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    • 专利摘要:
    PROCESS TO MANUFACTURE A DRY AND STABLE HESMOSTATIC COMPOSITION, METHOD TO DISPENSING A HEMOSTATIC COMPOSITION TO A TARGET SITE, FINAL FINISHED CONTAINER, METHOD TO PROVIDE A READY-TO-USE HEMOSTATIC COMPOSITION, AND KIT TO MANAGE A HEMOSTATIC COMPOSITION to manufacture a process a dry and stable hemostatic composition, said process comprising a) providing a first component comprising a dry preparation of a clotting inducing agent, b) providing a second component comprising a dry preparation of a biocompatible polymer suitable for use in hemostasis, c) providing said first component and said second component in a combined form in a final container, c1) either by filling said first component and said second component in said final container so as to obtain a dry mixture in said final container, c2) or by providing said first component or referred to second component in referred reci final component and adding said second component or said first component so as to obtain a combination of said first component with said second component in said final container d) finishing the final container to a storable pharmaceutical device containing said first component and said second component in a combined form as a dry and stable hemostatic composition.
    公开号:BR112012030455B1
    申请号:R112012030455-0
    申请日:2011-06-01
    公开日:2021-08-17
    发明作者:Andreas Goessl；Atsushi Edward Osawa；Cary J. Reich
    申请人:Baxter Healthcare S.A.；Baxter International Inc；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [001] The present invention relates to manufacturing processes of hemostatic decompositions in storage-stable form. BACKGROUND OF THE INVENTION
    [002] Hemostatic compositions in dry and storage-stable form, comprising dry stable, biocompatible and biodegradable granular material, are known, for example, from WO 98/008550 A or WO 2003/007845 A. Such products have been successfully applied in the art for hemostasis. Floseal® is an example for a powerful and versatile hemostatic agent consisting of a granular gelatin matrix swollen in a solution containing thrombin to form a flowable paste.
    [003] Since such products must be applied to humans, it is necessary to provide higher safety standards for quality, storage stability and sterility of the final products and their components. On the other hand, manufacturing and handling must be made as convenient and efficient as possible. If hemostatic compositions require a thrombin component for use, provision of that thrombin component in the final product is challenging. Since thrombin and matrix material generally have different properties with respect to manufacturing requirements, they must be manufactured and supplied separately. For example, sterilization requirements can differ significantly between relatively stable granular (often also cross-linked) matrix material and proteinaceous components such as thrombin. Since such matrix materials can generally be sterilized by powerful sterilization methods (such as autoclaving, gamma irradiation, etc.), thrombin (as an enzyme) must be treated with more care. Those powerful sterilization methods are generally not possible for thrombin, due to the loss of enzymatic activity caused by such harsh treatments. For stability reasons, such products (as well as products according to the present invention) are generally provided in a dry form and brought into a "ready-to-use" form (which is generally in the form of a (hydro-)gel, suspension or solution) immediately before use, requiring the addition of wetting or solvating (suspension) agents and mixing of the matrix material component with the thrombin component. Thrombin reconstitution or the step of mixing a thrombin solution with the granular matrix material are steps that generally require some time and handling and can cause problems especially in intensive care.
    [004] It is an object of the present invention to overcome such problems and provide suitable methods for manufacturing a dry and storage stable hemostatic composition that can be conveniently provided and usable. These methods should provide product formats enabling a convenient provision of “ready-to-use” hemostatic compositions, especially in intensive care medicine where the number of manipulation steps should be kept as low as possible. SUMMARY OF THE INVENTION
    [005] Therefore, the present invention provides a process for manufacturing a dry and stable hemostatic composition, said process comprising: a) providing a first component comprising a dry preparation of a coagulation inducing agent, such as a dry thrombin preparation,b ) providing a second component comprising a dry preparation of a biocompatible polymer suitable for use in hemostasis, c) providing said first component and said second component in a combined form in a final container, c1) either filling said first component and said second component in said final container in order to obtain a dry mixture in said final container, c2) either by providing said first component or said second component in said final container and adding said second component or said first component so as to obtain a combination of said first component with said second component in said container f final, d) finishing the final container for a storable pharmaceutical device containing said first component and said second component in a combined form as a dry and stable hemostatic composition.
    [006] The process provides the dry and stable composition according to the invention in a convenient manner allowing the composition to be easily reconstituted for medical use. The invention further relates to a method for dispensing a hemostatic composition to a target site on a patient's body, said method comprising dispensing a hemostatic composition produced by the process of the present invention to the target site. According to another aspect, the present invention relates to a finished final container obtained by the process according to the present invention. The invention also relates to a method for providing a ready-to-use hemostatic composition comprising contacting a hemostatic composition produced by the process of the present invention with a pharmaceutically acceptable diluent as well as a kit comprising the finished final container and other means for applying the composition ( for example, a diluent container). Compositions according to the present invention are particularly useful for providing hemostasis at bleeding sites, including surgical bleeding sites, traumatic bleeding sites and the like. An exemplary use of the compositions may be in sealing the tissue tract above a blood vessel penetration created for vascular catheterization. DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
    [007] The present invention provides an improvement for dispensing and handling hemostatic compositions, primarily by providing a two-component product in a convenient single-composition format. The hemostatic compositions according to the invention contain a first component comprising a dry preparation of a coagulation-inducing agent, such as a dry thrombin preparation (the "thrombin component") and a second component comprising a dry preparation of a polymer biocompatible suitable for use in hemostasis (the "biocompatible hemostatic polymer component"). Other components may be present. Products of this type are known in principle in the art, yet in a different format: generally, the components are provided as separate entities in dry form. Prior to mixing the components for administration to a patient, the dry components are generally contacted separately with suitable diluents. Mixing the components is then carried out by mixing the separately reconstituted components. For example, a dry thrombin component can be provided which is reconstituted by a pharmaceutically acceptable (aqueous) diluent. The thrombin solution obtained after reconstitution is then used to wet or solubilize the polymer, usually under formation of a hydrogel which is then applied to the patient. Since this is at least a two-step process before the product is “ready to use”, it would be convenient if a product only needed one step before it was ready to use. two components prevents a simple mixing of the components in the course of the production method, mainly due to losses of stability and activity.
    [008] With the present invention, production processes are provided that enable the two components to be supplied already in a combined dry form ready to be reconstituted together. The processes according to the invention are not only feasible for benchtop scientific experiments, but are suitable for pharmaceutical industrial mass production. With the present invention it was possible to provide such an already mixed hemostatic composition without the risk of unwanted degradation or loss of enzyme activity. The resulting compositions have comparable storage stability to previously known products, but are more convenient in handling because separate reconstitution and mixing prior to medical administration is not necessary with the products obtainable with the present invention. Providing a ready-to-use hydrogel, suspension or solution of the hemostatic composition is possible in a one-step process, simply by adding an appropriate pharmaceutically acceptable diluent to the composition in the final container. The final container is preferably a syringe designed to directly administer the reconstituted hemostatic composition after contact with the diluent.
    [009] The coagulation inducing agent is a substance selected from the group consisting of thrombin, a snake venom, a platelet activator, a thrombin receptor activating peptide and a fibrinogen precipitating agent, preferably it is a thrombin.
    [010] The "dry thrombin preparation" can be made from any thrombin preparation that is suitable for use in humans (i.e., pharmaceutically acceptable). Appropriate sources of thrombin include human or bovine blood, plasma or serum (thrombin from other animal sources may be applied if no adverse immune reactions are expected) and thrombin of recombinant origin (eg, human recombinant thrombin); Autologous human thrombin may be preferred for some applications. Preferably, the hemostatic composition contains 10 to 100,000 International Units (I.U.) of thrombin, more preferred 100 to 10,000 I.U., especially 500 to 5,000 I.U. The thrombin concentration in the "ready to use" composition is preferably in the range from 10 to 10,000 I.U., more preferred from 50 to 5,000 I.U., especially from 100 to 1,000 I.U./ml. The diluent is used in an amount to achieve the desired final concentration in the “ready to use” composition.
    [011] The "dry preparation of a biocompatible polymer" according to the present invention is known, for example, from WO 98/08550 A. Preferably, the polymer is a dry stable, biodegradable, granular material.
    [012] A "dry" hemostatic composition according to the present invention has only a residual moisture content that can roughly match the moisture content of comparable available products such as Floseal® (Floseal, for example, has about 12% moisture as a dry product). Generally, the dry composition according to the present invention has a residual moisture content below these products, preferably below 10% moisture, more preferred below 5% moisture, especially below 1% moisture. The hemostatic composition according to the present invention may also have a lower wetting content, for example 0.1% or even lower. Preferred wetting contents of the dry hemostatic composition according to the present invention are 0.1 to 10%, especially 0.5 to 5%.
    [013] According to the present invention, the hemostatic composition is provided in dry form in the final container. In dry form, degradation or deactivation processes for the components are significantly and appropriately reduced to allow for storage stability. Appropriate storage stability can be determined based on thrombin activity. Consequently, a dry hemostatic composition of the present type is storage stable, if not less than 400 IU/ml (for a 500 IU/ml product) after reconstitution after 24 months storage in dry form at room temperature (25°C) are still present (ie 80% thrombin activity or more remaining compared to initial activity before lyophilization). Preferably, the composition according to the present invention has greater storage capacity, i.e. at least 90% thrombin activity remaining, especially at least 95% thrombin activity remaining after these 24 months of storage.
    [014] However, providing a dry blend of thrombin and a biocompatible polymer is not trivial, because blending must be done in dry form. Mixing the components in soluble form (suspended) and then starting the drying process results in intolerable material degradation. For example, even if thrombin and gelatin are kept at 4°C, clear degradation is visible after 24 h.
    [015] The "dry" polymer and thrombin according to the present invention are generally provided with particle sizes from 0.1 to 5,000 µm. Generally, the thrombin particles used here may be better than polymer particles; thrombin particles preferably have an average particle diameter ("average particle diameter" is the median size as measured by laser diffraction; "median size" (or mass median particle diameter) is the particle diameter that divides a distribution frequency in half; fifty percent of the particles in a given preparation have a larger diameter, and fifty percent of the particles have a smaller diameter) from 1 to 100 µm, especially 5 to 50 µm; polymer particles from 10 to 1000 μm, especially 50 to 500 μm (median size). Applying larger particles is primarily dependent on medical needs; particles with smaller average particle diameters are often more difficult to handle in the production process. The dry polymer and thrombin are therefore provided in granular form, especially in powder form. Although the terms powder and granular (or granular) are sometimes used to distinguish separate classes of material, powders are defined here as a special subclass of granular materials. In particular, powders refer to those granular materials which have the finest grain sizes, and which therefore have a greater tendency to form lumps when flowing; dry thrombin powders according to the present invention preferably have a median size between 1 and 10 µm. Coarser granules granular materials that do not tend to form lumps except when wet.
    [016] Consequently, the present invention uses in principle two embodiments to achieve this goal. The first principle includes mixing the two components in solid state before filling the final container; alternatively, the components can be successively added to the final container. Mixing can then be achieved by shaking the final container, if desired. Specifically when carrying out step c1), in the process of the present invention it is preferred to use dry preparation of a coagulation inducing agent, such as thrombin in dry powder form, i.e., with an average diameter of preferably 1 to 10 µm (size median). Lyophilized preparation of a coagulation inducing agent, such as thrombin, may comprise larger particles, they may even be obtained as a discontinuous, solid, porous phase (also depending on the technique in which thrombin was lyophilized). If such a lyophilizate is crushed into particles, the particles obtained could have a wide particle size distribution. In such cases, it is advantageous to narrow the particle size distribution to grind the lyophilized coagulation inducing agent such as thrombin to obtain a powder. For such grinding, the grinding techniques and instruments generally applied for grinding lyophilized proteinaceous material are applied. A preferred particle size range of particles of a coagulation inducing agent such as thrombin particles (especially for spray dried thrombin particles) is 0.1 to 500 µm, more preferred 0.5 to 100 µm, especially 1 to 50 µm. According to a specifically preferred embodiment, the first component contains thrombin obtained by spray drying, preferably by aseptic spray drying. Spray drying can be carried out in any spray drying apparatus, especially for proteinaceous material, preferably the apparatus is sterilized just before bringing the thrombin solution to spray drying. Preferably, the spray drying step is followed by an agglomeration step to create a thrombin powder.
    [017] According to the second principle, one of the dry components is provided in the final container and then the second component is added. This can be done by placing one of the components in dry form in the final container and then adding the second component. This, however, can also be done by placing one of the components as a solution or suspension (or other wet preparation) in the final container, drying the component, preferably by lyophilization, and then - after completion of the drying process (in situ in the final container ) - add the other component in dry form. Preferably, a clotting inducing agent such as thrombin is provided in the final container, then dried, preferably by lyophilization, and then combined with the second component. In a preferred embodiment of the present invention step c2) is therefore carried out by lyophilizing an aqueous composition containing coagulation inducing agent, such as an aqueous composition containing thrombin in said final container so as to provide said first component in said final container and adding said second component after lyophilization.
    [018] Preferably, the process according to the present invention is carried out in an aseptic environment, especially the step of combining in the final container (step c1) or c2)) should be carried out aseptically. It is also preferred to start the process with components that have already been properly sterilized and then carry out all other steps aseptically.
    [019] The final step of the method is a finishing step. During this step, the final container is properly sealed and made ready for storage and/or sale. A finishing step may comprise labeling the final container, packaging and performing (other) sterilization processes (performed, for example, on the final container or on the packaged product or kit comprising the final container).
    [020] Preferably, step d) comprises a sterilization with EO (ethylene oxide). Sterilization with EO is common in the present field of technology. Ethylene oxide gas kills bacteria (and their endospores), molds, and fungi. EO Sterilization is used to sterilize substances that would be damaged by high temperature techniques such as pasteurization or autoclaving.
    [021] Other preferred embodiments for sterilization include application of ionizing irradiation such as β or Y irradiation or use of vaporized hydrogen peroxide.
    [022] According to a preferred embodiment, the final container further contains an amount of a stabilizer effective to inhibit polymer modification when exposed to sterilizing radiation, preferably ascorbic acid, sodium ascorbate, other salts of ascorbic acid, or an antioxidant .
    [023] The final container may be any container suitable for housing (and storing) pharmaceutically administrable compounds. Syringes, vials, tubes, etc. can be used; however, providing the hemostatic compositions in accordance with the present invention in a syringe is specifically preferred. Syringes were a preferred means of administration for hemostatic compositions as described in the prior art also because of the advantages of syringe handling in medical practice. The compositions can then preferably be applied (after reconstitution) through specific syringe needles or through appropriate catheters. The reconstituted hemostatic compositions (which are preferably reconstituted to form a hydrogel) can also be applied by various other means, for example, by a spatula, brush, spray, manually by pressing, or by any other conventional technique. Generally, the reconstituted hemostatic compositions in accordance with the present invention will be applied using a syringe or similar applicator capable of expelling the reconstituted composition through an orifice, opening, needle, tube, or other passageway to form a blister, layer, or similar portion. of material. Mechanical disruption of the compositions may be effected by extrusion through an orifice in the syringe or other applicator, typically having a size in the range of 0.01mm to 5.0mm, preferably 0.5mm to 2.5mm. Preferably, however, the hemostatic composition will initially be prepared in a dry form having a desired particle size (which on reconstitution, especially by hydration, provides subunits of the required size (eg hydrogel subunits)) or will be partially or entirely mechanically disrupted to the required size before a final extrusion or other application step. It is clearly evident that these mechanical components need to be provided in sterile form (inside and out) in order to satisfy safety requirements for human use.
    [024] Especially when step c2) is applied with a drying step, the design of the final container can preferably be adapted for a drying process in the final container.
    [025] The dry hemostatic compositions according to the present invention are generally reconstituted (rehydrated) before use by contacting the dry composition with an appropriate diluent. The diluent in accordance with the present invention may be any means of reconstitution suitable for the dry hemostatic composition which allows proper wetting of the dry composition. Preferably, the dry hemostatic composition is reconstituted into a hydrogel as a "ready to use" format.
    [026] Suitable diluents are pharmaceutically acceptable aqueous fluids, for example, pharmaceutical type deionized water (if all ionic or buffer components are already provided in the dry composition; "water for injection") or pharmaceutical type aqueous solutions containing ions and/or specific buffers. Such aqueous solutions can further comprise other ingredients, such as excipients. An "excipient" is an inert substance that is added to the solution, for example, to ensure that thrombin retains its chemical stability and biological activity in storage (or sterilization (eg, by irradiation)), or for aesthetic reasons, for example, color. Preferred excipients include human albumin, mannitol and sodium acetate. Preferred concentrations of human albumin in the reconstituted product are from 0.1 to 100 mg/ml, preferably from 1 to 10 mg/ml. Preferred mannitol concentrations may be in the concentration range from 0.5 to 500 mg/ml, especially 10 to 50 mg/ml. Preferred sodium acetate concentrations are in the range of from 1 to 10 mg/ml, especially 2 to 5 mg/ml.
    [027] For example, a suitable diluent comprises water for injection, and - independently of each other - NaCl (preferably 50 to 150 mM, especially 10 mM), CaCl2 (preferably 10 to 80 mM, especially 40 mM), human albumin (preferably up to 2% by weight, especially 0.5% by weight), sodium acetate (preferably 0 to 50 mM, especially 20 mM) and mannitol (preferably up to 10% by weight, especially 2% by weight). Preferably, the diluent may also include a buffer or buffer system in order to buffer the pH of the reconstituted dry composition, preferably at a pH of 6.4 to 7.5, especially a pH of 6.9 to 7.1.
    [028] In a preferred embodiment, the diluent is provided in a separate container. This can preferably be a syringe. The diluent in the syringe can then easily be applied to the final container for reconstitution of the dry hemostatic compositions in accordance with the present invention. If the final container is also a syringe, both syringes can be finished together in a package. It is, therefore, preferred to provide the dry hemostatic compositions according to the present invention in a syringe which is finished with a syringe of diluent with a pharmaceutically acceptable diluent to reconstitute said dry and stable hemostatic composition.
    [029] The dry preparation of a biocompatible polymer suitable for use in hemostasis (the "dry hemostatic polymers") of the present invention can be formed from biological and non-biological polymers. Suitable biological polymers include proteins, such as gelatin, soluble collagen, albumin, hemoglobin, casein, fibrinogen, fibrin, fibronectin, elastin, keratin, and laminin; or derivatives or combinations thereof. Particularly preferred is the use of gelatin or soluble non-fibrillary collagens, most preferably gelatin, and exemplary gelatin formulations are set out below. Other suitable biological polymers include polysaccharides, such as glycosaminoglycans, starch derivatives, xylan, cellulose derivatives, hemicellulose derivatives, agarose, alginate, and chitosan; or derivatives or combinations thereof. Appropriate non-biological polymers will be selected to be degradable by either of two mechanisms, i.e. (1) disruption of the polymeric backbone or (2) degradation of side chains that result in aqueous solubility. Exemplary non-biological hydrogel-forming polymers include synthetic ones, such as polyacrylates, polymethacrylates, polyacrylamides, polyvinyl resins, polylactide glycolides, polycaprolactones, and polyoxyethylenes; or derivatives or combinations thereof. Also combinations of different types of polymers are possible (eg proteins with polysaccharides, proteins with non-biological hydrogel-forming polymer, etc.)
    [030] An uncrosslinked polymer together with a suitable rehydration aid may be crosslinked in any suitable manner to reconstitute, for example, to form a suitable hydrogel base. For example, polymer molecules can be cross-linked using bi- or poly-functional cross-linking agents that covalently attach to two or more strands of polymer molecules. Exemplary bifunctional crosslinking agents include aldehydes, epoxides, succinimides, carbodiimides, maleimides, azides, carbonates, isocyanates, divinyl sulfone, alcohols, amines, imidates, anhydrides, halides, silanes, diazoacetate, aziridines, and the like. Alternatively, crosslinking can be achieved using oxidants and other agents, such as periodates, which activate side chains or moieties in the polymer so that they can react with other side chains or moieties to form the crosslink bonds. An additional method of crosslinking comprises exposing the polymers to radiation, such as gamma radiation, to activate the polymer chains to allow crosslinking reactions. Dehydrothermal crosslinking methods may also be desirable. Preferred methods for crosslinking gelatin molecules are described below.
    [031] According to a preferred embodiment, the biocompatible polymer suitable for use in hemostasis, therefore, contains a cross-linked polysaccharide, a cross-linked protein, or a cross-linked non-biological polymer; or mixtures thereof.
    [032] Preferably, the biocompatible polymer suitable for use in hemostasis is a granular material. This granular material can rapidly swell when exposed to a fluid (ie the diluent) and in this swollen form is able to contribute to a flowable paste that can be applied to a bleeding site. The biocompatible polymer, eg gelatin, can be provided as a film which can then be ground to form a granular material. Most of the particles contained in such granular material preferably have particle sizes of 100 to 1000 µm, especially 300 to 500 µm (median size).
    [033] According to a preferred embodiment, the biocompatible polymer suitable for use in hemostasis is a cross-linked gelatin. Dry cross-linked gelatin powder can be prepared to rehydrate rapidly if contacted with an appropriate diluent. The gelatin powder preferably comprises relatively large particles, also referred to as fragments or subunits, as described in WO 98/08550 A and WO 2003/007845 A. A preferred (median) particle size will be in the range of 20 to 1000 µm, preferably 100 to 750 µm, especially 150 to 500 µm, but particle sizes outside this preferred range may find use in many circumstances. Dry compositions will also exhibit significant "equilibrium swelling" when exposed to an aqueous rehydration medium (=diluents). Preferably the swelling will be in the range of 400% to 1000%. "Equilibrium swelling" can be determined by subtracting the dry weight of the gelatin hydrogel powder from its weight when fully hydrated or thus fully swollen. The difference is then divided by the dry weight and multiplied by 100 given the measure of swelling. Dry weight should be measured after exposing the material to an elevated temperature for a time sufficient to remove substantially all residual moisture, eg two hours at 120°C. Equilibrium hydration of the material can be achieved by soaking the dry material in a suitable diluent, such as aqueous saline, for a period of time sufficient for the water content to become constant, typically for 18 to 24 hours at room temperature.
    [034] An uncrosslinked gelatin together with the rehydration aid may be crosslinked in any suitable manner to form a suitable hydrogel base. Dry cross-linked gelatin powders according to this preferred embodiment are preferably obtained by preparing the powders in the presence of certain rehydration aids. Such rehydration aids will be present during the preparation of powders, but will generally be removed from the final products. For example, rehydration aids that are present at about 20% of the total solids content will typically be reduced to below 1% in the final product, often below 0.5% by weight. Exemplary rehydration aids include polyethylene glycol (PEG), preferably having a molecular weight of about 1000; polyvinylpyrrolidone (PVP), preferably having an average molecular weight of about 50,000; and dextran, typically having an average molecular weight of about 40,000. It is preferred to employ at least two such rehydration aids when preparing the compositions of the present invention, and more particularly preferred to employ all three.
    [035] Exemplary methods for producing cross-linked gelatins are as follows. Gelatin is obtained and suspended in an aqueous solution to form an uncrosslinked hydrogel, typically having a solids content of 1% to 70% by weight, generally 3% to 10% by weight. Gelatin is cross-linked, typically by exposure to either glutaraldehyde (eg 0.01% to 0.05% by weight, overnight at 0°C. to 15°C in aqueous buffer), sodium periodate (eg. , 0.05 M, held at 0°C. to 15°C. for 48 hours) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide ("EDC") (eg 0.5% to 1, 5% by weight overnight at room temperature), or by exposure to about 0.3 to 3 megarads of gamma radiation or electron beam. Alternatively, gelatin particles can be suspended in an alcohol, preferably methyl alcohol or ethyl alcohol, at a solids content of 1% to 70% by weight, generally 3% to 10% by weight, and cross-linked by exposure to a crosslinking agent, typically glutaraldehyde (eg 0.01% to 0.1% by weight overnight at room temperature). In the case of aldehydes, the pH should be kept from about 6 to 11, preferably from 7 to 10. When crosslinking with glutaraldehyde, crosslinks are formed via Schiff bases which can be stabilized by subsequent reduction, eg by treatment. with sodium borohydride. After crosslinking, the resulting granules can be washed in water and optionally rinsed in an alcohol, and dried. The resulting dry powders can then be provided in the final container as described herein.
    [036] After crosslinking, at least 50% (by weight) of the rehydration aid will be removed from the resulting hydrogel. Generally, the rehydration aid is removed by filtration of the hydrogel followed by washing of the resulting filter cake. Such filtration/washing steps may be repeated one or more additional times in order to clean the product to a desired level and remove at least 50% of the rehydration aid, preferably removing at least 90% (by weight) of the rehydration aid originally gift. After filtration, a gelatin is dried, typically drying the final filter cake that has been produced. The dried filter cake can then be broken or ground to produce the crosslinked powder having a particle size in the desired ranges set forth above.
    [037] According to a preferred embodiment, the final container further contains an amount of a stabilizer effective to inhibit polymer modification when exposed to sterilizing radiation, preferably ascorbic acid, sodium ascorbate, other salts of ascorbic acid, or an antioxidant .
    [038] According to another aspect, the present invention also provides a method for dispensing a hemostatic composition to a target site in a patient's body, said method comprising dispensing a hemostatic composition produced by the process according to the present invention to the target site. Although in some embodiments, also the dry composition can be directly applied to the target site (and optionally be contacted with the target site diluent, if necessary), it is preferred to contact the dry hemostatic composition with a pharmaceutically acceptable diluent prior to administration to the target site, so as to obtain a hemostatic composition in a moistened form, especially a hydrogel form.
    [039] The present invention also relates to a final finished container obtained by the process according to the present invention. This finished container contains the combined components in a sterile, storage-stable, marketable form.
    [040] Another aspect of the invention relates to a method for providing a ready-to-use hemostatic composition comprising contacting a hemostatic composition produced by the process according to the present invention with a pharmaceutically acceptable diluent.
    [041] The present invention also relates to a kit comprising the dry and stable hemostatic composition according to the present invention in finished form and a container with a suitable diluent. Other components of the kit can be instructions for use, means of administration such as syringes, catheters, brushes, etc. (if the compositions are not already placed in the administration means) or other components necessary for use in medical (surgical) practice, such as replacement needles or catheters, extra vials or other wound covering means. Preferably, the kit according to the present invention comprises a syringe housing a dry and stable hemostatic composition and a syringe containing the diluent (or provided to absorb the diluent from another container of diluent). Preferably, these two syringes are provided in a form adapted to each other so that the diluent can be delivered to a dry hemostatic composition via an inlet other than an outlet for administering the reconstituted composition.
    [042] The invention is further described in the examples below, although not limited to them.EXAMPLES1. Preparation of the dry hemostatic composition according to the present inventionMaterials and methods
    [043] All variants use the same scheme of presenting a kit with a syringe containing both a Floseal gelatin matrix and thrombin in a stable form, and a syringe containing an appropriate liquid reconstitution medium (eg 0.9% NaCl , or 40 mM CaCl2). Both syringes are sterile inside and out, so a complete reconstitution can take place on the nursing side of the operating site. Reconstitution is achieved by coupling the two syringes in a familiar fashion and mixing the contents of the two syringes by ''squirting'' (ie repeated transfer of contents back and forth between the two syringes). "Powder mix" variant (d )
    [044] The "powder mix" variant is made by mixing dry gelatin and freeze-dried thrombin, and filling this into a simple syringe. If applicable, the gelatin matrix is mass sterilized by irradiation (same as used for the final sterilization of the already marketed product). Variant "Thrombin in Lyo Syringe" (c2)
    [045] "Thrombin in Lyo Syringe" is made by first lyophilizing the thrombin solution into the Floseal syringe, and then filling the gelatin granules on top of the lyophilized thrombin. If applicable, the gelatin matrix is mass sterilized by irradiation (same as used for final sterilization of the actual product).
    [046] The thrombin solution is formulated and filled in capped Floseal syringes that allow evacuation into the syringe for container closure. The thrombin solution is frozen and lyophilized using an appropriate lyophilization program.
    [047] Syringes are not capped on the back to allow filling of the gelatin powder from the back. The required amount of gelatin is filled into the thrombin lyophilisate. The plunger is then attached to the syringe barrel. Syringes are placed in a suitable tray inside an evacuation chamber with movable plates to cap the syringes. The plates are moved down on the syringe plungers after evacuation to close the syringes. This also serves to compact the freeze-drying cake which takes up a little space inside the syringe. The product is now ready for packaging with the diluent syringe, EPO sterilization of the bags, and storage. Diluent syringe
    [048] The diluent syringe contains an appropriate reconstitution medium to hydrate the product. It can be coupled with a Floseal syringe either directly or via a connector. Diluent is transferred into the Floseal syringe, and the hydrated product is transferred in a back and forth motion between the coupled syringes repeatedly to generate a flowable paste. The diluent syringe can be prepared, for example, by a process such as the following: the medium is sterile filtered and filled into suitable syringes (such as Toppac, Clearshot,... syringes); and, if necessary, end sterilized by irradiation. gelatin granules
    [049] The manufacture of mass of gelatin granules is carried out according to established methods (WO 98/08550 A; WO 2003/00785 A; etc.). The granules ("Floseal" beads; "Floseal" matrix) are immediately sterilized by gamma irradiation. For pre-clinical sterilization the Floseal matrix is stored in appropriately sized Schott glass vials.
    [050] The required irradiation dose at the current maximum bioburden level (1000 cfu/sample) is 25 - 40 kGy for the product in the final container. The dough material is then stored at -20°C for further fabrication.c1: "powder mix" Preparation of thrombin
    [051] Sterile thrombin powder in this example is manufactured in two distinct ways: by grinding freeze-dried thrombin in an aseptic manner or by aseptic spray drying.
    [052] Thrombin solution formulated with 500 lU/ml thrombin, 50g/l HSA and 4.4 g/l NaCl is transferred to an appropriately sized sterile lyophilization tray in the laminar flow chamber, and the tray covered with a plate. sterile aluminum to transport in freeze drying. The freeze-drying tray is placed in the clean freeze-dryer, and the freeze-drying carried out with the appropriate program. After freeze drying is completed the freeze dryer is vented using medical grade nitrogen, and the lyo tray is again covered with sterile aluminum foil.
    [053] For grinding using Retsch MM200 Ball Mill, the 25 ml screw top grinding vessels and the appropriate grinding balls (12 mm) are sterilized by either autoclave or alcohol immersion, and sterile grinding vessels are transported to the laminar flow chamber. The grinding vessels are filled with an appropriate amount of the lyophilized thrombin, and a sterile grinding ball is added. The vessels are then closed with the screw top and taken to the ball mill for grinding. After grinding the vessels are returned to the laminar flow chamber, where they are emptied with sterile spatulas into a sterile collection vessel (50 ml Falcon or glass bottle) and filled again for repeat grinding. Aseptic Spray Drying
    [054] For preclinical production, spray drying is accomplished using a Buchi spray drying configuration with gas conditioning for the carrier gas. Aseptic filling of thrombin and gelatin powder into syringes
    [055] The two sterile powders are sequentially filled into the Floseal syringe on an analytical scale. The weight of Floseal matrix is calculated as fill weight in g =70.4/solids content in %, ensuring that 704 mg of dry Floseal matrix is loaded into the syringe. The weight of thrombin powder, containing 2000 IU thrombin for 5 ml of Floseal final product, is 4 (ml) x 55 (mg/ml) = 220 mg. Filling is done with an accuracy of +/5%, limits have been calculated for each lot of Floseal matrix.
    [056] First, the ground thrombin powder is filled into sterile Floseal syringes which have been closed with the appropriate sterile luer lock cap and which are placed on an analytical scale using a small shelf. The scale is calibrated, and the appropriate amount of thrombin powder is filled into the syringe using either a sterile hand spatula or a vibrating spatula with the appropriate fixation. Then the scale is calibrated again, and the appropriate amount of Floseal matrix is filled into the syringe using either a sterile hand spatula or a vibrating spatula with the appropriate fixation. The plunger is then secured from the rear to a position just on top of the Floseal array, if necessary slightly opening the luer lock if necessary.
    [057] Alternatively the filling order can be reversed, resulting in the thrombin powder being at the rear of the syringe.
    [058] Alternatively, the two powders can be mixed before filling, eliminating the second filling step.c2: "thrombin in Lyo syringe"
    [059] 4.0 ml of 500IU/ml thrombin were filled into a lyophilization syringe, lyophilized and compacted under vacuum. Then Floseal gelatin was weighed into the syringe filling on top of the compacted thrombin. The syringe was closed and compacted again under vacuum. All preparation steps were carried out under aseptic conditions.2. Effectiveness in the porcine liver abrasion model
    [060] The purpose of this study is to compare the effectiveness of the hemostatic dry composition according to the present invention with an established standard product (Floseal VH S/D; Baxter Healthcare) in the porcine liver abrasion model. Floseal VH S/D is a thrombin-dispensing gelatin matrix to stop active bleeding within 2 minutes of application. This product requires a 2-step preparation, (1) reconstitution of thrombin and (2) hydration of the gelatin particles with the reconstituted thrombin. The product according to the present invention is designed to reconstitute the dry hemostatic composition in 1 step and is a major improvement over the 2-step preparation which is unfavorable when the product is needed quickly or in large quantities. Porcine liver abrasion model.
    [061] Six female domestic pigs, average weight 55.0 kg (range 52.4 - 58.4 kg), are obtained from Oak Hill Genetics (Ewing, Illinois) and weighed at the time of surgery. Upon arrival, the animals were quarantined for 6 days. At the time of surgery, all six pigs show no signs of clinical illness. Ear tags are used to identify animals and cross-reference to evaluated identification numbers. Animals are housed in groups in pens. Pigs are given water ad libitum and a standard pig diet once a day.
    [062] Pigs are a well-accepted and appropriate cardiovascular model for this type of study. The multiple large lobes of the liver allowed multiple lesions for direct comparisons of different test items. Anesthetics and fluid therapy
    [063] Pigs are medicated with Midazolam (0.3 mg/kg, IM) and masked with Isoflurane in a 2:1 nitrogen to oxygen carrier. Pigs are intubated and ventilated at a rate of 10-15 breaths per minute. Anesthesia is maintained with Isoflurane in an oxygen carrier. Pigs receive a continuous rate infusion of heated lactated Ringer's solution. Liver Abrasion Procedure
    [064] A porcine liver abrasion model is used for this study. Six pigs are groomed with the goal that 120 lesions (40 per treatment group) are evaluated and sufficient to detect a difference in rates of 80 percent versus 40 percent with a=0.05 and potency=90%. Each series is confidently aimed at either the medial, left lateral, or right lateral lobe.
    [065] Each lesion series contains three 1 cm diameter, 2-4 mm deep liver abrasions created using a hand drill with fixed sandpaper. Bleeding is assessed and the lesion is randomly and blindly treated with a reference or test article. Reference and test article is randomized using a random number generator. Each article is placed in the lesion, kept in a place with moist gauze for 2 minutes and blindly evaluated for hemostasis 2, 5 and 10 minutes following treatment. Excess reference or test article is flushed out with irrigation after the 5 minute evaluation. Heparinization protocol
    [066] A baseline activated clotting time (ACT) is taken and each pig receives a loading dose of heparin, 200 lU/kg. ACT is assessed every 10 minutes until ACT is at least 2 times baseline. If the ACT measures less than or close to 2 times baseline, the pig was treated with a dose of bolus heparin, 75 IU/kg.
    [067] Since baseline is greater than 2 times, ACT is measured every 20 minutes. If ACT measures less than or close to the target 2 times baseline, the pig receives a bolus dose of heparin, 40 IU/kg. If the ACT measures more than the target 2 times baseline, the pig is untreated or receives a bolus maintenance dose of heparin, limited to no more than 2000 lU/hour.
    [068] All heparin is administered through a peripheral venous catheter. All blood samples are taken from a jugular catheter. Blood pressure or heart rate reference values are recorded at the time of ACT measurements. hemostasis evaluation
    [069] Hemostasis is assessed at 0, 2, 5, and 10 minutes after the series is created and treated, where 0 minutes refers to pretreatment. Scores of 0, 1, 2, 3, 4, and 5 are rated for no bleeding, slow flow, very mild, mild, moderate, and severe; respectively. All three lesions are treated at approximately the same time to avoid differences in location and clotting that can result from treating each independently. Blood from the wound is wiped off after each assessment as needed. Measurements and Records
    [070] ACT, hemostasis, blood pressure and heart rate are evaluated according to standard methods. Statistical analysis
    [071] The sampling unit for this study is the liver injury site with 40 lesions per treatment group for a total of 120 lesions.
    [072] Multiple logistic regression is used to assess treatment effect on bleeding score (0=none, 1=slow flow, 2=very mild, 3=mild, 4=moderate, and 5=severe) at 2, 5 , and 10 minutes post treatment. Independent variables include treatment group, pig, hepatic lobe (medial, right or left) and initial bleeding score. Odds ratios for the effects of FB/FS, Lyo/FS, FB/Lyo, and their confidence intervals are computed at each post-treatment time point.
    [073] Lesions locations are not evenly distributed across the three lobes and pigs. The wolf effect is found not to be significant, and therefore analyzes are performed again without this effect. The conclusions are based on analyzes without the wolf effect in the model.
    [074] The performance of the dry hemostatic composition according to the present invention is not significantly different from Floseal VH S/D at all time points. This shows that the production method according to the present invention (c1/c2) and the 1-step reconstitution mode do not negatively impact the performance of the composition but provide a desired advantage in practical handling thus providing the object of the present invention is resolved.Other animal experiments
    [075] A preclinical evaluation is performed to compare INVIVO efficacy of Floseal "powder mix" and Floseal "thrombin in syringe Lyo" to Floseal VH in a very stringent (highly anticoagulated) model. This model consists of a puncture. full-thickness liver grafts of 5 mm with 4 additional incisions radiating from the puncture defect in a transverse manner. 6 animals are used per study group, these animals are heparinized to 4,000 IU/kg. After the lesion is placed, reconstituted floseal is applied, and light pressure for 2 min with moist gauze is applied. After this time primary hemostasis is assessed. If primary hemostasis is not achieved, product is reapplied until hemostasis is achieved, or product (5 ml)/time (15 min) is Primary end points are primary hemostasis achievements (Yes/No) and time to hemostasis (min).
    [076] If primary hemostasis is achieved, the animals are surgically closed, and after 24 animals are evaluated for bleeding again.
    [077] All variants (c1/c2) gave results in terms of time to hemostasis that are equivalent to or better than standard Floseal in that particular preclinical lab session.
    权利要求:
    Claims (11)
    [0001]
    1. Process for manufacturing a dry and stable hemostatic composition, characterized in that it comprises a) providing a first component comprising a dry preparation of thrombin, b) providing a second component comprising a dry preparation of a cross-linked gelatin, c) providing said first component and said second component in a combined form in a final container, filling said first component and said second component in said final container so as to obtain a dry mixture in said final container, d) finishing the final container to a storable pharmaceutical device containing said first component and said second component in a combined form as a dry stable hemostatic composition.
    [0002]
    2. Process according to claim 1, characterized in that step c) is carried out under aseptic conditions.
    [0003]
    3. Process according to claim 1 or 2, characterized in that step d) comprises a sterilization step with ethylene oxide or a treatment with ionizing irradiation.
    [0004]
    4. Process according to any one of claims 1 to 3, characterized in that said first component is a dry thrombin preparation, preferably in particulate form, preferably in powder form.
    [0005]
    5. Process according to any one of claims 1 to 4, characterized in that said first component contains thrombin obtained by spray drying, preferably by aseptic spray drying.
    [0006]
    6. Process according to any one of claims 1 to 5, characterized in that a syringe is used as said final container, preferably wherein said syringe is a finished syringe together with a syringe of diluent with a pharmaceutically acceptable diluent to reconstitute said dry and stable hemostatic composition.
    [0007]
    7. Process according to any one of claims 1 to 6, characterized in that said first component comprises human thrombin, especially recombinant human thrombin.
    [0008]
    8. Process according to any one of claims 1 to 7, characterized in that said dry preparation of cross-linked gelatin is a particulate material, preferably a granular material.
    [0009]
    9. Process according to any one of claims 1 to 12, characterized in that said final container still contains an amount of a stabilizer effective to inhibit polymer modification when exposed to sterilizing radiation, preferably ascorbic acid, sodium ascorbate, others ascorbic acid salts, or an antioxidant.
    [0010]
    10. Final finished container, characterized in that it is obtained by the process as defined in any one of claims 1 to 9.
    [0011]
    11. Kit for administering a hemostatic composition, characterized in that it comprises the finished container as defined in claim 10 and a container with a pharmaceutically acceptable diluent.
    类似技术:
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    同族专利:
    公开号 | 公开日
    US20150367022A1|2015-12-24|
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    EP2575775B1|2018-04-04|
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    AU2011260258A1|2012-12-06|
    WO2011151384A1|2011-12-08|
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    KR20130121701A|2013-11-06|
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    US20210220512A1|2021-07-22|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-02| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-06-29| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-08-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 01/06/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |
    优先权:
    申请号 | 申请日 | 专利标题
    US35026610P| true| 2010-06-01|2010-06-01|
    US61/350,266|2010-06-01|
    PCT/EP2011/059062|WO2011151384A1|2010-06-01|2011-06-01|Process for making dry and stable hemostatic compositions|
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