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    • 专利摘要:
    sponge, use of a sponge, method of treating an injury, kit, method of manufacturing a hemostatic sponge, and hemostatic composite. The present invention provides a hemostatic porous composite sponge comprising i) a matrix of a biomaterail and ii) a hydrophilic polymeric component comprising reactive groups wherein i) and ii) are associated with each other such that the reactivity of the polymeric component is retained. wherein associated means that - said polymeric component is coated on a surface of said matrix of a biomaterial, or - said matrix is impregnated with said polymeric material, or - both.
    公开号:BR112012025391B1
    申请号:R112012025391-3
    申请日:2011-04-07
    公开日:2019-05-14
    发明作者:Hans Christian Hedrich；Joris Hoefinghoff
    申请人:Baxter International Inc；Baxter Healthcare S.A；
    IPC主号:
    专利说明:

    "POROUS COMPOSITE SPONGE HEMOSTATIC, KIT, METHOD OF MANUFACTURING A HEMOSTATIC SPONGE, AND, HEMOSTATIC COMPOSITE"
    Field of invention
    The present invention relates to the field of hemostatic sponges, a method of producing said sponges and their various uses. Fundamentals of the Invention
    Biological glues based on human or animal coagulation factors have been known for a long time. A method for producing tissue adhesives based on fibrinogen and factor XIII has been described in US 4,362,567, US 4,298,598 and US 4,377,572. Tissue patches are generally applied together with a separate component containing thrombin, which is enzymatically acting on fibrinogen to form fibrin, and on factor XIII to form active factor XIIIa, which cross-links fibrin to obtain a stable fibrin clot.
    Collagen tampons have been used for many years to improve wound healing or to stop bleeding. Its mechanism of action in hemostasis is based on aggregation and activation of platelets, the formation of thrombin on the surface of activated platelets and the formation of a hemostatic fibrin clot by the catalytic action of thrombin on fibrinogen. To improve the hemostatic action of collagen plugs or sheets, the inclusion of hemostasis factors within such plugs has been suggested.
    In US 4,600,574 a collagen-based tissue adhesive combined with fibrinogen and factor XIII is described. This material is supplied in lyophilized form, ready for use. Fibrinogen and factor XIII are combined with collagen through the impregnation of collagenous flat material, with a solution comprising fibrinogen and factor XIII, and lyophilization of said material.
    Petition 870180060542, of 07/13/2018, p. 24/86
    WO 97/37694 describes a collagen-based hemostatic sponge and a blood clotting activator or proactivator homogeneously distributed therein. The sponge is supplied in a dry form, which can be air dried or lyophilized. However, it still contains a water content of at least 2%.
    US 5,614,587 describes bioadhesive compositions comprising cross-linked collagen using a multifunctionally activated synthetic hydrophilic polymer, as well as methods of using such compositions to effect adhesion between a first surface and a second surface, where at least one of the first and second surfaces can be a surface of native tissue.
    W02004028404 describes a fabric sealant composed of a synthetic collagen or gelatin and an electrophilic cross-linking agent, which are supplied in a dry state. After moistening this composition to an appropriate pH the reaction between the 2 components occurs and a gel with the sealing properties is formed. Such a sealant works in an essentially analogous way with other known two-component seals (composed of a reagent with multiple electrophilic groups, and a reagent with multiple nucleophilic groups), which are known in the art, or are available on the market, for example. example, Coseal ™. In a special embodiment of the invention, the two components of the sealant (the electrophilic crosslinker and the synthetic collagen / gelatin) are coated on a biomaterial.
    Compositions containing collagen that have been mechanically disrupted to alter their physical properties are described in US 5,428,024, US 5,352,715, and US 5,204,382. These patents generally refer to fibrillar and insoluble collagens. An injectable collagen composition is described in US 4,803,075. An injectable bone / cartilage composition is described in US 5,516,532. A collagen-based distribution matrix comprising dry particles in the size range from 5 pm to 850 pm, which can be suspended in water and which has a particular surface charge density is described in WO 96/39159. The collagen preparation having a particle size of 1 pm to 50 pm, usable as an aerosol spray to form a wound dressing is described in US 5,196,185. Other patents describing collagen compositions include US 5672336 and US 5356614.
    Summary of the Invention
    The object of the invention is a porous hemostatic composite sponge comprising
    i) a matrix of a biomaterial and ii) a hydrophilic polymeric component comprising reactive groups in which i) and ii) are associated with each other, so that the reactivity of the polymeric component is retained, where associated means that
    - said polymeric component is coated on a surface of said matrix of a biomaterial, or
    - said matrix is impregnated with said polymeric material, or
    - both.
    Previous buffers of fibrous biomaterials, in particular collagen buffers, for wound healing have been found to fail to induce hemostasis in conditions with impaired hemostasis (for example, after heparinization). The sponge according to the present invention improves hemostasis. In addition, the sponge according to the present invention shows strong adherence to the fabric when applied to a wound. The sponge of the present invention shows even improved swelling behavior, i.e., low swelling after application to a wound.
    Another aspect refers to a method of treating an injury, comprising administering a porous, hemostatic composite sponge to the injury site.
    Also provided is a kit for preparing a wound dressing, comprising a sponge, as described herein, and a buffer solution. This kit and its components are, in particular, for the manufacture of a medical sponge for the treatment of an injury.
    Those skilled in the art will readily understand that all of the preferred embodiments described below are examples of specific embodiments, but are not necessarily limiting the general inventive concept. In addition, all special embodiments can be read in all aspects and embodiments of the invention in any combination, if they are not mutually exclusive. All obvious equivalents or changes or modifications, as recognized by those skilled in the art, are included in the present invention.
    Detailed Description of the Invention
    The object of the invention is a porous hemostatic composite sponge comprising a porous hemostatic composite sponge comprising
    i) a matrix of a biomaterial and ii) a hydrophilic polymeric component comprising reactive groups in which i) and ii) are associated with each other, so that the reactivity of the polymeric component is retained, where associated means that
    - said polymeric component is coated on a surface of said matrix of a biomaterial, for example, as a continuous or discontinuous layer of at least one surface of said sponge, or
    - said matrix is impregnated with said polymeric material or
    - both.
    The term impregnated, as used here, includes the term absorption of polymeric material in a matrix of a biomaterial.
    The terms sponge, buffer and blanket are used interchangeably in the description of the present invention.
    Preferably, the biomaterial is collagen, a protein, a biopolymer or a polysaccharide. Especially preferred is a biomaterial selected from the group consisting of collagen, gelatin (especially cross-linked gelatin), fibrin, a polysaccharide (especially chitosan, oxidized cellulose, aldehyde-activated dextrans, starch-based polyaldehydes (obtainable by periodate oxidation)), a synthetic biodegradable biomaterial (especially polylactic acid or polyglycolic acid, and derivatives thereof, more preferably collagen).
    In accordance with the present invention, a porous composite material comprising a water-insoluble matrix of a biomaterial with hemostatic properties and a hydrophilic polymeric crosslinking agent is provided in association with it.
    In contact with the bleeding tissue, the crosslinking reaction of the hydrophilic polymeric crosslinker with the proteins in the blood leads to the formation of a gel with sealing and hemostatic properties. Cross-linking also occurs for tissue surface proteins and, depending on the nature of the water-insoluble matrix biomaterial, it can also occur for the matrix biomaterial. The latter reaction contributes to an improved adhesion of the composite material to the surface of the injured tissue.
    Furthermore, it is important for the hemostatic effectiveness of the composite according to the present invention that the biomaterial matrix has imbibition capabilities, that is, it is capable of imbibing / absorbing liquids, such as blood, serum, plasma.
    These embedding capabilities are especially dependent on the hydrophilic nature of the polymer from which the matrix is made, and a three-dimensional structure of open interconnected pores, or a three-dimensional mesh of hydrophilic fibers. The pore size and the elasticity of the matrix are also important for imbibition capacity. Elasticity means that the matrix can be compressed in an aqueous solution and return to its initial volume after the force causing the compression to be relieved.
    The sponge is a porous network of a biomaterial capable of absorbing body fluids when applied to the site of an injury. This allows blood from a wound (including all blood components, such as blood cells or clotting proteins) to enter the sponge. The porous sponge according to the present invention therefore has an interior volume that is accessible to external fluids, such as blood, when applied to a patient. For example, a porous collagen sponge can be made by lyophilizing a gel, suspension or collagen solution, by lyophilization (whereas drying by normal air leads to a collagen film). It follows that, in the case of collagen, the resulting porous sponge according to the present invention typically has from 5 to 100 mg of collagen / cm 3 , while collagen films have 650 to 800 mg of collagen / cm 3 . If external fluids, such as blood, come in contact with the sponge according to the present invention, the hydrophilic polymeric component comprising reactive groups can react with the blood components and / or with the surface of the biomaterial matrix in order to cross-link the components that bind to reactive groups (at least two). In addition, the sponge is generally flexible and suitable to be applied to various fabrics and locations with various shapes.
    The collagen used for the present invention can be of any collagen material, including liquid, pasty, fibrous or powder materials that can be processed into a porous matrix, especially a porous and fibrous one. The preparation of a collagen gel for the production of a sponge is, for example, described in EP 0891193 (incorporated by reference) and can include acidification until gel formation and subsequent pH neutralization occurs. To improve gel-forming or solubility capabilities, collagen can be (partially) hydrolyzed or modified, as long as the property to form a stable sponge when dry is not diminished.
    The collagen or gelatin in the sponge matrix is preferably of animal origin, preferably bovine or equine. However, human collagen can also be used in the event of a patient's hypersensitivity to xenogenic proteins. In addition, synthetic or recombinant collagen can be used. The additional components of the sponge are preferably of human origin, which makes the sponge especially suitable for application to a human.
    In a preferred embodiment, the porous collagen sponge contains about 5 to about 50, for example, about 10 to about
    30, preferably about 25 mg of collagen / cm of dry sponge.
    The biomaterial can be non-cross-linked or cross-linked, preferably the biomaterial has been cross-linked.
    The hydrophilic polymeric component of the sponge according to the present invention is a hydrophilic crosslinker, which is able to react with its reactive groups, once the sponge is applied to a patient (for example, to a wound of a patient or another where the patient is in need of hemostatic activity). Therefore, it is important for the present invention that the reactive groups of the polymeric component are reactive when applied to the patient. Therefore, it is necessary to manufacture the sponge according to the present invention so that the reactive groups of the polymeric component that are to react once they are applied to a wound are retained during the manufacturing process.
    This can be done in several ways. For example, common hydrophilic polymeric components have reactive groups that are susceptible to hydrolysis after contact with water. Therefore, premature contact with water or aqueous liquids needs to be avoided before administering the sponge to the patient, especially during manufacture. However, processing of the hydrophilic polymeric component during manufacture may also be possible in an aqueous medium under conditions where the reactions of the reactive groups are inhibited (for example, at a low pH). If the hydrophilic polymeric components can be melted, the melted hydrophilic polymeric components can be sprayed or printed on the biopolymer matrix. It is also possible to sprinkle a dry form (for example, a powder) of the hydrophilic polymer component on the matrix. If necessary, then a temperature rise can be applied to melt the hydrophilic polymer component sprinkled on the matrix to achieve a permanent sponge coating. Alternatively, these polymeric hydrophilic components can be absorbed in inert organic solvents (inert to the reactive groups of the hydrophilic polymeric components) and carried into the biomaterial matrix. Examples of such organic solvents are dry ethanol, dry acetone or dry dichloromethane (which are, for example, inert to the polymeric, hydrophilic components, such as NHS-ester substituted PEG).
    In a preferred embodiment, the hydrophilic polymer component is a single hydrophilic polymer component and is a polyalkylene oxide polymer, especially preferred a polymer comprising PEG hereinafter called the material. The reactive groups of said material are preferably electrophilic groups.
    The material can be a multielectrophilic polyalkylene oxide polymer, for example, a multielectrophilic PEG. The material can include two or more electrophilic groups such as -CON (COCH 2 ) 2, -CHO, -N = C = O, and / or -N (COCH 2 ) 2, for example, a component as described in W02008 / 016983 (incorporated herein by reference in its entirety) and one of the components of those commercially available under the trademark CoSeal® '
    Preferred electrophilic groups of the hydrophilic polymeric crosslinker according to the present invention are reactive groups for the amino-, carboxy-, thiol and hydroxy groups of proteins, or mixtures thereof.
    Specific reactive groups for preferred amino groups are NHS-ester groups, imidoester groups, aldehyde groups, carboxy groups, in the presence of carbodiimides, isocyanates, or THPP (beta- [tris (hydroxymethyl) phosphino] -propionic acid), being especially preferred pentaerythritolpoli (ethylene glycol) tetrasuccinimidyl glutarate ether (= pentaerythritol tetrakis [1-Γoxo-5'-succinimidylpentanoate-2-poly-oxoethylene glycol] ether (= an NHS-PEG with 10,000 MW).
    Preferred reactive groups for the carboxy group are amino groups in the presence of carbodiimides.
    The reactive groups specific groups for thiol group are maleiimides or haloacetyls.
    The preferred reactive group for the preferred thiol group is the isocyanate group. The reactive groups in the hydrophilic crosslinker can be identical (homofunctional) or different (heterofunctional). The hydrophilic polymeric component can have two reactive groups (homobifunctional or heterobifunctional) or more (homo / heterotrifunctional or more).
    In special embodiments, the material is a synthetic polymer, preferably comprising PEG. The polymer can be a PEG derivative comprising active side groups suitable for crosslinking and adhering to a fabric.
    By reactive groups the hydrophilic polymer has the ability to cross-link blood proteins and also tissue surface proteins. Crosslinking with biomaterial is also possible.
    Multielectrophilic polyalkylene oxide can include two or more succinimidyl groups. Multielectrophilic polyalkylene oxide can include two or more maleimidyl groups.
    Preferably, the multielectrophilic polyalkylene oxide is a polyethylene glycol or a derivative thereof.
    In a more preferred embodiment, the polymeric component is pentaerythritolpoli (ethylene glycol) tetraassuccinimidyl glutarate ether (= COH102, also pentaerythritol tetraquis [l-l'-oxo-5'succinimidylpentanoate-2-poly-oxoethyleneglycol) is.
    In a preferred embodiment, the sponge of the present invention comprises as collagen as a biomaterial and the polymeric component, for example, COH102, is coated on the surface of the collagen (= coated form). The especially preferred coating is a batch coating, for example, as shown in Figure 6.
    In another preferred embodiment, the coating is a continuous thin coating, as obtained, for example, by spraying the polymeric component from the melt onto the biomaterial matrix. This coating is comparable to a film-like or glass-like structure, as, for example, shown in Figure 7.
    In another preferred embodiment, the sponge of the present invention comprises collagen as a biomaterial and the polymeric component, for example, COH102, is impregnated in the collagen (= impregnated form).
    The molecular weight of the polymeric component is preferably in the range of 500 to 50,000, preferably about 10,000.
    The amount of polymeric component coating on the sponge of said biomaterial is preferably from about 1 mg / cm 2 to about 20 mg / cm, more preferably about 2 mg / cm to about 14 mg / cm, for the sponge coated. The concentration of polymeric component
    3 is preferably from about 5 mg / cm to about 100 mg / cm, more preferably from about 10 mg / cm to about 70 mg / cm for an impregnated sponge.
    In another preferred embodiment, the sponge of the present invention comprises a combination of impregnated and coated forms. In addition, the sponge according to the present invention maintains the reactivity of the reactive groups of the hydrophilic polymeric component comprising reactive groups when dry, for example, with a total water content of less than 10%, especially less than 2% and, especially below 1% in the case of the polymeric component having hydrolyzable reactive groups, for example, NHS-PEG. Higher water contents (for example, greater than 10%) can also result in a functional sponge, but the storage stability would be worsened. Therefore, water contents below 2% (w / w) are preferred, below 1% is even more preferred, below 0.5% is specifically preferred.
    In another preferred embodiment, another layer of another biomaterial is present. The additional layer may be the same biomaterial as the matrix or it may be a different biomaterial, for example, the biomaterial matrix is collagen and the other layer is oxidized cellulose. All combinations of biomaterials as mentioned above can be included.
    The sponge as a whole can be biodegradable, being suitable for biological decomposition in vivo, or bioresorbable, that is, capable of being reabsorbed in vivo, for example, through degradation by proteases that are present in vivo and groups that are hydrolyzable in alive. Complete resorption means that no significant extracellular fragments remain. A biodegradable material differs from a non-biodegradable material in that a biodegradable material can be biologically decomposed into units that can be either removed from the biological system and / or chemically incorporated into the biological system. In a preferred embodiment, the material in particular, the matrix material or a sponge as a whole can be degraded by an individual, in particular a human individual, in less than six months, less than 3 months, less than 1 month less than 2 weeks.
    The sponge may further comprise a blood clotting activator or proactivator, including fibrinogen, thrombin or a thrombin precursor, for example, as described in US 5,714,370 (incorporated herein by reference). Thrombin or the precursor of thrombin is understood as a protein that has thrombin activity, and that induces thrombin activity, when it is contacted with blood or after application to the patient, respectively. Its activity is expressed in thrombin activity (NIH Unit) or the equivalent thrombin activity developing the corresponding NIH unit. The activity on the sponge can be 100-10,000, preferably 500-5,000. In the following thrombin activity is understood to comprise either thrombin activity or any equivalent activity. The protein with thrombin activity can be selected from the group consisting of alpha-thrombin, meizothrombin, a derivative of thrombin or recombinant thrombin. An appropriate precursor is possibly selected from the group consisting of: prothrombin, factor Xa, optionally together with phospholipids factor IXa, activated prothrombin complex, FEIBA, any activator or a proactivator of intrinsic or extrinsic coagulation, or mixtures thereof.
    The hemostatic sponge according to the invention can be used in conjunction with other physiological substances. For example, the sponge preferably further comprises pharmacologically active substances, including antifibrinolytics, such as a plasminogen activator inhibitor or plasmin inhibitor or fibrinolytic inactivator. The preferred antifibrinolytic is selected from the group consisting of an aprotinin or aprotinin derivative, alpha2-macroglobulin, inhibitor or inactivator of protein C or activated protein C, a substrate mimetic binding plasmin, which acts competitively with natural substrates, and an antibody inhibiting fibrinolytic activity.
    As another pharmacologically active substance, an antibiotic, such as an antibacterial or antimycotic, can be used together with the sponge according to the invention, preferably as a component homogeneously distributed in the sponge. Other bioactive substances such as growth factors and / or pain relievers may also be present in the inventive sponge. Such a sponge can be useful in healing wounds, for example.
    Other combinations are preferred with specific enzymes or enzyme inhibitors, which can regulate, that is, accelerate or inhibit, the resorption of the sponge. Among these are collagenase, its enhancers or inhibitors. In addition, an appropriate preservative may be used in conjunction with the sponge or may be contained in the sponge.
    Although a preferred embodiment relates to the use of the hemostatic sponge containing the blood clotting activator or proativator as the only active component, additional substances that influence blood clotting speed, hemostasis and the quality of the sealing, such as tensile strength , internal resistance (adhesive) and durability can be understood.
    Pro-coagulants that increase or improve intrinsic or extrinsic coagulation, such as blood clotting factors or cofactors, factor XIII, tissue factor, prothrombin complex, activated prothrombin complex, or parts of the complexes, a prothrombinase complex, phospholipids and calcium ions, protamine, can be used. In the case of a surgical procedure in which precise sealing is required, it may be preferable to extend the working period after the hemostatic sponge is applied to the patient and before coagulation is performed. The prolongation of the clotting reaction will be ensured, if the sponge according to the invention still comprises blood clotting inhibitors in appropriate amounts. Inhibitors, such as antithrombin III, optionally together with heparin, or any other serine protease inhibitor, are preferred.
    It is also preferable to have such additives, in particular thrombin or a thrombin precursor uniformly distributed in the material in order to avoid local instability or hypercoagulability of the material. Even with a certain water content, thrombin activity is surprisingly stable, probably due to the intimate contact of thrombin and collagen in the homogeneous mixture. Even so, thrombin stabilizers preferably selected from the group consisting of a polyol, a polysaccharide, a polyalkylene glycol, amino acids or mixtures thereof, can be used according to the invention. Exemplary use of sorbitol, glycerol, polyethylene glycol, propylene glycol, mono- or disaccharides, such as glucose or sucrose or any sulfonated sugar or amino acid capable of stabilizing thrombin activity is preferred.
    Other examples of additives that can be used in accordance with the present invention include substances such as vasoconstrictors, antibiotics or fucoidans.
    The sponge of the present invention may further contain a dye, for example, riboflavin, or another dye known in the prior art to be biocompatible. The dye can be included, for example, as an additional layer (coating) and can especially assist the surgeon in identifying which of the surfaces of a coated sponge of the present invention is the active or inactive surface, respectively.
    The sponge of the present invention preferably has a total thickness of less than 3 cm, preferably about 1 mm to about 3 cm, more preferably about 1 mm to about 2 cm, more preferably about 1 mm to about 2 mm.
    In a sponge of the present invention, the thickness of the coating is preferably from about 0.01 mm to about 1 mm.
    The sponge of the present invention is preferably used in minimally invasive surgery, for example, for laparoscopic application.
    The sponge can be dried and after drying, the sponge can have a water content of at least 0.5 (percentages given in w / w here). In some embodiments, the sponge can be lyophilized or air dried.
    The present invention also provides a wound cover comprising a sponge according to the invention. The sponge and all additional layers can be provided in a ready-to-use wound cover in appropriate dimensions. The sponge and / or cover may be a plug or sheet, preferably having a thickness of at least 1 mm or at least 2 mm or at least 5 mm and / or up to 20 mm, depending on the indication. When the relatively thick flexible sponge is applied to a wound, it is important that blood and fibrinogen can be absorbed throughout the sponge before fibrin is formed, which can act as a barrier to the absorption of another wound secretion.
    Another aspect of the invention relates to a method of manufacturing a hemostatic sponge (= process I) comprising
    a) provide a sponge comprising a matrix of a biomaterial in dry form,
    b) provide a reactive polymeric material in the form of dry powder,
    c) contacting a) and b), so that the material of b) is present on at least one surface of said sponge, and
    d) fix the material of b) on the sponge of a).
    Fixation can be achieved by melting the polymeric component on the sponge in a preheated oven, for example, at temperatures between 30 ° C to 80 ° C, preferably between 60 ° C to 65 ° C, for a period of time sufficient to fixing, for example, between 1 minute to 10 minutes, preferably about 4 minutes. Alternatively, fixation can be achieved by an infrared heater, or any other heat source. The distance between the plug and the heater, the intensity of the heating and the time of exposure to infrared radiation are adjusted to achieve melting of the coating in a minimum of exposure to heat.
    Another aspect of the invention relates to a method of manufacturing a hemostatic sponge (= process II), comprising:
    a) provide a sponge comprising a matrix of a biomaterial in dry form,
    b) providing a reactive polymeric material in the form of a solution, for example, an aqueous solution with a pH below 5, preferably about 3 or a solution based on water-free organic solvent, for example, based on ethanol, acetone, methylene chloride, and the like,
    c) contact a) and b), so that the material of a) is impregnated with b), and
    d) dry the material obtained in step c).
    Contact to achieve impregnation can be carried out by placing the polymeric solution on top of the sponge and allowing the solution to be soaked in said sponge for a period of time sufficient for said absorption, for example, from about 2 minutes to about 2 hours, preferably 30 minutes.
    Drying can include freeze drying (lyophilization) or air drying and comprises the removal of volatile components from the fluid.
    In another aspect, the present invention provides a hemostatic sponge obtainable by a manufacturing method according to process (I) or (II).
    Another aspect of the invention relates to the use of a sponge of the present invention for the treatment of an injury selected from the group consisting of an injury, bleeding, damaged tissue and / or bleeding tissue. Preferably, a sponge of the present invention is used for sealing tissues, for example, lung, spleen, liver, and for hemostasis.
    The composite of the present invention can also be used as a ready-to-use tissue sealant, where the concentration of proteins in body fluids is high enough to allow the formation of a sealant gel, as described above.
    The sponge of the present invention is especially indicated in open and endoscopic / laparoscopic / thoracoscopic / MIS (minimally invasive surgery) surgical procedures as an adjunct to hemostasis, to treat surgical bleeding, from drip to active, when bleeding control by ligation or conventional procedures it is ineffective or impractical.
    In a preferred embodiment, the sponge of the present invention is applied together with a buffer solution, for example, an alkaline buffer solution, such as a bicarbonate solution, such as 8.4% NaHCO 3 , pH 8.3, for example. example, on gauze.
    It was found that the reaction speed is increased after the application of gauze soaked in NaHCO 3 solution at 8.4% compared to a gauze soaked in saline solution. This was observed by a greater adherence of the sponge to the fabric after 2 minutes, in the case of the application of NaHCO 3 .
    The present invention further provides a kit comprising a sponge according to any one of claims 1 to 5 and a buffer solution, for example, an alkaline buffer solution, such as a bicarbonate or carbonate, together with instructions for its use. The alkaline buffer solution preferably has a pH of about 8, such as 8.3.
    Another aspect of the present invention relates to a hemostatic composite comprising a water insoluble hemostatic material (matrix) and a hydrophilic polymeric crosslinker with reactive groups, said composite comprising pores that allow external fluids, especially human blood, to have access to said composite. The hemostatic material can be any material mentioned above as a matrix of a biomaterial, which alone already has a certain hemostatic property. Such materials are known, in principle, in the art, as well as their hemostatic properties. The composite material according to the present invention has pores that allow external fluids to have access to the inner part of the composite, so that, for example, if applied to a wound, blood from that wound can enter the composite. The composite can get soaked through these pores. Practically important examples include non-woven cloth or fabric from a hemostatic fiber or a porous hemostatic sponge. Preferably, this hemostatic material is a collagen sponge, an oxidized regenerated cellulose tissue, a fibrin sponge or a gelatin sponge. It is specifically preferred that the collagen sponge is essential native collagen (i.e., native collagen fiber structure is conserved or regenerated to a large extent by fibrillogenesis during processing).
    The reactivity of the crosslinker in the hydrophilic polymer in the composite according to the present invention is retained. This means that the reactive groups of the crosslinker have not yet reacted with the (surface of) the hemostatic material and are not hydrolyzed by water. This can be achieved by combining the hemostatic material with the crosslinker in a way that does not lead to the reaction of the reactive groups of the crosslinker with the hemostatic material or with water, for example, as described here by melting, spraying, soaking under inert conditions, etc. This usually includes omitting aqueous conditions (or humectants), especially humectants without the presence of acidic conditions (if the crosslinkers are not reactive under acidic conditions). This allows for the provision of reactive hemostatic materials. Preferably, the hemostatic composite according to the present invention contains a polyethylene glycol (PEG) as a hydrophilic polymeric crosslinker with reactive groups, especially a PEG comprising two or more, preferably four, reactive groups selected from succinimidyl esters (-CON (COCH 2 ) 2 ), aldehydes (-CHO) and isocyanates (-N = C = O), succinimidyl esters are especially preferred as a COH102 component as defined below Coseal.
    In a preferred embodiment, the matrix material forming the porous sponge network constitutes between 1-50%, 1-10%, or about 3% of the dry porous sponge (w / w-%).
    The matrix of a biomaterial, especially collagen, according to the present invention, in general is not soluble, in particular, it is not soluble in water. However, since the sponge must be porous and / or hygroscopic, it is allowed to swell when it is contacted with aqueous fluids, especially blood, serum, plasma, etc. and other liquids present in wounds and absorbs those fluids.
    The hemostatic sponge according to the present invention is a fluid absorber. Fluid absorber should be considered as the physical process to retain fluids by contact, which may or may not cause the sponge to swell. Preferably, the sponge can retain an amount of a fluid, in particular blood, at least 1 time, at least 2 times, at least 4 times, or at least 10 times and / or up to 100 times, up to 20 times or up to 10 of the dry weight of the sponge. The sponge material according to the present invention can absorb fluids even under pressure.
    The porous sponge material according to the present invention preferably has a pore size of 5 to 500 pm, preferably 10 to 200 pm. This pore size can be appropriately adjusted in the course of the production of the sponge biomaterial, especially by directing a drying process to the course of such production.
    The sponge according to the present invention is preferably provided in a ready-to-use form so that it is directly applicable to a patient in need of it, for example, in a wound of the patient (after which the crosslinking starts) . The sponge according to the present invention is therefore packaged in a sterile package, which protects the sponge from contamination (for example, by moisture or microorganisms) during storage. Before use, the package can be opened (preferably also under sterile conditions) and the sponge can be applied directly to the patient (ready to use).
    As already mentioned, the hydrophilic polymeric component is a hydrophilic crosslinker. According to a preferred embodiment, this crosslinker has more than two reactive groups for crosslinking (arms), for example, three, four, five, six, seven, eight, or more arms with reactive groups for crosslinking. For example, NHS-PEGNHS is an effective hydrophilic crosslinker according to the present invention. However, for some embodiments, a 4-arm polymer (for example, 4-arm-p-NP-PEG) may be more preferred, based on the same reasoning, an 8-arm polymer (for example, 8- arms-NHS-PEG) may even be more preferred for those embodiments where multi-reactive cross-linking is beneficial. In addition, the hydrophilic crosslinker according to the present invention is a polymer, that is, a large molecule (macromolecule), composed of structural repeating units that are typically connected by covalent chemical bonds. The polymers according to the present invention must have a molecular weight of at least
    1000 Da (to suitably serve as crosslinkers for the sponge according to the present invention), preferably the crosslinking polymers according to the present invention have a molecular weight of at least 5000 Da, especially at least 8000 Da.
    For some hydrophilic crosslinkers, the presence of basic reaction conditions (for example, at the administration site) is preferred or necessary for functional performance (for example, for a faster cross-linking reaction at the administration site). For example, carbonate or bicarbonate ions (for example, as a buffer with a pH of 7.6 or higher, preferably 8.0 or higher, in particular 8.3 and higher) can be additionally provided at the site of administration (for example example, as a buffer solution, or as a tissue or tampon soaked with such a tampon, so as to allow a better performance of the sponge according to the present invention, or to allow efficient use as a hemostatic and / or adhesive material in the wound .
    Description of Figures:
    Figure 1: Hemostatic efficacy of a collagen buffer coated with NHS-PEG
    A hemostatic buffer is produced according to example 2 and coated with 14 mg / cm COH102 (as defined below). Hemostatic efficacy is assessed according to the animal, as described below. Bleeding is stopped 2 min after applying the buffer. No further bleeding is observed.
    Figure 2: Hemostatic efficacy of a buffer impregnated with collagen NHS-PEG
    A hemostatic buffer is produced according to example 3 and impregnated with 8 mg / cm COH102. Hemostatic efficacy is assessed according to the animal, as described below. Bleeding is stopped 2 min after applying the buffer. No further bleeding is observed.
    Figure 3: Hemostatic effectiveness of a collagen buffer containing oxidized cellulose tissue coated with NHS-PEG
    A hemostatic buffer is produced according to example 5 and coated with 14 mg / cm COH102. Hemostatic efficacy is assessed according to the animal, as described below. Bleeding is stopped 2 min after applying the buffer. No further bleeding is observed.
    Figure 4: Hemostatic effectiveness of an oxidized cellulose tissue coated with NHS-PEG
    A hemostatic buffer is produced according to example 6 and coated with 14 mg / cm COH102. Hemostatic efficacy is assessed according to the animal, as described below. Bleeding is stopped 2 min after applying the buffer. No further bleeding is observed.
    Figure 5: Hemostatic efficacy of a collagen buffer containing fucoidan as a hemostasis-improving substance coated with NHS-PEG
    A hemostatic buffer is produced according to example 7 and coated with 14 mg / cm COH102. Hemostatic efficacy is assessed according to the animal, as described below. Bleeding is stopped 2 min after applying the buffer. No further bleeding is observed.
    Figure 6: Scanning electron microscopy image (magnification: x500) of the surface of a discontinued coated collagen sponge
    Figure 7: Scanning electron microscopy image (magnification: x500) of the surface of a continuously coated collagen sponge
    Figure 8: Gelfoam coated with 14 mg / cm COH102 in the liver lobe abrasion model r
    Figure 9: Chitoskin coated with 14 mg / cm COH102 in the liver lobe abrasion model
    The present invention is further exemplified by the following examples without being limited to them.
    In subsequent sections the following abbreviations are used:
    ACT activated clotting time AcOH Acetic Acid Not AC sodium acetate aq.COH102 aqueousPentaerythritolpoli (ethylene glycol) ether
    tetrasuccinimidyl glutarate = Pentaerythritol tetrakis [1-r-oxo-5'-succinimidyl pentanoate-2-polyoxoethylene glycol] ether (= an NHS-PEG with 10,000 MW)
    EtOH ethanol PEG polyethylene glycol PET polyethylene terephthalate min minutes
    NHS-PEG-NHS a- [6- [2,5-dioxo-1-pyrrolidinyl) oxy] -6oxohexyl] -ω- [6- [(2,5 -dioxo-1-pyrrolidinyl) oxy [-6-oxohexyloxy ] - polyoxyethylene
    8-arms-NHS-PEG glutaryl) polyoxyethylene
    4-arms-p-NP-PEG polyoxyethylene
    Homobifunctional CHO-PEG-CHO
    Epoxy-PEG-Homobifunctional epoxy
    Hexaglycerol octa (succinimidyloxy
    Pentaerythrioletetra (4-nitrophenoxycarbonyl) aldehyde-polyethylene glycol epoxy-polyethylene glycol
    4-arm-Epoxy-PEG epoxy-polyethylene glycol homomultifunctional
    ISC-PEG-ISC homobifunctional isocyanate-polyethylene glycol
    AA-dextran
    DSS
    EGS activated dextran - disuccinimidyl suberate aldehyde
    Ethylene glycol-bis (succinic acid N hydroxysuccinimide ester)
    EXAMPLES:
    Animal hemostasis model to test the effectiveness of hemostatic buffers of the present invention (liver surface abrasion model)
    The effectiveness of the hemostatic buffers of the present invention is tested in an abrasion model on the liver surface in heparinized pigs (2xACT). With a rotary, round, flat abrasion tool, a circular bleeding wound (1.8 cm in diameter) is created on the surface of the liver. The buffer of the present invention (= 3x3 cm size) is applied, in its dry state to the bleeding wound and held in place, applying light pressure with a gauze moistened with saline solution for 2 min. The effectiveness in stopping bleeding is assessed.
    Example 1: Preparation of the bovine collagen g suspension of sliced bovine corium are dispersed in 500 ml of a 2M NaOH solution and stirred approximately 90 min at 25 ° C. The corium is sieved and washed with distilled H 2 O water until H 2 O effluents reach a pH of about 8.0. The washed corium slices are resuspended in H 2 O and the pH is adjusted with HCl to approximately 2.0. The obtained suspension is stirred overnight at approximately 25 ° C and a solution of collagen is obtained. The solution obtained is cooled to 5 ° C and the pH adjusted with NaOH to the neutral position. Collagen precipitation is carried out overnight, keeping the solution at 18 ° C without stirring. Precipitated collagen obtained is separated by filtration. The collagen concentration of the material obtained is determined by gravimetry. Optionally, a chemical crosslinking with glutaraldehyde can be carried out as a suspension of 1% aqueous collagen. is prepared and 5000 ppm of glutaraldehyde is added at 12 ° C. The obtained suspension is stirred overnight. Cross-linked collagen obtained is filtered and washed with H 2 O. The concentration of collagen in the material obtained is determined as described above.
    Example 2: Collagen buffer coated with NHS-PEG
    COH102 powder is evenly distributed on a commercially available collagen sponge surface (Matristypt®, Dr. Suwelack Skin- and Healthcare, Germany, thickness 1 mm or 2 mm). The amounts of COH102 of 2 mg / cm, 7 mg / cm, 10 mg / cm, 14 mg / cm 2 , 20 mg / cm 2 are used for the coating. The COH102 powder is fixed on the surface of the sponge by melting. This is done at 60 ° C to 65 ° C for 4 minutes, placing the sponge with a mixture of PEG powder in a preheated oven.
    A dry sponge obtained is sealed together with a sachet of desiccant in a gas-impermeable pouch and γ-sterilized at 25 kGray. Example 3: Collagen buffer impregnated with NHS-PEG
    Aqueous acidic solutions (pH 3.0, AcOH) of COH102 with
    3 3 3 concentrations of 10 mg / cm, 20 mg / cm, 30 mg / cm and 40 mg / cm are prepared and placed in 9x7 cm PET trays. The commercially available bovine collagen sponges (Matristypt®), 9x7x0.1 or 0.2 cm, with the same volume as the previously loaded COH102 solution are placed on top of the impregnation solutions for 20 min. The COH102 solution is absorbed and the collagen material obtained is lyophilized. Sponges obtained can be additionally coated with COH102 as described in example 2.
    After lyophilization and / or coating, each dry sponge obtained is sealed together with a sachet containing desiccant inside a gas-impermeable bag capable and sterilized by γ-irradiation in 25 kGray.
    Example 4: Collagen buffer containing oxidized cellulose powder coated with NHS-PEG
    0.5 g or 1 g of powdered Traumastem® P (Bioster, Czech Republic) is homogeneously distributed in 22 ml of aqueous neutral collagen suspension (2.15 mg / ml; 4.3 mg / ml and 10 mg / ml ) produced according to example 1. The obtained mixture is placed in 9x7cm PET flat trays and freeze dried. A blanket is obtained with a thickness of about 34mm and is coated with COH102 as described in example 2.
    After coating, each sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch and sterilized by γ-irradiation at 25 kGray.
    Example 5: Collagen buffer containing oxidized cellulose tissue coated with NHS-PEG
    A light 6x5cm Traumastem® TAF fabric (Bioster, Czech Republic) is immersed in a 1% bovine collagen suspension as described in example 1. The 6x5 cm oxidized cellulose fabric retains approximately 6 g of the collagen suspension. A tissue soaked with the collagen suspension is obtained and placed on a tray and lyophilized. A mat obtained has a thickness of about 3-4mm and is coated with COH102, as described in example 2.
    After coating, each sponge obtained is sealed together with a sachet containing desiccant inside a gas-impermeable bag and sterilized by γ-irradiation in 25 kGray.
    Example 6: Oxidized cellulose fabric coated with NHS-PEG
    A double layer blanket Traumastem® P (Bioster, Czech Republic) is coated with 14 mg / cm COH102 as described in example 2. The thickness of the obtained buffer is about 1 to 2 mm.
    Example 7: Collagen buffer containing fucoidan as a hemostasis-enhancing substance coated with NHS-PEG
    A Matristypt® bovine collagen sponge (9x7x0.2cm) is impregnated with the same volume of an A. nodosum Fucoidan solution (10 μΜ and 200 pm, in 40 mM Ca-Solution) and lyophilized. A obtained sponge is coated with COH102 as described in example 2.
    Example 8: Collagen buffer containing thrombin as a hemostasis-enhancing substance coated with NHS-PEG
    The Matristypt® bovine collagen sponge (9x7x0.2cm) is impregnated with the same volume of a thrombin solution (500IU / ml) and lyophilized. A obtained sponge is coated with COH102 as described in example 2.
    Example 9: Sealing effectiveness of a collagen buffer coated with NHS-PEG
    A hemostatic plug coated with 14 mg / cm COH102 is produced according to example 2. The lesion of about 1.5 to 2 cm in diameter is defined by a scalpel in the lung of a pig. A 3x3 cm sample of said buffer it is applied over the wound and held in position, applying light pressure with the aid of gauze, for 2 min. The gauze is pre-coated with saline solution or a bicarbonate or basic solution (pH 8.3). After application, the tampon is firmly adhered to the lung surface (see Figure 6). The speed of obtaining adhesion is increased with gauze moistened with bicarbonate. In order to control air permeability and the adherence of the buffer to the tissue, the breast is filled with Ringer's solution after 10 min. No gas leak or detachment of the plug is observed.
    Example 10: Sealing efficiency of a collagen buffer impregnated with NHS-PEG o
    A hemostatic buffer impregnated with 40 mg / cm COH102 is produced according to example 3.
    The lesion about 1.5 to 2 cm in diameter is defined by a scalpel in a pig's lung. A 3x3 cm sample of the said buffer is applied over the wound and held in position, applying light pressure with the aid of gauze, for 2 min. The gauze is pre-moistened with a basic bicarbonate solution (pH 8.3). After application, the tampon is adhering firmly to the surface of the lung. Air tightness and adherence of the buffer to the fabric are determined as described in Example 9.
    Example 11: Colored marking of a buffer surface
    A mask made of a stainless steel plate (1 mm thick) with a pattern of holes is placed on one side of a collagen sponge 1 or 2 mm thick (Matristypt®, Dr. Suwelack Skin- and Healthcare, Germany). The holes in the mask have a diameter of 2 mm and are placed at a distance of 1 cm from each other at the nodes of a square vertical crosshair. A 0.5% aqueous solution of Erioglaucine (Fluka, Switzerland) is sprayed with a standard air brush device over the mask holes. The mask is removed and a collagen sheet with the blue dot pattern obtained is dried in an ambient atmosphere, in a vacuum oven or a desiccator. The dot pattern on one side of the paper has the role of distinguishing the active and inactive surface from a coated plug. It is possible to apply the coating either on the dotted or non-dotted side.
    Example 12: Preparation of a fibrin blanket
    A 2.5 mg / ml solution of fibrinogen, 10 mM Tris / HCl, 150 mM NaCl, pH 7.4 and an equal volume of 55 IU thrombin / ml, 10 mM CaCl 2 are mixed using a static mixer, and immediately placed in a tray at a height of 0.7 cm. A fibrin clot is obtained in the tray. By lyophilizing the clot, a fibrin blanket is obtained. Example 13: Preparation of collagen buffer coated with NHSPEG-NHS and its test in an animal model
    On the non-colored side of a collagen buffer of
    Ο
    6x6 cm (prepared as described in example 11) and 28 mg / cm and 14 mg / cm of bifunctional NHS-PEG-NHS (MW 10000, NOF Corporation, Japan) are homogeneously distributed and fixed by fusion. This is done at approximately 70 ° C for 4 minutes, by placing the sponge coated with PEG powder in a preheated oven.
    Obtained sponges are sealed with a sachet containing desiccant inside a gas-impermeable pouch.
    The hemostatic performances of these buffers are tested in pigs in the liver abrasion model, as described above. After 2 minutes, hemostasis is achieved. No further bleeding is observed after 10 minutes. The adhesion of the buffer on the fabric is sufficient.
    Example 14: Preparation of collagen buffer coated with 8-arms NHS-PEG and its tests on an animal model
    On the non-colored side of a 6x6 cm collagen buffer, made as described in example 11, 14 mg / cm 8-arms -NHS-PEG (MW 15000, NOF Corporation, Japan) are homogeneously distributed and fixed by fusion. This is done at 65 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the liver abrasion model, as described above. After 2 minutes, hemostasis is achieved. No further bleeding is observed after 10 minutes. The adhesion of the buffer on the fabric is sufficient.
    Example 15a: Preparation of the collagen buffer coated with 4 arms-p-NP-PEG and its test in an animal model
    On the non-colored side of a 6x6cm collagen buffer, made as described in example 11, 14 mg / cm 2 4-arms-p-NP-PEG (MW 10000,
    NOF Corporation, Japan) are homogeneously distributed and fixed by fusion. This is done at 65 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The performance of the said hemostatic buffer is tested in pigs in the liver abrasion model, as described above. After 2 minutes, hemostasis is achieved. No further bleeding is observed after 10 minutes. The adhesion of the buffer on the fabric is not sufficient.
    Example 15b: Preparation of collagen buffer coated with 4 arms-p-NP-PEG and its test in animal model
    The hemostatic performance of the buffer as prepared in Example 15a is tested in pigs in the liver abrasion model, as described above, but with the modification that the buffer is applied with gauze moistened with 8% basic sodium bicarbonate solution. After 2 minutes, hemostasis is achieved. No further bleeding is observed after 10 minutes. The adhesion of the buffer on the fabric is sufficient.
    Example 16a: Preparation of collagen buffer coated with CHOPEG-CHO and its test in an animal model
    On the non-colored side of a 6x6 cm collagen buffer, made as described in example 11, 9.5 mg / cm 2 CHO-PEG-CHO (MW 3400, Interchim, France) were homogeneously distributed and fixed by fusion. This is done at 70 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the liver abrasion model, as described above. After 2 minutes, hemostasis is achieved. No further bleeding is observed after 10 minutes. The adhesion of the buffer on the fabric is sufficient.
    Example 16b: Preparation of collagen buffer coated with CHOPEG-CHO and its test in an animal model
    The hemostatic performance of the buffer as prepared in Example 16a is tested on pigs in the liver abrasion model, as described above, but with the modification that the buffer is applied with gauze pre-moistened with a basic sodium bicarbonate solution. After 2 min, hemostasis is achieved. No further bleeding is observed after 10 min. The adhesion of the buffer on the fabric is sufficient.
    Example 17a: Preparation of collagen buffer coated with epoxyPEG-epoxy and its test in animal model
    On the non-colored side of a 6x6 cm collagen plug made as described in example 11, 9, mg / cm Epoxy-PEG-Epoxy (MW 3400, Interchim, France) are homogeneously distributed and fixed by fusion. This is done at 70 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    The sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the liver abrasion model, as described above. After 2 min, hemostasis is not achieved. The adhesion of the buffer on the fabric is not sufficient.
    Example 17b: Preparation of collagen buffer coated with epoxy-PEG-epoxy and its test in animal model
    The hemostatic performance of the buffer as prepared in Example 17a is tested on pigs in the liver abrasion model, as described above, but with the modification that the buffer is applied with gauze pre-moistened with a basic sodium bicarbonate solution. After 2 min, hemostasis is achieved. No further bleeding is observed after 5 min. The adhesion of the buffer on the fabric is sufficient.
    Example 18: Preparation of collagen buffer coated with 4-arms Epoxy-PEG and its test in animal model
    On the non-colored side of a 6x6cm collagen buffer, A made as described in example 11, 14 mg / cm 4-arms-epoxy-PEG (MW 10000, Interchim, France) are homogeneously distributed and fixed by fusion. This is done at 70 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of this buffer is tested in pigs in the liver abrasion model, as described above, but with the modification that the buffer is applied with gauze pre-moistened with the basic sodium bicarbonate solution. After 2 min, hemostasis is achieved. No further bleeding is observed after 5 min. The adhesion of the buffer on the fabric is sufficient.
    Example 19: Preparation of collagen buffer coated with ISC-PEGISC and its test in animal model
    On the non-colored side of a 6x6 cm collagen buffer, made as described in example 11, 9.5 mg / cm 2 ISC-PEG-ISC (MW 3400, Interchim, France) are homogeneously distributed and fixed by fusion. This is done at 70 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the liver abrasion model, as described above. After 2 min, hemostasis is achieved. No further bleeding is observed after 10 min. The adhesion of the buffer on the fabric is sufficient.
    Example 20: Preparation of AAdextran-coated collagen buffer and testing it on an animal model
    On the non-colored side of a 6x6cm collagen buffer made as described in example 11, 14 mg / cm of a mixture of 0.1 mg / cm 2 AA-dextran (MW 40000, Pierce, US) and 13.9 mg / cm 2 unsubstituted PEG (MW 10000, Sigma Aldrich, Germany) are homogeneously distributed and fixed by fusion. This is done at 80 ° C for 4 minutes, placing the sponge with the powder mixture in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of the said buffer is tested in pigs in the abrasive liver lobe model, as described above, but with the modification that the buffer is applied with gauze pre-moistened with a basic sodium bicarbonate solution. After 2 min, hemostasis is achieved. No further bleeding after 10 min is observed. The adhesion of the buffer on the fabric is sufficient.
    Example 21a: Preparation of collagen from DSS-coated buffer and testing it on an animal model
    On the non-colored side of a 6x6cm collagen buffer made as described in example 11, 20 mg / cm of a 1: 1 mixture of DSS (MW 368.35, Sigma Aldrich, Germany) and unsubstituted PEG (MW 10000, Sigma Aldrich , Germany) are homogeneously distributed and fixed by fusion. This is done at 80 ° C for 4 minutes, placing the sponge with the powder mixture in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the abrasive lobe model of the liver, as described above. After 2 min, hemostasis is not achieved. The adhesion of the buffer on the fabric is not sufficient.
    Example 21b: Preparation of collagen buffer coated with DSS and its test in animal model
    The hemostatic performance of the buffer as prepared in Example 21a is tested on pigs in the abrasive liver lobe model, as described above, but with the modification that the buffer is applied with gauze pre-moistened with a base bicarbonate solution. After 2 min, hemostasis is achieved. No further bleeding is observed after 10 min. The adhesion of the buffer on the fabric is sufficient.
    Example 22a: Preparation of EGS-coated collagen buffer and testing it on an animal model
    On the non-colored side of a 6x6cm collagen buffer made as described in example 11, 26 mg / cm of a 1: 1 mixture of EGS (MW 456.36, Sigma Aldrich, Germany) and unsubstituted PEG (MW 10000, Sigma Aldrich, Germany) are homogeneously distributed and fixed by fusion. This is done at 80 ° C for 4 minutes, placing the sponge with the powder mixture in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the liver abrasion model, as described above. After 2 min, hemostasis is not achieved. The adhesion of the buffer on the fabric is not sufficient.
    Example 22b: Preparation of EGS-coated collagen buffer and testing it on an animal model
    The hemostatic performance of the buffer as prepared in Example 22a is tested on pigs in the liver abrasion model, as described above, but with the modification that the buffer is applied with gauze pre-moistened with a basic sodium bicarbonate solution. After 2 min, hemostasis is achieved. No further bleeding is observed after 10 min. The adhesion of the buffer on the fabric is sufficient.
    Example 23: Fibrin blanket coated with NHS-PEG
    On one side of the fibrin blanket, prepared as described in example 12, 14 mg / cm of COH102 are homogeneously distributed and fixed by fusion. This is done at 65 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the liver abrasion model, as described above. After 2 min, hemostasis is achieved. No further bleeding is observed after 10 min. The adhesion of the buffer on the fabric is sufficient.
    Example 24: Correlation between the adhesion force to the fabric and the reticulate used for the collagen buffer coating
    After the application of bleeding tissue buffers to the liver abrasion model, the adherence of the buffer to the liver tissue is assessed. A slight tangential force is applied to the side of a clamp. Adhesion presence (connection with the fabric) is considered if it is not possible to move the plug from the application site. Adherence score: 1 - without displacement of 5 min after application, 2 - without displacement of 10 min after application, 3 = displacement (without adhesion) 10 min after application.
    Example No. Crosslinker Adherence score 13 NHS-PEG-NHS 1 14 8-arms-NHS-PEG 1 15th 4-arms-p-NP-PEG 3 15b 4-arms-p-NP-PEG - basic application 2 16th CHO-PEG-CHO 1 16b CHO-PEG-CHO - basic application 2 17th Epoxy-PEG-Epoxy 3 17b Epoxy-PEG-Epoxy - basic application 2 18 4-arm-Epoxy-PEG - basic application 2 19 ISC-PEG-ISC 1
    20 AA-dextran - basic application 1 21st DSS 3 21b DSS - basic application 2 22a EGS 3 22b EGS - basic application 2
    Example 25: Chitosan / gelatin sponge coated with NHS-PEG and its test on an animal model
    In a commercially available chitosan / gelatin sponge (Chitoskin®, Beese Medicai, Germany) 14 mg / cm 2 of COH102 are homogeneously distributed and fixed by fusion. This is done at 65 ° C for 4 minutes, placing the sponge with the PEG powder in a preheated oven.
    A sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable pouch.
    The hemostatic performance of said buffer is tested in pigs in the liver abrasion model, as described above. After 2 min, hemostasis is achieved. No further bleeding is observed after 10 min (figure 9). The adhesion of the buffer on the fabric is sufficient.
    Example 26: Preparation of a NHSPEG-coated gelatin buffer and testing it on an animal model
    On a commercially available gelatin sponge (Gelfoam®, Pfizer, US), 14 mg / cm 2 COH102 are homogeneously distributed and fixed by fusion. This is done at approximately 70 ° C for 4 min, placing the sponges coated with the PEG powder in a preheated oven.
    The sponge obtained is sealed together with a sachet containing desiccant in a gas-impermeable bag.
    The hemostatic performance of this buffer is tested in pigs in the liver surface abrasion model, as described above. After 10 minutes, hemostasis is not achieved due to a lack of adhesion on the tissue and slow absorption of liquid from the sponge.
    Example 27: Water absorption speeds
    A 2 x 2 cm piece of dry collagen sponge (Matristypt®, Dr. Suwelack, Germany), or a cross-linked gelatin sponge (Gelfoam®, Pfizer) is placed on the surface of 5 H2O distilled water in a beaker. The dry sponges are floating on the water surface and the water is absorbed on the 2 x 2 cm contact surface. After 6 s Matristypt® is completely soaked in H 2 O and removed from the water surface. The thicker Gelfoam® sponge is not completely soaked in H 2 O after 13 s, but removed after 13 s from the water surface. From 10 of the 2 x 2 cm sponge weights before and after contact with the water surface, the time of contact with the water surface and the area of contact with the water surface, the initial water absorption speeds of sponges (in mg water / s) per contact surface (in cm) are calculated. Initial water absorption rates are 35 mg cm x ' 1 s' 1 for Matristypt® 15 and 0.8 mg x cm _1 s _1 for Gelfoam®.
    权利要求:
    Claims (13)
    [1]
    1. Porous hemostatic composite sponge, characterized by the fact that it consists essentially of:
    i) a matrix of a biomaterial selected from the group consisting of collagen, gelatin, fibrin, polysaccharide, for example, chitosan, a biodegradable synthetic biomaterial, for example, polylactic acid or polyglycolic acid, and ii) a single component hydrophilic polymer comprising electrophilic reactive groups, wherein said hydrophilic polymer component is a hydrophilic crosslinker being a polyalkylene oxide polymer, especially preferred a polymer comprising PEG, for example, a multielectrophilic polyalkylene oxide polymer, for example, a multielectrophilic PEG , as pentaerythritolpoli (ethylene glycol) tetrasuccinimidyl glutarate ether where i) and ii) are associated with each other, so that the reactivity of the polymeric component is retained, and where associated means that
    - said polymeric component is coated on a surface of said matrix of a biomaterial, or
    - said matrix is impregnated with said polymeric material, or
    - both.
    [2]
    2 Sponge according to claim 1, characterized by the fact that the biomaterial is collagen and the polymeric component is pentaerythritolpoli (ethylene glycol) tetrasuccinimidyl glutarate ether, in which the polymeric form is coated on the collagen.
    [3]
    Sponge according to any one of claims 1 to 2, characterized by the fact that the biomaterial is collagen and the polymeric component is pentaerythritolpoli (ethylene glycol) tetrasuccinimidyl glutarate ether,
    Petition 870190022901, of 03/11/2019, p. 17/20 in which the polymeric form is impregnated in the collagen.
    [4]
    Sponge according to any one of claims 1 to
    3, characterized by the fact that it is for use in the treatment of a lesion selected from the group consisting of an injury, bleeding, damaged tissue and / or bleeding tissue.
    [5]
    5. Sponge according to claim 4, characterized by the fact that the treatment comprises the administration of the sponge to the injury site.
    [6]
    6. Sponge according to claim 5, characterized by the fact that the sponge is applied to said lesion together with a buffer solution, especially a bicarbonate solution, preferably in a gauze.
    [7]
    7. Kit, characterized in that it comprises a sponge as defined in any one of claims 1 to 6, and a buffer solution, for example, an alkaline buffer solution, such as a bicarbonate together with instructions for its use.
    [8]
    8. Method of manufacturing a hemostatic sponge as defined in any one of claims 1 to 3, characterized in that it consists essentially of:
    a) provide a porous sponge comprising a matrix of a biomaterial in dry form,
    b) providing a single hydrophilic polymeric component comprising reactive electrophilic groups in the form of dry powder, wherein said hydrophilic polymeric component is a hydrophilic crosslinker,
    c) contacting a) and b), so that the material of b) is present on at least one surface of said sponge, and
    d) fix the material of b) on the sponge of a).
    [9]
    9. Method according to claim 8, characterized by the fact that fixation is obtained by melting at temperatures between 30 ° C to 80 ° C,
    Petition 870190022901, of 03/11/2019, p. 18/20 preferably between 60 ° C to 65 ° C, for a period of time sufficient for fixation, preferably between 1 minute to 10 minutes, especially about 4 minutes.
    [10]
    10. Method of manufacturing a hemostatic sponge as defined in any one of claims 1 to 3, characterized by the fact that it comprises:
    a) provide a porous sponge comprising a matrix of a biomaterial in dry form,
    b) providing a single hydrophilic polymeric component comprising electrophilic reactive groups in the form of a solution, wherein said hydrophilic polymeric component is a hydrophilic crosslinker,
    c) contact a) and b), so that the material of a) is impregnated with b), and
    d) dry the material obtained in step c).
    [11]
    11. Hemostatic composite, characterized by the fact that it comprises a hemostatic material and a single hydrophilic polymeric crosslinker with electrophilic reactive groups, said composite comprising pores that allow external fluids, especially human blood, to have access to said composite, in which said hemostatic material is a non-woven cloth or fabric made of a hemostatic fiber.
    [12]
    Hemostatic composite according to claim 11, characterized in that said hemostatic material is a collagen sponge, an oxidized cellulose tissue, a fibrin sponge or a gelatin sponge.
    [13]
    13. Hemostatic composite according to claim 11 or 12, characterized in that said hydrophilic polymeric crosslinker with electrophilic reactive groups is a polyethylene glycol (PEG), preferably a PEG comprising two or more reactives among
    Petition 870190022901, of 03/11/2019, p. 19/20 succinimidyl esters (-CON (COCH2) 2), aldehydes (-CHO) and isocyanates (N = C = O), especially preferred succinimidyl esters.
    类似技术:
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    同族专利:
    公开号 | 公开日
    TWI511753B|2015-12-11|
    US8703170B2|2014-04-22|
    US20110251574A1|2011-10-13|
    PE20130695A1|2013-06-15|
    ZA201207502B|2013-06-26|
    MX2012011635A|2013-02-27|
    EP2555804A1|2013-02-13|
    JP5856142B2|2016-02-09|
    CN102939113B|2014-12-24|
    EP2555804B1|2015-06-03|
    EP2939697A1|2015-11-04|
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    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2018-04-17| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2018-12-11| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2019-03-26| B09A| Decision: intention to grant|
    2019-05-14| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/04/2011, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/04/2011, OBSERVADAS AS CONDICOES LEGAIS |
    优先权:
    申请号 | 申请日 | 专利标题
    US32166110P| true| 2010-04-07|2010-04-07|
    US61/321661|2010-04-07|
    US42403110P| true| 2010-12-16|2010-12-16|
    US61/424031|2010-12-16|
    PCT/EP2011/055418|WO2011124640A1|2010-04-07|2011-04-07|Hemostatic sponge|
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