprenant un cryoprécipité de sang total, et un constituant B comportant une enzyme protéolytique apte à cliver spécifiquement le fibrinogène présent dans le constituant A et à provoquer la formation d'un polymère de fibrine. Selon un mode préféré de réalisation, le constituant A de la colle tissulaire comporte de 3 000 à 5 000 KIU/ml d'aprotinine. Selon un autre mode préféré de réalisation, le constituant B de la colle tissulaire est une protéase dérivée du venin du Bothrops sud-américain. Cette protéase est connue sous le nom de batroxobine.
PCT/EP1991/001850 1991-09-27 1991-09-27 Colle tissulaire preparee a l'aide d'un cryoprecipite WO1993005822A1 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
CS922942A CZ280540B6 (cs) 1991-09-27 1991-09-27 Tkáňové lepidlo obsahující kryoprecipitát, způsob jeho výroby a použití aprotininu, proteázy z hadího jedu a batroxobinu pro jeho přípravu
PCT/EP1991/001850 WO1993005822A1 (fr) 1991-09-27 1991-09-27 Colle tissulaire preparee a l'aide d'un cryoprecipite
SK2942-92A SK294292A3 (en) 1991-09-27 1991-09-27 Tissue adhesive and method of its production
DE69231791T DE69231791T2 (de) 1991-09-27 1992-09-02 Verbesserter Gewebekleber, zubereitet aus Kryopräzipitat
ES92114942T ES2155437T3 (es) 1991-09-27 1992-09-02 Cola mejorada para tejidos preparada a partir de un crioprecipitado.
EP92114942A EP0534178B1 (fr) 1991-09-27 1992-09-02 Colle améliorée pour tissus préparée à partir de cryoprécipité
AT92114942T ATE200631T1 (de) 1991-09-27 1992-09-02 Verbesserter gewebekleber, zubereitet aus kryopräzipitat
IL10311892A IL103118A (en) 1991-09-27 1992-09-09 Tissue glue produced by using cryoprecipitate
AU25288/92A AU648198B2 (en) 1991-09-27 1992-09-22 Improved tissue glue prepared by using cryoprecipitate
CA002079077A CA2079077C (fr) 1991-09-27 1992-09-24 Colle physiologique preparee au moyen d'un cryoprecipite
FI924306A FI924306A (fi) 1991-09-27 1992-09-25 Foerbaettrat vaevnadslim som framstaellts genom anvaendning av kryofaellning
NO19923737A NO316155B1 (no) 1991-09-27 1992-09-25 Forbedret vevslim fremstilt ved anvendelse av kryopresipitat, fremgangsmåtefor fremstilling derav, samt anvendelse av en mengde avproteaseinhibitor
BR929203763A BR9203763A (pt) 1991-09-27 1992-09-25 Cola para tecido;processo para a fabricacao de uma cola de fibrina e aplicacao de aprotinina,de uma protease de veneno de cobra e de batroxobina
ZA927360A ZA927360B (en) 1991-09-27 1992-09-25 Improved tissue glue prepared by using cryoprecipitate
HU9203070A HUT67051A (en) 1991-09-27 1992-09-25 Improved tissue glue prepared by using cryoprecipitate
JP28112592A JP2668762B2 (ja) 1991-09-27 1992-09-28 寒冷沈降物を用いて製造した改良組織接着剤
HU95P/P00739P HU211631A9 (en) 1991-09-27 1995-06-30 Improved tissue glue prepared by using cryoprecipitate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1991/001850 WO1993005822A1 (fr) 1991-09-27 1991-09-27 Colle tissulaire preparee a l'aide d'un cryoprecipite

Publications (1)

Publication Number Publication Date
WO1993005822A1 true WO1993005822A1 (fr) 1993-04-01

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PCT/EP1991/001850 WO1993005822A1 (fr) 1991-09-27 1991-09-27 Colle tissulaire preparee a l'aide d'un cryoprecipite

Country Status (15)

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JP (1) JP2668762B2 (fr)
AT (1) ATE200631T1 (fr)
AU (1) AU648198B2 (fr)
BR (1) BR9203763A (fr)
CA (1) CA2079077C (fr)
CZ (1) CZ280540B6 (fr)
DE (1) DE69231791T2 (fr)
ES (1) ES2155437T3 (fr)
FI (1) FI924306A (fr)
HU (2) HUT67051A (fr)
IL (1) IL103118A (fr)
NO (1) NO316155B1 (fr)
SK (1) SK294292A3 (fr)
WO (1) WO1993005822A1 (fr)
ZA (1) ZA927360B (fr)

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WO2004024198A1 (fr) * 2002-09-10 2004-03-25 New Dawn-Consultores E Servicos Lda Activateur utilise pour former un gel plaquettaire, un gel de plasma pauvre en plaquettes ou un gel de plasma riche en plaquettes
WO2009027814A1 (fr) 2007-08-30 2009-03-05 Omrix Biopharmaceuticals Ltd. Compositions appropriées pour le traitement d'une maladie, d'un trouble ou d'un état de la moelle épinière
WO2011092694A2 (fr) 2010-01-28 2011-08-04 Omrix Biopharmaceuticals Ltd. Procédé d'obturation améliorée par fibrine
EP2508211A1 (fr) 2007-07-02 2012-10-10 Omrix Biopharmaceuticals Ltd. Solutions contenant des quantités permissives par voie enzymatique d'agents de visualisation et leurs utilisations
WO2013001524A1 (fr) 2011-06-30 2013-01-03 Omrix Biopharmaceuticals Ltd. Procédé d'élimination d'une enzyme lytique d'un mélange hétérogène
WO2014102763A1 (fr) 2012-12-30 2014-07-03 Omrix Biopharmaceuticals Ltd. Dispositif et procédé d'application d'une composition fluide durcissable sur une partie d'un organe corporel
WO2015097688A1 (fr) 2013-12-24 2015-07-02 Omrix Biopharmaceuticals Ltd. Colle de fibrine à un composant comprenant un inhibiteur de polymérisation
WO2015097687A1 (fr) 2013-12-24 2015-07-02 Omrix Biopharmaceuticals Ltd. Colle de fibrine monocomposant comprenant des zymogènes
WO2015128858A1 (fr) 2014-02-27 2015-09-03 Omrix Biopharmaceuticals Ltd. Formulation enrichie de plasma
WO2015145416A1 (fr) 2014-03-27 2015-10-01 Omrix Biopharmaceuticals Ltd. Dispositif et procédé pour préparer et administrer un agent d'étanchéité à base de fibrine à un constituant
WO2016027263A2 (fr) 2014-08-21 2016-02-25 Omrix Biopharmaceuticals Ltd. Thrombine stabilisée
USD754325S1 (en) 2013-06-06 2016-04-19 Omrix Biopharmaceuticals Ltd. Device of a curable fluid composition to a bodily organ
WO2016132357A1 (fr) 2015-02-16 2016-08-25 Nayacure Therapeutics Ltd. Caillots modifiés
WO2018051324A1 (fr) 2016-09-14 2018-03-22 Omrix Biopharmaceuticals Ltd. Formulations de produit d'étanchéité et leurs utilisations
WO2018116287A1 (fr) 2016-12-22 2018-06-28 Omrix Biopharmaceuticals Ltd. Composition hémostatique comprenant un échangeur d'anions et un sel de calcium
US10039865B2 (en) 2008-09-22 2018-08-07 Omrix Biopharmaceuticals Ltd. Implantable device comprising a substrate pre-coated with stabilized fibrin
US10130346B2 (en) 2012-07-24 2018-11-20 Omrix Biopharmaceuticals Ltd. Device and method for the application of a curable fluid composition to a bodily organ
US20200188489A1 (en) * 2018-12-12 2020-06-18 Omrix Biopharmaceuticals Ltd. Low concentrated protein compositions for preventing tissue adhesion

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FI924306A (fi) 1993-03-28
SK294292A3 (en) 1994-06-08
IL103118A0 (en) 1993-02-21
NO316155B1 (no) 2003-12-22
JPH05194263A (ja) 1993-08-03
JP2668762B2 (ja) 1997-10-27
NO923737D0 (no) 1992-09-25
ATE200631T1 (de) 2001-05-15
CA2079077C (fr) 1999-11-30
DE69231791D1 (de) 2001-05-23
FI924306A0 (fi) 1992-09-25
HU211631A9 (en) 1995-12-28
ZA927360B (en) 1993-05-03
AU648198B2 (en) 1994-04-14
CZ280540B6 (cs) 1996-02-14
DE69231791T2 (de) 2001-11-22
BR9203763A (pt) 1993-04-20
HU9203070D0 (en) 1992-12-28
IL103118A (en) 1996-11-14
NO923737L (no) 1993-03-29
CZ294292A3 (en) 1994-02-16
ES2155437T3 (es) 2001-05-16
HUT67051A (en) 1995-01-30
AU2528892A (en) 1993-04-01
CA2079077A1 (fr) 1993-03-28

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