Hemostatic composition, method for preparing a hemostatic composition, container, e, kit

Description

57 Hemostatic composition, method for preparing a hemostatic composition, container, and kit. Technical field

[001] The present description refers to hemostatic compositions comprising a biocompatible polymer, thrombin and fibrinogen and methods for the preparation of such compositions. Fundamentals

[002] Protein-based hemostatic materials such as gelatin are commercially available in the form of a solid sponge and loose or unpackaged powder for use in surgical procedures. Mixing the loose or unpackaged powder with a fluid such as saline solution or a thrombin solution can form a paste or fluid paste that is useful as a hemostatic composition for use in cases of diffuse bleeding, particularly from irregular surfaces or hard-to-reach areas, depending on the mixing conditions and relative ratios of the materials.

[003] Hemostatic pastes are usually prepared at the point of use by mechanical agitation and mixing of particulate, cross-linked gelatin with a liquid, for example, a thrombin solution, to provide uniformity of composition. Mixing to form a paste usually requires extensive mixing, such as mixing or transferring between two syringes.

[004] Surgiflo® Haemostatic Matrix (Ethicon) is a commercially available kit for producing a hemostatic gelatin paste comprising thrombin, which is prepared by transferring a mixture of gelatin matrix-thrombin solution back and forth between two connected syringes. Floseal® Haemostatic Matrix (Baxter) is also a kit for producing a hemostatic gelatin paste. Once a substantially homogeneous paste composition is obtained, the hemostatic pastes can be applied to a hemorrhage to promote hemostasis by extrusion of the Petition 870260065366, dated 02 / 07 / 2026, page 10 / 66 / 57 folders from the syringe.

[005] Thrombin is a well-known hemostatic adjuvant in hemostatic compositions, acting as a serine protease that converts soluble fibrinogen into insoluble fibrin filaments, as well as catalyzing many other coagulation-related reactions. The combination of thrombin and fibrinogen is also used in certain hemostatic products currently in clinical use, such as sponges, plasters, glues, and sealants containing thrombin and fibrinogen. However, since thrombin acts on fibrinogen in the presence of water, thrombin and fibrinogen are provided separately or together in dry form to prevent premature action of thrombin on fibrinogen. For application, the thrombin and fibrinogen components can be applied to the patient in dry form or mixed with an aqueous medium at the time of application.

[006] Although currently available hemostatic products are effective in controlling mild and moderate bleeding, it would be beneficial to have hemostatic compositions that are able to control such bleeding even faster and more efficiently, thus making them useful in controlling more severe bleeding. It would be even more beneficial to have hemostatic products that are effective in controlling bleeding in minimally invasive surgical procedures where sponges, plasters, glues, and sealants are impractical or ineffective. Summary

[007] The present description provides compositions with improved hemostatic properties and methods for preparing such hemostatic compositions. The improved hemostatic properties are due to an optimized combination of components that lead to improved adhesive properties. Such compositions are highly valuable in the operating room, where bleeding must be controlled in a fast and efficient manner. Petition 870260065366, dated 02 / 07 / 2026, page 11 / 66 / 57

[008] Surprisingly, the present inventors have shown that the hemostatic paste compositions described herein comprising a biocompatible polymer, thrombin and fibrinogen remain fluid after reconstitution for more than 1.5 hours. Consequently, the paste compositions of the present description can be prepared ahead of time and used for an extended period of time, which is highly advantageous in the operating room and in early surgical procedures.

[009] Thus, in one aspect, the present description provides a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 to 150 mg per gram of biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of biocompatible polymer.

[0010] In a second aspect, the present description refers to a method for preparing a hemostatic composition comprising the steps of: a) provide the dry hemostatic composition as described herein, and b) add a quantity of an aqueous medium to the dry hemostatic composition of a).

[0011] The amount of aqueous medium added is usually sufficient to obtain a hemostatic composition in the form of a paste.

[0012] In another aspect, the present description provides a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form in an amount of 7 to 34% by weight, b) fibrinogen in an amount of 0.008 to 5% by weight, c) thrombin in an amount of 7 to 1700 IU per gram, and Petition 870260065366, dated 02 / 07 / 2026, p. 12 / 66 / 57 d) an aqueous medium.

[0013] The hemostatic composition is usually provided in the form of a paste, that is, the aqueous medium is present in a sufficient quantity to provide a paste-like composition.

[0014] In another aspect, the present description refers to the hemostatic composition described herein for use in promoting hemostasis and / or healing of wounds, bone, tendon and / or tissue in an individual in need thereof.

[0015] In another aspect, the present description refers to a container comprising the hemostatic composition described herein.

[0016] In a final aspect, the present description provides a kit comprising: a) a first container comprising a hemostatic composition as described herein, b) a second container comprising an aqueous medium; and c) optionally an outer packaging, in which the two containers are interconnectable. Definitions

[0017] The term “about” as used here refers to an amount or percentage that should be interpreted as a variation of ± 10% with respect to the value of the amount or percentage to which it refers, such as ± 5%.

[0018] A “bioactive agent” is any agent, drug, compound, composition of matter or mixture that provides some pharmacological effect, often beneficial, that can be demonstrated in vivo or in vitro. An agent is thus considered bioactive if it interacts with or has an effect on cellular tissue in the human or animal body. As used herein, this term additionally includes any physiologically or pharmacologically active substance that produces a localized or systemic effect on Petition 870260065366, dated 02 / 07 / 2026, page 13 / 66 / 57 an individual. Bioactive agents may be a protein, such as an enzyme. Additional examples of bioactive agents include, but are not limited to, agents comprising or consisting of an oligosaccharide, a polysaccharide, an optionally glycosylated peptide, an optionally glycosylated polypeptide, an oligonucleotide, a polynucleotide, a lipid, a fatty acid, a fatty acid ester, and secondary metabolites. They may be used prophylactically, therapeutically, in connection with the treatment of an individual, such as a human being or any other animal. The term “bioactive agent” as used herein does not encompass cells, such as eukaryotic or prokaryotic cells.

[0019] “Biocompatible” refers to a material’s ability to perform its intended function without evoking any substantial undesirable local or systemic effects in the host.

[0020] “Biologically absorbable” or “reabsorbable” are terms used in this context to describe that the materials from which the said powder is made can be broken down in the body into smaller molecules of a size that allows them to be transported within the bloodstream. Through said degradation and absorption, said powdered materials are gradually removed from the application site. For example, gelatin can be broken down by proteolytic tissue enzymes into smaller absorbable molecules, so that gelatin, when applied to tissues, is typically absorbed within about 4 to 6 weeks and when applied to bleeding surfaces and mucous membranes typically within 3 to 5 days.

[0021] “Hemostasis” is a process that causes bleeding to slow down or stop. Hemostasis occurs when blood is present outside the body or blood vessels and is the body's instinctive response to stop bleeding and blood loss. During hemostasis, three steps occur in rapid sequence. Vascular spasm is the first response as the Petition 870260065366, dated 02 / 07 / 2026, page 14 / 66 / 57 blood vessels constrict to allow less blood to be lost. In the second stage, platelet plug formation, platelets stick together to form a temporary seal to cover the rupture in the vessel wall. The third and final stage is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin strands that act as a “molecular glue”. Consequently, a hemostatic compound is able to stimulate hemostasis.

[0022] “International Unit (IU)”. In pharmacology, the International Unit is a unit of measurement for the quantity of a substance, based on its biological activity or effect. It is abbreviated as IU, UI, or IE. It is used to quantify vitamins, hormones, some medications, vaccines, blood products, and similar biologically active substances.

[0023] A “paste” according to the present description has a malleable, dough-like consistency, like toothpaste. A paste is a thick, fluid mixture of pulverized solid / solid in powder form with a liquid. A paste is a substance that behaves like a solid until a sufficiently large load or stress is applied, at which point it flows like a fluid, i.e., a paste is fluid. Fluids conform efficiently to irregular surfaces upon application. Pastes typically consist of a suspension of granular material in a background fluid. The individual grains are piled up like sand on a beach, forming a disordered, glassy or amorphous structure and giving pastes their solid character. It is this “piling up” that gives pastes some of their most usual properties; this causes a paste to exhibit properties of brittle matter. A paste is not a gel / jelly.A "fluid paste" is a fluid mixture of a powdered / pulverized solid with a liquid, such as water. Fluid pastes behave in some ways like thick fluids, flowing under gravity and being able to be pumped. Petition 870260065366, dated 02 / 07 / 2026, page 15 / 66 / 57 not very thick. A fluid paste can be functionally considered as a thin, watery paste, but a fluid paste generally contains more water than a paste. Substantially, water-insoluble powder particles, such as cross-linked gelatin particles, will form a paste or fluid paste when mixed with an aqueous medium.

[0024] “Percentage”. Unless otherwise indicated, the percentage is percentage by weight: % w / w or % by weight. Ratios are given as weight by weight (w / w). Detailed description

[0025] The present description provides compositions with improved hemostatic properties and methods for preparing said hemostatic compositions.

[0026] Thus, in one aspect, the present description provides a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 to 150 mg per gram of biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of biocompatible polymer.

[0027] In a second aspect, the present description refers to a method for preparing a hemostatic composition comprising the steps of: a) provide the dry hemostatic composition as described herein, and b) add a quantity of an aqueous medium to the dry hemostatic composition of a).

[0028] The advantages of the hemostatic compositions described here are numerous and include: • Improved hemostatic effect, for example, more severe bleeding can be stopped in less time. Petition 870260065366, dated 02 / 07 / 2026, page 16 / 66 / 57

[0029] · Less time spent preparing the hemostatic composition, for example, bleeding can be stopped faster.

[0030] • Reduced risk of compromising the sterility of the hemostatic composition during preparation due to fewer handling steps.

[0031] • Reduced risk of making mistakes during preparation due to simplified paste preparation.

[0032] • Reliable and consistent reconstitution within a short period of time.

[0033] • Superior consistency and adhesive properties reducing the need for compression.

[0034] • Superior for Minimally Invasive Surgery (MIS) including robotic surgery.

[0035] • Application in sprayable plasters possible.

[0036] • Avoids the time-consuming and error-prone dilution steps of standard hemostatic composition preparations.

[0037] • It minimizes operating room costs since the preparation of the product currently described is so simple and quick that there is no reason to pre-prepare hemostatic fluids before surgery that need to be discarded. Dry hemostatic composition

[0038] The present invention relates to a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen, and c) thrombin.

[0039] In one embodiment, the present description refers to a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, Petition 870260065366, dated 02 / 07 / 2026, page 17 / 66 / 57 b) fibrinogen in an amount of 1 to 150 mg per gram of biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of biocompatible polymer.

[0040] The hemostatic composition is usually provided in a substantially dry form, stable during storage. In one embodiment, the dry composition is stable during storage at room temperature for at least 12 months, preferably at least 24 months.

[0041] In one embodiment, the hemostatic composition comprises one or more biocompatible polymers in particulate form in an amount of at least 80% by weight of the composition, such as at least 81% by weight, such as at least 83% by weight, such as at least 85% by weight, such as at least 87% by weight, such as at least 90% by weight, such as at least 91% by weight, such as at least 95% by weight of the composition.

[0042] In one embodiment, the hemostatic compositions comprise one or more biocompatible polymers in particulate form in an amount between 80% and 99% by weight of the composition, such as between 81% and 99%, such as between 82% and 99%, such as between 83% and 99%, such as between 84% and 99%, such as between 85% and 99%, such as between 86% and 99%, such as between 87% and 99%, such as between 88% and 99%, such as between 89% and 99%, such as between 90% and 99% by weight of the composition.

[0043] In one embodiment, the hemostatic compositions comprise one or more biocompatible polymers in particulate form in an amount between 85% and 99% by weight of the composition, such as between 85% and 98%, such as between 85% and 97%, such as between 85% and 96%, such as between 85% and 96%, such as between 85% and 95% by weight of the composition.

[0044] For example, in one embodiment, the hemostatic composition comprises one or more biocompatible polymers in particulate form in Petition 870260065366, dated 02 / 07 / 2026, page 18 / 66 / 57 a quantity of 83% to 97% by weight of the composition, such as 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% or 97% by weight of the composition.

[0045] In one embodiment, the hemostatic composition comprises one or more biocompatible polymers in particulate form in an amount of 85% to 97% by weight of the composition. In one embodiment, the hemostatic composition comprises one or more biocompatible polymers in particulate form in an amount of 89% to 97% by weight of the composition. In one embodiment, the hemostatic composition comprises one or more biocompatible polymers in particulate form in an amount of 90% to 97% by weight of the composition. In one embodiment, the hemostatic composition comprises one or more biocompatible polymers in particulate form in an amount of 92% to 97% by weight of the composition. In one embodiment, the hemostatic composition comprises one or more biocompatible polymers in particulate form in an amount of 92%, 93%, 94%, 95%, 96% or 97% by weight of the composition.

[0046] In one embodiment, the present description refers to a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 to 150 mg per gram of biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of biocompatible polymer; wherein one or more biocompatible polymers in particulate form are present in an amount of at least 80% by weight of the composition, such as at least 81% by weight, such as at least 83% by weight, such as at least 85% by weight, such as at least 87% by weight, such as at least 90% by weight, such as at least 91% by weight, such as at least 95% by weight of the composition. Petition 870260065366, dated 02 / 07 / 2026, page 19 / 66 / 57

[0047] In one embodiment, the present description refers to a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 to 150 mg per gram of biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of biocompatible polymer; wherein one or more biocompatible polymers in particulate form are present in an amount of 85% to 97% by weight of the composition, such as 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% or 97% by weight of the composition.

[0048] In one embodiment, the present description refers to a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 to 150 mg per gram of biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of biocompatible polymer; wherein, one or more biocompatible polymers in particulate form are present in an amount of 90% to 97% by weight of the composition.

[0049] In one embodiment, the hemostatic composition contains less than 10% by weight of water, preferably less than 5% by weight of water, preferably less than 1% by weight of water. Biocompatible polymer

[0050] The biocompatible polymer of the present description may be a biological or a non-biological polymer. Biological polymers include proteins such as gelatin, collagen, albumin, hemoglobin, casein, fibrinogen, fibrin, fibronectin, elastin, keratin and laminin; or derivatives thereof. Petition 870260065366, dated 02 / 07 / 2026, page 20 / 66 / 57 or combinations thereof. Particularly preferred is the use of gelatin or collagen, more preferably gelatin. Other suitable biological polymers include polysaccharides, such as glycosaminoglycans, starch derivatives, xylan, cellulose derivatives, hemicellulose derivatives, agarose, alginate and chitosan; or derivatives or combinations thereof. Suitable non-biological polymers will be selected to be degradable by either of two mechanisms, i.e., (1) rupture of the polymeric main chain or (2) degradation of side chains resulting in aqueous solubility. Exemplary non-biological polymers include synthetics, such as polyacrylates, polymethacrylates, polyacrylamides, polyvinyl resins, polylactide-glycolides, polycaprolactones and polyoxyethylenes; or derivatives or combinations thereof. Combinations of different types of polymers are also possible.

[0051] In one embodiment, the biocompatible polymer in particulate form comprises or consists of a biocompatible polymer selected from the group consisting of: gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, carboxymethylcellulose, polyglycolic acid, polyacetic acid and combinations thereof.

[0052] In one embodiment, the biocompatible polymer comprises or consists of powder particles that are substantially insoluble in an aqueous medium.

[0053] In one embodiment, the biocompatible polymer is biologically absorbable. Examples of suitable biologically absorbable materials include gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, polyglycolic acid, polyacetic acid, and combinations thereof. It will be understood that various forms thereof, such as linear or cross-linked forms, salts, esters, and the like, are also considered for the purposes of this description. In a preferred embodiment of the invention, the biologically absorbable material comprises or consists of Petition 870260065366, dated 02 / 07 / 2026, page 21 / 66 / 57 gelatin. Gelatin is preferred because gelatin is highly biologically absorbable. Furthermore, gelatin is highly biocompatible, meaning it is not toxic to an animal, just as it is not toxic to a human being, when / if it enters the bloodstream or is in prolonged contact with human tissues.

[0054] Gelatin typically originates from a porcine source, but it can originate from other animal sources, such as bovine or fish sources. Gelatin can also be synthetically manufactured, that is, manufactured by recombinant means.

[0055] In a preferred embodiment, the biocompatible polymer is crosslinked. Crosslinking usually renders the polymer substantially insoluble in an aqueous medium. In one embodiment, the biocompatible polymer consists of powder particles that are substantially insoluble in an aqueous medium. Any suitable crosslinking methods known to a skilled person may be used, including both chemical and physical crosslinking methods.

[0056] In one embodiment of the present description, the polymer has been crosslinked by physical means, such as by dry heat. The dry heat treatment is usually carried out at temperatures between 100°C and 250°C, such as about 110°C to about 200°C. In particular, the temperature may be in the range of 110 to 160°C, for example in the range of 110 to 140°C or in the range of 120 to 180°C or in the range of 130 to 170°C or in the range of 130 to 160°C or in the range of 120 to 150°C. The time period for crosslinking can be optimized by a skilled person and is normally a period between about 10 minutes and about 12 hours, such as about 1 hour to about 10 hours, for example between about 2 hours and about 10 hours, such as between about 4 hours and about 8 hours, for example between about 5 hours and about 7 hours, such as about 6 hours.

[0057] In another embodiment, the polymer was crosslinked by means Petition 870260065366, dated 02 / 07 / 2026, page 22 / 66 / 57 chemicals, that is, by exposure to a chemical crosslinking agent. Examples of suitable chemical crosslinking agents include, but are not limited to, aldehydes, in particular glutaraldehyde and formaldehyde, acyl azide, carbodiimides, hexamethylene diisocyanate, polyether oxide, 1,4-butanedioldiglycidyl ether, tannic acid, aldose sugars, for example D-fructose, genipin and dye-mediated photo-oxidation. Specific compounds include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and dithiobis(propanoic dihydrazide) (DTP).

[0058] In one embodiment, the biocompatible polymer particles according to the present description are obtained from cross-linked sponges, for example of gelatin or collagen, in particular cross-linked gelatin sponges (such as commercially available Spongostan® and Surgiespuma® sponges).Cross-linked sponges are micronized by methods known in the art to obtain a biocompatible cross-linked polymer in powder form, such as by rotary bed, extrusion, granulation and treatment in an intensive mixer or grinding (for example using a hammer mill or a centrifugal mill).

[0059] Spongostan® / Surgiespuma® available from Ethicon is a reticulated, absorbable hemostatic sponge based on gelatin. It absorbs > 35 g of blood / ge within 4 to 6 weeks and is completely absorbed into the human body.

[0060] In one embodiment, the biocompatible polymer in particulate form comprises or consists of cross-linked gelatin particles.

[0061] In one embodiment, the crosslinked gelatin particles are obtained from a micronized porous gelatin sponge or dry hydrogel. In another embodiment, the porous gelatin sponge or dry hydrogel has been crosslinked by dry heat treatment.

[0062] Porous gelatin sponges can be prepared by mixing a quantity of soluble gelatin with an aqueous medium of Petition 870260065366, dated 02 / 07 / 2026, p. 23 / 66 / 57 in order to create a foam comprising a discontinuous gas phase, drying said foam and crosslinking the dried foam by exposure to dry heat. The crosslinked sponge obtained can be micronized by methods known in the art. The gelatin foam usually has a gelatin concentration of about 1% to 70% by weight, usually 3% to 20% by weight. Drying is usually carried out at about 20°C to about 40°C for about 5 to 20 hours. The dried foam is usually crosslinked by exposure to a temperature of about 110°C to about 200°C for about 15 minutes to about 8 hours, as well as from about 150°C to about 170°C for about 5 to 7 hours.The time period for crosslinking can be optimized by a skilled person and is normally a period between about 10 minutes and about 12 hours, such as about 1 hour to about 10 hours, for example between about 2 hours and about 10 hours, such as between about 4 hours and about 8 hours, for example between about 5 hours and about 7 hours, such as about 6 hours.

[0063] Drying of the foam or hydrogel can also be achieved by freeze-drying using methods known to a person skilled in the art.

[0064] In one embodiment, crosslinked gelatin particles are obtained by micronizing a crosslinked porous gelatin sponge or a substantially non-porous crosslinked dry hydrogel. The gelatin can be crosslinked, for example by exposure to glutaraldehyde (e.g. 0.01% to 0.05% w / w, overnight at 0°C to 15°C in aqueous buffer), sodium periodate (e.g. 0.05 M, maintained at 0°C to 15°C for 48 hours) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (e.g. 0.5% to 1.5% w / w, overnight at room temperature) or by exposure to about 0.3 to 3 megarads of gamma radiation or electron beam. When crosslinking with glutaraldehyde, the crosslinks are formed by means of Schiff bases which can be stabilized by subsequent reduction, for example. Petition 870260065366, dated 02 / 07 / 2026, p. 24 / 66 / 57 for treatment with sodium borohydride.

[0065] The particles can be obtained from dry product by methods known to a person skilled in the art. In one embodiment, the gelatin particles are obtained by micronizing the dry product, such as by granulation and treatment in an intensive mixer, grinding, for example using a hammer mill, ball mill or centrifugal mill. In another embodiment, the particles are obtained by grinding the dry product to an appropriate size. This can, for example, be done by mortar and pestle, crushing and any other available physical process.

[0066] In one embodiment, the particles are obtained by hammer milling a dry sponge or hydrogel. Preferably, the hammer mill has a built-in sieve resulting in a desired particle size distribution.

[0067] In one embodiment of the present invention, the gelatin particles have a diameter between about 1 µm and 1000 µm, such as between about 10 µm and 800 µm, for example between about 50 µm and 600 µm, such as between about 100 µm and 500 µm, for example between about 200 µm and 500 µm, such as about 450 µm.

[0068] The particles are in a smaller embodiment than approximately 1000 microns in size, that is, so that they are able to pass through a 1 x 1 mm sieve.

[0069] Generally, at least 90% of powder particles have a size between 1 µm and 1200 µm.

[0070] In another embodiment, the average particle size of the dry particles is between 1 pm and 1000 pm, such as between about 10 pm and 800 pm, for example between about 50 pm and 600 pm, such as between about 100 pm and 500 pm, for example between about 200 pm and 500 pm, such as about 450 pm. Petition 870260065366, dated 02 / 07 / 2026, p. 25 / 66 / 57

[0071] The average particle size of dry particles can, for example, be measured by laser diffraction.

[0072] In one embodiment, the biocompatible polymer in particulate form is present in an amount of about 0.05 to 20 g, such as about 0.2 to 10 g, such as about 0.5 to 2 g, such as about 1 g.

[0073] In one embodiment, the biocompatible polymer in particulate form is present in an amount of about 1 g.

[0074] The biocompatible polymers in particulate form used in this description are usually provided in sterile form. Fibrinogen

[0075] Fibrinogen or factor I is a glycoprotein complex that circulates in the blood of vertebrates. During tissue and vascular injury, it is enzymatically converted by thrombin to fibrin and is involved in blood clot formation.

[0076] In one embodiment, fibrinogen is human fibrinogen.

[0077] In one embodiment, the fibrinogen is recombinant human fibrinogen.

[0078] In other forms, the origin of fibrinogen is from a mammal other than humans, such as bovine fibrinogen.

[0079] In one embodiment, fibrinogen is a dry fibrinogen composition. For example, fibrinogen may be in the form of particles or a powder. The dry fibrinogen composition may be prepared by any method known to the skilled person and is usually provided in sterile form. Thus, in one embodiment the dry fibrinogen composition is sterile.

[0080] Fibrinogen can also be coated onto the biocompatible polymer in particulate form. The coating of fibrinogen onto the biocompatible polymer can be achieved by any methods known in the art, for example by spray techniques, which can be carried out Petition 870260065366, dated 02 / 07 / 2026, page 26 / 66 / 57 in any spraying apparatus. For example, a well-known method for coating particles by spraying is a fluid bed process. Thus, in one embodiment, fibrinogen is coated onto biocompatible polymer particles in order to obtain a fibrinogen layer on the biocompatible polymer particle. In another embodiment, fibrinogen is sprayed onto biocompatible polymer particles, for example by fluid bed process techniques.

[0081] In one embodiment, the hemostatic composition comprises fibrinogen in an amount of about 1 to about 150 mg per gram of biocompatible polymer, such as about 5 to about 150 mg of fibrinogen per gram of biocompatible polymer, such as about 10 to about 150 mg, such as about 15 to about 150 mg, such as about 20 to about 150 mg, such as about 25 to about 150 mg, such as about 30 to about 150 mg, such as about 30 to about 125 mg, such as about 30 to about 100 mg of fibrinogen per gram of biocompatible polymer.

[0082] In one embodiment, the hemostatic composition comprises fibrinogen in an amount of about 20 to about 80 mg of fibrinogen per gram of biocompatible polymer, such as about 30 mg, such as about 35 mg, such as about 40 mg, such as about 45 mg, such as about 50 mg, such as about 55 mg, such as about 60 mg, such as about 70 mg, such as about 75 mg of fibrinogen per gram of biocompatible polymer. In one embodiment, the composition comprises about 35 mg of fibrinogen per gram of biocompatible polymer. In one embodiment, the composition comprises about 70 mg of fibrinogen per gram of biocompatible polymer.

[0083] In one embodiment, the hemostatic composition comprises fibrinogen in an amount of about 20 mg to about 100 mg of fibrinogen per gram of biocompatible polymer, such as about 25 Petition 870260065366, dated 02 / 07 / 2026, page 27 / 66 / 57 mg to approximately 100 mg, as well as from approximately 30 mg to approximately 100 mg, as well as from 30 mg to approximately 95 mg, as well as from 30 mg to approximately 90 mg, as well as from 30 mg to approximately 85 mg of fibrinogen per gram of biocompatible polymer.

[0084] In one embodiment, the hemostatic composition comprises no more than 100 mg of fibrinogen per gram of biocompatible polymer. In another embodiment, the composition comprises more than 10 mg of fibrinogen per gram of biocompatible polymer.

[0085] In one embodiment, the hemostatic composition comprises from about 20 to about 100 mg of fibrinogen per gram of biocompatible polymer, such as from about 20 to about 30 mg, such as from about 30 mg to about 40 mg, such as from about 40 mg to about 50 mg, such as from about 50 mg to about 60 mg, such as from about 60 mg to about 70 mg, such as from 70 mg to about 80 mg, such as from 80 mg to about 90 mg, such as from 90 mg to about 100 mg of fibrinogen per gram of biocompatible polymer.

[0086] In one embodiment, the hemostatic composition, when in dry form, that is, before mixing with an aqueous medium, comprises fibrinogen in an amount of 1 to 15% by weight, such as 1 to 10% by weight, such as 1 to 2%, such as 2 to 3%, such as 3 to 4%, such as 4 to 5%, such as 5 to 6%, such as 6 to 7%, such as 7 to 8%, such as 8 to 9%, such as 9 to 10% by weight.

[0087] In one embodiment, the hemostatic composition, before mixing with an aqueous medium, comprises fibrinogen in an amount of 2 to 15% by weight, such as 2.5% to 15% by weight, such as 3% to 15% by weight, such as about 3% by weight, such as about 3.5% by weight, such as about 4% by weight, such as about 4.5% by weight, such as about 5% by weight, such as about 5.5% by weight, such as about 6% by weight, such as about 6.5% by weight, such as about 7% by weight, such Petition 870260065366, dated 02 / 07 / 2026, page 28 / 66 / 57 as approximately 7.5% by weight, as approximately 8% by weight, as approximately 8.5% by weight, as approximately 9% by weight, as approximately 9.5% by weight, as approximately 10% by weight. Thrombin

[0088] Thrombin is a “trypsin-like” serine protease protein that in humans is encoded by the F2 gene. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the coagulation cascade, which ultimately results in the containment of blood loss. Thrombin, in turn, acts as a serine protease that converts soluble fibrinogen into insoluble fibrin filaments, as well as catalyzing many other reactions related to coagulation. In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, and fibrinogen to fibrin.

[0089] In one embodiment, thrombin is human thrombin.

[0090] In one embodiment, the thrombin is recombinant human thrombin.

[0091] In other forms, the origin of thrombin is from a mammal other than humans, such as bovine thrombin.

[0092] In one embodiment, thrombin is in the form of prothrombin.

[0093] In one embodiment, thrombin is a dry thrombin composition. For example, thrombin may be in the form of particles or a powder. The dry thrombin composition may be prepared by any methods known to the skilled person and is usually provided in sterile form. Thus, in one embodiment the dry thrombin composition is sterile.

[0094] Thrombin can also be coated onto the biocompatible polymer in particulate form. The coating of thrombin onto the biocompatible polymer can be achieved by any methods known in the art, for example by spray techniques, which can be carried out Petition 870260065366, dated 02 / 07 / 2026, page 29 / 66 / 57 in any spraying apparatus. For example, a well-known method for coating particles by spraying is a fluid bed process. Thus, in one embodiment, thrombin is coated onto the biocompatible polymer particles in order to obtain a thrombin layer on the biocompatible polymer particle. In another embodiment, thrombin is sprayed onto the biocompatible polymer particles.

[0095] In some embodiments, the biocompatible polymer in particulate form is coated with either thrombin or fibrinogen using known coating methods. A person skilled in the art will be aware of how to perform such coatings in a spray apparatus, such as in a fluid bed process. For example, a first coating of fibrinogen or thrombin can be applied to the biocompatible polymer particles to obtain a first layer on the biocompatible polymer particles. Subsequently, a second coating of thrombin or fibrinogen can be applied to obtain a second layer on the first layer.

[0096] It is also possible to combine both thrombin and fibrinogen in the same layer. For example, by simultaneously coating both thrombin and fibrinogen onto biocompatible polymer particles in order to obtain a layer combining fibrinogen and thrombin. For example, thrombin and fibrinogen can each be sprayed simultaneously from separate spray sources or sprayed from the same spray source.

[0097] In some embodiments, the medium used to pulverize thrombin and / or fibrinogen is a non-aqueous medium in order to prevent the catalytic reaction of thrombin on fibrinogen.

[0098] In one embodiment, a mixture of particles coated with thrombin and fibrinogen, respectively, is obtained by coating a subset of polymeric particles with thrombin and another subset Petition 870260065366, dated 02 / 07 / 2026, page 30 / 66 / 57 of polymeric particles with fibrinogen and then combining the two coated subsets in the correct ratio to obtain an ideal polymer:fibrinogen:thrombin ratio.

[0099] In one embodiment, the dry thrombin composition is prepared by spray drying or freeze drying.

[00100] In one embodiment, the dry thrombin composition is prepared by freeze-drying.

[00101] In one embodiment, the composition of dry thrombin comprises less than 2% water, such as less than 1% water.

[00102] In one embodiment, the hemostatic composition comprises thrombin in an amount of 400 to 4000 IU of thrombin per gram of biocompatible polymer, such as 400 to 600 IU, such as 600 to 800 IU, such as 800 to 1000 IU, such as 1000 to 1200 IU, such as 1200 to 1400 IU, such as 1400 to 1600 IU, such as 1600 to 1800 IU, such as 1800 to 2000 IU, such as 2000 to 2200 IU, such as 2200 to 2400 IU, such as 2400 to 2600 IU, such as 2600 to 2800 IU, such as 2800 to 3000 IU, such as 3000 to 3200 IU, such as 3200 to 3400 IU, such as 3400 to 3600 IU, such as 3600 to 3800 IU, such as 3800 to 4000 IU, such as 4000 to 4200 IU of thrombin per gram of biocompatible polymer.

[00103] In one embodiment, the hemostatic composition comprises thrombin in an amount of about 500 IU to 2500 IU of thrombin per gram of biocompatible polymer, such as about 600 IU to 2500 IU, such as about 700 IU to 2500 IU, such as about 800 IU to 2500 IU, such as about 900 IU to 2500 IU, such as about 1000 IU to 2500 IU, such as about 1100 IU to 2500 IU, such as about 1200 IU to 2500 IU, such as about 1300 IU to 2500 IU, such as about 1400 IU to 2500 IU, such as about 1500 IU to 2500 IU, such as approximately 1600 IU to 2500 IU, such as approximately 1700 IU to 2500 IU, such as Petition 870260065366, dated 02 / 07 / 2026, page 31 / 66 / 57 approximately 1800 IU to 2500 IU, such as approximately 1900 IU to 2500 IU of thrombin per gram of biocompatible polymer, such as approximately 500 IU, such as approximately 1000 IU, such as approximately 1500 IU, such as approximately 2000 IU, such as approximately 2500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the composition comprises approximately 2000 IU of thrombin per gram of biocompatible polymer.

[00104] In one embodiment, the hemostatic composition comprises a thrombin to fibrinogen ratio of 0.5 IU / mg to 5000 IU / mg, such as 1 IU / mg to 2000 IU / mg, such as 2 IU / mg to 1000 IU / mg, such as 2 IU / mg to 300 IU / mg, such as 2 IU / mg to 250 IU / mg, such as 2 IU / mg to 200 IU / mg, such as 2 IU / mg to 150 IU / mg.

[00105] In one embodiment, the hemostatic composition comprises 30 to 40 mg of fibrinogen and 500 to 1000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 30 to 40 mg of fibrinogen and 1000 to 1500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 30 to 40 mg of fibrinogen and 1500 to 2000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 30 to 40 mg of fibrinogen and 2000 to 2500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 40 to 50 mg of fibrinogen and 500 to 1000 IU of thrombin per gram of biocompatible polymer. In another embodiment, the hemostatic composition comprises 40 to 50 mg of fibrinogen and 1000 to 1500 IU of thrombin per gram of biocompatible polymer.In one embodiment, the hemostatic composition comprises 40 to 50 mg of fibrinogen and 1500 to 2000 IU of thrombin per gram of biocompatible polymer. In another embodiment, the hemostatic composition comprises 40 to 50 mg of fibrinogen and 2000 to 2500 IU of thrombin per gram of biocompatible polymer. In another embodiment... Petition 870260065366, dated 02 / 07 / 2026, page 32 / 66 / 57: The hemostatic composition comprises 50 to 60 mg of fibrinogen and 500 to 1000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 50 to 60 mg of fibrinogen and 1000 to 1500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 50 to 60 mg of fibrinogen and 1500 to 2000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 50 to 60 mg of fibrinogen and 2000 to 2500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 60 to 70 mg of fibrinogen and 500 to 1000 IU of thrombin per gram of biocompatible polymer. In another embodiment, the hemostatic composition comprises 60 to 70 mg of fibrinogen and 1000 to 1500 IU of thrombin per gram of biocompatible polymer.In one embodiment, the hemostatic composition comprises 60 to 70 mg of fibrinogen and 1500 to 2000 IU of thrombin per gram of biocompatible polymer. In another embodiment, the hemostatic composition comprises 60 to 70 mg of fibrinogen and 2000 to 2500 IU of thrombin per gram of biocompatible polymer.

[00106] In one embodiment, the hemostatic composition comprises 35 mg of fibrinogen and 500 to 1000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 35 mg of fibrinogen and 1000 to 1500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 35 mg of fibrinogen and 1500 to 2000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 35 mg of fibrinogen and 2000 to 2500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 50 mg of fibrinogen and 500 to 1000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises Petition 870260065366, dated 02 / 07 / 2026, page 33 / 66 / 57 mg of fibrinogen and 1000 to 1500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 50 mg of fibrinogen and 1500 to 2000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 50 mg of fibrinogen and 2000 to 2500 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 70 mg of fibrinogen and 500 to 1000 IU of thrombin per gram of biocompatible polymer. In one embodiment, the hemostatic composition comprises 70 mg of fibrinogen and 1000 to 1500 IU of thrombin per gram of biocompatible polymer. In another embodiment, the hemostatic composition comprises 70 mg of fibrinogen and 1500 to 2000 IU of thrombin per gram of biocompatible polymer. In another embodiment, the hemostatic composition comprises 70 mg of fibrinogen and 2000 to 2500 IU of thrombin per gram of biocompatible polymer.

[00107] In a particular embodiment, the hemostatic composition comprises: a) approximately 1 g of a biocompatible polymer in particulate form, such as gelatin, b) approximately 35 mg of fibrinogen, c) approximately 2000 IU of thrombin.

[00108] In one embodiment, the hemostatic composition contains less than 10% by weight of water, preferably less than 5% by weight of water, preferably less than 1% by weight of water. Hydrophilic compounds

[00109] In one embodiment, the hemostatic composition additionally comprises one or more hydrophilic compounds. Hydrophilic compounds usually contain polar or charged functional groups, making them water-soluble. The inclusion of one or more hydrophilic compounds in the hemostatic composition of the present description is believed to have Petition 870260065366, dated 02 / 07 / 2026, page 34 / 66 / 57, has a beneficial effect on thrombin stability and may improve the reconstitution efficiency of the dry thrombin composition. Hydrophilic compounds may also improve the consistency of the hemostatic composition.

[00110] In one embodiment, the hydrophilic compound is a hydrophilic polymer. The hydrophilic polymer may be natural or synthetic, linear or branched, and have any suitable length.

[00111] In one embodiment, the hydrophilic polymer is selected from the group consisting of Polyethyleneimine (PEI), Poly(ethylene glycol) (PEG), Poly(ethylene oxide), Poly(vinyl alcohol) (PVA), Poly(styrene sulfonate) (PSS), Poly(acrylic acid) (PAA), Poly(allylamine chloride) and Poly(vinyl acid).

[00112] In one embodiment, the hydrophilic compound is polyethylene glycol (PEG).

[00113] In one embodiment, the hydrophilic compound is selected from the group consisting of Cetylpyridinium Chloride, Sodium Docusate, Glycine, Hypromellose, Phthalate, Lecithin, Phospholipids, Poloxamer, Polyoxyethylene Alkyl Ethers, Polyoxyethylene Castor Oil Derivatives, Polyoxyethylene Sorbitan Fatty Acid Esters, Polyoxyethylene Stearates, Polyvinyl Alcohol, Sodium Lauryl Sulfate, Sorbitan Esters (Sorbitan Fatty Acid Esters) and Tricaprylin.

[00114] In a preferred embodiment, the hydrophilic compound is a polyol. Thus, according to one embodiment of the invention, one or more polyols may be included in the hemostatic composition. Polyols can enhance the reconstitution rate of the dry thrombin composition, stabilize thrombin activity, and play a role in ensuring optimal consistency of the hemostatic composition.

[00115] A polyol as defined here is a compound with multiple hydroxyl functional groups. Polyols include sugars (mono, di and Petition 870260065366, dated 02 / 07 / 2026, page 35 / 66 / 57 polysaccharides), sugar alcohols and derivatives thereof. Sugar alcohols are especially preferred.

[00116] Monosaccharides include, but are not limited to, glucose, fructose, galactose, xylose, and ribose.

[00117] Disaccharides include, but are not limited to, sucrose (sucrose), lactulose, lactose, maltose, trehalose, and cellobiose.

[00118] Polysaccharides include, but are not limited to, starch, glycogen, cellulose, and chitin.

[00119] A sugar alcohol, also known as a polyalcohol, is a hydrogenated form of carbohydrate whose carbonyl group (aldehyde or ketone, reducing sugar) has been reduced to a primary or secondary hydroxyl group (consequently the alcohol). Sugar alcohols have the general formula H(HCHO)n+1H, while sugars have H(HCHO)nHCO. Some common sugar alcohols that can be used in the method of the present description include, but are not limited to: Glycol (2 carbons), Glycerol (3 carbons), Erythritol (4 carbons), Threitol (4 carbons), Arabitol (5 carbons), Xylitol (5 carbons), Ribitol (5 carbons), Mannitol (6 carbons), Sorbitol (6 carbons), Dulcitol (6 carbons), Fucitol (6 carbons), Iditol (6 carbons), Inositol (6 carbons; a cyclic sugar alcohol), Volemitol (7 carbons), Isomalt (12 carbons), Maltitol (12 carbons), Lactitol (12 carbons), Polyglycolic acid.

[00120] In one embodiment, the hemostatic composition comprises a single hydrophilic compound, such as a single polyol.

[00121] In one embodiment of the invention, the hemostatic composition comprises more than one hydrophilic compound, such as two, three, four, five, six, or even more distinct hydrophilic compounds.

[00122] In a preferred embodiment, the hydrophilic compound is a polyol.

[00123] In one embodiment of the invention, the hemostatic composition Petition 870260065366, dated 02 / 07 / 2026, page 36 / 66 / 57, comprises two polyols, for example mannitol and glycerol or trehalose, and a glycol.

[00124] In one embodiment of the invention, the hemostatic composition comprises one or more sugar alcohols, such as one or more sugar alcohols selected from the group consisting of Glycol, Glycerol, Erythritol, Threitol, Arabitol, Xylitol, Ribitol, Mannitol, Sorbitol, Dulcitol, Fucitol, Iditol, Inositol, Volemitol, Isomalt, Maltitol, Lactitol, Polyglycitol.

[00125] In one embodiment, the hemostatic composition comprises one or more sugar alcohols and one or more sugars, such as a sugar alcohol and a sugar.

[00126] In one embodiment, the hemostatic composition comprises a sugar alcohol and optionally one or more additional hydrophilic compounds, such as one or more polyols, which may be sugar alcohols or sugars.

[00127] In one embodiment, the hemostatic composition does not comprise a sugar as the sole polyol.

[00128] In one embodiment of the invention, the hemostatic composition comprises mannitol.

[00129] In one embodiment of the invention, the hemostatic composition comprises sorbitol.

[00130] In one embodiment of the invention, the hemostatic composition comprises glycerol.

[00131] In one embodiment of the invention, the hemostatic composition comprises trehalose.

[00132] In one embodiment of the invention, the hemostatic composition comprises glycol, such as propylene glycol.

[00133] In one embodiment of the invention, the hemostatic composition comprises xylitol.

[00134] In one embodiment of the invention, the hemostatic composition Petition 870260065366, dated 02 / 07 / 2026, page 37 / 66 / 57 includes maltitol.

[00135] In one embodiment of the invention, the hemostatic composition comprises sorbitol.

[00136] In one embodiment, the hemostatic composition comprises 0.01 g to 0.5 g of hydrophilic compound per gram of biocompatible polymer, such as 0.01 g to 0.4 g, such as 0.01 to 0.3 g, such as 0.01 to 0.2 g, such as 0.01 to 0.1 g, such as 0.01 to 0.05 g of hydrophilic compound per gram of biocompatible polymer. Additional bioactive agents

[00137] In one embodiment of the invention, the hemostatic composition comprises one or more additional bioactive agents capable of stimulating hemostasis, wound healing, bone healing, tissue healing and / or tendon healing.

[00138] In one embodiment, the hemostatic composition comprises one or more additional bioactive agents that stimulate bone and / or tendon and / or tissue healing, such as one or more growth factors selected from the group consisting of matrix metalloproteinases (MMPs), insulin-like growth factor 1 (IGF-I), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor beta (TGF-β).

[00139] In one embodiment, the hemostatic composition comprises one or more Bone Morphogenic Proteins (BMPs). Bone morphogenic proteins (BMPs) are a subgroup of the TGF-β superfamily. Bone morphogenic proteins (BMPs) are a group of growth factors also known as cytokines and metabologens. Originally recognized for their ability to induce bone and cartilage formation, BMPs are now considered to constitute a group of essential morphogenetic signals, orchestrating tissue architecture throughout. Petition 870260065366, dated 02 / 07 / 2026, page 38 / 66 / 57 the body.

[00140] In one embodiment, the hemostatic composition comprises one or more matrix metalloproteinases (MMPs). MMPs are zinc-dependent endopeptidases. MMPs play a very important role in the degradation and remodeling of the extracellular matrix (ECM) during the healing process after an injury. Certain MMPs, including MMP-1, MMP-2, MMP-8, MMP-13, and MMP-14, have collagenase activity, meaning that, unlike many other enzymes, they are capable of degrading type I collagen fibrils.

[00141] These growth factors all have different roles during the healing process. IGF-1 increases collagen and proteoglycan production during the first stage of inflammation, and PDGF is also present during the initial stages after injury and promotes the synthesis of other growth factors along with DNA synthesis and cell proliferation. The three isoforms of TGF-β (TGF-p1, TGF-p2, TGF-p3) are known to play a role in wound healing and scar formation. VEGF is well known to promote angiogenesis and induce endothelial cell proliferation and migration.

[00142] In one embodiment, the hemostatic composition of the present description comprises flakes or particles of extracellular matrix (ECM). ECM is the extracellular part of animal tissue that usually provides structural support for animal cells in addition to performing several other important functions. ECM has been shown to have a very beneficial effect on wound healing as it facilitates the regeneration of functional tissue.

[00143] The variety of additional bioactive agents that can be used in conjunction with the hemostatic composition of the invention is vast. In general, bioactive agents that can be administered via the hemostatic composition of the invention include, without limitation, anti-infectives, such as antibiotics and antiviral agents; analgesics and analgesic combinations; anti Petition 870260065366, dated 02 / 07 / 2026, page 39 / 66 / 57 anthelmintics; antiarthritics; anticonvulsants; antidepressants; antihistamines; anti-inflammatory agents; antimigraine preparations; antineoplastics; antiparkinsonism drugs; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators, including coronary, peripheral and general cerebral; central nervous system stimulants; hormones, such as estradiol and other steroids, including corticosteroids; immunosuppressants; muscle relaxants; parasympatholytics; psychostimulants; naturally derived or genetically engineered proteins, polysaccharides, glycoproteins or lipoproteins;Oligonucleotides, antibodies, antigens, cholinergic agents, chemotherapeutic products, radioactive agents, osteoinductive agents, cystostatic heparin neutralizers, procoagulants and hemostatic agents, such as fibrin, fibronectin, heparinase, Factor X / Xa, Factor VII / VIa, Factor VIII / VIIIa, Factor IX / IXa, Factor XI / XIa, Factor XII / XIIa, Factor XIII / XIIIa, tissue factor, batroxobin, ancrodo, ecarin, von Willebrand factor, platelet surface glycoproteins, vasopressin, vasopressin analogs, epinephrine, selectin, procoagulant venom, plasminogen activator inhibitor, platelet-activating agents and synthetic peptides having hemostatic activity. Additional compounds

[00144] The hemostatic composition of the invention may further comprise one or more of the following: DMSO (dimethyl sulfoxide) and / or 2-Methyl-2,4-pentanediol (MPD).

[00145] In one embodiment, the hemostatic composition of the present description comprises one or more antimicrobial agents, such as one or more antibacterial agents.

[00146] In one embodiment, the hemostatic composition of the present Petition 870260065366, dated 02 / 07 / 2026, page 40 / 66 / 57 description includes benzalkonium chloride (BAC).

[00147] In one embodiment, the hemostatic composition of the present description does not comprise an antimicrobial agent.

[00148] In one embodiment, the hemostatic composition further comprises an extrusion enhancer, that is, a compound that facilitates the extrusion of a paste from a syringe.

[00149] It has been previously shown that the provision of certain extrusion enhancers, such as albumin in an appropriate quantity, enables the use of higher gelatin concentrations since they decrease the amount of force required to extrude the gelatin paste composition from, for example, a syringe. The use of higher gelatin concentrations can in turn improve the hemostatic properties of such products. It is necessary to provide the extrusion enhancers in appropriate quantities.The quantities are preferably high enough to obtain the extrusion effect, that is, to enable a flowable paste even for relatively high quantities of the biocompatible polymer, for example cross-linked gelatin, so that the hemostatic composition can be accurately applied by a surgeon using, for example, a syringe comprising an applicator tip; on the other hand, the quantities should be low enough to prevent potential negative functional properties of the hemostatic composition.

[00150] The extrusion enhancer is preferably albumin, especially human serum albumin.

[00151] In one embodiment, the hemostatic composition in paste form, i.e., after reconstitution with an aqueous medium, comprises an extrusion enhancer, such as albumin, in an amount of between about 0.1% and about 10%, such as between about 0.2% and about 8%, for example between about 0.3% and about 7%, preferably between about 0.5% and about 5%, such as between about 1% and about 4%. Petition 870260065366, dated 02 / 07 / 2026, p. 41 / 66 / 57

[00152] In one embodiment, the hemostatic composition of the present description comprises only trace amounts of albumin, such as less than 0.1%, for example less than 0.01%, such as less than 0.001%, for example less than 0.0001%. Method for preparing a hemostatic composition

[00153] In one aspect, the present description provides a method for preparing a hemostatic composition comprising the steps of: a) to provide the hemostatic composition as described herein, and b) add a quantity of an aqueous medium to the hemostatic composition of a).

[00154] In one embodiment, the amount of aqueous medium added is between 2 and 12 mL per gram of hemostatic composition provided in step a), such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mL of aqueous medium.

[00155] In one embodiment, the amount of aqueous medium added is between 4 and 7, such as between 5 and 6 mL per gram of hemostatic composition provided in step a).

[00156] In one aspect, the present description provides a method for preparing a hemostatic composition comprising the steps of: a) to provide a hemostatic composition comprising a biocompatible polymer in particulate form and fibrinogen, wherein said biocompatible polymer and fibrinogen are as described herein, and b) add a quantity of an aqueous medium comprising thrombin.

[00157] In one embodiment, the present description provides a method for preparing a hemostatic composition comprising the steps of: a) to provide a hemostatic composition comprising a biocompatible polymer in particulate form, fibrinogen and an aqueous medium, wherein said biocompatible polymer, fibrinogen and aqueous medium are as described herein, and Petition 870260065366, dated 02 / 07 / 2026, page 42 / 66 / 57 b) add a quantity of an aqueous medium comprising thrombin.

[00158] The components are mixed with the aqueous medium by conventional means, such as by transfer between two connected syringes, in order to form a paste.

[00159] The hemostatic composition obtained by the methods described herein is suitable for use in hemostasis and / or wound healing.

[00160] In one aspect, the present description provides the hemostatic composition obtained by the methods described herein. The hemostatic composition obtained by the methods described herein is preferably a flowable paste composition.

[00161] Surprisingly, the present inventors show that hemostatic paste compositions comprising a biocompatible polymer, thrombin, and fibrinogen remain fluid after reconstitution, i.e., after mixing with an aqueous medium, for more than 1.5 hours as shown in the examples. This finding was highly unexpected since current sealants comprising thrombin and fibrinogen readily react upon combination and form a fibrin clot that will coagulate in the device and therefore may not be applicable from a syringe for an extended period of time after the components have been combined.

[00162] In one embodiment, the hemostatic composition remains fluid after the addition of an aqueous medium for at least 4 hours, such as at least 2 hours, such as at least 90 minutes, such as at least 60 minutes, such as at least 30 minutes.

[00163] In one embodiment, the hemostatic composition is applied from a syringe after the addition of an aqueous medium for at least 4 hours, such as at least 2 hours, such as at least 90 minutes, such as at least 60 minutes, such as at least 30 minutes. Petition 870260065366, dated 02 / 07 / 2026, p. 43 / 66 / 57

[00164] In one embodiment, the hemostatic composition is a paste. Thus, in one embodiment the amount of aqueous medium added to the biocompatible polymer in particulate form, such as cross-linked gelatin particles, is an amount suitable for forming a paste.

[00165] In one embodiment, the hemostatic composition has a consistency within the range of about 100 gxs to about 15,000 gxs, such as about 500 gxs to about 8,000 gxs, for example about 1,000 gxs to about 5,000 gxs, such as about 1,500 gxs to about 3,000 gxs.

[00166] In one embodiment, the hemostatic composition has a consistency of less than about 5000 gxs, for example less than about 4000 gxs, such as less than about 3000 gxs, for example less than about 2000 gxs.

[00167] Consistency can be measured using a texture analyzer (TA.XT.plus, Stable micro systems) with the following TA settings: Table 1 Test mode Compression Speed ​​in pre-test 5.00 mm / s Speed ​​in test 0.5 mm / s Speed ​​in post-test 10 mm / s Distance 30.0 mm Actuator type Auto Actuating force 4.0 g Probe P / 0.5R *Λ” Dia Cylinder

[00168] For a medical paste to be dispensed from a syringe and an applicator tube, it must be flowable when subjected to a force applied by a syringe. Thus, the term "flowable paste" refers to a paste having a viscosity that facilitates a constant flow when subjected to a force applied by a syringe. The flowability of a paste can, for example, be measured from 25 to 30°C and a Petition 870260065366, dated 02 / 07 / 2026, p. 44 / 66 / 57 relative humidity between 65 and 75%.

[00169] In one embodiment of the present description, the hemostatic composition in paste form has a viscosity in the range of about 500 Pa-s to about 8000 Pa-s, such as from about 500 to about 7000 Pa-s, such as from about 500 Pa-s to about 6000 Pa-s, such as from about 600 Pa-s to about 5000 Pa-s, such as from about 700 Pa-s to about 4000 Pa-s, such as from 800 Pa-s to about 3000 Pa-s, such as from about 1000 Pa-s to about 2500 Pa-s, such as about 1500 Pa-s. In one embodiment, the hemostatic composition has a viscosity of less than about 2500 Pa-s.

[00170] The viscosity of the paste can be measured by rheometers, and preferably rotational shear-based rheometers. Viscosity can be measured using a Waters TA Instruments Discovery Hybrid Rheometer (DHR-1) with controlled voltage and the following measurement conditions: oscillation measurement mode with time sweep, oscillation voltage of 1%, angular frequency of 1 rad / s, a 20 mm diameter top geometry plate and a 1.25 mm gap size. Measurements can be performed at temperatures of or between 25 and 30°C, and preferably at 25°C, and at a relative humidity between 65 and 75%.

[00171] Thus, in one embodiment the present description provides a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen, c) thrombin, and d) an aqueous medium.

[00172] Preferably, the hemostatic composition comprises a quantity of aqueous medium sufficient to form a flowable paste.

[00173] In one embodiment, the aqueous medium is selected from the group consisting of water, saline solution, a calcium chloride solution and Petition 870260065366, dated 02 / 07 / 2026, page 45 / 66 / 57, a buffered aqueous medium. The water may be WFI (Water for Injection). In one embodiment, the aqueous medium is selected so that the reconstituted paste product is essentially isotonic. The aqueous medium is preferably sterile.

[00174] In one embodiment, the aqueous medium comprises calcium ions.

[00175] The aqueous medium of the present description is, in one embodiment, a saline solution.

[00176] In one embodiment, the aqueous medium is a calcium chloride solution.

[00177] In other modalities, the aqueous medium is water.

[00178] The aqueous medium may also be a buffered aqueous medium. Any suitable buffering agent known to a person skilled in the art may be used, such as one or more buffering agents selected from the group consisting of: Sodium citrate; Citric acid, Acetic acid, Sodium acetate, K2HPO4, KH2PO4, Na2HPO4, NaH2PO4, CHES, Borax, Sodium hydroxide; TAPS; Bicin; Tris; Tricin; TAPSO; HEPES; TES; MOPS; PIPES; Cacodylate; SSC; MES or others. The pH of the buffered aqueous medium must be suitable to create an intended hemostatic composition for human use and may be determined by a person skilled in the art.

[00179] The amount of aqueous medium is sufficient to provide a paste-like composition, such as between 2 and 12 mL per gram of biocompatible polymer, such as 4 to 10 mL, such as 4 to 8 mL, such as 4 to 7 mL, such as 5 to 6 mL of aqueous medium per gram of biocompatible polymer.

[00180] In one embodiment, the present description provides a hemostatic composition comprising: a) one or more biocompatible polymers in particulate form in an amount of 7 to 34% by weight, Petition 870260065366, dated 02 / 07 / 2026, p. 46 / 66 / 57 b) fibrinogen in an amount of 0.008 to 5% by weight, c) thrombin in an amount of 7 to 1700 IU per gram, d) an aqueous medium.

[00181] In one embodiment, the hemostatic composition comprises the biocompatible polymer in particulate form in an amount of about 7% to 20%, such as about 9% to 19%, for example about 11% to 18%, such as about 12% to 17%, for example about 14% to 17% by weight.

[00182] In one embodiment, the hemostatic composition comprises the biocompatible polymer in particulate form in an amount of about 7% to 20%, such as about 10% to 20%, for example about 11% to 20%, such as about 12% to 20%, for example about 13% to 20%, such as about 14% to 20%, for example about 14% to 19%, such as about 14% to 18%, for example about 14% to 17% by weight.

[00183] In one embodiment, the hemostatic composition comprises the biocompatible polymer in particulate form in an amount of about 13 to 15%, such as about 14%. In another embodiment, the hemostatic composition comprises the biocompatible polymer in particulate form in an amount of about 16 to 18%, such as about 17% by weight.

[00184] In one embodiment, the hemostatic composition comprises between about 60% and about 93% water, for example between about 70% and about 90% water, such as between about 75% and about 90% water, for example between about 80% and about 90% water.

[00185] In one embodiment, the hemostatic composition, in the form of a flowable paste, comprises fibrinogen in an amount of 0.01% to 2.5% by weight, such as 0.1% to 2% by weight, such as 0.2% to 2% by weight, such as 0.3% to 2% by weight, such as 0.4% to 2% by weight, such as 0.4% to 1.8% by weight, such as 0.4% to 1.7% by weight, such as 0.4% to 1.6% by weight, such as 0.4% to 1.5% by weight. In one embodiment, the composition Petition 870260065366, dated 02 / 07 / 2026, page 47 / 66 / 57 hemostatic composition comprises fibrinogen in an amount between 0.3 and 1.2%, such as approximately 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% or approximately 1.1% by weight. In one embodiment, the hemostatic composition comprises fibrinogen in an amount of 0.3 to 1.2% by weight.

[00186] In one embodiment, the hemostatic composition, in the form of a flowable paste, comprises thrombin in an amount of 16 to 900 IU / g, such as 100 to 700 IU / g, such as 100 to 200 IU / g, such as 100 to 200 IU / g, such as 200 to 300 IU / g, such as 300 to 400 IU / g, such as 400 to 500 IU / g, such as 500 to 600 IU / g or 600 to 700 IU / g. In another embodiment, the hemostatic composition comprises thrombin in an amount of 280 to 350 IU / g of the hemostatic composition.

[00187] In one embodiment, the hemostatic composition as described herein is sterile. Containers

[00188] In one embodiment, the hemostatic composition as described herein is provided in a first container and an aqueous solution is provided in a second container, which upon connection can form the final hemostatic paste composition to be applied to a hemorrhage.

[00189] The first and second containers may be manufactured from any suitable material such as plastic, glass, ceramic, plastic or metal, such as stainless steel. Examples of suitable plastic materials include, but are not limited to, polyethylene, polypropylene, polystyrene, polyvinyl chloride and polytetrafluoroethylene (PTFE).

[00190] In one embodiment, the hemostatic composition is provided in a container that may be selected from a syringe, a bottle, a jar, a tube, a tray or a cartridge.

[00191] In a preferred embodiment, the first container holding the hemostatic composition is an administration device. Petition 870260065366, dated 02 / 07 / 2026, p. 48 / 66 / 57, medically appropriate for dispensing fluid hemostatic compositions to a patient in need thereof, such as a syringe, such as a single-use plastic syringe.

[00192] The first container is usually made of a material suitable for chemical surface sterilization without affecting the contents of the container. For example, said first container may be made from a material that is impermeable to ethylene oxide, such as for example made of metal, glass or a plastic that is impermeable to ethylene oxide.

[00193] In one embodiment, an aqueous solution is provided in a second container which may be selected from a syringe, a bottle, a jar, a tube, a tray or a cartridge.

[00194] In a preferred embodiment, the aqueous solution retaining container is a medical administration device suitable for dispensing fluid hemostatic compositions to a patient in need thereof, such as a syringe. In another embodiment, the second container is a single-use plastic syringe.

[00195] In one embodiment, the first and second containers are interconnectable. The connecting portion may be a connecting portion of a standard type, such as a Luer closure or Luer sliding connector. The connecting portion may be provided with a threaded portion to secure the connection with the corresponding connector. The dimensions of said Luer closure or Luer sliding connector may be able to change the air mixing capacity of the hemostatic composition during mixing of the hemostatic composition and the aqueous medium. Additionally, the dimensions of the Luer closure or Luer sliding connector may be able to influence the consistency of the hemostatic composition.

[00196] In one embodiment, the connecting portion comprises a static mixer. The dimensions of said static mixer may be Petition 870260065366, dated 02 / 07 / 2026, pp. 49 / 66 / 57 capable of changing the air mixing capacity of the hemostatic composition during mixing of the hemostatic composition and the aqueous medium. Additionally, the dimensions of the static mixer may be able to influence the consistency of the hemostatic composition. Sterilization

[00197] The hemostatic compositions according to the present description are preferably sterile.

[00198] Thus, in one embodiment, the hemostatic composition described herein is a sterile hemostatic composition.

[00199] Any suitable sterilization technique known in the art may be used. Sterilization refers to any process that effectively kills or eliminates transmissible agents (such as forms of fungi, bacteria, viruses, prions and spores, etc.). Sterilization can be achieved, for example, through the application of heat, chemicals and / or irradiation.

[00200] Sterilization can be achieved by thermal sterilization, including autoclaving (use of steam at high temperatures) and dry heat.

[00201] Sterilization can also be achieved by irradiation, for example ionizing radiation, in order to provide sterility to the components. Such irradiation may include beam (beta irradiation), X-rays, gamma and beta rays, UV light and subatomic particles. The level of irradiation and conditions for sterilization, including the time, are those that provide sterile compositions. The sterilization conditions are similar to those currently used in the art and can be determined by a skilled person.

[00202] Sterilization can be carried out by chemical sterilization such as using ethylene oxide gas, ozone, nitrogen dioxide, chlorine bleach, glutaraldehyde, formaldehyde, ortho-phthalaldehyde, hydrogen peroxide and / or peracetic acid.

[00203] The hemostatic composition or biocompatible polymer in Petition 870260065366, dated 02 / 07 / 2026, page 50 / 66 / 57 particulate form can also be prepared using aseptic methods. Medical use

[00204] The present description further refers to the hemostatic composition as described herein or obtained by the methods of this description for use in promoting hemostasis and / or healing of wounds, bone, tendon and / or tissue in an individual in need thereof.

[00205] In one embodiment, the present description provides a hemostatic composition as described herein for use in promoting hemostasis in an individual in need thereof. In another embodiment, the present description provides a hemostatic composition as described herein for use in promoting wound healing in an individual in need thereof.

[00206] The hemostatic composition of the present description can, for example, be used in a range of surgical procedures where hemorrhage control is desired. The hemostatic composition is preferably applied to a patient in the form of a paste that conforms to irregular surfaces and is therefore useful for providing rapid hemostasis on rough or irregular surfaces where hemostatic sponges are not effective.

[00207] Due to its superior hemostatic and adhesive properties, the hemostatic composition as described herein is particularly suitable for minimally invasive / robotic surgery where manual compression is impractical or impossible and / or where classic hemostatic fibrin sealants are ineffective. For example, the hemostatic composition in paste form as described herein can be sprayed onto a bleeding surface during minimally invasive surgery to provide a plaster-like hemostatic composition that adheres sufficiently to the bleeding and provides effective hemostasis without compression.

[00208] The hemostatic composition as described here was also Petition 870260065366, dated 02 / 07 / 2026, pp. 51 / 66 / 57, shows it to be capable of controlling severe hemorrhages. Thus, in one embodiment, the hemostatic composition as described herein is useful in the treatment of severe hemorrhages classified as level 4 or level 5 hemorrhages.

[00209] In general, hemostatic pastes are prepared directly at the surgical site at the time of need by a medical professional by adding liquid to a container, such as a syringe, containing a quantity of a hemostatic product. The hemostatic product may be pre-moistened with the liquid or be essentially dry (e.g., a free-flowing powder). The paste is thus frequently prepared under extremely stressful conditions, and it is therefore essential that the process for preparing the paste be simple and quick to ensure that bleeding is stopped as quickly as possible and that no errors are made during the preparation of the paste so that the nurse can maintain focus on the surgeon's needs rather than on the preparation of the hemostat. It is also important that the consistency of the paste is suitable for use as a hemostatic paste and that the consistency of the product is independent of preparation to preparation and over time.Currently available flowable paste products (Floseal® and Surgiflo®) require separate reconstitution of thrombin before mechanical mixing of said reconstituted thrombin solution with the biocompatible polymer by passing the biocompatible polymer and the liquid between two connected syringes several times to obtain a substantially homogeneous paste. Thrombin reconstitution is time-consuming and error-prone, two undesirable factors in an OR setting. These products are often pre-prepared in the OR before surgery in case they are needed during surgery, and unused product is frequently discarded, causing unnecessarily high OR costs.

[00210] Given that the hemostatic composition of the present description, in Petition 870260065366, dated 02 / 07 / 2026, page 52 / 66 / 57. In dry form, stable during storage, already including thrombin and fibrinogen, the hemostatic paste for application to a patient can be prepared more easily since separate reconstitution and addition of, for example, thrombin is not necessary. To obtain the hemostatic composition of the present description in paste form, one can simply add an adequate amount of an aqueous medium to a container containing the hemostatic composition (in dry form) and mix by transferring the contents between two interconnected syringes several times, after which a ready-to-use hemostatic paste is formed.

[00211] A notable advantage of the compositions and methods of the present invention is that they allow better control of the consistency of the hemostatic compositions, while providing a superior hemostatic effect. This is highly valuable in RO, where hemostasis needs to be achieved efficiently and as quickly as possible.

[00212] Another advantage of the composition and methods of the present description is that a kit consisting of fewer components can be prepared when compared with current hemostatic flowable kits. All that is required to prepare a flowable paste composition in the OR is the dry, storage-stable hemostatic composition comprised within a first container, such as a syringe, and a second container, such as a syringe, comprising an aqueous solution. Upon connecting the two and mixing, a ready-to-use flowable paste containing all the agents necessary for highly effective hemostasis is formed. Thus, no extra syringes, vial adapters, needles, or mixing vessels are required. This means that manufacturing costs can be reduced and also ensures good patient safety, since there are fewer components for OR personnel to monitor during surgery.Needle-free preparation of the hemostat also ensures the safety of the OR personnel. Petition 870260065366, dated 02 / 07 / 2026, pages 53 / 66 / 57

[00213] In one embodiment, the present description refers to a method for stopping bleeding / promoting hemostasis in an individual in need thereof by applying the hemostatic composition as described herein to a bleeding site. In the application, the hemostatic composition is preferably in the form of a flowing paste.

[00214] The hemostatic composition of the present description can be used for any type of surgery including general surgery, cardiothoracic surgery, vascular surgery, plastic surgery, pediatric surgery, colorectal surgery, transplant surgery, surgical oncology, trauma surgery, endocrine surgery, breast surgery, skin surgery, otorhinolaryngology, gynecology, oral and maxillofacial surgery, dental surgery, orthopedic surgery, neurosurgery, ophthalmology, podiatric surgery, urology. The hemostatic composition is particularly suitable for minimally invasive / robotic surgery where manual compression is impractical or impossible.

[00215] In one embodiment, the present description refers to a method for promoting wound healing in an individual in need thereof by applying the hemostatic composition as described herein to the wound.

[00216] A “wound” broadly refers to injuries to the skin and / or underlying (subcutaneous) tissue initiated in different ways (e.g., pressure ulcers from prolonged bed rest and trauma-induced wounds) and with varying characteristics. Wounds can be classified into one of four grades depending on the depth of the wound: i) Grade I: wounds limited to the epithelium; ii) Grade II: wounds extending into the dermis; iii) Grade III: wounds extending into the subcutaneous tissue; and iv) Grade IV (or full-thickness wounds): wounds in which bones are exposed (e.g., a bony pressure point such as the greater trochanter or sacrum). The present description refers to the treatment of Petition 870260065366, dated 02 / 07 / 2026, p. 54 / 66 / 57 any type of wound mentioned above using the hemostatic composition of the present description.

[00217] Wound treatment can in principle result in wound healing or accelerated wound healing. Accelerated healing can be a result, for example, of administering a wound healing-promoting substance. Alternatively, wound healing can be promoted by preventing bacterial or viral infection or by reducing the risk of such an infection that would otherwise have prolonged the wound treatment process.

[00218] In one embodiment, the present description refers to a method for promoting bone and / or tendon healing in an individual in need thereof by applying the hemostatic composition as described herein to the injured bone / tendon.

[00219] The “individual” referred to here may be any mammal, including but not limited to mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits. It is preferred that the mammals be of the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals be of the order Artiodactyla, including Bovines (cows) and Swine (pigs), or of the order Persodactyla, including Equines (horses). It is more preferred that the mammals be of the order Primates, Ceboids or Simoids (monkeys), or of the order Anthropoids (humans and howler monkeys). A particularly preferred mammal is the human being.

[00220] In one embodiment, the present description refers to a hemostatic composition as described herein, for use in the treatment of a wound, for example to stop bleeding or to promote wound healing. A hemostatic kit

[00221] This description also refers to a kit Petition 870260065366, dated 02 / 07 / 2026, page 55 / 66 / 57 hemostatic comprising the dry hemostatic composition as described herein and an aqueous solution or an aqueous medium such that upon mixing, a hemostatic composition suitable for use in hemostasis will be formed.

[00222] Consequently, in one embodiment the present description refers to a hemostatic kit comprising: a) a first syringe comprising a dry hemostatic composition as described herein, b) a second syringe comprising an aqueous medium; and c) optionally an outer packaging in which the two syringes are interconnectable.

[00223] Consequently, in one embodiment the present description refers to a hemostatic kit comprising: a) a first syringe comprising a dry hemostatic composition comprising one or more biocompatible polymers in particulate form, such as cross-linked gelatin particles, thrombin and fibrinogen as described herein, b) a second syringe comprising an aqueous medium; and c) optionally an outer packaging in which the two syringes are interconnectable.

[00224] In one embodiment, the kit additionally includes one or more applicator tips.

[00225] The kit may optionally contain instructions for use of the kit.

[00226] The components of the hemostatic kit may be as described herein or elsewhere.

[00227] In one embodiment, the kit comprises an outer packaging. The outer packaging is usually made from a flexible, semi-rigid or rigid material and typically consists of materials such as plastic, aluminum foil and / or plastic laminate, where the plastic may be selected from the group consisting of PET, PETG, PE, LLDPE, CPP, Petition 870260065366, dated 02 / 07 / 2026, pages 56 / 66 / 57 PA, PETP, METPET, Tyvek and optionally bonded with an adhesive, such as polyurethane or coextruded.

[00228] In one embodiment, the outer packaging is an aluminum foil outer packaging.

[00229] The outer packaging preferably forms a complete barrier to moisture.

[00230] The outer packaging is preferably capable of withstanding sterilization treatment such as radiation. Items

[00231] 1. A hemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 to 150 mg per gram of biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of biocompatible polymer.

[00232] 2. The hemostatic composition according to item 1, wherein one or more biocompatible polymers comprise or consist of powdered particles that are substantially insoluble in an aqueous medium.

[00233] 3. The hemostatic composition according to any of the preceding items, wherein one or more biocompatible polymers in particulate form comprise or consist of cross-linked gelatin particles.

[00234] 4. The hemostatic composition according to any of the preceding items, wherein the composition comprises from 5 to 100 mg of fibrinogen per gram of biocompatible polymer, such as from 20 to 80 mg, such as approximately 35 mg or approximately 70 mg of fibrinogen per gram of biocompatible polymer.

[00235] 5. The hemostatic composition according to any of the preceding items, wherein the composition comprises from 400 to 4000 IU of thrombin per gram of biocompatible polymer, such as from 300 to 3000 IU, Petition 870260065366, dated 02 / 07 / 2026, page 57 / 66 / 57, such as 500 to 2500 IU, such as approximately 2000 IU of thrombin per gram of biocompatible polymer.

[00236] 6. The hemostatic composition according to any of the preceding items, wherein the composition comprises: a) approximately 1 g of a biocompatible polymer in particulate form, such as gelatin, b) approximately 20 to 100 mg of fibrinogen, c) approximately 2000 IU of thrombin.

[00237] 7. The hemostatic composition according to any of the preceding items, wherein said composition contains less than 10% by weight of water, preferably less than 5% by weight of water, preferably less than 1% by weight of water.

[00238] 8. A method for preparing a hemostatic composition comprising the steps of: a) provide the hemostatic composition in accordance with any of items 1 to 7, and b) add a quantity of an aqueous medium to the hemostatic composition of a).

[00239] 9. A hemostatic composition obtained by the method according to item 8.

[00240] 10. The hemostatic composition according to item 9, wherein said composition remains fluid after the addition of the aqueous medium for at least 4 hours, such as at least 2 hours, such as at least 1 hour, such as at least 30 min.

[00241] 11. A hemostatic composition comprising: a) one or more biocompatible polymers in particulate form in an amount of 14 to 18% by weight of the hemostatic composition, b) fibrinogen in an amount of 0.3 to 1.2% by weight of the hemostatic composition, Petition 870260065366, dated 02 / 07 / 2026, pages 58 / 66 / 57 c) thrombin in an amount of 150 to 700 IU per gram of the hemostatic composition, and d) an aqueous medium, in which the hemostatic composition is a paste.

[00242] 12. The hemostatic composition according to any one of items 1 to 7 or 9 to 11, for use in promoting hemostasis and / or healing of wounds, bone, tendon and / or tissue in an individual in need thereof.

[00243] 13. A container comprising the hemostatic composition according to any one of items 1 to 7 or according to any one of items 9 to 11.

[00244] 14. The container according to item 13, wherein the container is an applicator, such as a syringe.

[00245] 15. A kit comprising, a) a first container comprising a composition according to any one of items 1 to 7, b) a second container comprising an aqueous medium; and c) optionally an outer packaging, in which the two containers are interconnectable. Examples Example 1: Applicability of paste compositions comprising thrombin, fibrinogen and a biocompatible polymer. Objective

[00246] To study the time that compositions according to the present description remain applicable from a syringe. Materials

[00247] 5 mL of a gelatin paste containing 1 g of cross-linked gelatin particles and recombinant human fibrinogen in a 10 mL syringe (first syringe). Three different amounts of fibrinogen were Petition 870260065366, dated 02 / 07 / 2026, pp. 59 / 66 / 57 tested: 7, 35 and 70 mg.

[00248] 1 mL of a recombinant human thrombin solution 2000 IU in a 10 mL syringe (second syringe).

[00249] The gelatin particles used in the paste were obtained from ground reticulated gelatin sponges (Spongostan). Method

[00250] The two syringes were interconnected using a Luer closure and the paste was transferred back and forth between the first and second syringes until mixed.

[00251] The pastes containing mixed fibrinogen contained approximately 14% w / w gelatin, approximately 285 IU of thrombin per gram of paste, and approximately 0.1% w / w (7 mg), 0.5% w / w (35 mg), or 1% w / w (70 mg) of fibrinogen, respectively.

[00252] The syringes were left at room temperature for the time periods indicated in Table 2 and the syringes were evaluated for paste coagulation within the syringe and the ability to apply the paste from the syringes via manual pressure on the plunger. Results

[00253] As can be seen in Table 2, the compositions according to the present description with varying amounts of fibrinogen remain applicable from a syringe for at least 90 minutes after mixing. In contrast, the compositions without biocompatible polymer coagulated in the syringe and could not be applied at any time point. Pastes containing gelatin, thrombin, and 105 mg fibrinogen / g gelatin were also tested (data not shown). Pastes containing 105 mg fibrinogen could be applied from a syringe, but it was found that the force required to apply the samples was markedly increased compared to samples containing less fibrinogen and produced pastes that were more likely to break or Petition 870260065366, dated 02 / 07 / 2026, pages 60 / 66 / 57 developing cracks consequently impacting the integrity and performance of the paste. Table 2: Syringe application capacity test with different compositions. Fibrinogen (mg / g of gelatin) Time Control 70 35 7 10 s Coagulated Approved Approved Approved 1 min Coagulated Approved Approved Approved 5 min Coagulated Approved Approved Approved 10 min Coagulated Approved Approved Approved 30 min Coagulated Approved Approved Approved 90 min Coagulated Approved Approved Approved a control that contained no gelatin and 35 mg of fibrinogen. Conclusion

[00254] The results surprisingly demonstrate that the paste compositions according to the present description remain applicable from a syringe for at least 90 minutes after mixing. Consequently, paste compositions comprising a biocompatible polymer, for example gelatin, thrombin and fibrinogen can be prepared and remain in the form of an applicable paste for a period of time compatible with clinical use during surgery. Example 2: Efficacy test of gelatin-thrombin pastes comprising various amounts of fibrinogen. Objective

[00255] To study the hemostatic efficacy of the paste compositions of Example 1, that is, the paste compositions comprising cross-linked gelatin, thrombin and fibrinogen compared with the paste compositions comprising only gelatin and thrombin. Hemostatic efficacy was tested in a porcine spleen biopsy model as described below. Materials and methods

[00256] Experimental model: A porcine spleen biopsy perforation model was used applying 8 mm perforations (3 mm of Petition 870260065366, dated 02 / 07 / 2026, page 61 / 66 / 57 depth) in the spleen with an initial compression period of 5 seconds followed by an evaluation period of 120 seconds and subsequent compression periods of 5 seconds.

[00257] The porcine spleen biopsy puncture model is an established model for evaluating the hemostatic efficacy of hemostatic pastes in vivo (Hutchinson et al., 2015, Surgical Technology International XXVII). The porcine spleen biopsy puncture model in the present study is similar to that used in Hutchinson et al., 2015.

[00258] Experimental animal: The pig is the animal of choice for this model since it has a large blood volume (70 ml / kg) and a large vascular spleen, which allows for many hemostatic comparisons in a single animal.

[00259] Sample preparation: The pastes were prepared as described in example 1. Three different amounts of fibrinogen of 7, 35 and 70 mg were studied. As a control, a paste without the addition of fibrinogen was used. The chemical content and water content in the tested samples and the control were identical, but with a difference in fibrinogen content.

[00260] Surgical procedures: A midline abdominal incision was made to expose the spleen. An 8 mm (3 mm deep) perforation was made in the spleen. The intensity of hemorrhage was assessed on a scale of 0 to 5 as described below. Only hemorrhage intensities of 3 and 4 were considered acceptable. The perforation was now prepared for either a control sample or a test sample. A new perforation was made for each test sample. Each type of sample was tested 7 times (n = 7). The samples were tested in a randomized order.

[00261] A 12-minute negative control, using only moistened gauze, was performed at the beginning and end of the test period on each pig. The negative controls were used as an indication of Petition 870260065366, dated 02 / 07 / 2026, page 62 / 66 / 57 the animal's ability to bleed throughout the study.

[00262] The primary test parameter was to measure time to hemostasis (TTH). TTH is defined as the total time minus the final hemostasis assessment period ensuring that no further bleeding occurred, i.e., no resumption of bleeding.

[00263] The assessment of hemorrhage intensity and the application of test samples and negative controls are described in detail below.

[00264] Hemorrhage intensity: The hemorrhage intensity of each perforation was assessed by the surgeon on a scale of 0 to 5 (see Table below). Hemorrhage intensity was observed at t = 0 for each perforation. Only the tests performed on wounds with hemorrhage intensity of 3 and 4 were used for further analysis. Table 3: Levels of hemorrhage intensity Level 0 No bleeding (for at least 30 seconds) Level 1 No bleeding observed initially, bleeding observed within the first 30 seconds of injury Level 2 Bleeding observed immediately following injury, wound site fills in approximately 30 seconds Level 3 Bleeding observed immediately following injury, wound site fills in approximately 3 seconds Level 4 Bleeding observed immediately following injury, wound site fills immediately following injury (does not include arterial or pulsating bleeding) Level 5 Bleeding observed immediately following injury, wound site fills immediately following injury (including arterial or pulsating bleeding)

[00265] Negative control: Moistened gauze was placed directly over the puncture site. Digital pressure was applied for 30 seconds followed by a 120-second hemostasis assessment period. Hemostasis was assessed (defined as no blood seepage under the test item for 30 seconds). If hemostasis was not achieved within 120 seconds, an additional 30 seconds of digital pressure was applied and a reassessment of hemostasis was performed in 120 seconds. Tamponade and observation periods were carried out until bleeding stopped and hemostasis was achieved, or until the test period reached 12 seconds. Petition 870260065366, dated 02 / 07 / 2026, page 63 / 66 / 57 minutes. Hemostasis was not achieved within the 12-minute test period for the negative controls, thus demonstrating the pig's ability to bleed throughout the study.

[00266] Application of test samples: Approximately 1 to 2 mL of paste were applied directly into the perforation using an applicator tip. During application, the tip penetrated the perforation to ensure tissue contact. After application, gauze moistened with 0.9% saline solution was placed over the perforation. Digital pressure (tamponade) was applied for 5 seconds. The pressure was then stopped and the gauze removed, followed by hemostasis assessment. If no blood sieving was observed under the test article for 120 seconds, hemostasis was considered achieved and the experiment terminated. If blood sieved under the test article within the 120-second time interval, the sieving time was recorded and digital pressure was again applied for 5 seconds, after which hemostasis was inspected. This procedure was continued until hemostasis was achieved or for 12 minutes, whichever occurred first.

[00267] Example of calculation for the evaluation of Time to Hemostasis: 5 seconds of digital pressure, inspection for hemostasis: blood sieves after 39 seconds, digital pressure for another 5 seconds, inspection for hemostasis for 120 seconds: no sieving conclusion: hemostasis was achieved after 5+39+5 seconds = 49 s. that is, the last observation period is not included in the TTH calculation. Results

[00268] The results are shown in Table 4. The results show that using samples containing 70 and 35 mg of fibrinogen, a shorter mean time to hemostasis was obtained compared to 7 mg of fibrinogen or the control (gelatin paste with thrombin, but without fibrinogen). Petition 870260065366, dated 02 / 07 / 2026, pages 64 / 66 / 57 Table 4: TTH composition of gelatin-thrombin + / - fibrinogen paste Fibrinogen (mg / g of gelatin) 0 (control) 70 35 7 Time to Hemostasis / s 21 ± 23 9 ± 10 9 ± 11 31 ± 22 Values ​​reported as mean ± standard deviation. Each sample was tested 7 times (n = 7) in randomized order. Conclusion

[00269] The paste compositions comprising gelatin, thrombin, and fibrinogen led to faster and more consistent hemostasis than the control paste without fibrinogen. Thus, the present study shows that it is beneficial to include fibrinogen in hemostatic paste compositions comprising gelatin and thrombin. Example 3: Efficacy test of gelatin-thrombin pastes comprising fibrinogen Objective

[00270] To study the hemostatic efficacy of the compositions according to the present description. Materials

[00271] 1 g of dry cross-linked gelatin particles, 2000 IU of thrombin and 70 or 105 mg of fibrinogen in a 10 mL syringe (first syringe).

[00272] 6 mL of aqueous solution into a 10 mL syringe (second syringe).

[00273] The gelatin particles were obtained from ground cross-linked gelatin sponges (Spongostan) and the chemical content and water content in the tested samples and the control were identical, but with a difference in fibrinogen content. Methods

[00274] The two syringes were interconnected using a Luer fitting, and 6 mL of aqueous solution were transferred to the syringe containing the dry powder composition. The resulting mixture was transferred back and forth. Petition 870260065366, dated 02 / 07 / 2026, page 65 / 66 / 57 between the first and second syringes until mixed, resulting in a hemostatic composition contained in the second syringe.

[00275] The same porcine spleen biopsy perforation model as described in example 2 was used. Each sample type was tested 11 times (n = 11). Samples were tested in a randomized order. Results

[00276] The results for the reconstituted hemostatic paste are shown in Table 5. The results show a shorter mean time to hemostasis obtained using the reconstituted paste with fibrinogen compared to the control. Table 5: TTH composition of gelatin-thrombin + / - fibrinogen paste Fibrinogen (mg / g of gelatin) 0 (control) 70 105 Time to Hemostasis / s 34 ± 28 15 ± 16 27 ± 24 Values ​​reported as mean ± standard deviation. Each sample was tested 11 times (n=11) in randomized order.

[00277] The force required to apply samples with 105 mg of fibrinogen was markedly increased compared to samples containing 70 mg of fibrinogen, and the pastes produced were more likely to break or develop cracks, impacting the integrity and performance of the paste. Conclusion

[00278] The hemostatic compositions according to the present invention led to faster and more consistent hemostasis than the fibrinogen-free control paste. Petition 870260065366, dated 02 / 07 / 2026, p. 66 / 66

Claims

1 / 8 CLAIMS 1. Hemostatic composition, characterized in that it comprises: a) a biocompatible polymer in particulate form selected from gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, carboxymethylcellulose, polyglycolic acid, polyacetic acid and combinations thereof, b) fibrinogen in an amount of 1 to 150 mg per gram of the biocompatible polymer, and c) thrombin in an amount of 100 to 5000 IU per gram of the biocompatible polymer.

2. Hemostatic composition according to claim 1, characterized in that the biocompatible polymer in particulate form is present in an amount between 80% and 99% by weight of the composition, such as between 81% and 99%, such as between 82% and 99%, such as between 83% and 99%, such as between 84% and 99%, such as between 85% and 99%, such as between 86% and 99%, such as between 87% and 99%, such as between 88% and 99%, such as between 89% and 99%, such as between 90% and 99% by weight of the composition.

3. Hemostatic composition according to claim 1 or 2, characterized in that the biocompatible polymer in particulate form is present in an amount of 0.05 to 20 g, such as 0.2 to 10 g, such as 0.5 to 2 g, such as about 1 g.

4. Hemostatic composition according to any of the preceding claims, characterized in that the biocompatible polymer comprises or consists of powdered particles that are substantially insoluble in an aqueous medium.

5. Hemostatic composition according to any of the preceding claims, characterized in that the biocompatible polymer is cross-linked. Petition 870250024947, dated 03 / 28 / 2025, page 77 / 84 2 / 8 6. Hemostatic composition according to any of the preceding claims, characterized in that the biocompatible polymer is biologically absorbable.

7. Hemostatic composition according to any of the preceding claims, characterized in that the biocompatible polymer in particulate form comprises or consists of cross-linked gelatin particles.

8. Hemostatic composition according to claim 7, characterized in that the gelatin is obtained from a micronized gelatin sponge or hydrogel.

9. Hemostatic composition according to any one of claims 1 to 8, characterized in that the biocompatible polymer particles have an average size between 1 and 1000 µm, such as between 100 and 800 µm, such as between 300 and 500 µm, such as about 450 micrometers as measured by laser diffractometry.

10. Hemostatic composition according to any of the preceding claims, characterized in that the fibrinogen is human fibrinogen.

11. Hemostatic composition according to any of the preceding claims, characterized in that the fibrinogen is recombinant human fibrinogen.

12. Hemostatic composition according to any of the preceding claims, characterized in that the composition comprises from 5 to 100 mg of fibrinogen per gram of biocompatible polymer, such as from 20 to 80 mg, such as about 35 mg or about 70 mg of fibrinogen per gram of biocompatible polymer.

13. Hemostatic composition according to any of the preceding claims, characterized in that the composition comprises from 20 to 100 mg of fibrinogen per gram of the biocompatible polymer, such as from about 30 mg to about 100 mg.

14. Hemostatic composition according to any of the preceding claims, characterized in that the composition comprises fibrinogen in an amount of 1 to 10% by weight, such as 2 to 5% by weight, such as about 3.5% by weight.

15. Hemostatic composition according to any of the preceding claims, characterized in that the thrombin is human thrombin.

16. Hemostatic composition according to any of the preceding claims, characterized in that the thrombin is recombinant human thrombin.

17. Hemostatic composition according to any of the preceding claims, characterized in that the composition comprises from 400 to 4000 IU of thrombin per gram of biocompatible polymer, such as from 300 to 3000 IU, such as from 500 to 2500 IU, such as about 2000 IU of thrombin per gram of biocompatible polymer.

18. Hemostatic composition according to any of the preceding claims, characterized in that the composition comprises a thrombin to fibrinogen ratio of 0.5 IU / mg to 5000 IU / mg, such as from 1 IU / mg to 2000 IU / mg, such as from 2 IU / mg to 150 IU / mg, such as from about 10 to 100 IU / mg.

19. Hemostatic composition according to any of the preceding claims, characterized in that the composition comprises: a) about 1g of said biocompatible polymer in particulate form, such as gelatin, b) about 35 mg of fibrinogen, c) about 2000 IU of thrombin.

20. Hemostatic composition according to any of the preceding claims, characterized in that it additionally comprises one or more additional active ingredients capable of stimulating hemostasis, wound healing, bone healing, tissue healing and / or tendon healing.

21. Hemostatic composition according to claim 20, characterized in that one or more active ingredients are selected from the group consisting of: Factor XIII, tranexamic acid, bone morphogenetic proteins, metalloproteinases, insulin-like growth factor 1 (IGF-I), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor, transforming growth factor beta (TGF-β) and extracellular matrix (ECM) flakes or particles.

22. Hemostatic composition according to any of the preceding claims, characterized in that it additionally comprises one or more hydrophilic compounds.

23. Hemostatic composition according to claim 22, characterized in that one or more hydrophilic compounds comprise polyethylene glycol (PEG).

24. Hemostatic composition according to claim 22, characterized in that one or more hydrophilic compounds are one or more polyols selected from sugar alcohols, sugars and / or derivatives thereof.

25. Hemostatic composition according to claim 24, characterized in that the sugar alcohol is selected from the group consisting of: glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, dulcitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, polyglycitol and mixtures thereof.

26. Hemostatic composition according to any one of claims 22 to 25, characterized in that the hydrophilic compound Petition 870250024947, dated 03 / 28 / 2025, p. 80 / 84 5 / 8 is present in an amount of 0.01 g to 0.5 g of hydrophilic compound per gram of biocompatible polymer, such as 0.01 g to 0.4 g, such as 0.01 to 0.3 g, such as 0.01 to 0.2 g, such as 0.01 to 0.1 g, such as 0.01 to 0.05 g of hydrophilic compound per gram of biocompatible polymer.

27. Hemostatic composition according to any of the preceding claims, characterized in that it further comprises one or more extrusion enhancers, such as albumin, preferably human serum albumin.

28. Hemostatic composition according to any of the preceding claims, characterized in that said composition contains less than 10% by weight of water, preferably less than 5% by weight of water, preferably less than 1% by weight of water.

29. Hemostatic composition according to any of the preceding claims, characterized in that the composition is sterile.

30. Method for preparing a hemostatic composition, characterized in that it comprises the steps of: a) providing the hemostatic composition as defined in any one of claims 1 to 29, and b) adding a quantity of an aqueous medium to the hemostatic composition of a).

31. Method according to claim 30, characterized in that the amount of aqueous medium added is between 2 and 12 mL per gram of hemostatic composition provided in step a), such as between 3 and 10 mL, such as between 4 and 8 mL, such as between 4 and 7 mL, such as between 5 and 6 mL per gram of hemostatic composition.

32. Hemostatic composition, characterized by being obtained by the method as defined in claim 30 or 31.

33. Hemostatic composition, characterized by the fact that it is obtained by the method as defined in claim 30 or 31, wherein said hemostatic composition is a fluid composition.

34. Hemostatic composition according to claim 32 or 33, characterized in that said composition remains fluid after the addition of the aqueous medium for at least 4 hours, such as at least 2 hours, such as at least 1 hour, such as at least 30 min.

35. Hemostatic composition according to any one of claims 32 to 34, characterized in that said composition is applicable from a syringe after the addition of the aqueous medium for at least 4 hours, such as at least 2 hours, such as at least 1 hour, such as at least 30 min.

36. Hemostatic composition, characterized in that it comprises: a) a biocompatible polymer in particulate form in an amount of 7 to 34% by weight, wherein said biocompatible polymer is selected from gelatin, collagen, chitin, chitosan, alginate, cellulose, oxidized cellulose, carboxymethylcellulose, polyglycolic acid, polyacetic acid and combinations thereof; b) fibrinogen in an amount of 0.008 to 5% by weight; c) thrombin in an amount of 7 to 1700 IU per gram of the hemostatic composition; and d) an aqueous medium.

37. Hemostatic composition according to claim 36, characterized in that said biocompatible polymer in particulate form comprises or consists of cross-linked gelatin particles.

38. Hemostatic composition according to claim 36 or 37, characterized in that the biocompatible polymer is present in an amount of 10% to 30%, such as 10% to 25%, such as 10% to 20%, such as about 15% by weight. Petition 870250024947, dated 03 / 28 / 2025, pp. 82 / 84 7 / 8 39. Hemostatic composition according to any one of claims 36 to 38, characterized in that fibrinogen is present in an amount of 0.01% to 2.5% by weight, such as 0.1% to 1.5% by weight, such as 0.3% to 1.2% by weight.

40. Hemostatic composition according to any one of claims 36 to 39, characterized in that fibrinogen is present in an amount of 0.5% to 1.2% by weight.

41. Hemostatic composition according to any one of claims 36 to 40, characterized in that thrombin is present in an amount of 16 to 900 IU per gram, such as 150 to 700 IU per gram of the hemostatic composition.

42. Hemostatic composition according to any one of claims 36 to 41, characterized in that thrombin is present in an amount of 280 to 350 IU per gram of the hemostatic composition.

43. Hemostatic composition according to any one of claims 36 to 42, characterized in that the hydrophilic compound is present in an amount of 1% to 20% by weight, such as 1% to 15% by weight, or 1% to 10% by weight.

44. Hemostatic composition according to any one of claims 36 to 43, characterized in that the aqueous medium is selected from the group consisting of water, saline solution, a calcium chloride solution and a buffered aqueous medium.

45. Hemostatic composition according to any one of claims 36 to 44, characterized in that the aqueous medium comprises calcium ions.

46. ​​Hemostatic composition according to any one of claims 36 to 45, characterized in that the composition is sterile.

47. Hemostatic composition according to any one of claims 36 to 46, characterized in that the composition is a flowable composition.

48. Hemostatic composition according to any one of claims 36 to 47, characterized in that the composition is a paste.

49. Hemostatic composition according to any one of claims 1 to 29 or 32 to 48, characterized by being for use in promoting hemostasis and / or healing of wounds, bone, tendon and / or tissue in an individual in need thereof.

50. Container, characterized in that it comprises the hemostatic composition as defined in any one of claims 1 to 29 or the hemostatic composition as defined in any one of claims 32 to 48.

51. Container according to claim 50, characterized in that the container is an applicator, such as a syringe.

52. Kit, characterized in that it comprises a) a first container comprising a composition as defined in any one of claims 1 to 29, b) a second container comprising an aqueous medium; and c) optionally, an outer packaging, wherein the two containers are interconnectable.

53. Kit according to claim 52, characterized in that the first and / or second containers are syringes. Petition 870250024947, dated 03 / 28 / 2025, pp. 84 / 84