Hemostatic composite aggregate material having a surface reinforced with a hemostatic promoter

Abstract

The present invention relates to a hemostatic absorbent composition comprising a plurality of flowable, discrete aggregates, each aggregate comprising a plurality of absorbent carrier particles coated on its surface by a plurality of smaller particles comprising an absorbable auxiliary hemostatic promoting agent. In some embodiments, the absorbent carrier particles comprise gelatin or collagen, and the auxiliary hemostatic promoting agent comprises oxidized cellulose, oxidized regenerated cellulose, carboxyl-oxidized cellulose, carboxyl-oxidized regenerated cellulose, thrombin, or tranexamic acid.

Description

Technical Field

[0001] The present invention relates to a hemostatic absorbent composition comprising a plurality of separate, flowable aggregates, each aggregate comprising a plurality of absorbent carrier particles whose surface is coated with a plurality of smaller particles containing an absorbent auxiliary hemostatic promoter. In some embodiments, the absorbent carrier particles comprise gelatin or collagen and the auxiliary hemostatic promoter comprises oxidized cellulose, oxidized regenerated cellulose, thrombin, or tranexamic acid.

Background Art

[0002] In a wide variety of situations, animals, including humans, may be subjected to bleeding due to trauma or during surgical procedures. Depending on the situation, the bleeding may be relatively minor and normal blood clotting, combined with the implementation of simple first aid measures, may be sufficient. In other situations, significant bleeding may occur. In these situations, specialized equipment and supplies, as well as personnel trained to provide appropriate assistance, are usually required. Bleeding during surgical procedures can manifest in many forms. The bleeding can be discrete or spread from a large surface area. The bleeding can be from large or small blood vessels, arteries (high pressure) or veins (low pressure), of high or low volume. The bleeding may be easily accessible or may originate from a site that is difficult to access. Control of bleeding is essential and important in surgical procedures to minimize blood loss, reduce postoperative complications, and shorten the time of surgery in the operating room.

[0003] Conventional methods for achieving hemostasis include surgical techniques, sutures, ligatures or clips, and the use of energy-based coagulation or cauterization. When these conventional measures are ineffective or impractical, auxiliary hemostatic techniques and products are typically used. The selection of an appropriate method or product for controlling bleeding depends on many factors, including, but not limited to, the severity of the bleeding, the anatomical location of the bleeding source and its proximity to adjacent critical structures, whether the bleeding is from a discrete source or from a larger surface area, the visibility and accurate identification of the bleeding source, and access to the bleeding source.

[0004] To address the aforementioned problems, substances have been developed to control excessive bleeding. Topical absorbable hemostats (TAHs) are widely used in surgical applications. TAHs encompass products based on various forms of gelatin, collagen, chitin, chitosan, etc., with or without thrombin solution, including oxidized cellulose (OC), oxidized regenerated cellulose (ORC), and thrombin solution. To improve hemostatic ability, scaffolds based on the above substances can be combined with biological coagulation factors such as thrombin and fibrinogen.

[0005] One of the most commonly used topical hemostatic agents is SURGICEL® Original absorbable hemostatic agent, made from oxidized regenerated cellulose (ORC). ORC was introduced in 1960 as a safe and effective hemostatic agent for many surgical procedures. ORC fabrics have a loosely woven matrix structure, allowing them to quickly and snugly conform to their adjacent periphery, not adhere to surgical instruments, and be easily sized, making them easier to manage than other absorbents. This allows surgeons to firmly hold the cellulose in place until all bleeding has stopped.

[0006] Due to their biodegradability, bactericidal properties, and hemostatic characteristics, oxidized cellulose and oxidized regenerated cellulose have long been used as local hemostatic wound dressings in various surgical procedures, including neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, and skin and subcutaneous tissue treatment. Numerous methods are known for forming various types of hemostatic materials based on oxidized cellulose, whether in powder, woven, nonwoven, knitted, or other forms. Hemostatic wound dressings currently in use include knitted or nonwoven fabrics or powders containing oxidized regenerated cellulose (ORC), which is oxidized cellulose with increased homogeneity of cellulose fibers.

[0007] SURGICEL® absorbable hemostatic agents are used adjunctly in surgical procedures to assist in controlling capillary, venous, and arterial bleeding when ligation or other conventional control methods are impractical or ineffective. The SURGICEL family of absorbable hemostatic agents consists of four main product groups, all of which are commercially available from Ethicon, Inc. (Somerville, NJ) and Johnson & Johnson Company.

[0008] SURGICEL Original hemostatic material is a white fabric material similar to a pale yellow plaster cast bandage. This material is strong and can be sutured or cut without fraying.

[0009] SURGICEL NU-KNIT® absorbable hemostatic material is similar to the Original but has a denser knit, resulting in higher tensile strength. This material can be wrapped or sutured in place to control bleeding, making it particularly recommended for use in trauma and transplant surgery.

[0010] SURGICEL FIBRILLAR™ absorbable hemostatic material has a layered structure that allows surgeons to peel and grasp any amount of material needed with forceps to achieve hemostasis at the bleeding site, which can be more convenient than a knitted form for bleeding sites that are difficult to reach or have an irregular shape, and is particularly recommended for use in orthopedic / spinal and neurosurgical procedures.

[0011] SURGICEL SNoW® absorbable hemostatic material is a structured nonwoven fabric that is highly adaptable and may be more convenient than other forms for endoscopic applications, and is recommended for both incision and minimally invasive procedures.

[0012] SURGICEL Powder Absorbable Hemostat is a powdered auxiliary hemostatic agent made from aggregates of ORC fiber fragments.

[0013] Protein-based hemostatic materials such as collagen and gelatin are commercially available for use in surgical procedures in the form of solid sponges, fibrils, and loose or uncoated powders. Mixing loose or uncoated powders with fluids such as saline or thrombin can form pastes or slurries that are useful as hemostatic compositions, depending on the mixing state and relative ratio of the materials, particularly for use in cases of diffusive bleeding from uneven surfaces or hard-to-reach areas.

[0014] Gelatin-based hemostatic agents are commercially available in both solid sponge and powder forms and are used in surgical procedures. When mixed with a fluid, gelatin powder can form a paste or slurry that is fluid, extrudeable, and injectable as a hemostatic agent, particularly useful for diffusive bleeding from uneven surfaces or hard-to-reach areas. Conventional slurries are prepared at the time of use by mechanical stirring and mixing of the powder and liquid to impart uniformity to the composition.

[0015] Hemostatic fluid pastes (such as gelatin particles mixed with or dispersed in water or an aqueous solution) are often homogeneously mixed with additional or auxiliary hemostatic agents (such as thrombin) that, upon contact with plasma before administration to the wound, activate, initiate, promote, or otherwise enhance the effectiveness of the hemostatic cascade. These additional hemostatic agents are consequently primarily contained within the paste bulk and are not exposed to the bleeding wound surface in the earliest possible time. Therefore, these additional hemostatic agents within the paste bulk cannot immediately contribute to the biological process of hemostasis at the bleeding surface and may potentially add unnecessary costs and needs for absorbing agents that were not available for timely hemostasis.

[0016] The SURGIFLO® Hemostatic Matrix Kit, available from Ethicon, Inc. (Somerville, NJ), contains a SURGIFLO hemostatic gelatin matrix containing thrombin, providing a matrix for platelet adhesion, promoting platelet plug formation, and assisting fibrin clot formation. It contains EVITHROM® thrombin, a lyophilized powder form for topical (human) use and reconstitution in solution, which can be combined with an absorbable hemostatic gelatin to form a flowable matrix or absorbable gelatin paste intended for hemostatic applications by application to bleeding surfaces. The gelatin paste is supplied in a pre-filled syringe and homogeneously mixed with 2 ml of additional liquid (sterile saline solution or thrombin).

[0017] U.S. Patent Application Publication No. 2019 / 0134258, "Hemostatic Paste Having Surface Enriched With Hemostasis-Promoting Agents and Devices For Delivery," discloses a hemostatic semi-solid paste material comprising a) a bioabsorbable carrier hemostatic material and b) an auxiliary hemostatic agent, wherein the paste material has an elongated form extending along the longitudinal axis with an aspect ratio of at least 3, the paste material is self-supporting and syringe extrudeable, and the auxiliary hemostatic agent has a heterogeneous distribution profile across a cross section obtained transversely to the longitudinal axis.

[0018] U.S. Patent No. 10,034,957, "Compacted Hemostatic Cellulosic Aggregates," discloses a method for producing multiple hemostatic aggregates, comprising: a) grinding a cellulose source material to form fibers; b) humidifying the fibers to a water content of 11.0% to 20% by weight; c) roller compressing the fibers to form hemostatic aggregates; d) sieving the hemostatic aggregates; e) dehumidifying the hemostatic aggregates to a water content of less than 5.5% determined by loss on drying; and f) optionally placing the obtained hemostatic aggregates into a storage container or delivery device.

[0019] U.S. Patent No. 9,539,358, "Oxidized Regenerated Cellulose Hemostatic Powders And Methods Of Making," discloses a hemostatic material comprising roller-compressed ORC powder containing particles having an average aspect ratio of approximately 1 to approximately 18, a particle size greater than 180 microns, and a tap density of at least 0.44 g / mL.

[0020] European Patent No. 1952828(B1) "Hemostatic Textile Material" discloses a hemostatic textile material for stopping bleeding, comprising a dialdehyde cellulose (DAC) carrier having an oxidation degree of dialdehyde cellulose ranging from 1.5% to 12%, a blood coagulation factor selected from chitosan and gelatin, wherein the blood coagulation factor is chemically immobilized thereon, and optionally further comprising a lytic agent selected from lysozyme enzyme, silver nitrate, and chlorhexidine, and optionally further comprising a selected component for preventing hemolysis, which is chemically immobilized thereon, and is selected from tranexamic acid and ε-aminocaproic acid, wherein the aldehyde groups are spread evenly and uniformly on and within the carrier to allow only 85-90% covalent bonding with the amino groups of the blood coagulation factor.

[0021] U.S. Patent No. 6,797,260, "Bleeding Control And Healing Aid Compositions And Methods Of Use," discloses a method for producing an improved hemostatic composition, comprising the steps of: preparing a slurry containing (a) a hemostatic agent selected from the group consisting of ferric sulfate, ferric subsulfate, and mixtures thereof; (b) aluminum chloride; (c) aluminum ammonium sulfate; and (d) regenerated oxidized cellulose; preparing a substantially dry composition by dehydrating the slurry; and preparing a paste composition by adding a sufficient amount of solvent to the dry composition to reconstitute it to a paste-like viscosity.

[0022] U.S. Patent Application Publication 2012 / 0302640, "Oral Formulations," discloses topical oral formulations in gel form comprising 1 to about 70% by weight of tranexamic acid, an antimicrobial agent, and having a viscosity of about 100 to about 15,000 cP, further disclosing compositions in which the gel is a polysaccharide gel, cellulose gel, methylcellulose gel, hydrogel, agarose, or gelatin, or any combination of two or more thereof.

[0023] European Patent No. 1786480(B1) "Haemostatic Composition Comprising Hyaluronic Acid" discloses a hemostatic composition comprising gelatin and hyaluronic acid or a derivative thereof, wherein the hyaluronic acid or derivative thereof is incorporated into the composition up to a final content of at least 10% (w / w) hyaluronic acid, the composition does not contain chemical crosslinking agents or their residues, and the composition is obtained by dry heat treatment of a mixture of gelatin, hyaluronic acid or a derivative thereof and a solvent at a temperature of 110 to 200°C.

[0024] The published PCT patent application WO2015 / 013106A1, "Bone Paste Compositions And Methods Of Using The Same," discloses a thrombus-forming bone paste composition comprising: a) a matrix material; b) a plurality of nanoparticles, each nanoparticle containing at least one antibiotic, at least one growth factor, or a combination of at least one antibiotic and at least one growth factor; and c) at least one hemostatic agent.

[0025] U.S. Patent Application Publication No. 2015 / 0017225, "Hemostatic Pad Assembly Kit And Method," discloses a hemostatic wound treatment device comprising a bioabsorbable scaffold having a wound-side surface and an opposite surface, which is moistened with a biocompatible liquid that is neither blood nor plasma, and a hemostatic powder that adheres to at least the wound-side surface of the bioabsorbable scaffold due to the moisture.

[0026] U.S. Patent No. 8,961,544, "Dry Composition Wound Dressings And Adhesives Comprising Gelatin And Transglutaminase In A Cross-Linked Matrix," relates to patches containing a dry gelatin composition.

[0027] Chinese Patent Publication No. CN105148317A, "Hemostatic Implant", relates to a hemostatic implant, and is characterized in that the gelatin sponge is a gelatin sponge impregnated with tranexamic acid.

[0028] Chinese Patent Publication No. CN105727345A, "Absorbable Hemostasis Film Material And Preparation Method Thereof", discloses an absorbable hemostasis film material, the main components of which include starch, carboxymethyl cellulose and gelatin, and the weight ratio of starch, carboxymethyl cellulose and gelatin is (1-4):(1-2):(1-3).

[0029] Czech Patent Publication No. CZ201400005A3, "Composition For Preparing Modified Gelatin Nanofilaments, Nanofilaments And Process Of Their Preparation", discloses a composition for preparing modified gelatin nanofibers, which includes gelatin, oxidized cellulose having an alkali metal and / or a salt of oxidized cellulose with an alkaline earth metal or ammonium, and a solvent containing formic acid and / or acetic acid, and the weight ratio of the salt of oxidized cellulose or oxidized cellulose to gelatin is 0.1-2.

Summary of the Invention

Problems to be Solved by the Invention

[0030] Specific hemostatic materials such as gelatin, oxidized cellulose and starch in particulate form are known, but simply mixing these particles results in separation of the mixture due to their different physicochemical properties and no improvement in hemostatic properties. There is a need for a hemostatic material in particulate form for delivery and uniform coating of the wound site, and such a material should have high hemostatic efficacy, adhesiveness, delivery ability, and action speed.

Means for Solving the Problems

[0031] The present invention relates to a hemostatic and absorbable composition comprising a plurality of flowable, distinct aggregates, each aggregate comprising a plurality of absorbable carrier particles whose surface is coated with a plurality of smaller particles containing an absorbable auxiliary hemostatic agent. In some embodiments, the absorbable carrier particles comprise gelatin or collagen, and the auxiliary hemostatic agent comprises oxidized cellulose, oxidized regenerated cellulose, thrombin, or tranexamic acid. In some embodiments, the auxiliary hemostatic agent is exclusively or primarily present on the outer surface of the carrier particles or in the outer layer of the carrier particles, and the internal portion of the carrier particles substantially does not contain the auxiliary hemostatic agent.

[0032] In some embodiments, the auxiliary hemostatic agent comprises oxidized regenerated cellulose, and the absorbent carrier particles comprise gelatin, with an ORC:gelatin mass ratio greater than 10:1, greater than 17:1, or 17:1 to 30:1.

[0033] In some embodiments, the present invention relates to a method for preparing a hemostatic absorbent composition, comprising the steps of: hydrating absorbent carrier particles; mixing the hydrated absorbent carrier particles with smaller particles containing an absorbent auxiliary hemostatic agent; forming a mixture of the absorbent carrier particles and the smaller particles containing the absorbent auxiliary hemostatic agent adhering to them; drying the mixture; and sieving the mixture.

[0034] In some embodiments, the present invention relates to a method for treating a wound, comprising the step of applying a hemostatic and absorbable composition described herein to and / or into a patient's wound. [Brief explanation of the drawing]

[0035] [Figure 1] This is a schematic cross-sectional view of the components of the present invention. [Figure 2] This is a schematic cross-sectional view of one embodiment of the present invention. [Figure 3] This is a schematic cross-sectional view of one embodiment of the present invention. [Figure 4] This is a schematic cross-sectional view of one embodiment of the present invention. [Figure 5] This is a diagram showing gelatin particles. [Figure 6] This is a diagram showing ORC microfibers. [Figure 7] This figure shows gelatin particles coated with ORC microfibers. [Figure 8] This figure shows gelatin particles coated with ORC microfibers. [Figure 9] This figure shows gelatin particles coated with ORC microfibers. [Figure 10] This figure shows the particle size distribution and the number of particles versus particle size in microns for ORC. [Figure 11] This figure shows the particle size distribution and the number of particles versus particle size in microns for gelatin particles and gelatin coated with ORC microfiber aggregates. [Figure 12] This figure shows the comparative results of in vitro coagulation tests. [Figure 13] This figure shows the comparative results of in vitro coagulation tests. [Modes for carrying out the invention]

[0036] According to embodiments of the present invention, the hemostatic absorbable composition powder or aggregate material comprises solid microparticles containing a core, scaffold, or carrier particle made of a first hemostatic agent, the surface of which is reinforced or coated with a second or auxiliary hemostatic promoter. The auxiliary agent is exposed on the surface of the microparticles of the present invention and exists mainly as an outer coating or layer of the core particle, preferably spreading outwards from the core particle. The auxiliary agent is exclusively or primarily located on the outer surface of the core particle or within the outer layer of the core particle. A portion of the auxiliary agent can be embedded on the surface of the core particle.

[0037] Referring to Figure 1, a schematic representation of the components used to produce the hemostatic absorbable powder or aggregate material of the present invention is shown in a schematic cross-sectional view, along with a relatively large carrier particle 10, and a relatively small auxiliary particle 20 and 30 in the form of elongated particles 20 having an aspect ratio (length:width or diameter ratio) greater than 1, for example, 2, 3, 5, or more, or an auxiliary hemostatic promoter in the form of particles 30 having an aspect ratio of about 1 to 2. The carrier particle 10 preferably has an aspect ratio of about 1 to 5, more preferably 1 to 3. The carrier particle is a discrete solid particle in the form of a powder.

[0038] The carrier or core particle 10 is preferably larger than the auxiliary hemostatic agent particles 20 and 30, for example, by at least 2, 3, 5, 10, 15, 20, 50, 100, or even 1000 times larger in maximum dimensions, diameter, volume, or weight. In some embodiments, the carrier or core particle 10 has a maximum dimension of 150, 200, 300, 500, 1000, or 2000 microns, while the auxiliary particles 20 and 30 have a maximum dimension of 3, 5, 10, 20, 30, 50, 75, or 100 microns. In some embodiments, the larger core particle 10 has a maximum dimension of 500, 1000, 2000, or 3000 microns, while the auxiliary particles 20 and 30 have a maximum dimension of 150, 200, or 300 microns.

[0039] Referring to Figure 2, a schematic representation of one embodiment of the hemostatic absorbable powder or aggregate material 50 of the present invention is shown in a schematic cross-sectional view, in which the carrier particle 10 has elongated auxiliary hemostatic promoting particles 22, 24 on its surface, which are either partially embedded in the carrier particle 10 as shown by elongated auxiliary hemostatic promoting particles 22, 24, or attached to the surface of the carrier particle 10 as shown by elongated auxiliary hemostatic promoting particles 24.

[0040] Referring to Figure 3, a schematic representation of another embodiment of the hemostatic absorbable powder or aggregate material 60 of the present invention is shown in a schematic cross-sectional view, in which carrier particles 10 have particles 30 on their surface that are partially embedded in the carrier particles 10 or attached to the surface of the carrier particles 10.

[0041] Referring to Figure 4, a schematic representation of yet another embodiment of the hemostatic absorbable powder or aggregate material 70 of the present invention is shown in a schematic cross-sectional view, in which carrier particles 10 have a non-particulate coating 40 on their surface containing an auxiliary hemostatic promoter.

[0042] Advantageously, on average, a larger portion of the auxiliary hemostatic promoter in the form of particles 22, 24, 30 or coating 40 is exposed on the surface compared to a smaller portion of particles 22, 24, 30 or coating 40 embedded within or within the core or carrier particle 10. The auxiliary hemostatic promoter particles 22, 24, 30 and coating 40 are primarily present on the surface of the hemostatic absorbent powder or aggregate material 50, 60, 70, and therefore the auxiliary hemostatic promoter is more readily available at the wound site for hemostasis compared to a system in which the auxiliary hemostatic promoter is homogeneously mixed with the carrier or core particle material and dispersed within the carrier or core particle material. Advantageously, the amount of auxiliary hemostatic promoter required in embodiments of the present invention is less than in a system in which the auxiliary hemostatic promoter is homogeneously mixed with the carrier or core particle material and distributed within the carrier or core particle material, due to the readily available surface access of the auxiliary hemostatic promoter for interaction with blood and tissue at the wound site.

[0043] The hemostatic performance of the hemostatic absorbable powder or aggregate material of the present invention is expected to be better than that of a simple mechanical mixture of carrier particles 10 and auxiliary hemostatic promoters 20, 30, or separate carrier particles 10 and auxiliary hemostatic promoter particles 20, 30, or auxiliary hemostatic promoters homogeneously mixed with a carrier or core particle material and dispersed within the carrier or core particle material. The auxiliary hemostatic promoter is not only more biologically available when present on the core particles 10, but its biomechanics, availability, retention on tissue, and adhesion to tissue and wound surfaces to interact with tissue and blood are improved when very small particles 20, 30 with a very large surface area are supported on larger carrier particles. Conversely, while small particles 20, 30 have excellent surface area and reactivity, they are difficult to deliver to wounds because they exist alone (i.e., not supported on the carrier 10). Furthermore, such particles often cannot remain on the wound long enough to perform hemostasis and are easily dislodged by blood flow or any other mechanical interference, which is undesirable.

[0044] Advantageously, the hemostatic absorbable powder or aggregate material of the present invention, which contains a given amount Qc of carrier particles 10 and a given amount Qh of hemostatic promoter particles 20, 30, wherein the hemostatic promoter is disposed on or within the surface layer 54, is assumed to have better hemostatic performance than comparative test samples containing the same given amounts Qc and Qh of each carrier particle and hemostatic promoter, as follows. a. A comparative test sample in which the hemostatic agent is homogeneously mixed into the material of the carrier particle 10, or b. A comparative test sample in which a hemostatic agent is simply mixed with carrier particles 10.

[0045] Furthermore, for the present invention test specimen which includes carrier particles 10 in a given amount Qc and hemostatic promoting particles 20, 30 in a given amount Qh, and the hemostatic promoting agent is disposed on or within the surface layer 54, it is assumed that the hemostatic performance is equivalent to or better than that of comparative test specimens which include a larger amount of hemostatic promoting agent, for example 1.25Qh, 1.5Qh, 2Qh, 3Qh, 5Qh, and so on. Thereafter, such a hemostatic promoting agent is as follows. a. Homogeneously mixed into the material of the carrier particles 10, or b. Simply mixed with the carrier particles 10.

[0046] Advantageously, according to the present invention, the hemostatic performance is improved when the same amount Qh of hemostatic agent is placed on or within the surface layer 54 compared to the same amount Qh of hemostatic accelerator homogeneously mixed with or with the carrier particles. Furthermore, the same hemostatic performance can be achieved with a smaller amount Qh of hemostatic agent placed on or within the surface layer 54 compared to 1.25 Qh or more of hemostatic accelerator homogeneously mixed with or with the carrier particles.

[0047] According to the present invention, the presence of a hemostatic accelerator placed on or within the surface layer 54 results in faster access of the hemostatic agent to the bleeding site and / or tissue in the first few seconds or minutes when hemostasis is required. Conversely, comparative hemostatic accelerators embedded deep within the carrier particles are consequently less able to influence hemostasis during the crucial first few seconds or minutes when hemostasis is required.

[0048] In one example, the carrier particles 10 are represented by gelatin particles, and the auxiliary hemostatic agent particles 20 are represented by oxidized regenerated cellulose (ORC) powder. Thereafter, the hemostatic composite aggregate material 50 of the present invention exhibits better hemostatic performance compared to a simple mechanical mixture of gelatin carrier particles 10 and ORC-based auxiliary hemostatic agent particles 20, or separate gelatin carrier particles 10 and ORC-based auxiliary hemostatic agent particles 20, or an ORC-based auxiliary hemostatic agent homogeneously mixed with gelatin-based carrier or core particles 10 and distributed therein.

[0049] Advantageously, the core particle 10 and the auxiliary particles 22, 24, 30, or coating 40 are physically or physiologically bonded and integrated together. The carrier particle 10 is reinforced only on its surface by relatively small auxiliary hemostatic promoter particles or coating exposed on the surface of the carrier particle 10.

[0050] Materials: Core particles In one embodiment, the carrier or core hemostatic particle 10 comprises gelatin, collagen, or a combination thereof. Figure 5 shows a typical gelatin particle.

[0051] Many sources of gelatin and gelatin powder are available, including the WVR catalog. Gelatin available from Ethicon, Inc. (Somerville, NJ) as SURGIFLO Hemostatic Matrix contains sterile, absorbable, cross-linked gelatin intended for hemostatic use by application to bleeding surfaces.

[0052] Gelatin or collagen particles can be obtained by many techniques known to those skilled in the art. In one embodiment, gelatin can be obtained by grinding SURGIFOAM® Absorbable Gelatin Sponge, available from Ethicon, Inc. (Somerville, NJ). Another source of gelatin core particles may be SURGIFOAM Absorbable Gelatin Powder Kit, available from Ethicon, Inc. (Somerville, NJ).

[0053] In some embodiments, gelatin particles can be obtained by grinding any medical-grade gelatin to an appropriate size.

[0054] Materials: Auxiliary hemostatic agent The auxiliary hemostatic agents 20, 22, 24, 30, and 40 include any hemostatic and / or coagulation-promoting and / or platelet aggregation-promoting active drug materials, such as enzymes, proteins, peptides, molecules, natural materials, modified natural materials such as oxidized cellulose (OC) or oxidized regenerated cellulose (ORC), solvent extracts, or particles or particle aggregates, and combinations thereof.

[0055] U.S. Patent No. 9,539,358 by Yi-Lan Wang and Guanghui Zhang, “Oxidized Regenerated Cellulose Hemostatic Powders And Methods Of Making,” which is incorporated herein by reference in its entirety, discloses various ORC coarse and fine fibrous particles that can be used as auxiliary hemostatic agents in the practice of the present invention.

[0056] Incorporated herein by reference, U.S. Patent Nos. 9,717,820 and 9,149,511, "Procoagulant Peptides And Their Derivatives And Uses Therefor" by Yi-Lan Wang and Guanghui Zhang, disclose hemostatic peptides that can be used as auxiliary hemostatic agents in the practice of the present invention.

[0057] U.S. Patent No. 9,028,851, "Hemostatic Materials And Devices With Galvanic Particulates" by Yi-Lan Wang et al., incorporated herein by reference, discloses hemostatically active galvanic microparticles that can be used as auxiliary hemostatic agents when carrying out the present invention.

[0058] In preferred embodiments, auxiliary hemostatic agents include: (A) oxidized cellulose particles, (B) oxidized regenerated cellulose particles, (C) hemostatic enzymes such as thrombin or thrombin equivalents, optionally mixed with excipients, (D) platelet aggregation peptides, (E) hemostatic solvent extracts of natural materials, (F) tranexamic acid, and (G) combinations or analogues with optionally selected excipients such as gelatin, polyethylene glycol, and carboxymethylcellulose (CMC).

[0059] ORC crude and fine fibers can be obtained as follows; refer to U.S. Patent No. 9,539,358, Oxidized Regenerated Cellulose Hemostatic Powder and Method for Production, which is incorporated herein by reference in its entirety for all purposes.

[0060] One method for directly obtaining ORC crude and fine fibers from cellulose materials such as ORC fabrics or nonwoven fabrics is as follows:

[0061] Simply put, the manufacturing process begins with an ORC material, such as SURGICEL Original absorbent hemostatic material, which is cut into 1-2 inch wide sections. The material is then fed to a blade that cuts the fabric into smaller pieces. The cut ORC fabric pieces are then ground into intermediate ORC fine fibers through two consecutive grinding processes (hammer grinding and air classification grinding). In an alternative embodiment, the cut ORC fabric pieces are directly converted into intermediate fine fibers in a ball mill.

[0062] More specifically, one process for producing ORC fine fibers includes a) a step of cutting a cellulose raw material into elongated strips, b) a step of grinding the material obtained from step a), and c) a second grinding step in an air classifier.

[0063] Shredding can preferably be carried out to cut the fabric into strips of appropriate size between approximately 1 inch x 3 inches or 2 inches x 3 inches, although smaller strips can also be used. The main operations performed for shredding are to unwind the roll of fabric, cut the fabric into strips, cut the strips to size, and feed the cut pieces to the first grinding process. Many cutting and shredding machines are known and commercially available, such as the AZCO Model FTW-1000 available from AZCO. In the first grinding process, the processed cellulosic fabric is converted from the intermediate crude fibers produced in the shredding process to materials with a D90 value of less than 452 μm and a D50 value of less than 218 μm, while minimizing the impact on the color index and water solubility content of the material. Many grinding machines are commercially available, such as the Model DASO6 and WJ-RS-D6A manufactured by Fitzpatrick, which are hammer mill type grinders equipped with a 497-micrometer round screen and a pair of blades that crush the fabric until the fabric passes through the screen to produce intermediate crude cellulose fibers.

[0064] In an example of processing operation, the mill speed may be approximately 7000 RPM, the processing temperature less than 80°C, the screen size may be 1534 to 9004, the number of blades may be 8 (2 impellers each), the blade type may be 225 knives, the blade may be impact type, and the blade orientation may be set to "impact".

[0065] In this preferred stage of the process, the size of the intermediate coarse fibers generated in the first grinding step is further reduced to a D90 value of less than 177 μm and a D50 value of less than 95 μm, while minimizing the impact on the color index and water solubility content of the material. Many machines, such as the Quadro Air Classifier / F10 Quadro Fine Grind, can be used for the second grinding step.

[0066] The intermediate coarse fibers from the first grinding process are fed into the second mill at a controlled speed and can pass through two grinding chambers separated by a grinding screen. The material can be drawn out of the grinding chambers by a blower. The intermediate coarse fibers can be processed by passing them through an air classifier three times to obtain the desired size. At the end of the second grinding process, the intermediate fine fibers can be collected.

[0067] In an exemplary processing run, a Quadro Air Classifier F10 may be used in the second grinding step with a grinding speed of 8400 rpm, a blower speed of 1800 rpm, a 0.0018-inch round-hole screen, and three passes. ORC intermediate fine fibers can also be produced in a single step by ball grinding instead of the two-step grinding process described above. In an alternative ball grinding embodiment, 50 g of pre-cut ORC fabric (2 inches x 2 inches) is ball-ground using 12 high-density zirconia (zirconium dioxide ZrO2, 20 mm in diameter, Glen Mills Inc. (Clifton, NJ, USA)) by placing the balls and sample in a 500 mL grinding jar. This jar can then be crimped into a latch bracket and balanced on a planetary ball mill PM100 (Retsch, Inc. (Newtown, Pa, USA)). Grinding is then performed bidirectionally at 450 rpm for 20 minutes.

[0068] Typical ORC particles usable in carrying out the present invention are preferably ORC fine fiber particles having an aspect ratio or length-to-diameter ratio of about 2 to about 100, for example 3 to 50, for example 10, and a particle size of about 10 to about 300 microns, for example 20 to 200 microns.

[0069] Referring now to Figure 6, ORC microfibers useful for carrying out the present invention are shown.

[0070] Embodiments of the present invention having an ORC-coated gelatin core In one embodiment, the carrier or core hemostatic particle 10 contains gelatin, and the auxiliary hemostatic agents 20, 22, and 24 contain elongated ORC fine particles.

[0071] The aspect ratio or length-to-diameter ratio of ORC microfiber particles is preferably about 2 to about 100, for example, 3 to 50. Preferably, on average, the smaller portions of the ORC particles are embedded in the gelatin, while on average, the larger portions of the ORC particles are exposed. ORC present on the surface is more readily available at the wound site for hemostasis. The amount of ORC required is relatively small, since only the ORC on the surface of the gelatin particles is active for immediate reaction with the tissue and blood on the wound. Smaller amounts of ORC should have the same or better hemostatic effect when the ORC is present on the surface compared to a larger amount of ORC when it is homogeneously mixed into the gelatin particles. The hemostatic performance of the particles of the present invention is better than that of a simple mixture of gelatin and ORC powder, and also better than that of individual ORC powders and individual gelatin powders. The auxiliary hemostatic agent in particle form on the surface of the core particle 10 is expected to have better and faster reactivity compared to a homogeneous coating on the surface of the core particle 10, due to the larger surface area of ​​the auxiliary hemostatic agent available for interaction with blood.

[0072] The following describes several methods for producing the hemostatic composite aggregate material of the present invention. In a preferred embodiment, the core particles 10 comprise gelatin or collagen, and the auxiliary hemostatic agent comprises ORC particles, thrombin, tranexamic acid, or a combination thereof.

[0073] Preparation Method: Example 1A. Hydrated Gelatin Particles + ORC. In one embodiment, gelatin particles are first hydrated by exposure to a small amount of water or saline solution, absorbing some water. Then, ORC fine particles are mixed in, the components are thoroughly mixed, and then dried. Any selected gentle shreds of any clusters formed, if any, can then be provided.

[0074] Preparation method: Example 1B. Gelatin particles + ORC in the presence of a rapidly evaporable solvent. Instead of water, a solvent such as ethanol can be used as shown in Example 1A (gelatin does not dissolve in 100% ethanol). In this embodiment, ethanol is used instead of water, or as an ethanol-water mixture.

[0075] Preparation Method: Example 1C. Ball milling of gelatin particles and ORC. Gelatin particles and ORC fine particles are mixed in a ball mill and ground together in a controlled high-humidity atmosphere, then dried. Instead of a humid atmosphere, a small amount of water or ethanol (anhydrous or containing 1-10% water) may be added.

[0076] Preparation method: Example 1D. ORC fabric + gelatin coating and pulverization. In this embodiment, an ORC nonwoven fabric or fabric material is coated with gelatin, the coating is completely dried, and then the fabric or nonwoven fabric is pulverized or shredded to obtain gelatin / ORC particles having ORC partially exposed on the surface.

[0077] Preparation Method: Example 1E. Gelatin + Tranexamic Acid. Tranexamic acid (TA) is soluble in water (167 mg / mL) and sparingly soluble in ethanol (<1 mg / mL). Gelatin particles are mixed with a small amount of water or an ethanol / water mixture containing tranexamic acid, and then dried to form a TA coating on the surface.

[0078] Preparation Method: Example 1F. Gelatin + Tranexamic Acid. Gelatin particles are hydrated by exposure to a small amount of water or ethanol / water and absorb some water. Then the TA powder is mixed in, the ingredients are thoroughly mixed, and then dried. Optional - if any, gently shred any clusters formed.

[0079] Preparation Method: Example 1G. Gelatin + Tranexamic Acid. Gelatin particles and TA powder are mixed in a ball mill, ground together in a controlled high-humidity atmosphere, and then dried. Instead of a humid atmosphere, a small amount of water or ethanol (anhydrous or aqueous) can be added.

[0080] Referring now to Figures 7 and 8, gelatin particles coated with ORC microfibers containing the hemostatic and absorbable composite powder or aggregate material of the present invention are shown, prepared by the method of Example 1a.

[0081] Example 2. Preparation, characterization, and testing of hemostatic and absorbable composite aggregate powder material for in vitro testing. The reagents were mixed. The reagent-grade gelatin powder was 9764-500G obtained from VWR. The preparation steps included: Weighing approximately 0.1 g of gelatin; adding 500 μL of purified water and mixing thoroughly to ensure all gelatin was hydrated; then adding 1 g of ORC fine fibers and mixing by shaking in a sealed container to ensure the fibers were uniformly dispersed and all gelatin particles were coated. In this example, the initial ratio of gelatin to water to ORC fibers was 1:0.5:10 by weight for the initial mixing (for preparation), and the time elapsed for the mixing process was approximately 30 seconds. Excess ORC fibers were then removed by sieving (see below). Larger ORC-gelatin particles were also homogenized into smaller particles and then further coated during a multi-layer sieving process. To ensure that all particles were properly coated, they were examined under a microscope, and the coating ratio was observed (see below for expected characterization).

[0082] Drying. Excess moisture was removed from the ORC-coated gelatin particles using a heating oven: Isotemp (Fisher Scientific, Model: 2001FS). The heating oven was preheated to 60°C and the well-mixed reagents were placed inside. Before the next step, the mass of the sample on the balance used was checked periodically until the sample mass stabilized.

[0083] Sieving. Using sieves (106 μm, 180 μm, 300 μm) from WSTyler Company (8570 Tyler Boulevard, Mentor, Ohio), a homogeneous size distribution of the composite aggregate powder material of the present invention was obtained. The three sieves were placed on top of each other in order of decreasing size (300 μm on top, 106 μm on the bottom). A sample of the composite aggregate powder material from the drying process was placed on the top sieve along with zirconium balls. The zirconium balls were used to gently crush the ORC-gelatin particle clusters into smaller, homogeneous pieces. The upper sieve layer was shaken until no large particles remained. The composite aggregate powder material containing ORC-coated gelatin particles (approximately 180-300 μm in size) on the 180 μm layer was then used to evaluate its hemostatic properties, as shown below.

[0084] Characterization. The coating ratio of ORC fibers per gelatin particle was evaluated using optical studies under a microscope. Microscope: A ZEISS SteREO Discovery V20 (Carl Zeiss Microscopy, LLC (One North Broadway, White Plains, NY)) was used to evaluate the mass ratio of components in ORC-coated gelatin particles. ORC-coated gelatin aggregates (diameter 180-300 μm) used in this example were analyzed under a microscope and found to contain an average of 29 ORC microfibers per gelatin particle. An example of the particles is shown in Figure 9.

[0085] Using 0.2 g of gelatin and 2 g of ORC, gelatin-to-ORC mixtures in the same weight ratio as the 1:10 mixture described above were prepared in a dry form. To compare the initial bulk mass of the powder with the final coating ratio, this was repeated with water to form ORC-coated gelatin particles, which were then dried to remove excess moisture before testing.

[0086] Next, the number of particles in each bulk mass of ORC and gelatin powder was counted using a particle size and shape analyzer.

[0087] Particle number and particle size distribution. The number of ORC microfibers and gelatin particles was determined for a given mass (2 g and 0.2 g of bulk powder, respectively). The mass ratio was found to be 0.289 g:1 g for ORC:gelatin in the average ORC-coated gelatin aggregate. The data was obtained using a Particle Size and Shape Analyzer QICPIC Sympatec (Sympatec GmbH, Am Pulverhaus 1, 38678 Clausthal-Zellerfeld, Germany), which was used to count the particles and determine the mass ratio of particles within the aggregate. Referring to Figures 10 and 11, the particle size distribution and particle number are plotted against particle size in microns for ORC (Figure 10), gelatin, and gelatin coated with ORC microfibers forming the aggregate of the present invention (Figure 11). These figures provide details of the general characterization of the aggregate of the present invention for the individual components that may play a role in the hemostatic efficacy of the material.

[0088] Coagulation test. Human citrated blood (obtained from Lampire Biological Laboratories (Pipersville, PA, USA), donor sex: male, blood was aseptically collected from a normal, healthy, drug-free donor showing no signs of coagulation disorders) was stored at 2-8°C before use in the in vitro coagulation test performed as follows.

[0089] Remove the citrated blood from storage, warm it, and gently shake it using an orbital shaker or rotator (Belly Button Orbital Platform Shaker, (Stovall BBUAAUV1S or IBI Scientific® BBUAAUV1S, Fisher Scientific, Thermo Fisher Scientific Inc. 81 Wyman Street, Waltham, MA)) to thoroughly mix the citrated blood at room temperature for 60 minutes prior to the test, or until the blood color is uniform.

[0090] An in vitro coagulation test was performed on a control sample (without the addition of hemostatic material) as follows: An empty vial was weighed using a calibrated balance. 300 μL of citrated blood was added to the vial. A 3-minute wait was allowed for clot formation. The vial filled with blood was weighed, and the vial was inverted for 1 minute to drain any uncoagulated blood. After the first inversion, the bottom of the vial was firmly tapped 5 times. The vial containing the remaining coagulated blood was weighed again, and the mass percentage held between the first and last measurements was calculated and subtracted from the mass of the vial. The coagulation efficiency was then characterized using the percentage of blood held in the vial after inversion (higher percentages correspond to better coagulation).

[0091] In vitro coagulation test samples (containing added hemostatic material) were prepared as follows: An empty vial was weighed using a calibrated balance. A suitable 0.02 g sample was prepared using a calibrated balance. 300 μL of citrated blood was added to the vial. Then, the test sample was added to each vial using a microfunnel.

[0092] Three minutes were allowed to form a blood clot. The vial filled with blood and the test sample were weighed, and the vial was inverted for one minute to drain any uncoagulated blood. After the first inversion, the bottom of the vial was tapped firmly five times to remove excess material and reduce false coagulation due to adhesion between the blood and the vial wall. The vial containing the remaining coagulated blood was weighed again, and the mass percentage held between the first and last measurements was calculated and subtracted from the mass of the vial. The coagulation efficiency was then characterized using the percentage of blood held in the vial after inversion (higher percentages correspond to better coagulation). The process was repeated for each test sample, and the mass percentage of blood held (i.e., coagulated) was recorded. One sample from each test group, including the control, was tested simultaneously for coagulation effectiveness to minimize variability in the experimental setup. At least four trials were performed to reduce variability within each experimental trial.

[0093] Each trial of the study was also performed on four samples of citrated blood, with different combinations of ORC and gelatin added to each sample. These samples were used to compare the in vitro coagulation efficacy of ORC-coated gelatin to other test products under similar conditions. These four samples were also compared to a control group consisting of four samples of citrated human blood without any test products added. At least four trials were performed to minimize experimental variability.

[0094] For all samples except the control group, each test substance was administered in 20 mg / 300 μL of blood. This ratio was selected to be clinically relevant and to adequately capture coagulation performance.

[0095] To reduce variability, one sample from each test group and control was used in each trial.

[0096] Referring to Figure 12, the results of the in vitro coagulation test are shown. The maximum mass retained, showing most coagulation within a given time, was observed with the ORC / gelatin aggregate of the present invention. The individual materials tested, ORC, gelatin, and physical mixtures of ORC and gelatin that do not form the composite ORC / gelatin aggregate of the present invention, showed lower retained masses compared to the composite ORC / gelatin aggregate of the present invention, and therefore lower hemostatic or coagulation performance. The lowest mass retained was observed, as expected, with blood (control) without any hemostatic material added. The results show a significant synergistic effect in accelerating coagulation for the composite ORC / gelatin aggregate of the present invention.

[0097] Example 3. Evaluation of electromechanical solidification properties In vitro coagulation / gelation performance was determined by electromechanical blood clot detection (viscosity-based detection system), and coagulation / gelation times were measured for various weights of test materials using recalcified citrate-treated human blood. This in vitro coagulation / gelation performance was evaluated using a Diagnostica Stago ST4 coagulation analyzer (Diagnostica Stago Inc. (5 Century Drive, Parsippany, NJ) or Diagnostica Stago SAS (3 allee Theresa, CS 10009, 92665 Asnieres sur Seine Cedex, France)).

[0098] Except for the control group (blood sample with no hemostatic material added), the test material was applied at a ratio of 5 mg / 200 μL. The ratio of the test material to blood was evaluated before performing this in vitro coagulation test.

[0099] Human citrate-treated blood was removed from storage, warmed, and gently shaken at room temperature for 60 minutes using an orbital rotator before testing. The citrate-treated blood was purchased from Lampire Biological Laboratories (Pipersville, PA, USA). Blood was aseptically collected from normal, healthy, drug-free male donors showing no signs of clotting disorders.

[0100] Calibration was performed using a benchtop coagulator before the test, following the Neoplastine CI PLUS STA manual. PT times for abnormal controls ranged from 33 to 48 seconds, while normal PT times ranged from 11.5 to 15.5 seconds.

[0101] A 0.02M CaCl2 saline stock solution was prepared [1.33 μL of 1M standard CaCl2 (Fluka Analytical) solution in 65.33 μL of saline (washed with 0.9% sodium chloride, USP, Baxter Healthcare Corporation)]. 66.67 μL of the 0.02M CaCl2 saline stock solution was added to each cuvette containing one iron ball, and the cuvettes were placed in the incubation area to preheat at 37°C for at least 60 seconds. Then, 133.33 μL of citrated human blood was added to the cuvettes, followed immediately by the addition of pre-weighed test material to each cuvette via a microfunnel (QOSMEDIX 20038, 0.78 inches × 0.83 inches), and the test was started by pressing the start button. No test material was added to the control group's blood. Coagulation time was recorded for each application.

[0102] Referring here to Figure 13, the test results are shown. As shown, the results indicate that the composite ORC / gelatin aggregates of the present invention exhibit faster in vitro coagulation / gelation times, overall faster than 50 seconds for ORC / gelatin aggregates with mass ratios of 17:1 and 30:1, and faster than 25 seconds for ORC / gelatin with a mass ratio of 30:1. The coagulation / gelation of these aggregates is much faster than that observed for comparative mixtures of ORC and gelatin (not aggregates) with the same amounts and ratios of material, which show times exceeding 100 seconds or 150 seconds, respectively. Similarly, pure ORC and pure gelatin showed slower coagulation / gelation times exceeding 100 seconds or 150 seconds, respectively. The control (without added hemostatic material) showed the longest coagulation time exceeding 300 seconds, as expected. Notably, the 8:1 ORC / gelatin aggregates showed no improvement over the same amount and material ratio, i.e., the comparative mixture (not aggregates) of 8:1 ORC and gelatin, and the time to solidification was approximately 150 seconds for both the aggregate form and the comparative mixture. The experimental data demonstrate significant synergistic effects and improvements in hemostatic efficacy for the composite ORC / gelatin aggregates of the present invention, particularly for aggregates with ratios greater than 8:1, e.g., greater than 10:1, or greater than e.g., greater than 15:1, e.g., 18:1, 30:1 and above.

[0103] Having described the present invention with reference to specific embodiments thereof, it is evident that many changes, modifications, and variations are possible without departing from the concept of the present invention disclosed herein. Accordingly, this shall encompass all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0104] [Implementation Method] (1) A hemostatic and absorbable composition, A hemostatic and absorbent composition comprising a plurality of separate, flowable aggregates, each aggregate being an absorbent carrier particle having a first size dimension, wherein the surface of the absorbent carrier particle is coated with a plurality of hemostatic-promoting particles having a size dimension smaller than the first size dimension. (2) The hemostatic and absorbent composition according to Embodiment 1, wherein the auxiliary hemostatic promoting agent is exclusively or primarily present on the outer surface of the carrier particles or in the outer layer of the carrier particles. (3) The hemostatic and absorbable composition according to Embodiment 1, wherein the internal portion of the carrier particles is substantially free of the auxiliary hemostatic promoter. (4) The hemostatic and absorbent composition according to Embodiment 1, wherein the separate aggregates have an average size of 100 to 500 μm (100 to 500 microns). (5) The hemostatic absorbent composition according to Embodiment 1, wherein the absorbent carrier particles include gelatin or collagen.

[0105] (6) The hemostatic absorbent composition according to Embodiment 1, wherein the absorbent carrier particles include thermally crosslinked gelatin. (7) The hemostatic and absorbable composition according to Embodiment 1, wherein the auxiliary hemostatic promoting agent comprises carboxylated cellulose, carboxylated regenerated cellulose, thrombin, or tranexamic acid. (8) The hemostatic and absorbent composition according to Embodiment 1, wherein the auxiliary hemostatic promoting agent comprises oxidized regenerated cellulose in the form of fine, elongated particles having an aspect ratio of at least 3 on average. (9) The hemostatic absorbent composition according to Embodiment 1, wherein the absorbent carrier particles include particles having an aspect ratio of less than 3 on average. (10) The hemostatic and absorbable composition according to Embodiment 1, wherein the auxiliary hemostatic promoting agent comprises oxidized regenerated cellulose, and the absorbable carrier particles comprise gelatin, with an ORC:gelatin mass ratio greater than 10:1.

[0106] (11) The hemostatic and absorbable composition according to Embodiment 10, wherein the mass ratio of ORC to gelatin is greater than 17:1. (12) The hemostatic and absorbable composition according to Embodiment 11, wherein the mass ratio of ORC to gelatin is approximately 17:1 to 30:1. (13) A method for preparing the hemostatic and absorbable composition described in Embodiment 1, a) A step of hydrating the absorbent carrier particles, b) A step of mixing the hydrated absorbent carrier particles with smaller particles containing the absorbent auxiliary hemostatic agent, c) A step of forming a mixture of the absorbent carrier particles and the smaller particles containing the absorbent auxiliary hemostatic agent attached thereto, d) A step of drying the mixture, and optionally e) A method comprising the step of sieving the mixture. (14) The method according to Embodiment 13, wherein the mixing step includes shaking the mixture in a container or grinding the mixture in a ball mill. (15) A method for treating a wound, comprising applying a hemostatic and absorbable composition described in any of Embodiments 1 to 12 to the wound or into the wound.

Claims

1. A hemostatic and absorbable composition, The material comprises a plurality of separate, flowable aggregates, each aggregate being an absorbent carrier particle having a first size dimension, wherein the surface of the absorbent carrier particle is coated with a plurality of hemostatic-promoting particles having a size dimension smaller than the first size dimension. A hemostatic and absorbent composition in which the hemostatic promoting particles contain oxidized regenerated cellulose, and the absorbent carrier particles contain gelatin, wherein the mass ratio of oxidized regenerated cellulose to gelatin is greater than 10:

1.

2. The hemostatic absorbent composition according to claim 1, wherein the hemostatic promoting particles are exclusively or primarily present on the outer surface of the absorbent carrier particles or in the outer layer of the absorbent carrier particles.

3. The hemostatic and absorbent composition according to claim 1, wherein the internal portion of the absorbent carrier particles substantially does not contain the hemostatic promoting particles.

4. The hemostatic and absorbent composition according to claim 1, wherein the separate aggregates have an average size of 100 to 500 μm (100 to 500 microns).

5. The hemostatic absorbent composition according to claim 1, wherein the absorbent carrier particles include thermally crosslinked gelatin.

6. The hemostatic and absorbent composition according to claim 1, wherein the hemostatic promoting particles include oxidized regenerated cellulose in the form of fine, elongated particles having an aspect ratio of at least 3 on average.

7. The hemostatic absorbent composition according to claim 1, wherein the absorbent carrier particles include particles having an aspect ratio of less than 3 on average.

8. The hemostatic and absorbable composition according to claim 1, wherein the mass ratio of oxidized regenerated cellulose to gelatin is 17:1 to 30:

1.

9. A method for preparing the hemostatic and absorbable composition described in claim 1, a) A step of hydrating the absorbent carrier particles, b) A step of mixing the hydrated absorbent carrier particles with the smaller particles containing the hemostatic-promoting particles, c) A step of forming a mixture of the absorbable carrier particles and the smaller particles including the hemostatic promoting particles attached to the absorbable carrier particles, d) A step of drying the mixture, and optionally e) A method comprising the step of sieving the mixture.

10. The method according to claim 9, wherein the mixing step includes shaking the mixture in a container or grinding the mixture in a ball mill.

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