Improved Hemostatic Agent Reconstitution Method and Device

Abstract

Disclosed herein are hemostatic materials and methods of making and using the hemostatic materials.

Description

Detailed Description of the Invention

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS]

[0001] This application claims priority to U.S. patent application Ser. No. 63 / 283,781, filed Nov. 29, 2021, the disclosure of which is incorporated by reference herein for all purposes.

[0002] [Field] This specification relates to the preparation and use of hemostatic materials.

[0003] [background]

[0003] Control of localized bleeding is of critical importance in wound management, particularly in the management of wounds resulting from, for example, traumatic injury or surgery. Typical methods of controlling bleeding employ the use of "passive" devices, including cotton gauze pads. Passive devices, however, do not initiate or accelerate blood clotting.

[0004] In contrast to passive devices, hemostatic agents are "active" materials that promote hemostasis through the use of hemostatic agents, such as fibrinogen or thrombin, and actively participate in the coagulation cascade to form fibrin clots. Thrombin is a serine protease that plays a key role in blood clotting (clotting). As an important coagulation protease, thrombin converts soluble fibrinogen into a fibrin network cross-linked by transglutaminase (FXIII). Furthermore, thrombin is the most potent activator of platelets by stimulating protease-activated receptors (PARs). After activation by thrombin, platelets physically modify the structure of the GPIIb / IIIa receptor, forming a high-affinity binding site for fibrinogen, leading to fibrinogen-cross-linked platelet aggregation.

[0005]

[0005] However, while current hemostatic agents are effective, preparing the hemostatic agent for use can require trained personnel to spend significant seconds in the preparation process. Thus, improved methods and systems are desirable.

[0006] [overview]

[0006] The present disclosure provides a novel class of delivery systems, devices, and methods that allow for more rapid reconstitution of hemostatic materials. For example, preparation of FLOSEAL™ requires reconstitution of a granular gelatin matrix with a thrombin solution. This process, while not complicated, is time consuming and requires the operator to first prepare the thrombin solution and then mix the thrombin solution with the gelatin matrix. In contrast, the present disclosure provides systems and devices that simplify and accelerate this process. For example, the disclosed embodiments combine a hemostatic agent, such as thrombin, with a matrix carrier material, such as gelatin granules, in a single container, such as a syringe.

[0007] The disclosed systems and devices also provide improved stability of the hemostatic material, for example, by maintaining a moisture-free environment for the hemostatic agent.

[0008]

[0008] The disclosed embodiments also include kits comprising the disclosed hemostatic materials, devices, and systems.

[0009]

[0009] The disclosed embodiments also include methods of use. For example, the disclosed systems, devices, and methods can be used to reduce or stop bleeding, etc., associated with surgery, injuries, wounds, etc. Embodiments can include treatment of various categories of bleeding, including:

[0010] Grade 1: Mild For example, liver capsule abrasion. Grade 1 bleeding represents generalized exudate that oozes after 1-2 minutes of wiping with gauze.

[0010]

[0011] Grade 2: Moderate Grade 2 bleeding is visibly oozing after swabbing and is usually considered to interfere with surgery.

[0011]

[0012] Grade 3: Severe For example, rupture of the venous plexus during posterior lumbar laminectomy. Grade 3 bleeding is oozing immediately after wiping and requires intervention to continue with the surgery.

[0012]

[0013] Grade 4: Fatal For example, abdominal aortic laceration. Grade 4 bleeding is life-threatening and requires immediate surgical treatment. [Brief description of the drawings]

[0013] [Figure 1] 1 shows the disclosed syringe pre-filled with thrombin and gelatin, in this embodiment the two components are spatially separated. [Diagram 2] 1 shows the disclosed syringe pre-filled with thrombin and gelatin, the two components being physically separated by a gelatin membrane. [Diagram 3] 1 shows the disclosed syringe pre-filled with a mixture of thrombin and gelatin. [Figure 4] 1 shows the disclosed syringe pre-filled with a mixture of thrombin powder and swollen gelatin particles. [Diagram 5] 1 shows the disclosed syringe pre-filled with a foam of thrombin and swollen gelatin particles. [Figure 6] 1 shows the disclosed syringe pre-filled with thrombin and gelatin, in this embodiment the two components are spatially separated. [Figure 7] 1 shows the disclosed syringe pre-filled with thrombin and gelatin, the components being physically separated by a gelatin membrane. [Figure 8] 1 shows the disclosed syringe pre-filled with a mixture of thrombin and swollen gelatin particles. [Figure 9] 1 shows an embodiment of the disclosed kit having an application device, a diluent syringe, and an applicator. [Figure 10]1 illustrates the disclosed method of reconstituting the disclosed hemostatic material comprising gelatin granules and thrombin. [Figure 11] 1 shows the disclosed syringe pre-filled with a thrombin tablet or lyophilized thrombin surrounded by a gelatin pellet. [Figure 12] The disclosed syringe is shown pre-filled with a first layer of gelatin pellets and a second layer of lyophilized or frozen thrombin, followed by alternating layers of gelatin and thrombin.

[0014] [Detailed Description]

[0026] The disclosed embodiments include a novel class of delivery systems, devices, and methods that allow for more rapid reconstitution of hemostatic materials. The disclosed embodiments combine a hemostatic agent, e.g., thrombin, and a matrix material, e.g., gelatin particles, pellets, or granules, in a single container, such as a syringe. The disclosed systems may include at least one additional container, such as a syringe, containing a diluent, e.g., saline or water.

[0015]

[0027] Further embodiments include a barrier or membrane that physically separates the matrix material particles and the hemostatic agent inside the syringe. The disclosed membrane or barrier can prevent interactions between the components, so that the hemostatic agent is not affected by moisture associated with particles, such as cross-linked gelatin particles, prior to mixing of the components. This physical separation can provide significant advantages, especially when used in embodiments that include pre-swollen matrix particles, since typical hemostatic agents can degrade over time in the presence of moisture.

[0016]

[0028] In embodiments, the membrane may comprise any biocompatible, dissolvable, or friable film that forms an effective moisture barrier between the hemostatic agent component, such as thrombin, and the matrix particles, such as cross-linked gelatin particles. Such a moisture barrier may be particularly advantageous in embodiments that include pre-swollen particles, such as cross-linked gelatin particles.

[0017]

[0029] In embodiments, the membrane comprises a material that has suitable separation characteristics upon mechanically (e.g., manually) applied liquid force, such as via a syringe plunger, such that the membrane barrier quickly degrades upon exposure to liquid.

[0018]

[0030] In embodiments, suitable membrane or barrier materials may include, for example, gelatin or hydrogels. Suitable hydrogels may be resorbable and may include small subunits that have a size and other physical properties that enhance the performance of the gel membrane. In particular, the subunits may be sized such that the hydrogel will flow when the hemostatic material components are subjected to a stress above a threshold level, e.g., when extruded through a syringe. The threshold stress is typically greater than 3×10 4 Pa~5×10 5 In embodiments, the membrane may be generally immobile when subjected to a stress below a threshold level.

[0019]

[0031] The disclosed embodiments may also include foams, which provide a pre-matrix structure that is rapidly "wettable," thus forming a deliverable hemostatic paste material more quickly than dry powder mixtures or sequentially filled syringes.

[0020]

[0032] In embodiments, the disclosed device provides improved stability of the formulation, for example, the stability of thrombin. For example, by separately loading a hemostatic agent such as thrombin and a matrix material such as gelatin granules, the separate components are placed in close physical proximity in a single device (thus simplifying storage and transport) while maintaining thrombin in a dry state. In embodiments, separation is achieved spatially (without a membrane or barrier), while in some embodiments separation is maintained through the use of a membrane or barrier.

[0021]

[0033] The disclosed embodiments may further include a diluent, for example in a separate container such as a syringe, hi embodiments, the diluent may include, for example, saline or water.

[0022]

[0034] The disclosed embodiments may include a means for connecting multiple syringes, such as, for example, luer locks, tubing, etc.

[0023]

[0035] Definition:

[0036] "Administration" or "administering" refers to the step of giving (i.e., administering) a hemostatic device, material, or agent to a subject. The materials disclosed herein can be administered via a number of suitable routes.

[0024]

[0037] "Co-loading" or "co-loaded" means that multiple components are loaded into a container or vessel, such as a syringe. Co-loading can include loading multiple components sequentially or simultaneously. The co-loaded materials can form a mixture in the vessel or can be separated, for example, spatially or physically, by a membrane or barrier.

[0025]

[0038] "Equilibrium swelling" is defined as the swelling ratio at equilibrium after immersion of a polymer pellet or particulate material in a wetting agent for a time sufficient for the water content to remain constant, typically 18 to 24 hours. Equilibrium swelling is typically determined by the amount of crosslinking within the polymer pellet or particulate.

[0026]

[0039] "Hemostatic agents" refers to agents capable of initiating and stabilizing the growth of a thrombus during bleeding, including biologics such as thrombin, small molecules such as tranexamic acid (TXA), polymers such as fecracrilam, peptides such as thrombin receptor activating peptide (TRAP), polysulfonic acid polymers, sulfated icodextrin, sulfated carbohydrates, and inorganic materials such as kaolin.

[0027]

[0040] "Hemostatic material" means a material that contains a hemostatic agent in a form suitable for application to a patient.

[0028]

[0041] "Patient" means a human or non-human receiving medical or veterinary care.

[0029]

[0042] "Therapeutically effective amount" refers to the level, amount, or concentration of a drug, material, or composition needed to achieve a therapeutic goal.

[0030]

[0043] "Treat", "treating", or "treatment" means to alleviate or relieve (which includes some relief, significant relief, near complete relief, and complete relief), eliminate, or prevent (either temporary or permanent) symptoms, disease, disorder, or condition, such as by healing damaged or injured tissue, or by altering, altering, enhancing, ameliorating, ameliorating, and / or beautifying an existing or perceived disease, disorder, or condition to achieve a desired therapeutic or cosmetic result.

[0031]

[0044] The present disclosure provides systems and devices for the storage and administration of hemostatic material, the hemostatic material comprising at least one hemostatic agent and at least one matrix carrier.

[0032]

[0045] hemostatic material

[0046] The disclosed hemostatic materials include at least one hemostatic agent and at least one particulate matrix material.

[0033]

[0047] Hemostatic agents

[0048] The disclosed hemostatic materials include at least a hemostatic agent, including, for example, small molecules such as thrombin, tranexamic acid (TXA), peptides such as felacrylam, thrombin receptor activating peptide (TRAP), polysulfonic acid polymers, sulfated icodextrin, sulfated carbohydrates, analogs thereof, and inorganic materials such as kaolin. In embodiments, the hemostatic agent can be of natural or recombinant origin. In embodiments, multiple hemostatic agents can be used.

[0034]

[0049] particle matrix

[0050] The disclosed hemostatic materials include a carrier matrix such as particles, pellets, or granules, e.g., granules comprising crosslinked materials including at least one biological or non-biological polymer, e.g., proteins, polysaccharides, and synthetic polymers.

[0035]

[0051] In embodiments, the matrix polymer is biodegradable. Biodegradable polymers release the contained drug when the matrix is ​​consumed or biodegraded during treatment. The polymer is usually selected to break down into subunits that are biocompatible with the surrounding tissue. The persistence of the biodegradable polymer in vivo depends on the molecular weight and crosslinking of the biodegradable polymer, the higher the molecular weight and the higher the crosslinking, the longer the life span. Common biodegradable polymers include polylactic acid (PLA, also called polylactide), polyglycolic acid (PGA), copolymers of PLA and PGA, polyamides, and copolymers of polyamides and polyesters.

[0036]

[0052] In various embodiments, the matrix material comprises a recombinant polymer. In particular, the recombinant polymer may be recombinant human collagen, such as, for example, recombinant human collagen type I, recombinant human collagen type III, or a combination thereof. In one embodiment, the matrix material comprises recombinant human collagen type III. In another embodiment, the matrix material comprises recombinant human collagen type I. For example, recombinant human gelatin can be derived from recombinant human collagen type III. In yet another embodiment, the matrix material comprises recombinant gelatin derived from recombinant human collagen type I. In a further embodiment, the matrix material comprises recombinant gelatin produced directly by expression of an encoding polynucleotide. In an embodiment, the collagen can be derived from animal tissue, such as bovine, porcine, or equine tissue, or from a human source.

[0037]

[0053] Polysaccharides for use as biocompatible matrix materials in the disclosed embodiments can include, for example, cellulose, alkyl cellulose, methyl cellulose, alkyl hydroxyalkyl cellulose, hydroxyalkyl cellulose, cellulose sulfate, salts of carboxymethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, chitin, carboxymethyl chitin, hyaluronic acid, salts of hyaluronic acid, alginate, alginic acid, propylene glycol alginate, glycogen, dextran, dextran sulfate, curdlan, pectin, pullulan, xanthan, chondroitin, chondroitin sulfate, carboxymethyl dextran, carboxymethyl chitosan, chitosan, heparan, heparan sulfate, dermatan sulfate, keratan sulfate, carrageenan, chitosan, starch, amylose, amylopectin, poly-N-glucosamine, polymannuronic acid, polyglucuronic acid, polyguluronic acid, derivatives of the aforementioned polysaccharides, or combinations thereof.

[0038]

[0054] The biocompatible matrix material may also be based on synthetic polymers. The synthetic absorbable polymer may be an aliphatic polyester polymer, an aliphatic polyester copolymer, or a combination thereof.

[0039]

[0055] In embodiments, the polymers can be crosslinked and hydrated to form hydrogels. Exemplary polymers include proteins selected from gelatin, collagen (e.g., soluble collagen), albumin, fibrinogen, fibrin, fibronectin, elastin, keratin, laminin, casein, and derivatives and combinations thereof. Alternatively, the polymers can include polysaccharides such as glycosaminoglycans (e.g., hyaluronic acid or chondroitin sulfate), starch derivatives, cellulose derivatives, hemicellulose derivatives, xylan, agarose, alginate, chitosan, and combinations thereof. As a further alternative, the polymers can include non-biological hydrogel-forming polymers such as polyacrylates, polymethacrylates, polyacrylamides, polyvinyl polymers, polylactide-glycolides, polycaprolactones, polyoxyethylenes, and derivatives and combinations thereof.

[0040]

[0056] Crosslinking of polymers can be accomplished by any conventional technique. For example, in the case of proteins, crosslinking can be accomplished using a suitable crosslinking agent, such as an aldehyde, sodium periodate, or an epoxy compound. Alternatively, crosslinking can be induced by exposure to radiation, such as gamma radiation or electron beam radiation. Polysaccharides and non-biological polymers can also be crosslinked using a suitable crosslinking agent and radiation. Additionally, non-biological polymers can be synthesized as crosslinked polymers and copolymers. For example, reactions between monounsaturated and polyunsaturated monomers can result in synthetic polymers with controlled degrees of crosslinking. Typically, the polymer molecules each have a molecular weight in the range of 20 kD to 200 kD, have at least one bond to another polymer molecule in the network, and often have 1 to 5 bonds, and the actual level of crosslinking is selected to partially provide the desired rate of biodegradability and "swelling", in the ranges described below. An exemplary method for producing molecularly crosslinked gelatin is as follows:

[0041]

[0057] The gelatin is obtained and placed in an aqueous buffer to form a non-crosslinked hydrogel, typically having a solids content of 1%-70% w / w, usually 3%-10% by weight. The gelatin is then typically crosslinked by exposure to either glutaraldehyde (e.g., 0.01%-0.05% w / w in aqueous buffer, overnight at 0° C.-15° C.), sodium periodate (e.g., 0.05M, kept at 0° C.-15° C. for 48 hours), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ("EDC") (e.g., 0.5%-1.5% w / w, overnight at room temperature), or by exposure to about 0.3-3 megarads of gamma radiation or electron beam radiation.

[0042]

[0058] Alternatively, the gelatin particles may be suspended in alcohol, preferably methyl or ethyl alcohol, at a solids content of 1% to 70% by weight, typically 3% to 10% by weight, w / w, and crosslinked by exposure to a crosslinking agent, typically glutaraldehyde (e.g., 0.01% to 0.1% w / w, overnight at room temperature). In the case of aldehydes, the pH should be kept at about 6 to 11, preferably 7 to 10. When crosslinking with glutaraldehyde, the crosslinks are formed via Schiff bases, which can be stabilized by subsequent reduction, for example, by treatment with sodium borohydride. After crosslinking, the resulting granules can be washed with water, optionally rinsed with alcohol, dried, and resuspended in an aqueous medium with the desired buffer and pH to the desired degree of hydration. The resulting hydrogel can then be loaded into an applicator of the present disclosure. Alternatively, the hydrogel can be mechanically disrupted before or after crosslinking. In an embodiment, genipin can be used as a crosslinking agent.

[0043]

[0059] The degree of crosslinking of the polymer affects several functional properties of the hydrogel, including extrudability, adsorption of surrounding biological fluids, cohesion, space-filling ability, swelling ability, and ability to adhere to tissue sites. The degree of crosslinking of the polymer hydrogel composition can be controlled by adjusting the concentration of the crosslinker, controlling the exposure to crosslinking radiation, varying the relative amounts of monounsaturated and polyunsaturated monomers, altering the reaction conditions, etc. Typically, the degree of crosslinking is controlled by adjusting the concentration of the crosslinker.

[0044]

[0060] The disclosed hydrogels of the present disclosure will typically have a solids content in the range of 1% to 70% w / w. Optionally, the composition may include at least one plasticizer, as described in more detail below. Suitable plasticizers include polyethylene glycol, sorbitol, glycerol, and the like.

[0045]

[0061] The equilibrium swelling of the crosslinked polymer of the present invention may range from 400% to 5000%, 400% to 3000%, 400% to 2000%, usually 400% to 1300%, preferably 500% to 1100%, depending on its intended use. Such equilibrium swelling may be controlled by varying the degree of crosslinking, which is also achieved by varying the crosslinking conditions, such as the type of crosslinking method, the duration of exposure to the crosslinking agent, the concentration of the crosslinking agent, the crosslinking temperature, etc.

[0046]

[0062] Exposure to radiation, such as gamma radiation, may also be used to sterilize the components before or after packaging. If the composition is comprised of radiation-sensitive materials, it may be necessary to protect the composition from the undesirable effects of sterilization radiation. For example, in some cases it may be desirable to add a stabilizer, such as ascorbic acid, to inhibit the degradation and / or further excessive cross-linking of the materials by free radical mechanisms.

[0047]

[0063] In embodiments, x-ray, e-beam, and beta sterilization may be used.

[0048]

[0064] Systems and Devices

[0065] Disclosed embodiments include systems and devices that include a container, such as a syringe. Disclosed systems can include at least one syringe that includes at least one hemostatic agent and at least one substrate that includes particles, pellets, or granules. For example, in embodiments, the hemostatic agent can include thrombin, fibrinogen, clotting factors, and the like.

[0049]

[0066] In embodiments, the particles, pellets, or granules may include a material that includes hemostatic properties.

[0050]

[0067] In embodiments, the hemostatic agent and carrier matrix are co-loaded into a container, such as a syringe. For example, in embodiments, the hemostatic agent and carrier matrix are loaded into a syringe sequentially or loaded into a syringe simultaneously. In embodiments, the matrix components may be "pre-swollen" by exposure to a liquid prior to loading the components. In embodiments, the components may be frozen prior to loading the components. In embodiments, the disclosed syringes may include luer locks, tubing, and the like.

[0051]

[0068] Looking at the embodiment of FIG. 1, the system comprises a device including a first layer including gelatin particles, pellets, or granules and a second layer including a hemostatic agent such as thrombin. The first layer includes pellets having a spherical or irregular shape. The thrombin layer may include lyophilized thrombin, powdered thrombin, or thrombin tablets. In this embodiment, the two layers are not separated by a membrane. The device can be filled either through the connector at the tip of the syringe body or through the large opening of the syringe body before the insertion of the piston and plunger. A cap on the connector at the tip of the syringe body prevents moisture from the inside of the device.

[0052]

[0069] Turning to the embodiment of Figure 2, the system comprises a device including a first layer including pellets or particles, e.g., gelatin pellets or particles, a membrane, e.g., a gelatin or hydrogel membrane, and a second layer including a hemostatic agent, such as thrombin. In an embodiment, the pellets or particles include spherical or irregular shapes.

[0053]

[0070] The hemostatic agent (such as thrombin) layer may include, for example, lyophilized thrombin, powdered thrombin, or thrombin tablets.

[0054]

[0071] In this embodiment, the two layers are physically separated by a membrane, such as a brittle, fragmentable, or soluble membrane, for example composed of gelatin. The membrane maintains the physical separation of the two layers until a diluent is applied and the components are mixed. In an embodiment, the membrane separating the two layers provides improved stability of the formulation. For example, the membrane separating the hemostatic agent from the particles or pellets can protect the hemostatic agent from moisture migration from the particle or pellet phase. The membrane can also prevent interaction of the hemostatic agent with the stopper of the syringe; typical stopper materials can include oils or treatments that can inactivate the hemostatic agent during long-term storage.

[0055]

[0072] The device can be filled through a large opening in the syringe body prior to insertion of the piston and plunger. A cap on the connector at the tip of the syringe body prevents moisture from entering the interior of the device.

[0056]

[0073] Looking at the embodiment of Figure 3, the system includes a device containing gelatin pellets mixed with thrombin, coated with thrombin, or adsorbed to thrombin. A cap over the connector at the tip of the syringe body prevents moisture from the inside of the device. In embodiments that include thrombin-coated gelatin pellets, the coating can ensure uniform distribution of gelatin and thrombin within the syringe.

[0057]

[0074] Looking at the embodiment of FIG. 4, the system comprises a device that includes a mixture of hydrated particles or pellets of gelatin and a hemostatic agent (such as thrombin). The mixture can be swollen or deswollen prior to filling, for example by exposure to a liquid. For example, in embodiments, preswollen crosslinked gelatin particles, pellets, or granules allow for rapid reconstitution and paste formation due to increased particle porosity and also form more efficient liquid flow paths around the particles, thus accelerating thrombin dissolution and increasing the distribution of thrombin in the hemostatic agent matrix. Swollen particles also provide increased particle surface area for more rapid thrombin binding to the particles, further accelerating the reconstitution process.

[0058]

[0075] A cap on the connector at the tip of the syringe body prevents moisture from the inside of the device. The device can be frozen for storage and then thawed for use. The disclosed embodiments including pre-swollen particles and hemostatic agent may be particularly suitable for planned future use, such as within 4, 6, 8, 10, or 12 hours of thawing, for example, for use in a planned operation on the same day, or in mass casualty situations. For example, multiple frozen embodiments can be thawed in preparation for later use upon notification of a potential mass casualty incident. Pre-swelling the particles or pellets also reduces the volume of diluent required for proper reconstitution.

[0059]

[0076] In embodiments, the degree of pre-swelling can be determined based on the desired use. For example, materials with different equilibrium swelling values ​​perform differently in different applications; bleeding control in certain applications may be most easily achieved with cross-linked gelatin materials having swelling in the range of 700%-950%. For other applications, lower equilibrium swelling values ​​in the range of 500%-600% may be more successful. Thus, the ability to control cross-linking and equilibrium swelling allows the disclosed hemostatic materials to be optimized for a variety of uses.

[0060]

[0077] Looking at the embodiment of FIG. 5, the system comprises a device that includes a foam of swollen cross-linked gelatin and a hemostatic agent such as thrombin. In embodiments, the foam may include a wet foam containing a liquid such as water or saline, or may be dried into a sponge for subsequent rehydration. The device can be filled through a large opening in the syringe body prior to insertion of the piston and plunger. A cap on the connector at the tip of the syringe body prevents moisture from the inside of the device. In embodiments, the device can be frozen for storage. In use, the foam can be applied as a spray, for example to treat a wide area.

[0061]

[0078] Looking at the embodiment of FIG. 6, the system comprises a device including a first layer of, for example, gelatin particles or pellets and a second layer of a lyophilized or frozen hemostatic agent such as thrombin. The first layer includes pellets having a spherical or irregular shape. The two layers are not physically separated by a membrane or barrier. The device can be filled either through a connector at the tip of the syringe body or through a large opening in the syringe body prior to insertion of the piston and plunger. A cap over the connector at the tip of the syringe body prevents moisture from the inside of the device.

[0062]

[0079] Looking at the embodiment of FIG. 7, the system comprises a device including a first layer of gelatin particles or pellets and a second layer of frozen hemostatic agent, such as thrombin. The first layer includes pellets having a spherical or irregular shape. The two layers are separated by a membrane, e.g., a gelatin membrane. The device can be filled through a large opening in the syringe body prior to insertion of the piston and plunger. In an embodiment, the hemostatic agent layer is frozen in the syringe, then substrate particles or pellets are added, and then the device is re-frozen.

[0063]

[0080] A cap over the connector at the tip of the syringe body prevents moisture from entering the inside of the device.

[0064]

[0081] Looking at the embodiment of Figure 8, the system comprises a device containing a foam of swollen gelatin and thrombin that are mixed and then freeze-dried. The foam provides a pre-matrix structure that is rapidly "wettable" and therefore forms a deliverable hemostatic paste material more quickly than dry powder mixtures or sequentially filled syringes. A cap over the connector at the tip of the syringe body prevents moisture from the inside of the device.

[0065]

[0082] Looking at the embodiment of Figure 11, the system comprises a device that includes a hemostat (such as thrombin) tablet or cylinder surrounded by gelatin pellets or granules. The thrombin may include lyophilized thrombin. The hemostat cylinder presents an increased surface area to the diluent, thus accelerating the reconstitution process.

[0066]

[0083] The device can be filled through a large opening in the syringe body prior to insertion of the piston and plunger. A cap over the connector at the tip of the syringe body keeps moisture out of the interior of the device. The use of a separate thrombin tablet or cylinder may allow for the use of a simpler manufacturing process.

[0067]

[0084] Looking at the embodiment of FIG. 12, the system comprises a device that includes a first layer of pellets or particles (such as gelatin pellets or particles) and a second layer of lyophilized or frozen hemostatic agent (such as thrombin), followed by alternating layers of gelatin and thrombin. The gelatin layer includes pellets having a spherical or irregular shape. The two layers are not separated by a membrane. The device can be filled either through the connector at the tip of the syringe body or through a large opening in the syringe body before the insertion of the piston and plunger. A cap on the connector at the tip of the syringe body prevents moisture from the inside of the device. The use of multiple separate thrombin tablets can allow the use of a simpler manufacturing process. Furthermore, a thinner layer of thrombin can result in rapid dissolution of thrombin and easier mixing of the formulation.

[0068]

[0085] Commercially available products / kits

[0086] The hemostatic material can be finalized as a commercial product by the usual steps practiced in the art, e.g., appropriate sterilization and packaging steps. The hemostatic material according to the present disclosure can ultimately be packaged in a suitable container (such as a box) in a sterile package to preserve sterility until use (e.g., by adding a specific product information leaflet).

[0069]

[0087] According to further embodiments, the hemostatic material may be provided in kit form in combination with other components necessary for administration of the material to a patient. Buffer components, e.g., phosphate, carbonate, TRIS, etc., divalent metal ions, preferably Ca 2+ ions, or other functional components (if not already present on or within the matrix), e.g., antimicrobial agents, immunosuppressants, anti-inflammatory agents, antifibrinolytic agents such as aprotinin or ECEA, growth factors, vitamins, cells, etc. The kit may further include a means for administering or arranging for administration of a hemostatic material, such as a syringe, tubing, catheter, forceps, scissors, sterile pads, or lotion.

[0070]

[0088] The disclosed kits, such as for use in surgery and / or in treating injuries and / or wounds, can include the disclosed hemostatic materials and at least one administration device, such as a buffer, a syringe, a tube, a catheter, forceps, scissors, gauze, a sterile pad, or a lotion.

[0071]

[0089] In embodiments, the buffer solution further comprises an antibacterial agent, an immunosuppressant, an anti-inflammatory agent, an antifibrinolytic agent, particularly aprotinin or ECEA, a growth factor, a vitamin, cells, or a mixture thereof. Alternatively, the kit may further comprise an antibacterial agent, an immunosuppressant, an anti-inflammatory agent, an antifibrinolytic agent, particularly aprotinin or ECEA, a growth factor, a vitamin, cells, or a mixture thereof.

[0072]

[0090] The kits are designed in various forms based on the particular defect that they are intended to treat. For example, Figure 9 shows an exemplary kit with a dual thermoformed blister containing an application device, a diluent syringe, and an applicator. Additional components, such as a cannula or desiccant, may be added.

[0073]

[0091] How to use

[0092] Methods of use of the disclosed embodiments may include reconstituting a matrix, e.g., cross-linked gelatin granules, with a solution containing a hemostatic agent, e.g., thrombin, followed by application to the site where it is desired to reduce bleeding. For example, Figure 10 shows an exemplary method of reconstituting the hemostatic material, in which a diluent syringe is connected to the matrix / hemostatic agent syringe, and the contents are repeatedly "swooshed" from one syringe to the other.

[0074]

[0093] The disclosed methods of use include applying the disclosed embodiments to a site where it is desired to reduce bleeding, such as the site of an injury or surgery. These methods are further described in the Examples below.

[0075] [Example]

[0094] The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of representative embodiments, and should not be construed as limiting any of the embodiments described herein.

[0076] Example 1 Manufacturing of co-filled syringes

[0095] The first syringe is filled with the 0.9% NaCl diluent.

[0077]

[0096] The second syringe is first filled with the dry cross-linked gelatin granules through the large opening, and then filled with the lyophilized thrombin through the large opening.

[0078] Example 2 Manufacturing of co-filled syringes

[0097] The first syringe is filled with the water diluent.

[0079]

[0098] Through the large opening, the second syringe is simultaneously filled with the dry cross-linked gelatin granules and the lyophilized thrombin.

[0080] Example 3 Preparation of hemostatic material

[0099] The first syringe containing a diluent of 0.9% NaCl (w / v) is "docked" to the second syringe containing a layer of pre-swollen cross-linked gelatin granules and a layer of freeze-dried thrombin. The two components are separated by a gelatin membrane. The diluent is injected from the first syringe into the second syringe, and then the contents of the second syringe are injected back into the first syringe. This is repeated several times to hydrate the gelatin granules and reconstitute the thrombin.

[0081]

[0100] The hemostatic material is then ready for use.

[0082] Example 4 Treatment of injuries

[0101] A victim of an automobile accident sustains a traumatic injury to the abdomen. To stop blood loss, the disclosed hemostatic material is applied to the injury site using the disclosed hemostatic material delivery device. Blood loss is reduced within minutes.

[0083] Example 5 Surgical incision management

[0102] To stop blood loss, the disclosed hemostatic material is applied to the site of a surgical incision using the disclosed hemostatic material delivery device. Blood loss is reduced within minutes, and the hemostatic material also provides a germicidal effect.

[0084]

[0103] Finally, although aspects of the present specification are emphasized by reference to specific embodiments, it should be understood that those skilled in the art can easily see that these disclosed embodiments merely exemplify the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methodology, procedures, and / or reagents, etc. described herein. Thus, various modifications or alterations to the disclosed subject matter or alternative configurations thereof can be made in accordance with the teachings of the present specification without departing from the spirit of the specification. Finally, the terms used in the present specification are intended only to describe specific embodiments and are not intended to limit the scope of the present disclosure, which is defined solely by the claims. Thus, the embodiments of the present disclosure are not limited to those precisely shown and described.

[0085]

[0104] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the methods and devices described herein. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed in this disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0086]

[0105] Groupings of alternative embodiments, elements, or steps in the present disclosure should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is considered to include the group as modified, and thus fulfills the description of all Markush groups used in the appended claims.

[0087]

[0106] Unless otherwise indicated, all numbers expressing features, items, quantities, parameters, properties, terms, etc. used in the specification and claims should be understood to be modified in all instances by the term "about". As used herein, the term "about" means that the feature, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus 10 percent of the value of the referenced feature, item, quantity, parameter, property, or term. Thus, unless specifically indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the disclosure are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of numerical ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range, and unless otherwise stated herein, each individual value of the numerical range is incorporated herein as if it were individually recited herein.

[0088]

[0107] The terms "a," "an," "the," and similar directives used in the context of describing this disclosure (particularly in the context of the claims below) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") described herein is intended merely to better explain this disclosure and does not limit the scope of what is otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the embodiments disclosed herein.

[0089]

[0108] Certain embodiments disclosed herein may be further limited in the claims using the language consisting of or consisting essentially of. When used in the claims, whether as filed or added in an amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic novel characteristic(s). The embodiments of the present disclosure as claimed in this manner are inherently or explicitly described and enabled herein.

Claims

1. 1. A system for administering a hemostatic material to a patient, the system comprising: a first syringe co-filled with at least one matrix material and at least one hemostatic agent; a second syringe filled with a diluent; The first syringe has a membrane separating the matrix material and the hemostatic agent.

2. The system of claim 1 , wherein the at least one substrate material comprises gelatin.

3. The system of claim 2 , wherein the gelatin comprises cross-linked gelatin.

4. The system of claim 3 , wherein the cross-linked gelatin comprises gelatin granules.

5. The system of claim 1 , wherein the at least one hemostatic agent comprises thrombin.

6. The system of claim 1 , wherein the diluent comprises sterile water.

7. The system of claim 1 , wherein the diluent comprises saline.

8. The system of claim 7 , wherein the saline solution contains 0.9% (w / v) NaCl.

9. The system of claim 1 , wherein the matrix material is pre-swollen.

10. The system of claim 1 , wherein the membrane comprises a material that is soluble, prone to fragmentation, or friable.

11. 11. The system of claim 10, wherein the soluble, fragmentable, or friable material comprises gelatin.

12. 1. A kit for use in establishing local hemostasis, comprising: a first syringe co-filled with at least one matrix material and at least one hemostatic agent; a second syringe filled with a diluent; The first syringe has a membrane separating the matrix material and the hemostatic agent.

13. 13. The kit of claim 12, wherein the at least one substrate material comprises gelatin.

14. The kit of claim 13 , wherein the gelatin comprises cross-linked gelatin.

15. 15. The kit of claim 14, wherein the cross-linked gelatin comprises gelatin granules.

16. The kit of claim 12 , wherein the at least one hemostatic agent comprises thrombin.

17. 13. The kit of claim 12, wherein the diluent comprises sterile water.

18. The kit of claim 12 , wherein the diluent comprises saline.

19. 19. The kit of claim 18, wherein the saline solution contains 0.9% (w / v) NaCl.

20. The kit of claim 12 , wherein the matrix material is pre-swollen.

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