hemostatic materials

Abstract

To provide a hemostatic agent that is effective in controlling blood flow from wounds in both normal and impaired coagulation cases, while simultaneously maintaining a shortened compression time, minimizing the need for resuscitation fluids, and being easy and safe to use. [Solution] A hemostatic composition comprising a hemostatic agent, a bioadhesive, and an antifibrinolytic solvent or a derivative thereof.

Description

Technical Field

[0001] The present invention relates to a hemostatic material for use in controlling bleeding.

Background Art

[0002] There are many situations in which animals, whether human or non - human, can receive injuries or wounds that cause bleeding. In the case of minor injuries, the bleeding can be stopped by the body's natural hemostatic mechanism, which causes blood coagulation and forms a solid blood clot that prevents bleeding and aids in the repair of damaged blood vessels.

[0003] Conventionally, the technique mainly employed to stop the blood flow from a wound is to continuously apply pressure to the wound. By this, coagulation factors can gather at the site of the wound and form a coagulated blood mass to stop the blood flow. However, this technique is not suitable for cases of severe injuries and wounds with multiple bleeding points. Therefore, bleeding continues to be a major cause of death.

[0004] Deaths caused by bleeding are particularly a problem on the battlefield. Typically, the wounds that occur in this situation are accompanied by significant bleeding and often result in death. Bleeding is also a significant cause of death among the general public after trauma.

[0005] Efforts have been made to provide products that promote the stopping of blood flow from wounds. These include products sold under the trade name Quick - clot®. Briefly stated, this product contains a carrier material coated with an active compound that can stop blood flow when applied to the wound together with pressure.

[0006] More specifically, Quick - clot® contains a zeolite compound that absorbs water from the blood flowing from the wound, thereby concentrating the coagulation factors present in the blood and causing the blood to coagulate more quickly. Thus, the zeolite and the coagulated blood together form a blood clot to stop the blood flow.

[0007] While effective, these compositions are not without their problems because they require continuous pressure to control the bleeding. Guidance provided by Tactical First Line Care (TCCC) in November 2009 indicated that when using hemostatic bandages, specifically Combat Gauze®, compression should be applied for at least 3 minutes. Other examples of hemostatic products requiring at least 3 minutes of compression include, but are not limited to, Celox® Gauze (Medtrade Products Ltd) and Chitogauze® (Hemcon).

[0008] More recently, as described in U.S. Patent Application Publication 2014 / 105950, bioadhesives have been used and incorporated into the aforementioned hemostatic dressings to shorten compression time, potentially reducing blood loss and overall treatment time.

[0009] A further aspect of this research, as emphasized by physicians, is the dysfunction of the body's ability to control bleeding due to clotting disorders. Clotting disorders can be defined as a medical condition in which the ability of blood to clot (form a blood clot) is impaired. This condition can lead to a tendency for prolonged or excessive bleeding, which may occur after injury or medical procedures. The resulting effect on treatment with the hemostatic products mentioned above is that pressure needs to be applied for a longer period, i.e., a longer compression period is required compared to patients without clotting disorders.

[0010] In situations where a patient has a clotting disorder, this can lead to prolonged bleeding after treatment, requiring further medical intervention before surgical treatment in a hospital (battlefield or civilian). Prolonged treatment time to achieve hemostasis in patients with clotting disorders can also endanger the lives of physicians during treatment under attack, or result in delays in responding to other injured or wounded.

[0011] A further aspect of treating bleeding injuries is the need to administer body fluids and resuscitation fluids.

[0012] Studies conducted by the U.S. Institute of Surgery have reported, using in vivo coagulation disorder models, that some existing products provide insufficient hemostasis, or that products containing bioadhesives cause prolonged compression. [Overview of the project] [Problems that the invention aims to solve]

[0013] Therefore, the object of the present invention is to provide a hemostatic material that is effective in controlling blood flow from wounds in both normal and impaired coagulation cases, while simultaneously maintaining a shortened compression time, minimizing the need for resuscitation fluids, and being easy and safe to use. [Means for solving the problem]

[0014] Accordingly, according to a first aspect of the present invention, a hemostatic composition is provided comprising a hemostatic agent, a bioadhesive, and an antifibrinolytic solvent or a derivative thereof.

[0015] The compositions of the present invention may be in several forms, including but not limited to granules, powders, flakes, foams, solutions, or gels, which may be applied directly to a wound or coated, supported, or delivered on a carrier material.

[0016] In this specification, "hemostatic agent" means a substance that promotes hemostasis. The hemostatic agent may have the ability to form a blood clot or embolus to prevent or suppress bleeding when in contact with blood.

[0017] The physiological target site for the hemostatic agent may be any part of the animal's body or on its body. The animal may be human or a non-human animal. The physiological target site may be a wound, or it may be an opening in the body that occurs in the course of a medical procedure, for example, in the course of surgery. Hereinafter, the physiological target site will be referred to as a wound for convenience and illustrative purposes only.

[0018] Beneficially, the hemostatic agent of the present invention can be applied by a person with only basic medical training. It simply involves applying the material to the physiological target site and then applying pressure.

[0019] Furthermore, the hemostatic agent is easy to handle and apply. Typically, it is stored in a dry state until application. [Modes for carrying out the invention]

[0020] Products that utilize biological processes tend to be temperature-dependent. Often, patients experiencing blood loss are either extremely hot due to strenuous activity on the battlefield or extremely cold due to exposure to low temperatures. Products currently available are less effective at such extreme temperatures. Advantageously, the materials of this invention are substantially unaffected by temperature fluctuations and therefore function equally well at both temperatures higher and lower than normal body temperature. "Normal body temperature" refers to approximately 37°C.

[0021] The hemostatic composition of the present invention can effectively control bleeding in a shorter treatment time compared to the TCCC guidance of at least 3 minutes of compression after wrapping with a hemostatic bandage, in both normal and coagulation disorder states. Advantageously, this results in the subject being stabilized in a shorter time before being transported to the medical area. "Treatment" means the time taken to wrap and seal the wound or incision with the hemostatic composition, including compression of the bleeding site.

[0022] This invention can effectively control bleeding with treatment lasting approximately 45 seconds, compared to at least 3 minutes as indicated in the TCCC guidance.

[0023] The hemostatic agent may be any substance having hemostatic properties. The hemostatic agent may contain a polymer containing one or more glucosamine units. Examples of hemostatic agents, but are not limited to, include oxidized regenerated cellulose, kaolin, gelatin, calcium ions, zeolite, collagen, chitin, chitosan or chitosan salts, derivatives of chitosan, derivatives of chitin, and any combination thereof. Glucosamine is, of course, part of the structure of chitosan and chitin. The hemostatic agent is preferably a chitosan salt.

[0024] The term “derivative” is used herein to mean a compound derived from chitosan or chitin after one or more chemical reactions or modifications. The one or more chemical reactions or modifications may include one or more substitutions of amino or hydroxyl protons in chitosan or chitin, or partial deacetylation of chitin. For example, a chitin derivative may include partially deacetylated chitin, which may have different deacetylation rates as desired. Typically, the partially deacetylated chitin suitable for use in the present invention has a degree of deacetylation of more than about 50%, more typically more than about 75%, and most typically more than about 85%. Reaction products of chitosan or chitin with other compounds are also included in the term “chitosan or chitin derivative.” Examples of such reaction products, though not limited to them, include carboxymethyl chitosan, hydroxylbutyl chitin, N-acyl chitosan, O-acyl chitosan, N-alkyl chitosan, O-alkyl chitosan, N-alkylidene chitosan, O-sulfonyl chitosan, sulfated chitosan, phosphorylated chitosan, nitrated chitosan, alkali chitin, alkali chitosan, or metal chelates with chitosan.

[0025] Chitosan is a derivative of solid waste from the processing of shells and crustaceans and can be extracted from fungal cultures. It is a water-insoluble polymer material. Therefore, chitosan for use in the present invention is first converted into a water-soluble salt. The chitosan salt is soluble in blood and forms a gel that stops blood flow.

[0026] Chitosan salts are ideally suitable for the uses described herein because chitosan is easily decomposed in the body. Chitosan is converted to glucosamine by the enzyme lysozyme and is thus naturally excreted from the body. No treatment is required to remove the chitosan from the body.

[0027] Furthermore, chitosan salts exhibit mild antibacterial properties, and therefore the risk of infection is reduced by their use.

[0028] Exemplary chitosan salts suitable for use in the present invention include, but are not limited to, acetate, lactate, succinate, malate, sulfate, or acrylate, either alone or in combination. These are typically in powder form.

[0029] Good results were obtained when the chitosan salt contained chitosan lactate or was chitosan lactate.

[0030] The chitosan salt is prepared by combining chitosan with a suitable acid. It is understood that the acid may be any inorganic or organic acid that results in a chitosan salt that is soluble under the conditions attendant to the human or animal body, particularly in blood. Suitable acids will be recognized by those skilled in the art. For example, phosphoric acid is not suitable because chitosan phosphate is insoluble under such conditions.

[0031] The hemostatic agent may comprise at least 20% by weight, or more typically at least about 80% by weight, of the hemostatic material. Typically, the hemostatic agent comprises 20 - 99% by weight of the hemostatic material, preferably 45 - 95% by weight of the hemostatic material.

[0032] The hemostatic agent is typically in granular form, but may include short fibers, sponges, cloths, films, powders, liquids, gels, or liquid coatings. The short fibers may be about 7.5 mm or less in length, more typically about 5 mm or less.

[0033] The hemostatic agent typically has a pH of about 3.5 to about 8.0. The pH depends primarily on the specific hemostatic agent used, because each hemostatic agent has a different pH.

[0034] "Bioadhesive" means a natural or synthetic biocompatible substance that binds to a biological substrate. The biological substrate may be, for example, moist tissue at a wound site. In practice, a bioadhesive can facilitate adhesion between two substances, one of which is of biological nature, thereby allowing the substances to be held together for an extended period of time. The bioadhesive typically exhibits low adhesion to dry surfaces, such as gloves or intact skin, and high adhesion to wet / moist surfaces, such as wounds or internal organs. Therefore, the hemostatic material, comprising the bioadhesive and the hemostatic agent, should preferably exhibit low adhesion to dry surfaces and high adhesion to wet / moist surfaces. Preferably, the hemostatic material does not adhere to dry surfaces. Beneficially, this property of the bioadhesive provides a hemostatic material that is easy to handle and can effectively control bleeding within a shorter compression time compared to the TCCC guidance of at least 3 minutes of compression.

[0035] The bioadhesive should preferably be compatible with the hemostatic agent and should not interfere with the effect of the hemostatic agent. The bioadhesive is typically a solid, dry material.

[0036] "Low adhesion" means adhesion to a surface with a peel strength of 0.05 N per 25 mm of material (expressed as 0.05 N / 25 mm) or less. No adhesion is actually measured as 0.0 N / 25 mm.

[0037] "High adhesion" means adhesion to a surface with a peel strength of 0.25 N / 25 mm or higher. Preferably, the adhesion to a wet / humid surface exhibits a peel strength of 0.7 N / 25 mm or higher, more preferably 1.0 N / 25 mm or higher. Typically, the adhesion to a wet / humid surface exhibits a peel strength in the range of 0.6 to 2.0 N / 25 mm.

[0038] Therefore, the bioadhesive can promote the adhesion of the hemostatic agent to the moist tissue at the wound site. Beneficially, this can shorten the compression time required for coagulation, without the hemostatic agent being pushed out of the wound site by blood pressure.

[0039] The bioadhesive may constitute up to 90% by weight of the hemostatic material. Preferably, the bioadhesive may constitute up to 20% by weight of the hemostatic material, more preferably 2 to 20% by weight of the hemostatic material, even more preferably 5 to 10% by weight of the hemostatic material, and most preferably 7 to 8% by weight of the hemostatic material. Within these preferred ranges, the bioadhesive is optimized for adhesion to wet or moist tissue without causing adverse effects such as wound reopening upon removal.

[0040] The bioadhesive should be a material that generates high adhesion when applied to a wet substrate / moist substrate. The bioadhesive may be selected, alone or in combination, from carbomer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 2-acrylamido-2-methylpropanesulfonic acid, or a high molecular weight acrylic acid polymer or a salt of polyacrylic acid crosslinked with divinyl glycol. Preferably, the bioadhesive contains a high molecular weight crosslinked polymer of acrylic acid. "High molecular weight" means a molecular weight of at least 50,000 g / mol. Preferably, the molecular weight is at least 60,000 g / mol, more preferably 100,000 to 300,000 g / mol. In such embodiments, the bioadhesive is a homopolymer containing a polymer of acrylic acid crosslinked with allyl pentaerythritol; acrylic acid and C crosslinked with allyl pentaerythritol. 10 ~C 30 Copolymers containing alkyl acrylate polymers; copolymers containing carbomer homopolymers or block copolymers of polyethylene glycol and long-chain alkyl acid esters; or mixtures thereof. Examples of such polymers include Carbopol® NF934, NF974, NF971, and NF980.

[0041] The bioadhesive provides the composition of the present invention, which has excellent wet adhesion properties. "Wet adhesion" means adhesion to wet or moist tissue. This allows the bioadhesive to promote adhesion between the hemostatic agent and the moist tissue at the wound site.

[0042] In some embodiments, the hemostatic agent and the bioadhesive are typically present in a ratio of at least 3:1. Typically, the hemostatic agent and the bioadhesive are present in a ratio of at least 4:1, more preferably at least 9:1.

[0043] "Antifibrinolytic agents" refer to natural or synthetic substances that inhibit fibrinolysis. Fibrinolysis is the process that prevents the growth of blood clots. This process has two types: primary fibrinolysis and secondary fibrinolysis. Primary fibrinolysis is a normal bodily process, while secondary fibrinolysis is the breakdown of blood clots due to medicine, medical disorders, or some other cause. Therefore, antifibrinolytic agents prevent the breakdown of blood clots, and the blood clots should be stronger and last longer than if the antifibrinolytic agent were not present.

[0044] The antifibrinolytic solvent may be chemically bound, salt-formed, or associated with the hemostatic agent, or it may be independent of the hemostatic agent and the bioadhesive.

[0045] The antifibrinolytic agent may include plasminogen activator inhibitors, such as serine protease inhibitors. An unspecified example of such a serine protease inhibitor is plasminogen activator inhibitor-1 (PAI-1), also known as endothelial plasminogen activator inhibitor, serpin E1, or aprotinin. PAI-1 is a serine protease inhibitor that functions as the primary inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), which are activators of plasminogen and therefore fibrinolysis. Aprotinin is a competitive inhibitor of several serine proteases, specifically trypsin, chymotrypsin, and plasmin at a concentration of approximately 125,000 IU / ml, and kallikrein at a concentration of approximately 300,000 IU / ml. Its action on kallikrein leads to inhibition of factor XIIa formation. As a result, both the intrinsic pathways of coagulation and fibrinolysis are inhibited. Its effect on plasmin independently delays fibrin dissolution.

[0046] Alternatively, the antifibrinolytic solvent may contain a glycoprotein such as fibrinogen, or tranexamic acid.

[0047] Alternatively, the antifibrinolytic solvent may contain C2-C12 aminocarboxylic acids, C4-C8 aminocarboxylic acids, or C5-C7 aminocarboxylic acids, such as C6 aminocarboxylic acids, for example, aminocaproic acid or epsilon-aminocaproic acid.

[0048] Alternatively, the antifibrinolytic solvent may contain an aminobenzoic acid such as aminomethylbenzoic acid.

[0049] One or more of these antifibrinolytic solvents or their derivatives may be used individually or in combination.

[0050] In this specification, the term "derivative" in relation to the antifibrinolytic solvent is used to mean any compound that can be directly derived from or derived from any of the compounds listed above and that also exhibits antifibrinolytic behavior.

[0051] The antifibrinolytic solvent is typically present in an amount of about 0.01 to about 99.9% by weight of the hemostatic composition, more typically about 0.1 to about 90% by weight, more typically about 1 to about 80% by weight, more typically about 2 to about 70% by weight, more typically about 5 to about 60% by weight, more typically about 10 to about 50% by weight, more typically about 12 to about 40% by weight, more typically about 15 to about 35% by weight, more typically about 20 to about 30% by weight, more typically about 22 to about 28% by weight, and so on.

[0052] The hemostatic agent may further contain an inert material. "Inert" means a material that does not have hemostatic properties or has low hemostatic properties and low adhesion to wet or damp surfaces, that is, a material that, when used alone, does not exhibit any significant hemostasis for a period of time of approximately 3 minutes, 5 minutes, or even 10 minutes after application to the bleeding site.

[0053] Examples of inert materials include, but are not limited to, non-hemostatic cellulose, non-hemostatic sand, non-hemostatic clay, non-hemostatic alginate, microcrystalline cellulose, guar gum, xanthan gum, non-hemostatic chitosan, non-hemostatic chitin, dextran, sucrose, lactose, pectin, carboxymethylcellulose, hydroethylcellulose, ground corn flour, polyacrylic acid, barium sulfate, starch, or any two or more of these. Typically, one or more inert materials selected from non-hemostatic chitosan, non-hemostatic chitin, and carboxymethylcellulose are used.

[0054] The inert material may be added to the hemostatic agent in an amount of up to about 95% by weight of the total composition, typically up to about 80% by weight, and more typically up to about 50% by weight. The inert material is typically blended with the hemostatic agent, but may also be dispersed in a solution together with the hemostatic agent and dried.

[0055] Typically, the inert material is in the form of granules, but may also be in the form of powder, foam, fibers, or film.

[0056] The hemostatic agent may further contain a medical surfactant. “Medical surfactant” means any surfactant that is pharmaceutically acceptable for contact with or administration to the human or animal body and does not cause any significant adverse effects to the human or animal body. Exemplary medical surfactants for use in the present invention include, alone or in combination, any ethylene oxide and propylene oxide-based block copolymers (e.g., BASF Pluronics®), glycerol, polyethylene glycol, propylene glycol, lauric acid, oleic acid, fatty acids and fatty acid salts such as other fatty acids, silicone surfactants, and emulsifiers. Typically, the medical surfactant includes lauric acid and oleic acid.

[0057] The medical surfactant may typically constitute about 0.001 to about 10% by weight of the hemostatic agent.

[0058] More advantageously, the medical surfactant constitutes about 0.5 to about 1% by weight of the hemostatic agent. Advantageously, the presence of the surfactant results in very good wetting properties. The way the hemostatic agent weats is important to its performance. That is, the hemostatic agent may absorb the blood too quickly, merely mixing with the blood without causing sufficient gelation to form a gel clot capable of stopping blood flow. On the other hand, if the hemostatic agent absorbs the blood too slowly, gelation may only occur in a small amount of the hemostatic agent, generally only in the first few millimeters of thickness of the hemostatic agent closest to the wound site. In this case, the formed gel clot is not dense enough to stop the blood flow for a sufficient amount of time to allow the patient to be moved to a medical center. Typically, such a gel clot will break down during the patient's transfer, leading to re-bleeding.

[0059] It has been found that the performance of the hemostatic agent is actually further improved by adding a certain amount of an inert material and / or a certain amount of a medical surfactant to the hemostatic agent, that is, by effectively diluting the amount of the hemostatic agent. The combination of the inert material and the medical surfactant is particularly advantageous because the presence of the inert material further improves the properties of the medical surfactant, and vice versa.

[0060] The particle size of the hemostatic agent may affect the performance of the hemostatic material of the present invention. The particle size is measured by the size of the sieve through which the particles passed or were held.

[0061] For example, if the hemostatic agent is in the form of particles or granules, it may have an average particle size greater than about 200 mesh so as not to pass through a 200 mesh sieve. The average particle size may typically be greater than about 100 mesh, and more typically greater than about 50 mesh, and it is not desirable for the particles or granules to be able to pass through a 40 mesh sieve.

[0062] More advantageously, the particle size of the inert material is substantially equivalent to the particle size of the hemostatic agent. "Substantially equivalent" means that the relative size difference of the particles does not exceed about 25%, more typically about 10%. The optimal particle size is achieved by grinding the hemostatic agent and classifying it by any suitable means, such as sieving. Such a process for achieving size uniformity is known to those skilled in the art and will not be described further.

[0063] The hemostatic composition may be administered to the wound in any specific form, such as a dry powder, solution, foam, or gel.

[0064] The hemostatic composition may be applied to a carrier material for application to a wound site. The carrier material may include a woven material or a viscose nonwoven material, or, as an alternative, it may include a thin flexible substrate, woven gauze, film, foam, solution, or sheet gel. The composition of the present invention may also be in a freeze-dried format.

[0065] The composition may or may not be biodegradable under conditions associated with wounds on or within the body of a human or animal. In one example, the material of the carrier material may be safely biodegradable in the body over a reasonable period, such as about 30 days, so that the entire hemostatic piece can remain in the correct position after surgical use or treatment. Examples of safe and biodegradable materials for use in the composition include, but are not limited to, oxidized cellulose, gelatin, dextran, collagen, polycaprylactone, polylactic acid, polylactide-co-glycolide, polyglycolide, and chitin.

[0066] The hemostatic agent may be applied to the carrier material by various methods. These include bonding the hemostatic agent to the carrier material using an adhesive; applying a solution containing the hemostatic agent to the carrier material, coating the carrier material, and drying the solution; or heat bonding. The hemostatic agent may also be incorporated into the carrier material during the processing of the carrier material.

[0067] The composition may take any suitable form and may be supplied in various different sizes, shapes, and thicknesses necessary for treating wounds, such as square, rectangular, circular, or oval shapes. For example, the material may be in a generally flat shape with little height relative to its width / depth. Any regular or irregular shape may be used. It may be supplied in a large sheet that can be cut to the required size.

[0068] The hemostatic composition may be provided in sterile or non-sterile form. If the material is provided in sterile form, sterilization may be carried out using any conventionally known method, such as gamma irradiation, electron beam treatment, heat treatment, or ethylene oxide (EtO) sterilization. The material in non-sterile form may be provided in combination with one or more preservatives or antimicrobial agents, such as silver and its salts.

[0069] If the hemostatic composition is sterilized using ethylene oxide, this may include exposing the intermediate device to gaseous ethylene oxide. The sterilization phase may be carried out in a chamber that is preferably sealed.

[0070] A further aspect of the present invention provides a method for hemostasis, which includes the steps of: applying a hemostatic composition comprising a hemostatic agent, a bioadhesive, and an antifibrinolytic solvent or a derivative thereof to a physiological target site; and applying pressure to the hemostatic material for a period of time less than about 1 minute, or less than about 55 seconds, or less than about 50 seconds, or less than about 45 seconds.

[0071] A further aspect of the present invention provides a hemostatic composition comprising a hemostatic agent, a bioadhesive, and an antifibrinolytic solvent or derivative thereof, for use in stopping blood flow from a physiological target site.

[0072] The pressure may be applied to the target site for a period of about 30 seconds to 1 minute. In some embodiments, the pressure may be applied to the wound site for about 35 seconds to 55 seconds, or about 40 seconds to 50 seconds, or about 45 seconds. An advantage of the present invention is that it takes a short time to sufficiently coagulate the blood flow from the wound site. Therefore, sufficient coagulation is formed within about 1 minute, and thus the pressure applied to the target site may be for a shorter period of time to obtain the desired effect. In some embodiments, the pressure may be applied to the wound site for less than about 55 seconds, preferably less than about 50 seconds, to obtain the desired effect.

[0073] A further aspect of the present invention provides a carrier material to which a hemostatic composition comprising a hemostatic agent, a bioadhesive, and an antifibrinolytic solvent or a derivative thereof is applied.

[0074] The carrier material may contain any of the characteristics of the carrier material described above. Preferably, the carrier material includes viscose gauze.

[0075] A further aspect of the present invention provides a method for producing a hemostatic composition comprising a hemostatic agent, a bioadhesive, and an antifibrinolytic solvent or a derivative thereof, the method comprising the step of combining the hemostatic agent with the bioadhesive and the antifibrinolytic solvent or a derivative thereof.

[0076] Preferably, the method for producing the hemostatic material includes: (1) distributing a predetermined weight of a hemostatic agent and optionally an inert material into a mixing container; (2) distributing a predetermined weight of a bioadhesive into the mixing container containing the hemostatic agent and optionally an inert material; (3) distributing a predetermined weight of an antifibrinolytic solvent or a derivative thereof; and (4) mixing the hemostatic agent, the bioadhesive, and the antifibrinolytic solvent or a derivative thereof.

[0077] The present invention will be further described below with reference to the following examples, which are merely illustrative and do not limit the scope of the invention. [Examples]

[0078] A 7% by weight bioadhesive (high molecular weight crosslinked polymer of acrylic acid (Carbopol® 980NF)) was blended with a chitosan derivative / non-hemostatic chitosan blend. The chitosan derivative consisted of chitosan lactate and chitosan tranexamate, and the chitosan was prepared as a salt using a combination of chitosan, lactic acid, and tranexamic acid. The mixture was double-coated onto viscose gauze with a coating weight of 45 gsm. This obtained a hemostatic composition according to the present invention.

[0079] in vivo To confirm that the present invention exhibits practical advantages in terms of compression time and provides evidence of its effectiveness over a total wrapping and compression time of 45 seconds, the composition of Example 1 was tested in a pig model using a 6 mm femoral artery transection model, such as an ISR model, under both normal and coagulation disorder conditions.

[0080] For a normal state, a 6 mm severed section was surgically created in the femoral artery of a pig model. The artery was allowed to bleed for 45 seconds, and then the hemostatic agent was applied to the bleeding site for a total of 45 seconds of wrapping and compression. After the compression time, the wound was evaluated for bleeding. If bleeding recurred, the hemostatic agent was applied with pressure for an additional minute. Any rebleeding after this point was classified as a failure.

[0081] In cases of coagulation disorders, 25% of the pig's blood volume was replaced with Hextend solution (25% hemodilution) to induce hypothermia (core body temperature 34-35°C) in the pig before arterial injury and bleeding. A 6 mm incision was surgically made in the femoral artery of the pig model. The hemostatic composition was applied to the bleeding site using a total time of bleeding for 45 seconds, followed by wrapping and compressing for 45 seconds. After the compression time, the wound was evaluated for bleeding. If bleeding recurred, the hemostatic material was compressed for an additional minute. Any rebleeding after this point was classified as a failure.

[0082] The results showed that 66% of the models treated under normal and coagulation-impaired conditions achieved hemostasis within the initial 45 seconds using the femoral artery model protocol. After a further minute of pressure, 82% of the models treated under normal conditions achieved hemostasis using the femoral artery model protocol, while 83% of the models treated under coagulation-impaired conditions achieved hemostasis using the femoral artery model protocol.

[0083] Under normal conditions, currently available Celox Rapid hemostatic products require a care protocol of 1 minute of continuous compression followed by another minute of compression (if necessary) to achieve hemostasis. However, in coagulation disorders, recent ISR results indicate that Celox Rapid requires 2 minutes of continuous compression to achieve hemostasis.

[0084] In contrast, the compositions of the present invention can achieve hemostasis in almost all cases, i.e., in both normal and impaired coagulation conditions, in as little as 45 seconds in 66% of cases, and in 82% of cases under normal conditions and 83% under impaired coagulation conditions after an additional minute of pressure. This represents a significant improvement, particularly in the art where the time required to stop bleeding from a wound is critically important and can be a matter of life and death for the patient.

[0085] Naturally, it should be understood that the present invention is not intended to be limited to the examples described above.

Claims

1. A hemostatic composition comprising a hemostatic agent, a bioadhesive, and an antifibrinolytic solvent or its derivative.

2. The composition according to claim 1, wherein the antifibrinolytic solvent comprises one or more selected from tranexamic acid, aminocaproic acid, aminomethylbenzoic acid, aprotinin, epsilon-aminocaproic acid, and fibrinogen.

3. The composition according to claim 1 or claim 2, wherein the hemostatic agent comprises one or more selected from oxidized regenerated cellulose, kaolin, gelatin, calcium ions, zeolite, collagen, chitosan, or chitosan salts.

4. The composition according to claim 3, wherein the hemostatic agent comprises a chitosan salt.

5. The composition according to claim 4, wherein the chitosan salt comprises one or more selected from chitosan acetate, chitosan lactate, chitosan succinate, chitosan malate, chitosan sulfate, or chitosan acrylate.

6. The composition according to claim 5, wherein the chitosan salt comprises a lactate and / or chitosan succinate.

7. The composition according to any one of claims 1 to 6, wherein the bioadhesive comprises one or more selected from carbomer, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 2-acrylamido-2-methylpropanesulfonic acid, or a high molecular weight acrylic acid polymer or a salt of polyacrylic acid crosslinked with divinyl glycol.

8. The composition according to claim 7, wherein the bioadhesive comprises a crosslinked polymer of acrylic acid, and the polymer has a molecular weight of at least about 50,000 g / mol.

9. The bio-adhesive comprises a homopolymer containing a polymer of acrylic acid crosslinked with allyl pentaerythritol; acrylic acid and C crosslinked with allyl pentaerythritol. １０ ~C ３０ The composition according to claim 8, comprising one or more copolymers selected from alkyl acrylate polymers and / or carbomer homopolymers or copolymers comprising polyethylene glycol and long-chain alkyl acid ester block copolymers.

10. The composition according to any one of claims 1 to 9, wherein the composition is applied to a carrier material.

11. The composition according to claim 10, wherein the carrier material is selected from woven fabrics, nonwoven fabrics, flexible substrates, films, foams, or sheet gels.

12. A hemostatic composition according to any one of claims 1 to 10, for use in stopping blood flow from a physiological target site.

13. A method for producing a hemostatic composition according to any one of claims 1 to 11, wherein the method comprises the step of combining a hemostatic agent with a bioadhesive and an antifibrinolytic solvent or a derivative thereof.

14. The method according to claim 13, comprising: (1) distributing a predetermined weight of a hemostatic agent and optionally an inert material into a mixing container; (2) distributing a predetermined weight of a bioadhesive into the mixing container containing the hemostatic agent and optionally an inert material; (3) distributing a predetermined weight of an antifibrinolytic solvent or a derivative thereof; and (4) mixing the hemostatic agent, the bioadhesive, and the antifibrinolytic solvent or a derivative thereof.

15. A method for stopping bleeding, comprising the steps of: applying a hemostatic composition according to any one of claims 1 to 11 to a physiological target site; and applying pressure to the hemostatic material.

16. The method according to claim 15, wherein the pressure is applied for a period of time of approximately one minute or less.

17. A carrier material comprising the hemostatic composition described in any one of claims 1 to 11.