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    • 专利摘要:
    The invention provides a process for the preparation of an adhesive hemostatic product, said process comprising the steps of: - providing a porous solid substrate; ? coating the substrate with a coating liquid comprising an electrophilic activated polyoxazoline (EL-POX) and a solvent to produce a coated substrate, said EL-POX containing at least 2 reactive electrophilic groups; ? remove the solvent from the coated substrate. The present process allows the application of an EL-POX coating that leaves the pore structure fully intact so that the ability of the porous substrate to absorb fluids, such as blood, remains essentially unchanged. The hemostatic product coated with EL-POX obtained by means of the present process has excellent adhesive properties due to the presence of reactive electrophilic groups that are capable of reacting with, for example, the amine groups that are naturally present in the tissue, under formation covalent bonds. The present invention also provides a tissue adhesive hemostatic product selected from a coated mesh, a coated foam and a coated powder, said hemostatic product comprising:? A porous solid substrate which is provided with a porosity (... ).
    公开号:BR112017006943B1
    申请号:R112017006943-1
    申请日:2015-10-05
    公开日:2020-12-01
    发明作者:Johannes Caspar Mathias Elizabeth Bender；Marcel Alexander Boerma
    申请人:Gatt Technologies B.V；
    IPC主号:
    专利说明:

    TECHNICAL FIELD OF THE INVENTION
    [0001] The invention relates to an adhesive hemostatic fabric product comprising a porous solid substrate and a coating containing an electrophilically activated polyoxazoline (EL-POX). This new hemostatic product exhibits excellent biodegradability, adhesiveness and hemostatic properties. Examples of hemostatic products that are covered by the present invention include hemostatic meshes, hemostatic foams and hemostatic powders.
    [0002] A process is also provided for preparing an adhesive hemostatic fabric product that involves coating a solid porous substrate with an electrophilically activated polyoxazoline (EL-POX). BACKGROUND OF THE INVENTION
    [0003] Wound dressings are an important segment of the global wound care market. These products are widely used in the treatment of injuries, such as wounds, bleeding, damaged tissue and bleeding tissue. The ideal dressing should prevent excessive bleeding and promote rapid healing at a reasonable cost with minimal inconvenience to the patient.
    [0004] The hemostatic properties of a wound dressing are determined by the texture and porosity of the material. With regard to porosity, the dressing pores are usually so small that they are not visible to the human eye after casual inspection. However, they are of sufficient size not only to allow a large sweat of the skin unit and vapors from the wound, but also to allow the absorption of blood so that the dressing is firmly anchored to the tissue once the blood has clotted.
    [0005] Wound dressings should be able to maintain a moist environment around the wound, effective circulation of oxygen to aid cell and tissue regeneration and a low bacterial load. The wound dressings that are used during surgery and remain in the body must be biodegradable and completely resorbable.
    [0006] Dressings for conventional tissue adhesive wounds include fibrin sealing agents, cyanoacrylate sealing agents and other synthetic sealing agents and polymerizable monomers. These fabric adhesives are only suitable for specific applications due to several disadvantages, including the release of toxic degradation products, the high cost, the need for refrigerated storage, the time to cure, the limited mechanical strength and the risk of infection. For this reason, hydrogel fabric adhesives have been developed based on reactive polyethylene glycol (PEG) precursors. However, these hydrogel fabric adhesives swell or dissolve very quickly, or lack sufficient cohesion, thereby decreasing their effectiveness as a surgical adhesive. In addition, the properties of this PEG-based material cannot be easily controlled.
    [0007] Hemostatic powders are another example of a hemostatic product that is widely used. Examples of commercially available hemostatic powders, also known as styptic powders, include an adsorbable hemostatic gelatin powder (Spongostan® powder) and a calcium-loaded zeolite form also known as QuikClot®. These hemostatic powders can be used to stop severe bleeding.
    [0008] US 5 614 587 describes collagen-based compositions useful for fixing tissues or affixing tissues to synthetic implant materials. The compositions comprise fibrillar collagen, a fiber disassembly agent and a multifunctional activated synthetic hydrophilic polymer, such as polyethylene glycol, in which the collagen and the synthetic polymer covalently bond to form a synthetic collagen polymer conjugate.
    [0009] WO 2004/028404 describes a tissue sealing agent composed of a synthetic collagen or synthetic gelatin and an electrophilic cross-linking agent which are provided in a dry state. In this international publication the cross-linking agent comprises an electrophilically activated poly (ethylene glycol) (EA) (PEG) or EA PEG derivative, such as PEG succinimidyl ester, in particular PEG succinimidyl propionate, PEG-succinimidyl butanoate or PEG- glutarate succinimidil. After moistening this composition to an appropriate pH, a reaction occurs between the 2 components and a gel with sealing properties is formed.
    [0010] US 2011/0251574 describes a porous and hemostatic composite sponge comprising a matrix of a biomaterial and a hydrophilic polymeric component that comprises reactive groups, wherein 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. According to a preferred embodiment the polymer is comprised of a polyalkylene oxide polymer, more particularly a multi-electrophilic polyethylene glycol (PEG). The matrix material can be selected from collagen, gelatin, fibrin, a polysaccharide (such as chitosan), a synthetic biodegradable biomaterial (such as polylactic acid, or polyglycolic acid) and its derivatives.
    [0011] US 2010/069579 describes a terminally activated polyoxazoline compound (POZ), said POZ compound comprising a POZ polymer which is endowed with a single active functional group at one end of it, said being functional group capable of reacting with a group on a target molecule to create a loop molecule - POZ conjugate, in which all bonds between the target molecule and the POZ compound are comprised of hydrolytically stable bonds.
    [0012] WO 2012/057628 describes cross-linked polyoxazoline polymers that have adhesive properties to the fabric due to the presence of electrophilic groups that are capable of reacting with the chemical entities that contain nucleophiles present in the natural tissue.
    [0013] It is an object of the present invention to provide an adhesive tissue hemostatic product with improved properties. SUMMARY OF THE INVENTION
    [0014] The inventors have discovered that a hemostatic adhesive fabric product that is endowed with improved properties can be produced by means of a process comprising the following steps: • providing a porous solid substrate; • coating the substrate with a coating liquid comprising an electrophilically activated polyoxazoline (EL-POX) and a solvent to produce a coated substrate, said EL-POX containing at least 2 reactive electrophilic groups; • remove the solvent from the coated substrate.
    [0015] Surprisingly, inventors have found that EL-POX can be applied to a solid porous substrate using this method without adversely affecting the porous structure of the substrate. The present process allows the application of an EL-POX coating that leaves the structure of pores of the substrate largely intact, so that the ability of the porous substrate to absorb bodily fluids, such as blood, remains essentially unaffected. The hemostatic product coated with EL-POX obtained by means of the present process has excellent adhesive properties due to the presence of reactive electrophilic groups capable of reacting with, for example, amine groups that are naturally present in the tissue, under the formation of bonds covalent.
    [0016] The present invention also provides an adhesive hemostatic product of selected fabric from a coated mesh, a coated foam and a coated powder, said hemostatic product comprising: • a porous solid substrate with a porosity of at least 5%, by volume, and comprising an outer surface comprising a nucleophilic polymer containing reactive nucleophilic groups; • an adhesive coating that covers at least a part of the solid substrate, said coating comprising an electrophilic deformed polyoxazoline (EL-POX), said EL-POX containing on average at least 1 reactive electrophilic group.
    [0017] The EL-POX polymer contained in the coating of the hemostatic product offers the advantage that it can carry a high number of reactive electrophilic groups due to the fact that the opolymer of the EL-POX polymer can contain a large number of outstanding groups where each can carry one or more of these reactive groups. In this way, the adhesive properties of the hemostatic product can be optimized for a given application by selecting an EL-POX with an excellent density of electrophilic groups. Also other properties of EL-POX, such as hydrophilic / hydrophobic balance and crucial temperature of the lowest solution can be adequately optimized by changing the concentration and / or properties of the pendant groups. DETAILED DESCRIPTION OF THE INVENTION
    [0018] For this reason, an aspect of the invention relates to a process for preparing a hemostatic tissue adhesive product, said process comprising the steps of: • providing a porous solid substrate; • coat the substrate with a coating liquid that comprises an electrophilically activated polyoxazoline (EL-POX) and a solvent to produce a coated substrate, said EL-POX containing at least 2 reactive electrophilic groups; • remove the solvent from the coated substrate.
    [0019] As used in this context, the term "tissue adhesive" refers to the property of the hemostatic product clinging to the tissue due to the formation of covalent bonds between said product and the tissue.In the case of the present adhesive tissue hemostatic product adherence to the tissue may require the presence of water.
    [0020] As used in this context, the term "porous", unless otherwise specified, means that the hemostatic product comprises pores and / or interstices that allow liquid to enter the product.
    [0021] The term “porosity” refers to a measure of the voids (ie, "hollow") in the substrate or in the hemostatic product, and is understood to mean the percentage volume of voids over the total volume. The porosity of the hemostatic products of the present invention can be suitably determined by methods that are known in the art, such as gas adsorption analysis. Gas adsorption analysis involves exposing solid porous materials to gases or vapors according to a variety of conditions and assessing weight absorption or change in sample volume. The analysis of this data provides information about the physical characteristics of the solid, including: skeletal density, porosity and total pore volume. Skeletal density is typically assessed by helium pycnometry experiments and represents the true solid density of a material when there is no closed porosity. It should be understood that, in case the substrate is composed of more than one item, the porosity refers to the average porosity of the individual items. Thus, if the substrate is a porous powder, the porosity is equal to the percentage of the volume of the porous particles that is occupied by pores.
    [0022] As used in this context, the term "average pore size" refers to the average pore diameter as determined by scanning electron microscopy (SEM). A suitable method is described in Faraj et al., Tissue Engineering, 2007, 13, 10, 2387-2394.
    [0023] As used in this context, the term "water absorption capacity" is a measure of the ability of the porous solid substrate to absorb water. The water absorption capacity of the porous solid substrate is determined by weighing a sample of the dry porous substrate (weight = Wd) followed by immersing the porous substrate in distilled water (37 ° C) for 45 minutes. Then, the sample is removed from the water and the water that clings to the outside of the substrate is removed, after which the sample is weighed again (weight = Ww). The water absorption capacity = 100% x (Ww-Wd) / Wd. The water adsorption capacity is indicative of the substrate porosity, as well as its ability to swell in the presence of water.
    [0024] As used in this context, the term "polyoxazoline" refers to a poly (N-acylalkylenimine) or a poly (aroylalkylenimine) and is further referred to as POX. An example of POX is comprised of poly (2-ethyl -2-oxazoline). The term "polyoxazoline" also covers POX copolymers.
    [0025] The term "electrophilic group" refers to a functional group that is susceptible to nucleophilic attack by a nucleophilic group and that is capable of reacting with that nucleophilic group under the formation of a covalent bond. Nucleophilic groups are typically positively charged and / or deficient in electrons.
    [0026] The term "nucleophilic group" refers to a functional group that is susceptible to electrophilic attack by an electrophilic group and that is capable of reacting with an electrophilic group under the formation of a covalent bond. Typically, nucleophilic groups are rich in electrons, having a pair of unshared electrons that function as a reactive site.
    [0027] The term “activated”, unless otherwise specified, refers to a modification of a polymer to generate or introduce a new reactive functional group, in which the new reactive functional group is capable of being subjected to reaction with another functional group to form a covalent bond.
    [0028] As used in this context, the term "crosslinked" refers to components such as polymers that are linked in an intermolecular manner by means of covalent bonds. The covalent bond between two cross-linkable components can be direct, or indirect through a bonding group.
    [0029] As used in this context, the term “buffering system” refers to a substance or combination of substances that can be used in aqueous systems to move a solution to a given buffering pH and in which the buffering system has the ability to prevent the change in this buffering pH.
    [0030] As used in this context, the "buffering pH" of a liquid refers to the pH value under 20 ° C measured after the liquid has been diluted 10 times with distilled water.
    [0031] As used in this context, "buffering capacity" refers to the ability of the liquid to resist changes in pH. The buffer capacity β of a liquid (coating liquid or buffer liquid) is measured at 20 ° C after dilution 10 times with distilled water and is expressed in mmol.l-1.pH-1. Buffer capacity is defined as follows:
    dn β = dWFv where dn is comprised of an infinitesimal amount of the base added and d (p [H +]) is the resulting infinitesimal change in the hydrogen ion concentration co-logarithm.
    [0032] The EL-POX employed in accordance with the present invention is preferably derived from a polyoxazoline whose repeating units are represented by the following formula (I): (CHR1) mNCOR2 being R2, and each of R1 selected independently from H, optionally substituted C1-22 alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted aryl; and m being comprised of 2 or 3.
    [0033] According to a preferred embodiment, the polyoxazoline is comprised of a polymer, even more preferably a 2-alkyl - 2-oxazoline homopolymer, said 2-alkyl -2-oxazoline being selected from 2-methyl -2-oxazoline, 2-ethyl -2-oxazoline, 2-propyl -2-oxazoline, 2-butyl -2-oxazoline and their combinations. Preferably, polyoxazoline is comprised of a homopolymer of 2-propyl -2-oxazoline and most preferably 2-ethyloxazoline.
    [0034] EL-POX can carry electrophilic groups on its side chains (also referred to as pendant electrophilic groups), on its terminals, or both. An example of a terminal, capped at the end, EL-POX is comprised of a succinimidyl succinate ester such as CH3O-POX-O2C-CH2-C (CH2CO2-NHS) 3. An example of side chain-activated EL-POX is comprised of POX containing NHS groups on the alkyl side chain. Yet another example of EL-POX are star-shaped POX polymers with end functionality with NHS esters.
    [0035] The electrophilic groups present in EL-POX are preferably selected from: carboxylic acid esters, sulfonate esters, phosphonate esters, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrothiophenyl esters, groups of acid halides, anhydrides, ketones, aldehydes, isocyanate, thioisocyanate (isothiocyanate), isocyanine, epoxides, glycidyl esters, carboxyl, succinimidyl esters, succinimidyl carbonates, succinimidyl carbamates, sulfosuccinimide sulfate sulfides (maleimidyl), ethylene sulfonyl, imido groups, acetate acetate, haloacetal, orthopyridyl disulfide, dihydroxy phenyl derivatives, vinyl, acrylate, acrylamide, acetamide iodine and combinations thereof. Most preferably, the electrophilic groups present in EL-POX are selected from: carboxylic acid esters, acid chloride groups, anhydrides, ketones, aldehydes, isocyanate, thioisocyanate, epoxides, activated hydroxyl groups, olefins, carboxyl, succinimidyl ester, succinimidyl carbonate, succinimidyl carbamates, sulfosuccinimidyl ester, sulfosuccinimidyl carbonate, maleimido, ethenesulfonyl and their combinations. Even more preferably, the electrophilic groups present in EL-POX are selected from aldehydes, isocyanate, thioisocyanate, succinimidyl ester, sulfosuccinimidyl ester, maleimido and their combinations. Most preferably, the electrophilic groups present in EL-POX are selected from isocyanate, thioisocyanate, succinimidyl ester, sulfosuccinimidyl ester, maleimido and their combinations.
    [0036] Examples of sulfonate esters that can be used as electrophilic groups include mesylate, tosylate, nosylate, triflate and combinations thereof. Examples of olefins that can be used include acrylate, methacrylate, ethylacrylate and combinations thereof. Examples of activated hydroxyl groups include hydroxyl groups that have been activated with an activating agent selected from p-nitrophenyl chlorocarbonates, carbonyl diimidazois (e.g., 1,1-carbonyl diimidazole) and sulfonyl chloride.
    [0037] The EL-POX used in the present method preferably contains at least 10 reactive agents of the electrophilic group. Most preferably, EL-POX contains at least 25, even more preferably at least 35 and preferably at least 50 reactive electrophilic groups.
    [0038] The EL-POX of the present invention advantageously contains one or more pendant electrophilic groups. Typically, EL-POX contains 3 to 50 pendant electrophilic groups per 100 monomers, more preferably 4 to 35 pendant electrophilic groups per 100 monomers, even more preferably at least 5 to 25 pendant electrophilic groups per 100 monomers.
    [0039] The EL-POX used in accordance with the present invention is typically endowed with an average molecular weight in the range of 1,000 to 100,000 g / mol, more preferably 5,000 to 50,000 and even more preferably 10,000 to 30,000 g / mol.
    [0040] According to one embodiment, the porous solid substrate contains at least 50% by weight, more preferably at least 80% by weight, of a polysaccharide selected from dextran, alginates, oxidized cellulose, oxidized regenerated cellulose (ORC), hydroxyethylcellulose, hydroxymethylcellulose, hyaluronic acid; and their combinations. According to a particularly preferred embodiment, the porous solid substrate contains at least 50% by weight, more preferably at least 80% by weight of ORC.
    [0041] Cellulose is comprised of a glycopyranose polysaccharide homo polymerized through β-glycosidic bonds. Before oxidation, cellulose can remain unregenerated with unorganized fibers or it can be regenerated to form organized fibers. When cellulose fibers are treated with dinitrogen tetroxide, the hydroxyl groups are oxidized to groups of carboxylic acid thus producing a polyuronic acid. Although polyuronic acid is the main component of oxidized cellulose, the non-oxidized hydroxyl groups remain as a fibrous component.
    [0042] According to another embodiment of the invention the porous solid substrate comprises an outer surface comprising a nucleophilic polymer which contains reactive nucleophilic groups. Preferably, the porous solid substrate contains at least 5% by weight, more preferably at least 10% by weight, and even more preferably at least 50% by weight of the nucleophilic polymer. Most preferably, the substrate consists of said nucleophilic polymer.
    [0043] Typically, the nucleophilic polymer contains at least 2 nucleophilic groups, more preferably at least 10 nucleophilic groups, even more preferably at least 20 nucleophilic groups.
    [0044] The nucleophilic groups of the nucleophilic polymer are preferably selected from amine groups, thiol groups, phosphine groups and combinations thereof. Most preferably, these nucleophilic groups are comprised of amine groups. These amine groups are preferably selected from primary amine groups, secondary amine groups and their combinations.
    [0045] The nucleophilic polymer on the outer surface of the porous solid substrate is preferably comprised of a nitrogen-rich polymer having a nitrogen content of at least 1% by weight, more preferably 5-10% by weight and still with most preferably 15-25% by weight.
    [0046] The nucleophilic polymer is preferably selected from proteins, chitosan and synthetic polymers or carbohydrates that include reactive nucleophilic groups selected from amine, thiol, phosphine and combinations thereof. Most preferably, the nucleophilic polymer is selected from collagen, chitosan and their combinations.
    [0047] The term collagen, as used in this context, refers to all forms of collagen including processed derivatives. Preferred collagens do not have telopeptide regions ("aelopeptide collagen"), are soluble and can be in fibrillar or non-fibrillar form. Collagen can be selected from a group of micro fibrillar collagen, synthetic human collagen such as type I collagen, type III collagen or a combination of type I collagen and type III collagen. Cross-linked collagen that uses heat, radiation or chemical agents such as glutaraldehyde can also be used to form particularly rigid cross-linked compositions. Dry, porous and lyophilized collagen sponges are specifically preferred.
    [0048] Chitosan is comprised of a complex, non-toxic, biodegradable carbohydrate derivative of chitin (poly- [134] -N-acetyl-D-glucosamine), a naturally occurring substance. Chitosan is the form deacetylated chitin. In general, the generic term chitosan is applied when the extent of deacetylation is greater than 70% and the generic term chitin is used when the extent of deacetylation is insignificant or less than 20%. With less than 100% deacetylation, the chitosan polysaccharide is in the form of a linear block copolymer containing units of N-acetyl-D-glucosamine and D-glucosamine monomer.
    [0049] According to a preferred embodiment, the nucleophilic groups of the nucleophilic polymer present on the surface of the porous solid substrate are comprised of amine groups and the electrophilic groups comprised in EL-POX are selected from carboxylic acid esters, sulfonate esters , phosphonate esters, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrothiophenyl esters, acid halide groups, anhydrides, ketones, aldehydes, isocyanate, thioisocyanate, isocyanate, epoxides, activated hydroxyl groups, glycerol esters, ethers carboxyl, succinimidyl, succinimidyl carbonates, succinimidyl carbamates, sulfosuccinimidyl esters, sulfosuccinimidyl carbons, imido esters, dihydroxy-phenyl derivatives and combinations thereof.
    [0050] Examples of succinimidyl derivatives that can be used include succinimidyl glutarate, succinimidyl propionate, succinimidyl succinamide, succinimidyl carbonate, disuccinimidyl suberate, bis (sulfosuccinimidyl) suberate, (dithiobisate (2- succinimidyl propionate) succinimido oxycarbonyloxy) e3,3'-dithiobis (sulfosuccinimidyl propionate) .Examples of sulfosuccinimidil derivatives thatcanbeusedincludesulfosuccinimidil (4- iodoacetyl) aminobenzoate, bis (sulfosuccinimidyl) suberate, 4- -sulfosuccinimidylpropionate, tartaratodedisulfo-succinimidyl; bis [2- (sulfo-succinimidyl oxycarbonyl oxyethyl sulfone)], ethylene glycol bis (sulfo succinimiclil succinate), dithiobis- (succinimidyl propionate). Examples of dihydroxyphenyl derivatives include dihydroxyphenyl alanine, 3,4-dihydroxyphenyl alanine (DOPA), dopamine, 3,4-dihydroxy hydroxamic cinnamic (DOHA), norepinephrine, epinephrine and catechol.
    [0051] According to another preferred embodiment, the nucleophilic groups of nucleophilic polymer on the outer surface of the porous solid substrate are comprised of thiol groups and the electrophilic groups contained in EL-POX are selected from halo-acetals, ortho-disulfide pyridyl, maleimides, vinylsulfone, dihydroxyphenyl derivatives, vinyl, acrylate, acrylamide, iodine acetamide, succinimidyl ester, succinimidyl carbonate, succinimidyl carbamates, sulfosuccinimidyl esters, sulfosuccinimidyl carbonate and their combinations are preferred. from succinimidyl esters, halo acetals, maleimides or dihydroxyphenyl derivatives and their combinations. Most preferably, electrophilic groups are selected from maleimides or dihydroxyphenyl derivatives and their combinations.
    [0052] The porous solid substrate that is used in the present process is preferably provided with a porosity of at least 5% by volume. In the case where the substrate is comprised of a foam or a mesh, preferably the substrate has a porosity of at least 50% by volume, more preferably at least 70% by volume and even more preferably at least 85% by volume. In the case where the substrate is comprised of a porous powder, the porosity is preferably at least 20% by volume, more preferably at least 50% by volume and even more preferably at least 75% by volume .
    [0053] The porous solid substrate that is used in the present process preferably has an average pore size of at least 2 μm. In the event that the substrate is comprised of a foam or a mesh, the substrate preferably has an average pore size of 5 to 500 µm, preferably 10 to 200 µm. If the substrate is comprised of a porous powder, the average pore size is preferably between 4 and 50 μm, more preferably between 6 and 25 μm.
    [0054] Typically, the porous solid substrate has a water absorption capacity of at least 25%, more preferably at least 100%, even more preferably at least 250% and most preferably at least 1000 %.
    [0055] The porous solid substrate that is used in the present process is preferably comprised of an object in the form of a mesh or a foam, said object having a shape that facilitates the application of the coated substrate in the form of a wound dressing , for example, from a leaf. Typically, the substrate has a length of 10 mm to 200 mm, a width of 5 mm to 200 mm and a thickness of 0.5 mm to 10 mm.
    [0056] According to one embodiment of the present invention, the porous solid substrate is comprised of a mesh. An example of a mesh is comprised of a sheet or gauze made of woven or non-woven fibers. The fibers contained in the mesh are preferably manufactured from bio-compatible and biodegradable polymers, such as gelatin, collagen, ORC or their combinations.
    [0057] According to another embodiment of the present invention, the porous solid substrate is comprised of a solid foam, sometimes also referred to as sponges. The solid foam is manufactured preferably from crosslinked gelatine (gelfoam).
    [0058] According to another embodiment of the invention, the porous solid substrate is in the form of a powder. The powder is porous and is preferably made of gelatin or polysaccharide. Suitable polysaccharides are starch, modified starches, alginates, chitosan, dextran and combinations thereof. More preferably, the polysaccharide used is comprised of the modified starch.
    [0059] Preferably, the porous powder is in the form of a free flowing sterile powder. Advantageously, the powder is comprised of a micro porous powder.
    [0060] Typically, the porous powder has a mass-weighted average particle size in the range of 10-200 μm, more preferably 25-100 μm and even more preferably 50-75 μm.
    [0061] The coating liquid used in the present process preferably contains at least 50% by weight, more preferably at least 60% by weight, most preferably at least 80% by weight of solvent. The solvent is preferably selected from 2-propanol, ethyl alcohol, methanol, dichloromethane, acetone, anisol, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, ether ethyl, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol , propyl acetate and their combinations. Most preferably, the solvent is selected from 2-propanol, ethyl alcohol, methanol, acetone and their combinations.
    [0062] The coating liquid may adequately contain some water. Typically, the coating liquid contains less than 5% by weight of water, more preferably less than 1% by weight of water.
    [0063] The coating liquid used in this process preferably contains at least 1% by weight of EL-POX. Most preferably, the EL-POX content of the coating liquid is at least 5% by weight, even more preferably at least 10% by weight and most preferably at least 20% by weight.
    [0064] According to a preferred embodiment, the porous solid substrate is coated by spraying the coating liquid onto the substrate. According to a particularly preferred embodiment, the coating liquid is sprayed onto the substrate through an ultrasonic nozzle. The inventors have found that the use of an ultrasonic nozzle allows to homogeneously coat the substrate with a coating liquid that contains a considerable amount of EL-POX.
    [0065] The solvent can be properly removed from the coated substrate by evaporation. Evaporation is preferably carried out under reduced pressure, and under a pressure of less than 1 mbar.
    [0066] Alternatively, the solvent can be removed from the coated substrate by contacting the coated substrate with a liquefied gas or super crucial fluid. Preferably, the liquefied gas or the super crucial fluid has a pressure of at least 30 bar.
    [0067] According to an advantageous embodiment of the present invention, the porous solid substrate comprises an outer surface comprising a nucleophilic polymer, as described herein before and after coating the substrate with the coating liquid and before and / or during removal of the solvent, the reactive electrophilic group of EL-POX reacts with the reactive nucleophilic groups of the nucleophilic polymer under the formation of covalent bonds. Preferably, said reaction occurs under a temperature below 50 ° C, more preferably under a temperature in the range of 1525 ° C (environmental conditions). This embodiment of the present process offers the advantage that the reaction between the reactive electrophilic group and the reactive nucleophilic groups can occur in the absence of a buffer system.
    [0068] In the present process the reactive electrophilic groups in the EL-POX can react with reactive nucleophilic groups present in the porous solid substrate and / or with nucleophilic groups present in other components that are used in the process (for example, nucleophilic crosslinking agents). Preferably, after removing the solvent from the coated substrate, EL-POX still contains, on average, at least one, more preferably at least 5 and even more preferably at least 40 reactive electrophilic groups. These electrophilic groups provide adhesive properties to the coated substrate, since they can form covalent bonds with, for example, the amine groups naturally present in the fabric.
    [0069] The coating liquid used in the present process may contain EL-POX in dissolved and / or dispersed form.
    [0070] According to one embodiment, the coating liquid contains EL-POX in completely dissolved form and the coating liquid also contains a dispersed buffer system. Preferably, the coating liquid has a buffer pH in the range of 7 to 11, more preferably in the range of 8 to 10. The buffering capacity of the coating liquid is preferably at least 10 mmol.l-1. pH-1. Most preferably, the buffering capacity is at least 25 mmol.l-1.pH-1, more preferably the buffering capacity is at least 50 mmol.l-1.pH-1.
    [0071] According to another embodiment, the coating liquid contains EL-POX in completely dissolved form and the process comprises covering the solid porous substrate with a buffer liquid before the substrate is coated with the coating liquid containing EL- POX, said buffer liquid comprising a buffer system. Preferably, the buffer liquid has a buffer pH in the range 7 to 11, more preferably in the range 8 to 10. The buffer capacity of the buffer liquid is preferably at least 10 mmol.l-1.pH -1. Most preferably, the buffer capacity is at least 25 mmol.l-1.pH-1, more preferably the buffer capacity is at least 50 mmol.l-1.pH-1. If the buffer liquid is aqueous, the substrate is preferably subjected to drying after covering with the buffer liquid before coating with the coating liquid. In this way, the unwanted cross-linking between the EL-POX and the substrate and the decomposition of the EL-POX can be minimized. This embodiment provides the advantage that EL-POX can penetrate the pores of the porous solid substrate and form a coating within these pores. The buffer liquid used according to this embodiment can suitably contain a nucleophilic crosslinking agent, said nucleophilic crosslinking agent containing at least 2 reactive nucleophilic groups.
    [0072] According to yet another embodiment, at least 80% by weight of the EL-POX present in the coating liquid is undissolved when the coating liquid is applied as a coating to the porous solid substrate. Advantageously, in addition to the undissolved EL-POX, the coating liquid contains a dissolved or undissolved buffer system. The coating liquid is preferably provided with a buffer pH in the range of 7 to 11, more preferably in the range of 8 to 10. The buffering capacity of the coating liquid is preferably at least 10 mmol.l-1. pH-1. Most preferably, the buffer capacity is at least 25 mmol.l-1.pH-1, even more preferably the buffer capacity is at least 50 mmol.l-1.pH-1. Preferably, after coating the substrate with the coating liquid containing the undissolved EL-POX, the substrate is covered with a liquid solvent composition in which EL-POX is soluble. This embodiment provides the advantage that EL-POX does not penetrate the pores and that the EL-POX layer of the coating is concentrated on the surface of the porous substrate. According to a particularly preferred embodiment, the liquid solvent composition contains a nucleophilic crosslinking agent.
    [0073] Examples of nucleophilic crosslinking agents that can be used appropriately include nucleophilic activated PEG, nucleophilic activated POX, trilisine and combinations thereof.
    [0074] The nucleophilic cross-linking agent preferably contains at least 3 reactive nucleophilic groups. The nucleophilic groups of the nucleophilic cross-linking agent are preferably selected from amine groups, thiol groups, phosphine groups and combinations thereof. Most preferably, these nucleophilic groups are comprised of amine groups. According to a preferred embodiment, the nucleophilic groups present in the nucleophilic crosslinking agent are comprised of primary amine groups.
    [0075] According to one embodiment, the nucleophilic crosslinking agent is comprised of a low molecular weight polyamine, with a molecular weight of less than 1000 g / mol, more preferably less than 700 g / mol and even more preferably less at 400 g / mol. Even more preferably, the nucleophilic crosslinking agent is selected from the group of dilisin; trilisine; tetralysin; pentalisin; dicysteine; tricysteine; tetracysteine; pentacysteine; oligopieptides comprising two or more amino acid residues selected from lysine, ornithine, cysteine, arginine and combinations thereof, and other amino acid residues; sperm; tris (aminomethyl) amine; arginine and its combinations.
    [0076] According to another embodiment of the invention, the nucleophilic crosslinking agent is comprised of a high molecular weight polyamine selected from the group of: nucleophilically activated POX (NU-POX) comprising at least two amine groups; chitosan; chitosan derivatives (e.g., chitosan polymers derivatized with dicarboxyl as described in WO 2009/028965), polyethyleneimines; polyvinylamine; polyalylamine; poly (meth) acrylates functionalized with amine; polysaccharides that contain amine functional moieties. such as aminoglycosides, such as 4,6-disubstituted deoxystreptamine (Kanamycin A, Amikacin, Tobramycin, Dibekacin, Gentamicin, Sisomycin, Netilmycin), 4,5-di-substituted deoxystreptamine (Neomycin B, C and Neomycin E Paromycin) and aminoglycosides not deoxystreptamine, for example, streptomycin; Styrenics; Polypeptides comprising two or more amino acid residues selected from lysine, ornithine, cysteine, arginine and combinations thereof, and other amino acid residues; and their combinations. Natural or recombinant albumin is an example of a polypeptide that can be used appropriately as a polypeptide. Amine-functionalized polyethylene glycol is another example of a high molecular weight polyamine that can be properly used as the nucleophilic crosslinking agent.
    [0077] According to another preferred embodiment, the nucleophilic groups present in the nucleophilic cross-linking agent are comprised of thiol groups (sulfohydril).
    [0078] According to one embodiment, the nucleophilic crosslinking agent used in the crosslinked polymer is comprised of a low molecular weight polythiol comprising 2 or more thiol groups with a molecular weight less than 1000 g / mol, more preferably less than 700 g / mol and more preferably less than 400 g / mol. Even more preferably, the nucleophilic crosslinking agent is selected from the group of trimercapto propane, ethanedithiol, propanedithiol, 2-mercapto ethyl ether, 2,2'- (ethylenedioxy) diethylethiol, tetra (ethylene glycol) dithiol, penta (ethylene glycol) dithiol, hexamethylene glycol dithiol; thiol modified pentaerythritol, dipenta erythritol, trimethylolpropane or ditrimethylol propane; oligopeptides containing at least two cysteine units.
    [0079] According to another embodiment of the invention, the nucleophilic crosslinking agent used in the crosslinked polymer is comprised of a high molecular weight polyol selected from the group of: NU-POX comprising at least two thiol groups; poly (meth) acrylates functionalized with thiol; polysaccharides containing functional fractions and styrenics; polypeptides comprising two or more thiol groups.
    [0080] The nucleophilic crosslinking agent, as previously defined in this context, can be suitably used in the coating liquid and / or in the buffer liquid to covalently bond the EL-POX to a solid porous substrate with an outer surface comprising a polymer that contains reactive electrophilic groups. Suitable polymers with electrophilic groups are comprised of poly (lactic-co-glycolic acid), chondroitin sulfate-NHS, chondroitin sulfate succinimidyl succinate, alginate-NHS, hyaluronic acid-NHS, copolymers comprising methacrylate monomers containing N carbonate -hydroxy succinimide (as described in Cengiz et al., 2010, J. of Polymer Science Part A: Polymer Chemistry, vol. 48, issue 21, 4737-4746), low molecular weight biological derivatives obtained by modifying at least one carboxyl group of a low molecular weight biological molecule, composed of two or more carboxyl groups, with N-hydroxysuccinimide, N-hydroxysulfo succinimide, or a derivative thereof (as described in EP1548004). Preferably, the nucleophilic crosslinking agent is used in the coating liquid.
    [0081] According to another preferred embodiment of the invention, EL-POX and the nucleophilic crosslinking agent are present in separate fluids, but are applied as a coating simultaneously on the solid porous substrate. This can be obtained properly using two nozzles ultrasound spraying. Consequently, the method according to this advantageous embodiment comprises: • providing a solid porous substrate, • providing the coating liquid, which comprises EL-POX in a first solvent; • providing a second liquid comprising a buffer system and / or a nucleophilic crosslinking agent, in the same way as a second solvent; • create a first spray stream by passing the coating liquid through a first ultrasonic nozzle; • create a second spray stream by passing the second liquid through a second ultrasonic nozzle; • simultaneously exposing at least a part of the surface of the porous solid substrate to both the first spray stream and the second spray stream to cover said part of the porous solid substrate with a coating mixture comprising the EL-POX as well as the nucleophilic crosslinking and / or the buffer system; • removing the first and second solvent from the coating mixture to obtain a porous solid substrate that is at least partially coated with a dry layer containing EL-POX and the nucleophilic cross-linking agent.
    [0082] EL-POX in this method can be suitably replaced by PVP -NHS acrylic acid or (poly - ((N-vinylpyrrolidone) 50-co- (acrylic acid) 25-co- (N-hydroxy acrylic acid ester succinimide) 25).
    [0083] If a nucleophilic crosslinking agent is used in the double spraying method described above, EL-POX and the nucleophilic crosslinking agent can react with each other to form a crosslinked polymer before, during or after solvent removal. According to a preferred embodiment, the crosslinked polymer that is comprised in the dry layer comprises electrophilic groups that have not reacted. Suitable solvents are as defined above in this context. According to a preferred embodiment, the first and second solvents are miscible, according to a most preferred embodiment, the first and second solvents are the same.
    [0084] If the second liquid contains a buffer system, the second liquid preferably has a buffer pH in the range of 7 to 11, more preferably in the range of 8 to 10. The buffering capacity of the second liquid is, preferably at least 10 mmol. L-lpH-l.More preferably, the buffer capacity is at least 25 mmol.l-1.pH-1, even more preferably the buffer capacity is at least 50 mmol.l-1.pH-1.
    [0085] Another aspect of the invention relates to an adhesive hemostatic product selected from a coated mesh, a coated foam or a coated powder, said hemostatic product comprising: • a porous solid substrate that is provided with a porosity at least 20% by volume and comprising an outer surface comprising a nucleophilic polymer containing reactive nucleophilic groups; • an adhesive coating that covers at least part of the solid substrate, the said coating comprising EL-POX containing on average at least 1 reactive electrophilic group.
    [0086] This adhesive hemostatic product can be obtained properly through the process described earlier in this context.
    [0087] As previously explained in this context, the hemostatic product has excellent adhesive properties due to the presence of reactive electrophilic groups that are able to react with the nucleophilic groups that are naturally present in the tissue. In addition, this hemostatic product offers the advantage that, upon contact with blood or other aqueous fluids, the adhesive coating will be anchored to the porous substrate, since the reactive electrophilic groups on the EL-POX will react with reactive nucleophilic groups of the nucleophilic polymer under the formation of covalent bonds.
    [0088] The EL-POX present in the coating of the adhesive hemostatic material can be covalently bonded to the porous solid substrate. In addition, EL-POX can be cross-linked.
    [0089] Preferred forms of the porous solid substrate, EL-POX and the nucleophilic polymer have been described previously in this context.
    [0090] EL-POX in the coating of the hemostatic product preferably contains 5 reactive electrophilic groups, more preferably 25 reactive electrophilic groups and even more preferably 50 reactive electrophilic groups.
    [0091] The substrate typically represents at least 10% by weight, more preferably at least 50% by weight, and even more preferably at least 75% by weight of the hemostatic product.
    [0092] The coating containing EL-POX typically represents 5-75%, by weight, of the hemostatic product. Most preferably, the coating represents 10-50% by weight, more preferably 1225% by weight of the hemostatic product.
    [0093] The coating preferably contains 25-100% by weight of EL-POX. Most preferably, the EL-POX content of the coating is at least 50% by weight, more preferably at least 75% by weight.
    [0094] The present invention allows the preparation of the coated hemostatic product in which the coating adhesive contains pores that are interconnected with the pores of the porous solid substrate.
    [0095] According to a particularly preferred embodiment, the hemostatic adhesive has a pore density of at least 50%, more preferably at least 80%
    [0096] The invention is further illustrated by means of the non-limiting examples set out below. EXAMPLES Example 1
    [0097] The poly [2- (propyl / NHS-ethyl-ethyl) -2-oxazoline] copolymer activated by NHS side chain, containing 25% NHS ester units (= EL-POX, 25% NHS) was synthesized as follows:
    [0098] A polycopolymmer of [2- (propylmethoxy-carbonyl-ethyl) -2-oxazoline] (Degree of polymerization = DP = about 100) was synthesized using the cationic ring-opening polymerization (CROP) using 75% 2-n-Propyl-2-oxazoline (nPropOx) and 25% 2-methoxycarbonyl-ethyl-2-oxazoline (MestOx). A statistical copolymer was obtained which contained 25% of 2-methoxycarbonyl-ethyl groups (1H-NMR). The polymer containing 25% 2-methoxycarbonyl-ethyl groups was hydrolyzed using sodium hydroxide (1M), producing a copolymer with 25% 2-carboxy-ethyl-groups (1H-NMR). The 2-carboxy-ethyl groups were activated by N-hydroxysuccinimide (NHS) and diisopropylcarbodiimide (DIC), producing a copolymer 2- (propyl / NHS-ester-ethyl) - 2-oxazoline] = EL-POX, NHS) . The polymer contained 25% NHS ester groups according to 1H-NMR and UV spectroscopy.
    [0099] Bovine collagen sponges were prepared according to the procedure described in Faraj et al., Tissue Engineering, 2007,13,10,2387-2394. Collagen was extracted from a cow's tendon. The collagen sponges thus obtained had a porosity of 95% to 98% and average pore dimensions of 80-100 μm. Porosity was calculated by comparing the density of a collagen film (without empty spaces) with the density of collagen sponges. The pore dimensions were determined using scanning electron microscopy according to the method described in Faraj et al., Tissue Engineering, 2007,13,10,2387-2394.
    [0100] EL-POX, 25% NHS was dissolved in acetone (180 mg / ml). The solution was evenly distributed dropwise over lyophilized bovine collagen sponges. Immediately after coating, the sponges were dried at room temperature in vacuum (1 mbar) for 8 hours. Collagen adhesive sponges were obtained with an EL-POX, 25% NHS coating (15 mg / cm2).
    [0101] To assess the possible cross-linking between EL-POX, 25% NHS and the nucleophilic amine groups present in the collagen, the coated collagen sponge was rinsed with acetone. All EL-POX, 25% NHS were recovered in the acetone extract, indicating that the electrophilic groups in EL-POX had not reacted with the amine groups in the collagen during coating and / or drying.
    [0102] The hemostatic properties of the coated collagen sponges were assessed as follows: • 100 μL of freshly heparinized whole blood was added dropwise to the top of the EL-POX coated side, 25% NHS from a collagen sponge. • Another EL-POX-coated collagen sponge, 25% NHS was placed on top of the blood-coated collagen sponge, with the EL-POX-coated side facing the blood (“sandwich method”). • Light pressure was applied for 10 seconds using gauze. Then, the sandwich was placed in a glass containing water and the water was subjected to stirring for two minutes. The two collagen sponges remained adherent under these conditions and no blood leaked from the sponges, indicating hemostasis and adherence.
    [0103] In a control experiment using uncoated collagen sponges, the sponges were released after 20 seconds in the water and the water turned red, indicating no hemostasis. Example 2
    [0104] Poly 2- (propyl / hydroxy-ethyl-amide-ethyl / NHS-ester-ethyl-ester-ethyl-amide-ethyl) -2-oxazoline terpolymer] activated by NHS side chain-containing ester groups 15% NHS (= EL-POX, 15% NHS) was synthesized as follows:
    [0105] The poly [2- (propyl / methoxy-carbonyl-ethyl) -2-oxazoline] copolymer (DP = + / - 100) was synthesized by CROP using 2-propyl-2-oxazoline at 70 % and 2-methoxycarbonyl-Ethyl-2-oxazoline. A statistical copolymer was obtained that contained 30% of 2-methoxycarbonyl-ethyl groups (1H-NMR). Secondly, the polymer containing 30% of 2-methoxycarbonyl-ethyl groups was reacted with ethanolamine a copolymer with 30% 2-hydroxy-ethylamide-ethyl groups (1H-NMR). After that, a part of the 2-hydroxy-ethylamide-ethyl groups was reacted with succinic anhydride, obtaining a terpolymer with 70% of 2-propyl groups, 15% of 2-hydroxy-ethylamide-ethyl groups and 15% -carboxy-ethyl-ester-ethylamide-ethyl, according to 1H-NMR. Finally, the 2-carboxy-ethyl-ester-ethylamide-ethyl groups were activated by means of N-hydroxysuccinimide (NHS) and diisopropyl carbodiimide (DIC ), producing EL-POX, 15% NHS. The polymer contained 15% NHS ester groups according to 1H-NMR.
    [0106] EL-POX, 15% NHS (130 mg) and anhydrous sodium borate (47 mg) were weighed and an isopropanol / 2-butanone solution (1.6 mL, v / v, 1: 1) resulting in a fine suspension since the anhydrous sodium borate is insoluble in isopropanol / 2-butanone (v / v, 1: 1). The suspension was evenly distributed drop by drop over the lyophilized bovine collagen sponges. Immediately after coating, the sponges were dried at room temperature under vacuum (1 mbar) for 8 hours. Thus, adhesive collagen sponges were obtained with an EL-POX, 15% NHS and an anhydrous sodium borate (19 mg / cm2).
    [0107] The hemostatic properties of the coated collagen sponges were assessed as follows: • 100 μL of fresh heparinized whole blood was added dropwise over EL-POX, 15% NHS and a side coated with anhydrous sodium borate a collagen sponge. • Another EL-POX, 15% NHS and a sponge coated with anhydrous sodium borate were placed on the blood-covered collagen sponge, with the side coated with the EL-POX facing the blood ("sandwich method" ). • A gentle pressure was applied for 10 seconds using gauze. Then, the sandwich was placed in a glass containing water and the water was stirred for three minutes.
    [0108] The two collagen sponges remained adhered under these conditions and no blood leaked from the sponges, indicating hemostasis and adherence. Example 3
    [0109] In the present example, several polymers were tested for shear strength, and a synthesis of the samples is shown in Table 1. The Polymers (DP = + / - 100) were synthesized with CROP of 2-n-propyl-2-oxazoline, 2-ethyl-2-oxazoline and 2-methoxy-ethyl-2-oxazoline. The EL-POX used as sample 1-3 were post-modified using the route described in example 1. The EL-POX used as sample 4-6 was synthesized using the route described in example 2. All activated polymers were analyzed through 1H- NMR and UV spectroscopy for NHS content. PEG 4-arm NHS (pentaerythritolpoli (ethylene glycol) tetrasuccinimidyl glutarate ether, sample 7) was obtained from NOF America Corporation. Bovine collagen sponges (5 x 7 x 1 cm (b x l x h)) were tested as a control (sample 8). All coated sponges were prepared as described in Example 1. Preparation procedure • Porous collagen sponges were weighed (n = 7). • EL-POX solutions were prepared by dissolving a defined amount of polymer in organic solvent (dichloromethane (DCM) / isopropyl alcohol (IPA) (v / v, 1: 1)) to a final concentration of 300 mg / mL. • The EL-POX solution was applied to a dropwise coating on a portion of the porous collagen sponges (14 cm2) to obtain the desired coating density of 15 mg / cm2. The coated porous collagen sponges were dried overnight in a vacuum oven (5 mbar) at room temperature. • The coated porous collagen sponges were reweighed and the coating density was determined. A synthesis of the polymers and coating densities used is shown in Table 1. TEST PROCEDURE
    [0110] These polymers were tested for shear strength as follows: • Constructions were cut in equal parts of 5 x 1 cm (bxl). • The coated sides were placed together with the adhesive sides facing each other using 200 μL of human heparinized blood. A weight (10 g) was applied for 10 seconds to a standardized pressure. • Buildings were allowed to be reticulated for defined times: 1 minute (t1) or 15 minutes (t15). • At the defined time points, the constructions were placed in a shear tester (Zwicky Roell, load cell at 20 N) and the shear strength was measured to failure. • Output: The measured force (N) is divided by the overlapping area of the constructions (cm2) resulting in shear strength (in kPa). The results are listed in Table 1.Table 1: Results of the resistance test to

    From these results, it can be concluded that: • EL-POX polymers (1–6) have greater shear strength with increased crosslinking times. • EL-POX polymers (2 and 5) show higher shear strength values than the PEG 4-arm NHS polymer (7) at t15. • The control sample (8) shows limited to no shear strength, indicating that the crosslinking is caused by the NHS ester groups.
    [0111] This example illustrates that collagen-coated EL-POX is able to be cross-linked in the presence of blood by providing greater shear strength than the same concentration of collagen-coated NHS 4-arm NHP. Example 4
    [0112] NHS ester -ethyl-ester-ethyl -amide - ethyl) -2-oxazoline] activated by NHS chain, containing 20% of NHS ester groups (= EL-POX, 20% NHS) was synthesized as follows:
    [0113] Ocopolímerodepoli [2- (propylmethoxy-carbonyl-ethyl) -2-oxazoline] (DP = + / - 100) was synthesized by means of CROP using 70% 2-propyl-2-oxazoline and 2-methoxycarbonyl- Ethyl-2-oxazoline 30%. A statistical copolymer was obtained which contained 30% of 2-methoxycarbonyl-ethyl groups (1H-NMR). Second, the polymer containing 30% of 2-methoxycarbonyl-ethyl groups was reacted with ethanolamine, giving rise to a copolymer with 30% of 2-hydroxy-ethylamide-ethyl groups (1H-NMR). Then, part of the 2-hydroxy-ethylamide-ethyl groups were reacted with succinic anhydride to produce a terpolymer with 70% of 2-propyl groups, 10% of 2-hydroxy-ethylamide-ethyl groups and 20% of carboxy-ethyl-ester-ethylamide-ethyl according to 1H-NMR. Finally, the 2-carboxy-ethyl-ester-ethylamide-ethyl groups were activated by means of N-hydroxy succinimide (NHS) and diisopropyl carbodiimide (DIC), producing EL-POX, 20% NHS. The polymer contained 20% of NHS ester groups according to 1H-NMR.
    [0114] The propyl and amine groups that contained amine-functionalized NU-POX on the alkyl side chain were synthesized by means of CROP denPropOx and MestOx and subsequent amidation of the methyl methyl methyl methyl diamine side chains to provide a poly (2-propyl / aminoethyl-2-amino-methylamidoethyl). oxazoline) (NU-POX). The polymer contained 20% NH2 according to 1H-NMR.
    [0115] Bovine collagen sponges (7 x 5 x 1 cm) were used, which were prepared as described in Example 1. For these experiments, an ExactaCoat SC ultrasonic spraying device (Sono-Tek) was used. equipped with a heating plate to coat the collagen sponges.
    [0116] A solution of EL-POX (EL-POX, 20% NHS) in IPA / 2-butanone (v / v, 1: 1) (90 mg / mL) was distributed evenly over the collagen by spraying ultrasonic, according to the configurations shown in Table 2, leading to a coating density of 5 mg / cm2. SEM images showed that the porous structure of the collagen was maintained.
    [0117] The constructions were cut into pieces (2 cm2) and tested using the shear strength test at t15 as described in example 3. The results were 10.9 +/- 3.3 kPa (n = 4 ), indicating good adherence and hemostasis. Table 2: Ultrasonic spray parameters

    Test 4B: EL-POX with suspended buffer
    [0118] A solution of EL-POX in IPA / 2-butanone (v / v, 1: 1) (10 mg / mL) with HEPES buffer in suspension (1.7 g) was distributed evenly over the collagen by ultrasonic spraying, according to the adjustments shown in Table 2, leading to a coating density of 5 mg / cm2. SEM images showed that the porous structure of the collagen was maintained. The constructions were cut into pieces (2 cm2) and tested using the shear strength test at t15 as described in example 3. The average shear strength measured was 2.6 +/- 0.8 kPa (n = 3), indicating good adherence and hemostasis. 4C test: (1) NU-POX solution and buffer + (2) EL-POX solution
    [0119] A solution of NU-POX in water (10 mg / mL) with HEPES (1.7 g) was distributed evenly over the collagen by ultrasonic spraying, according to the configurations shown in Table 2. The solvent was allowed to evaporate for 30 min. After that, a solution of EL-POX in IPA / 2-butanone (v / v, 1: 1) (15 mg / mL) was homogeneously distributed by means of ultrasound spraying, according to the settings shown in Table 2, on top of the coated collagen. After coating, a coating density of 5 mg / cm2 (± 40% by weight of NU-POX and ± 60% by weight of EL-POX) was obtained. SEM images showed that the porous structure of the collagen was maintained. The constructions were cut into pieces (2 cm2) and tested using the t15 shear strength test as described in example 3. The average shear strength measured was 3.9 +/- 2.9 kPa (n = 2), indicating good adherence and hemostasis. 4D test: Buffer solution (EL-POX suspension)
    [0120] A suspension of EL-POX in IPA / diethyl ether / triethylamine (v / v / v, 50: 50: 1) was homogeneously distributed over collagen by ultrasonic spray according to the configurations exposed in Table 2. After coating, a coating density of 4 mg / cm2 was obtained. SEM images showed that the porous structure of the collagen was maintained. The constructions were cut into pieces (2 cm2) and tested using the shear strength test as described in example 3. The average shear strength measured was 4.2 +/- 3.5 kPa (n = 3) , indicating good adherence and hemostasis.
    [0121] In addition, the hemostatic properties of 4A-4D ultrasound-coated collagen sponges were assessed as follows: • 100 μL of fresh heparinized whole blood was added dropwise to the top of the EL-POX-coated side of a sponge collagen. •• Another EL-POX-coated sponge was placed on the blood-covered collagen sponge, with the EL-POX-coated side facing the blood (sandwich method). • Soft pressure was applied for 10 seconds using gauze. Then, the sandwich was placed in a glass containing water and the water was stirred for two minutes.
    [0122] The two collagen sponges 4A-4D remained fully adherent under these conditions and no blood leaked from the sponges, indicating hemostasis and adhesion. Example 5
    [0123] Poly (2- (propyl / hydroxy-ethylamide-ethyl / NHS-ester-ethyl-ester-ethylamide-ethyl) -2-oxazoline terpolymer) activated by NHS side chain (= EL-POX, NHS a 20%) was synthesized as described in example 2.
    [0124] AEL-POX, NHSa20% was dissolved in methanol (180 mg / ml). The solution was evenly distributed dropwise over a plaster of Oxidized Regenerated Cellulose (ORC, Gelita-Cel). Immediately after coating, the spots were dried at room temperature under air flow for 4 hours. ORC was obtained with an EL-POX coating, 20% NHS (12 mg / cm2).
    [0125] The hemostatic properties of the coated ORC were assessed as follows: • 100 μL of fresh heparinized whole blood was added dropwise over the EL-POX, side coated with NHS at 20% ORC (1 x 1 cm ). • Another EL-POX, 20% NHC-coated ORC was placed on top of the blood-coated ORC, with the EL-POX-coated side facing the blood ("sandwich method"). • A gentle pressure was applied for 10 seconds using gauze. Then, the sandwich was placed in a glass containing water and the water was stirred for five minutes. The two pieces of ORC remained adherent in these conditions for five minutes and the middle didn't turn red.
    [0126] In a control experiment using uncoated ORC, the ORC separated within one minute under water during agitation and the water turned red, indicating no hemostasis. Example 6
    [0127] poly (2- (propyl / hydroxy-ethylamide-ethyl / NHS-ester-ethyl-ester-ethylamide-ethyl) -2-oxazoline terpolymer) activated by NHS side chain (= EL-POX, 20% NHS ) was synthesized as described in example 2. Chitosan powder was obtained from Sigma-Aldrich. (Deacetylation grade 75-85%, Mn 10,000). Powdered starch (HaemoCer®) was obtained from BioCer, Germany.
    [0128] The powders were coated separately with EL-POX, 20% NHS (EL-POX) as follows. • Powder (chitosan or starch) was weighed and coated with a solution of EL-POX (15 mg / mL) in DCM. • The suspension was subjected to drying under reduced pressure. • After this, the coated dry powder was ground to form a fine homogeneous powder. The coated chitosan powder contained about 25% by weight of EL-POX. The coated starch powder contained about 10% by weight of EL-POX.
    [0129] As controls, crushed uncoated chitosan powder, crushed uncoated starch powder and crushed EL-POX were tested.
    [0130] EL-POX-coated powders and control samples were mixed with (1) carbonate buffer (0.1 M, pH 9) or (2) heparinized human blood (pH 7.4) to evaluate the hemostatic properties. This condition was tested as follows: the powders were weighed in an Eppendorf tube and mixed with 250 µL of buffer (1) or blood (2). The gelation time was determined by inverting the tube up and down until it was form a gel.
    [0131] The amount of materials used and the results of the crosslinking tests are shown in Table 3.Table 3: Results of the crosslinking tests
    * calculated from the%, by weight, of EL-POX in coated powders
    [0132] These results show that chitosan is capable of cross-linking with EL-POX (sample 2) and that starch is not capable of cross-linking with EL-POX (sample 7). Both chitosan and EL-POX-coated starch were able to crosslink with blood (samples 1 and 10) while uncoated chitosan and starch powders did not form gel in the presence of the buffer and / or blood (samples 3,4,8 and 9) . The EL-POX powder was able to form a gel by reacting with amines in the blood (sample 5), while no gel formation was observed when the EL-POX powder was combined with buffer (sample 6).
    [0133] Gels containing EL-POX were found to be stable under water. In contrast to blood gels prepared by adding 200 mg of starch or chitosan to 250 μL of blood, they were not stable in water. Example 7
    [0134] Poly (2- (propyl / hydroxy-ethylamide-ethyl / NHS-ester-ethyl-ester-ethylamide-ethyl) -2-oxazoline terpolymer) activated by NHS side chain (= EL-POX, 20% NHS) was synthesized as described in Example 3. PEG 4-arm NHS (Pentaerythritol poly (ethylene glycol) tetrasuccinimidyl glutarate ether, EL-PEG) was obtained from NOF America Corporation. Bovine collagen sponges (7 x 5 x 1 cm) as described in Example 1.
    [0135] Two application methods were compared: (I) melting method and (II) coating liquid method. (I) Fusion method (comparative examples)
    [0136] A known quantity of polymer powders, EL-POX, 20% NHS and EL-PEG, were distributed homogeneously over the collagen sponges to obtain the coating densities indicated in table 4. EL-POX, 20% NHS and EL-PEG were heated to the temperatures indicated in Table 4, in a preheated oven for 5 min. to melt the polymer powder. Within this time and temperature setting range, both EL-POX and EL-PEG remained stable.
    [0137] SEM-images of the prepared constructions showed that the polymer film formed showed that the polymer film formed sealed the porous structure of the upper collagen layer.Table 4: Definitions (I) fusion method
    (II) Coating liquid method
    [0138] Powder of 20% NHS, EL-POX, was dissolved in IPA / DCM (v / v, 1: 1) (15 mg / mL) and distributed evenly over the collagen sponges by dripping, to obtain a coating density of 12 mg / cm2. The sponges were subjected to drying in a vacuum oven for 2 hours. SEM images showed that the porous collagen structure was maintained.
    [0139] The hemostatic properties of the coated collagen sponges were evaluated as follows: • 100 μL of fresh heparinized whole blood was added dropwise over the coated side of the EL-POX, 20% NHS or EL-PEG from a sponge. collagen. • Another coated sponge was placed on top of the blood-covered collagen sponge, with the coated sides facing the blood ("sandwich method"). • Soft pressure was applied for 10 seconds using gauze. Then, the sandwich was placed in a glass containing water and the water was stirred for one minute.
    [0140] Collagen sponges prepared by fusion (both EL-POX and EL-PEG), separated in one minute, indicated absence of hemostasis and adherence. Collagen sponges (with EL-POX), prepared by drip, remained adherent for 1 minute, indicating hemostasis and adherence.
    [0141] This example shows that the application method affects the accessibility of pores in collagen and explains the difference in hemostasis and adherence between sponges obtained by melting and sponges obtained by coating with liquid. Example 8
    [0142] The treatment of traumatic rupture of the liver and spleen is a major challenge for a surgeon, since the spleen has an excellent blood supply and rupture of the spleen is often associated with massive abdominal bleeding.
    [0143] Standardized combined penetrating spleen rupture was inflicted on anesthetized pigs n = 1 (domestic pig, male, body weight range: 40 kg, adult). A midline laparotomy was performed to access the spleen. Using a scalpel, standardized subcapsular lesions (10 mm x 10 mm) n = 3 (S1 ... S3) were performed.
    [0144] Three types of hemostatic products have been tested, with an overview given in Table 5. Table 5: Description of tested products

    [0145] Hemostatic products were applied with gentle pressure. After applying the product, the hemostasis time was assessed, see Table 6.
    [0146] Table 6: Results of the Animal model
    TTH = time for hemostasis; n = none of the products needed to achieve hemostasis
    [0147] This example shows the hemostatic effectiveness of the EL-POX-coated sponge on a pig's spleen. Based on the end points of Table 6, the sponge coated with EL-POX performed equally well in this model in obtaining hemostasis as a reference product (HemopatchTM) and better than the control. In addition, it was observed that the blood-absorbing capacity of the EL-POX-coated sponge was superior to that of the reference product. Thus, the hemostasis achieved with the EL-POX-coated sponge was aided by a rapid onset of blood clotting.
    权利要求:
    Claims (15)
    [0001]
    1. Process to prepare an adhesive hemostatic product characterized by understanding the steps of: • providing a porous solid substrate; • coating the substrate with a coating liquid comprising an electrophilic activated polyoxazoline (EL-POX) and a solvent to produce a coated substrate, with said EL-POX containing at least 10 reactive electrophilic groups; • remove the solvent from the coated substrate.
    [0002]
    2. Process according to claim 1, characterized by the fact that the solid substrate has a porosity of at least 20% by volume, preferably at least 50% by volume and most preferably at least 85% by volume.
    [0003]
    Process according to claim 1 or 2, characterized in that the substrate comprises an outer surface comprising a nucleophilic polymer containing reactive nucleophilic groups.
    [0004]
    4. Process according to any one of the preceding claims, characterized in that the solid substrate is a mesh or foam in the form of a sheet with a length of 10 to 200 mm, a width of 5 to 200 mm and a thickness from 0.5 to 10 mm.
    [0005]
    Process according to any one of claims 1 to 3, characterized by the fact that the solid substrate is a powder, said powder having an average weighted mass particle size in the range of 10 to 200 μm.
    [0006]
    6. Process according to any one of the preceding claims, characterized by the fact that the substrate is coated by spraying the coating liquid through an ultrasonic nozzle onto the substrate.
    [0007]
    7. Process according to any of the preceding claims, characterized by the fact that EL-POX contains at least 2 reactive electrophilic groups selected from esters of carboxylic acids, sulfonate esters, phosphonate esters, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrothiophenyl esters, acid halide groups, anhydrides, ketones, aldehydes, isocyanate, thioisocyanate, isocyanate, epoxides, activated hydroxyl groups, olefins, glycidyl ethers, carboxyl, succinimidyl ester, carbon , succinimidyl carbamates, sulfosuccinimidyl ester, sulfosuccinimidyl carbonate, maleimido (maleimidyl), ethenesulfonyl, imido esters, acetate acetate, halo acetal, orthopyridyl disulfide, dihydroxyphenyl derivatives, vinyl, acrylate and acrylamide, its acrylamide, acrylamide and acrylamide .
    [0008]
    Process according to any one of claims 3 to 7, characterized in that the nucleophilic polymer is selected from protein, chitosan and synthetic polymers or carbohydrates and in which the reactive nucleophilic groups can be selected from amine, thiol, phosphine and their combinations.
    [0009]
    Process according to any one of the preceding claims, characterized in that the coating liquid contains at least 50% by weight of a solvent selected from 2-propanol, ethyl alcohol, methanol, dichloromethane, acetone, anisole , 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, propyl acetate and combinations thereof.
    [0010]
    10. Process according to any of claims 3 to 9, characterized by the fact that after coating the substrate with the coating liquid and before and / or during solvent removal, the reactive electrophilic groups of the EL-POX react with the reactive nucleophilic groups of the nucleophilic polymer that is present on the surface of the substrate under the formation of covalent bonds.
    [0011]
    11. Process according to any one of the preceding claims, characterized in that the EL-POX is dissolved in the coating liquid and the coating liquid contains a dispersed, undissolved buffer system, said coating liquid being provided with a buffer pH in the range of 7 to 11 and a buffer capacity of at least 10 mmol.l-1.pH-1.
    [0012]
    Process according to any one of claims 1 to 10, characterized in that the EL-POX is dissolved in the coating liquid and the process comprises covering the substrate with a buffer liquid before the substrate is coated with the coating liquid containing EL-POX, said buffer liquid having a buffer pH in the range of 7 to 11 and a buffer capacity of at least 10 mmol.l-1.pH-1.
    [0013]
    13. Process according to any one of claims 1 to 10, characterized by the fact that at least 80% by weight of the EL-POX present in the coating liquid is not dissolved when the coating liquid is applied on the substrate and in that the coating liquid contains a dissolved or undissolved buffer system, said coating liquid having a buffer pH in the range of 7 to 11 and a buffer capacity of at least 10 mmol.l-1.pH-1.
    [0014]
    14. Process according to any of the preceding claims, characterized by the fact that after removal of the solvent, EL-POX contains on average at least one reactive electrophilic group.
    [0015]
    15. Adhesive hemostatic product characterized by being selected from a coated mesh, a coated foam or a coated powder, the said hemostatic product comprising: • a porous solid substrate with a porosity of at least 5%, in volume, and comprising an outer surface comprising a nucleophilic polymer containing reactive nucleophilic groups; • an adhesive coating that covers at least part of the solid substrate, said coating comprising an electrophilic activated polyoxazoline (EL-POX), said EL-POX containing on average at least 5 reactive electrophilic groups; wherein the adhesive hemostatic product is obtainable by means of a process as defined in any of the preceding claims.
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    Lih et al.2012|Search Docs
    同族专利:
    公开号 | 公开日
    EP3204057A1|2017-08-16|
    WO2016056901A1|2016-04-14|
    KR20170066450A|2017-06-14|
    US20190125922A1|2019-05-02|
    CN107106719B|2021-06-01|
    US20180221531A1|2018-08-09|
    RU2704259C2|2019-10-25|
    AU2015328825B2|2019-02-21|
    US10751441B2|2020-08-25|
    RU2017115407A|2018-11-14|
    RU2017115407A3|2019-04-10|
    CN107106719A|2017-08-29|
    AU2015328825A1|2017-04-20|
    JP2017531488A|2017-10-26|
    CA2963057A1|2016-04-14|
    BR112017006943A2|2018-01-09|
    JP6683398B2|2020-04-22|
    EP3204057B1|2019-12-04|
    US10232077B2|2019-03-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB760311A|1951-10-06|1956-10-31|Allied Colloids Mfg Company Lt|Improvements in and relating to derivatives of ethylene imine|
    US3442975A|1967-01-11|1969-05-06|Allied Chem|Polyimine/polycarbonamide graft polymers|
    US3996237A|1974-07-17|1976-12-07|The Dow Chemical Company|Oxazoline- or oxazine-substituted acrylic esters|
    US5614587A|1988-11-21|1997-03-25|Collagen Corporation|Collagen-based bioadhesive compositions|
    US5635571A|1995-06-30|1997-06-03|Cornell Research Foundation, Inc.|Polymerizable macromonomers and polymers prepared therefrom|
    US6458889B1|1995-12-18|2002-10-01|Cohesion Technologies, Inc.|Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use|
    US6833408B2|1995-12-18|2004-12-21|Cohesion Technologies, Inc.|Methods for tissue repair using adhesive materials|
    CA2353642C|1998-12-04|2009-11-10|Amarpreet S. Sawhney|Biocompatible crosslinked polymers|
    EP1183298A1|1999-05-19|2002-03-06|Basf Aktiengesellschaft|Cross-linked polymers that contain condensed alkaline amino acids and method for producing said polymers|
    US6703047B2|2001-02-02|2004-03-09|Incept Llc|Dehydrated hydrogel precursor-based, tissue adherent compositions and methods of use|
    DE10152407A1|2001-10-24|2003-05-08|Aesculap Ag & Co Kg|Composition of at least two biocompatible chemically crosslinkable components|
    RU2226406C1|2002-07-22|2004-04-10|Шканакин Лев Геннадьевич|Hemostatic, antiseptic and wound-healing sponge|
    JP5156890B2|2002-09-11|2013-03-06|独立行政法人物質・材料研究機構|Crosslinked polymer and method for producing the same|
    AU2003279730A1|2002-09-30|2004-04-19|Fibrogen, Inc.|Dry tissue sealant compositions|
    US7300738B2|2003-02-10|2007-11-27|Fujifilm Corporation|Azolinyl acetic acid derivative and azolinyl acetic acid derivative containing recording material|
    JP2005161698A|2003-12-03|2005-06-23|Fuji Photo Film Co Ltd|Recording material|
    US20050238825A1|2004-04-26|2005-10-27|Isp Investments Inc.|Crosslinked polymeric composition|
    NZ550964A|2004-04-28|2011-05-27|Angiodevice Internat Gmbh|Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use|
    WO2006034128A2|2004-09-17|2006-03-30|Angiotech Biomaterials Corporation|Multifunctional compounds for forming crosslinked biomaterials and methods of preparation and use|
    JP5615558B2|2007-02-28|2014-10-29|セリナ・セラピユーテイツクス・インコーポレーテツド|Active polyoxazoline and compositions containing the same|
    WO2009028965A1|2007-08-28|2009-03-05|Theodore Athanasiadis|Surgical hydrogel|
    WO2009043027A2|2007-09-27|2009-04-02|Serina Therapeutics, Inc.|Multi-armed forms of activated polyoxazoline and methods of synthesis thereof|
    WO2009089542A2|2008-01-11|2009-07-16|Serina Therapeutics, Inc.|Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same|
    FR2928373B1|2008-03-05|2010-12-31|Centre Nat Rech Scient|LINEAR POLYETHYLENIMINE DERIVATIVE POLYMER FOR GENE TRANSFER.|
    US8883211B2|2008-07-10|2014-11-11|Serina Therapeutics, Inc.|Polyoxazolines with inert terminating groups, polyoxazolines prepared from protected initiating groups and related compounds|
    AU2009292643B2|2008-09-19|2016-02-18|Nektar Therapeutics|Polymer conjugates of therapeutic peptides|
    AU2009305115B2|2008-10-17|2014-09-25|Sofradim Production|Auto-sealant matrix for tissue repair|
    EP2346538B1|2008-11-19|2018-06-27|Actamax Surgical Materials LLC|Fibrous tissue sealant and method of using same|
    EP2228955B1|2009-03-13|2017-02-22|OCT Circuit Technologies International Limited|System and method for OFDM reception in the presense of Doppler effect based on time domain windowing|
    US20130029030A1|2010-03-15|2013-01-31|Kristian Larsen|Method for promotion of hemostasis and/or wound healing|
    PT2555804E|2010-04-07|2015-09-25|Baxter Int|Hemostatic sponge|
    CN103429268B|2011-01-04|2015-11-25|本德尔分析控股有限公司|The polymer through being cross-linked derived from parent's electricity activation Ju oxazoline and implant|
    WO2012122044A2|2011-03-04|2012-09-13|Orthovita, Inc.|Flowable collagen-based hemostat and methods of use|
    ES2563246T3|2012-03-16|2016-03-11|Bender Analytical Holding B.V.|Cross-linked polymers and medical products derived from nucleophilically activated polyoxazoline|GB201020236D0|2010-11-30|2011-01-12|Convatec Technologies Inc|A composition for detecting biofilms on viable tissues|
    EP2648793B1|2010-12-08|2020-03-11|ConvaTec Technologies Inc.|Integrated system for assessing wound exudates|
    ES2748519T3|2010-12-08|2020-03-17|Convatec Technologies Inc|Wound exudate system accessory|
    GB2497406A|2011-11-29|2013-06-12|Webtec Converting Llc|Dressing with a perforated binder layer|
    WO2018009873A1|2016-07-08|2018-01-11|Convatec Technologies Inc.|Fluid collection apparatus|
    CN108478849B|2018-02-07|2021-04-16|广州迈普再生医学科技股份有限公司|Absorbable and adherable hemostatic sponge and preparation method thereof|
    CN108785732B|2018-06-21|2021-04-09|广州迈普再生医学科技股份有限公司|Hemostatic plugging material, preparation method thereof and hemostatic plugging product|
    CN108815560B|2018-06-21|2021-03-12|广州迈普再生医学科技股份有限公司|Porous tissue plugging material, preparation method thereof and plugging product|
    CN108742750B|2018-06-21|2020-09-22|广州迈普再生医学科技股份有限公司|Tissue plugging material, preparation method thereof and plugging product|
    CN108939174B|2018-07-16|2020-06-19|浙江大学|Layer-by-layer self-assembled multilayer film of pH response type polyoxazoline-nano silver and preparation method thereof|
    CA3146680A1|2019-07-12|2021-01-21|Gatt Technologies B.V.|Haemostatic powder|
    WO2021009016A1|2019-07-12|2021-01-21|Gatt Technologies B.V.|Method for preparing a tissue-adhesive sheet|
    CA3146839A1|2019-07-12|2021-01-21|Gatt Technologies B.V.|Biocompatible, flexible, haemostatic sheet|
    CA3146724A1|2019-07-12|2021-01-21|Gatt Technologies B.V.|Biocompatible, flexible, haemostatic sheet|
    WO2022023375A1|2020-07-28|2022-02-03|Gatt Technologies B.V.|Bone-adhesive sheet|
    CN112007204B|2020-08-12|2021-10-01|山东百多安医疗器械股份有限公司|Anti-infection, healing-promoting, hemostatic and anti-adhesion membrane and preparation method thereof|
    法律状态:
    2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-09-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/10/2015, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP14187781.1|2014-10-06|
    EP14187781|2014-10-06|
    PCT/NL2015/050696|WO2016056901A1|2014-10-06|2015-10-05|Tissue-adhesive porous haemostatic product|
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