Haemostatic composition

Abstract

The present disclosure relates to haemostatic compositions comprising a biocompatible polymer, thrombin, fibrinogen and optionally further components as well as methods for the preparation of such compositions.

Description

[0001] Haemostatic composition

[0002] Technical field

[0003] The present disclosure relates to haemostatic compositions comprising a biocompatible polymer, thrombin, fibrinogen and optionally further components as well as methods for the preparation of such compositions.

[0004] Background

[0005] Protein-based haemostatic materials such as gelatine are commercially available in solid sponge and loose or unpacked powder form for use in surgical procedures. Mixing of the loose or unpacked powder with a fluid such as saline or a thrombin solution may form a paste or slurry that is useful as a haemostatic composition for use in cases of diffuse bleeding, particularly from uneven surfaces or hard to reach areas, depending on mixing conditions and relative ratios of the materials.

[0006] Haemostatic pastes are usually prepared at the point of use by mechanical agitation and mixing of gelatine in particulate, crosslinked form and a liquid, e.g. a thrombin solution, to provide uniformity of the composition. Mixing to form a paste usually requires extensive mixing, such as kneading or transfer between two syringes.

[0007] Surgiflo® Haemostatic Matrix (Ethicon) is a commercially available kit for producing a haemostatic gelatine paste comprising thrombin, which is prepared by transferring a gelatine matrix-thrombin solution mixture back and forth between two connected syringes. Floseal® Haemostatic Matrix (Baxter) is likewise a kit for producing a haemostatic gelatine paste. Once a substantially homogenous paste composition is achieved, the haemostatic pastes can be applied to a bleeding to promote haemostasis by extruding the paste from the syringe.

[0008] Thrombin is a well-known haemostatic adjuvant in haemostatic compositions, which acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalysing many other coagulation-related reactions. The combination of thrombin and fibrinogen is also used in certain haemostatic products currently in clinical use, such as thrombin and fibrinogen-containing sponges, patches, glues and sealants. However, since thrombin acts on fibrinogen in the presence of water, the thrombin and fibrinogen are either provided separately or provided together in dry form to prevent premature action of thrombin on fibrinogen. For application, the thrombin and fibrinogen components can either be applied to the patient in dry form or be mixed with an aqueous medium upon application to the patient.

[0009] Although the currently available haemostatic products are effective in controlling mild and moderate bleedings, it would be beneficial to have haemostatic compositions that are able to control such bleedings even faster and more efficiently as well as being useful in controlling more severe bleedings. It would be even more beneficial to have haemostatic products that are efficient in controlling bleedings in minimally invasive surgical procedures where sponges, patches, glues and sealants are impractical or inefficient.

[0010] Summary

[0011] The present disclosure provides compositions with improved haemostatic properties and methods for preparing such haemostatic compositions. The improved haemostatic properties are due to an optimised combination of components leading to improved adhesive properties. Such compositions are highly valuable in the operating room, where bleeding must be controlled in a fast and efficient manner.

[0012] Surprisingly, the present inventors have shown that the haemostatic paste compositions disclosed herein comprising a biocompatible polymer, thrombin and fibrinogen remain flowable after reconstitution for more than 1 .5 hours. Accordingly, the paste compositions of the present disclosure can be prepared in advance and used for an extended period of time, which is highly advantageous in the operating room and in advanced surgical procedures.

[0013] Thus, in one aspect, the present disclosure provides a haemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 mg to 150 mg per gram of the biocompatible polymer, c) thrombin in an amount of 100 III to 5000 IU per gram of the biocompatible polymer, and d) one or more surfactant(s). The inventors have shown that the addition of one or more surfactant(s) improves the water absorption capacity of the haemostatic composition.

[0014] In a second aspect, the present disclosure relates to a method for preparing a haemostatic composition comprising the steps of: a) providing the dry haemostatic composition as described herein, and b) adding an amount of an aqueous medium to the dry haemostatic composition of a).

[0015] The amount of aqueous medium added is usually an amount sufficient to achieve a haemostatic composition in the form of a paste.

[0016] In another aspect, the present disclosure provides a haemostatic 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 III to 1700 IU per gram, d) one or more surfactant(s), and e) an aqueous medium.

[0017] The haemostatic composition is usually provided in the form of a paste, i.e. the aqueous medium is present in an amount sufficient to provide a composition in paste form.

[0018] The examples herein demonstrate that addition of one or more surfactants results in advantageous properties of the paste compositions of the present disclosure. It is demonstrated that addition of the one or more surfactants as described herein produce a paste with lower complex viscosity, meaning that the paste is easier to express from a syringe and flows more easily. A further advantage is that the resulting paste is more uniform, as seen by the reduced differences in the complex viscosity between different sections of the paste along the length of the syringe.

[0019] In yet another aspect, the present disclosure relates to the haemostatic composition described herein for use in promoting haemostasis and / or wound, bone, tendon and / or tissue healing in an individual in need thereof.

[0020] In another aspect, the present disclosure relates to a container comprising the haemostatic composition described herein. In a final aspect, the present disclosure provides a kit comprising; a) a first container comprising a haemostatic composition as described herein, b) a second container comprising an aqueous medium; and c) optionally an outer package, wherein the two containers are interconnectable.

[0021] Definitions

[0022] A “bioactive agent” is any agent, drug, compound, composition of matter or mixture which provides some pharmacologic, often beneficial, effect that can be demonstrated in vivo or in vitro. An agent is thus considered bioactive if it has interaction with or effect on a cell tissue in the human or animal body. As used herein, this term further includes any physiologically or pharmacologically active substance that produces a localized or systemic effect in an individual. Bioactive agents may be a protein, such as an enzyme. Further 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. It may be used either prophylactically, therapeutically, in connection with treatment of an individual, such as a human or any other animal. The term “bioactive agent” as used herein does not encompass cells, such as eukaryotic or prokaryotic cells.

[0023] “Biocompatible” refers to a material’s ability to perform its intended function without eliciting any substantial undesirable local or systemic effects in the host.

[0024] "Biologically absorbable" or “resorbable” are terms which in the present context are used to describe that the materials of which the said powder are made can be degraded in the body to smaller molecules having a size which allows them to be transported into the blood stream. By said degradation and absorption the said powder materials will gradually be removed from the site of application. For example, gelatine can be degraded by proteolytic tissue enzymes to absorbable smaller molecules, whereby the gelatine, when applied in tissues, typically is absorbed within about 4-6 weeks and when applied on bleeding surfaces and mucous membranes typically within 3-5 days. “Haemostasis” is a process which causes bleeding to diminish or stop. Haemostasis occurs when blood is present outside of the body or blood vessels and is the instinctive response for the body to stop bleeding and loss of blood. During haemostasis three steps occur in a rapid sequence. Vascular spasm is the first response as the blood vessels constrict to allow less blood to be lost. In the second step, platelet plug formation, platelets stick together to form a temporary seal to cover the break in the vessel wall. The third and last step is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a “molecular glue”. Accordingly, a haemostatic compound is capable of stimulating haemostasis.

[0025] “International Unit (IU)”. In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, Ul, or as IE. It is used to quantify vitamins, hormones, some medications, vaccines, blood products, and similar biologically active substances.

[0026] A “paste” according to the present disclosure has a malleable, putty-like consistency, such as 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 as a solid until a sufficiently large load or stress is applied, at which point it flows like a fluid, i.e. a paste is flowable. Flowables conform efficiently to irregular surfaces upon application. Pastes typically consist of a suspension of granular material in a background fluid. The individual grains are jammed together like sand on a beach, forming a disordered, glassy or amorphous structure, and giving pastes their solid-like character. It is this "jamming together" that gives pastes some of their most unusual properties; this causes a paste to demonstrate properties of fragile matter. A paste is not a gel / jelly. A “slurry” is a fluid mixture of a powdered / pulverized solid with a liquid, such as water. Slurries behave in some ways like thick fluids, flowing under gravity and being capable of being pumped if not too thick. A slurry may functionally be regarded as a thin, watery paste, but a slurry generally contains more water than a paste. Substantially water-insoluble powder particles, such as cross-linked gelatine particles, will form a paste or slurry upon mixing with an aqueous medium.

[0027] “Percentage”. If nothing else is indicated, the percentage is percentage by weight: % w / w or wt%. Ratios are indicated as weight by weight (w / w). “Particle size”. A particle of the biocompatible polymer described herein is typically not perfectly spherically shaped. In most cases, the particle is not spherical, and will instead have an irregular shape, for example an elongated or branched shape. Thus, its size is not unambiguously defined by a single dimension such as its diameter or radius. When applying the common techniques as known to the skilled person for evaluating the particle size, the particle size is often quantified in terms of a representative particle diameter of an equivalent sphere. For example, the size of a non-spherical particle may be quantified by the diameter of an equivalent sphere having the same property as the actual particle, for example equivalent mass, volume, sedimentation rate, passing the same sieve aperture, or optical scattering or diffraction properties. Techniques and equipment to measure the particle size of a sample will be known to someone of skill in the art e.g. light scattering (such as laser diffraction), sieving, sedimentation, etc. Usually a sample comprising particles is characterized by a mean or average particle size, which corresponds to taking the average of the equivalent sphere diameter of the particles in the sample as measured by the corresponding technique.

[0028] “Particle size distribution” refers to the range of sizes that particles in a sample have. Particle size distribution is typically expressed in terms of the range of particle diameters present within a sample. It can be described using various metrics, such as the mean particle size, median particle size, and the distribution's width.

[0029] Particle size distribution can be characterized by the percentiles of diameters of particles, in the population. For example by identifying the sizes that correspond to the 10th, 50th, or 90thpercentile within the population of particle sizes. In general, the size corresponding to the X percentile within a population is defined as “dX”. For example:

[0030] • d50 (50thpercentile): Also known as median particle size, is the size below which 50% of the particles are smaller and 50% of the particles are larger. It’s the size that divides the population into two equal sizes.

[0031] • d10 (10thpercentile): is the particle size below which 10% of the particles in the distribution are smaller. In other words, 10% of the particles have sizes equal to or less than the d10 value.

[0032] • d90 (90thpercentile): is the particle size below which 90% of the particles in the distribution are smaller. In other words, 90% of the particles have sizes equal to or less than the d90 value. Description of drawings

[0033] Figure 1 . Effect of surfactants on the complex viscosity of pastes comprising 1 g gelatine, 2000 III thrombin, and 17.5 mg fibrinogen. The Y axis shows the measured complex viscosity from different sections of the syringe (start, middle, or end) for each sample. Further experimental details are given in Example 4. BAC: benzalkonium chloride.

[0034] Detailed description

[0035] The present disclosure provides compositions with improved haemostatic properties and methods to prepare said haemostatic compositions.

[0036] Thus, in one aspect, the present disclosure provides a haemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 to 150 mg per gram of the biocompatible polymer, c) thrombin in an amount of 100 to 5000 IU per gram of the biocompatible polymer, and d) one or more surfactant(s).

[0037] In a second aspect, the present disclosure relates to a method for preparing a haemostatic composition comprising the steps of: a) providing the dry haemostatic composition as described herein, and b) adding an amount of an aqueous medium to the dry haemostatic composition of a).

[0038] The advantages of the haemostatic compositions disclosed herein are numerous and include:

[0039] • Improved haemostatic effect, e.g. more severe bleedings can be stopped in less time.

[0040] • Less time spent preparing the haemostatic composition, e.g. bleeding can be stopped faster.

[0041] • Decreased risk of compromising the sterility of the haemostatic composition during preparation due to less handling steps.

[0042] • Decreased risk of making mistakes during preparation due to the simplified preparation of the paste.

[0043] • Reliable and consistent reconstitution within a short time period. • Superior consistency and adhesive properties decreasing the need for compression.

[0044] • Superior for Minimally Invasive Surgery (MIS) including robotic surgery.

[0045] • Application in sprayable patches possible.

[0046] • Avoids the time-consuming and error-prone dilution steps of standard haemostatic composition preparations.

[0047] • Minimises Operation Room costs since preparation of the currently described product is so simple and fast that there is no reason to pre-prepare haemostatic flowables before surgery which need to be discarded.

[0048] Dry haemostatic composition

[0049] The haemostatic composition is usually provided in substantially dry, storage stable form. In one embodiment, the dry composition is storage stable at room temperature for at least 12 months, preferably at least 24 months.

[0050] In one embodiment, the haemostatic composition comprises the one or more biocompatible polymer 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 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.

[0051] In one embodiment, the haemostatic compositions comprises the one or more biocompatible polymer in particulate form in an amount from 80% to 99% by weight of the composition, such as from 81% to 99%, such as from 82% to 99%, such as from 83% to 99%, such as from 84% to 99%, such as from 85% to 99%, such as from 86% to 99%, such as from 87% to 99%, such as from 88% to 99%, such as from 89% to 99%, such as from 90% to 99% by weight of the composition.

[0052] In one embodiment, the haemostatic compositions comprises the one or more biocompatible polymer in particulate form in an amount from 85% to 99% by weight of the composition, such as from 85% to 98%, such as from 85% to 97%, such from as 85% to 96%, such as from 85% to 96%, such as from 85 % to 95 % by weight of the composition.

[0053] For example, in one embodiment, the haemostatic composition comprises the one or more biocompatible polymers in particulate form in an amount 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.

[0054] In one embodiment, the haemostatic composition comprises the one or more biocompatible polymers in particulate form in an amount of 85 % to 97% by weight of the composition. In one embodiment, the haemostatic composition comprises the one or more biocompatible polymers in particulate form in an amount of 89 % to 97% by weight of the composition. In one embodiment, the haemostatic composition comprises the one or more biocompatible polymers in particulate form in an amount of 90% to 97% by weight of the composition. In one embodiment, the haemostatic composition comprises the one or more biocompatible polymers in particulate form in an amount of 92% to 97% by weight of the composition. In one embodiment, the haemostatic composition comprises the one or more biocompatible polymers in particulate form in an amount of 92 %, 93 %, 94 %, 95 %, 96 % or 97% by weight of the composition.

[0055] In one embodiment, present disclosure relates to a haemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 mg to 150 mg per gram of the biocompatible polymer, c) thrombin in an amount of 100 III to 5000 IU per gram of the biocompatible polymer, and d) one or more surfactant(s); wherein the one or more biocompatible polymers in particulate form is 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 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.

[0056] In one embodiment, present disclosure relates to a haemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 mg to 150 mg per gram of the biocompatible polymer, c) thrombin in an amount of 100 I U to 5000 IU per gram of the biocompatible polymer, and d) one or more surfactant(s); wherein the one or more biocompatible polymers in particulate form is 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.

[0057] In one embodiment, present disclosure relates to a haemostatic composition comprising: a) one or more biocompatible polymers in particulate form, b) fibrinogen in an amount of 1 mg to 150 mg per gram of the biocompatible polymer, c) thrombin in an amount of 100 III to 5000 IU per gram of the biocompatible polymer, and d) one or more surfactant(s); wherein, the one or more biocompatible polymers in particulate form is present in an amount of 90 % to 97 % by weight of the composition.

[0058] In one embodiment the haemostatic composition contains less than 10% water by weight, preferably less than 5% water by weight, preferably less than 1 % water by weight.

[0059] Biocompatible polymer

[0060] The biocompatible polymer of the present disclosure may be a biologic or a non-biologic polymer. Suitable biologic polymers include proteins, such as gelatine, collagen, albumin, hemoglobin, casein, fibrinogen, fibrin, fibronectin, elastin, keratin, and laminin; or derivatives or combinations thereof. Particularly preferred is the use of gelatine or collagen, more preferably gelatine. Other suitable biologic polymers include polysaccharides, such as glycosaminoglycans; starch derivatives, such as amylose, or amylopectin; xylan, cellulose derivatives, hemicellulose derivatives, agarose, alginate, and chitosan; or derivatives or combinations thereof. Suitable non-biologic polymers will be selected to be degradable by either of two mechanisms, i.e. (1) break down of the polymeric backbone or (2) degradation of side chains which result in aqueous solubility. Exemplary nonbiologic polymers include synthetics, such as polyacrylates, polymethacrylates, polyacrylamides, polyvinyl resins, polylactide- glycolides, polycaprolactones, and polyoxyethylenes; or derivatives or combinations thereof. Also combinations of different kinds of polymers are possible. In one embodiment, the biocompatible polymer in particulate form comprises or consists of a biocompatible polymer selected from the group consisting of: gelatine, collagen, chitin, chitosan, alginate, cellulose, oxidised cellulose, carboxymethylcellulose, polyglycolic acid, polyacetic acid and combinations thereof.

[0061] In one embodiment, the biocompatible polymer comprises or consists of powder particles, which are substantially insoluble in an aqueous medium.

[0062] In one embodiment, the biocompatible polymer is biologically absorbable. Examples of suitable biologically absorbable materials include gelatine, collagen, chitin, chitosan, alginate, cellulose, oxidised 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 contemplated for the present disclosure. In a preferred embodiment of the invention, the biologically absorbable material comprises or consists of gelatine. Gelatine is preferred since gelatine is highly biologically absorbable. Furthermore, gelatine is highly biocompatible, meaning that it is non-toxic to an animal, such as a human being, when / if entering the blood stream or being in long-term contact with human tissues.

[0063] The gelatine typically originates from a porcine source, but may originate from other animal sources, such as from bovine or fish sources. The gelatine may also be synthetically made, i.e. made by recombinant means.

[0064] In a preferred embodiment, the biocompatible polymer is cross-linked. Cross-linking usually renders the polymer substantially insoluble in an aqueous medium. In one embodiment, the biocompatible polymer consists of powder particles which are substantially insoluble in an aqueous medium. Any suitable cross-linking methods known to a person of skill may be used including both chemical and physical cross-linking methods.

[0065] In one embodiment of the present disclosure the polymer has been cross-linked by physical means, such as by dry heat. The dry heat treatment is usually performed 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 110-160°C, e.g. in the range of 110- 140°C, or in the range of 120-180°C, or in the range of 130-170°C, or in the range of 130-160°C, or in the range of 120-150°C. The period of time for cross-linking may be optimised by a skilled person and is normally a period between about 10 minutes to about 12 hours, such as about 1 hour to about 10 hours, for example between about 2 hours to about 10 hours, such as between about 4 hours to about 8 hours, for example between about 5 hours to about 7 hours, such as about 6 hours.

[0066] In another embodiment, the polymer has been cross-linked by chemical means, i.e. by exposure to a chemical cross-linking agent. Examples of suitable chemical cross-linking 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, e.g. 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).

[0067] In one embodiment, the biocompatible polymer particles according to the present disclosure are obtained from cross-linked sponges of e.g. gelatine or collagen, in particular cross-linked sponges of gelatine (such as the commercially available Spongostan® sponges and Surgifoam® sponges). The cross-linked sponges are micronized by methods known in the art to obtain a cross-linked biocompatible polymer in powder form, such as by rotary bed, extrusion, granulation and treatment in an intensive mixer, or milling (e.g. by using a hammer mill or a centrifugal mill).

[0068] Spongostan® / Surgifoam® available from Ethicon is a gelatine based cross-linked absorbable haemostatic sponge. It absorbs > 35 g of blood / g and within 4-6 weeks it is completely absorbed in the human body.

[0069] In one embodiment, the biocompatible polymer in particulate form comprises or consists of cross-linked gelatine particles.

[0070] In one embodiment, the cross-linked gelatine particles are obtained from a micronized porous gelatine sponge or dried hydrogel. In one embodiment, the porous gelatine sponge or dried hydrogel has been cross-linked by dry heat treatment.

[0071] Porous gelatine sponges may be prepared by mixing an amount of soluble gelatine with an aqueous medium 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 obtained cross-linked sponge can be micronized by methods known in the art. The gelatine foam usually has a gelatine concentration from about 1% to 70% by weight, usually from 3% to 20% by weight. Drying is usually performed at about 20°C to about 40°C for about 5 to 20 hours. The dried foam is usually cross-linked by exposure to a temperature of about 110°C to about 200°C for about 15 minutes to about 8 hours, such as at about 150°C to about 170°C for about 5 to 7 hours. The period of time for cross-linking may be optimised by a skilled person and is normally a period between about 10 minutes to about 12 hours, such as about 1 hour to about 10 hours, for example between about 2 hours to about 10 hours, such as between about 4 hours to about 8 hours, for example between about 5 hours to about 7 hours, such as about 6 hours.

[0072] Drying of the foam or hydrogel may also be achieved by freeze-drying by methods known to a person skilled in the art.

[0073] In one embodiment, the cross-linked gelatine particles are obtained by micronizing a crosslinked porous gelatine sponge or a substantially non-porous crosslinked dried hydrogel. The gelatine may be cross-linked, for example by exposure to either 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, held 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 or electron beam radiation. When cross-linking with glutaraldehyde, the cross-links are formed via Schiff bases which may be stabilized by subsequent reduction, e.g. by treatment with sodium borohydride.

[0074] Particles may be obtained from the dried product by methods known to a person skilled in the art. In one embodiment the gelatine particles are obtained by micronization of the dry product, such as by granulation and treatment in an intensive mixer, milling, e.g. by using a hammer mill, ball milling, or a centrifugal mill. In another embodiment, the particles are obtained by grinding of the dry product to an appropriate size. This can e.g. be done by mortar and pestle, crushing and any other available physical process.

[0075] In one embodiment, the particles are obtained by hammer milling of a sponge or dried hydrogel. Preferably, the hammer mill has a built-in sieve resulting in a desired particle size distribution. In one embodiment of the present invention, the gelatine particles have a diameter between about 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.

[0076] The particles are in one embodiment less than approximately 1000 microns in size, i.e. so that they are able to pass through a 1x1 mm sieve.

[0077] Generally, at least 90% of the powder particles have a size of between 1 pm and 1200 pm.

[0078] 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.

[0079] In one embodiment, the average particle size of the dry particles is from 601 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 750 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 700 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 680 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 670 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 660 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 650 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 640 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 630 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 620 pm. In one embodiment, the average particle size of the dry particles is from 601 pm to 610 pm.

[0080] In one embodiment, the average particle size of the dry particles is from 602 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 750 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 700 pm. In one embodiment, the average particle size of the dry particles is from 602 m to 680 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 670 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 660 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 650 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 640 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 630 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 620 pm. In one embodiment, the average particle size of the dry particles is from 602 pm to 610 pm.

[0081] In one embodiment, the average particle size of the dry particles is from 603 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 750 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 700 pm. In one embodiment, the average particle size of the dry particles is from

[0082] 603 pm to 680 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 670 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 660 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 650 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 640 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 630 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 620 pm. In one embodiment, the average particle size of the dry particles is from 603 pm to 610 pm.

[0083] In one embodiment, the average particle size of the dry particles is from 604 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 750 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 700 pm. In one embodiment, the average particle size of the dry particles is from

[0084] 604 pm to 680 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 670 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 660 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 650 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 640 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 630 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 620 pm. In one embodiment, the average particle size of the dry particles is from 604 pm to 610 pm.

[0085] In one embodiment, the average particle size of the dry particles is from 605 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 750 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 700 pm. In one embodiment, the average particle size of the dry particles is from

[0086] 605 pm to 680 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 670 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 660 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 650 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 640 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 630 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 620 pm. In one embodiment, the average particle size of the dry particles is from 605 pm to 610 pm.

[0087] In one embodiment, the average particle size of the dry particles is from 606 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 750 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 700 pm. In one embodiment, the average particle size of the dry particles is from

[0088] 606 pm to 680 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 670 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 660 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 650 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 640 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 630 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 620 pm. In one embodiment, the average particle size of the dry particles is from 606 pm to 610 pm.

[0089] In one embodiment, the average particle size of the dry particles is from 607 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 750 pm. In one embodiment, the average particle size of the dry particles is from 607 m to 700 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 680 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 670 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 660 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 650 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 640 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 630 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 620 pm. In one embodiment, the average particle size of the dry particles is from 607 pm to 610 pm.

[0090] In one embodiment, the average particle size of the dry particles is from 700 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 700 pm to

[0091] 790 pm. In one embodiment, the average particle size of the dry particles is from 700 pm to 780 pm. In one embodiment, the gelatine particles have an average particle size of 700 pm to 770 pm. In one embodiment, the average particle size of the dry particles is from 700 pm to 760 pm. In one embodiment, the average particle size of the dry particles is from 700 pm to 750 pm.

[0092] In one embodiment, the average particle size of the dry particles is from 700 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 710 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 720 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 730 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 740 pm to 799 pm. In one embodiment, the average particle size of the dry particles is from 750 pm to 799 pm.

[0093] In one embodiment, the average particle size of the dry particles is from 610 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 620 pm to

[0094] 791 pm. In one embodiment, the average particle size of the dry particles is from 630 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 640 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 650 pm to 791 pm.

[0095] In one embodiment, the average particle size of the dry particles is from 700 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 710 pm to 791 m. In one embodiment, the average particle size of the dry particles is from 720 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 730 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 740 pm to 791 pm. In one embodiment, the average particle size of the dry particles is from 750 pm to 791 pm.

[0096] The inventors have shown that haemostatic compositions prepared with particles having an average particle size from 601 pm to 799 pm have improved water absorption capacity. The absorption capacity may be measured by the methods known in the art e.g. using the droplet test. The droplet test may be performed by adding a predetermined amount of haemostatic paste, e.g. 1 g, onto a hanging net and thereafter adding a liquid, e.g. water, at a predetermined rate onto the paste until the first drop of liquid passes through the net, at which point the paste is considered saturated. The liquid may be added at a rate of ca. 0.5 mL / min but other rates may be possible. The water absorption capacity of the paste is calculated according to the following equation (Eq. I):

[0097] (g\ amount of water absorbed (g) water absorption capacity — = - - - — - (Eq. I)

[0098] \g / amount of paste (g)

[0099] In one embodiment, the dry particles have a d90 particle size from about 450 pm to 1300 pm, such from about 450 pm to about 550 pm, such from about 550 pm to about 650 pm, such from about 650 pm to about 750 pm, such from about 750 pm to about 850 pm, such as from about 850 pm to about 950 pm, such from about 950 pm to about 1050 pm, such from about 1050 pm to about 1150 pm, such from about 1150 pm to about 1300 pm.

[0100] In one embodiment, the dry particles have a d10 particle size from about 40 pm to 150 pm, such from about 40 pm to about 130 pm, such as from about 40 pm to about 110 pm, such from about 40 pm to about 100 pm.

[0101] In one embodiment, the dry particles have a d10 particle size from about 40 pm to 150 pm, such from about 50 pm to about 150 pm, such as from about 60 pm to about 150 pm, such from about 70 pm to about 150 pm. one embodiment, the dry particles have a d10 particle size from about 70 pm to 80 pm, such as from 80 pm to 90 pm, such as from 90 pm to 100 pm, such as from 100 pm to 110 pm, such as from 110 pm to 120 pm, such as from 120 pm to 130 pm, such as from 130 pm to 140 pm, such as from 140 pm to 150 pm.

[0102] In one embodiment, the dry particles have: i. an average particle size from 601 pm to 799 pm, as described herein; ii. a d10 particle size from about 80 pm to 150 pm, such as from 90 pm to about 120 pm, such as a d10 particle size of about 100 pm; and iii. a d90 particle size from about 1000 pm to about 1500 pm, such as from about 1000 pm to about 1300 pm, such as a d90 particle size of about 1250 pm as measured by e.g. laser diffraction.

[0103] In one embodiment, the dry particles are cross-linked gelatine particles having: i. an average particle size from 601 pm to 799 pm, as described herein; ii. a d10 particle size from about 80 pm to 150 pm, such as from 90 pm to about 120 pm, such as a d10 particle size of about 100 pm; and iii. a d90 particle size from about 1000 pm to about 1500 pm, such as from about 1000 pm to about 1300 pm, such as a d90 particle size of about 1250 pm as measured by e.g. laser diffraction.

[0104] The average particle size of the dry particles can e.g. be measured by laser diffraction. In one embodiment, the particle size of the dry particles described herein is measured by laser diffraction.

[0105] In one embodiment, the biocompatible polymer in particulate form is present in an amount from about 0.05 to 20 g, such as from about 0.2 to 10 g, such as from about 0.5 to 2g, such as about 1 g.

[0106] In one embodiment, the biocompatible polymer in particulate form is present in an amount of about 1 g.

[0107] The biocompatible polymers in particulate form used in the present disclosure are usually provided in sterile form. Fibrinogen

[0108] Fibrinogen or factor I is a glycoprotein complex that circulates in the blood of vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and is involved in the blood clot formation.

[0109] In one embodiment, the fibrinogen is human fibrinogen.

[0110] In one embodiment, the fibrinogen is recombinant human fibrinogen.

[0111] In other embodiments, the origin of the fibrinogen is from a mammal other than human, such as bovine fibrinogen.

[0112] In one embodiment, the fibrinogen is a dry fibrinogen composition. For example, the fibrinogen may be in the form of particles or a powder. The dry fibrinogen composition may be may be prepared by any methods known to the skilled person and is usually provided in sterile form. Thus, in one embodiment the dry fibrinogen composition is sterile.

[0113] The fibrinogen may be also coated onto the biocompatible polymer in particulate form. The coating of the fibrinogen onto the biocompatible polymer may be obtained by any methods known in the art, for example by spraying techniques, which can be performed in any spraying apparatus. For example, one well-known method for coating particles by spraying is a fluid bed process. Thus in one embodiment, the fibrinogen is coated onto the biocompatible polymer particles so as to obtain a layer of fibrinogen on the biocompatible polymer particle. In one embodiment, the fibrinogen is sprayed onto the biocompatible polymer particles, e.g. by fluid bed process techniques.

[0114] In one embodiment, the haemostatic composition comprises fibrinogen in an amount of about 1 to about 150 mg per gram of the biocompatible polymer, such as from about 5 to about 150 mg of fibrinogen per gram of the biocompatible polymer, such as from about 10 to about 150 mg, such as from about 15 to about 150 mg, such as from about 20 to about 150 mg, such as from about 25 to about 150 mg, such as from about 30 to about 150 mg, such as from about 30 to about 125 mg, such as from about 30 to about 100 mg of fibrinogen per gram of the biocompatible polymer.

[0115] In one embodiment, the haemostatic composition comprises fibrinogen in an amount from about 20 to about 80 mg of fibrinogen per gram of the 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 the biocompatible polymer. In one embodiment, the composition comprises about 35 mg of fibrinogen per gram of the biocompatible polymer. In one embodiment, the composition comprises about 70 mg of fibrinogen per gram of the biocompatible polymer.

[0116] In one embodiment, the haemostatic composition comprises fibrinogen in an amount from about 20 mg to about 100 mg of fibrinogen per gram of the biocompatible polymer, such as from about 25 mg to about 100mg, such as from about 30 mg to about 100mg, such as from 30 mg to about 95 mg, such as from 30 mg to about 90 mg, such as from 30 mg to about 85 mg of fibrinogen per gram of the biocompatible polymer.

[0117] In one embodiment, the haemostatic composition comprises no more than 100 mg of fibrinogen per gram of the biocompatible polymer. In one embodiment, the composition comprises more than 10 mg of fibrinogen per gram of the biocompatible polymer.

[0118] In one embodiment, the haemostatic composition comprises from about 20 to about 100 mg of fibrinogen per gram of the 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 the biocompatible polymer.

[0119] In one embodiment, the haemostatic composition comprises from about 6 mg to about 19 mg of fibrinogen per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, or 19 mg of fibrinogen per gram of biocompatible polymer.

[0120] In one embodiment, the haemostatic composition comprises from about 6 mg to about 10 mg of fibrinogen per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises from about 10 mg to about 15 mg of fibrinogen per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises from about 15 mg to about 19 mg of fibrinogen per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises from about 21 mg to about 25 mg of fibrinogen per gram of the biocompatible polymer. In one embodiment, the haemostatic composition, when in the dry form, i.e. prior to mixing with an aqueous medium, comprises fibrinogen in an amount from 1 to 15% by weight, such as 1 to 10% by weight, such as from 1 to 2%, such as from 2 to 3%, such as from 3 to 4%, such as from 4 to 5%, such as from 5 to 6%, such as from 6 to 7%, such as from 7 to 8%, such as from 8 to 9%, such as from 9 to 10% by weight.

[0121] In one embodiment, the haemostatic composition, prior to mixing with an aqueous medium, comprises fibrinogen in an amount from 2 to 15% by weight, such as from 2.5% to 15% by weight, such as from 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 as about 7.5% by weight, such as about 8% by weight, such as about 8.5% by weight, such as about 9% by weight, such as about 9.5% by weight, such as about 10% by weight.

[0122] Thrombin

[0123] Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin (coagulation factor II) is proteolytical ly cleaved to form thrombin in the coagulation cascade, which ultimately results in the stemming of blood loss. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalysing many other coagulation-related reactions. In the blood coagulation pathway, thrombin acts to convert factor XI to Xia, VIII to Villa, V to Va, and fibrinogen to fibrin.

[0124] In one embodiment, the thrombin is human thrombin.

[0125] In one embodiment, the thrombin is recombinant human thrombin.

[0126] In other embodiments, the origin of the thrombin is from a mammal other than human, such as bovine thrombin.

[0127] In one embodiment, the thrombin is in the form of prothrombin.

[0128] In one embodiment, the thrombin is a dry thrombin composition. For example, the thrombin may be in the form of particles or a powder. The dry thrombin composition may be 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. The thrombin may be also coated onto the biocompatible polymer in particulate form. The coating of the thrombin onto the biocompatible polymer may be obtained by any methods known in the art, for example by spraying techniques, which can be performed in any spraying apparatus. For example, a well-known method for coating particles by spraying is a fluid bed process. Thus in one embodiment, the thrombin is coated onto the biocompatible polymer particles so as to obtain a layer of thrombin on the biocompatible polymer particle. In one embodiment, the thrombin is sprayed onto the biocompatible polymer particles.

[0129] In some embodiments, the biocompatible polymer in particulate form is coated with both thrombin and fibrinogen using known methods of coating. A person of skill in the art will be aware on how to perform such coatings in a spraying apparatus, such as in a fluid bed process. For example, a first coating of fibrinogen or thrombin can be applied onto the biocompatible polymer particles, so as to obtain a first layer on the biocompatible polymer particles. Thereafter, a second coating of thrombin or fibrinogen may be applied, so as to obtain a second layer on the first layer.

[0130] It is also possible to combine both thrombin and fibrinogen in the same layer. For example, by simultaneously coating both thrombin and fibrinogen onto the biocompatible polymers particles so as to obtain a layer combining fibrinogen and thrombin. For example, thrombin and fibrinogen may each be sprayed simultaneously from separate spraying sources, or sprayed from the same spraying source.

[0131] In some embodiments, the medium used to spray thrombin and / or fibrinogen is a nonaqueous medium so as to prevent the catalytic reaction of thrombin on fibrinogen.

[0132] In one embodiment, a mixture of particles coated with thrombin and fibrinogen, respectively, is obtained by coating one subset of polymer particles with thrombin and another subset of polymer particles with fibrinogen and then combining the two coated subsets in the right ratio so as to obtain an optimal polymer:fibrinogen:thrombin ratio.

[0133] In one embodiment, the dry thrombin composition is prepared by spray-drying or freeze- drying.

[0134] In one embodiment, the dry thrombin composition is prepared by freeze-drying. In one embodiment, the dry thrombin composition comprises less than 2% water, such as less than 1 % water.

[0135] In one embodiment, the haemostatic composition comprises thrombin in an amount from 400 to 4000 III of thrombin per gram of the biocompatible polymer, such as from 400 to 600 IU, such as from 600 to 800 I U, such as from 800 to 1000 IU, such as from 1000 to 1200 IU, such as from 1200 to 1400 IU, such as from 1400 to 1600 IU, such as from 1600 to 1800 IU, such as from 1800 to 2000 IU, such as from 2000 to 2200 IU, such as from 2200 to 2400 IU, such as from 2400 to 2600 IU, such as from 2600 to 2800 IU, such as from 2800 to 3000 IU, such as from 3000 to 3200 IU, such as from 3200 to 3400 IU, such as from 3400 to 3600 IU, such as from 3600 to 3800 IU, such as from 3800 to 4000 IU, such as from 4000 to 4200 IU of thrombin per gram of the biocompatible polymer.

[0136] In one embodiment, the haemostatic composition comprises thrombin in an amount from about 500 IU to 2500 IU of thrombin per gram of the biocompatible polymer, such as from about 600 IU to 2500 IU, such as from about 700 IU to 2500 IU, such as from about 800 IU to 2500 IU, such as from about 900 IU to 2500 IU, such as from about 1000 IU to 2500 IU, such as from about 1100 IU to 2500 IU, such as from about 1200 IU to 2500 IU, such as from about 1300 IU to 2500 IU, such as from about 1400 IU to 2500 IU, such as from about 1500 IU to 2500 IU, such as from about 1600 IU to 2500 IU, such as from about 1700 IU to 2500 IU, such as from about 1800 IU to 2500 IU, such as from about 1900 IU to 2500 IU of thrombin per gram of the biocompatible polymer, such as about 500 IU, such as about 1000 IU, such as about 1500 IU, such as about 2000 IU, such as about 2500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the composition comprises about 2000 IU of thrombin per gram of the biocompatible polymer.

[0137] In one embodiment, the haemostatic composition comprises form about 101 IU to about 399 IU of thrombin per gram of the biocompatible polymer.

[0138] In one embodiment, the haemostatic composition comprises a ratio of thrombin to fibrinogen from 0.5 lU / mg to 5000 lU / mg, such as from 1 lU / mg to 2000 lU / mg, such as 2 lU / mg to 1000 lU / mg, such as from 2 lU / mg to 300 lU / mg, such as from 2 lU / mg to 250 lU / mg, such as from 2 lU / mg to 200 lU / mg, such as from 2 lU / mg to 150 lU / mg. In one embodiment, the haemostatic composition comprises a ratio of thrombin to fibrinogen of 4 lll / mg to 360 lll / mg, such as from 4 lll / mg to 50 lll / mg, such as from 50 lll / mg to 100 lll / mg, such as from 100 lll / mg to 150 lll / mg, such as from 150 lll / mg to 200 lll / mg, such as from 200 lll / mg to 250 lll / mg, such as from 250 lll / mg to 300 lll / mg, such as from 300 lll / mg to 360 lll / mg.

[0139] In one embodiment the haemostatic composition comprises 30 to 40 mg fibrinogen and 500 to 1000 III of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 30 to 40 mg fibrinogen and 1000 to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 30 to 40 mg fibrinogen and 1500 to 2000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 30 to 40 mg fibrinogen and 2000 to 2500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 40 to 50 mg fibrinogen and 500 to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 40 to 50 mg fibrinogen and 1000 to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 40 to 50 mg fibrinogen and 1500 to 2000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 40 to 50 mg fibrinogen and 2000 to 2500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 to 60 mg fibrinogen and 500 to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 to 60 mg fibrinogen and 1000 to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 to 60 mg fibrinogen and 1500 to 2000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 to 60 mg fibrinogen and 2000 to 2500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 60 to 70 mg fibrinogen and 500 to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 60 to 70 mg fibrinogen and 1000 to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 60 to 70 mg fibrinogen and 1500 to 2000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 60 to 70 mg fibrinogen and 2000 to 2500 III of thrombin per gram of the biocompatible polymer.

[0140] In one embodiment the haemostatic composition comprises 35 mg fibrinogen and 500 to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 35 mg fibrinogen and 1000 to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 35 mg fibrinogen and 1500 to 2000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 35 mg fibrinogen and 2000 to 2500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 mg fibrinogen and 500 to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 mg fibrinogen and 1000 to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 mg fibrinogen and 1500 to 2000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 50 mg fibrinogen and 2000 to 2500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 70 mg fibrinogen and 500 to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 70 mg fibrinogen and 1000 to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 70 mg fibrinogen and 1500 to 2000 IU of thrombin per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises 70 mg fibrinogen and 2000 to 2500 IU of thrombin per gram of the biocompatible polymer.

[0141] In one embodiment, the haemostatic composition comprises 5 mg to 25 mg fibrinogen and 100 IU to 1800 IU of thrombin per gram of the biocompatible polymer.

[0142] In one embodiment, the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 100 IU to 500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 500 IU to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 1000 IU to 1250 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 1250 IU to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 1500 III to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 1000 IU to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 1000 IU to 1800 IU of thrombin per gram of the biocompatible polymer.

[0143] In one embodiment, the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 100 IU to 500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 500 IU to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 1000 IU to 1250 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 1250 IU to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 1500 IU to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 1000 IU to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 1000 IU to 1800 IU of thrombin per gram of the biocompatible polymer.

[0144] In one embodiment, the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 100 IU to 500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 500 IU to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 1000 IU to 1250 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 1250 IU to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 1500 IU to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 1000 IU to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 1000 III to 1800 IU of thrombin per gram of the biocompatible polymer.

[0145] In one embodiment, the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 100 IU to 500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 500 IU to 1000 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 1000 IU to 1250 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 1250 IU to 1500 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 1500 IU to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 1000 IU to 1700 IU of thrombin per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 1000 IU to 1800 IU of thrombin per gram of the biocompatible polymer.

[0146] In one embodiment, the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 35 mg of fibrinogen, c) about 2000 IU of thrombin, and d) one or more surfactant(s) as described herein.

[0147] In one embodiment, the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as crosslinked gelatine particles, b) about 20 mg to 80 mg of fibrinogen, c) about 1000 IU to 4000 IU of thrombin, and d) one or more surfactant(s) as described herein. In one embodiment, the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as crosslinked gelatine particles, b) about 5 mg to 25 mg of fibrinogen, such as 10 mg to 25 mg of fibrinogen, such as 15 mg to 25 mg of fibrinogen, c) about 1000 III to 1800 IU of thrombin, such as 1200 IU to 1700 IU thrombin, such as 1500 IU to 1700 IU thrombin, and d) one or more surfactant(s) as described herein.

[0148] In one embodiment, the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 10 mg to 20 mg of fibrinogen, c) about 1000 IU to 1800 IU of thrombin, and d) one or more surfactant(s) as described herein.

[0149] In one embodiment, the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as crosslinked gelatine particles, b) about 15 mg to 20 mg of fibrinogen, c) about 1000 IU to 1800 IU of thrombin, and d) one or more surfactant(s) as described herein.

[0150] In one embodiment, the haemostatic composition contains less than 10% water by weight, preferably less than 5% water by weight, preferably less than 1% water by weight.

[0151] In one embodiment, the haemostatic composition is substantially dry. In one embodiment, the haemostatic composition is dry. Hydrophilic compounds

[0152] In one embodiment, the haemostatic composition further comprises one or more hydrophilic compounds. Hydrophilic compounds usually contain polar or charged functional groups, rendering them soluble in water. Inclusion of one or more hydrophilic compounds in the haemostatic composition of the present disclosure is believed to have a beneficial effect on thrombin stability and may improve reconstitution efficiency of the dry haemostatic composition. Hydrophilic compounds may also improve consistency of the haemostatic composition.

[0153] It has also been observed that haemostatic compositions comprising one or more hydrophilic compounds as described herein, in addition to the one or more surfactant(s) according to the present disclosure provide with reduced paste viscosity, meaning the paste is easier to express from a syringe, and results in a more uniform paste as seen by reduced differences of the complex viscosity between different sections of the paste measured along the length of the syringe. The hydrophilic compounds may also improve the absorption capacity of the haemostatic composition. The absorption capacity refers to the amount of water, or of an aqueous solution, that the composition can absorb per gram. The absorption capacity may be measured by the methods known in the art e.g. using the droplet test. The inventors have shown that the addition of hydrophilic compounds improves the water absorption capacity of the haemostatic composition. Absorption capacity can be measured as described elsewhere herein.

[0154] The one or more hydrophilic compound(s) described herein may be present in the haemostatic composition when in dry form, i.e. prior to mixing with an aqueous medium. The one or more hydrophilic compound(s) described herein may also (alternatively or additionally) be present in the aqueous medium prior to mixing with the haemostatic composition in dry form. When the hydrophilic compound is a liquid at normal conditions of temperature and pressure, it may be preferably present in the aqueous medium prior to mixing with the haemostatic composition in dry form. 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. When the haemostatic composition comprises one or more hydrophilic polymers as described herein, the one or more hydrophilic polymers are different than the biocompatible polymer in particulate form. In one embodiment, the hydrophilic polymer is selected from the group consisting of Polyethylenimine (PEI), Poly(ethylene glycol) (PEG), Poly(ethylene oxide), Poly(vinyl alcohol) (PVA), Poly(styrenesulfonate) (PSS), Poly(acrylic acid) (PAA), Poly(allylamine hydrochloride) and Poly(vinyl acid). Different forms of said polymer such as salts, crosslinked forms, esters, or other derivatives thereof are also contemplated for the present disclosure.

[0155] In one embodiment, the hydrophilic compound is polyethylene glycol (PEG).

[0156] 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 haemostatic composition. Polyols may enhance the reconstitution rate of the dry thrombin composition, stabilize thrombin activity and play a role in ensuring an optimal consistency of the haemostatic composition.

[0157] A polyol as defined herein is a compound with multiple hydroxyl functional groups. Polyols include sugars (mono-, di- and polysaccharides), sugar alcohols and derivatives thereof. Especially preferred are sugar alcohols.

[0158] Monosaccharides include but are not limited to glucose, fructose, galactose, xylose and ribose.

[0159] Disaccharides include but are not limited to sucrose (saccharose), lactulose, lactose, maltose, trehalose and cellobiose.

[0160] Polysaccharides include but are not limited to starch, glycogen, cellulose and chitin. Different forms of said polysaccharides, such as salts, cross-linked forms, esters, or other derivatives thereof are also contemplated for the present disclosure.

[0161] 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 (hence the alcohol). Sugar alcohols have the general formula H(HCHO)n+iH, whereas sugars have H(HCHO)nHCO. Some common sugar alcohols which may be used in the method of the present disclosure include but are not limited to: Glycol (2-carbon), Glycerol (3-carbon), Erythritol (4-carbon), Threitol (4-carbon), Arabitol (5-carbon), Xylitol (5-carbon), Ribitol (5-carbon), Mannitol (6- carbon), Sorbitol (6-carbon), Dulcitol (6-carbon), Fucitol (6-carbon), Iditol (6-carbon), Inositol (6-carbon; a cyclic sugar alcohol), volemitol (7-carbon), Isomalt (12-carbon), Maltitol (12-carbon), Lactitol (12-carbon), Polyglycitol.

[0162] In one embodiment, the haemostatic composition comprises a single hydrophilic compound, such as a single polyol.

[0163] In one embodiment of the invention, the haemostatic composition comprises more than one hydrophilic compound, such as two, three, four, five, six or even more different hydrophilic compounds.

[0164] In a preferred embodiment, the hydrophilic compound is a polyol.

[0165] In one embodiment of the invention, the haemostatic composition comprises two polyols, for example mannitol and glycerol or trehalose and a glycol.

[0166] In one embodiment of the invention, the haemostatic 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.

[0167] In one embodiment, the haemostatic composition comprises one or more sugar alcohols and one or more sugars, such as one sugar alcohol and one sugar.

[0168] In one embodiment, the haemostatic composition comprises one sugar alcohol and optionally one or more additional hydrophilic compounds, such as one or more polyols, which may be either sugar alcohols or sugars.

[0169] In one embodiment, the haemostatic composition does not comprise a sugar as the only polyol.

[0170] In one embodiment of the invention, the haemostatic composition comprises mannitol.

[0171] In one embodiment of the invention, the haemostatic composition comprises sorbitol.

[0172] In one embodiment of the invention, the haemostatic composition comprises glycerol.

[0173] In one embodiment of the invention, the haemostatic composition comprises trehalose.

[0174] In one embodiment of the invention, the haemostatic composition comprises glycol, such as propylene glycol. In one embodiment of the invention, the haemostatic composition comprises xylitol.

[0175] In one embodiment of the invention, the haemostatic composition comprises maltitol.

[0176] In one embodiment, the haemostatic composition comprises mannitol and glycerol.

[0177] In one embodiment, the haemostatic composition comprises from 0.01 g to 0.5 g of hydrophilic compound per gram of the biocompatible polymer, such as from 0.01 g to 0.4 g, such as from 0.01 to 0.3 g, such as from 0.01 to 0.2 g, such as from 0.01 to 0.1 g, such as from 0.01 to 0.05 g of hydrophilic compound per gram of the biocompatible polymer.

[0178] In one embodiment, the haemostatic composition comprises from 0.6 g to 1.5 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer, such as from 0.6 g to 0.7 g, such as from 0.7 g to 0.8 g, such as from 0.7 g to 0.8 g, such as from 0.8 g to 0.9 g, such as from 0.9 g to 1 .0 g, such as from 1.0 g to 1.1 g, such as from 1 .1 g to 1.2 g, such as from 1.2 g to 1 .3 g, such as from 1 .3 g to 1 .4 g, such as from 1.4 g to 1.5 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer.

[0179] In one embodiment, the haemostatic composition comprises from 0.6 g to 1.5 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer.

[0180] In one embodiment, the haemostatic composition comprises from 0.6 g to 1.0 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer.

[0181] In one embodiment, the haemostatic composition comprises from 0.8 g to 1.5 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer.

[0182] In one embodiment, the haemostatic composition comprises from 1.0 g to 1.5 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer.

[0183] In one embodiment, the haemostatic composition comprises from 1.2 g to 1.5 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer.

[0184] In one embodiment, the haemostatic composition comprises 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, or 1.5 g of the one or more hydrophilic compound(s) as described herein per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 0.6 to 1.5 g of mannitol per gram of the biocompatible polymer.

[0185] In one embodiment, the haemostatic composition comprises 0.6 to 1.0 g of mannitol per gram of the biocompatible polymer. In one embodiment ,the haemostatic composition comprises 0.6 to 1.5 g of glycerol per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises from 1.0 g to 1.5 g of glycerol per gram of the biocompatible polymer.

[0186] In one embodiment, the haemostatic composition comprises up to 0.6 g of propylene glycol per gram of the biocompatible polymer, such as about 0.6 g of propylene glycol per gram of the biocompatible polymer.

[0187] In one embodiment, the haemostatic composition comprises 0.6 to 1.2 g of glycerol and about 0.6 g mannitol per gram of the biocompatible polymer.

[0188] In one embodiment, the haemostatic composition comprises about 0.36 g of glycerol and 0.6 to 1 .0 g of mannitol per gram of biocompatible polymer.

[0189] In one embodiment, the haemostatic composition comprises 0.6 to 1.8 g the one or more hydrophilic compounds per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 0.6 to 1.8 g of a combination of glycerol and mannitol per gram of the biocompatible polymer.

[0190] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 20 mg to 80 mg of fibrinogen, c) about 1000 III to 4000 IU of thrombin, d) one or more surfactant(s) as described herein, and e) 0.6 g to 1 .5 g of one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol, and / or mannitol.

[0191] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 5 mg to 25 mg of fibrinogen, c) about 100 III to 1800 III of thrombin, d) one or more surfactant(s) as described herein, and e) 0.6 g to 1.5 g of one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol, and / or mannitol.

[0192] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 20 mg to 80 mg of fibrinogen, c) about 1000 III to 4000 III of thrombin, d) one or more surfactant(s) as described herein, and e) 0.6 g to 1.8 g of one or more hydrophilic compound(s) as described herein, such as a combination of mannitol and glycerol.

[0193] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 5 mg to 25 mg of fibrinogen, c) about 100 III to 1800 III of thrombin, d) one or more surfactant(s) as described herein, and e) 0.6 g to 1.8 g of one or more hydrophilic compound(s) as described herein, such as a combination of mannitol and glycerol. Further bioactive agents

[0194] In one embodiment of the invention, the haemostatic composition comprises one or more further bioactive agents capable of stimulating haemostasis, wound healing, bone healing, tissue healing and / or tendon healing.

[0195] In one embodiment, the haemostatic composition comprises one or more further 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-P).

[0196] In one embodiment, the haemostatic composition comprises one or more Bone Morphogenetic Proteins (BMPs). Bone morphogenetic proteins (BMPs) are a subgroup of the TGF-p superfamily. Bone Morphogenetic Proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue architecture throughout the body.

[0197] In one embodiment, the haemostatic composition comprises one or more matrix metalloproteinases (MMPs). MMPs are zinc-dependent endopeptidases. MMPs have 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 collagen I fibrils.

[0198] 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 early stages after injury and promotes the synthesis of other growth factors along with the synthesis of DNA and the proliferation of cells. The three isoforms of TGF-p (TGF-pi , TGF- 2, TGF- 3) are known to play a role in wound healing and scar formation. VEGF is well known to promote angiogenesis and to induce endothelial cell proliferation and migration.

[0199] In one embodiment, the haemostatic composition of the present disclosure comprises flakes or particles of extracelluar matrix (ECM). ECM is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. ECM has been shown to have very beneficial effect in healing as it facilitates functional tissue regeneration.

[0200] The variety of further bioactive agents that can be used in conjunction with the haemostatic composition of the invention is vast. In general, bioactive agents which may be administered via the haemostatic composition of the invention include, without limitation, antiinfectives, such as antibiotics and antiviral agents; analgesics and analgesic combinations; antihelmintics; antiarthritics; anticonvulsants; antidepressants; antihistamines; antiinflammatory 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 general coronary, peripheral and cerebral; central nervous system stimulants; hormones, such as estradiol and other steroids, including corticosteroids; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins; oligonucleotides, antibodies, antigens, cholinergics, chemotherapeutics, radioactive agents, osteoinductive agents, cystostatics heparin neutralizers, procoagulants and haemostatic agents, such as fibrin, fibronectin, heparinase, Factor X / Xa, Factor Vll / Vlla, Factor Vlll / Vllla, Factor IX / IXa, Factor Xl / XIa, Factor Xll / Xlla, Factor XI I l / XI I la, tissue factor, batroxobin, ancrod, ecarin, von Willebrand Factor, platelet surface glycoproteins, vasopressin, vasopressin analogs, epinephrine, selectin, procoagulant venom, plasminogen activator inhibitor, platelet activating agents and synthetic peptides having haemostatic activity.

[0201] Adhesion enhancers

[0202] In some embodiments, the haemostatic composition further comprises one or more adhesion enhancer(s). The adhesion enhancer as defined herein can add beneficial properties to the paste, e.g. increase the adhesion properties. When the haemostatic composition comprises one or more adhesion enhancers as described herein, the one or more adhesion enhancer(s) are different than the biocompatible polymer in particulate form.

[0203] The adhesion enhancer(s) described herein may be present in the haemostatic composition when in dry form, i.e. prior to mixing with an aqueous medium. The one or more hydrophilic compound(s) described herein may also (alternatively or additionally) be present in the aqueous medium prior to mixing with the haemostatic composition in dry form. When the adhesion enhancer is a liquid at normal conditions of temperature and pressure, it may be preferably present in the aqueous medium prior to mixing with the haemostatic composition in dry form.

[0204] The adhesion enhancer may be a natural or synthetic polymer, which may provide increased adhesion by different chemical interactions, such as electrostatic, polar or hydrophobic interactions. The increased adhesion may result from interactions or bonds between ionic groups, polar groups, Van der Waals forces, or covalent bonding.

[0205] In one embodiment, the one or more adhesion enhancer(s) are substances, such as polymers or oligomers, having multiple hydrogen bond donors, hydrogen acceptors, ionizable groups, or combinations thereof.

[0206] In one embodiment, the adhesion enhancer is a natural polymer comprising, carboxylic acid groups, sulfonic acid groups, sulfate groups, phosphate groups, amino groups, hydroxyl groups, or combinations thereof. For example, the natural polymer may be but is not limited to different polysaccharides such as chitosan, hyaluronic acid, alginate, chondroitin, carrageenan, xanthan gum, arabinogalactan, or cell wall components. Different forms of said natural polymers, such as salts thereof, or derivatives prepared to comprise additional ionizable groups (such as amino, carboxylic acid, sulfonic acid, sulfate, or phosphate) or hydrogen bond donor / acceptors are also considered for the present disclosure.

[0207] In one embodiment, the adhesion enhancer is a synthetic polymer comprising carboxylic acid groups, sulfonic acid groups, sulfate groups, phosphate groups, amino groups, hydroxyl groups, or combinations thereof. For example, the synthetic polymer may comprise or consists of poly(acrylic acid), poly(vinyl alcohol), poly(ethyleneimine), poly(acrylamide), or copolymers thereof. Different forms of said synthetic polymers, such as linear, branched or cross-linked forms, salts thereof, or derivatives prepared to comprise additional ionizable groups (such as amino, carboxylic acid, sulfonic acid, sulfate, or phosphate) or hydrogen bond donor / acceptors are also considered for the present disclosure.

[0208] In one embodiment, the adhesion enhancer may be a polymer, natural or synthetic, comprising or consisting of a hydrophobic backbone. In one embodiment, the polymer may comprise or consist of a polyalkylene, which include but are not limited to polyethylene, polypropylene, polybutylene, or polyisobutylene. In one embodiment, the polymer may comprise or consist of a silicone, or derivatives thereof. In one embodiment, the polymer may comprise or consist of a polyacrylate. Different forms of the polymer comprising a hydrophobic backbone, such as linear, branched, cross-linked forms, copolymers thereof, or other derivatives are also considered for the present disclosure.

[0209] In one embodiment, the one or more adhesion enhancer (s) are selected from the group consisting of: alginate, hyaluronic acid, chitosan, chondroitin sulfate, and tannic acid.

[0210] The inventors have demonstrated that the presence of an adhesion enhancer(s) as described herein, such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and tannic acid improves the adhesion of the haemostatic compositions to tissue. For example, adhesion of the haemostatic composition to tissue may be studied by measuring the force required to separate two pieces of tissue joined using the haemostatic composition. A higher force required indicates an improved adhesion to tissue. Different equipment and methods to measure adhesion to tissue will be known to the skilled person and have been reported in literature, see Mathiowitz et al. The inventors have e.g. used a TA XT plus texture analyzer (Stable Micro Systems Ltd) to measure the force required to separate two pieces of equal thickness of a rat’s liver joined by the haemostatic composition in a method adapted from literature (Amoros- Galicia et al.). The results demonstrate that the haemostatic compositions comprising adhesion enhancers as described herein display enhanced tissue adhesion properties.

[0211] In one embodiment, the haemostatic composition comprises the one or more adhesion enhancer(s) in an amount from about 2 mg to 1.3 g of adhesion enhancer per gram of the biocompatible polymer.

[0212] In one embodiment, the haemostatic composition comprises the one or more adhesion enhancer(s) in an amount from about 2 mg to 240 mg of adhesion enhancer per gram of the biocompatible polymer. In one embodiment, the adhesion enhancer is present in an amount from about 25 mg to about 120 mg of adhesion enhancer per gram of biocompatible polymer. In one embodiment, the total amount of adhesion enhancers as described herein per gram of the biocompatible polymer is from 2 mg to 1.3 g of adhesion enhancers per gram of the biocompatible polymer. In one embodiment, the total amount of adhesion enhancers as described herein per gram of the biocompatible polymer is from 2 mg to 240 mg of adhesion enhancers per gram of the biocompatible polymer.

[0213] In one embodiment, the haemostatic composition comprises alginate in an amount from about 2 mg to 240 mg, such as from 25 mg to about 120 mg of alginate per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises hyaluronic acid in an amount from about 2 mg to 240 mg, such as from 25 mg to about 120 mg of hyaluronic acid per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chitosan in an amount from about 2 mg to 240 mg, such as from 25 mg to about 120 mg of chitosan per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 2 mg to 240 mg, such as from 25 mg to about 120 mg of chondroitin sulfate per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises tannic acid in an amount from about 2 mg to 240 mg, such as from 25 mg to about 120 mg of tannic acid per gram of biocompatible polymer.

[0214] In one embodiment, the haemostatic composition comprises alginate in an amount from about 2 mg to 120 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises alginate in an amount from about 5 mg to 60 mg per gram of biocompatible polymer, such as from 5 mg to 15 mg, such as from 15 mg to 30 mg, such as from 30 mg to 45 mg, such as from 45 mg to 60 mg alginate per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises alginate in an amount from about 10 mg to 40 mg per gram of biocompatible polymer.

[0215] In one embodiment, the haemostatic composition comprises hyaluronic acid in an amount from about 2 mg to 240 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises hyaluronic acid in an amount from about 10 mg to 240 mg per gram of biocompatible polymer, such as from 10 mg to 50 mg, such as from 50 mg to 100 mg, such as from 100 mg to 150 mg, such as from 150 mg to 200 mg, such as from 200 mg to 240 mg hyaluronic acid per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises hyaluronic acid in an amount from about 20 mg to 200 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chitosan in an amount from about 2 mg to 120 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chitosan in an amount from about 10 mg to 100 mg per gram of biocompatible polymer, such as from 10 mg to 20 mg, such as from 20 mg to 30 mg, such as from 30 mg to 40 mg, such as from 40 mg to 50 mg, such as from 50 mg to 60 mg, such as from 60 mg to 70 mg, such as from 70 mg to 80 mg, such as from 80 mg to 90 mg, such as from 90 mg to 100 mg chitosan per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chitosan in an amount from about 20 mg to 70 mg per gram of biocompatible polymer.

[0216] In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 2 mg to 1 .3 g per gram of the biocompatible polymer.

[0217] In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 2 mg to 60 mg per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 5 mg to 60 mg per gram of biocompatible polymer, such as from 5 mg to 15 mg, such as from 15 mg to 30 mg, such as from 30 mg to 45 mg, such as from 45 mg to 60 mg chondroitin sulfate per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 5 mg to 30 mg per gram of the biocompatible polymer.

[0218] In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 2 mg to 75 mg per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 2 mg to 120 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 2 mg to 720 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 75 mg to 120 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 75 mg to 720 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 75 mg to 1.3 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 120 mg to 720 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 120 mg to 1.3 g per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises chondroitin sulfate in an amount from about 720 mg to 1.3 g per gram of the biocompatible polymer.

[0219] In one embodiment, the haemostatic composition comprises about 10 mg of chondroitin sulfate per gram of the biocompatible polymer.

[0220] In one embodiment, the haemostatic composition comprises about 70 mg of chondroitin sulfate per gram of the biocompatible polymer.

[0221] In one embodiment, the haemostatic composition comprises about 90 mg of chondroitin sulfate per gram of the biocompatible polymer.

[0222] In one embodiment, the haemostatic composition comprises about 630 mg of chondroitin sulfate per gram of the biocompatible polymer.

[0223] In one embodiment, the haemostatic composition comprises about 1.05 g of chondroitin sulfate per gram of the biocompatible polymer.

[0224] In one embodiment, the haemostatic composition comprises tannic acid in an amount from about 2 mg to 120 mg per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises tannic acid in an amount from about 10 mg to 100 mg per gram of biocompatible polymer, such as from 10 mg to 20 mg, such as from 20 mg to 30 mg, such as from 30 mg to 40 mg, such as from 40 mg to 50 mg, such as from 50 mg to 60 mg, such as from 60 mg to 70 mg, such as from 70 mg to 80 mg, such as from 80 mg to 90 mg, such as from 90 mg to 100 mg tannic acid per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises tannic acid in an amount from about 20 mg to 70 mg per gram of the biocompatible polymer.

[0225] In one embodiment, the haemostatic composition comprises tannic acid in an amount from about 2 mg to 70 mg per gram of the biocompatible polymer, such as about 6 mg to 60 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises tannic acid in an amount of 6 mg per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises tannic acid in an amount of 60 mg per gram of the biocompatible polymer. In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 20 mg to 80 mg of fibrinogen, c) about 1000 III to 4000 IU of thrombin, d) one or more surfactant(s) as described herein, and e) 2 mg 1 .3 g of one or more adhesion enhancer(s), such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and / or tannic acid as described herein.

[0226] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 20 mg to 80 mg of fibrinogen, c) about 1000 IU to 4000 IU of thrombin, d) one or more surfactant(s) as described herein, and e) 2 mg to 240 mg of one or more adhesion enhancer(s), such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and / or tannic acid as described herein.

[0227] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 5 mg to 25 mg of fibrinogen, c) about 100 IU to 1800 IU of thrombin, d) one or more surfactant(s) as described herein, and e) 2 mg to 1.3 g of one or more adhesion enhancer(s), such as alginate, hyaluronic acid, chitosan, chondroitin sulfate, and / or tannic acid as described herein.

[0228] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 5 mg to 25 mg of fibrinogen, c) about 100 III to 1800 III of thrombin, d) one or more surfactant(s) as described herein, and e) 2 mg to 240 mg of one or more adhesion enhancer(s), such as alginate, hyaluronic acid, chitosan, chondroitin sulfate, and / or tannic acid as described herein.

[0229] Further compounds

[0230] The haemostatic composition described herein may comprise additional compounds. Said compounds may be present in the haemostatic composition when in dry form, i.e. prior to mixing with an aqueous medium. Said compound may also (alternatively or additionally) be present in the aqueous medium prior to mixing with the haemostatic composition in dry form. When the compound is a liquid at normal conditions of temperature and pressure, it may be preferably present in the aqueous medium prior to mixing with the haemostatic composition in dry form.

[0231] The haemostatic composition of the invention may further comprise one or more of the following: DMSO (dimethyl sulfoxide) and / or 2-Methyl-2,4-pentanediol (MPD).

[0232] In one embodiment, the haemostatic composition of the present disclosure comprises one or more antimicrobial agents, such as one or more antibacterial agents. In one embodiment, the haemostatic composition comprises one or more broad spectrum antibiotics. In one embodiment, the antimicrobial agent is a compound comprising quaternary ammonium groups, or aldehyde groups.

[0233] Examples of antimicrobial agents considered for the present disclosure include but are not limited to aminoglycosides, such as gentamicin; quinolones, such as ciprofloxacin; vancomycin, fluoroquinolones, benzalkonium chloride, or triclosan.

[0234] In one embodiment, the haemostatic composition of the present disclosure comprises triclosan.

[0235] In one embodiment, the haemostatic composition of the present disclosure comprises benzalkonium chloride (BAC).

[0236] In one embodiment, the haemostatic composition of the present disclosure does not comprise an antimicrobial agent. In one embodiment, the haemostatic composition further comprises an extrusion enhancer, i.e. a compound which facilitates extrusion of a paste from a syringe.

[0237] It has previously been shown that the provision of certain extrusion enhancers, such as albumin in an appropriate amount, enables the use of higher gelatine concentrations as it decreases the amount of force needed to extrude the gelatine paste composition from e.g. a syringe. The use of higher gelatine concentrations may in turn improve the haemostatic properties of such products. It is necessary to provide the extrusion enhancers in appropriate amounts. The amounts are preferably high enough so as to obtain the extrusion effect, i.e. to enable a flowable paste even for relatively high amounts of the biocompatible polymer, e.g. cross-linked gelatine, so that the haemostatic composition can be accurately applied by a surgeon using e.g. a syringe comprising an applicator tip; on the other hand, the amounts shall be as low as to prevent potential negative functional properties of the haemostatic composition.

[0238] The extrusion enhancer is preferably albumin, especially human serum albumin.

[0239] In one embodiment, the haemostatic 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% to about 10%, such as between about 0.2% to about 8%, for example between about 0.3% to about 7%, preferably between about 0.5% to about 5%, such as between about 1 % to about 4%.

[0240] In one embodiment, the haemostatic composition of the present disclosure 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%.

[0241] In one embodiment, the haemostatic composition comprises a biocompatible polymer as defined herein as well as a further polymer comprising or consisting of a reactive derivative of a polyalkylene oxide. For example, a derivative of a polyalkylene oxide comprising one or more reactive groups, preferably two or more reactive groups. The reactive derivative of a polyalkylene oxide may be for example a derivative of polyethylene glycol comprising reactive groups. The reactive groups may be electrophilic groups, for example succinimidylesters (NHS-ester), aldehydes (-CHO), isocyanates (- N=C=O), imidoester, among others. In one embodiment, the haemostatic composition comprises a further polymer comprising or consisting of a derivative of polyethylene glycol, said derivative comprising at least one or more ester(s) of N-hydroxysuccinimide. In one embodiment, reactive derivative of polyethlene glycol comprises 2 or more, 3 or more, or 4 or more ester(s) of N-hydroxysuccinimide. In one embodiment, the haemostatic composition comprises a further polymer comprising or consisting of pentaerythritolpoly(ethyleneglycol)ether tetrasuccinimidyl glutarate.

[0242] Surfactants

[0243] Surfactants are substances that reduce the surface tension of the medium they are present in or the interfacial tension with other phases. Surfactants usually contain polar or charged functional groups and also hydrophobic groups, thus rendering them capable of having both hydrophilic and hydrophobic interactions. Inclusion of one or more surfactants in the haemostatic composition of the present disclosure is believed to have a beneficial effect on water absorption capacity, reconstitution efficiency of the dry haemostatic composition, and may also improve consistency of the haemostatic composition. The consistency of the paste may be determined by measuring the complex viscosity or the distribution of water through the haemostatic compositions, as described elsewhere herein.

[0244] The inventors have shown that the addition of one or more surfactant(s) improves the water absorption capacity of the haemostatic composition. The absorption capacity may be measured by the methods known in the art e.g. using the droplet test as described elsewhere herein.

[0245] The one or more surfactant(s) described herein may be present in the aqueous medium prior to mixing with the haemostatic composition in dry form for reconstitution, or they can be mixed with the haemostatic composition prior to reconstitution with an aqueous medium. In one embodiment, the one or more surfactant(s) described herein are present in the aqueous medium prior to mixing with the haemostatic composition in dry form. If the surfactant is a liquid at normal conditions of ambient temperature and pressure, it is preferably present in the aqueous medium prior to mixing with the haemostatic composition in dry form for reconstitution.

[0246] In one embodiment, the one or more surfactant(s) is an amphiphilic polymer. Amphiphilic polymers comprise both hydrophobic and hydrophilic regions. In one embodiment, the amphiphilic polymer comprises or consist of a copolymer comprising hydrophobic segments and hydrophilic segments, such as poloxamers. In one embodiment, the amphiphilic polymer comprises or consists of a hydrophobic backbone modified with hydrophilic side chains. In one embodiment, the amphiphilic polymer comprises or consist of a hydrophilic backbone with one or more hydrophobic side chains. The amphiphilic polymer may comprise a backbone derived from a natural or a synthetic polymer, or a combination thereof. Different forms of said amphiphilic polymer, such as linear or branched forms, cross-linked forms, salts thereof, or other derivatives thereof are also considered for the present disclosure.

[0247] In one embodiment, the one or more surfactant(s) is an ionic surfactant, such as a anionic, cationic or zwitterionic surfactant.

[0248] In one embodiment, the one or more surfactant(s) is an anionic surfactant, these surfactants are characterized by having a net negative charge. For example, anionic surfactants comprise a hydrophobic group, e.g. derived from an alkyl chain, a fatty acid ester, a fatty alcohol; or a lipid, such as cholesterol; and a one or more groups that have a negative charge, such as carboxylates, sulfonates, sulfates or phosphates.

[0249] Examples of anionic surfactants include but are not limited to alkyl carboxylates, such as carboxylates of fatty acids i.e laurate, palmitate, or stearate; alkyl sulfates, such as lauryl sulfate, palmitoyl sulfate, or stearyl sulfate; alkyl sulfonates, such as lauryl sulfonate, palmitoyl sulfonate, stearyl sulfonate; or alkyl phosphates, such as lauryl phosphate, palmitoyl phosphate, or stearyl phosphate.

[0250] In one embodiment, the one or more surfactant(s) is a cationic surfactant, these surfactants are characterized by having net positive charge. For example, cationic surfactants comprise a hydrophobic group, e.g. derived from an alkyl chain, a fatty acid ester, a fatty alcohol; or a lipid, such as cholesterol; and a one or more groups that have or can have a positive charge, such as quaternary ammonium groups, tertiary amines, secondary amines, primary amines or pyridinium groups.

[0251] Examples of cationic surfactants include but are not limited to salts of quaternary ammonium compounds having long alky chains or hydrophobic groups, such as cetrimonium bromide, cetylpyridinium chloride, dimethyldioctadecylammonium chloride, or benzethonium chloride; or tertiary amines having alkyl chains or hydrophobic groups. In one embodiment, the one or more surfactant(s) is a zwitterionic surfactant, these surfactants are characterized by having the same amount of positive and negative charges. For example, zwitterionic surfactants comprise a hydrophobic group, e.g. derived from an alkyl chain, a fatty acid ester, a fatty alcohol; or a lipid, such as cholesterol; and groups having positive charge e.g. quaternary ammonium, and negative charge e.g. carboxylates, phosphates, sulfates or sulfonates in equal amounts.

[0252] Examples of zwitterionic surfactants include but are not limited to phosphatidylcholine phospholipids, such as dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), 1 ,2- Dioleoyl-sn-glycero-3-phosphocholine (DOPC); or hydrophobic betaine derivatives, such as cocamidopropyl betaine, or amidosulfobetaine-16.

[0253] In one embodiment, the one or more surfactant(s) is a non-ionic surfactant, these surfactants are characterized by the absence of ionizable groups. For example, non-ionic surfactants comprise a hydrophobic group, e.g. derived from an alkyl chain, a fatty acid ester, a fatty alcohol; or a lipid, such as cholesterol; and an uncharged hydrophilic group e.g. derived from hydrophilic oligomers or polymers, such as polyethylene glycol (PEG), oligosaccharides, or polyols.

[0254] In one embodiment, said non-ionic surfactant(s) is derived from an ester of sorbitan (CAS number: 12441-09-7) and a fatty acid. For example, different esters of sorbitan with different fatty acids are known non-ionic surfactants, sold under the commercial brand name Span®. Derivatives of fatty acid ester of sorbitan, further modified with polyethylene glycol units are known generally under the name polysorbates, and are sold under different commercial brand names e.g Tween®, Koliphor® PS, among others.

[0255] In one embodiment, the haemostatic composition comprises one or more non-ionic surfactant(s) according to formula (I): wherein each of R1, R2, R3and R4are individually selected from H, or RF; RFis a group comprising or consisting of a C3-C22 hydrocarbon chain; wherein at least one of R1, R2, R3and R4is according to RF.

[0256] In one embodiment, one of R1, R2, R3and R4is according to RF, and the remainder are H. In one embodiment, R1is according to RF, and R2, R3and R4are H. In one embodiment, R2is according to RF, and R1, R3and R4are H. In one embodiment, R3is according to RF, and R1, R2and R4are H. In one embodiment, R4is according to RF, and R1, R2and R3are H.

[0257] In one embodiment, RFcomprises or consist of a C3-C22 hydrocarbon chain. In one embodiment, RFcomprises or consists of a C8-C21, a C8-C20, a C9-C20, a C10-C20, a C12-C20, a C12-C19, or a C12-C18 hydrocarbon chain. In one embodiment, the hydrocarbon chain in RFis a linear hydrocarbon chain. In one embodiment, the hydrocarbon chain in RFmay comprise one or more branches.

[0258] In one embodiment, RFconsists of: , wherein n is an integer from 1 to 20. Preferably n is from 10 to 16, such as 12, 13, 14, 15, 16, 17 or 18.

[0259] In one embodiment, the hydrocarbon chain in RFcomprises 0, 1 , 2, or 3 double bonds, such as 0, 1 , or 2 double bonds, such as 0 or 1 double bonds, such as 0 double bonds or 1 double bond.

[0260] In one embodiment, RFconsists of: , wherein p is any integer from 9 to 19, and q is any integer from 0 to p.

[0261] In one embodiment, the haemostatic composition comprises one or more non-ionic surfactant(s) according to formula (II): wherein x1 , x2, x3, and x4 are integers, wherein the sum of x1+x2+x3+x4 is from 1 to 100; each of R5, R6, R7and R8are individually selected from H, or RK; RKis a group comprising or consisting of a C3-C22 hydrocarbon chain; wherein at least one of R5, R6, R7and R8is according to RK.

[0262] In one embodiment, the sum of x1+x2+x3+x4 is from 10 to 80, such as from 10 to 60, such as 10 to 50, 10 to 40, or 10 to 30. In one embodiment, the sum of x1 +x2+x3+x4 is 20.

[0263] In one embodiment, one of R5, R6, R7and R8is according to RK, and the remainder are H. In one embodiment, R5is according to RK, and R6, R7and R8are H. In one embodiment, R6is according to RK, and R5, R7and R8are H. In one embodiment, R7is according to RK, and R5, R6and R8are H. In one embodiment, R8is according to RK, and R5, R6and R7are H.

[0264] In one embodiment, RKcomprises or consists of a C3-C22 hydrocarbon chain. In one embodiment, RKcomprises or consists of a C8-C21, a C8-C20, a C9-C20, a C10-C20, a C12-C20, a C12-C19, a C12-C18 hydrocarbon chain. In one embodiment, the hydrocarbon chain in RKis a linear hydrocarbon chain. In one embodiment, the hydrocarbon chain in RKmay comprise one or more branches.

[0265] In one embodiment, RKconsists of: , wherein n is an integer from 1 to 20. Preferably n is from 10 to 16, such as 12, 13, 14, 15, 16, 17 or 18.

[0266] In one embodiment, the hydrocarbon chain in RKcomprises 0, 1 , 2, or 3 double bonds, such as 0, 1 , or 2 double bonds, such as 0 or 1 double bonds, such as 0 double bonds or 1 double bond. In one embodiment, RKconsists of: , wherein p is any integer from 9 to 19, and q is any integer from 0 to p. In one embodiment, the haemostatic composition comprises one or more surfactant(s) selected from any one of the compounds in Table A, or any mixture thereof.

[0267] Table A.

[0268] In one embodiment, the haemostatic composition comprises one or more non-ionic surfactant(s)selected from the group consisting of: sorbitan monostearate (Span® 60, CAS number: 1338-41-6), sorbitan monooleate (Span® 80, CAS number: 1338-43-8), sorbitan monopalmitate (Span® 40, CAS number: 26266-57-9), sorbitan monolaurate (Span® 20, CAS number: 1338-39-2), polysorbate-20 (Tween® 20, CAS number: 9005- 64-5), polysorbate-40 (Tween® 40, CAS number: 9005-66-7), polysorbate-60 (Tween® 60, CAS number: 9005-67-8), and polysorbate-80 (Tween® 80, CAS number: 9005-65- 6), or any combination thereof.

[0269] In one embodiment, the haemostatic composition comprises one non-ionic surfactant. In one embodiment, the haemostatic composition described herein comprises two non- ionic surfactants. When the haemostatic composition comprises two or more non-ionic surfactants as described herein, these may be present in any relative amount among each other.

[0270] In one embodiment, the haemostatic composition as described herein comprises from 0.02 mg to 2.4 mg of the one or more surfactant(s), such as one or more non-ionic surfactant(s) per gram of the biocompatible polymer. In one embodiment, the haemostatic composition comprises 0.05 mg to 1 .2 mg of the one or more surfactant(s), such as one or more non-ionic surfactant(s) per gram of the biocompatible polymer.

[0271] In one embodiment, the haemostatic composition as described herein comprises from 0.2 mg to 1.2 mg of the one or more surfactant(s), such as one or more non-ionic surfactant(s) per gram of the biocompatible polymer. In one embodiment, the haemostatic composition as described herein comprises preferably from 0.4 mg to 0.7 mg of the one or more surfactant(s) per gram of biocompatible polymer, preferably 0.5 mg to 0.6 mg of the one or more surfactant(s) per gram of biocompatible polymer. In one embodiment, the haemostatic composition comprises a non-ionic surfactant as described herein, wherein said surfactant is sorbitan monostearate (Span® 60, CAS number: 1338-41-6), or polysorbate-20 (Tween® 20, CAS number: 9005-64-5).

[0272] In one embodiment, the haemostatic composition comprises sorbitan monostearate (Span® 60, CAS number: 1338-41-6). In one embodiment, the haemostatic composition comprises polysorbate-20 (Tween® 20, CAS number: 9005-64-5). In one embodiment, the haemostatic composition comprises sorbitan monooleate (Span® 80, CAS number: 1338-43-8).

[0273] In one embodiment, the haemostatic composition comprises two non-ionic surfactants as described herein, wherein said two surfactants are sorbitan monostearate (Span® 60, CAS number: 1338-41-6) and polysorbate-20 (Tween® 20, CAS number: 9005-64-5).

[0274] In one embodiment, the haemostatic composition comprises two non-ionic surfactants as described herein, wherein said two surfactants are sorbitan monostearate (Span® 80, CAS number: 1338-43-8) and polysorbate-20 (Tween® 20, CAS number: 9005-64-5).

[0275] In one embodiment, the haemostatic composition comprises 0.1 mg of Tween® 20 per gram of the biocompatible polymer.

[0276] In one embodiment, the haemostatic composition comprises 0.1 mg of Span® 80 per gram of the biocompatible polymer.

[0277] In one embodiment, the haemostatic composition comprises one or more non-ionic surfactants as described herein and a hydrophilic compound as described herein.

[0278] In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 20 mg to 80 mg of fibrinogen, c) about 1000 III to 4000 IU of thrombin, and d) 0.02 mg to 2.4 mg of one or more surfactant(s) as described herein, such as sorbitan monostearate (Span® 60, CAS number: 1338-41-6) and / or polysorbate-20 (Tween® 20, CAS number: 9005-64-5); or sorbitan monooleate (Span® 80, CAS number: 1338-43-8) and / or polysorbate-20 (Tween® 20, CAS number: 9005-64-5). In one embodiment the haemostatic composition comprises: a) about 1g of a biocompatible polymer in particulate form, such as cross-linked gelatine particles, b) about 5 mg to 25 mg of fibrinogen, c) about 100 III to 1800 IU of thrombin, and d) 0.02 mg to 2.4 mg of one or more surfactant(s) as described herein, such as sorbitan monostearate (Span® 60, CAS number: 1338-41-6) and / or polysorbate-20 (Tween® 20, CAS number: 9005-64-5); or sorbitan monooleate (Span® 80, CAS number: 1338-43-8) and / or polysorbate-20 (Tween® 20, CAS number: 9005-64-5).

[0279] Method to prepare a haemostatic composition

[0280] In one aspect, the present disclosure provides a method of preparing a haemostatic composition comprising the steps of:

[0281] Step A1: providing a haemostatic composition comprising a biocompatible polymer in particulate form, fibrinogen and thrombin, wherein said biocompatible polymer, fibrinogen and thrombin are as described herein, and

[0282] Step B1: adding an amount of an aqueous medium to the haemostatic composition.

[0283] In one embodiment, the amount of aqueous medium added is from 2 to 12 mL per gram of haemostatic composition, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mL of aqueous medium.

[0284] In one embodiment, the amount of aqueous medium added is from 4 mL to 7 mL, such as from 5 mL to 6 mL per gram of haemostatic composition provided.

[0285] In one embodiment, the biocompatible polymer comprises or consist of cross-linked gelatine particles, as described herein.

[0286] In one aspect, the present disclosure provides a method of preparing a haemostatic composition comprising the steps of:

[0287] Step A2: providing a haemostatic composition comprising a biocompatible polymer in particulate form and fibrinogen, wherein said biocompatible polymer and fibrinogen are as described herein, and

[0288] Step B2: adding an amount of an aqueous medium comprising thrombin. In one embodiment, the present disclosure provides a method of preparing a haemostatic composition comprising the steps of:

[0289] Step A3: providing a haemostatic 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

[0290] Step B3: adding an amount of an aqueous medium comprising thrombin.

[0291] The one or more hydrophilic compound(s), the one or more further bioactive agent(s), the one or more adhesion enhancer (s), or the one or more surfactant(s) as described herein may be present together with the composition of any of step A1 , step A2 or step A3 or they may be added together with the aqueous medium of any one of step B1 , step B2 or step B3.

[0292] In one embodiment, the one or more hydrophilic compound(s) as described herein is present in the haemostatic composition of step A1 . In one embodiment, the one or more further bioactive agent(s) as described herein is present in the haemostatic composition of step A1. In one embodiment, the one or more adhesion enhancer(s) as described herein is present in the haemostatic composition of step A1 . In one embodiment, the one or more surfactant(s) as described herein is present in the haemostatic composition of step A1 .

[0293] In one embodiment, the aqueous medium of step B1 comprises from 7% to 25% by weight of the one or more hydrophilic compound(s) as described herein, for example glycerol, propylene glycol and / or mannitol. These amounts can be suitably used to prepare haemostatic compositions comprising 0.6 g to 1.5 g of the one or more hydrophilic compound(s) per gram of the biocompatible polymer.

[0294] In one embodiment, the aqueous medium of step B1 comprises from 7% to 10% by weight of the one or more hydrophilic compound(s), as described herein, for example as glycerol, propylene glycol, and / or mannitol.

[0295] In one embodiment, the aqueous medium comprises from 12% to 25% of the one or more hydrophilic compound(s) as described herein, for example glycerol, propylene glycol and / or mannitol.

[0296] In one embodiment, the aqueous medium of step B1 comprises from 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24% or 25% by weight of a hydrophilic compound as described herein, for example glycerol, propylene glycol and / or mannitol. In one embodiment, the aqueous medium of step B1 comprises from 0.1 % to 2% by weight of the one or more adhesion enhancer(s) as described herein, such as alginate, hyaluronic acid, chitosan, chondroitin sulfate, and / or tannic acid. These amounts can be suitably used to prepare haemostatic compositions comprising 2 mg to 240 mg of the one or more adhesion enhancer(s) per gram of the biocompatible polymer as described herein.

[0297] In one embodiment, the aqueous medium of step B1 comprises alginate in an amount from 0.1% to 1% by weight. In one embodiment, the aqueous medium comprises alginate in an amount of about 0.5% by weight.

[0298] In one embodiment, the aqueous medium of step B1 comprises hyaluronic acid in an amount from 0.5% to 2% by weight. In one embodiment, the aqueous medium comprises hyaluronic acid in an amount of about 1 % by weight. In one embodiment, the aqueous medium comprises hyaluronic acid in an amount of about 2% by weight.

[0299] In one embodiment, the aqueous medium of step B1 comprises chitosan in an amount from 0.5% to 2% by weight. In one embodiment, the aqueous medium comprises chitosan in an amount of about 1% by weight.

[0300] In one embodiment, the aqueous medium of step B1 comprises chondroitin sulfate in an amount from 0.1% to 0.5% by weight. In one embodiment, the aqueous medium comprises chondroitin sulfate in an amount of about 0.25% by weight.

[0301] In one embodiment, the aqueous medium of step B1 comprises chondroitin sulfate in an amount from 1% to 21 % by weight, such as 1% to 15% by weight of chondroitin sulfate.

[0302] In one embodiment, the aqueous medium of step B1 comprises tannic acid in an amount of about 0.1 % to 2 % by weight, such as 0.1 % to 1 % by weight of tannic acid. In one embodiment, the aqueous medium of step B1 comprises tannic acid in an amount of about 1 % by weight.

[0303] In one embodiment, the aqueous medium of step B1 comprises one or more of the one or more surfactant(s) as described herein in a total amount equal to or lower than 0.2 mg / mL. In one embodiment, the aqueous medium of step B1 comprises one or more surfactant(s) as described herein in a total amount from 0.01 to 0.2 mg / mL, such as from 0.05 to 0.2 mg / mL, such as from 0.05 to 1.5 mg / mL, such as about 0.1 mg / mL. These amounts can be suitably used to prepare haemostatic compositions comprising 0.02 mg to 2.4 mg of the one or more surfactant(s) per gram of the biocompatible polymer as described herein. In one embodiment, the aqueous medium of step B1 comprises a total amount of non-ionic surfactant(s) of about 0.1 mg / mL.

[0304] In one embodiment, the aqueous medium of step B1 comprises one or more non-ionic surfactant(s) selected from polysorbate-20 and / or sorbitan monostearate. In one embodiment, the aqueous medium of step B1 comprises sorbitan monooleate.

[0305] In one embodiment, the aqueous medium of step B1 of the haemostatic composition comprises one or more non-ionic surfactants as described herein and a hydrophilic compound as described herein.

[0306] In one embodiment, the aqueous medium of step B1 comprises one or more non-ionic surfactant(s) selected from polysorbate-20 and / or sorbitan monostearate and glycerol.

[0307] In one embodiment, the aqueous medium of step B1 comprises one or more non-ionic surfactant(s) selected from polysorbate-20 and / or sorbitan monostearate in a total amount of 0.05 to 1 .5 mg / mL; and glycerol in an amount of 6% to 25% by weight, such as 12% to 25% by weight. In one embodiment, the aqueous medium of step B1 comprises sorbitan monooleate and glycerol. In one embodiment, the aqueous medium of step B1 comprises polysorbate-20 and glycerol.

[0308] The components are mixed with the aqueous medium by conventional means, such as by transfer between two connected syringes, so as to form a paste.

[0309] The haemostatic composition obtained by the methods described herein is suitable for use in haemostasis and / or wound healing.

[0310] In one aspect, the present disclosure provides the haemostatic composition obtained by the methods described herein. The haemostatic composition obtained by the methods described herein is preferably a flowable paste composition.

[0311] Surprisingly, the present inventors show that the haemostatic paste compositions comprising a biocompatible polymer, thrombin and fibrinogen remain flowable 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 clog the device and can therefore not be deployed from a syringe for an extended period of time after combination of the components. In one embodiment, the haemostatic composition remains flowable after 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.

[0312] In one embodiment, the haemostatic composition is deployable from a syringe after 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.

[0313] In one embodiment, the haemostatic 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 gelatine particles, is an amount suitable to form a paste.

[0314] In one embodiment, the haemostatic composition has a consistency within the range of about 100 g x sec to about 15,000 g x sec, such as from about 500 g x sec to about 8000 g x sec, for example from about 1000 g x sec to about 5000 g x sec, such as from about 1500 g x sec to about 3000 g x sec.

[0315] In one embodiment, the haemostatic composition has a consistency of less than about 5000 g x sec, for example less than about 4000 g x sec, such as less than about 3000 g x sec, for example less than about 2000 g x sec.

[0316] The consistency can be measured using a texture analyser (TA.XT.plus, Stable micro systems) with the following TA settings:

[0317] For a medical paste to be discharged from a syringe and an applicator tube, it should be flowable, when subjected to a force applicable for a syringe. Thus, by the term “flowable paste” is meant a paste having a viscosity facilitating a steady flow, when subjected to a force applicable for a syringe Flowability of a paste can e.g. be measured at 25-30°C and a relative humidity between 65-75%. In one embodiment of the present disclosure, the haemostatic composition in paste form has a viscosity within 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 haemostatic composition has a viscosity of less than about 2500 Pa-s.

[0318] The viscosity of the paste may be measured by rheometers, and preferably rotational shear based rheometers. The viscosity can be measured using a Discovery Hybrid Rheometer (DHR-1) from Waters TA instruments with controlled stress and the following measurement conditions: oscillation measurement mode with time sweep, oscillation strain of 1 %, angular frequency 1 rad / s, a 20 mm plate as upper geometry diameter, and a gap size of 1 .25 mm. The measurements can be carried out at temperatures at or between 25-30 °C, and preferably at 25 °C and at a relative humidity between 65-75%.

[0319] The consistency of the haemostatic composition may also be assessed through rheological measurements of complex viscosity or by assessing how water is distributed within the haemostatic composition.

[0320] For example, the consistency may be assessed through measurements of the complex viscosity, which is the frequency-dependent viscosity function determined for a viscoelastic solid or liquid. Different methods will be known to the skilled person to determine complex viscosity by measuring resistance to flow of a sample in the presence of a oscillatory stress (e.g. shear stress) as a function of the angular frequency. Complex viscosity may for example be determined using a AR-G2 Magnetic Bearing Rheometer with a 20 mm sandblasted parallel plate as the geometry and by performing a time sweep over 15 min using a strain of 0.1 % and frequency of 1 rad / s. The gap can be set to 1.25 mm and a solvent trap can be used to prevent moisture loss and maintain temperature.

[0321] The distribution of water within a haemostatic composition in form of a paste may be tested by expressing a length of mixed paste of uniform thickness onto a sheet of absorbent paper and measuring the width of the watermark that appears on the paper after a set amount of time, for example 2 to 5 minutes. If water is uniformly distributed within the paste, the width of the watermark is homogenous through the length of the expressed paste. On the contrary, an irregular width of the watermark through the length of the expressed paste indicates an irregular distribution of water through the paste.

[0322] The consistency and / or water distribution of the haemostatic composition can be improved by the one or more hydrophilic compound(s), the one or more adhesion enhancer(s), and / or the one or more surfactants as described herein.

[0323] Thus, in one embodiment the present disclosure provides a haemostatic composition comprising: a) one or more biocompatible polymers in particulate form as described herein, b) fibrinogen as described herein, c) thrombin as described herein, d) one or more surfactant(s) as described herein, and e) an aqueous medium.

[0324] The haemostatic composition may comprise further components as described herein.

[0325] Preferably, the haemostatic composition comprises an amount of aqueous medium sufficient to form a flowable paste.

[0326] In one embodiment, the aqueous medium is selected from the group consisting of water, saline, a calcium chloride solution and 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.

[0327] In one embodiment, the aqueous medium comprises calcium ions.

[0328] The aqueous medium of the present disclosure is in one embodiment a saline solution.

[0329] In one embodiment, the aqueous medium is a calcium chloride solution.

[0330] In other embodiments, the aqueous medium is water.

[0331] The aqueous medium may also be a buffered aqueous medium. Any suitable buffering agent known to a person of skill 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; Na2HPC>4, NaH2PO4; CHES; Borax, Sodium hydroxide; TAPS; Bicine; Tris; Tricine; TAPSO; HEPES; TES; MOPS; PIPES; Cacodylate; SSC; MES, or others. The pH of the buffered aqueous medium should be suitable for creating a haemostatic composition intended for human use and can be determined by the skilled person.

[0332] The amount of aqueous medium is an amount sufficient to provide a composition in paste form, such as from 2 mL to 12 mL per gram of biocompatible polymer, such as from 4 to 10 mL such as from 4 to 8 mL, such as 4 mL to 7 mL, such as from 5 to 6 mL of aqueous medium per gram of biocompatible polymer. In one embodiment, the amount of aqueous medium is 5 mL to 6 mL per gram of the biocompatible polymer.

[0333] In one embodiment, the present disclosure provides a haemostatic 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 IU to 1700 IU per gram of the composition, d) one or more surfactant(s) as described herein, and e) an aqueous medium.

[0334] In one embodiment, the present disclosure provides a haemostatic 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 IU to 1700 IU per gram of the composition, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, in an amount of 0.0001% to 0.09%, and e) an aqueous medium.

[0335] This corresponds to compositions comprising 1 mg to 150 mg of fibrinogen and 100 to 5000 IU thrombin per gram of biocompatible polymer, prepared as described herein.

[0336] In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form 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 IU to 1700 IU per gram of the composition, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, in an amount of 0.0001 % to 0.09%, and e) an aqueous medium; wherein the composition comprises

[0337] 1 mg to 150 mg of fibrinogen per gram of the biocompatible polymer, as described elsewhere herein;

[0338] 100 to 5000 III thrombin per gram of the biocompatible polymer as described elsewhere herein;

[0339] 0.02 mg to 2.4 mg of the one or more surfactant(s) per gram of the biocompatible polymer as described elsewhere herein.

[0340] In one embodiment, the haemostatic 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%-17%, for example about 14%-17% by weight.

[0341] In one embodiment, the haemostatic 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.

[0342] In one embodiment, the haemostatic composition comprises the biocompatible polymer in particulate form in an amount of about 13 to 15%, such as about 14%. In another embodiment, the haemostatic composition comprises the biocompatible polymer in particulate form in an amount of about 16 to 18%, such as about 17% by weight.

[0343] In one embodiment, the haemostatic composition comprises from about 60% to about 93% of water, for example about 70% to about 90% of water, such as from about 75% to about 90% of water, for example from about 80% to about 90% of water.

[0344] In one embodiment, the haemostatic composition, in flowable paste form, 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 haemostatic composition comprises fibrinogen in an amount from 0.3 to 1.2%, such as about 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% or about 1.1% by weight. In one embodiment, the haemostatic composition comprises fibrinogen in an amount of 0.3 to 1.2% by weight.

[0345] In one embodiment, the haemostatic composition, in flowable paste form, comprises thrombin in an amount of 16 to 900 I U / g, such as 100 to 700 I U / g, such as 100 to 200 I U / g, such as 100 to 200 I U / g, such as 200 to 300 I U / g, such as 300 to 400 I U / g, such as 400 to 500 I U / g, such as 500 to 600 I U / g or 600 to 700 I U / g. In one embodiment, the haemostatic composition comprises thrombin in an amount of 280 to 350 I U / g of the haemostatic composition.

[0346] In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form 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 0.03% to 0.9% by weight, c) thrombin in an amount of 7 IU to 600 IU per gram of the composition, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, or polysorbate-20 and / or sorbitan monooleate, in an amount of 0.0001% to 0.09% by weight, and e) an aqueous medium.

[0347] This corresponds to compositions comprising 5 to 25 mg of fibrinogen and 100 to 1800 IU thrombin per gram of the biocompatible polymer, prepared as described herein.

[0348] In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.05% to 0.5% by weight, and thrombin in an amount from 201 I U / g to 299 I U / g, such as 201 to 279 I U / g.

[0349] In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.05% to 0.4% by weight, and thrombin in an amount from 201 I U / g to 299 I U / g, such as 201 to 279 I U / g.

[0350] In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.05% to 0.3% by weight, and thrombin in an amount from 201 I U / g to 299 I U / g, such as 201 to 279 I U / g. In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.1% to 0.5% by weight, and thrombin in an amount from 201 I U / g to 299 I U / g, such as 201 to 279 I U / g.

[0351] In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.2% to 0.5% by weight, and thrombin in an amount from 201 I U / g to 299 I U / g, such as 201 to 279 I U / g.

[0352] In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.3% to 0.5% by weight, and thrombin in an amount from 201 I U / g to 299 I U / g, such as 201 to 279 I U / g.

[0353] In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.05% to 0.5% by weight, and thrombin in an amount from 201 I U / g to 299 I U / g. In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.05% to 0.5% by weight, and thrombin in an amount from 50 I U / g to 99 I U / g. In one embodiment, the haemostatic composition, in flowable paste form, comprises fibrinogen in an amount of 0.05% to 0.099% by weight, and thrombin in an amount from 70 I U / g to 300 I U / g.

[0354] In one embodiment, the haemostatic composition, in flowable paste form, comprises one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol and / or mannitol, in an amount of 4% to 30% by weight.

[0355] In one embodiment, the haemostatic composition, in flowable paste form, comprises one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol and / or mannitol, in an amount from 6% to 30% by weight, such as from 6% to 10%, such as from 10% to 15%, such as from 15% to 20%, such as from 20% to 30% by weight. In one embodiment, the haemostatic composition, in flowable paste form, comprises one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol, and / or mannitol, in an amount from 6% to 25% by weight.

[0356] In one embodiment, the haemostatic composition, in flowable paste form, comprises one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol and / or mannitol, in an amount of 21% to 30% by weight, such as from 21% to 25%, such as from 21% to 23%. In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form, 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 III per gram, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, or polysorbate-20 and / or sorbitan monooleate, in an amount of 0.0001% to 0.09% by weight, e) one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol and / or mannitol, in an amount from 4% to 30% by weight, such as from 6% to 20%, such as 21 % to 30%, and f) an aqueous medium.

[0357] In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form 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 0.03% to 0.9% by weight, c) thrombin in an amount of 7 IU to 600 IU per gram of the composition, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, or polysorbate-20 and / or sorbitan monooleate, in an amount of 0.0001% to 0.09% by weight, e) one or more hydrophilic compound(s) as described herein, such as glycerol, propylene glycol and / or mannitol, in an amount from 4% to 30% by weight, such as from 6% to 20%, such as 21% to 30% by weight, and f) an aqueous medium.

[0358] In one embodiment, the haemostatic composition in flowable paste form as described herein, comprises the one or more hydrophilic compounds in an amount of 0.6 g to 1.5 g per gram of the biocompatible polymer. In one embodiment, the haemostatic composition, in flowable paste form, comprises the one or more adhesion enhancer (s) as described herein, such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and / or tannic acid, in an amount of 0.01 % to 8.5% by weight. This corresponds to compositions comprising 2 mg to 240 mg of the one or more adhesion enhancer(s) per gram of the biocompatible polymer, prepared as described herein.

[0359] In one embodiment, the haemostatic composition, in flowable paste form comprises the one or more adhesion enhancer(s) as described herein, such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and / or tannic acid, in an amount of 0.1 % to 8% by weight, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8%. In one embodiment, the haemostatic composition, in flowable paste form comprises the one or more adhesion enhancer(s) as described herein, such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and / or tannic acid, in an amount of 0.1% to 4% by weight, such as from 0.1 % to 2% by weight.

[0360] In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form, 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 III per gram, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, or polysorbate-20 and / or sorbitan monooleate, in an amount of 0.0001% to 0.09% by weight, e) one or more adhesion enhancer (s) as described herein, such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and / or tannic acid, in an amount from 0.01% to 15% by weight, such as 0.01 % to 8.5% by weight, and f) an aqueous medium.

[0361] In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form 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 0.03% to 0.9% by weight, c) thrombin in an amount of 7 III to 600 IU per gram of the composition, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, or polysorbate-20 and / or sorbitan monooleate, in an amount of 0.0001% to 0.09% by weight, e) one or more adhesion enhancer (s) as described herein, such as alginate, hyaluronic acid, chitosan, chondroitin sulfate and / or tannic acid, in an amount from 0.01% to 15% by weight, such as 0.01% to 8.5% by weight, and f) an aqueous medium.

[0362] In one embodiment, the haemostatic composition, in flowable paste form, comprises alginate in an amount from 0.01% to 4.1% by weight, such as from 0.07% to 1.4% by weight.

[0363] In one embodiment, the haemostatic composition, in flowable paste form, comprises hyaluronic acid in an amount from 0.01% to 8.5% by weight, such as from 0.14% to 6.8% by weight.

[0364] In one embodiment, the haemostatic composition, in flowable paste form, comprises chitosan in an amount from 0.01% to 4.1% by weight, such as from 0.14% to 2.4% by weight.

[0365] In one embodiment, the haemostatic composition, in flowable paste form, comprises chondroitin sulfate in an amount from 1% to 15% by weight

[0366] In one embodiment, the haemostatic composition, in flowable paste form, comprises chondroitin sulfate in an amount from 0.01% to 2.0% by weight, such as from 0.03% to 1.0% by weight.

[0367] In one embodiment, the haemostatic composition, in flowable paste form, comprises tannic acid in an amount from 0.01% to 4.1% by weight, such as from 0.07% to 3.4% by weight.

[0368] In one embodiment, the haemostatic composition, in flowable paste form, comprises tannic acid in an amount from 0.07% to 1.3% by weight. In one embodiment, the haemostatic composition, in flowable paste form, comprises tannic acid in an amount from 0.7% to 0.9% by weight. In one embodiment, the haemostatic composition, in flowable paste form, comprises tannic acid in an amount from 0.7% to 1.3% by weight. In one embodiment, the haemostatic composition in flowable paste form as described herein, comprises the one or more adhesion enhancer(s) in an amount of 2 mg to 24 mg per gram of the biocompatible polymer.

[0369] In one embodiment, the haemostatic composition, in flowable paste form, comprises the one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, in an amount of 0.0001 % to 0.09% by weight. This corresponds to compositions comprising 0.02 mg to 2.4 mg of the one or more surfactant(s) per gram of the biocompatible polymer, prepared as described herein.

[0370] In one embodiment, the haemostatic composition, in flowable paste form, comprises the one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, in an amount from 0.004% to 0.041% by weight. In one embodiment, the haemostatic composition, in flowable paste form, comprises the one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, in an amount from 0.004% to 0.02% by weight.

[0371] In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form 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 III per gram of the composition, d) one or more surfactant(s), surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, in an amount of 0.0001% to 0.09% by weight, and e) an aqueous medium.

[0372] In one embodiment, the present disclosure provides a haemostatic composition in flowable paste form 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 0.03% to 0.9% by weight, c) thrombin in an amount of 7 IU to 600 IU per gram of the composition, d) one or more surfactant(s) as described herein, such as polysorbate-20 and / or sorbitan monostearate, in an amount of 0.0001% to 0.09% by weight, and e) an aqueous medium.

[0373] In one embodiment, the haemostatic composition in flowable paste form as described herein, comprises the one or more surfactant(s) as described herein in an amount of 0.02 mg to 2.4 mg per gram of the biocompatible polymer.

[0374] In one embodiment, the haemostatic composition in flowable paste form as described herein, comprises the one or more surfactant(s) as described herein in an amount of 0.03 mg to 0.2 mg per gram of the flowable haemostatic composition. In one embodiment, the haemostatic composition in flowable paste form as described herein, comprises the one or more surfactant(s) as described herein in an amount of 0.06 mg to 0.2 mg per gram of the flowable haemostatic composition.

[0375] In one embodiment, the haemostatic composition as described herein is sterile.

[0376] Containers

[0377] In one embodiment the haemostatic 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 haemostatic paste composition to be applied to a bleeding.

[0378] The first and the second containers may be made 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).

[0379] In one embodiment, the haemostatic composition is provided in a container which may be selected from a syringe, a vial, a jar, a tube, a tray, or a cartridge.

[0380] In a preferred embodiment said first container holding the haemostatic composition is a medical delivery device suitable for dispensing flowable haemostatic compositions to a patient in need thereof, such as a syringe, such as a single use plastic syringe. The first container is usually made from a material suitable for chemical surface sterilisation without influencing the content of the container. For example, said first container may be made from a material which is impermeable to ethylene oxide, such as for example made from metal, glass or a plastic which is impermeable to ethylene oxide.

[0381] In one embodiment, an aqueous solution is provided in a second container which may be selected from a syringe, a vial, a jar, a tube, a tray, or a cartridge.

[0382] In a preferred embodiment the container holding the aqueous solution is a medical delivery device suitable for dispensing flowable haemostatic compositions to a patient in need thereof, such as a syringe. In one embodiment, the second container is a singleuse plastic syringe.

[0383] In one embodiment, the first and second containers are interconnectable. The connector portion may be a connector portion of a standard type, such as a Luer lock or Luer slip connector. The connector portion may be provided with a threaded portion for secure connection with matching connector. The dimensions of said Luer lock or Luer slip connection may be able to change the ability of mixing in air into the haemostatic composition during mixing of the haemostatic composition and the aqueous medium. Further, the dimensions of the Luer lock or Luer slip connection may be able to influence the consistency of the haemostatic composition.

[0384] In one embodiment, the connector portion comprises a static mixer. The dimensions of said static mixer may be able to change the ability of mixing in air into the haemostatic composition during mixing of the haemostatic composition and the aqueous medium. Further, the dimensions of the static mixer may be able to influence the consistency of the haemostatic composition.

[0385] Sterilisation

[0386] The haemostatic compositions according to the present disclosure are preferably sterile.

[0387] Thus, in one embodiment, the haemostatic composition described herein is a sterile haemostatic composition. Any suitable sterilisation technique known in the art may be utilised. Sterilisation refers to any process that effectively kills or eliminates transmissible agents (such as fungi, bacteria, viruses, prions and spore forms etc.). Sterilisation can be achieved through e.g. application of heat, chemicals, and / or irradiation.

[0388] Sterilisation may be achieved by heat sterilisation, include autoclaving (uses steam at high temperatures) and dry heat.

[0389] Sterilisation may also be achieved by irradiation, e.g. ionizing irradiation, so as to provide sterility to the components. Such irradiation may include e-beam (beta irradiation), X- rays, gamma and beta rays, UV light and subatomic particles. The level of irradiation and conditions for sterilisation, including the time, are those that provide sterile compositions. Sterilisation conditions are similar to those currently utilized in the art and can be determined by the skilled person.

[0390] Sterilisation may be performed by chemical sterilisation such as by using ethylene oxide gas, ozone, nitrogen dioxide, chlorine bleach, glutaraldehyde, formaldehyde, ortho phthalaldehyde, hydrogen peroxide and / or peracetic acid.

[0391] The haemostatic composition or the biocompatible polymer in particulate form may also be prepared using aseptic methods.

[0392] Medical use

[0393] The present disclosure further relates to the haemostatic composition as described herein or obtained by the methods of this disclosure for use in promoting haemostasis and / or wound, bone, tendon and / or tissue healing in an individual in need thereof.

[0394] In one embodiment, the present disclosure provides a haemostatic composition as described herein for use in promoting haemostasis in an individual in need thereof. In one embodiment, the present disclosure provides a haemostatic composition as described herein for use in promoting wound healing in an individual in need thereof.

[0395] The haemostatic composition of the present disclosure may e.g. be used in an array of surgical procedures wherein bleeding control is desired. The haemostatic composition is preferably applied to a patient in the form of a paste which conforms to irregular surfaces and is therefore useful for providing rapid haemostasis on rough or uneven surfaces where haemostatic sponges are not efficient.

[0396] Due to its superior haemostatic and adhesive properties, the haemostatic composition as disclosed herein is particularly suitable for minimally invasive / robotic surgery, where manual compression is impractical or impossible and / or where classical haemostatic fibrin sealants are ineffective. For instance, the haemostatic composition in paste form as disclosed herein can be sprayed onto a bleeding surface during minimally invasive surgery to provide a patch-like haemostatic composition which adheres sufficiently to the bleed and provides effective haemostasis without compression.

[0397] The haemostatic composition as disclosed herein has also been shown to be capable of controlling severe bleedings. Thus, in one embodiment, the haemostatic composition as disclosed herein is useful in the treatment of severe bleedings classified as level 4 or level 5 bleedings.

[0398] In general, haemostatic pastes are prepared directly at the surgical site at the time of need by the medical practitioner by addition of liquid to a container, such as a syringe, containing an amount of a haemostatic product. The haemostatic product may be prewetted with the liquid or be essentially dry (e.g. a free-flowing powder). The paste is thus often prepared under extremely stressful conditions and it is therefore essential that the process for preparing the paste is simple and fast to ensure that the bleeding is arrested as quickly as possible and that no mistakes are made while preparing the paste such that the nurse can keep focus on the needs of the surgeon instead of on preparing the haemostat. It is also important that the consistency of the paste is suitable for use as a haemostatic paste and that the consistency of the product is independent from preparation to preparation and over time. Currently available flowable paste products (Floseal® and Surgiflo®) require separate reconstitution of thrombin prior to mechanical mixing of said reconstituted thrombin solution with the biocompatible polymer by passing the biocompatible polymer and the liquid between two connected syringes a number of times to obtain a substantially homogenous paste. The reconstitution of the thrombin is time-consuming and error prone, two undesired factors in an OR setting. These products are often pre-prepared in the OR before surgery in case they are needed under surgery and unused product is often discarded causing unnecessary high OR costs.

[0399] Since the haemostatic composition of the present disclosure, in the dry, storage stable form, already includes thrombin and fibrinogen, the haemostatic paste for application to a patient can be prepared more easily since separate reconstitution and addition of e.g. thrombin is not necessary. To achieve the haemostatic composition of the present disclosure in the paste form one can simply add a suitable amount of an aqueous medium to a container comprising the haemostatic composition (in dry form) and mix by transferring the contents between two interconnected syringes a number of times, whereupon a ready-to-use haemostatic paste is formed.

[0400] A notable advantage of the compositions and methods of the present invention is that they allow for a better control of the consistency of the haemostatic compositions, while providing a superior haemostatic effect. This is highly valuable in the OR, where haemostasis needs to be achieved efficiently and as fast as possible.

[0401] Another advantage of the composition and methods of the present disclosure is that a kit consisting of fewer components can be prepared as compared to current haemostatic flowable kits. All that is required to prepare a flowable paste composition in the OR is the dry, storage-stable haemostatic composition comprised within a first container, such as a syringe, and a second container, such as a syringe, comprising an aqueous solution. Upon connection of the two and mixing, a ready-to-use flowable paste containing all necessary agents for highly effective haemostasis is formed. Thus, no extra syringes, vial adapters, needles and mixing bowls are required. This means that the manufacturing costs can be decreased and also ensures good patient safety, since there are less components for the OR staff to keep track of during surgery. Needle-free preparation of the haemostat also ensures the safety of the OR staff.

[0402] In one embodiment the present disclosure relates to a method for arresting bleeding / promoting haemostasis in an individual in need thereof by application of the haemostatic composition as disclosed herein to a site of bleeding. Upon application, the haemostatic composition is preferably in flowable, paste form.

[0403] The haemostatic composition of the present disclosure may be used for any type of surgery including general surgery, cardiothoracic surgery, vascular surgery, plastic surgery, paediatric surgery, colorectal surgery, transplant surgery, surgical oncology, trauma surgery, endocrine surgery, breast surgery, skin surgery, otolaryngology, gynaecology, oral and maxillofacial surgery, dental Surgery, orthopaedic surgery, neurosurgery, ophthalmology, podiatric surgery, urology. The haemostatic composition is particularly suitable for minimally invasive / robotic surgery where manual compression is impractical or impossible. In one embodiment, the present disclosure relates to a method for promoting wound healing in an individual in need thereof by application of the haemostatic composition as disclosed herein to the wound.

[0404] A "wound" refers broadly to injuries to the skin and / or underlying (subcutaneous) tissue initiated in different ways (e.g., pressure sores from extended bed rest and wounds induced by trauma) and with varying characteristics. Wounds may 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 wherein bones are exposed (e.g., a bony pressure point such as the greater trochanter or the sacrum). The present disclosure relates to treatment of any type of wound mentioned above using the haemostatic composition of the present disclosure.

[0405] The treatment of a wound can in principle result in healing of the wound or in accelerated healing of the wound. The accelerated healing can be a result of e.g. administration of a wound-healing promoting substance. Alternatively, the wound healing can be promoted by preventing bacterial or viral infection, or by reducing the risk of such an infection which would otherwise have prolonged the wound treatment process.

[0406] In one embodiment the present disclosure relates to a method for promoting bone and / or tendon healing in an individual in need thereof by application of the haemostatic composition as disclosed herein to the injured bone / tendon.

[0407] The “individual” referred to herein 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 are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.

[0408] In one embodiment the present disclosure relates to a haemostatic composition as disclosed herein, for use in the treatment of a wound, e.g. for arresting bleeding or for promoting wound healing. A haemostatic kit

[0409] The present disclosure further relates to a haemostatic kit comprising the dry haemostatic composition as described herein and an aqueous solution or an aqueous medium so that upon mixing, a haemostatic composition suitable for use in haemostasis will form.

[0410] Hence, in one embodiment the present disclosure relates to a haemostatic kit comprising: a) a first syringe comprising a dry haemostatic composition as described herein, b) a second syringe comprising an aqueous medium; and c) optionally an outer package, wherein the two syringes are interconnectable.

[0411] Hence, in one embodiment the present disclosure relates to a haemostatic kit comprising: a) a first syringe comprising a dry haemostatic 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 package, wherein the two syringes are interconnectable.

[0412] The first syringe or the second syringe may comprise further components as described herein. In one embodiment the first or the second syringe may comprise one or more hydrophilic compound(s) as described herein. In one embodiment the first or the second syringe may comprise one or more adhesion enhancer(s) as described herein. In one embodiment the first or the second syringe may comprise one or more surfactant(s) as described herein.

[0413] In one embodiment, the kit further comprises one or more applicator tips.

[0414] The kit may optionally contain instructions for use of the kit.

[0415] The components of the haemostatic kit may be as described elsewhere herein. In one embodiment the kit comprises an outer package. The outer package is usually made from a flexible, semi-rigid or rigid material and typically consists of materials such as plastic, aluminium foil and / or plastic laminate, where the plastic may be selected from the group consisting of PET, PETG, PE, LLDPE, CPP, PA, PETP, METPET, Tyvek and optionally bonded with an adhesive, such as polyurethane, or co-extruded.

[0416] In one embodiment, the outer package is an aluminium foil outer package.

[0417] The outer package preferably forms a complete barrier to moisture.

[0418] The outer package is preferably able to endure sterilisation treatment such as by radiation.

[0419] Examples

[0420] Example 1: Deployability of paste compositions comprising thrombin, fibrinogen and a biocompatible polymer

[0421] Aim

[0422] To study the time that the compositions according to the present disclosure remain deployable from a syringe.

[0423] Materials

[0424] 5 mL of a gelatine paste containing 1 g of crosslinked gelatine particles and human recombinant fibrinogen in a 10 mL syringe (first syringe). Three different amounts of fibrinogen were tested: 7, 35 and 70 mg.

[0425] 1 mL of a 2000 IU of human recombinant thrombin solution in a 10 mL syringe (second syringe).

[0426] The gelatine particles used in the paste were obtained from milled crosslinked gelatine sponges (Spongostan).

[0427] Method

[0428] The two syringes were interconnected via a luer lock and the paste was transferred back and forth between the first and the second syringes until mixed.

[0429] The mixed fibrinogen-containing pastes contained about 14% w / w of gelatine, about 285 IU of thrombin per gram of paste and about 0.1 % w / w (7 mg), 0.5% w / w (35 mg) or 1% w / w (70mg) of fibrinogen, respectively.

[0430] The syringes were left at room temperature for the time periods indicated in Table 1 and the syringes were evaluated for clogging of the paste within the syringe and the ability to deploy the paste from the syringes via manual pressure on the plunger.

[0431] Results

[0432] As can be seen in table 1 , the compositions according to the present disclosure with varying amounts of fibrinogen remain deployable from a syringe for at least 90 minutes after mixing. In contrast, the compositions without biocompatible polymer clogged in the syringe and could not be deployed at any time points. Pastes containing gelatine, thrombin and 105mg fibrinogen / g gelatin were also tested (data not shown). The pastes containing 105mg fibrinogen could be deployed from the syringe but it was found that the force required to deploy the samples was markedly increased compared to the samples containing less fibrinogen and produced pastes which were more likely to break or develop cracks hence impacting paste integrity and performance.

[0433] Table 1: Testing ability to deploy from syringe in different compositions. aControl contained no gelatin and 35 mg fibrinogen.

[0434] Conclusion

[0435] The results surprisingly demonstrate that paste compositions according to the present disclosure remain deployable from a syringe for at least 90 minutes after mixing. Accordingly, paste compositions comprising a biocompatible polymer, e.g. gelatine, thrombin and fibrinogen can be prepared and remain in deployable paste form for a time period compatible with clinical use during surgery.

[0436] Example 2: Efficacy test of gelatine-thrombin pastes comprising various amounts of fibrinogen

[0437] Aim

[0438] To study the haemostatic efficacy of the paste compositions of Example 1 , i.e. of paste compositions comprising crosslinked gelatine, thrombin and fibrinogen compared to paste compositions comprising gelatine and thrombin only. Haemostatic efficacy was tested in a porcine spleen biopsy model as described below.

[0439] Materials and Methods

[0440] Experimental model: A porcine spleen biopsy-punch model was used applying 8 mm punctures (3 mm deep) in the spleen with an initial compression period of 5 seconds followed by an evaluation period of 120 seconds and following compression periods of 5 seconds. The porcine spleen biopsy-punch model is an established model for evaluating haemostatic efficacy of haemostatic pastes in vivo (Hutchinson et al., 2015, Surgical Technology International XXVII). The porcine spleen biopsy-punch model of the present study is similar to the one used in Hutchinson et al., 2015.

[0441] Experimental animal: The pig is the animal of choice for this model since it has a large volume of blood (70 ml / kg) and a large vascular spleen that enables many haemostatic comparisons in a single animal.

[0442] 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 for the difference in fibrinogen content.

[0443] Surgical procedures: A midline abdominal incision was made to expose the spleen. An 8 mm punch (3 mm deep) was made in the spleen. The bleeding intensity was evaluated on a scale from 0-5 as described herein below. Only bleeding intensities 3 and 4 were regarded as acceptable. The punch was now ready for either a control sample or a test sample. A new punch was made for every test sample. Each sample type was tested 7 times (n=7). The samples were tested in a randomized order.

[0444] A 12 minute negative control, using only wetted gauze, was performed at the initiation and completion of the testing period on each pig. The negative controls were used as an indication of the animal’s ability to bleed throughout the study.

[0445] The primary test parameter was to measure the time to haemostasis (TTH). TTH is defined as the total time minus the final haemostasis evaluation period ensuring that no further bleeding occurred, i.e. no re-bleed.

[0446] The evaluation of bleeding intensity and the application of test samples and negative controls are described in detail below.

[0447] Bleeding intensity: The bleeding intensity of each punch was evaluated by the surgeon on a scale from 0-5 (see Table below). Bleeding intensity was noted at t=0 for each punch. Only tests performed on wounds with bleeding intensity of 3-4 were used for further analysis.

[0448] Table: Bleeding intensity levels

[0449] Negative control: Wetted gauze was placed directly on the punch. Digital pressure was applied for 30 seconds followed by a 120 second haemostasis evaluation period. Haemostasis was evaluated (defined as no sieving of blood from under test article for 30 seconds). If haemostasis was not achieved within the 120 seconds, additional 30 seconds digital pressure was applied and a 120 second re-evaluation for haemostasis was performed. Tamponade application and observation periods were performed until bleeding stopped, and haemostasis achieved, or until the testing period reached 12 minutes. Haemostasis was not achieved within the 12 minutes testing period for the negative controls, thus showing the ability of the pig to bleed throughout the study.

[0450] Application of test samples: Approximately 1-2 mL paste was applied directly into the punch with an applicator tip. During application the tip penetrated into the punch to ensure tissue contact. After application, gauze wetted in 0.9 % saline was placed on the punch. Digital pressure (tamponade) was applied for 5 seconds. The pressure was stopped and the gauze removed followed by evaluation of haemostasis. If no sieving of blood was seen from under the test article for 120 seconds, it was concluded that haemostasis was achieved and the experiment is ended. If blood sieved from under the test article in the 120 second time frame, the time for sieving was recorded and digital pressure was again applied for 5 seconds, after which haemostasis was inspected. This procedure was continued until haemostasis was achieved or for 12 minutes, whichever came first.

[0451] Calculation example for evaluation of Time to Haemostasis (TTH): 5 seconds of digital pressure, inspect for haemostasis: blood sieves after 39 seconds, digital pressure for another 5 seconds, inspect for haemostasis for 120 seconds: no sieving - conclusion: haemostasis was achieved after 5+39+5 seconds = 49 sec. i.e. the last observation period is not included in calculating the TTH.

[0452] Results

[0453] Results are shown in Table 2. The results show that using samples containing 70 and 35 mg fibrinogen a shorter average time to haemostasis was achieved compared to 7 mg fibrinogen or control (gelatine paste with thrombin but without fibrinogen).

[0454] Table 2: TTH of gelatine-thrombin paste composition + / - fibrinogen aValues reported as average + standard deviation. Each sample was tested 7 times (n=7) in randomized order

[0455] Conclusion

[0456] The paste compositions comprising gelatine, thrombin and fibrinogen led to haemostasis faster and more consistently than the control paste without fibrinogen. Thus, the present study shows that it is beneficial to include fibrinogen in haemostatic paste compositions comprising gelatine and thrombin. Example 3: Efficacy test of gelatine-thrombin pastes comprising fibrinogen

[0457] Aim

[0458] To study the haemostatic efficacy of the compositions according to the present disclosure.

[0459] Materials

[0460] 1 g dry crosslinked gelatine particles, 2000 III thrombin and 70 or 105 mg fibrinogen in a 10 mL syringe (first syringe).

[0461] 6 mL of aqueous solution in a 10 mL syringe (second syringe).

[0462] The gelatine particles were obtained from milled crosslinked gelatine sponges (Spongostan) and the chemical content and water content in the tested samples and the control were identical but for the difference in fibrinogen content.

[0463] Methods

[0464] The two syringes were interconnected via a luer lock and the 6 mL of aqueous solution was transferred to the syringe containing the dry powder composition. The resulting mixture was transferred back and forth between the first and the second syringes until mixed, resulting in a haemostatic composition contained in the second syringe.

[0465] The same porcine spleen biopsy-punch model as described in example 2 was used. Each sample type was tested 11 times (n=11). The samples were tested in a randomized order.

[0466] Results

[0467] Results for the reconstituted haemostatic paste are shown in Table 3. The results show a shorter average time to haemostasis achieved using the reconstituted paste with fibrinogen compared to control.

[0468] Table 3: TTH of gelatine-thrombin paste composition + / - fibrinogen aValues reported as average + standard deviation. Each sample was tested 11 times (n=11) in randomized order

[0469] The force required to deploy the samples with 105 mg fibrinogen was markedly increased compared to the samples containing 70 mg fibrinogen and produced pastes which were more likely to break or develop cracks hence impacting paste integrity and performance.

[0470] Conclusion

[0471] The haemostatic compositions according to the present invention led to haemostasis faster and more consistently than the control paste without fibrinogen.

[0472] Example 4: Effect of surfactants on complex viscosity

[0473] Aim

[0474] To study the effect of different surfactants on the viscosity properties of composition according to the present disclosure.

[0475] Materials

[0476] 1 g of crosslinked gelatine particles, 2000 III of thrombin, and 17.5 mg human recombinant fibrinogen was placed in a 10 mL syringe (first syringe).

[0477] 6 mL of an aqueous medium in a 10 mL syringe (second syringe). Different solutions were tested: a solution of saline,

[0478] 6% glycerol + 0.01% benzalkonium chloride (BAG) in saline,

[0479] 20% glycerol in saline,

[0480] 0.1 mg / mL Tween20® + 20% glycerol in saline

[0481] 0.1 mg / mL Span80® + 20% glycerol in saline

[0482] The gelatine particles used in the paste were obtained from milled crosslinked gelatine sponges (Spongostan).

[0483] Method

[0484] The two syringes were interconnected via a luer lock and the paste was transferred back and forth between the first and the second syringes until mixed.

[0485] The mixed fibrinogen-containing pastes contained about 14% w / w of gelatine, about 285 IU of thrombin per gram of paste and about 0.25% w / w (17.5 mg) of fibrinogen, respectively. The syringes were mixed immediately before testing, and a sample from the start, middle, and end of the syringe were tested to evaluate the uniformity of the consistency.

[0486] Complex viscosity measurement. A Discovery Hybrid Rheometer (TA Instruments) calibrated in the range of 100-10,000 Pa s was used for the measurements. Each sample of the paste was loaded onto a 25 °C Peltier plate and by lowering a 20 mm plate flat stainless steel upper plate geometry the paste is sandwiched between them. Excess sample material is removed. The measurement is carried out over a period of 60 sec. where an oscillation movement with a fixed strain of 1 % and a fixed angular frequency of 1 rad / s is applied. The result is given as the complex viscosity.

[0487] Results

[0488] As shown in Figure 1 , pastes comprising 0.6 mg of Tween 20® or Span 80® per gram of gelatine had a lower viscosity compared to control and comparative samples. This means that the pastes were easier to express from the syringe and flowed more easily.

[0489] It is also seen that the pastes were more uniform compared to control as demonstrated by the reduced differences in viscosity between samples taken from different sections (start, middle, or end) of the syringe after forming the paste. The lower viscosity for the start sample and high viscosity at the end indicates that the paste is very watery in the beginning and more dry at the end section.

[0490] Conclusion

[0491] Addition of surfactants to the paste lowers the complex viscosity, allowing preparation of a more flowable product. Addition of surfactants led to a product that is more uniform in consistency throughout the syringe compared to control or saline.

[0492] References

[0493] Mathiowitz Edith, Chickeringl III DE, Lehr CMichael. Bioadhesive drug delivery systems : fundamentals, novel approaches, and development. Chickering III DE, Lehr CMichael, Mathiowitz Edith, editors. New York: Marcel Dekker; 1999. (Drugs and the pharmaceutical sciences ; 98.)

[0494] Amoros-Galicia L, Nardi-Ricart A, Verdugo-Gonzalez C, Arroyo-Garcia CM, GarciaMontoya E, Perez-Lozano P, et al. Development of a Standardized Method for Measuring Bioadhesion and Mucoadhesion That Is Applicable to Various Pharmaceutical Dosage Forms. Pharmaceutics. 2022 Oct 1 ;14(10).

Claims

Claims1 . A haemostatic composition comprising: a) a biocompatible polymer in particulate form, b) fibrinogen in an amount of 1 mg to 150 mg per gram of the biocompatible polymer, c) thrombin in an amount of 100 III to 5000 IU per gram of the biocompatible polymer, and d) one or more surfactant(s).

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

3. The haemostatic composition according to claim 1 or 2, wherein the biocompatible polymer in particulate form is present in an amount from 0.05 to 20 g, such as from 0.2 to 10 g, such as from 0.5 to 2g, such as about 1 g.

4. The haemostatic composition according to any one of the preceding claims, wherein the biocompatible polymer in particulate form comprise or consist of a biocompatible polymer selected from the group consisting of: gelatine, collagen, chitin, chitosan, alginate, cellulose, oxidised cellulose, carboxymethylcellulose, polyglycolic acid, polyacetic acid and combinations thereof.

5. The haemostatic composition according to any one of the preceding claims, wherein the biocompatible polymer comprises or consists of powder particles, which are substantially insoluble in an aqueous medium.

6. The haemostatic composition according to any one of the preceding claims, wherein the biocompatible polymer is cross-linked.

7. The haemostatic composition according to any one of the preceding claims, wherein the biocompatible polymer is biologically absorbable.

8. The haemostatic composition according to any one of the preceding claims, wherein the biocompatible polymer in particulate form comprises or consists of cross-linked gelatine particles.

9. The haemostatic composition according to claim 8, wherein the gelatine is obtained from a micronized gelatine sponge or hydrogel.

10. The haemostatic composition according to any one of claims 1 to 9, wherein the biocompatible polymer particles have an average size of from 1 to 1000 pm, such as from 100 to 800 pm, such as from 300 to 500 pm, such as about 450 pm, e.g. as measured by laser diffraction.

11. The haemostatic composition according to any one of the preceding claims, wherein the biocompatible polymer particles have an average size from 601 pm to 799 pm, e.g. as measured by laser diffraction.

12. The haemostatic composition according to any one of the preceding claims, wherein the fibrinogen is human fibrinogen.

13. The haemostatic composition according to any one of the preceding claims, wherein the fibrinogen is recombinant human fibrinogen.

14. The haemostatic composition according to any one of the preceding claims, wherein the thrombin is human thrombin.

15. The haemostatic composition according to any one of the preceding claims, wherein the thrombin is recombinant human thrombin.

16. The haemostatic composition according to any one of the preceding claims, wherein the composition comprises from 5 to 100 mg of fibrinogen per gram of the biocompatible polymer, such as from 20 to 80 mg, such as about 35 mg or such about 70 mg of fibrinogen per gram of the biocompatible polymer.

17. The haemostatic composition according to any one of the preceding claims, wherein the composition comprises from 20 to 100 mg of fibrinogen per gram of the biocompatible polymer, such as from 30 mg to 100mg.

18. The haemostatic composition according to any one of the preceding claims, wherein the composition comprises fibrinogen in an amount of from 1 to 10% by weight, such as from 2 to 5% by weight, such as about 3.5% by weight.

19. The haemostatic composition according to any one of the preceding claims, wherein the composition comprises from 400 to 4000 III of thrombin per gram of the 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 the biocompatible polymer.

20. The haemostatic composition according to any one of the preceding claims, wherein the composition comprises a ratio of thrombin to fibrinogen from 0.5 lU / mg to 5000 lU / mg, such as from 1 lU / mg to 2000 lU / mg, such as from 2 lU / mg to 150 lU / mg, such as about 10 to 100 lU / mg.

21. The haemostatic composition according to any one of claims 1 to 15, wherein the haemostatic composition comprises 5 mg to 25 mg fibrinogen and 100 I U to 1800 IU of thrombin per gram of the biocompatible polymer.

22. The haemostatic composition according to any one of claims 1 to 15, wherein the haemostatic composition comprises 5 mg to 10 mg fibrinogen and 100 I U to 1800 IU of thrombin per gram of the biocompatible polymer.

23. The haemostatic composition according to any one of claims 1 to 15, wherein the haemostatic composition comprises 10 mg to 15 mg fibrinogen and 100 1 U to 1800 IU of thrombin per gram of the biocompatible polymer.

24. The haemostatic composition according to any one of claims 1 to 15, wherein the haemostatic composition comprises 15 mg to 20 mg fibrinogen and 100 1 U to 1800 IU of thrombin per gram of the biocompatible polymer.

25. The haemostatic composition according to any one of claims 1 to 15, wherein the haemostatic composition comprises 20 mg to 25 mg fibrinogen and 100 1 U to 1800 IU of thrombin per gram of the biocompatible polymer.

26. The haemostatic composition according to any one the preceding claims, further comprising one or more additional active ingredients capable of stimulating haemostasis, wound healing, bone healing, tissue healing and / or tendon healing.

27. The haemostatic composition according to claim 26, wherein the one or more additional active ingredient(s) is 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), vascularendothelial growth factor (VEGF), basic fibroblast growth factor, transforming growth factor beta (TGF-P) and flakes or particles of extracelluar matrix (ECM).

28. The haemostatic composition according to any one the preceding claims, further comprising one or more hydrophilic compound(s).

29. The haemostatic composition according to claim 28, wherein the one or more hydrophilic compound(s) comprise or consist of polyethylene glycol (PEG).

30. The haemostatic composition according to claim 28, wherein the one or more hydrophilic compound(s) is one or more polyol(s) selected from sugar alcohols, sugars and / or derivatives thereof.

31. The haemostatic composition according to claim 30, wherein the one or more hydrophilic compound(s) is 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 and mixtures thereof.

32. The haemostatic composition according to any one of claims 28 to 31 , wherein the one or more hydrophilic compound(s) are present in an amount from 0.01 g to 0.5 g of hydrophilic compound per gram of biocompatible polymer, such as from 0.01 g to 0.4 g, such as from 0.01 g to 0.3 g, such as from 0.01 g to 0.2 g, such as from 0.01 g to 0.1 g, such as from 0.01 g to 0.05 g of hydrophilic compound per gram of the biocompatible polymer.

33. The haemostatic composition according to any one of claims 28 to 31 , wherein the one or more hydrophilic compound(s) are present in an amount from 0.6 g to 1.5 g of the one or more hydrophilic compound(s) per gram of biocompatible polymer, such as from 0.8 g to 1.5 g, such as from 1.0 g to 1.5 g of the one or more hydrophilic compound(s) per gram of biocompatible polymer.

34. The haemostatic composition according to any one of claims 28 to 33, wherein the one or more hydrophilic compound(s) is glycerol.

35. The haemostatic composition according to any one of claims 28 to 33, wherein the one or more hydrophilic compound(s) is mannitol.

36. The haemostatic composition according to any one of claims 28 to 33, wherein the one or more hydrophilic compound(s) is propylene glycol.

37. The haemostatic composition according to any one of claims 28 to 33, wherein the one or more hydrophilic compound(s) is sorbitol.

38. The haemostatic composition according to any one of claims 28 to 33, wherein the one or more hydrophilic compound(s) trehalose.

39. The haemostatic composition according to any one of claims 28 to 33, wherein the one or more hydrophilic compound(s) is xylitol.

40. The haemostatic composition according to any one of claims 28 to 33, wherein the one or more hydrophilic compound(s) is maltitol.

41. The haemostatic composition according to any one of claims 28 to 33, wherein the hydrophilic compounds are glycerol and mannitol.

42. The haemostatic composition according to any one the preceding claims, further comprising one or more extrusion enhancer(s), such as albumin, preferably human serum albumin.

43. The haemostatic composition according to any one of the preceding claims, wherein said composition contains less than 10% water by weight, preferably less than 5% water by weight, preferably less than 1 % water by weight.

44. The haemostatic composition according to any one of the preceding claims, further comprising one or more adhesion enhancer(s).

45. The haemostatic composition according to any one of the preceding claims, wherein the one or more adhesion enhancer(s) are present in an amount from 2 mg to 1 .3 g per gram of the biocompatible polymer.

46. The haemostatic composition according to claim 45, wherein the one or more adhesion enhancer(s) is present in an amount from about 2 mg to 240 mg, such as from about 25 mg to about 120 mg of adhesion enhancer(s) per gram of the biocompatible polymer.

47. The haemostatic composition according to any one of claims 45 to 46, wherein the adhesion enhancer(s) is a natural or synthetic polymer comprising, carboxylic acid groups, sulfonic acid groups, sulfate groups, phosphate groups, amino groups, hydroxyl groups, or combinations thereof.

48. The haemostatic composition according to any one of claims 45 to 46, wherein the adhesion enhancer(s) is a natural or synthetic polymer comprising orconsisting of a hydrophobic backbone, such as a polyalkylene, a silicone, or a polyacrylate.

49. The haemostatic composition according to any one claims 45 to 46, wherein the adhesion enhancer(s) is selected from the group consisting of: alginate, hyaluronic acid, chitosan, chondroitin sulfate and tannic acid, or any combination thereof.

50. The haemostatic composition according to any one of claims 45 to 46, wherein the adhesion enhancer(s) is alginate.

51. The haemostatic composition according claim 50, wherein the alginate is present in an amount from 2 mg to 120 mg per gram of biocompatible polymer, such as from 5 mg to 60 mg per, such as from 5 mg to 15 mg, such as from 15 mg to 30 mg, such as from 30 mg to 45 mg, such as from 45 mg to 60 mg alginate per gram of the biocompatible polymer.

52. The haemostatic composition according to any one of claims 45 to 46, wherein the adhesion enhancer(s) is hyaluronic acid.

53. The haemostatic composition according claim 52, wherein the hyaluronic acid is present in an amount from 2 mg to 240 mg per gram of biocompatible polymer, such as from 10 mg to 50 mg, such as from 50 mg to 100 mg, such as from 100 mg to 150 mg, such as from 150 mg to 200 mg, such as from 200 mg to 240 mg hyaluronic acid per gram of the biocompatible polymer.

54. The haemostatic composition according to any one of claims 45 to 46, wherein the adhesion enhancer(s) is chitosan.

55. The haemostatic composition according claim 54, wherein the chitosan is present in an amount from 2 mg to 120 mg per gram of biocompatible polymer such as from 10 mg to 20 mg, such as from 20 mg to 30 mg, such as from 30 mg to 40 mg, such as from 40 mg to 50 mg, such as from 50 mg to 60 mg, such as from 60 mg to 70 mg, such as from 70 mg to 80 mg, such as from 80 mg to 90 mg, such as from 90 mg to 100 mg chitosan per gram of the biocompatible polymer.

56. The haemostatic composition according to any one of claims 45 to 46, wherein the adhesion enhancer(s) is chondroitin sulfate.

57. The haemostatic composition according claim 56, wherein the chondroitin sulfate is present in an amount from 2 mg to 60 mg per gram of biocompatible polymer,such as from 5 mg to 15 mg, such as from 15 mg to 30 mg, such as from 30 mg to 45 mg, such as from 45 mg to 60 mg chondroitin sulfate per gram of the biocompatible polymer.

58. The haemostatic composition according to claim 56, wherein the chondroitin sulfate is present in an amount from 2 mg to 1 .3 g per gram of the biocompatible polymer.

59. The haemostatic composition according to any one of claims 45 to 46, wherein the adhesion enhancer(s) is tannic acid.

60. The haemostatic composition according claim 59, wherein the tannic acid is present in an amount from about 2 mg to 120 mg per gram of biocompatible polymer such as from 10 mg to 20 mg, such as from 20 mg to 30 mg, such as from 30 mg to 40 mg, such as from 40 mg to 50 mg, such as from 50 mg to 60 mg, such as from 60 mg to 70 mg, such as from 70 mg to 80 mg, such as from 80 mg to 90 mg, such as from 90 mg to 100 mg tannic acid per gram of the biocompatible polymer.

61. The haemostatic composition according to any one of the preceding claims, wherein the haemostatic composition comprises a further polymer comprising or consisting of a reactive derivative of a polyalkylene oxide, such as a derivative of polyethylene glycol, comprising one or more reactive groups selected from succinimidylester (NHS-ester), aldehyde (-CHO), isocyanate (- N=C=O), or imidoester.

62. The haemostatic composition according to any one of claims 1 to 61 , wherein the one or more surfactants are an anionic or cationic surfactant.

63. The haemostatic composition according to any one of claims 1 to 61 , wherein the one or more surfactants are a zwitterionic surfactant.

64. The haemostatic composition according to any one of claims 1 to 61 , wherein the one or more surfactant(s) are a non-ionic surfactant.

65. The haemostatic composition according to any one claims 1 to 61 , wherein the one or more surfactants are according to formula (I):wherein each of R1, R2, R3and R4are individually selected from H, or RF;RFis a group comprising or consisting of a C3-C22 hydrocarbon chain; wherein at least one of R1, R2, R3and R4is according to RF.

66. The haemostatic composition according to claim 65, wherein one of R1, R2, R3and R4is according to RF, and the remainder are H; such as R1is according to RF, and R2, R3and R4are H.

67. The haemostatic composition according to any one of claims 65 to 66, wherein RFcomprises or consist of a C10-C22 hydrocarbon chain.

68. The haemostatic composition according to any one of claims 65 to 67, wherein RFcomprises 0, 1 , 2, or 3 double bonds.

69. The haemostatic composition according to any one of claims 65 to 68, wherein RFconsists of:, wherein n is an integer from 1 to 20.

70. The haemostatic composition according to any one of claims 65 to 68, wherein RFconsists of: o, wherein p is any integer from 9 to 19, and q is any integer from 0 to p.

71. The haemostatic composition according to any one of claims 65 to 68, wherein the one or more surfactant(s) are selected from:

72. The haemostatic composition according to any one claims 1 to 61 , wherein the one or more surfactants are according to formula (II):wherein x1 , x2, x3, and x4 are integers, wherein the sum of x1+x2+x3+x4 is from 1 to 100; each of R5, R6, R7and R8are individually selected from H, or RK; RKis a group comprising or consisting of a C3-C22 hydrocarbon chain; wherein at least one of R5, R6, R7and R8is according to RK.

73. The haemostatic composition according to claim 72, wherein the sum of x1+x2+x3+x4 is from 10 to 80, such as from 10 to 60, such as 10 to 50, 10 to 40, or 10 to 30.

74. The haemostatic composition according to any one of claims 72 to 73, wherein one of R5, R6, R7and R8is according to RK, and the remainder are H; such as R5is according to RK, and R6, R7and R8are H.

75. The haemostatic composition according to any one of claims 72 to 74, wherein RKcomprises 0, 1 , 2, or 3 double bonds.

76. The haemostatic composition according to any one of claims 72 to 75, wherein RKconsist of:, wherein n is an integer from 1 to 20.

77. The haemostatic composition according to any one of 72 to 75, wherein RKconsists of:wherein p is any integer from 9 to 19, and q is any integer from 0 to p.

78. The haemostatic composition according to any one of 72 to 75, wherein the one or more surfactant(s) are selected from:any combination thereof; wherein the sum of x1+x2+x3+x4 is 20.

79. The haemostatic composition according to any one of claims 1 to 61 , wherein the one or more surfactant(s) are selected from: sorbitan monooleate (Span® 80, CAS number: 1338-43-8), sorbitan monostearate (Span® 60, CAS number: 1338- 41-6), sorbitan monopalmitate (Span® 40, CAS number: 26266-57-9), sorbitan monolaurate (Span® 20, CAS number: 1338-39-2), polysorbate-20 (Tween® 20, CAS number: 9005-64-5), polysorbate-40 (Tween® 40, CAS number: 9005-66-7),polysorbate-60 (Tween® 60, CAS number: 9005-67-8), and polysorbate-80 (Tween® 80, CAS number: 9005-65-6), or any combination thereof.

80. The haemostatic composition according to claim 79, wherein the haemostatic composition comprises sorbitan monostearate (Span® 60, CAS number: 1338- 41-6).81 . The haemostatic composition according to any one of claim 79 to 80, wherein the haemostatic composition comprises polysorbate-20 (Tween® 20, CAS number: 9005-64-5).

82. The haemostatic composition according to any one of claims 79 to 81 , wherein the haemostatic composition comprises sorbitan monooleate (Span® 80, CAS number: 1338-43-8).

83. The haemostatic composition according to any one of the preceding claims, wherein the haemostatic composition comprises two or more non-ionic surfactants.

84. The haemostatic composition according to claim 83, wherein the haemostatic composition comprises sorbitan monostearate (Span® 60, CAS number: 1338- 41-6) and polysorbate-20 (Tween® 20, CAS number: 9005-64-5).

85. The haemostatic composition according to any one of claims 64 to 84, wherein the haemostatic composition comprises 0.02 mg to 2.4 mg, such as 0.4 mg to 0.7 mg, of the one or more non-ionic surfactant(s), such as sorbitan monostearate, sorbitan monooleate, and / or polysorbate-20, per gram of the biocompatible polymer.

86. The haemostatic composition according to any one of claims 64 to 85, wherein the haemostatic composition comprises 0.5 mg to 0.6 mg of the one or more non- ionic surfactant(s), such as sorbitan monooleate and / or polysorbate-20, per gram of the biocompatible polymer.

87. The haemostatic composition according to any one of the preceding claims, wherein the composition is sterile.

88. A method of preparing a haemostatic composition comprising the steps of:Step A1 : providing a haemostatic composition comprising a biocompatible polymer in particulate form, fibrinogen and thrombin; andStep B1 : adding an amount of an aqueous medium to the haemostatic composition.

89. The method according to claim 88, wherein the biocompatible polymer is as defined in any one of claims 3 to 11 .

90. The method according to any one of claims 88 to 89, wherein the fibrinogen is as defined in any one of claims 12, 13, 16, 17 or 21 to 25.91 . The method according to any one of claims 88 to 90, wherein the thrombin is as defined in any one of claims 14, 15, or 19 to 25.

92. The method according to any one of claims 88 to 91 , wherein the amount of aqueous medium added is from 2 to 12 mL per gram of haemostatic composition provided in step A1 , such as from 3 to 10 mL, such as from 4 to 8 mL, such as from 4 and 7 mL, such as from 5 to 6 mL per gram of the haemostatic composition provided step A1 .

93. The method according to any one of claims 88 to 92, wherein the haemostatic composition in step A1 comprises one or more hydrophilic compound(s), wherein said hydrophilic compound(s) is as defined in any one of claims 29 to 41 .

94. The method according to any one of claims 88 to 93, wherein the haemostatic composition in step A1 comprises one or more adhesion enhancer(s), wherein said adhesion enhancer(s) is as defined in any one of claims 46 to 60.

95. The method according to any one of claims 88 to 94, wherein the haemostatic composition in step A1 comprises one or more surfactant(s), wherein said surfactant(s) is as defined in any one of claims 62 to 86.

96. The method according to any one of claims 88 to 95, wherein the aqueous medium of step B1 comprises from 7% to 25% by weight of the one or more hydrophilic compound(s), wherein said one or more hydrophilic compound(s) is as defined in any one of claims 29 to 41 .

97. The method according to claim 96, wherein the aqueous medium of step B1 comprises from 0.1 % to 2% by weight of one or more adhesion enhancer(s), wherein said one or more adhesion enhancer(s) is as defined in any one of claims 46 to 60.

98. The method according to any one of claims 96 to 97, wherein the aqueous medium of step B1 comprises 0.01 to 0.2 mg / mL of one or more of surfactant(s), wherein said one or more surfactant(s) is as defined in any one of claims 62 to 87.

99. A haemostatic composition obtained by the method according to any one of claims 88 to 98.

100. The haemostatic composition obtained by the method according to any one of claims 88 to 98, wherein said haemostatic composition is a flowable composition.

101. The haemostatic composition according to any one of claims 99 to 100, wherein said composition remains flowable after addition of the aqueous medium for at least 4 hours, such at least 2 hours, such as at least 1 hour, such as at least 30 min.

102. The haemostatic composition according to any one of claims 99 to 101 , wherein said composition is deployable from a syringe after addition of the aqueous medium for at least 4 hours, such at least 2 hours, such as at least 1 hour, such as at least 30 min.

103. A haemostatic 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 III per gram of the haemostatic composition, d) one or more surfactant(s) in an amount of 0.0001% to 0.09% by weight, and e) an aqueous medium.

104. The haemostatic composition according to claim 103, wherein the biocompatible polymer in particulate form comprises or consist of cross-linked gelatine particles.

105. The haemostatic composition according to any one of claims 103 to 104, wherein 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.

106. The haemostatic composition according to any one of claims 103 to 105, wherein the 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.

107. The haemostatic composition according to any one of claims 103 to 106, wherein the fibrinogen is present in an amount of 0.5% to 1.2% by weight.

108. The haemostatic composition according to any one of claims 103 to 107, wherein the thrombin is present in an amount of 16 to 900 III per gram of the haemostatic composition, such as 150 to 700 IU per gram of the haemostatic composition.

109. The haemostatic composition according to any one of claims 103 to 108, wherein the thrombin is present in an amount of 280 to 350 IU per gram of the haemostatic composition.

110. The haemostatic composition according to claim 103, wherein the fibrinogen is present in an amount from 0.03% to 0.9% by weight, such as 0.05% to 0.5% by weight, such as 0.05% to 0.4% by weight, such as 0.05% to 0.3% by weight of f the haemostatic composition; and the thrombin is present in an amount from 7 to 600 IU per gram, such as 70 to 300 IU per gram, such as 70 to 299 IU per gram, such as 200 to 299 IU per gram, such as 200 to 279 IU per gram of the haemostatic composition.

111. The haemostatic composition according to any one of claims 99 to 110, wherein the haemostatic composition comprises one or more hydrophilic compound(s) in an amount from 6% to 30% by weight, such as from 6% to 10%, such as from 10% to 15%, such as from 15% to 20%, such as from 21 % to 30% by weight of the haemostatic composition.

112. The haemostatic composition according to claim 111 , wherein the hydrophilic compound is as defined in any one of claims 29 to 41.

113. The haemostatic composition according to any one of claims 99 to 112, wherein the haemostatic composition comprises one or more adhesion enhancer (s) in an amount of 0.01% to 15% by weight, such as 0.01 % to 8.5% by weight, of the haemostatic composition.

114. The haemostatic composition according to claim 113, where said one or more adhesion enhancer is as defined in any one of claims 46 to 60.

115. The haemostatic composition according to any one of claims 99 to 114, wherein the haemostatic composition comprises one or more surfactant(s) in an amount of 0.004% to 0.041% by weight of the haemostatic composition.

116. The haemostatic composition according to claim 115, wherein said one or more surfactant(s) is as defined in any one of claims 62 to 86.

117. The haemostatic composition according to any one of claims 103 to 116, wherein the aqueous medium is selected from the group consisting of water, saline, a calcium chloride solution and a buffered aqueous medium.

118. The haemostatic composition according to any one of claims 103 to 117, wherein the aqueous medium comprises calcium ions.

119. The haemostatic composition according to any one of claims 103 to 118, wherein the composition is sterile.

120. The haemostatic composition according to any one of claims 103 to 119, wherein the composition is a flowable composition.

121. The haemostatic composition according to any one of claims 103 to 120, wherein the composition is a paste.

122. A haemostatic composition according to any one of claims 1 to 87 or 99 to 121 , for use in promoting haemostasis and / or wound, bone, tendon and / or tissue healing in an individual in need thereof.

123. A container comprising the haemostatic composition according to any one of claims 1 to 87 or the haemostatic composition according to any one of claims 99 to 122.

124. The container according to claim 123, wherein the container is an applicator, such as a syringe.

125. A kit comprising, a) a first container comprising a composition according to any one of claims 1 to 87, b) a second container comprising an aqueous medium; andc) optionally an outer package, wherein the two containers are interconnectable.

126. The kit according to claim 125, wherein the first and / or the second containers are syringes.

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