Haemostatic material

Abstract

The present invention relates to a haemostatic material comprising a fibrous material having at least one polyphenol associated therewith, and methods of making said haemostatic material. The polyphenol preferably being a tannin and the method of manufacturing the haemostatic material comprising the steps of contacting a fibrous material with a polyphenol to form a fibrous material having at least one polyphenol associated therewith.

Description

[0001] HAEMOSTATIC MATERIAL

[0002] Technical Field of the Invention

[0003] The present invention relates to a haemostatic material comprising a fibrous material having at least one polyphenol associated therewith, and methods of making said haemostatic material.

[0004] Background to the Invention

[0005] There are many circumstances where injury or wounding results in bleeding. Traditionally the primary technique adopted for stemming blood flow from a wound is the application of continuous pressure to the wound. This enables clotting factors to collect at the wound site and form a congealed blood mass to stem blood flow. However, this technique is not suitable for severe wounds and wounds with multiple bleed points. Consequently, exsanguination continues to be a major cause of death.

[0006] Bleeding can also be a problem during surgical procedures. Bleeding is sometimes addressed by suturing or stapling an incision or an internally bleeding area, as well as using gauze, sponge, or other material to exert pressure against the bleed site or absorb the blood. However, when the bleeding becomes excessive, these measures may not be sufficient to stop the blood flow as quickly as necessary.

[0007] Historically, this area has been served by products containing minerals such as zeolite or kaolin marketed under the brand name QuickClot®. The minerals contained within these products are known to activate factor XII of the intrinsic blood clotting process expediting formation of a clot and consequently haemostasis.

[0008] However, these products are not without drawbacks. The mineral content responsible for the blood clotting activation is not robustly bound to the gauze carrier and is seen to shed from the gauze. If left within the wound, this residual mineral content may enter the blood stream and cause further thromboses remote from the primary wound site. This shedding of the active mineral content has been reduced in recent developments such as QuickClot® Control+ but in doing so the product has become stiff and non-conformable affecting its effectiveness and not entirely solving the particle shedding issues.As such, it is an aim of the present invention to provide an improved haemostatic material comprising a fibrous material having at least one polyphenol associated therewith, which does not substantially shed the polyphenol and / or still exhibits similar conformability to the untreated fibrous material.

[0009] Moreover, it is an aim of the present invention to provide a haemostatic material which is able to promote improved blood clot firmness and / or a reduced clotting time.

[0010] It is also an aim of the present invention to provide a haemostatic material and / or a method of producing a haemostatic material that addresses at least one disadvantage of the prior art or to provide an alternative to existing haemostatic materials and / or existing methods of producing haemostatic materials.

[0011] It is therefore an aim of embodiments of the invention to overcome or mitigate at least one problem of the prior art, whether disclosed herein or not.

[0012] Summary of the Invention

[0013] According to a first aspect of the present invention, there is provided a haemostatic material comprising a fibrous material having at least one polyphenol associated therewith.

[0014] The inventors found that a fibrous material having a polyphenol associated therewith was able to provide improved clot firmness and reduced clotting time when compared with existing products.

[0015] It is thought that the structure of the polyphenol can interact with proteins involved in the coagulation cascade, such as factor XII, thereby expediting formation of a clot and consequently haemostasis.

[0016] Surprisingly, the inventors observed that the combination of the fibrous material and polyphenol led to a synergistic improvement in clotting ability as the fibrous material provides a surface for blood cells to adhere to, while the polyphenol stimulates clot formation. This leads to faster clot formation, together with improved clot firmness.

[0017] Moreover, by association of the polyphenol with the fibrous material, the polyphenol is held by the fibrous material at the wound site, and less likely to be released into the bloodstream.In this regard, the inventors found the combination of a fibrous material and polyphenol to be difficult as, typically, the solubility of the polyphenols are limited and in a powder form. Thus, the ability to associate the polyphenol with the fibrous material without substantial shedding of the polyphenol, as is the case in the present invention, was surprising. In a preferred embodiment, the polyphenol may be a Tannin.

[0018] By the term “Tannin” it is meant herein a polyphenolic compound that binds to and precipitates proteins. The tannin may be derived from a natural source or obtained by synthetic methods.

[0019] In one embodiment, the tannin may be a condensed tannin or hydrolysed tannin. In such embodiments, the tannin may be selected from the group consisting of gallotannin, an ellagitannin, an epicatechin, a catechin, a proanthocyanidin, a derivative thereof, and one or more combinations thereof.

[0020] In one embodiment, the tannin may be selected from the group consisting of tannic acid, ellagic acid, Hamamelitannin, Eugeniin, Casuarictin, Corilagin, Geraniin, Davidiin, Castalagin, Vescalagin, Euphorbin, Oenethein B, Epicatechenin, Catechin, Epigallocatechin, Gallocatechin, Epiafzelechin, Afzelechin, Aurantinidin, Cyanidin, Delphinidin, Europinidin, Luteolinidin, Pelargonidin, Malvidin, Peonidin, Petunidin, Apigeninidin, Robinetinidin, Fisetinidin, Guibourtinidin, Profisetinidin, Leucofisetinidin, Leucopelargonidin, Leucocyanidin, Leucodelphinidin, Leucoapigeninidin, Punicalagin, Tellimagrandin I, Pedunculagin, Sanguiin H-6, Cornusiin A, Chebulagic acid, Roburin A, Granatin B, derivatives thereof, and one or more combinations thereof.

[0021] By the term “derivative” it is meant herein any chemically related compound that can be obtained from the parent compound by one or more chemical reactions and / or structural modifications. The modifications may be selected from the group consisting of substitutions, such as methylation, esterification, glycosylation etc.; hydrolysis; additive reactions, such as hydrogenation, halogenation, amination etc.; elimination reactions, such as dehydration decarboxylation, cleavage oxidation, etc; and combination thereof.In one embodiment, the polyphenol may be a hydrolysable tannin and / or derivative thereof.

[0022] By the term “hydrolysable tannin” it is meant herein gallotannins and ellagitannins which can be hydrolysed to form gallic acid and / or ellagic acid.

[0023] Preferably, the polyphenol is an ellagitannin and / or derivative thereof.

[0024] By “ellagitannin” it is meant a tannin in which at least two galloyl units are C-C coupled to each other, and which does not contain a glycosidically linked catechin unit.

[0025] The ellagitannin may be selected from the group consisting of ellagic acid Eugeniin, Casuarictin, Geraniin, Davidiin, Castalagin, Vescalagin, Punicalagin, Tellimagrandin I, Pedunculagin, Sanguiin H-6, Cornusiin A, Chebulagic acid, Roburin A, Granatin B, derivatives thereof, and one or more combinations thereof.

[0026] In one embodiment, the polyphenol may comprise one or more functional groups selected from an ester, lactone, carboxylic acid, and one or more combinations thereof.

[0027] Preferably, the polyphenol possesses an ester, lactone and carboxylic acid functional group.

[0028] In one embodiment, the polyphenol is a haemostatic polyphenol.

[0029] By the term “haemostatic polyphenol” it is meant herein a compound having more than one aromatic ring containing one or more hydroxy substituents, which exhibits one or more haemostatic properties. The haemostatic property may be any property or ability which promotes stoppage or reduction of bleeding. The property may be selected from the group consisting of promoting platelet aggregation, activating the clotting cascade, vasoconstriction, astringency, or one or more combinations thereof.

[0030] In one preferred embodiment, the polyphenol may be ellagic acid or a derivative thereof.

[0031] In such embodiments, the ellagic acid derivative may be any compound that is chemically related to ellagic acid and that can be obtained from ellagic acid by one ormore chemical reactions and / or structural modifications. The modifications may include esterification, glycosylation, methylation, phosphorylation and / or acetylation.

[0032] In one embodiment the derivative may be selected from the group consisting of Punicalagin, Castalagin, glycosides, such as ellagic acid-3-O-glucoside and ellagic acid-3-O-rutinoside, methylated derivatives such as methyl ellagic acid, ester derivatives, such as ellagic acid ethyl ester and ellagic acid acetate, ellagic acid phosphate, metabolites (such as urolithin), and one or more combinations thereof.

[0033] Most preferably, the polyphenol is ellagic acid.

[0034] Beneficially, the inventors observed that the use of ellagic acid was able to provide a haemostatic material which was able to provide improved clot firmness and reduced clotting time, together with demonstrating antioxidant properties.

[0035] In one embodiment, the polyphenols is derived from natural sources.

[0036] Beneficially, the use of a polyphenol derived from natural sources is seen to have improved biocompatibility and benefit from a more sustainable manufacturing process.

[0037] In such an embodiment, the polyphenol may be derived from fruit, juice, seeds, nuts, bark, fungi, macrophytes or other source.

[0038] In such an embodiment, the polyphenol may be derived from one or more ingredients selected from the group consisting of pomegranates, raspberries, strawberries, blackberries, grapes, walnuts, pecans, barks (such as Quercus, Myrica cerifera and Juglans regia), fungi (such as Ganoderma, Inonotus obliquus and Ganoderma lucidum), macrophytes (such as green algae, Phragmites australis, Euglena), tea, and cranberries.

[0039] More preferably, the polyphenol is derived from fruit extracts.

[0040] In such an embodiment, the fruit extract may be selected from the group consisting of pomegranates, raspberries, strawberries, blackberries, grapes, walnuts, and cranberries.

[0041] Most preferably the polyphenol is derived from pomegranates.The polyphenol may be present in an amount of at least 0.1wt.%, 0.11wt.%, 0.12wt.%, 0.13wt.%, 0.14wt.%, 0.15wt.%, 0.16wt.%, 0.17wt.%, 0.18wt.%, 0.19wt.%, 0.2wt.%, 0.21wt.%, 0.22wt.%, 0.23wt.%, 0.24wt.%, 0.25wt.%, 0.26wt.%, 0.27wt.%, 0.28wt.%, 0.29wt.%, 0.3wt.%, 0.31wt.%, 0.32wt.%, 0.33wt.%, 0.34wt.%, 0.35wt.%, 0.36wt.%, 0.37wt.%, 0.38wt.%, 0.39wt.%, 0.4wt.%, 0.41wt.%, 0.42wt.%, 0.43wt.%, 0.44wt.%, 0.45wt.%, 0.46wt.%, 0.47wt.%, 0.48wt.%, 0.49wt.%, or at least 0.5wt.% by weight of the haemostatic material.

[0042] The polyphenol may be present in an amount of no more than 0.6wt.%, 0.59wt.%, 0.58wt.%, 0.57wt.%, 0.56wt.%, 0.55wt.%, 0.54wt.%, 0.53wt.%, 0.52wt.%, 0.51wt.%, 0.5wt.%, 0.49wt.%, 0.48wt.%, 0.47wt.%, 0.46wt.%, 0.45wt.%, 0.44wt.%, 0.43wt.%, 0.42wt.%, 0.41wt.%, 0.4wt.%, 0.39wt.%, 0.38wt.%, 0.37wt.%, 0.36wt.%, 0.35wt.%, 0.34wt.%, 0.33wt.%, 0.32wt.%, 0.31wt.%, 0.3wt.%, 0.29wt.%, 0.28wt.%, 0.27wt.%, 0.26wt.%, 0.25wt.%, 0.24wt.%, 0.23wt.%, 0.22wt.%, 0.21wt.%, or no more than 0.2wt.%by weight of the haemostatic material.

[0043] The polyphenol may be present in an amount of from 0.1 - 0.6 wt.%, 0.1 - 0.55 wt.%, 0.1 - 0.5 wt.%, 0.1 - 0.45 wt.%, 0.1 - 0.4 wt.%, 0.1 - 0.35 wt.%, 0.15 - 0.6 wt.%, 0.15 - 0.55 wt.%, 0.15 - 0.5 wt.%, 0.15 - 0.45 wt.%, 0.15 - 0.4 wt.%, 0.15 - 0.35 wt.%, 0.2 - 0.6 wt.%, 0.2 - 0.55 wt.%, 0.2 - 0.5 wt.%, 0.2 - 0.45 wt.%, 0.2 - 0.4 wt.%, 0.2 -0.35 wt.%, 0.25 - 0.6 wt.%, 0.25 - 0.55 wt.%, 0.25 - 0.5 wt.%, 0.25 - 0.45 wt.%, 0.25 -0.4 wt.%, 0.25 - 0.35 wt.%, 0.3 - 0.6 wt.%, 0.3 - 0.55 wt.%, 0.3 - 0.5 wt.%, 0.3 - 0.45 wt.%, 0.3 - 0.4 wt.%, 0.3 - 0.35 wt.% by weight of the haemostatic material.

[0044] Preferably, the polyphenol may be present in an amount of from 0.25 - 0.5 wt.%, 0.25 - 0.45 wt.%, 0.25 - 0.4 wt.%, 0.25 - 0.35 wt.%, most preferably 0.3 - 0.35 wt.%.

[0045] By the term “associated with” it is meant herein that the polyphenol exhibits some form of interaction and / or attachment with the fibrous material.

[0046] The interaction and or attachment may be a physical and / or chemical interaction and / or attachment.

[0047] In one embodiment, the interaction and / or attachment may be selected from the group consisting of covalent bond formation, crosslinking, adsorption, complexformation, hydrogen bonding, hydrophobic interactions, crosslinking, encapsulation, coating, and one or more combinations thereof.

[0048] The interaction may be reversible and / or irreversible.

[0049] The irreversible interaction of the polyphenol with the fibrous material ensures that the polyphenol is not substantially shed from the fibrous material such that the ellagic acid may substantially enter the bloodstream. Beneficially, this ensures a high concentration of polyphenol at the wound site thereby increasing the haemostatic abilities of the polyphenol.

[0050] In one embodiment, the irreversible interaction may be in the form of covalent bond formation.

[0051] In such an embodiment, the polyphenol may form one or more covalent bonds with one or more functional groups present within the fibrous material. These functional groups may be a hydroxyl, carboxyl, and / or amino group.

[0052] In one embodiment, the interaction is reversible.

[0053] In such embodiment, the polyphenol may be adsorbed onto and / or into the fibrous material or form one or more crosslinks with the fibrous material.

[0054] Preferably, the polyphenol is adsorbed onto the surface of the fibrous material. In such embodiments, the polyphenol may form one or more hydrogen bonds and / or hydrophobic interactions with the fibrous material.

[0055] The fibrous material may be any fibrous material that is suitable for application to a wound.

[0056] Preferably, the fibrous material is non-gelling.

[0057] By “non-gelling” it is meant herein a material which substantially does not gel upon contact with water or body fluid(s). For example, substantially all of the fibres of the fibrous material are incapable of gelling upon contact with water or body fluid(s).

[0058] In one embodiment, the fibrous material may comprise a natural fibre.The natural fibre may be selected from the group consisting of chitin, chitin derivatives, cellulose, cellulose derivatives, cotton, bamboo, silk, hemp, and one or more combinations thereof.

[0059] The cellulose derivative may be any non-gelling chemically related compound that can be obtained from cellulose by one or more chemical reactions and / or structural modifications. The one or more chemical reactions or modifications may involve substitution of one or more of the hydroxyl groups on the cellulose polymer chain. The substitution may include esterification, etherification (such as methylation, ethylation, hydroxyethylation, hydroxypropylation and / or carboxymethylation), sulfonation and / or xanthanation.

[0060] The cellulose derivative may be selected from the group consisting of cellulose acetate, ethyl cellulose, microcrystalline cellulose (MCC), cellulose nitrate, cellulose phosphate, cellulose sulfonate, cellulose xanthate, and cellulose nitrate, and one or more combinations thereof.

[0061] The chitin derivative may be any chemically related non-gelling compound derived from chitin following one or more chemical reactions or modifications. The one or more chemical reactions or modifications may involve substitution of one or more of the amino or hydroxyl protons in chitin or partial deacetylation of chitin. For example, a chitin derivative may include a partially deacetylated chitin, which may have different percentages of deacetylation, as desired. Typically, the partially deacetylated chitin suitable for use in the present invention has a deacetylation degree above about 50%, more typically above about 75%, and most typically above about 85%. Also included within the term ‘chitin derivatives’ are reaction products of chitin with other compounds. Such reaction products include, but are not limited to, carboxymethyl chitin, hydroxyl butyl chitin, N-acyl chitin, O-acyl chitin, N-alkyl chitin, O-alkyl chitin, N-alkylidene chitin, O-sulfonyl chitin, sulphated chitin, phosphorylated chitin, nitrated chitin, alkalichitin, or metal chelates with chitin, etc.

[0062] In one embodiment, the fibrous material may comprise a semi-synthetic fibre. The semi synthetic fibre may be selected from the group consisting of chitosan, chitosan derivatives, viscose, rayon, lyocell, acetate and combination thereof.The chitosan derivative may be any non-gelling chemically related compound that can be obtained from chitosan by one or more chemical reactions and / or structural modifications. The one or more chemical reactions or modifications may involve substitution of one or more of the amino or hydroxyl protons in chitosan. Also included within the terms ‘chitosan or chitin derivatives’ are reaction products of chitosan or chitin with other compounds. Such reaction products include, but are not limited to, carboxymethyl chitosan, hydroxyl butyl chitin, N-acyl chitosan (such as N acetyl chitosan), O-acyl chitosan, N-alkyl chitosan (N-trimethyl chitosan), O-alkyl chitosan (such as hydroxypropyl chitosan), N-alkylidene chitosan, O-sulfonyl chitosan, sulphated chitosan (such as chitosan sulphate), phosphorylated chitosan, hydroxyl butyl chitosan, quaternized chitosan, nitrated chitosan, chitosan-PEG (polyethylene glycol) conjugates, alkalichitin, alkalichitosan, or metal chelates with chitosan, etc.

[0063] In one embodiment, the fibrous material may comprise a synthetic fibre.

[0064] The synthetic fibre may be selected from the group consisting of polypropylene, polyethylene, Nylon, and one or more combinations thereof.

[0065] Preferably, the fibrous material may comprise a fibre selected from the group consisting of cellulose, cellulose derivatives, viscose, rayon, chitosan, chitosan derivatives, polypropylene, polyethylene, nylon, and one or more combinations thereof.

[0066] Preferably still, the fibrous material comprises a fibre derived from a natural material.

[0067] Most preferably, the fibrous material may be selected from the group consisting of cellulose, cellulose derivatives, viscose, chitosan, chitosan derivatives and one or more combinations thereof.

[0068] Most preferably still, the fibrous material is a natural cellulose and / or a natural cellulose derivative.

[0069] By the term “natural cellulose fibre” it is meant herein a fibre derived directly from naturally occurring cellulose sources. The fibres are obtained through mechanical, thermal, or chemical processes that do not fundamentally alter the cellulose structure or composition into a regenerated or synthetic form. The term excludes semi-synthetic fibres such as viscose, rayon, and other chemically regenerated cellulose materials.The natural cellulose fibrous material may comprise one or more fibres selected from the group consisting of cotton, flax, hemp, jute, sisal, coir, abaca, ramie, kapok, kenaf, bamboo-derived cellulose fibres (excluding chemically regenerated forms), wood-derived cellulose fibres (excluding chemically regenerated forms), and combinations thereof.

[0070] The fibrous material may be present in an amount of at least 80wt.%, 81wt.%, 82wt.%, 83wt.%, 84wt.%, 85wt.%, 86wt.%, 87wt.%, 88wt.%, 89wt.%, 90wt.%, 91wt.%, 92wt.%, 93wt.%, 94wt.%, 95wt.%, 96wt.%, 97wt.%, 98wt.%, 99wt.%, 99.05wt.%, 99.1wt.%, 99.15wt.%, 99.2wt.%, 99.25wt.%, 99.3wt.%, 99.35wt.%, 99.4wt.%, 99.45wt.%, 99.5wt.%, 99.55wt.%, 99.6wt.%, 99.65wt.%, 99.7wt.%, or at least 99.75wt.% by weight of the haemostatic material.

[0071] The fibrous material may be present in an amount of no more than 99.9wt.%, 99.8wt.%, 99.7wt.%, 99.6wt.%, 99.5wt.%, 99.4wt.%, 99.3wt.%, 99.2wt.%, 99.1wt.%, 99wt.%, 98wt.%, 97wt.%, 96wt.%, 95wt.%, 94wt.%, 93wt.%, 92wt.%, 91wt.%, 90wt.%, 89wt.%, 88wt.%, 87wt.%, 86wt.%, or no more than 85wt.% by weight of the haemostatic material.

[0072] The fibrous material may be present in an amount of from 80 - 99.9 wt.%, 80 - 99.8 wt.%, 80 - 99.6 wt.%, 80 - 99.5 wt.%, 80 - 99.25 wt.%, 80 - 99 wt.%, 80 - 98 wt.%, 80 - 97 wt.%, 80 - 96 wt.%, 82 - 99.9 wt.%, 82 - 99.8 wt.%, 82 - 99.6 wt.%, 82 - 99.5 wt.%, 82 - 99.25 wt.%, 82 - 99 wt.%, 82 - 98 wt.%, 82 - 97 wt.%, 82 - 96 wt.%, 84 - 99.9 wt.%, 84 - 99.8 wt.%, 84 - 99.6 wt.%, 84 - 99.5 wt.%, 84 - 99.25 wt.%, 84 - 99 wt.%, 84 - 98 wt.%, 84 - 97 wt.%, 84 - 96 wt.%, 86 - 99.9 wt.%, 86 - 99.8 wt.%, 86 -99.6 wt.%, 86 - 99.5 wt.%, 86 - 99.25 wt.%, 86 - 99 wt.%, 86 - 98 wt.%, 86 - 97 wt.%, 86 - 96 wt.%, 88 - 99.9 wt.%, 88 - 99.8 wt.%, 88 - 99.6 wt.%, 88 - 99.5 wt.%, 88 - 99.25 wt.%, 88 - 99 wt.%, 88 - 98 wt.%, 88 - 97 wt.%, 88 - 96 wt.%, 90 - 99.9 wt.%, 90 - 99.8 wt.%, 90 - 99.6 wt.%, 90 - 99.5 wt.%, 90 - 99.25 wt.%, 90 - 99 wt.%, 90 - 98 wt.%, 90 - 97 wt.%, 90 - 96 wt.%, 92 - 99.9 wt.%, 92 - 99.8 wt.%, 92 - 99.6 wt.%, 92 - 99.5 wt.%, 92 - 99.25 wt.%, 92 - 99 wt.%, 92 - 98 wt.%, 92 - 97 wt.%, 92 - 96 wt.%, 94 - 99.9 wt.%, 94 - 99.8 wt.%, 94 - 99.6 wt.%, 94 - 99.5 wt.%, 94 - 99.25 wt.%, 94 - 99 wt.%, 94 - 98 wt.%, 94 - 97 wt.%, 94 - 96 wt.%, 95 - 99.9 wt.%, 95 - 99.8 wt.%, 95 - 99.6wt.%, 95 - 99.5 wt.%, 95 - 99.25 wt.%, 95 - 99 wt.%, 95 - 98 wt.%, 95 - 97 wt.%, 95 -96 wt.% by weight of the haemostatic material

[0073] Most preferably, the fibrous material may be present in an amount of from 80 -99.9 wt.%, 85 - 99.9 wt.%, 90 - 99.9 wt.%, 95 - 99.9 wt.%, 96 - 99.9 wt.%, 97 - 99.9 wt.%, 98 - 99.9 wt.%, or from 99 - 99.9 wt.% by weight of the haemostatic material.

[0074] In one embodiment, the fibrous material may comprise a blend of fibres. In such an embodiment, the blend may comprise at least one natural cellulose fibre and at least one other fibre.

[0075] The at least one other fibre may be a synthetic or semi-synthetic fibre.

[0076] The synthetic fibre may be selected from the group consisting of polypropylene, polyethylene, Nylon, and one or more combinations thereof.

[0077] The semi synthetic fibre may be selected from the group consisting of chitosan, chitosan derivatives, viscose, rayon, lyocell, acetate and combination thereof.

[0078] In embodiments, wherein the fibrous material may comprise a blend of fibres the natural cellulose fibres may be present in an amount of at least 50wt.%, 51 wt.% 52wt.%, 53wt.%, 54wt.%, 55wt.%, 56wt.%, 57wt.%, 58wt.%, 59wt.%, 60wt.% 61wt.%, 62wt.%, 63wt.%, 64wt.%, 65wt.%, 66wt.%, 67wt.%, 68wt.%, 69wt.% 70wt.%, 71wt.%, 72wt.%, 73wt.%, 74wt.%, 75wt.%, 76wt.%, 77wt.%, 78wt.% 79wt.%, 80wt.%, 81wt.%, 82wt.%, 83wt.%, 84wt.%, 85wt.%, 86wt.%, 87wt.% 88wt.%, 89wt.%, 90wt.%, 91wt.%, 92wt.%, 93wt.%, 94wt.%, 95wt.%, 96wt.% 97wt.%, 98wt.%, or at least 99wt.% by weight of the fibrous material.

[0079] The natural cellulose fibres may be present in an amount of no more than 99wt.%, 98wt.%, 97wt.%, 96wt.%, 95wt.%, 94wt.%, 93wt.%, 92wt.%, 91wt.%, 90wt.%, 89wt.%, 88wt.%, 87wt.%, 86wt.%, 85wt.%, 84wt.%, 83wt.%, 82wt.% 81wt.%, 80wt.%, 79wt.%, 78wt.%, 77wt.%, 76wt.%, 75wt.%, 74wt.%, 73wt.% 72wt.%, 71wt.%, 70wt.%, 69wt.%, 68wt.%, 67wt.%, 66wt.%, 65wt.%, 64wt.% 63wt.%, 62wt.%, 61 wt.%, or no more than 60wt.% by weight of the fibrous material.

[0080] The natural cellulose fibre may be present in an amount of from 50 - 99.9 wt.%, 50 - 99 wt.%, 50 - 98 wt.%, 50 - 97 wt.%, 50 - 96 wt.%, 50 - 95 wt.%, 50 - 94 wt.%, 50- 92 wt.%, 50 - 90 wt.%, 55 - 99.9 wt.%, 55 - 99 wt.%, 55 - 98 wt.%, 55 - 97 wt.%, 55 - 96 wt.%, 55 - 95 wt.%, 55 - 94 wt.%, 55 - 92 wt.%, 55 - 90 wt.%, 60 - 99.9 wt.%, 60 - 99 wt.%, 60 - 98 wt.%, 60 - 97 wt.%, 60 - 96 wt.%, 60 - 95 wt.%, 60 - 94 wt.%, 60 -92 wt.%, 60 - 90 wt.%, 65 - 99.9 wt.%, 65 - 99 wt.%, 65 - 98 wt.%, 65 - 97 wt.%, 65 -96 wt.%, 65 - 95 wt.%, 65 - 94 wt.%, 65 - 92 wt.%, 65 - 90 wt.%, 70 - 99.9 wt.%, 70 -99 wt.%, 70 - 98 wt.%, 70 - 97 wt.%, 70 - 96 wt.%, 70 - 95 wt.%, 70 - 94 wt.%, 70 - 92 wt.%, 70 - 90 wt.%, 75 - 99.9 wt.%, 75 - 99 wt.%, 75 - 98 wt.%, 75 - 97 wt.%, 75 - 96 wt.%, 75 - 95 wt.%, 75 - 94 wt.%, 75 - 92 wt.%, 75 - 90 wt.%, 80 - 99.9 wt.%, 80 - 99 wt.%, 80 - 98 wt.%, 80 - 97 wt.%, 80 - 96 wt.%, 80 - 95 wt.%, 80 - 94 wt.%, 80 - 92 wt.%, or from 80 - 90 wt.% by weight of the fibrous material.

[0081] The fibrous material may be woven or non-woven.

[0082] Preferably, the fibrous material is non-woven.

[0083] In such embodiments, the fibrous material may be formed into a cotton wool like material.

[0084] The fibrous material may be manufactured using any suitable manufacturing technique known in the art.

[0085] In some embodiments, the fibrous material may be manufactured using needle punching, spunbonding and / or meltblowing.

[0086] The cotton wool like material may be formed into sheets, pads, balls and / or buds for use.

[0087] In one embodiment, the fibrous material can be formed into a textile fabric or a pad for use. In such embodiments, the fibrous material may be woven and / or nonwoven.

[0088] In such embodiments, the fibrous material may be woven or knitted into a fabric. The fabric may be used to create any suitable textile material. Suitable textile materials may be selected from the group consisting of bags, wound dressings, clothing, bandages, cloths, towels, and one or more combinations thereof.

[0089] The fibrous material may be of any desired diameter or length.In one embodiment, the length of the fibres can be up to about 100 mm, and is typically from about 20-75 mm, more typically from about 32-51 mm.

[0090] In one embodiment, the haemostatic material may also comprise a metal ion. The metal ion may be any metal ion suitable for application to a wound.

[0091] In one embodiment, the metal ion may be selected from the group consisting of alkaline earth metals, transition metals, actinides, lanthanides, post transition metals, and one or more combinations thereof.

[0092] Preferably, the metal ion is selected from the group consisting of a silver metal ion (Ag+), divalent (2+) metal ion, trivalent (3+) metal ion, and combinations thereof.

[0093] In such embodiments, the metal ion may be selected from the group consisting of silver (Ag+), calcium (Ca2+), magnesium (Mg2+), copper (Cu2+), zinc (Zn2+), iron (Fe2+), manganese (Mn2+), cobalt (Co2+), nickel (Ni2+), barium (Ba2+), and lead (Pb2+), iron (Fe3+), aluminium (Al3+), chromium (Cr3+), manganese (Mn3+), cobalt (Co3+), gold (Au3+), gallium (Ga3+), scandium (Sc3+), and rhodium (Rh3+), and one or more combinations thereof.

[0094] Most preferably, the metal ion is selected from the group consisting of copper (Cu2+), zinc (Zn2+), iron (Fe2+), iron (Fe3+), and one or more combinations thereof.

[0095] Preferably, the metal ion is a non-toxic metal ion.

[0096] In a preferred embodiment, the metal ion is provided from a salt.

[0097] In such embodiments, the fibrous material comprises a metal ion salt. The metal ion salt may be a salt of one or more of the metal ions described herein above.

[0098] Preferably, the metal ion salt is an aqueous soluble metal ion salt.

[0099] In such embodiments, the metal ion salt may be selected from the group consisting of silver nitrate (AgNCh), silver chloride (AgCl), calcium chloride (CaCh), calcium sulphate (CaSCh), magnesium sulphate (MgSCh), magnesium chloride (MgCb), copper(II) sulphate (CuSCh), copper(II) chloride (CuCh), zinc sulphate (ZnSCh), zinc oxide (ZnO), iron(II) sulphate (FeSCh), iron(II) chloride (FeCh), iron(III) chloride (FeCh), aluminium chloride (AlCh), aluminium sulphate (A h(S 04)3),chromium(III) chloride (CrCE), chromium(III) sulphate (Cr2(SO4)a), cobalt(II) sulphate (CoSO4), and nickel chloride (NiCh).

[0100] The metal ion salt may be applied to the fibrous material in any suitable way known in the art. Examples of such methods include coating of the metal ion salt using methods such as dipping, spraying, or brushing; soaking of the fibrous material with a solution of the metal ion salt; chemical grafting of the metal salt to the surface of the fibrous material; and / or electrochemical deposition of the metal ion salt.

[0101] Beneficially, the inventors found that the presence of a metal ion in the haemostatic material facilitates complexation of the fibrous material with the polyphenol, thereby creating a multiway complex between the fibrous material and polyphenol. This enhances the association of the polyphenol with the fibrous material.

[0102] The metal ion may be present in an amount of at least 0.005wt.%, 0.01wt.%, 0.015wt.%, 0.02wt.%, 0.025wt.%, 0.03wt.%, 0.035wt.%, 0.04wt.%, 0.045wt.%, 0.05wt.%, 0.055wt.%, 0.06wt.%, 0.065wt.%, 0.07wt.%, 0.075wt.%, or at least 0.08wt.% by weight of the haemostatic material.

[0103] The metal ion may be present in an amount of no more than 0.2wt.%, 0.19wt.%, 0.18wt.%, 0.17wt.%, 0.16wt.%, 0.15wt.%, 0.14wt.%, 0.13wt.%, 0.12wt.%, 0.11wt.%, O.lwt.%, 0.09wt.%, 0.08wt.%,by weight of the haemostatic material.

[0104] The metal ion may be present in an amount of from 0.01 - 0.2 wt.%, 0.01 - 0.18 wt.%, 0.01 - 0.16 wt.%, 0.01 - 0.14 wt.%, 0.01 - 0.12 wt.%, 0.01 - 0.1 wt.%, 0.01 - 0.08 wt.%, 0.02 - 0.2 wt.%, 0.02 - 0.18 wt.%, 0.02 - 0.16 wt.%, 0.02 - 0.14 wt.%, 0.02 - 0.12 wt.%, 0.02 - 0.1 wt.%, 0.02 - 0.08 wt.%, 0.03 - 0.2 wt.%, 0.03 - 0.18 wt.%, 0.03 - 0.16 wt.%, 0.03 - 0.14 wt.%, 0.03 - 0.12 wt.%, 0.03 - 0.1 wt.%, 0.03 - 0.08 wt.%, 0.04 - 0.2 wt.%, 0.04 - 0.18 wt.%, 0.04 - 0.16 wt.%, 0.04 - 0.14 wt.%, 0.04 - 0.12 wt.%, 0.04 - 0.1 wt.%, 0.04 - 0.08 wt.%, 0.05 - 0.2 wt.%, 0.05 - 0.18 wt.%, 0.05 - 0.16 wt.%, 0.05 - 0.14 wt.%, 0.05 - 0.12 wt.%, 0.05 - 0.1 wt.%, 0.05 - 0.08 wt.%, 0.06 - 0.2 wt.%, 0.06 - 0.18 wt.%, 0.06 - 0.16 wt.%, 0.06 - 0.14 wt.%, 0.06 - 0.12 wt.%, 0.06 - 0.1 wt.%, 0.06 - 0.08 wt.%, 0.07 - 0.2 wt.%, 0.07 - 0.18 wt.%, 0.07 - 0.16 wt.%, 0.07 - 0.14 wt.%, 0.07 - 0.12 wt.%, 0.07 - 0.1 wt.%, 0.07 - 0.08 wt.% by weight of the haemostatic material.Preferably, the metal ion may be present in an amount of 0.05 - 0.1 wt.%, 0.055 - 0.095 wt.%, 0.06 - 0.09 wt.%, 0.065 - 0.085 wt.%, or from 0.07 - 0.08 wt.% by weight of the haemostatic material.

[0105] In some embodiments, the metal ion may be a combination of calcium (Ca2+) ions and at least one other metal ion.

[0106] The inventors found that the combination of calcium ions (Ca2+) with at least one further metal ion interact synergistically to result in improved clot forming properties. Without being bound by theory, the inventors found that the presence of calcium ions appeared to reduce the clot formation time, whilst the presence of a further metal ion improved the clot strength and integrity. Surprisingly, the inventors found the improved clotting effect to be much greater than the effect seen from use of the metal ions individually.

[0107] The at least one other metal ion may be any of the metal ions described herein. In such embodiments, the calcium ion may be present in an amount of at least 0.005wt.%, 0.01wt.%, 0.015wt.%, 0.02wt.%, 0.025wt.%, 0.03wt.%, 0.035wt.%, 0.04wt.%, 0.045wt.%, 0.05wt.%, 0.055wt.%, or at least 0.06wt.% by weight of the haemostatic material.

[0108] The calcium ion may be present in an amount of no more than 0.2wt.%, 0.19wt.%, 0.18wt.%, 0.17wt.%, 0.16wt.%, 0.15wt.%, 0.14wt.%, 0.13wt.%, 0.12wt.%, 0.11wt.%, 0.1wt.%, 0.09wt.%, 0.08wt.%, 0.07wt.%, 0.06wt.%, 0.05wt.%, 0.04wt.% by weight of the haemostatic material.

[0109] The calcium ion may be present in an amount of from 0.005 - 0.07 wt.%, 0.005 - 0.065 wt.%, 0.005 - 0.06 wt.%, 0.005 - 0.055 wt.%, 0.005 - 0.05 wt.%, 0.005 - 0.045 wt.%, 0.005 - 0.04 wt.%, 0.01 - 0.07 wt.%, 0.01 - 0.065 wt.%, 0.01 - 0.06 wt.%, 0.01 -0.055 wt.%, 0.01 - 0.05 wt.%, 0.01 - 0.045 wt.%, 0.01 - 0.04 wt.%, 0.015 - 0.07 wt.%, 0.015 - 0.065 wt.%, 0.015 - 0.06 wt.%, 0.015 - 0.055 wt.%, 0.015 - 0.05 wt.%, 0.015 -0.045 wt.%, 0.015 - 0.04 wt.%, 0.02 - 0.07 wt.%, 0.02 - 0.065 wt.%, 0.02 - 0.06 wt.%, 0.02 - 0.055 wt.%, 0.02 - 0.05 wt.%, 0.02 - 0.045 wt.%, 0.02 - 0.04 wt.%, 0.025 - 0.07 wt.%, 0.025 - 0.065 wt.%, 0.025 - 0.06 wt.%, 0.025 - 0.055 wt.%, 0.025 - 0.05 wt.%, 0.025 - 0.045 wt.%, 0.025 - 0.04 wt.%, 0.03 - 0.07 wt.%, 0.03 - 0.065 wt.%, 0.03 - 0.06wt.%, 0.03 - 0.055 wt.%, 0.03 - 0.05 wt.%, 0.03 - 0.045 wt.%, 0.03 - 0.04 wt.%, 0.035 - 0.07 wt.%, 0.035 - 0.065 wt.%, 0.035 - 0.06 wt.%, 0.035 - 0.055 wt.%, 0.035 - 0.05 wt.%, 0.035 - 0.045 wt.%, or from 0.035 - 0.04 wt.% by weight of the haemostatic material.

[0110] Preferably, the calcium ions may be present in an amount of from 0.015 - 0.06 wt.%, 0.02 - 0.055 wt.%, 0.025 - 0.05 wt.%, 0.03 - 0.045 wt.%, or from 0.035 - 0.04 wt.% by weight of the haemostatic material.

[0111] The other metal ion may be present in an amount of at least 0.005wt.%, 0.01wt.%, 0.015wt.%, 0.02wt.%, 0.025wt.%, 0.03wt.%, 0.035wt.%, 0.04wt.%, 0.045wt.%, 0.05wt.%, 0.055wt.%, or at least 0.06wt.% by weight of the haemostatic material.

[0112] The other metal ion may be present in an amount of no more than 0.2wt.%, 0.19wt.%, 0.18wt.%, 0.17wt.%, 0.16wt.%, 0.15wt.%, 0.14wt.%, 0.13wt.%, 0.12wt.%, 0.11wt.%, 0.1wt.%, 0.09wt.%, 0.08wt.%, 0.07wt.%, 0.06wt.%, 0.05wt.%, 0.04wt.% by weight of the haemostatic material.

[0113] The other metal ion ion may be present in an amount of from 0.005 - 0.07 wt.%, 0.005 - 0.065 wt.%, 0.005 - 0.06 wt.%, 0.005 - 0.055 wt.%, 0.005 - 0.05 wt.%, 0.005 -0.045 wt.%, 0.005 - 0.04 wt.%, 0.01 - 0.07 wt.%, 0.01 - 0.065 wt.%, 0.01 - 0.06 wt.%, 0.01 - 0.055 wt.%, 0.01 - 0.05 wt.%, 0.01 - 0.045 wt.%, 0.01 - 0.04 wt.%, 0.015 - 0.07 wt.%, 0.015 - 0.065 wt.%, 0.015 - 0.06 wt.%, 0.015 - 0.055 wt.%, 0.015 - 0.05 wt.%, 0.015 - 0.045 wt.%, 0.015 - 0.04 wt.%, 0.02 - 0.07 wt.%, 0.02 - 0.065 wt.%, 0.02 - 0.06 wt.%, 0.02 - 0.055 wt.%, 0.02 - 0.05 wt.%, 0.02 - 0.045 wt.%, 0.02 - 0.04 wt.%, 0.025 - 0.07 wt.%, 0.025 - 0.065 wt.%, 0.025 - 0.06 wt.%, 0.025 - 0.055 wt.%, 0.025 - 0.05 wt.%, 0.025 - 0.045 wt.%, 0.025 - 0.04 wt.%, 0.03 - 0.07 wt.%, 0.03 - 0.065 wt.%, 0.03 - 0.06 wt.%, 0.03 - 0.055 wt.%, 0.03 - 0.05 wt.%, 0.03 - 0.045 wt.%, 0.03 - 0.04 wt.%, 0.035 - 0.07 wt.%, 0.035 - 0.065 wt.%, 0.035 - 0.06 wt.%, 0.035 - 0.055 wt.%, 0.035 -0.05 wt.%, 0.035 - 0.045 wt.%, or from 0.035 - 0.04 wt.% by weight of the haemostatic material.

[0114] Preferably, the other metal ion may be present in an amount of from 0.015 -0.06 wt.%, 0.02 - 0.055 wt.%, 0.025 - 0.05 wt.%, 0.03 - 0.045 wt.%, or from 0.035 -0.04 wt.% by weight of the haemostatic material. The haemostatic material may comprise one or more additional ingredients. The additional ingredient may be any ingredient commonly used in the medical field.

[0115] Such additional components may include, but are not limited to pharmaceutical agents, medical surfactants, wetting agents such as surfactants, growth factors, cytokines, agents which absorb agents which delay healing such as MMP’s (matrix metalloproteinases) and elastase, and / or another wound dressing component, such as calcium, vitamin K, fibrinogen, thrombin, factor VII, factor VIII, clays such as kaolin, oxidised regenerated cellulose, gelatin, or collagen, antifibrinolytic agents etc.

[0116] By “antifibrinolytic agent”, it is meant a natural or synthetic substance which inhibits fibrinolysis. Fibrinolysis is a process that prevents blood clots from growing. This process has two types: primary fibrinolysis and secondary fibrinolysis. The primary type is a normal body process, whereas secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause. Therefore, antifibrinolytic agents prevents the breakdown of blood clots, which should be stronger and last longer than if the antifibrinolytic agent was not present.

[0117] The antifibrinolytic agent may comprise a plasminogen activator inhibitor, such as a serine protease inhibitor. Non-limiting examples of such serine protease inhibitors include plasminogen activator inhibitor- 1 (PAI-1), which is also known as endothelial plasminogen activator inhibitor or serpin El, or aprotinin. PAI-1 is a serine protease inhibitor that functions as the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis. Aprotinin is a competitive inhibitor of several serine proteases, specifically trypsin, chymotrypsin and plasmin at a concentration of about 125,000 lU / ml, and kallikrein at 300,000 lU / ml. Its action on kallikrein leads to the inhibition of the formation of factor Xlla. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.

[0118] The antifibrinolytic agent may comprise a glycoprotein, such as fibrinogen; or tranexamic acid.The antifibrinolytic agent may comprise a C2-C12 aminocarboxylic acid, a C4-C8 aminocarboxylic acid, or a C5-C7 aminocarboxylic acid, such as a C6 aminocarboxylic acid, e.g. aminocaproic acid or epsilon-aminocaproic acid.

[0119] The antifibrinolytic agent may comprise an aminobenzoic acid, such as aminomethylbenzoic acid.

[0120] Any one or more of these antifibrinolytic agents, or derivatives thereof, may be used either alone or in combination.

[0121] The term ‘derivative’ in relation to the antifibrinolytic agents is used herein to refer to any compounds which are directly derived or derivable from any of the abovelisted compounds and which also exhibit antifibrinolytic behaviour.

[0122] The haemostat material may further comprise a medical surfactant. By "medical surfactant" it is meant any surfactant that is pharmaceutically acceptable for contact with or administration to a human or animal body and does not cause any significant detrimental effects to the human or animal body. Exemplary medical surfactants for use in the present invention include any of the following either alone or in combination: block copolymers based on ethylene oxide and propylene oxide (e.g. BASF Pluronics®), glycerol, polyethylene glycol, propylene glycol, fatty acids such as lauric acid, oleic acid, other fatty acids and fatty acid salts, silicone-based surfactants and emulsifiers. Typically, the medical surfactants include lauric acid and oleic acid.

[0123] The additional component may be present in an amount of at least 0.1wt.%, 0.2wt.%, 0.3wt.%, 0.4wt.%, 0.5wt.%, 0.6wt.%, 0.7wt.%, 0.8wt.%, 0.9wt.%, lwt.%, 1.5wt.%, 2wt.%, 2.5wt.%, 3wt.%, 3.5wt.%, 4wt.%, 4.5wt.%, 5wt.%, 5.5wt.%, 6wt.%, 6.5wt.%, 7wt.%, 7.5wt.%, 8wt.%, 8.5wt.%, 9wt.%, 9.5wt.%, or at least 10wt.% wt.% by weight of the haemostatic material.

[0124] The additional component may be present in an amount of no more than 10wt.%, 9wt.%, 8wt.%, 7wt.%, 6wt.%, 5wt.%, 4wt.%, 3wt.%, 2wt.%, lwt.%, 0.9wt.%, 0.8wt.%, 0.7wt.%, 0.6wt.%, 0.5wt.%, 0.4wt.%, 0.3wt.%, 0.2wt.%, or no more than 0.1wt.%by weight of the haemostatic material.

[0125] The additional component may be present in an amount of from 0.2 - 10 wt.%, 0.2 - 9 wt.%, 0.2 - 8 wt.%, 0.2 - 7 wt.%, 0.2 - 6 wt.%, 0.2 - 5 wt.%, 0.2 - 4 wt.%, 0.2 -3 wt.%, 0.2 - 2 wt.%, 0.3 - 10 wt.%, 0.3 - 9 wt.%, 0.3 - 8 wt.%, 0.3 - 7 wt.%, 0.3 - 6 wt.%, 0.3 - 5 wt.%, 0.3 - 4 wt.%, 0.3 - 3 wt.%, 0.3 - 2 wt.%, 0.4 - 10 wt.%, 0.4 - 9 wt.%, 0.4 - 8 wt.%, 0.4 - 7 wt.%, 0.4 - 6 wt.%, 0.4 - 5 wt.%, 0.4 - 4 wt.%, 0.4 - 3 wt.%, 0.4 -2 wt.%, 0.5 - 10 wt.%, 0.5 - 9 wt.%, 0.5 - 8 wt.%, 0.5 - 7 wt.%, 0.5 - 6 wt.%, 0.5 - 5 wt.%, 0.5 - 4 wt.%, 0.5 - 3 wt.%, 0.5 - 2 wt.%, 0.6 - 10 wt.%, 0.6 - 9 wt.%, 0.6 - 8 wt.%, 0.6 - 7 wt.%, 0.6 - 6 wt.%, 0.6 - 5 wt.%, 0.6 - 4 wt.%, 0.6 - 3 wt.%, 0.6 - 2 wt.%, 0.7 -10 wt.%, 0.7 - 9 wt.%, 0.7 - 8 wt.%, 0.7 - 7 wt.%, 0.7 - 6 wt.%, 0.7 - 5 wt.%, 0.7 - 4 wt.%, 0.7 - 3 wt.%, 0.7 - 2 wt.%, 0.8 - 10 wt.%, 0.8 - 9 wt.%, 0.8 - 8 wt.%, 0.8 - 7 wt.%, 0.8 - 6 wt.%, 0.8 - 5 wt.%, 0.8 - 4 wt.%, 0.8 - 3 wt.%, 0.8 - 2 wt.%, 0.9 - 10 wt.%, 0.9 - 9 wt.%, 0.9 - 8 wt.%, 0.9 - 7 wt.%, 0.9 - 6 wt.%, 0.9 - 5 wt.%, 0.9 - 4 wt.%, 0.9 - 3 wt.%, 0.9 - 2 wt.%, 1 - 10 wt.%, 1 - 9 wt.%, 1 - 8 wt.%, 1 - 7 wt.%, 1 - 6 wt.%, 1 - 5 wt.%, 1 - 4 wt.%, 1 - 3 wt.%, or from 1 - 2 wt.% by weight of the haemostatic material.

[0126] The one or more additional components may be in any suitable form for application to a fibrous material. For example, the additional component may be in the form of a dry powder, solution, foam, fibre or gel.

[0127] The one or more additional components may be applied to the fibrous material in any suitable way.

[0128] The additional component may be applied to the fibrous material by a variety of methods. These include bonding the additional component to the fibrous material using an adhesive; applying a solution containing the additional component to the fibrous material, coating the fibrous material and drying the solution; or by heat bonding. The additional component may also be incorporated into the fibrous material during the processing of the fibrous material.

[0129] The fibrous material may be provided in a sterile or non- sterile form. Where the material is provided in a sterile form, sterilisation may be carried out using any of the conventionally known methods, such as gamma irradiation, electron beam treatment, heat treatment, ethylene oxide (EtO) sterilization etc. A material in a non-sterile form may be provided in combination with one or more preservatives or antimicrobial agent, such as silver and its salts.In a second aspect of the present invention, there is provided an article comprising a haemostatic material of the first aspect of the invention.

[0130] The article may be any material capable of comprising a fibrous material. For example, any suitable textile material. Suitable textile materials may be selected from the group consisting of bags, swabs, lap-pads (laparotomy sponge), gauze, clothing, wound dressings, bandages, cloths, towels, and one or more combinations thereof.

[0131] In a preferred embodiment, the article may be a wound dressing, swab, gauze or lap-pad (laparotomy sponge).

[0132] In one preferred embodiment, the article may be a wound dressing.

[0133] In such an embodiment, the one or more layers of the wound dressing may comprise or consist of the haemostatic material of the first aspect of the invention.

[0134] Preferably, the haemostatic material of the first aspect of the invention is a wound contact layer of the wound dressing.

[0135] In some embodiments, the wound dressing is substantially the shape of a circle, a regular polygon, an irregular polygon, a geometric shape, or an irregular (organic shape). The shape of the wound dressing depends on its intended use and to which anatomical area it is to be applied.

[0136] In addition to the haemostatic material, the wound dressing may comprise one or more further materials.

[0137] One or more of the further materials may be an absorbent material. Absorbent material is used herein to refer to a physiologically acceptable material that is capable of absorbing liquid, such as wound exudate, and which is capable of absorbing liquid to greater than about 500% by weight of the absorbent material, and with a liquid retention of greater than about 40%.

[0138] The absorbent material may comprise a fibrous, foam, non-woven or woven material.

[0139] The absorbent material may be in the form of fibres. Typically, the absorbent material may be in the form of non-woven fibres.The absorbent material may be a superabsorbent material.

[0140] The superabsorbent material may be selected from polymeric materials such as poly( vinyl alcohol) (PVA), poly (ethylene oxide) (PEO) and poly (aery lie acid).

[0141] The superabsorbent material may be chemically modified. For example, the superabsorbent material may be a polymeric material obtained by graft polymerisation of acrylic acid onto a chain of carboxymethyl cellulose.

[0142] The superabsorbent material may comprise a chemically modified material selected from starch, cellulose and polymeric materials such as poly( vinyl alcohol) (PVA), poly (ethylene oxide) (PEO), and poly (aery lie acid).

[0143] The poly(acrylic acid) may be a partially neutralised, lightly cross-linked poly(acrylic acid).

[0144] The superabsorbent material may be in the form of fibres. Typically, the superabsorbent material is in the form of non-woven fibres.

[0145] The superabsorbent material may comprise or consist of an air laid nonwoven fibre. By air laid nonwoven fibre, it is meant a continuous web formed by a mixture of short fibres and / or 100% pulped fibres. The absorbent material may comprise a chemical pulp made from long fibre softwoods. Preferably, the absorbent material may be a fluff pulp. By the term “fluff pulp”, it is meant a chemical pulp made of cellulose fibres obtained from long softwoods.

[0146] In preferred embodiments, the absorbent materials may comprise a superabsorbent material and fluff pulp. Preferably, the absorbent material of the present invention comprises a poly(acrylic acid) and fluff pulp fibre blend.

[0147] In some embodiments, the absorbent material may consist of or comprise a gelling or semi-gelling material.

[0148] The gelling or semi-gelling material may be in any available form, such as for example, fibres, granules, powder, flakes, sheet, foam, freeze dried foam, compressed foam, film, perforated film, beads, and combinations of two or more of the aforesaid.

[0149] The gelling or semi-gelling material may be selected from carboxymethylcellulose, alginate, chitosan salt or a chitosan salt derivative.Typically, the gelling or semi gelling material is in the form of fibres. The fibres can be of any desired diameter or length and can be formed into a textile fabric or a pad for use. The fibres may be woven or non-woven. Preferably, the fibres are non-woven.

[0150] The wound dressing may be a single layer. The wound dressing may comprise more than one layer. The wound dressing may comprise two, three, four, five, six, seven, eight, nine, ten, or more than ten layers. The wound dressing may comprise a plurality of layers.

[0151] In such an embodiment, at least one of the layers comprises a fibrous material according to a first aspect of the invention.

[0152] In some embodiments at least one of the wound dressing may be fenestrated. The wound dressing may comprise decoupled layers.

[0153] Alternatively, the wound dressing may have a laminate structure.

[0154] The layers of the wound dressing may be bonded together using an adhesive between the layers. The surfaces of the wound dressing which are to be bonded may be fully or partially coated with an adhesive.

[0155] The adhesive may be any suitable physiologically acceptable adhesive known in the art. The adhesive may be any suitable skin-contact adhesive known in the art.

[0156] The adhesive may be a silicone adhesive (such as a polydimethylsiloxane adhesive), an acrylic adhesive, a polyurethane adhesive, a hydrogel adhesive, or any combinations thereof.

[0157] The adhesive may be in the form of a powder, a liquid, a web or a net. The web may be an acrylic web.

[0158] The adhesive may comprise a meltable adhesive and / or a pressure sensitive adhesive, or the like. The meltable adhesive may be a heat-bonding adhesive or a heat-activated adhesive. The pressure sensitive adhesive may be acrylic based.

[0159] The adhesive may be a thermal adhesive. The adhesive may comprise any suitable thermal adhesive known in the art. For example, the thermal adhesive may be a thermoplastic adhesive, such as polycaprolactone.The adhesive may be a powder. The powder may be scattered onto either or both surfaces of the wound dressing to be attached and then passed through a heat tunnel to laminate the layers of the wound dressing.

[0160] In a third aspect of the present invention, there is provided a method of manufacturing a haemostatic material according to the first aspect of the present invention comprising the steps of contacting a fibrous material with a polyphenol to form a fibrous material having at least one polyphenol associated therewith.

[0161] The fibrous material and polyphenol may be as described in the first aspect of the invention.

[0162] In some embodiments, the method may further comprise contacting the fibrous material with a solution comprising a metal ion. The metal ion may be as described in the first aspect of the invention.

[0163] The step of contacting the fibrous material with a solution comprising a metal ion may be performed before or after the step of contacting the fibrous material with a polyphenol.

[0164] Preferably, the step of contacting the fibrous material with a solution comprising a metal ion is performed before the step of contacting the fibrous material with a polyphenol.

[0165] In an alternative embodiment, the step of contacting a fibrous material with a polyphenol may comprise reacting the polyphenol with the fibrous material in a transesterification or esterification reaction to form a fibrous material having at least one polyphenol associated therewith.

[0166] In such an embodiment, the method may further comprise the addition of a catalyst.

[0167] The catalyst may be any catalyst known in the art suitable for use in a transesterification or esterification reaction.

[0168] In one embodiment, the catalyst may be selected from the group consisting of a strong base, strong acid, lewis acid and one or more combinations thereof.By the term “strong base” it is meant herein basic substance that is able to dissociate completely in an aqueous solution. For example, the strong acid may have a dissociation constant (kb)of greater than 1.

[0169] The strong base may be selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methoxide (NaOCHs), sodium ethoxide (NaCKTTL), and one or more combinations thereof.

[0170] By the term “strong acid” it is meant herein an acidic substance that is able to dissociate completely in an aqueous solution. For example, the strong acid may have a dissociation constant (Ka) of greater than 1.

[0171] The strong acid may be selected from the group consisting of sulfuric acid (H2SO4), hydrochloric acid (HC1), nitric acid (HNO3), phosphoric acid (H3PO4), p-toluenesulfonic acid (TsOH), trifluoroacetic acid (TFA), and one or more combinations thereof.

[0172] The term “Lewis acid” is used herein in accordance with its commonly accepted meaning in the chemical field, i.e. a substance that can accept an electron pair to form a covalent bond.

[0173] The Lewis acid may be selected from the group consisting of boron trifluoride (BF3), aluminium chloride (A1CL), iron (III) chloride (FeCL), titanium tetrachloride (TiCL), zinc chloride (ZnCL), and one or more combinations thereof.

[0174] In either embodiment, the method may further comprise a step of washing and / or rinsing the fibrous material.

[0175] The washing and / or rinsing step may be performed after the step of contacting the fibrous material with the polyphenol.

[0176] Beneficially, washing ensures that all polyphenol and / or metal ions not associated with the fibrous material are removed from the surface of the material. This reduces the shed of any particulates when the material is applied to a physiological target site, such as a wound.

[0177] The step of washing the fibrous material may comprise contacting the fibrous material with water. Preferably, distilled water.The washing step is configured to remove any unreacted or excess substances left over from the step of contacting the fibrous material with the polyphenol.

[0178] The method may further comprise a step of drying the fibrous material.

[0179] The step of drying the fibrous material may be carried out after one or more the preceding steps described herein. Preferably, the step of drying the fibrous material is be carried out after all of the preceding steps described herein

[0180] In some embodiments, the method may further comprise the step of contacting the fibrous material with an additional ingredient. The additional material may be as described in the first aspect of the invention.

[0181] In a fourth aspect of the invention there is provided a method of manufacturing an article according to the second aspect of the present invention.

[0182] The method of manufacturing an article may comprise the steps of forming the haemostatic material into an article according to the second aspect of the invention.

[0183] The method of forming the haemostatic material into the article may comprise the step of attaching the haemostatic material to a further material and / or second haemostatic material according to the first aspect of the invention.

[0184] The fibrous material may be adhered to the further material and / or second fibrous material using an adhesive as described herein.

[0185] Additionally or alternatively, the haemostatic material may be attached to a further material and / or second haemostatic material through any method of textile bonding, such as sewing.

[0186] The further material may comprise a woven material, or a non-woven material. The further material may be any of the materials described in relation to the second aspect of the invention.

[0187] The method may further comprise a step of cutting and shaping the article as desired or as appropriate.

[0188] According to a fifth aspect of the present invention, there is provided a method of absorbing fluid (e.g. wound exudate) discharged from a physiological target site ofa human or animal body, or of stemming a flow of a fluid discharged from a physiological target site of a human or animal body, comprising applying to the physiological target site a haemostatic material according to the first aspect of the invention or an article according to the second aspect of the invention.

[0189] According to a sixth aspect of the present invention, there is provided a haemostatic material according to a first aspect of the invention, or an article according to a second aspect of the invention, for use in stemming blood flow from a physiological target site.

[0190] Preferably, the physiological target site may be a wound.

[0191] The further aspects of the present invention may incorporate any of the features of the other aspects of the invention described herein as desired or as appropriate. Detailed Description of the Invention

[0192] In order that the invention may be more clearly understood one or more embodiments thereof will now be described, by way of example only, with reference to the accompanying drawings, of which:

[0193] Figure 1 Plot of blood clot firmness over time following exposure to various products.

[0194] Figure 2 Plot of clot firmness showing the initiation of clot formation for ellagic acid / iron fibre (example 1) in two separate lots of blood against free ellagic acid.

[0195] Example 1

[0196] A cellulose fibrous material was immersed in a 0.08 wt.% solution of ferrous chloride hexahydrate, a source of Iron (Fe2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and dried. This provided a cellulose fibrous material according to the present invention having ellagic acid associated therewith.The resulting haemostatic material demonstrated improved haemostatic properties, such as improved clot firmness and reduced clotting time when compared with existing products. Moreover, it was found that the ellagic acid was not shed from the fibrous material during use and the fibrous material was seen to have conformability equivalent to the non-treated fibre.

[0197] Example 2

[0198] A cellulose fibrous material was immersed in a 0.08 wt.% solution of ferrous chloride hexahydrate, a source of Iron (Fe2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and washed extensively with distilled water until the water ran clear. The fibrous material was then dried. This provided a cellulose fibrous material according to the present invention having ellagic acid associated therewith.

[0199] The resulting haemostatic material demonstrated improved haemostatic properties, such as improved clot firmness and reduced clotting time when compared with existing products. Moreover, it was found that the ellagic acid was not shed from the fibrous material during use and the fibrous material was seen to have conformability equivalent to the non-treated fibre.

[0200] Example 3

[0201] A cellulose fibrous material was immersed in a 0.08wt% solution of zinc chloride, a source of Zinc (Zn2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and washed extensively with distilled water until the water ran clear. The fibrous material was then dried. This provided a cellulose fibrous material according to the present invention having ellagic acid associated therewith.

[0202] The resulting haemostatic material demonstrated improved haemostatic properties, such as improved clot firmness and reduced clotting time when comparedwith existing products. Moreover, it was found that the ellagic acid was not shed from the fibrous material during use and the fibrous material was seen to have conformability equivalent to the non-treated fibre.

[0203] Example 4

[0204] A cellulose fibrous material was immersed in a 0.08wt.% solution of copper sulphate, a source of Copper (Cu2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and washed extensively with distilled water until the water ran clear. The fibrous material was then dried. This provided a cellulose fibrous material according to the present invention having ellagic acid associated therewith.

[0205] The resulting haemostatic material demonstrated improved haemostatic properties, such as improved clot firmness and reduced clotting time when compared with existing products. Moreover, it was found that the ellagic acid was not shed from the fibrous material during use and the fibrous material was seen to have conformability equivalent to the non-treated fibre.

[0206] Example 5

[0207] A cellulose fibrous material was immersed in a 0.08wt.% solution of silver sulphate, a source of Silver (Ag2+) ions, for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and washed extensively with distilled water until the water ran clear. The fibrous material was then dried. This provided a cellulose fibrous material according to the present invention having ellagic acid associated therewith.

[0208] The resulting haemostatic material demonstrated improved haemostatic properties, such as improved clot firmness and reduced clotting time when compared with existing products. Moreover, it was found that the ellagic acid was not shed fromthe fibrous material during use and the fibrous material was seen to have conformability equivalent to the non-treated fibre.

[0209] Example 6

[0210] A cellulose fibrous material was immersed in a 0.04wt.% solution of calcium chloride, a source of Calcium (Ca2+) ions, for a period of 1 minute. A 0.04 wt.% solution of ferrous chloride hexahydrate, a source of Iron (Fe2+) ions was then added and the reaction mixture was left for a period of 1 minute. A 0.32wt.% solution of ellagic acid was then added to the mixture and the mixture was left for a period of 5 minutes. The pH of the mixture was then raised to approximately pH 8 and the fibrous material was left in the mixture for a period of 1 hour. The mixture was then removed from the solution and washed extensively with distilled water until the water ran clear. The fibrous material was then dried. This provided a cellulose fibrous material according to the present invention having ellagic acid associated therewith.

[0211] The resulting haemostatic material demonstrated improved haemostatic properties, such as improved clot firmness and reduced clotting time when compared with existing products. Moreover, it was found that the ellagic acid was not shed from the fibrous material during use and the fibrous material was seen to have conformability equivalent to the non-treated fibre.

[0212] The inventors also found that the combination of Ca2+ions and Fe2+ions were able to act synergistically and expedite the formation of a clot, whilst also improving the integrity and strength of the clot over time.

[0213] Example 8

[0214] A fibrous material comprising cellulose was immersed in DMSO and 5M NaOH for a period of 5 minutes After this period the temperature was raised to 110 °C and Ellagic acid was added to the reaction mixture. After 10 minutes, the fibrous material was removed from the solution and washed with distilled water. After washing, the fibrous material was then dried at a temperature of 21° C overnight. This resulted in a cellulose fibrous material having an ellagic acid associated therewith.

[0215] The resulting haemostatic material demonstrated improved haemostatic properties, such as improved clot firmness and reduced clotting time when comparedwith existing products. Moreover, it was found that the ellagic acid was not shed from the fibrous material during use.

[0216] Clot Firmness Testing

[0217] The clotting ability of the fibrous material of the present invention was measured by measuring the clot firmness over time following exposure of a wound to various haemostatic products.

[0218] The clot firmness testing was performed using an ElastoSens™ Bio device under controlled conditions. Anticoagulated blood (ACD) was prepared by gently inverting the collection tube 10 times to ensure thorough mixing without vigorous shaking. The blood was then warmed to 37°C in an oven for 30-40 minutes to reach physiological temperature.

[0219] The ElastoSens™ Bio chamber temperature was set to 37°C. An empty sample holder was placed into the chamber, and initialization was performed using the "soft" mode. Following this, 4.975 mL of pre-warmed blood was added to the sample holder. To initiate clotting, 25 pL of 5M CaCE solution was added to the blood sample and gently mixed by pipetting up and down four times using a 1000 pL pipette.

[0220] After mixing, the sample was carefully placed in the holder, and silicone oil was added to the top of the sample to minimize evaporation and maintain optimal testing conditions. The chamber lid was securely closed, and the test was programmed to run for 30 minutes, with measurements taken every 20 seconds. This process ensured consistent and accurate analysis of clot firmness.

[0221] The samples were a plain cotton swab, a fibrous material prepared according to Example 1 and a sample of a commercial product titled QuickClot® control +. All samples were compared for clot firmness to a control in which the wound was not treated with any haemostatic product and thus this represents the natural clotting process.

[0222] As seen in Figure 1 , when the wound was treated with the material of Example 1 , a more firm and robust blood clot was formed in a reduced time when compared to the plain swab and control. Moreover, when compared with the existing commercialproduct QuickClot® control +, the clot firmness was much greater. This leads to a more robust clot which is less likely to be disturbed and thus trigger rebleeding.

[0223] Additionally, as seen in Figure 2, the haemostatic material of Example 1 demonstrated much faster clot initiation and firmness in two separate lots of blood when compared with a control of cellulose alone and ellagic acid alone. This demonstrates that the combination of the fibrous material and polyphenol work synergistically to provide a haemostatic material having improved haemostatic and clot formation properties.

[0224] The one or more embodiments are described above by way of example only. Many variations are possible without departing from the scope of protection afforded by the appended claims.

Claims

CLAIMS1. A haemostatic material comprising a fibrous material having at least one polyphenol associated therewith.

2. A haemostatic material according to claim 1 , wherein the polyphenol is a tannin.

3. A haemostatic material according to claim 2, wherein the tannin is selected from the group consisting of gallotannin, an ellagitannin, an epicatechin, a catechin, a proanthocyanidin, a derivative thereof, and one or more combinations thereof.

4. A haemostatic material according to claim 3, wherein the tannin is an ellagitannin.

5. A haemostatic material according to claim 4, wherein the ellagitannin is selected from the group consisting of ellagic acid Eugeniin, Casuarictin, Geraniin, Davidiin, Castalagin, Vescalagin, Punicalagin, Tellimagrandin I, Pedunculagin, Sanguiin H-6, Cornusiin A, Chebulagic acid, Roburin A, Granatin B, derivatives thereof, and one or more combinations thereof.

6. A haemostatic material according to claim 5, wherein the polyphenol is ellagic acid or a derivative thereof.

7. A haemostatic material according to any preceding claim, wherein the polyphenol is present in an amount of from 0.25 - 0.5 wt.% by weight of the haemostatic material.

8. A haemostatic material according to any preceding claim, wherein the fibrous material is selected from the group consisting of cellulose, cellulose derivatives, viscose, rayon, chitosan, chitosan derivatives, polypropylene, polyethylene, nylon, and one or more combinations thereof.

9. A haemostatic material according to any preceding claim, wherein the fibrous material is non-woven.

10. A haemostatic material according to any preceding claim, wherein the fibrous material further comprises a metal ion.

11. A haemostatic material according to claim 10, wherein the metal ion is selected from the group consisting of alkaline earth metals, transition metals, actinides, lanthanides, post transition metals, and one or more combinations thereof.

12. A haemostatic material according to any one of claims 10-11, wherein the metal ion is selected from the group consisting of silver (Ag+), calcium (Ca2+), magnesium (Mg2+), copper (Cu2+), zinc (Zn2+), iron (Fe2+), manganese (Mn2+), cobalt (Co2), nickel (Ni2+), barium (Ba2+), and lead (Pb2+), iron (Fe3+), aluminium (Al3+), chromium (Cr3+), manganese (Mn3+), cobalt (Co3+), gold (Au3+), gallium (Ga3+), scandium (Sc3+), and rhodium (Rh3+), and one or more combinations thereof.

13. A haemostatic material according to claim 12, wherein the metal ion is selected from the group consisting of copper (Cu2+), zinc (Zn2+), iron (Fe2+), iron (Fe3+), and one or more combinations thereof.

14. A haemostatic material according to any preceding claim, wherein the metal ion is a combination of calcium ions (Ca2+) with at least one other metal ion.

15. A haemostatic material according to claim 14, wherein the metal ion is a combination of calcium (Ca2+) and at least one metal ion selected from the group consisting of silver (Ag+), magnesium (Mg2+), copper (Cu2+), zinc (Zn2+), iron (Fe2+), manganese (Mn2+), cobalt (Co2+), nickel (Ni2+), barium (Ba2+), and lead (Pb2+), iron (Fe3+), aluminium (Al3+), chromium (Cr3+), manganese (Mn3+), cobalt (Co3+), gold (Au3+), gallium (Ga3+), scandium (Sc3+), and rhodium (Rh3+), and one or more combinations thereof.

16. A haemostatic material according to any preceding claim, wherein the metal ion is present in an amount of 0.05 - 0.1 wt.% by weight of the haemostatic material.

17. A method of manufacturing a haemostatic material according to any one of claims 1-16 comprising the steps of contacting a fibrous material with a polyphenol to form a fibrous material having at least one polyphenol associated therewith.

18. A method according to claim 17, wherein the method further comprises the step of contacting the fibrous material with a solution comprising a metal ion.

19. A method according to claim 17, wherein the method comprises the step of reacting the polyphenol with the fibrous material in a transesterification or esterification reaction to form a fibrous material having at least one polyphenol associated therewith.

20. A method according to claim 19, wherein the method further comprises the addition of a catalyst selected from the group consisting of a strong base, strong acid, lewis acid, and one or more combinations thereof21. An article comprising a haemostatic material according to any one of claims 1- 16.

22. An article according to claim 21, wherein the article is a wound dressing, swab, gauze or lap-pad (laparotomy sponge).

23. A method of manufacturing an article according to any one of claims 21-22, wherein the method comprises the step of attaching the haemostatic material to a further material and / or a second haemostatic material according to any one of claims 1-16.

24. A haemostatic material according to any one of claims 1 - 16, for use in stemming blood flow from a physiological target site25. An article according to any one of claims 21-22, for use in stemming blood flow from a physiological target site.

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