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    • 专利摘要:
    PROCESS FOR MANUFACTURING A DRY AND STABLE HESMOSTATIC COMPOSITION, METHOD FOR DISPENSING A HEMOSTATIC COMPOSITION TO A TARGET SITE, FINAL FINISHED CONTAINER, METHOD FOR PROVIDING A HEMOSTATIC COMPOSITION READY TO USE, AND, KIT FOR ADMINISTRATING A COMPOSITION. A process for making a dry and stable hemostatic composition is described, said process comprising a) providing a first component comprising a dry preparation of a coagulation inducing agent, b) providing a second component comprising a dry preparation of an appropriate biocompatible polymer for use in hemostasis, c) providing said first component under effective conditions to form a wet paste while essentially avoiding the degradation of the second component by said first component in a final container or transferring said wet paste into a final container, d) freeze and lyophilize said paste in said container thus obtaining a dry and stable hesmotactic composition comprising said first and said second component in lyophilized form, and e) ending said dry and stable hemostatic composition in said final container to obtain 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:BR112012030457B1
    申请号:R112012030457-7
    申请日:2011-06-01
    公开日:2021-03-09
    发明作者:Andreas Goessl；Atsushi Edward Osawa；Cary J. Reich
    申请人:Baxter International Inc.；Baxter Healthcare S.A.；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [0001] The present invention relates to processes for manufacturing hemostatic compositions in a stable form in storage. BACKGROUND OF THE INVENTION
    [0002] Hemostatic compositions in dry and storage-stable form, which comprise dry, granular, biocompatible and biodegradable stable material, are known, for example, from WO 98/008550 A or WO 2003/007845 A. These products have been successfully applied in technique for hemostasis. Floseal® is an example for a powerful and versatile hemostatic agent consisting of a matrix of granular gelatin swollen in a solution containing thrombin to form a paste able to flow.
    [0003] 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 the 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 material (often also cross-linked) of matrix and proteinaceous components, such as thrombin. Considering that such matrix materials can generally be sterilized by powerful sterilization methods (such as autoclave, gamma irradiation, etc.), thrombin (as an enzyme) should be treated with more care. Those powerful sterilization methods are generally not possible for thrombin, due to the loss of enzyme activity caused by such severe treatments. For reasons of stability, such products (as well as the products according to the present invention) are generally provided in a dry form and taken to 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 agents (suspension) and mixing the matrix material component with the thrombin component. Reconstitution of thrombin or the step of mixing a thrombin solution with the granular matrix material are steps that usually require some time and handling and can cause problems especially in intensive health care.
    [0004] It is an object of the present invention to overcome such problems and to provide appropriate methods for making 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 handling steps must be kept as low as possible. SUMMARY OF THE INVENTION
    [0005] Therefore, the present invention provides a process for manufacturing a dry and stable hemostatic composition, said process comprising:
    [0006] a) providing a first component comprising a dry preparation of a coagulation inducing agent, such as a dry thrombin preparation,
    [0007] b) providing a second component comprising a dry preparation of a biocompatible polymer suitable for use in hemostasis,
    [0008] c) mixing said first component and said second component under effective conditions to form a wet paste while essentially preventing degradation of the second component by said first component in a final container or transferring said wet paste into a final container,
    [0009] d) freeze and lyophilize said paste in said container thus obtaining a dry and stable hemostatic composition comprising said first and said second components in lyophilized form, and
    [00010] e) ending said dry and stable hemostatic composition in said final container to obtain a storable pharmaceutical device containing said first component and said second component in a combined form as a dry and stable hemostatic composition.
    [00011] 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 delivering a hemostatic composition to a target site on a patient's body, said method comprising delivering 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 for a kit comprising the finished final container and other means for applying the composition ( for example, a diluent container). The compositions according to the present invention are particularly useful for providing haemostasis 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
    [00012] The present invention provides an improvement for the delivery and handling of hemostatic compositions, mainly by providing a two-component product in a convenient simple 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 "coagulation component inducing agent" or "thrombin component") and a second component comprising a dry preparation of a biocompatible polymer 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, even in a different format: Generally, the components are provided as separate entities in dry form. Before mixing the components for administration to a patient, the dry components are usually contacted separately with appropriate diluents. Mixing of the components is then carried out by mixing the separately reconstituted components. For example, a dry preparation of a clotting agent such as, for example, a thrombin component can be provided which is reconstituted with a pharmaceutically acceptable (aqueous) diluent. The solution of a coagulation inducing agent, such as a thrombin solution obtained after reconstitution, is then used to moisten or solubilize the polymer, generally under formation of a hydrogel which is then applied to the patient. Since this is a process of at least two steps before the product is "ready for use", it would be more convenient if a product needed only one step before it was ready for use. However, as attested above, the nature of the two components prevents a simple mixing of the components in the course of the production method, mainly due to losses of stability and activity.
    [00013] 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 scientific bench experiments, but are suitable for industrial mass pharmaceutical production. With the present invention it was possible to provide that hemostatic composition already mixed without the risk of unwanted degradation or loss of enzyme activity. The resulting compositions have a storage stability comparable to previously known products, but are more convenient to handle because reconstitution and separate mixing before 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 deliver the reconstituted hemostatic composition after contact with the diluent.
    [00014] 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 thrombin.
    [00015] The "thrombin solution" 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 can be applied if no adverse immune reactions are expected) and thrombin of recombinant origin (for example, recombinant human thrombin); autologous human thrombin may be preferred for some applications. The concentration of the thrombin solution provided in the first component is generally adjusted to the planned thrombin concentration in the reconstituted hemostatic composition. 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 concentration of thrombin in the "ready to use" composition is preferably in the range of 10 to 10,000 I.U., more preferred from 50 to 5,000 I.U., especially from 100 to 1,000 I.U. The diluent is used in an amount to achieve the desired final concentration in the “ready to use” composition.
    [00016] 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, biodegradable granular material. The "dry" polymer according to the present invention is generally provided with particle sizes from 0.1 to 5,000 μm. Generally, polymer particles have an average particle diameter ("average particle diameter" is the median size as measured by laser diffractometry; "median size" (or mass median particle diameter) is the particle diameter that divides the frequency distribution in half; fifty percent of the particles of a given preparation have a larger diameter, and fifty percent of the particles have a smaller diameter) from 10 to 1000 μm, especially 50 to 500 μm (median size). Applying larger particles is mainly dependent on medical needs; particles with smaller average particle diameters are often more difficult to manipulate in the production process. The dry polymer is, therefore, provided in granular 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 granular materials that have the finest grain sizes, and therefore have a greater tendency to form lumps when flowing. Granulars include thicker granular materials that do not tend to form lumps except when wet.
    [00017] A "dry" hemostatic composition according to the present invention has only a residual moisture content that can approximately correspond to the wetting 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 wetting content below these products, preferably below 10% humidity, more preferably below 5% humidity, especially below 1% humidity. The hemostatic composition according to the present invention can also have a lower wetting content, for example, 0.1% or even below. Preferred wetting contents of the dry hemostatic composition according to the present invention are 0.1 to 10%, especially 0.5 to 5%.
    [00018] According to the present invention, the hemostatic composition is provided in dry form in the final container. In the 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 stable on storage, if not less than 400 IU / ml (for a 500 IU / ml product) after reconstitution after 24 months of dry storage at room temperature (25 ° C) they are still present (ie 80% thrombin activity or more remaining compared to the initial activity before lyophilization). Preferably, the composition according to the present invention has greater storage capacity, that is, at least 90% remaining thrombin activity, especially at least 95% remaining thrombin activity after those 24 months of storage.
    [00019] However, providing a wet paste made by mixing a solution of a coagulation-inducing agent, such as, for example, a thrombin solution and a biocompatible polymer to a wet paste and freeze-drying it is not trivial, because mixing and lyophilization must be carried out in such a way that relevant degradation of the polymer and / or the coagulation inducing agent, for example, thrombin is prevented. This is protected by the present invention by performing the mixing step under conditions essentially avoiding degradation and freezing of the wet paste resulting from the mixing process in the final container. Then the composition can be appropriately lyophilized without the risk of further degradation processes. It is important for the present invention that even the contact time (between the solution of a coagulation inducing agent, for example, the thrombin solution and the polymer) in a wet state during mixing and before lyophilization in the paste is kept as short as possible. The maximum contact times during wet state according to the present invention are dependent on several parameters based on which contact times appropriate for the present method can easily be adjusted by one skilled in the art based on the information described here. The most important parameters for defining an appropriate contact time are temperature, water content and thrombin concentration. For example, for a thrombin solution with 500 IE / ml in a paste with a solution of 4 ml of thrombin and 0.8 g of polymer (for example, gelatin granules associated with water and corresponding to 0.704 g of dry gelatin powder) , the maximum contact times with the polymer in the wet state (ie in the form of paste) are - for about 4 ° C, 15 ° C and room temperature (25 ° C) -25 h, 6 h and 2 h. Temperatures especially used in the present invention are about 2 ° C to about 25 ° C, preferably form about 2 ° C to 15 ° C, especially preferred about 4 ° C. Higher concentrations of the coagulation inducing agent, such as thrombin, or higher amounts of water content for shorter maximum contact times during wet conditions. Consequently, preferred wet contact times are in the range of 5 min to 6 h, even more preferred 5 min to 2 h, especially 5 to 30 min. Preferably, the mixing step is carried out at low temperatures, for example, between 1 and 10 ° C, especially between 2 and 6 ° C.
    [00020] It is also important that the mixing step according to the present invention results in a wet paste that does not contain a considerable liquid phase, that is, the paste according to the present invention is almost free of free liquid. The wet paste according to the present invention is flowable (has a degree of fluidity), yet it is also sufficiently viscous to be handled as a paste (for example, preferred viscosities of about 10 to 100 Pa.se above). important to prevent degradation processes during mixing before lyophilization. Mixing the components in soluble (suspended) form (and not in the form of paste according to the present invention) and then starting the drying process results in intolerable material degradation. For example, even if thrombin and gelatin are maintained at 4 ° C, a clear degradation is visible after 24 h.
    [00021] Another important parameter in this connection is the amount of the coagulation inducing agent, for example, thrombin component in the mixing step. It must be high enough to create a moist paste, but not so high as to create a significant liquid phase. Consequently, addition of more than 85% by weight of coagulation inducing agent, for example, thrombin solution, can result in an excess liquid coagulation inducing agent above the insignificant, for example, thrombin in the wet pulp of so that more than 85% by weight should preferably be avoided. Preferred mixing ratios start at about 80% by weight downwards (ie 80 ml thrombin solution / 20 g dry polymer. Lower content of a coagulation inducing agent, for example, thrombin content can easily be adjusted to specific polymers testing the handling performance of the resulting wet paste.Generally, a paste that is close to a 60 to 80% solution of a coagulation inducing agent, for example, the content of the thrombin solution is easier to handle; for extrusion mixtures also lower levels of coagulation inducing agent, for example, levels of thrombin do not create greater obstacles in handling. Wet pastes formed with less than 50% solution of a coagulation inducing agent, for example, thrombin solution they could become problematic due to a possible loss of fluidity that could make them problematic in handling (for example, in syringes).
    [00022] Consequently, the present invention in principle uses two embodiments to achieve this objective. The first principle includes mixing the two components in the final container, then lyophilizing the mixture; alternatively, the components can be mixed outside the container to form the wet paste and then transferred to the final container, for example, by extrusion. Mixing can be achieved, for example, by "splashing" between two connected containers (for example, syringes) or by bringing the two components into an extruder and expelling the extrusion product into the final container. Preferably, the obtained mixture (i.e., the wet slurry) is frozen and lyophilized.
    [00023] Preferably, the process according to the present invention is carried out in an aseptic environment, especially the mixing step must be carried out aseptically. It is also preferred to start the process with components that have already been properly sterilized and then perform all other steps aseptically.
    [00024] The final stage of the method is the finishing stage. During this stage, the final container is properly sealed and made ready for storage and / or sale. The finishing step may comprise labeling the final container, packaging and performing (other) sterilization processes (carried out, for example, on the final container or on the packaged product or kit comprising the final container).
    [00025] Preferably, the finishing step comprises a sterilization step 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. Sterilization with EO is used to sterilize substances that would be damaged by high temperature techniques such as pasteurization or autoclave.
    [00026] Other preferred embodiments for sterilization are application of ionizing irradiation such as β or y irradiation or use of vaporized hydrogen peroxide.
    [00027] According to a preferred embodiment, the final container still contains an amount of an effective stabilizer to inhibit polymer modification when exposed to sterilizing radiation, preferably ascorbic acid, sodium ascorbate, other salts of ascorbic acid, or a antioxidant.
    [00028] The final container can be any container suitable for storing (and storing) pharmaceutically administrable compounds. Syringes, vials, tubes, etc. can be used; however, providing the hemostatic compositions according to the present invention in a syringe is specifically preferred. Syringes have been a preferred means of administration for hemostatic compositions as described in the prior art also due to the advantages of syringe handling in medical practice. The compositions can then preferably be applied (after reconstitution) using specific needles from the syringe 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, a brush, a spray, manually by pressure, or by any other conventional technique. Generally, the reconstituted hemostatic compositions according to 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 passage to form a bubble, layer, or similar portion of material. Mechanical disruption of the compositions can be effected by extrusion through a hole in the syringe or other applicator, typically having a size in the range of 0.01 mm to 5.0 mm, preferably 0.5 mm to 2.5 mm. Preferably, however, the hemostatic composition will initially be prepared in a dry form having a desired particle size (which upon reconstitution, especially by hydration, provides subunits of the required size (for example, 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 outside) in order to satisfy safety requirements for human use.
    [00029] The design of the final container can preferably be adapted for the lyophilization process in the final container.
    [00030] 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 according to the present invention can be any suitable reconstitution medium for the dry hemostatic composition that allows for proper wetting of the dry composition. Preferably, the dry hemostatic composition is reconstituted in a hydrogel as a "ready to use" format.
    [00031] Suitable diluents are pharmaceutically acceptable aqueous fluids, for example, pharmaceutical grade deionized water (if all ionic or buffer components are already provided in the dry composition; "water for injection") or pharmaceutical grade aqueous solutions containing specific ions and / or tampons. These aqueous solutions can also contain other ingredients, such as excipients. An "excipient" is an inert substance that is added to the solution, for example, to ensure that, for example, thrombin retains its chemical stability and biological activity in storage (or sterilization (for example, 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 0.1 to 100 mg / ml, preferably 1 to 10 mg / m. Preferred concentrations of mannitol can 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.
    [00032] For example, an appropriate diluent comprises water for injection; and - independently of each other - NaCI (preferably 50 to 150 mM, especially 110 mM), CaCI2 (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 at a pH of 6.9 to 7.1.
    [00033] 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 be easily applied to the final container for reconstitution of the dried hemostatic compositions according to the present invention. If the final container is also a syringe, both syringes can be finished together in one package. It is therefore preferred to provide the dried hemostatic compositions according to the present invention in a syringe that is finished with a diluent syringe with a pharmaceutically acceptable diluent to reconstitute said dry and stable hemostatic composition.
    [00034] 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-fibrillar collagens, more 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. Suitable non-biological polymers will be selected to be degradable by any of two mechanisms, that is (1) rupture of the polymeric backbone or (2) degradation of side chains that result in aqueous solubility. Exemplary non-biological hydrogel-forming polymers include synthetics, such as polyacrylates, polymethacrylates, polyacrylamides, polyvinyl resins, polylactide-glycolides, polycaprolactones, and polyoxyethylenes; or derivatives or combinations thereof. Combinations of different types of polymers are also possible (for example, proteins with polysaccharides, proteins with non-biological hydrogel-forming polymer, etc.).
    [00035] A non-cross-linked polymer together with an appropriate rehydration aid can be cross-linked in any appropriate way to reconstitute, for example, to form an appropriate hydrogel base. For example, polymeric molecules can be cross-linked using bi or polyfunctional cross-linking agents that covalently attach to two or more chains of polymer molecules. Exemplary bifunctional cross-linking 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, that activate side chains or moieties in the polymer so that they can react with other side chains or moieties to form the crosslinking bonds. An additional method of crosslinking comprises exposing the polymers to radiation, such as gamma radiation, to activate the polymer chains to allow for crosslinking reactions. Dehydrothermal methods of cross-linking may also be desirable. Preferred methods for crosslinking gelatin molecules are described below.
    [00036] 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.
    [00037] Preferably, the biocompatible polymer suitable for use in hemostasis is a granular material. This granular material can quickly swell when exposed to a fluid (ie the diluent) and in that swollen form it is able to contribute to a flowable paste that can be applied to a bleeding site. The biocompatible polymer, for example, gelatin, can be provided as a film which can then be ground to form a granular material. Most of the particles contained in this granular material preferably have particle sizes of 100 to 1,000 μm, especially 300 to 500 μm.
    [00038] 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 quickly 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 1,000 μm, preferably from 100 to 750 μm, especially from 150 to 500 μm, but particle sizes outside this preferred range can find use in many circumstances. Dry compositions will also exhibit significant "balance swelling" when exposed to an aqueous rehydration medium (= diluents). Preferably, the swelling will be in the range of 400% to 1000%. "Balance swelling" can be determined by subtracting the dry weight of the gelatin hydrogel powder from its weight when fully hydrated or thereby completely swollen. The difference is then divided by the dry weight and multiplied by 100 one given the swelling measure. The dry weight should be measured after exposing the material to an elevated temperature for a time sufficient to remove substantially all residual moisture, for example, two hours at 120 ° C. The equilibrium hydration of the material can be achieved by dipping the dry material in an appropriate 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.
    [00039] An uncrosslinked gelatin together with the rehydration aid can be crosslinked in any appropriate way to form an appropriate hydrogel base. Dry crosslinked 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 the 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.
    [00040] Exemplary methods for producing cross-linked gelatins are as follows. Gelatin is obtained and suspended in an aqueous solution to form a non-cross-linked hydrogel, typically having a solids content of 1% to 70% by weight, generally 3% to 10% by weight. Gelatine 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, maintained at 0 ° C. To 15 ° C. For 48 hours) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ("EDC") (for example, 0.5% at 1.5% by weight overnight at room temperature), or by exposure to about 0.3 to 3 megarads of gamma radiation or electronic beam. Alternatively, gelatin particles can be suspended in an alcohol, preferably methyl alcohol or ethyl alcohol, in a solids content of 1% to 70% by weight, generally 3% to 10% by weight, and cross-linked by exposure to a cross-linking agent, typically glutaraldehyde (for example, 0.01% to 0.1% by weight, overnight at room temperature). In the case of aldehydes, the pH should be maintained at about 6 to 11, preferably from 7 to 10. When crosslinking with glutaraldehyde, the crosslinkers are formed using Schiff bases which can be stabilized by subsequent reduction, for example, 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 here.
    [00041] 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 can 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, the 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 out above.
    [00042] According to another aspect, the present invention also provides a method for delivering a hemostatic composition to a target site in a patient's body, said method comprising delivering a hemostatic composition produced by the process according to the present invention to the target site . Although in some embodiments, the dry composition can also be applied directly to the target site (and, optionally be contacted with the diluent at the target site, if necessary), it is preferred to contact the dry hemostatic composition with a pharmaceutically acceptable diluent prior to administration to the target site, in order to obtain a hemostatic composition in a moistened form, especially the hydrogel form.
    [00043] The present invention also relates to a finished final container obtained by the process according to the present invention. This finished container contains the combined components in a sterile, storage-stable and marketable form.
    [00044] 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.
    [00045] 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 an appropriate diluent. Other components of the kit may be instructions for use, means of administration, such as syringes, catheters, brushes, etc. (if the compositions are no longer 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 means of wound coverage. Preferably, the kit according to the present invention comprises a syringe housing the dry and stable hemostatic composition and a syringe containing the diluent (or provided to absorb the diluent from another diluent container). Preferably, these two syringes are provided in a form adapted to each other so that the diluent can be delivered to the dry hemostatic composition via another inlet than the outlet for administering the reconstituted composition.
    [00046] The invention is further described in the examples below, although not limited to them. EXAMPLES 1. Preparation of the dry hemostatic composition according to the present invention Materials and methods
    [00047] All variants use the same scheme of presenting a kit with a syringe containing both the Floseal gelatin matrix and thrombin in a stable form, and a syringe containing an appropriate liquid reconstitution medium (for example, 0.9% NaCI , or 40 mM CaCI2). Both syringes are sterile inside and out, so that complete reconstitution can take place on the nursing side of the operating site. Reconstitution is achieved by coupling the two syringes in a familiar way and mixing the contents of the two syringes by "squirt" (ie repeated transfer of the contents back and forth between the two syringes). "Syringe Lyo"
    [00048] The composition according to the present invention is made by mixing the gelatin and thrombin solution in a moist paste and lyophilizing the paste inside a simple syringe. The gelatin matrix can be sterilized by mass prior to irradiation. Gamma or beta irradiation is suitable for sterilizing gelatin. Sterile gelatin is hydrated en masse with a sterile thrombin solution. This produces a wet paste, ie a paste without a liquid-free phase. Preferably, this step is carried out in bulk gradually by dripping the gelatin granules into the constantly stirred thrombin solution and mixing until a homogeneous paste is formed or simultaneously feeding the granules and the thrombin solution into an appropriately configured extrusion machine where the two components are intimately mixed in a paste able to flow that can then be directly dispensed in syringes for further processing.
    [00049] The paste can then be filled in syringes to allow lyophilization inside the syringe.
    [00050] After the filled syringes are frozen, the slurry is freeze-dried using an appropriate freeze-drying program. The syringe is closed inside the freeze dryer by pushing on the plungers initially configured in the syringe. In the same step, the lyophilized matrix is compacted to close to the volume that would be occupied by the gelatin granules alone, to minimize the amount of air mixed in the product under reconstitution. The product is now ready for packaging with the diluent syringe, sterilization with EO of the bags, and storage. Diluent syringe
    [00051] The diluent syringe contains an appropriate reconstitution medium to hydrate the product. It can be coupled with the Floseal syringe either directly or via a connector. The diluent is transferred in the Floseal syringe, and the hydrated product is transferred back and forth between the syringes coupled repeatedly to generate a paste able to flow. The diluent syringe can be prepared, for example, by a process such as the following: the medium is sterile filtered and filled in appropriate syringes (such as Toppac, Clearshot syringes, ...); and, if necessary, sterilized at the end by irradiation. Gelatin granules
    [00052] The mass manufacture of gelatin granules is carried out according to established methods (WO 98/08550 A; WO 2003/00785 A; etc.). The granules ("Floseal" granules; "Floseal" matrix) are sterilized by gamma irradiation. For preclinical sterilization the Floseal matrix is filled into appropriately sized Schott glass bottles.
    [00053] The irradiation dose required at the maximum current biocharge 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 another manufacture. "In syringe Lyo" Floseal
    [00054] 0.81 g of gelatin Floseal (associated with water and corresponding to 0.704g of dry gelatin powder) are weighed in a lyophilization syringe. The syringe plunger is then attached above the gelatin granules at the rear. On the other hand, the Floseal thrombin syringe is filled with 4.0 ml thrombin 500IE / ml. Then the syringes are connected and squirted for at least 21 passes. After the last pass, the product must be inside the lyophilization syringe. The luer lock on this syringe is closed using the Floseal luer lock caps. The product undergoes lyophilization inside this syringe. For lyophilization the STIM5 thrombin 500 lU / ml lyophilization program is used. The syringes are placed on custom built shelves made of stainless steel. The shelf is constructed such that the luer lock cap on the syringe rests on the bottom floor of the shelf, while the syringe finger rests rest on the top floor. This ensures maximum stability of the syringes during the lyophilization pie compaction step.
    [00055] The dried product is compacted under vacuum by lowering the hydraulic “cap” plate of the lyophilizer and thereby pushing the plungers beyond the lyophilization orifices and into the syringes. This closes the syringes and compresses the lyophilization cake such that it takes up as little volume as possible after the lyophilization step. The low level at which the capping plates are lowered is limited by metal spacers that ensure that the syringes are compacted to the correct level without putting undue pressure on the product / devices. 2. Effectiveness in the swine liver abrasion model
    [00056] The purpose of this study is to compare the effectiveness of the dry hemostatic composition according to the present invention with an established standard product (Floseal VH S / D; Baxter Healthcare) in the swine liver abrasion model. Floseal VH S / D is a gelatin matrix that delivers thrombin to stop active bleeding within 2 minutes of application. This product requires a 2-step preparation, (1) thrombin reconstitution and (2) hydration of the gelatin particles with the reconstituted thrombin. The product according to the present invention is designed to reconstitute the dry 1-stage hemostatic composition and is a major improvement for the 2-stage preparation which is unfavorable when the product is needed quickly or in large quantities. Swine liver abrasion model.
    [00057] Six female domestic pigs, with an average weight of 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 are quarantined for 6 days. At the time of surgery, all six pigs show no signs of clinical disease. Ear tags are used to identify animals and cross-reference to assessed identification numbers. Animals are housed in groups in pens. Pigs receive water ad libitum and a standard pig diet once a day.
    [00058] 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 the different test items. Anesthetics and fluid therapy
    [00059] Pigs are medicated with Midazolam (0.3 mg / kg, IM) and induced with a mask with Isoflurane in a 2: 1 nitrogen carrier for oxygen. 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
    [00060] A swine liver abrasion model is used for this study. Six pigs are prepared with the aim 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 designed in confidence for either the medial, left-side or right-side lobe.
    [00061] Each series of lesions contains three liver abrasions 1 cm in diameter, 2-4 mm deep 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 are randomized using a random number generator. Each article is placed on the lesion, kept in 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 washed with irrigation after 5 minutes evaluation. Heparinization protocol
    [00062] A activated baseline clotting time (ACT) is taken and each pig receives a dose of heparin loading, 200 lU / kg. ACT is assessed every 10 minutes until ACT is at least 2 times the baseline. If the ACT measures less than or close to 2 times the baseline, the pig was treated with a dose and cake heparin, 75 lU / kg.
    [00063] 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 the baseline, the pig receives a dose of heparin bolus, 40 lU / kg. If the ACT measures more than the target 2 times the baseline, the pig is not treated or given a dose of heparin maintenance cake, limited to no more than 2,000 lU / hour.
    [00064] All heparin is administered through a peripheral venous catheter. All blood samples are taken from a jugular catheter. Reference blood pressure or heart rate values are recorded at the time of ACT measurements. Hemostasis assessment
    [00065] Hemostasis is evaluated at 0, 2, 5 and 10 minutes after the series of lesions is created and treated, where 0 minutes refer to pre-treatment. Scores of 0, 1, 2, 3, 4, and 5 are assessed for no bleeding, slow flow, very mild, mild, moderate, and severe; respectively. All three lesions are treated at approximately the same time to avoid a difference in location and clotting that can result from treating each independently. Blood from the lesion is wiped after each assessment as needed. Measurements and records
    [00066] ACT, hemostasis, blood pressure and heart rate are assessed according to standard methods. Statistical analysis
    [00067] The sampling unit for that study is the liver injury site with 40 injuries per treatment group for a total of 120 injuries.
    [00068] Multiple logistic regression is used to assess the treatment effect on bleeding scores (0 = no, 1 = slow flow, 2 = very light, 3 = mild, 4 = moderate, and 5 = severe) at 2, 5 , and 10 minutes after treatment. Independent variables include treatment group, pig, liver lobe (medial, right or left) and initial bleeding score. The probability ratios for the effects of FB / FS, Lyo / FS, FB / Lyo, and their confidence intervals are computed at each post-treatment time point.
    [00069] Injury locations are not evenly distributed across the three wolves and pigs. The wolf effect is verified as not being significant, and, therefore, the analyzes are carried out again without this effect. The conclusions are based on analyzes without the wolf effect on the model. Results:
    [00070] 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 and the 1-stage reconstitution mode has no negative impact on the performance of the composition, but does provide the desired advantage in practical manipulation thereby providing that the object of the present invention is resolved. Other animal experiments
    [00071] A preclinical evaluation is performed to compare in vivo efficacy of Floseal "in a lyophilization syringe" to Floseal VH in a very stringent (highly anticoagulated) model. This model consists of a 5 mm full-thickness liver puncture 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 I.U./kg. After the lesion is placed, reconstituted Floseal is applied, and light pressure for 2 min with wet gauze is applied. After this time, the post primary hemostasis is evaluated. If primary hemostasis is not achieved, product is reapplied until hemostasis is achieved, or product (5 ml) / time (15 min) is exhausted. Primary endpoints are primary hemostasis (Yes / No) and time to hemostasis (min).
    [00072] If primary hemostasis is achieved, the animals are surgically closed, and after 24 the animals are evaluated for bleeding again.
    [00073] The present composition provides results in terms of time for hemostasis that are equivalent to or better than standard Floseal in that particular preclinical laboratory session.
    权利要求:
    Claims (12)
    [0001]
    1. Process for making a dry and stable hemostatic composition, characterized in that said process comprises a) providing a first component comprising a dry preparation of a coagulation inducing agent, wherein the coagulation inducing agent is thrombin, b) providing a second component comprising a dry preparation of a biocompatible polymer suitable for use in hemostasis, wherein the biocompatible polymer is gelatin, c) mixing said first component and said second component under effective conditions to form a wet paste while essentially preventing degradation of the second component by said first component in a final container or transferring said wet paste into a final container, the wet paste being a paste without a liquid free phase, d) freezing and lyophilizing said paste in said container thus obtaining a dry and stable hemostatic composition comprising said first and said second component in lyophilized form, and e) ending said dry and stable hemostatic composition in said final container to obtain a storable pharmaceutical device containing said first component and said second component in a combined form as a dry and stable hemostatic composition, wherein said mixture is performed at a temperature of 2 ° C to 15 ° C.
    [0002]
    2. Process according to claim 1, characterized by the fact that step c) is performed under aseptic conditions.
    [0003]
    3. Process according to claim 1 or 2, characterized by the fact that step c) is carried out by extrusion.
    [0004]
    Process according to any one of claims 1 to 3, characterized in that step d) comprises a sterilization step with ethylene oxide or an ionizing irradiation.
    [0005]
    Process according to any one of claims 1 to 4, characterized in that said first component contains thrombin in a CaCl2 solution, preferably thrombin in a concentration of 10 to 10,000 IU / ml, more preferably 50 to 5,000 IU / ml, especially from 100 to 1,000 IU / ml.
    [0006]
    Process according to any one of claims 1 to 5, characterized in that said paste is frozen in said final container after performing step c).
    [0007]
    Process according to any one of claims 1 to 6, characterized in that said biocompatible polymer suitable for use in hemostasis is a granular material
    [0008]
    Process according to any one of claims 1 to 7, characterized in that said biocompatible polymer suitable for use in hemostasis is a cross-linked gelatin.
    [0009]
    Process according to any one of claims 1 to 8, characterized in that said final container additionally contains an amount of an effective stabilizer 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 by the fact that it is obtained by the process as defined in any one of claims 1 to 9.
    [0011]
    11. Method for providing a ready-to-use hemostatic composition, characterized in that it comprises contacting a hemostatic composition produced by the process as defined in any one of claims 1 to 9 with a pharmaceutically acceptable diluent.
    [0012]
    12. 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:
    公开号 | 公开日 | 专利标题
    US10994045B2|2021-05-04|Process for making dry and stable hemostatic compositions
    US9408945B2|2016-08-09|Process for making dry and stable hemostatic compositions
    AU2011260260B2|2015-09-03|Process for making dry and stable hemostatic compositions
    同族专利:
    公开号 | 公开日
    JP6289096B2|2018-03-07|
    JP2018016656A|2018-02-01|
    CO6660509A2|2013-04-30|
    CN102917691A|2013-02-06|
    EP2575776A1|2013-04-10|
    JP2013530955A|2013-08-01|
    ES2682302T3|2018-09-19|
    CA2801120A1|2011-12-08|
    KR20130121702A|2013-11-06|
    AU2011260274B2|2015-07-02|
    MX2012013999A|2013-01-28|
    US20120128653A1|2012-05-24|
    US9408945B2|2016-08-09|
    KR101865427B1|2018-06-07|
    BR112012030457A2|2017-06-20|
    EP2575776B1|2018-05-30|
    CA2801120C|2019-08-20|
    WO2011151400A1|2011-12-08|
    MX352875B|2017-12-13|
    JP2016135808A|2016-07-28|
    AU2011260274A1|2012-12-13|
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    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-04-24| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2020-03-10| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-03-31| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-02-17| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-03-09| 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. |
    优先权:
    申请号 | 申请日 | 专利标题
    US35021410P| true| 2010-06-01|2010-06-01|
    US61/350214|2010-06-01|
    PCT/EP2011/059114|WO2011151400A1|2010-06-01|2011-06-01|Process for making dry and stable hemostatic compositions|
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