EP1359947A2 - Suspension a base de fibrinogene, thrombine et alcool et methode pour revetir un support - Google Patents

Suspension a base de fibrinogene, thrombine et alcool et methode pour revetir un support

Info

Publication number
EP1359947A2
EP1359947A2 EP02734886A EP02734886A EP1359947A2 EP 1359947 A2 EP1359947 A2 EP 1359947A2 EP 02734886 A EP02734886 A EP 02734886A EP 02734886 A EP02734886 A EP 02734886A EP 1359947 A2 EP1359947 A2 EP 1359947A2
Authority
EP
European Patent Office
Prior art keywords
suspension
carrier
thrombin
fibrinogen
collagen
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.)
Ceased
Application number
EP02734886A
Other languages
German (de)
English (en)
Inventor
Alfred Schaufler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda AS
Original Assignee
Nycomed Pharma AS
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
Application filed by Nycomed Pharma AS filed Critical Nycomed Pharma AS
Publication of EP1359947A2 publication Critical patent/EP1359947A2/fr
Ceased legal-status Critical Current

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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
    • 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
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • 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
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/36—Surgical swabs, e.g. for absorbency or packing body cavities during surgery
    • 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
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/225—Mixtures of macromolecular compounds
    • 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
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A61L15/325—Collagen
    • 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
    • A61L15/425—Porous materials, e.g. foams or sponges
    • 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
    • A61L24/08—Polysaccharides
    • 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
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/044—Collagen
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/046—Fibrin; Fibrinogen
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
    • C08H1/00—Macromolecular products derived from proteins
    • C08H1/06—Macromolecular products derived from proteins derived from horn, hoofs, hair, skin or leather
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00365—Plasters use
    • A61F2013/00463—Plasters use haemostatic
    • A61F2013/00472—Plasters use haemostatic with chemical means
    • 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

Definitions

  • the present invention relates to a suspension comprising fibrinogen, thrombin, an alcohol and optionally aprotinin.
  • the invention further relates to a method for preparing such a suspension and to a method for coating a carrier with such a suspension.
  • the carrier may be a collagen carrier, such as a collagen sponge.
  • the invention further relates to a method of drying a coated carrier, in particular a collagen carrier coated with a suspension according to the invention, and thereby obtained coated collagen carrier having the active substances solidly fixated to the carrier.
  • the coated collagen carrier may be used as a ready-to-use absorbable composition for tissue gluing, tissue sealing and haemostasis consisting essentially of a carrier coated with solidlyfixed components of fibrin glue: fibrinogen and thrombin.
  • fibrinogen and thrombin This fixed combination can be applied directly to e.g. a wound surface.
  • the mechanism of this system mimics the final stage of the coagulation cascade, in which thrombin catalyses the conversion of fibrinogen to fibrin and the activation of factor XIII to give XHIa. Faktor XHIa, once formed, stabilises the fibrin clot by covalent cross-linking.
  • wound surface and carrier are glued together by polymerisation. During this process, which lasts approximately 3 to 5 minutes, the coated collagen carrier of the invention is preferably pressed onto the wound area.
  • the components of the composition of the invention are degraded enzymatically in about 4 - 6 months after application.
  • fibrin glues that mimic the last step of the coagulation cascade, consist of a highly concentrated fibrinogen solution to be mixed with a thrombin solution before application to the surgical wound exist. These mixtures contain a fibrinolysis inhibitor, e.g. aprotinin or ⁇ -aminocaproicacid, to prevent premature dissolution of the fibrin clot by the fibrinolytic enzyme plasmin.
  • a fibrinolysis inhibitor e.g. aprotinin or ⁇ -aminocaproicacid
  • the two-component fibrin glues furthermore need some preparatory steps including thawing or dissolution. Thus, they are rather impractical and cumbersome to work with and experience is needed for successful use of these fibrin glues.
  • Collagen has been used as a haemostatic agent since the late sixties. Collagen is the most frequent structural protein in all mammalians. The monomeric protein of approximately
  • collagen 10 300 kDa (tropocollagen) is covalently crosslinked at specific sites. The mature protein is therefore insoluble and forms characteristic fibrils with high tensile strength. Numerous sub-classes of collagen have been described, the most common of which is collagen type I, the main collagen type in skin, tendons bones and cornea. Collagen is a fibrous protein consisting of a triple helix with a length of approximately 290 nm. Five of these triple
  • microfibrils 15 helices (tropocollagen molecules) are staggered to form a microfibril with a diameter of approximately 3.6 nm. These microfibrils have polar and non-polar segments that are readily accessible for specific inter- and intrafibrillar interactions. Microfibrils are packed into a tetragonal lattice to form subfibrils with a diameter of about 30 nm. These subfibrils are then assembled into the collagen fibril, the basic unit of connective tissue, which has a
  • Collagen may be used as a material for sealing wounds, possibly with a coating comprising a fibrin glue.
  • Fibrin glues i.e. the combination of fibrinogen, thrombin and aprotinin, have
  • TachoComb ® A product that combines the haemostatic features of fibrin glue with the asset of collagen as a carrier has been developed and manufactured under the trademark TachoComb ® .
  • TachoComb ® is a ready-to-use and easily applicable fixed combination of a collagen patch coated with the following active components of fibrin glue: human fibrinogen, bovine thrombin and bovine aprotinin.
  • TachoComb ® has been sold since the early 1990s by Nycomed Pharma and has been used in clinical trials in Europe in more than 2500 patients. The product has furthermore been used in more than 700 patients in the Japanese clinical programme in a large variety of indications such as liver and lung resections, surgery of the biliary tract, splenic, renal and pancreatic surgery, ENT surgery, gynaecological surgery, and vascular surgery. TachoComb ® was found to be effective and safe.
  • TachoComb ® No clinical complications related to the application of TachoComb ® have been reported in the course of the clinical trials performed.
  • W097/37694 (Immuno France S.A.) it is disclosed in reference example 4 that when a collagen product or TachoComb ® was used, there was no haemostasis leading to bleeding to death when TachoComb ® was used in contrast to haemostasis within 5 minutes when a collagen product without a thrombin content prepared according to W097/37694 was prepared.
  • US 6,177,126 Bl discloses a device and a process for the production of a material for sealing and healing wounds.
  • the device comprises a container having, at its bottom part, two perforated plates which are movable relative to each other, so as to allow a suspension contained in the container to drip onto a carrier which is moving past the container under the bottom part thereof.
  • the invention provides a suspension comprising fibrinogen, thrombin and alcohol, the suspension having been obtained by a method comprising: providing a fibrinogen mixture of fibrinogen and an alcohol, providing a thrombin mixture of thrombin and an alcohol, mixing the fibrinogen mixture and the thrombin mixture, so as to obtain said suspension, the suspension containing fibrinogen and thrombin particles, the Folk Ward mean diameter of the particles being 25 - 100 ⁇ m, such as 35 - 80 ⁇ m, such as 40 - 78 ⁇ m, such as 40 - 75 ⁇ m, such as 45 - 60 ⁇ m, such as 47 - 55 ⁇ m, or such as 60 - 100 ⁇ m, such as 60 - 80 ⁇ m, such as 65 - 75 ⁇ m, preferably within +/- 5 ⁇ m, such as within +/- 4 ⁇ m, such as within +/- 3.5 ⁇ m, such as within +/- 2 ⁇ m, such as within +/- 1.5
  • a suspension when coated onto a carrier, such as a collagen carrier, is efficient in a ready-to-use absorbable composition for tissue gluing, tissue sealing and haemostasis.
  • the suspension may optionally comprise aprotinin, added to the fibribinogen mixture as a concentrated aqueous solution.
  • Riboflavin may be added as a colorant, so that the suspension may easily be identified once it has been coated onto a carrier and dried.
  • the suspension may have a viscosity so that a volume of 90 - 120 ml of suspension, when influenced by gravity only, exits through a bottom opening of a container having:
  • the container and the opening having the following dimensions:
  • the container and the opening having the following dimensions: - inner diameter of the cylindrical portion: 50 mm,
  • the above exit time for the suspension may be 25 - 60 seconds, such as 25 - 50 seconds, such as 30 - 50 seconds, such as 32 - 44 seconds, such as 34 - 38 seconds.
  • the invention provides a method of preparing a suspension with fibrinogen and thrombin, comprising:
  • the Folk Ward mean diameter of the particles being 25 - 100 ⁇ m.
  • the fibrinogen may be pre-micronised by a suitable method, e.g. sieving, to obtain particles having a Folk Ward mean diameter of 25-100 ⁇ m.
  • the micronised fibrinogen may, for example, be stirred into the alcohol to obtain said fibrinogen mixture.
  • the fibrinogen may be also directly homogenized in an alcohol, preferably at a temperature between 0°C and 12°C, such as between 2°C and 8°C. The temperature may be lowered during homogenization.
  • the step of mixing the fibrinogen mixture and the thrombin mixture may be carried out while stirring the suspension, whereby the stirring may be carried out at a temperature between 0°C and 12 °C, such as between 2° and 8°C.
  • the thrombin may comprise human thrombin, bovine thrombin, or recombinant thrombin
  • the fibrinogen may comprise human fibrinogen or recombinant fibrinogen.
  • the alcohol may be an organic alcohol, such as methanol, ethanol, propanol, isopropanol, such as an anhydrous organic alcohol, an anhydrous ethanol, an anhydrous propanol or an anhydrous isopropanol.
  • Human fibrinogen may be supplied in a solid freeze-dried form.
  • the invention provides a method for coating a carrier with a suspension comprising fibrinogen and thrombin, wherein the suspension has been derived from a method comprising the steps of:
  • the method of coating comprising: - providing the suspension of fibrinogen, thrombin and an alcohol at a location near the carrier,
  • the carrier may be a collagen carrier, such as a collagen sponge.
  • the collagen sponge may fulfil at least one and preferably a plurality of the following criteria :
  • the collagen sponge may be derived from a method comprising the steps of:
  • chamber diameter should be understood as the largest straight-line walt-to-wall distance in a chamber, i.e. the largest diagonal straight-line distance of a chamber.
  • the chambers may be of a polygonal shape, such as of an
  • a chamber diameter of more than 0.75 mm and less than 4 mm, or a chamber diameter of at most 3 mm renders the collagen sponge particularly useful for being coated with a suspension containing fibrinogen and thrombin. It has further been found that a coated collagen sponge prepared by the above method is air and liquid tight in the sense that, once the coated collagen sponge has been applied to
  • the step of applying the suspension to the carrier may be performed at an ambient temperature of 0° - 12°C, such as at 1° - 10 °C, such as at 2° - 8 °C. Further, the step of applying the suspension to the carrier may be carried out in an ambient atmosphere with a
  • a volume of 0.08 ml - 0.12 ml of suspension is preferably applied to the carrier pr. cm 2 of the coating surface.
  • the suspension is preferably distributed evenly over a given width of the coating surface, so that the mass of fibrinogen per area unit of the coating surface varies at most 25%, such as at most
  • An applicator comprising at least one jet may be used for applying the suspension to the carrier, whereby the suspension is forced through the jet while the carrier and the jet are moved relative to each other.
  • the applicator may comprise or be arranged near a conveyor belt, a stirring unit connected to a pump or a system of pumps or another supplying equipment, and a jet or a system of jets which moves transversely, e.g. at right angles to the conveyor belt.
  • the jet or the system of jets may have various shapes and sizes.
  • the jet or the system of jets may be connected to the supplying equipment via tubes.
  • the supplying equipment may promote the coating medium from the stirring unit to the jet systems. During the coating process the jet system may move across the carrier.
  • the coating process may be initiated by a light barrier sensing the presence of a carrier on the conveyor belt, and may likewise be stopped by a light barrier signal.
  • a light barrier sensing the presence of a carrier on the conveyor belt
  • Such an applicator confers a relatively small dead volume, and it is easy to handle, including easy to clean. Furthermore, it confers the possibility to interrupt the coating process at any time, it is applicable in a relatively broad range of viscosities, and it confers a homogenous coating.
  • an applicator comprising a container having a plurality of separate outlets may be used for applying the suspension to the carrier, whereby the suspension is forced from the container through the outlets onto the carrier.
  • the latter of type of applicator in the form of a container having movable plates at its bottom is disclosed in US patent No. 6,177,126 Bl which is hereby incorporated by reference in its entirety. Due to the even distribution conferred by the devices of US 6,177,126 Bl, one of those devices are applied in a preferred embodiment of the invention.
  • the carrier and the applicator are preferably moved relative to each other in a transport direction while the suspension is being applied to the carrier, whereby the rate of movement may be 0.025 m/s - 0.05 m/s, such as 0.03 - 0.04 m/s.
  • the flow rate of suspension applied to the carrier through the applicator may be 400 - 600 ml/min, such as 470 - 550 ml/min, such as 495 - 505 ml/min.
  • the invention in a fourth aspect relates to a method of drying a suspension of fibrinogen, thrombin and an alcohol applied as a wet coating on a coating surface of a carrier, the method comprising the step of submitting the coated carrier to a pressure below 1000 mbar, so as to obtain a dried coating surface on the carrier, so as to fixate the dried coating to the coating surface.
  • a low temperature (2 - 10°C) and a high relative humidity (80 - 95%) may be kept, whereby the structure and the physical properties of the carrier, in particular a carrier in the form of a collagen, such as a collagen sponge, as well as of the fibrinogen and thrombin may be maintained.
  • the suspension may be obtained by:
  • the carrier may be a collagen sponge which has been derived from a method comprising the steps of:
  • the coated carrier may be submitted to said pressure at a temperature of 0°C - 12°C, such as 1°C - 10°C, such as 2°C - 8°C, and/or at a relative humidity of the surrounding atmosphere of 75 - 99%, such as 85 - 95%.
  • a flow of air may pass across the coated carrier during drying, so as to convey vapor away from the coated carrier.
  • the coated carrier is preferably kept at said conditionsfor a period of at least 1 hour, such as at least 2 hours, such as at least 4 hours.
  • the area of the dried coating surface is smaller than the size of the area of the wet coating surface.
  • the area of the dried coating surface is at least 75% the size of the area of the wet coating surface, such as least 80%.
  • the carrier and the dried coating surface together preferably have a water content not exceeding 12% by weight, such as not exceeding 8% by weight.
  • the invention relates to a coated collagen sponge with a coating of fibrinogen and thrombin, wherein the coated collagen sponge has been obtained by a method comprising the steps of: - providing a collagen sponge by a method comprising:
  • the coated collagen sponge having at least one of the following properties:
  • the suspension is distributed evenly over a given width of the coating surface, so that the mass of fibrinogen per area unit of the coating surface varies at most 25%, - the abrasion of the coating is less than 2.0 mg/cm 2 when a sample of the coated material is shaken on a Vibrofix shaker at a frequency of 800 - 1200 rpm for 2 minutes.
  • the even distribution of the suspension over the coating surface improves the efficacy of the coated surface when applied, e.g. for tissue gluing, tissue sealing or haemostasis.
  • the low abrasion of the coating ensures that the coated collagen sponge may be transported, grabbed by a surgeon's hands and/or by a surgical instrument and otherwise handled without loosing the dried suspension, i.e. the coating.
  • the fibrinogen formulation may account for approximately 60 - 90% of the total weight of the coated collagen sponge.
  • the formulation usually contains about 50-60% of weight of the following substances: salts, amino acids and albumin. Fibrinogen alone usually constitutes 40-50% of the formulation.
  • the suspension preferably has a water content of 20 - 80 mg/ml, such as 24 - 32 mg/ml.
  • the thrombin content of the suspension may be 20 - 40 I.U./ml, such as 24 - 33 I.U./ml.
  • the thrombin content after coating may be 2 - 4 I.U./cm 2 over the coating surface, such as 2.3 - 3.3 I.U./cm 2 . It may be desirable that the thrombin content does not exceed 5 I.U./cm 2 at any location on the coating surface, or that it does not exceed 3.8 I.U./cm 2 at any location on the coating surface.
  • the microbiological purity of the coated carrier preferably is at most 4 CFU/cm 2 , such as at most 2.25 CFU/cm 2 .
  • the invention relates to the use of the above-mentioned coated collagen sponge for tissue gluing, tissue sealing and haemostasis.
  • Figs. 1-7 disclose various coated carriers and instruments for applying them, as discussed in Example VIII.
  • Fig. 8 is a flow chart illustrating a chain of sub-processes from producing a suspension to packing a coated collagen sponge
  • Fig. 9 is an illustration of devices used in obtaining a measure for the viscosity of the suspension
  • Figs. 10 and 11 contain a flow chart illustrating a process for obtaining a collagen sponge.
  • a suspension comprising fibrinogen, thrombin and alcohol may be produced by the method for producing a suspension according to the invention, as follows:
  • Fibrinogen is homogenised in a 100% ethanol at 2-8°C, resulting in a mixture of fibrinogen and alcohol, the mixture constituting approximately 80% of the volume of the final suspension volume. Then, riboflavin is added. The mixture is subsequently stirred in a closed vessel until further processing thereof.
  • Human or bovine thrombin is dissoluted with water for injection. The solution is added to a
  • thrombin suspension 35fold amount of 100% ethanol at 0-8°C.
  • the thereby achieved thrombin suspension is homogenised at 0-8°C for 80-100 sec.
  • an aprotinin solution and water for injectionare added to the fibrinogen mixture.
  • the thrombin mixture is added to the fibrinogen mixture.
  • Final volume of suspension is prepared by adding a 100% ethanol at
  • the method for producing a suspension according to the invention comprises the following steps:
  • the fibrinogen mixture is obtained by adding pre-micronised fibrinogen of a particle size of 35-80 ⁇ m Folk Ward mean diameter and riboflavin while stirring to a 94-97% ethanol at 2- 8°C.
  • the thereby resulting mixture of riboflavin and ethanol constitutes approximately 70- 80% of the final suspension volume.
  • the fibrinogen mixture is further stirred in a closed vessel until further processing thereof.
  • the thrombin mixture is obtained by adding thrombin to a 94-97% ethanol at - 30°C.
  • the thereby achieved thrombin mixture is homogenised for 80-lOOsec.
  • the thrombin mixture is obtained by solving thrombin in water for injection, and subsequently the thereby obtained thrombin solution is slowly added to 17-35fo!d amount of 100% ethanol at -30°C.
  • the suspension is homogenised 80-100sec.
  • An UltraTurrax equipment by IKA may be used as a homogenizing equipment.
  • the thrombin mixture is added to the mixture containing fibrinogen and riboflavin. An 94- 97% ethanol at 2-8°C is added.
  • collagen sponge strips are incubated at 2-8°C at 80-91% relative humidity for 2 - 30 hours, before coating of a carrier in the form of a collagen sponge.
  • the applicator for applying the suspension to the collagen sponge is described above.
  • the collagen sponge strips are incubated at 2-8°C and 80-90% relative humidity for 8 - 60 minutes.
  • the coated collagen sponge strips are dried in a vacuum drying chamber at an air temperature of 2-8°C, 80 - 90% relative humidity.
  • An air flow is passed over the collagen strips through an aspiration valve, at an air flow rate of 1,2 - 40 m 3 per hour.
  • a vacuum of 30-60 mbar is applied, i.e.
  • the device shown to the right in Fig. 9 is made from a plastic material, and the container and the bottom opening have the following dimensions: inner diameter of the cylindrical portion: 50 mm,
  • Examples I - VI below illustrate various procedures for preparation of a coated collagen sponge with a coating of fibrinogen and thrombin according to the invention.
  • the procedures include methods of preparing a suspension according to the invention, resulting, in the embodiments described below, in suspensions according to the invention. Further, methods for coating according to the invention and methods for drying according to the invention are applied.
  • the suspension contains human fibrinogen formulation B and human thrombin formulation B.
  • a final suspension volume of 3500 ml was obtained by a group II method by applying the following quantities and parameters: Fibrinogen mixture:
  • the fibrinogen mixture was stored for 20 hours at 2-8°C while being stirred.
  • Thrombin mixture :
  • the thrombin mixture was stored for l ⁇ hours at -30°C. Suspension:
  • thrombin mixture - 157 ml of thrombin mixture are added to the fibrinogen mixture. - A 94% ethanol at 2 - 8°C was added to fill to the final suspension volume of 3500 ml.
  • coated collagen sponge strips were dried as follows:
  • the coated strips were incubated for 15 minutes at a temperature of 5.2°C and an absolute humidity of 4.8 g water per kg air.
  • the coated strips were then dried in a vacuum drying chamber at the following drying conditions:
  • the abrasion of the obtained coating on the collagen sponge strips was approximately 0.2 mg/cm 2 when a sample of 1x5cm 2 is shaken in a test-tube on a Vibrofix shaker at a frequency of 800 - 1200 rpm for 2 minutes.
  • the suspension contains human fibrinogen formulation C and human thrombin formulation C.
  • a final suspension volume of 3500 ml was obtained by a group II method by applying the following quantities and parameters: Fibrinogen mixture:
  • the fibrinogen mixture was stored for 20 hours at 2-8°C while being stirred.
  • Thrombin mixture :
  • Sedimentation behaviour a) sedimentation volume 5 minutes after start: 94% of test volume, b) sedimentation volume 24 hours after start: 71% of test volume.
  • coated collagen sponge strips were dried as follows:
  • the coated strips were incubated for 13 minutes at a temperature of 4.9°C and an absolute humidity of 4.8 g water per kg air.
  • the coated strips were then dried in a vacuum drying chamber at the following drying conditions:
  • the abrasion of the obtained coating on the collagen sponge strips was approximately 0.2 mg/cm 2 when a sample of 1x5cm 2 is shaken in a test-tube on a Vibrofix shaker at a frequency of 800 - 1200 rpm for 2 minutes.
  • the suspension contains human fibrinogen formulation B and human thrombin formulation B, and aprotinin.
  • a final suspension volume of 1000 ml was obtained by a group II method by applying the following quantities and parameters: Fibrinogen mixture:
  • the thrombin mixture was stored for 16hours at -30°C. Suspension:
  • the total volume of thrombin mixture was added to the fibrinogen mixture.
  • Carriers in the form of collagen strips were coated with the suspension.
  • 16 collagen sponge strips were pre-incubated in a cooling chamber, at the following conditions:
  • coated collagen sponge strips were dried as follows:
  • the coated strips were incubated for 35 minutes at a temperature of 5°C and a relative humidity of 85%.
  • the coated strips were then dried in a vacuum drying chamber at the following drying conditions:
  • the abrasion of the obtained coating on the collagen sponge strips was approximately 0.2 mg/cm 2 when a sample of 1x5cm 2 is shaken in a test-tube on a Vibrofix shaker at a frequency of 800 - 1200 rpm for 2 minutes.
  • the suspension contains human fibrinogen formulation C and human thrombin formulation C.
  • a final suspension volume of 780 ml was obtained by a group II method by applying the following quantities and parameters: Fibrinogen mixture:
  • the fibrinogen mixture was stored for 20 hours at 2-8°C while being stirred.
  • the thrombin mixture was stored for 16 hours at -30°C. Suspension:
  • Sedimentation behaviour a) sedimentation volume 5 minutes after start: 92% of test volume, b) sedimentation volume 24 hours after start: 72% of test volume.
  • Carriers in the form of collagen strips were coated with the suspension.
  • 8 collagen sponge strips were pre-incubated in a cooling chamber, at the following conditions:
  • coated collagen sponge strips were dried as follows:
  • the coated strips were incubated for 45 minutes at a temperature of 5°C and a relative humidity of 85%.
  • the coated strips were then dried in a vacuum drying chamber at the following drying conditions: - Air condition: temperature of 5°C, relative humidity 85%
  • the abrasion of the obtained coating on the collagen sponge strips was approximately 0.2 mg/cm 2 when a sample of 1x5cm 2 is shaken in a test-tube on a Vibrofix shaker at a frequency of 800 - 1200 rpm for 2 minutes.
  • the suspension contains human fibrinogen formulation A and human thrombin formulation A.
  • a final suspension volume of 3120 ml was obtained by a group I method by applying the following quantities and parameters: Fibrinogen mixture:
  • coated collagen sponge strips were dried as follows: The coated strips were incubated for 10 minutes at a temperature of 6.5°C and a relative humidity of 90%.
  • the coated strips were then dried in a vacuum drying chamber at the following drying conditions:
  • Air condition temperature of 6.5°C, relative humidity 90% - Air flow through aspiration valve: 21 m 3 per hour
  • the abrasion of the obtained coating on the collagen sponge strips was approximately 0.2 mg/cm 2 when a sample of 1x5cm 2 is shaken in a test-tube on a Vibrofix shaker at a frequency of 800 - 1200 rpm for 2 minutes.
  • the suspension contains human fibrinogen formulation A and bovine thrombin formulation, and aprotinin.
  • a final suspension volume of 16720 ml was obtained by a group I method by applying the following quantities and parameters: Fibrinogen mixture:
  • coated collagen sponge strips were dried as follows:
  • the coated strips were incubated for 10 minutes at a temperature of 6.5°C and a relative humidity of 89%.
  • the coated strips were then dried in a vacuum drying chamber at the following drying conditions:
  • the abrasion of the obtained coating on the collagen sponge strips was approximately 0.2 mg/cm 2 when a sample of 1x5cm 2 is shaken in a test-tube on a Vibrofix shaker at a frequency of 800 - 1200 rpm for 2 minutes.
  • FIG. 7 endoscopic tool: Endodock® endoscopic tool: Endodock® endoscopic tool: Endodock® Comparison of coated Nycomed sponge (TachoComb S) with other carrier products coated identically as TachoComb S.
  • An area of 2x4,5cm 2 of each carrier was coated with TachoComb S coating suspension.
  • the amount of coating suspension corresponded to TachoComb specification (5,5mg fibrinogen/cm 2 ).
  • the samples were dried. 2.
  • a sample of about 5-7cm 2 was prepared of each coated carrier. The exact starting area of the dry sample was determined.
  • IKA PA-SF Peristaltic pump
  • a double sheet of about 8x8cm 2 is cut from a Latex glove. This sheet is fixed airtight to the glass funnel/ opening 1.
  • Latex sheet is expanded by putting on a pressure of about
  • the elasticity of the moistened Collagen sponge Nycomed is one of the important characteristics of the product. Elasticity is essential in thoracic and abdominal surgery. After gluing the carrier should be able to follow for example expansion and relaxation movements of the lungs or intestines. Especially Ethisorb ® showed no elasticity at all. It detached from the coating immediately. Coated Willospon ® Spezial and Opraskin ® showed structural defects during the test.
  • the amount of coating suspension corresponded to TachoComb specification (5,5mg fibrinogen/cm 2 ). The samples were dried.
  • Apparatus Endodock Endoscopic tool designed for the use of TachoComb ® in endoscopic surgery (see Figure 7). Digital photo-equipment. List of investigated carriers
  • TachoComb coated equine collagen sponge/Nycomed
  • endoscopic surgery is the most demanding application of the product.
  • TachoComb is inserted into an endoscopic equipment.
  • the tube of this equipment is generally 10-13mm in diameter.
  • TachoComb is flattened and then wrapped around a guiding felicitpin" and then inserted carefully into the tube. Therefore the connection of the coating to the carrier and within itself has to be strong but the product has to stay flexible enough in dry condition to be bent and rolled up.
  • TachoComb is carefully pulled out of the tube. Then it has to be unwrapped and placed to the wound surface. This often requires some adjustments. Therefore adhesion of the layer to the carrier should be strong enough to withstand this handling.
  • Nycomed collagen sponge The structure and texture of Nycomed collagen sponge is the basis of the high flexibility of TachoComb in dry or moistened conditions.
  • Nycomed collagen sponge is foamed and has polygonal chambers inside. On the surface these chambers are cut to caverns. These caverns enlarge the coating surface.
  • the coating suspension is distributed evenly onto the structured surface.
  • the solution containing both fibrinogen and thrombin is fixed as solids into the caverns. Therefore TachoComb can be cut to desired sizes and can be inserted into endoscopic equipment with only a small loss of coating material or no loss at all.
  • the high flexibility of dry TachoComb is a big advantage compared to all other investigated coated carriers.
  • the collagen sponge referred to in the present text may be manufactured by a method as generally illustrated in Figs. 10 and 11 and as described below:
  • a collagen sponge with a fibrin glue preparation depends on the texture of the collagen sponge. It is thus desirable to provide a method of producing a collagen sponge with a certain texture, in particular with the aim of making the collagen sponge suitable for coating with a fibrin glue preparation, so as to obtain a material for healing and sealing wounds. It is further desirable to provide a method of producing a collagen sponge having improved physical characteristics in relation to prior art sponges, in the sense of improved humidity, elasticity, density and elasticity module. It is further desirable to provide a method for preparing a collagen sponge which is air and liquid tight in the sense that, once the collagen sponge is applied to a wound, it will not allow air or liquid to soak through the collagen sponge.
  • the method of preparing the collagen sponge may comprise the steps of:
  • chamber diameter should be understood as the largest straight-line wall-to-wall distance in a chamber, i.e. as the largest diagonal straight-line distance of a chamber.
  • the chambers may be of a polygonal shape, such as of an octagonal shape.
  • the collagen gel has a dry mass in the range of 2-20 mg dry mass per 1 g gel, such as 4-18 mg, such as 5-13 mg, such as 6-11 mg per 1 g gel.
  • the dynamic viscosity of the collagen gel is preferably 2-20 Ncm, such as 4-10 Ncm, such as 6-8 Ncm.
  • the collagen sponge preferably has a water content of not more than 20%, such as 10-15%, such as about 18%.
  • the elasticity module of the collagen sponge is preferably in the range of 5-100 N/cm, such as 10-50 N/cm, and the density of the sponge is preferably 1-10 mg/cm 3 , such as 2-7 mg/cm 3 .
  • the collagen sponge may comprise material of different types, such as type I, II or III from mammalian, transgenic or recombinant sources, but all other types of collagen can be used.
  • the collagen may comprise material from tendons selected from the group consisting of equine tendons, human tendons, and bovine tendons.
  • the collagen gel may additionally or alternatively comprise recombinant collagen material.
  • the collagen content of the isolated parts of sponge is preferably 50% - 100% related to dry mass of the sponge, such as 75% - 100%, such as 80% - 100%, such as 85% - 100%, such as 90% - 100%, such as 92 - 100%, such as 92 - 98%, such as 93 - 97%, such as 94% - 96%.
  • the step of preparing the collagen gel preferably comprises the steps of:
  • the steps of storing, peeling, removing protein, reducing of germ content, and swelling aim at purifying the raw material, whereas the step of homogenising aims at obtaining the collagen in the form of a gel.
  • the step of reducing of germ content preferably comprises adding an acid, such as an organic acid, such as lactic acid to the tendons.
  • an organic solvent such as an alcohol, such as ethanol is preferably added to the tendons.
  • the step of swelling of the tendons preferably comprises adding lactic acid to the tendons.
  • the lactic acid used may be a 0.40 - 0.50% lactic acid, such as a 0.45% lactic acid.
  • the step of swelling of the tendons may comprise storing the tendons at a temperature of 4°C to 25°C, such as a temperature of 10°C to 20°C, for a period of 48 to 200 hours, such as a period of 100 to 200 hours.
  • the step of homogenising the swelled tendons is preferably carried out so as to obtain a particle size of collagen gel fragments, i.e. fibre balls, with a diameter of 0.8 - 1.2 cm, such as approximately 1 cm.
  • the physical characteristics of the collagen gel are preferably as stated above. The appropriate characteristics may for example be achieved by performing the step of homogenising the swelled tendons by means of a toothed disk mill or adequate homogenisation equipment.
  • the step of mixing air into the collagen gel preferably comprises the steps of:
  • the ratio between the amount of collagen gel which is led back to the mixer from the fractionising channel and the amount of fresh collagen gel led to the mixer is preferably between 0.1 and 0.5.
  • the step of separating collagen gel and collagen foam preferably comprises the steps of:
  • a temperature of 15°C to 40°C, such as 20°C to 25°C is maintained in the fractionising channel.
  • the collagen foam may be homogenised for a period of 2 to 4 minutes.
  • a neutraliser may be added to the collagen foam, and the collagen foam is preferably neutralised in order to arrive from a pH-value of, usually, between 2.5 and 3.5 to a pH-value in the collagen foam between 6.5 and 8.5.
  • a neutraliser comprising an ammonia solution may be used, and the collagen foam is preferably neutralised for a period of 5-30 hours, such as 10-20 hours, such as approximately 24 hours.
  • the collagen foam Prior to the step of drying the collagen foam, the collagen foam is preferably filled into a drying container in such a way that substantially no air is drawn into the foam while filling.
  • the step of drying preferably comprises drying at a temperature between 15°C and 60°C, such as between 20° and 40°C, for a period of 50-200 hours, such as 100-150 hours, so as to obtain a dry collagen sponge.
  • the drying may be performed at a pressure slightly under atmospheric pressure, such as at a pressure of between 700 and 900 mbar, such as approximately 800 mbar.
  • the collagen sponge produced by the above method preferably fulfils at least one of the following criteria: - pH-value between 5.0 and 6.0,
  • - density of 1-10 mg/cm 3 such as 2-7 mg/cm 3
  • - elasticity module of 5-100 N/cm such as 10-50 N/cm.
  • the step of isolating parts of collagen sponge may comprise dividing the collagen sponge into a plurality of parts by cutting.
  • the parts obtained may be shaped in any desirable form, such as conical, cylindrical, including cylindrical with an annular cross-section, rectangular, polygonal, cubic, and flat sheets or they may be transformed into a granulate by an appropriate granulating method etc.
  • the collagen sponge may be produced by a method, comprising the steps of: - preparing a collagen gel,

Abstract

La présente invention concerne une suspension à base de fibrinogène, de thrombine, d'alcool, et éventuellement d'aprotinine, obtenue par mélange de fibrinogène dans l'alcool avec de la thrombine dans l'alcool. La suspension contient des particules de fibrinogène et de thrombine d'un diamètre moyen de Folk Ward de 25 à 100 µm. La thrombine peut être d'origine humaine ou bovine, ou résulter d'une recombinaison. L'invention concerne également un procédé d'enrobage d'un support tel qu'une éponge de collagène, avec la suspension, et un procédé de séchage de l'enrobage. Le support de collagène enrobé convient particulièrement comme composition absorbable prête à l'emploi pour le collage des tissus, la fermeture de tissus et l'hémostase, auquel cas, le support est enrobé de composants solidement maintenus de colle fibrinique, c'est-à-dire fibrinogène et thrombine.
EP02734886A 2001-01-25 2002-01-25 Suspension a base de fibrinogene, thrombine et alcool et methode pour revetir un support Ceased EP1359947A2 (fr)

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DKPA200100135 2001-01-25
DK200100135 2001-01-25
DK200100235 2001-02-13
DKPA200100235 2001-02-13
PCT/IB2002/001454 WO2002058750A2 (fr) 2001-01-25 2002-01-25 Suspension à base de fibrinogène, thrombine et alcool et mode d'élaboration, procédés d'enrobage d'un support d'une telle suspension et de séchage de l'enrobage du support, et éponge enduite de collagène

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EP02718481A Expired - Lifetime EP1368419B1 (fr) 2001-01-25 2002-01-25 Procede permettant de preparer une eponge collagenique, dispositif permettant d'extraire une partie de mousse collagenique, et eponge collagenique allongee
EP02734886A Ceased EP1359947A2 (fr) 2001-01-25 2002-01-25 Suspension a base de fibrinogene, thrombine et alcool et methode pour revetir un support
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