• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    summary? composition, wound dressing, and, method of making a composition? the present invention relates to a composition that can be used as or as part of a wound dressing and to wound dressings comprising the same. more specifically, the present invention relates to a composition that breaks and kills bacteria within a biofilm and also prevents the formation of the biofilm. the composition comprises a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and combinations thereof; at least one triprotic acid and at least one solubilizing acid.
    公开号:BR112017016072B1
    申请号:R112017016072-2
    申请日:2016-01-27
    公开日:2021-03-23
    发明作者:Andrew Hoggarth；Craig Hardy
    申请人:Medtrade Products Limited；
    IPC主号:
    专利说明:

    [0001] [0001] The present invention relates to a composition that can be used as or as part of a wound dressing and for wound dressings comprising the same. More specifically, the present invention relates to a composition that breaks and kills bacteria within a biofilm and also prevents the formation of biofilms.
    [0002] [0002] A useful explanation of biofilms is presented by Philips PL, et al., Biofilms Made Easy, Wounds International 2010, 1 (3) and is summarized here. A biofilm is any group of microorganisms in which cells effectively adhere to one another on a surface. A biofilm can typically be a complex microbial community containing bacteria and fungi. Microorganisms are often incorporated into a self-produced matrix of extracellular polymeric substance (EPS). EPS biofilm, which is also called 'sludge' (although it is appreciated that not everything mentioned as sludge is a biofilm), is a polymeric conglomerate, usually composed of extracellular DNA, proteins and polysaccharides. The EPS matrix can fix the biofilm firmly to living or non-living surfaces.
    [0003] [0003] Biofilms are known to form on the surfaces of medical devices, such as urinary catheters, implants and sutures. They are problematic because they contribute to diseases that are characterized by an underlying bacterial infection and chronic inflammation.
    [0004] [0004] The field of the present invention is primarily that of wound care. Biofilms are commonly found in wounds, but it was only relatively recently that they were accepted as causing a delay in wound healing. It has even been suggested that almost all chronic wounds have biofilm communities on at least part of the wound bed.
    [0005] [0005] Biofilms can form on living or non-living surfaces and can prevail in natural, industrial and hospital environments. Under natural conditions, microorganisms, such as bacteria, can stick to surfaces and form biofilms. As the bacteria multiply, they become more firmly attached to the surface. Once attached, the bacteria secrete EPS to form a protective matrix. This then leads to small colonies of bacteria forming an initial biofilm. Over time, the biofilm can disperse and attach to other parts of the wound bed, forming new colonies of biofilm.
    [0006] [0006] Biofilm formation can occur relatively quickly, with a biofilm capable of forming in less than 24 hours.
    [0007] [0007] Biofilms are thought to stimulate a chronic inflammatory response in an attempt to eliminate the wound from the biofilm. This response results in abundant neutrophils and macrophages surrounding the biofilms. These inflammatory cells secrete high levels of reactive oxygen species (ROS) and proteases (matrix metalloproteinases (MMPs) and elastase). Proteases can help to break the fixations between biofilms and tissue, dislodging biofilms from the wound. However, ROS and proteases also damage normal and healing tissues, proteins and immune cells. The chronic inflammatory response is not always successful in removing the biofilm and the hypothesis has been formulated that the response is of interest to the biofilm. By inducing an ineffective inflammatory response, the biofilm protects the microorganisms it contains and increases the production of exudate, which provides a source of nutrition and helps to perpetuate the biofilm.
    [0008] [0008] Currently, one of the most effective methods to reduce the adverse effects of biofilms is to physically remove the biofilm, known as debridement. Debridement involves removing dead and contaminated tissue from the wound. However, this process has its limitations, since no form of debridement can remove the entire biofilm. Consequently, biofilm has the potential to restore itself in a short period of time. As a result, a patient must undergo debridement on a frequent basis.
    [0009] [0009] Attempts to prevent a biofilm restoration have also been researched. Predominantly, these methods use antimicrobial agents to kill microorganisms. However, there are several limitations to this method, in the sense that antimicrobial agents can be used in different ways and patients' sensitivities and allergies need to be considered.
    [0010] [0010] Therefore, there is a need to develop improved methods of killing bacteria within a biofilm and also preventing the restoration of the biofilm.
    [0011] [0011] The present invention was realized from a consideration of the above mentioned limitations and problems.
    [0012] [0012] According to a first aspect of the present invention, there is provided a composition comprising a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and any combination thereof; at least one triprotic acid and at least one solubilizing acid.
    [0013] [0013] It has been surprisingly discovered that a composition comprising the first component, at least one triprotic acid and at least one solubilizing acid is capable of breaking down and preventing biofilm formation and has an antimicrobial effect on microorganisms within the biofilm.
    [0014] [0014] The biofilm referred to herein is preferably a microbial based biofilm, although the invention is not thus limited.
    [0015] [0015] The term "triprotic acid" (which can also be referred to here as a "tribasic acid") is used here to refer to an acid having three hydrogen ions to donate to a base in an acid-base reaction. In other words, a triprotic molecule has three replaceable hydrogen atoms.
    [0016] [0016] The composition may comprise one or more triprotic acids. The composition can therefore comprise two, three, four or more triprotic acids. Typically, the composition comprises a triprotic acid.
    [0017] [0017] Triprotic acid can be selected from the group consisting of citric acid, phosphoric acid or mixtures thereof.
    [0018] [0018] Preferably, the triprotic acid is citric acid.
    [0019] [0019] Triptotic acids can be in the form of granules, flakes, powders or solutions. Typically, triprotic acid is obtained from a source in the form of a powder.
    [0020] [0020] In the preparation of the composition of the present invention, triprotic acid is typically in the form of an acidic solution. Such a solution is prepared by dissolving an amount of triprotic acid, typically in powder form, in a volume of water and / or a solvent. The solvent can be aqueous or non-aqueous, but it is preferably non-aqueous.
    [0021] [0021] The composition may comprise a mixture of the first component and the triprotic acid. Triprotic acid can be contacted with the first component.
    [0022] [0022] Typically, triprotic acid is absorbed in, or coated on, at least, a portion of the first component. Preferably, the triprotic acid is coated on at least a portion of the surface of the first component. More preferably, the triprotic acid is coated on substantially the entire surface of the first component.
    [0023] [0023] Antimicrobial agents are generally referred to as substances that kill, or inhibit the growth of, microorganisms. It is generally accepted in wound healing that, for a substance to claim antimicrobial efficacy, it must demonstrate a Log4 bacterial death rate.
    [0024] [0024] The term "antimicrobial" is used here to refer to an agent or substance capable of demonstrating a Log4 bacterial death rate within 24 hours. On the other hand, the term "non-antimicrobial" is used here to refer to an agent or substance that demonstrates below a Log4 bacterial death rate within 24 hours
    [0025] [0025] The first component can be non-antimicrobial.
    [0026] [0026] The ratio of the first component to at least one triprotic acid can be at least 2: 1.
    [0027] [0027] The ratio of at least one triprotic acid to at least one solubilizing acid is at least 1: 1.
    [0028] [0028] The first component can be in the form of fibers, granules, flakes, powder or combinations thereof.
    [0029] [0029] The first component can be coated in whole or in part with triprotic acid.
    [0030] [0030] Typically, the first component comprises fibers. The fibers can be woven or non-woven. Preferably, the fibers are non-woven. The fibers can be coated totally or partially with triprotic acid.
    [0031] [0031] Alternatively, the composition may comprise separate portions of the first component and the triprotic acid. For example, the first component may be in the form of fibers, granules, flakes, powder, one or more sheets or combinations thereof and the triprotic acid may be in the form of granules, flakes or powder in which the first component is tryptic acid are located in separate portions of the composition. The separate portions can, for example, be in the form of layers. Alternatively, the triprotic acid and the first component can be mixed.
    [0032] [0032] Additionally or alternatively, triprotic acid may be associated with a carrier material. The composition can therefore comprise a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives and combinations thereof; and at least one triprotic acid, wherein the triprotic acid is associated with a carrier material.
    [0033] [0033] The triprotic acid can be absorbed, or coated on, in the carrier material. The carrier material can act as a carrier for triprotic acid. In such modalities, the triprotic acid must not react or irreversibly bond with the carrier material. The carrier material can comprise any suitable material that can absorb, receive or act as a vehicle for a triprotic acid. Typical materials include, but are not limited to, polymers such as cellulose, cellulose derivatives (e.g., ethyl cellulose, methyl cellulose, etc.), cotton, alginate, viscose, polypropylene, polyethylene or any combination of such materials. Preferably, the carrier material is viscose.
    [0034] [0034] Typically, the carrier material is fibrous. In some embodiments, the first component and the carrier material can be combined together to form a non-woven cloth. The first component and the carrier material can be carded or needled together.
    [0035] [0035] Preferably, however, the composition does not comprise a carrier material. The triprotic acid is preferably coated on at least a portion of the first component, as explained above.
    [0036] [0036] The triprotic acid can be coated on the first component and / or the carrier material by any appropriate means known in the art.
    [0037] [0037] Generally, a triprotic acid, typically in powder form, is dissolved in water to form an acidic solution. The acidic solution can then be mixed with a solvent. The first component is then mixed with the acid / solvent solution mixture. The solvent and optionally at least a portion of the water can be removed by evaporation, for example, to give a solid composition of the present invention. Typically, the composition comprises the triprotic acid coated on the first component.
    [0038] [0038] Alternatively, the triprotic acid can be mixed with water and / or a solvent, as explained above, and sprayed on the first component.
    [0039] [0039] Preferably, the first component is not dissolved in a solvent during the preparation of the composition. Preferably, the first component is insoluble in the acid solution or acid / solvent solution mixture.
    [0040] [0040] It has been observed that the preparation of an initial composition of the first component and of the triprotic acid without initially dissolving the first component in a solvent, and / or so that the first component does not dissolve in the acid / solvent solution mixture, allows the efficient preparation of a composition having a greater amount of the first component that can be released into the wound. This is beneficial with regard to the use of a first component that is initially dissolved in a solvent, since the overall amount of first available component is diluted by the presence of the solvent. In addition, in situations where a first component is dissolved during preparation, the final composition cannot be in the form of fibers, granules or powder, which limits the potential uses and forms of the composition. The first component can therefore be insoluble in water and solvent.
    [0041] [0041] In cases where the first component comprises chitosan fibers, the solvent is preferably a non-aqueous solvent such as isopropyl alcohol.
    [0042] [0042] The triprotic acid is preferably released as an acidic solution. The acidic solution (acid in water) can have a concentration of around 5-80%, preferably around 20-60% and most preferably around 40-50%.
    [0043] [0043] The triprotic acid may be present in the composition in an amount greater than about 2% of the first component, preferably greater than about 5% of the first component, more preferably greater than about 10% of the first component. first component and most preferably greater than about 25% of the first component. The triprotic acid can be present in a composition in an amount of at least about 2% of the first component, preferably at least about 5% of the first component, more preferably at least about 10% of the first component and the more preferably at least about 25% of the first component.
    [0044] [0044] The triprotic acid can be present in an amount of around 2-75% of the first component, preferably around 10-75% of the first component, more preferably around 20-75% of the first component and the more preferably in an amount of about 25-60% of the first component. Good results were observed with triprotic acid present in an amount of around 60% of the first component. The percent acid values reported represent relative amounts of triprotic acid compared to the total amount of the first component in the composition. For example, if the total amount of the first component in a composition was 1g, a composition comprising 20% triprotic acid would contain 0.2g of the triprotic acid.
    [0045] [0045] The first component is selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and any combination thereof.
    [0046] [0046] The term "derivative" is used here to refer to a compound that is derived from chitosan or chitin after one or more chemical reactions or modifications. One or more chemical reactions or modifications may involve replacing one or more of the amino or hydroxyl protons in chitosan or 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, partially deacetylated chitin, suitable for use in the present invention, has a degree of deacetylation of at least about 50%, more typically at least about 75% and most typically at least about 85%. Also included in the terms "chitosan or chitin derivatives" are products of reaction of chitosan or chitin with other compounds. Such reaction products include, but are not limited to, carboxymethyl chitosan, hydroxyl butyl chitin, N-acyl chitosan, O-acyl chitosan, N-alkyl chitosan, O-alkyl chitosan, N-alkyl chitosan, N-arylidene chitosan, O -sulfonyl chitosan, chitosan or sulfated chitin, chitosan or phosphorylated chitin, chitosan or nitrated chitin, deoxy-halo chitosan, alkaline chitin, alkaline chitosan, or metal chelates with chitosan, organic salts, etc. Chitosan or chitin derivatives, including those mentioned herein, can also contain functional groups linked to them via covalent or non-covalent bonds.
    [0047] [0047] Typically, the first component is chitosan or a derivative of chitosan. Preferably, the first component is chitosan.
    [0048] [0048] Chitosan is a derivative of solid residues from the processing of seafood and can be extracted from the culture of fungi. It is a cationic polymeric material that is insoluble in water. Chitosan is a hemostatic known for use in wound dressings. The term "hemostatic" is used here to refer to any agent that is capable of producing a clot or tampon that stops or reduces bleeding when it comes in contact with blood or other body fluid, such as wound exudate, from a site. physiological target or wound site of a human or animal.
    [0049] [0049] There are many different types of chitosan that can be used as material in wound dressings, with different absorption properties. Different types of chitosan can have different molecular weights, different degrees of deacetylation, different arrangements of β - (1-4) linked D-glucosamine and N-acetyl-D-glucosamine monomers, different chiral forms or they can be derived from different species or sources (and fungi), or they may have been treated differently during manufacture. Each and all of these different variations of chitosan materials are intended for use in the present invention.
    [0050] [0050] The first chitosan component can have a degree of deacetylation greater than 70%, preferably greater than 80% and more preferably greater than 85%.
    [0051] [0051] Chitosan materials can exhibit gelling properties when in the form of a salt. To obtain a chitosan salt, chitosan is typically mixed with an appropriate acid. The gelling properties of chitosan salts make them desirable for use as materials in wound dressings.
    [0052] [0052] Chitosan and / or chitosan derivative can be in any appropriate form, such as, for example, fibers, granules, powder, flakes, sheet, foam, freeze-dried foam, compressed foam, film, perforated film, beads and combinations of two or more of the above. Typically, the chitosan and / or chitosan derivative is in the form of fibers. Preferably, the fibers are non-woven. The fibers can be of any desired diameter or length and can be formed in a textile fabric or a plug for use.
    [0053] [0053] Typically, the molecular weight of the first component used in a composition of the present invention is less than about 2,000,000, more typically less than about 1,000,000, and even more typically less than about 500,000, and the most typically less than about 175,000.
    [0054] [0054] The first component in a 1% acetic acid solution can have a viscosity greater than 150cps.
    [0055] [0055] The composition of the present invention comprises a solubilizing acid.
    [0056] [0056] The term "solubilizing acid" is used here to refer to an acid that, when applied to or associated with the first component, makes the first component more soluble in aqueous body fluids.
    [0057] [0057] The composition may comprise one or more solubilizing acids. The composition can thus comprise two, three, four or more solubilizing acids. Typically, the composition comprises a solubilizing acid.
    [0058] [0058] Solubilizing acid can be selected from the group consisting of succinic acid, malic acid, sulfuric acid, acrylic acid, lactic acid, formic acid, acetic acid, hydrochloric acid, nitric acid, and mixtures of any or more of the same .
    [0059] [0059] The solubilizing acid may preferably be a monoprotic acid.
    [0060] [0060] The term "monoprotic acid" (which can also be referred to here as a "monobasic acid") is used here to refer to an acid that has a hydrogen ion to donate to a base in an acid-base reaction. In other words, a monoprotic molecule has a replaceable hydrogen atom.
    [0061] [0061] Monoprotic acid can be selected from the group consisting of lactic acid, formic acid, acetic acid, hydrochloric acid, nitric acid and mixtures of any or more of them.
    [0062] [0062] Preferably, the monoprotic acid is lactic acid, acetic acid or a mixture thereof. Most preferably, the monoprotic acid is lactic acid.
    [0063] [0063] The solubilizing acid can be in the form of granules, flakes, powder or solution. Typically, the solubilizing acid is in the form of a solution. Such a solution is prepared by dissolving an amount of solubilizing acid in a volume of water and / or solvent.
    [0064] [0064] The composition comprises a mixture of the first component, at least one triprotic acid and at least one solubilizing acid.
    [0065] [0065] The solubilizing acid can be mixed with the triprotic acid and contacted with the first component in the same way as described above in relation to the triprotic acid alone. Alternatively, the triprotic and solubilizing acids can be contacted with separate portions of the first component and then combined into the composition. For example, where the first component is in the form of fibers, a selection of the fibers can be partially or completely coated with triprotic acid and a separate selection of the fibers can be partially or completely coated with a solubilizing acid.
    [0066] [0066] Typically, the solubilizing acid will be mixed with the triprotic acid and contacted with the first component.
    [0067] [0067] The at least one solubilizing acid or the mixture of at least one solubilizing acid and at least one triprotic acid can be absorbed into, or coated on, at least, a portion of the first component. Preferably, the at least one solubilizing acid or the mixture of at least one solubilizing acid and at least one triprotic acid is coated substantially over the entire surface of the first component. In some embodiments, the triprotic acid can be absorbed into, or coated over at least a portion of the first component, and the solubilizing acid can then be absorbed into or coated over at least a portion of it, or vice versa.
    [0068] Alternatively, the composition may comprise separate portions of the first component, at least one triprotic acid and at least one solubilizing acid. For example, the first component can be in the form of fibers, granules, flakes, powder, sheet or combinations thereof and the triprotic and solubilizing acids can be in the form of granules, flakes and / or a powder, so the first component is the acids are located in separate portions of the composition. For example, the separate portions can, for example, be in the form of layers. Alternatively, the first component, triprotic acid and solubilizing acid can be mixed.
    [0069] [0069] In some embodiments, at least one triprotic acid and at least one solubilizing acid may be associated with the same or separate carrier materials. The composition can thus comprise a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives and combinations thereof; at least one triprotic acid and at least one solubilizing acid, wherein the triprotic acid and / or the solubilizing acid are associated with the same or separate carrier materials.
    [0070] [0070] The solubilizing acid can be associated with the carrier material in the same way as described here with reference to triprotic acid.
    [0071] [0071] The solubilizing acid can be coated on the first component and the triprotic acid can be coated on a carrier material, or vice versa.
    [0072] [0072] The first component can comprise fibers coated with solubilizing acid and the carrier material can be coated with triprotic acid. The carrier material can be viscose.
    [0073] [0073] The at least one solubilizing acid can be coated on the first component and / or the carrier material by the same means as described for triprotic acid.
    [0074] [0074] The first component can be partially or completely coated with solubilizing acid.
    [0075] [0075] The solubilizing acid is preferably released as an acidic solution. The acidic solution (acid in water) can have a concentration of at least about 40%, preferably at least about 60% and most preferably at least about 80%.
    [0076] [0076] The at least one solubilizing acid may be present in an amount greater than about 2% of the first component, preferably greater than 5% of the first component, and more preferably greater than about 10% of the first component component. The at least one solubilizing acid can be present in a composition in an amount of at least about 2% of the first component, preferably at least about 5% of the first component, more preferably at least about 10% of the first component and most preferably at least about 25% of the first component.
    [0077] [0077] The at least one solubilizing acid can be present in an amount around 2-50% of the first component, preferably around 10-40% of the first component, or more preferably around 20-30% of the first component. Preferably, the at least one solubilizing acid can be present in an amount of about 25% of the first component. As with triprotic acid, the percentage values reported to represent the relative amounts of solubilizing acid are compared to the total amount of the first component.
    [0078] [0078] Without the presence of a solubilizing acid, it was observed that a greater amount of triprotic acid in a composition results in greater efficacy against microorganisms. Such a composition may comprise triprotic acid in an amount of at least about 25%, preferably at least about 35%, more preferably at least about 50% and most preferably at least about 60% of the first component .
    [0079] [0079] However, it has been discovered, in development, that a composition having a solubilizing acid content of around 15-30% of the first component can reduce the amount of triprotic acid required to achieve the desired effect. For example, a composition having a triprotic acid content greater than 20% has been shown to produce results comparable to a composition having a solubilizing acid content of 15-20%, but a reduced triprotic acid content of around 5% or smaller.
    [0080] Thus, an embodiment of the present invention comprises a composition comprising a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and combinations thereof; 20-75% of at least one triprotic acid and 10-40% of at least one solubilizing acid.
    [0081] [0081] Good results have been observed for a composition having a solubilizing acid content of 20-35%, particularly 25-30%, of the first component and a triprotic acid content of 25-45%, particularly 30-40%, of the first component.
    [0082] [0082] The combined acid may be present in a composition in an amount of at least about 4% of the first component, preferably at least about 10% of the first component, more preferably at least about 25% of the first component and most preferably at least about 45% of the first component.
    [0083] [0083] The composition of the present invention can be in the form of granules, flakes, fibers, powder, non-woven textile, or a woven textile, a gel, a hydrogel sheet, a hydrogel and / or a film. The fibers can be woven or non-woven. Preferably, the fibers are non-woven.
    [0084] [0084] Typically, the composition is in the form of fibers. More typically, the composition is in the form of non-woven fibers or a non-woven textile.
    [0085] [0085] Alternatively, the composition can be in the form of a gel, hydrogel or liquid. When in these forms, the composition can be used without further modification (for example, it can be applied directly to a wound) the composition can be applied to a release mechanism.
    [0086] [0086] A hydrogel is made by obtaining a solution of triprotic acid and solubilizing in water, optionally mixing the solution with a solvent and adding the first component to the solution. The first component will absorb the solution and gel. The extent of gelation and gel strength can be varied by the amount of the first component added to the solution. The greater the amount of the first component in the solution, the stronger the gel, and vice versa. The gel can then be dried to varying lengths, depending on the shape of the desired composition.
    [0087] [0087] Alternatively, a hydrogel is made by obtaining a composition of the present invention in dry form, for example, granules, flakes, fibers, powder, textile, and mixing with water. The composition will absorb water and gel. Again, extent of gelation and strength of the gel can be varied by the amount of composition mixed with water or the amount of water mixed with the composition. The greater the amount of the composition relative to water, the stronger the gel, and vice versa. The gel can then be dried to varying lengths, depending on the shape of the desired composition.
    [0088] [0088] For example, a sheet of hydrogel can be obtained by transferring the hydrogel into a mold, such as a tray, and drying the hydrogel to an extent so as not to remove the entire water content, but to remove enough water content to form a gel.
    [0089] [0089] Alternatively, a dry film can be obtained by transferring the hydrogel in a mold, such as a tray, and drying the hydrogel to an extent where substantially all of the water is removed. The resulting composition is in the form of a dry film. The film is preferably flexible.
    [0090] [0090] The release mechanism may include a polyurethane foam, a polyurethane film, a woven textile, a superabsorbent material, a medical device, such as a catheter, a stent and the like. The release mechanism may comprise more than one of each of the aforementioned components and / or may comprise a combination of one or more of the above.
    [0091] [0091] For example, the release mechanism may comprise one or more polyurethane foams and a polyurethane film. Alternatively, the release mechanism may comprise a woven viscose textile.
    [0092] [0092] The term "superabsorbent material" is used here to refer to a hydrophilic material that is swellable in water, but not soluble in water, and that is capable of absorbing fluid at more than 2000% with a fluid retention greater than 85%. Preferably, the superabsorbent material is capable of absorbing fluid at more than 2500% with a fluid retention greater than 90%.
    [0093] [0093] The term "water swellable" is used here to refer to a material which, when contacted with water or water-containing fluid, will absorb the fluid and swell, but will not substantially dissolve in that fluid.
    [0094] [0094] The term "water-soluble" is used here to refer to a material that, when contacted with water or a fluid containing water, will dissolve in that fluid.
    [0095] [0095] The superabsorbent material can be selected from polymeric materials, such as poly (vinyl) alcohol (PVA), poly (ethylene oxide) (PEO) and poly (acrylic acid). The superabsorbent material can be chemically modified. For example, the superabsorbent material can be a polymeric material obtained by polymerization by grafting acrylic acid onto a carboxymethyl cellulose chain. 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 (acrylic acid). The poly (acrylic acid) can be partially neutralized, highly cross-linked poly (acrylic acid).
    [0096] [0096] The terms "crosslinking" and "crosslinking" are used here to refer to two or more polymer chains being linked by a primary bond, such as a covalent bond. The term "lightly crosslinked" is used here to refer to modalities in which the number of primary crosslinking links in the superabsorbent material is less than the total number of possible crosslinking links.
    [0097] [0097] In some embodiments, the superabsorbent material is selected from polymeric materials, such as PVA, PEO and poly (acrylic acid), preferably a partially neutralized, slightly cross-linked poly (acrylic acid). Typically, the superabsorbent material is a partially neutralized and slightly crosslinked poly (acrylic acid).
    [0098] [0098] The superabsorbent material may be in the form of fibers. Typically, the superabsorbent material is in the form of non-woven fibers. The length of the fibers can be up to 100mm, and typically from 20-75mm, more typically from 32 to 51mm.
    [0099] [0099] The release mechanism can be a wound dressing known in the art.
    [0100] [00100] The composition of the present invention can be applied to the release mechanism by any appropriate means known in the art.
    [0101] [00101] The composition of the present invention may comprise a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and combinations thereof; at least one triprotic acid and at least one solubilizing acid, wherein the first component is at least partially coated with the triprotic acid and the solubilizing acid.
    [0102] [00102] The composition may comprise a first fibrous component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and combinations thereof; at least one triprotic acid and at least one solubilizing acid, wherein the fibers of the first component are at least partially coated with the triprotic acid and the solubilizing acid.
    [0103] [00103] Typically, the composition comprises a first fibrous chitosan component at least partially coated with a triprotic acid and a solubilizing acid. Preferably, the composition comprises a first fibrous component of non-woven chitosan at least partially coated with citric acid and lactic acid. Preferably further, the composition comprises a first fibrous component of non-woven chitosan substantially completely coated with a mixture of citric acid and lactic acid.
    [0104] [00104] In accordance with another aspect of the present invention, a wound dressing comprising a composition, as described herein, is provided.
    [0105] [00105] The wound dressing can be a wound dressing that gels after contact with a fluid, such as wound exudate. In the field of gelling wound dressings, which focus on containing the blood flow of a bleeding wound, the composition of the present invention is particularly surprising since triprotic acids over non-woven wound dressings tend not to gel and have been known to show harmful effects on water absorption and retention.
    [0106] [00106] The wound dressing may comprise a composition as described herein and a release mechanism, as described herein. The composition can be applied to the coating release mechanism or the like. The composition and release mechanism can form a layered wound dressing.
    [0107] [00107] The composition of the present invention, or a wound dressing comprising such a composition, may also comprise additional components. Such additional components include, but are not limited to, antimicrobial agents; pharmaceutical agents; chelating agents; wetting agents, such as surfactants; growth factors; cytokines; agents that absorb agents that delay healing, such as MMP (matrix metalloproteinases) and elastase; and / or another dressing component, such as calcium, vitamin K, fibrinogen, thrombin, factor VII, factor VIII, clays such as kaolin, oxidized regenerated cellulose, gelatin or collagen, etc.
    [0108] [00108] Appropriate antimicrobial agents can be selected from the list comprising silver, polyhexamethylene biguanide (PHMB), iodine, octenidine, copper, chlorhexidine gluconate (CHG), miconazole, metronidazole and combinations of one or more of the same.
    [0109] [00109] The antimicrobial agent can be coated on or absorbed in the first component and / or a carrier material in the same way as described here in relation to triprotic and / or solubilizing acids.
    [0110] [00110] The composition of the present invention can be mixed with other compositions usable in wound care. In some embodiments, the composition of the present invention can be mixed or mixed with one or more hemostatics. Hemostatics can be in the form or fibers, granules, flakes, powder or any combination thereof. Preferably, the hemostatic is in the form of granules.
    [0111] [00111] For example, a composition of the present invention as described herein can be mixed with a hemostatic such as granules of Celox®, a commercially available chitosan based hemostatic.
    [0112] [00112] In accordance with another aspect of the present invention, there is provided a composition as described herein for use as a therapeutic agent.
    [0113] [00113] In accordance with another aspect of the present invention, there is provided a composition as described herein for use in the treatment of wounds.
    [0114] [00114] In accordance with another aspect of the present invention, there is provided a composition as described herein for use in breaking and killing bacteria within a biofilm.
    [0115] [00115] In accordance with another aspect of the present invention, there is provided a composition as described herein for use in preventing the formation of a biofilm.
    [0116] (a) revestir pelo menos uma porção do primeiro componente com uma mistura compreendendo o pelo menos um ácido triprótico e o pelo menos um ácido solubilizante; e/ou (b) absorver em pelo menos uma porção do primeiro componente uma mistura compreendendo o pelo menos um ácido triprótico e o pelo menos um ácido solubilizante. [00116] In accordance with another aspect of the present invention, there is provided a method of making a composition comprising a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and combinations thereof; at least one triprotic acid and at least one solubilizing acid, the method comprising the steps of: (a) coating at least a portion of the first component with a mixture comprising at least one triprotic acid and at least one solubilizing acid; and / or (b) absorbing at least a portion of the first component a mixture comprising at least one triprotic acid and at least one solubilizing acid.
    [0117] (a) misturar um ácido triprótico com água e/ou um solvente para dar uma solução de ácido triprótico; (b) misturar a solução de ácido triprótico com uma solução de ácido solubilizante preparada por mistura de um ácido solubilizante com água e/ou um solvente, para dar uma solução de ácido misturada; (c) opcionalmente misturar a solução de ácido misturada com um solvente; e (d) adicionar o primeiro componente à solução obtida na etapa (c). [00117] According to another aspect of the present invention, there is provided a method of making a composition comprising a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and combinations thereof; at least one triprotic acid and at least one solubilizing acid, the method comprising the steps of: (a) mixing a triprotic acid with water and / or a solvent to give a solution of triprotic acid; (b) mixing the triprotic acid solution with a solubilizing acid solution prepared by mixing a solubilizing acid with water and / or a solvent, to give a mixed acid solution; (c) optionally mixing the mixed acid solution with a solvent; and (d) adding the first component to the solution obtained in step (c).
    [0118] [00118] The method may also comprise step (e) of drying the mixture obtained in step (d). The drying step can remove some or all of the solvent and / or water content from the composition.
    [0119] [00119] For compositions in which the first component comprises chitosan fiber, the solvent from steps (a) to (c) can typically be non-aqueous.
    [0120] [00120] The other aspects of the present invention can incorporate any or all of the features described with respect to the first aspect of the present invention, as desired or as appropriate.
    [0121] [00121] Modalities of the present invention will now be further described with reference to the following non-limiting examples and attached figures, in which:
    [0122] [00122] Figure 1: is a graph showing the results of tests using the MBEC Assay for Pseudomonas aeruginosa ATCC 13359;
    [0123] [00123] Figure 2: is a graph showing the results of tests using the MBEC Assay for Staphylococcus haemolyticus;
    [0124] [00124] Figure 3: is a graph showing the results of tests using the MBEC Assay for MRSA 308;
    [0125] [00125] Figure 4: is a graph showing the results of tests using the CDC Reactor Model for Pseudomonas aeruginosa ATCC 10434;
    [0126] [00126] Figure 5: is a graph showing the results of tests using the CDC Reactor Model for Staphylococcus haemolyticus NCTC 11042;
    [0127] [00127] Figure 6: is a graph showing the results of tests using the methicillin-resistant CDC Reactor Model for Staphylococcus aureus 308;
    [0128] [00128] Figure 7: is a graph showing the results of tests using the CDC Reactor Model for Pseudomonas aeruginosa ATCC 10434;
    [0129] [00129] Figure 8: is a graph showing the results of tests using the CDC Reactor Model for Pseudomonas aeruginosa ATCC 10434;
    [0130] [00130] Figure 9: is a graph showing the results of tests using the CDC Reactor Model for Staphylococcus aureus;
    [0131] [00131] Figure 10: is a graph showing the results of tests using the CDC Reactor Model for Staphylococcus aureus;
    [0132] [00132] Figure 11: is a graph showing the amount of viable Staphylococcus aureus recovered from a preformed 24-hour biofilm after 24-hour treatment with each agent;
    [0133] [00133] Figure 12: is a graph showing the amount of viable Staphylococcus aureus recovered from a preformed 72-hour biofilm after 24-hour treatment with each agent. General methods for sample preparation General method 1: First component and triprotic acid
    [0134] [00134] Triprotic acid powder (eg citric acid) was dissolved in deionized water and then mixed with non-aqueous solvent (eg IPA). The first component, typically in the form of non-woven fiber, was placed in the triprotic acid solution and allowed to absorb the solution. The solution was then dried using thermal drying, to leave a solid chitosan, chitin or derivative thereof coated with triprotic acid. General method 2: First component with triprotic acid and monoprotic acid
    [0135] [00135] Triprotic acid powder (for example, citric acid) was dissolved in deionized water and then mixed with a solution of solubilizing acid (for example, lactic acid). This was then mixed with a non-aqueous solvent (for example, IPA). The first component, typically in the form of non-woven fiber, was placed in the mixed acid solution and allowed to absorb the solution. The solution was then dried using thermal drying, to leave a solid chitosan, chitin or derivative thereof coated with a mixture of triprotic acid and solubilizing acid. Example compositions
    [0136] [00136] The following are examples of compositions prepared in accordance with the present invention. Example 1 (reference):
    [0137] [00137] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.439g) to give a nominal 32.5% composition. Example 2 (reference):
    [0138] [00138] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.027-0.068g) to give a nominal 2-5% composition. Example 3 (reference):
    [0139] [00139] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.27-0.41g) to give a nominal 20-30% composition. Example 4 (reference):
    [0140] [00140] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.81-0.94g) to give a nominal 60-70% composition. Example 5:
    [0141] [00141] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.027-0.068g) and lactic acid (0.34g) to give a composition of 2-5% nominal triprotic acid and acid monoprotic at 25% nominal. Example 6:
    [0142] [00142] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.27-0.41g) and lactic acid (0.34g) to give a 20-30% triprotic acid composition nominal and monoprotic acid at 25% nominal. Example 7:
    [0143] [00143] 100% chitosan fiber fabric (1.35g) was coated with citric acid (0.81-0.94g) and lactic acid (0.41g) to give a 60-70% nominal triprotic acid composition and a 30% monoprotic acid composition. Example 8:
    [0144] [00144] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.04g) and lactic acid (0.2g) to give a nominal 3% triprotic acid composition and monoprotic acid composition to 15% nominal. Example 9:
    [0145] [00145] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.34g) and lactic acid (0.2g) to give a 25% triprotic acid composition and monoprotic acid composition to Nominal 15%. Example 10:
    [0146] [00146] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.81g) and lactic acid (0.27g) to give a composition of 60% triprotic acid and 20% monoprotic acid nominal. Example 11:
    [0147] [00147] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.41g) and lactic acid (0.34g) to give a composition of 30% triprotic acid and 25% monoprotic acid nominal. Example 12:
    [0148] [00148] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.54g) and lactic acid (0.34g) to give a composition of 40% triprotic acid and 25% monoprotic acid nominal. Example 13:
    [0149] [00149] Non-woven 100% chitosan fiber (1.35g) was coated with citric acid (0.54g) and lactic acid (0.41g) to give a composition of 40% triprotic acid and 30% monoprotic acid nominal. Sample wound dressings Example 14 (reference):
    [0150] [00150] A composition of the present invention is prepared containing nominally 2g of 100% non-woven chitosan fiber in 8g deionized water with 0.6g citric acid. The composition was coated on the surface of a non-cross-linked polyurethane foam and allowed to dry. The foam containing the dried composition of the present invention was then adhesive-bonded to a polyurethane foam, away from a layer of bonded polyurethane film, to form a wound contact layer. Example 15 (reference):
    [0151] [00151] A composition of the present invention is prepared containing nominally 2g of 100% non-woven chitosan fiber in 8g of deionized water with 0.6g of citric acid. The composition was coated on the surface of a woven viscose textile and allowed to dry. MBEC assay 1
    [0152] [00152] To determine the effectiveness of antimicrobials against biofilms of various microorganisms, an MBEC Assay (Minimum Biofilm Eradication Concentration) was used.
    [0153] [00153] The MBEC Assay is a high-throughput screening assay used to determine the effectiveness of antimicrobials against biofilms of various microorganisms. The MBEC biofilm inoculator consists of a 96-pin plastic cap and a corresponding base. There are two types of bases that can be used with the MBEC cover. One base contains 96 individual wells. The individual cavities allow the growth of a variety of microorganisms in the same cap as the pin. The other type of base is a wavy through base that can contain only a single microorganism. Biofilms are established on the pins in batch conditions (with no flow of nutrients into or out of an individual cavity) with gentle mixing. The established biofilm is transferred to a new 96-well plate for testing antimicrobial effectiveness. The design of the assay allows for the simultaneous testing of multiple biocides in multiple concentrations with replicated samples, making it an efficient screening tool. Test microorganisms Pseudomonas aeruginosa ATCC 13359 Staphylococcus haemolyticus MRSA 308 Comparative samples tested Control: Phosphate buffered saline (PBS)
    [0154] [00154] Sample A: Non-woven 100% chitosan fiber with Ag (nominally 1%) and lactic acid to provide a nominal 25% monoprotic acid composition
    [0155] [00155] Sample B: Carboxymethylated cellulose fiber nonwoven with Ag (nominally 1%) (Aquacel Ag®)
    [0156] [00156] Sample C: Non-woven 100% chitosan fiber with lactic acid to provide a nominal 25% monoprotic acid composition
    [0157] [00157] Sample D: Non-woven 100% chitosan fiber with acetic acid to provide a nominal 25% monoprotic acid composition
    [0158] [00158] Sample E: 100% non-woven chitosan fiber with citric acid to provide a nominal 25% triprotic acid composition Preparation of bacterial inoculum
    [0159] [00159] A 24-hour culture from each microorganism was collected from either a tryptone and soy agar plate (TSA) or brain and heart infusion agar plate (BHIA) and suspended in or 20ml of tryptone broth and soy (TSB) or 20ml of brain and heart infusion broth (BHIB). The resulting bacterial suspension was diluted to give an initial OD590 = 0.10 ± 0.03, which corresponds to a bacterial concentration of 108 cfuml-1. This initial inoculum was serially diluted six more times in order to progressively represent smaller bacterial loads (ie, 107, 106, 105, 104, 103 cfuml-1). The starting bacterial concentration for each organism was typically 1 x 108 ± 5 x 107 cfuml-1. MBEC assay
    [0160] [00160] The biofilms of each microorganism were grown in pin cover projections of a microtiter plate for 48 hours at 37 ° C, 50 rpm. After 48 hours, the pin caps were removed, washed briefly in phosphate buffered saline (PBS) to remove planktonic bacteria and then placed on the agent's challenge plate for 24 hours. For the preparation of the challenge plate for wound dressings, 1 cm2 pieces were cut with sterile scissors and placed in the designated wells of a microtiter plate. The challenge plate for the granule test agents was prepared by weighing 30mg ± 3mg of each granule formulation in the wells of a microtiter plate. The wound dressings and granules were then activated with 150 µl of PBS. After treatment, the pin cover projections were washed twice in PBS, then transferred to 200 µl of neutralizer and placed in a sonic water bath for 5 minutes in order to recover remaining fixed bacteria. Serial dilutions were performed in the resulting recovery broth and drip plates were used to quantify the recovered bacteria. All samples were tested in triplicate unless otherwise noted.
    [0161] [00161] The results are shown in Table 1 and Figures 1 to 3. The results in Figures 1 to 3 refer to Samples B, C and E.
    [0162] [00162] It is evident from the graphs shown in Figures 1 to 3 that Sample E comprising chitosan coated with a triprotic acid is effective against the three microorganisms tested. Sample C comprising chitosan fibers coated with a monoprotic acid showed concentrations of microorganisms for all three microorganisms tested. Finally, Sample B comprising silver carboxymethyl cellulose showed good results for Staphylococcus haemolyticus which was not effective against both Pseudomonas aeruginosa ATCC 13359 and MRSA 308.
    [0163] [00163] To determine the biofilm removal capabilities of seven wound dressings, against three bacterial species, using a CDC reactor method. Test microorganisms Staphylococcus haemolyticus NCTC 11042 Pseudomonas aeruginosa ATCC 10434 Methicillin resistant Staphylococcus aureus 308 Tested Samples Control: Phosphate buffered saline (PBS)
    [0164] [00164] Sample F: Non-woven 100% chitosan fiber with 15% lactic acid and 3% citric acid. This is equivalent to 1.35g chitosan, 0.2g lactic acid and 0.04g citric acid (Example 8).
    [0165] [00165] Sample G: Non-woven 100% chitosan fiber with 15% lactic acid and 25% citric acid. This is equivalent to 1.35g chitosan, 0.2g lactic acid and 0.34g citric acid (Example 9).
    [0166] [00166] Sample H: Non-woven 100% chitosan fiber with 20% lactic acid and 60% citric acid. This is equivalent to 1.35g chitosan, 0.27g lactic acid and 0.81g citric acid (Example 10).
    [0167] [00167] Sample I: Non-woven 100% chitosan fiber with 3% citric acid. This is equivalent to 1.35g chitosan and 0.04g citric acid (Reference example 2).
    [0168] [00168] Sample J: Non-woven 100% chitosan fiber with 25% citric acid. This is equivalent to 1.35g chitosan and 0.34g citric acid (Reference example 3).
    [0169] [00169] Sample K: Non-woven 100% chitosan fiber with 60% citric acid. This is equivalent to 1.35g chitosan and 0.81g citric acid (Reference example 4).
    [0170] [00170] Samples were prepared following the methods described above.
    [0171] [00171] Dressing samples were cut into pieces of approximately 1.5 cm2 before use. Phosphate buffered saline (PBS) was used as the control. Preparation of bacterial inoculum
    [0172] [00172] A 24-hour culture of the test bacteria was collected from a tryptone and soy agar (TSA) plate using a sterile cotton swab and resuspended in 20ml tryptone and soy broth (TSB). The bacterial suspension was diluted to give an OD590 = 0.10 ± 0.03 which corresponds to a bacterial concentration of 108 ± 5 x107 cfuml-1. This was further diluted in TSB and used as the inoculum for the CDC reactor containing the test coupons. The CDC reactor was incubated for 48 hours at 37 ° C, shaking at 50 rpm in order to encourage biofilm growth. Biofilm treatment
    [0173] [00173] After 48 hours the test coupons were removed from the CDC reactor and washed 3 times in sterile PBS in order to remove planktonic bacteria. The washed coupons were then treated, sandwiching the coupon between two 1.5 cm2 dressing samples. The dressings were activated before the test by adding 350µl PBS (75% saturation) to each 1.5 cm2 piece. Control coupons were submerged in 2 ml of PBS for P. aeruginosa (or in the case of S. haemolyticus and MRSA in 2 ml PBS + 0.1% TSB). All samples were tested in triplicate. Microorganisms were recovered from the coupons after 24 hours of treatment and quantified by performing serial dilutions and drip plates.
    [0174] [00174] The results are shown in Figures 4 to 6.
    [0175] [00175] It is evident from the graphs shown in Figures 4 to 6 that Samples G, H and K are effective against all three microorganisms tested. Samples G and H comprise chitosan fibers coated with a triprotic acid and a monoprotic acid. Sample K comprises a chitosan fiber coated with a greater amount of a triprotic acid. While Samples F, I and J were effective against methicillin-resistant Staphylococcus aureus 308, they were less effective against both Staphylococcus haemolyticus NCTC 11042 and Pseudomonas aeruginosa ATCC 10434.
    [0176] [00176] The results of the CDC reactor model show that a chitosan coated with increasing amounts of triprotic acid, for example, around 60%, is more effective against microorganisms than a smaller amount of around 25% or less. Also, the results show that including a monoprotic acid with a triprotic acid can be effective in reducing the amount of triprotic acid required, for example, by reducing the amount of triprotic acid to around 25%. Reactor model CDC 2
    [0177] [00177] To determine the biofilm removal capabilities of six wound dressings, against two bacterial species, using the CDC reactor method. Test microorganisms Staphylococcus haemolyticus NCTC 8325 Pseudomonas aeruginosa ATCC 10434 Tested Samples Control: Phosphate buffered saline (PBS)
    [0178] [00178] Sample L: Non-woven 100% chitosan fiber with 25% lactic acid and 30% citric acid. This is equivalent to 1.35g chitosan, 0.34g lactic acid and 0.41g citric acid (Example 11).
    [0179] [00179] Sample M: Non-woven 100% chitosan fiber with 25% lactic acid and 40% citric acid. This is equivalent to 1.35g chitosan, 0.34g lactic acid and 0.54g citric acid (Example 12).
    [0180] [00180] Sample N: Non-woven 100% chitosan fiber with 30% lactic acid and 40% citric acid. This is equivalent to 1.35g chitosan, 0.41g lactic acid and 0.54g citric acid (Example 13).
    [0181] [00181] Sample O: Non-woven 100% chitosan fiber.
    [0182] [00182] Sample P: Non-woven 55% chitosan fiber / 45% Viscose fiber with 25% lactic acid. This is equivalent to 0.74g of chitosan fiber, 0.61g of Viscose fiber and 0.34g of lactic acid
    [0183] [00183] Sample Q: Non-woven carboxymethylcellulose with antibiofilm formulation containing ionic silver.
    [0184] [00184] The samples were prepared following the methods described above.
    [0185] [00185] Dressing samples were cut into pieces of approximately 1.5 cm2 before use. Phosphate buffered saline (PBS) was used as the control. Preparation of bacterial inoculum
    [0186] [00186] A 24-hour culture of each microorganism was collected from a tryptone and soy agar (TSA) plate and resuspended in 20ml of tryptone and soy broth (TSB). The resulting bacterial suspension was diluted to give an initial OD590 = 0.10 ± 0.03, which corresponds to a bacterial concentration of 108 ± 5 x 107 cfuml-1. This was further diluted to approximately 107 cfuml-1 in TSB and was used as the initial inoculum for the CDC reactor. The CDC reactor was incubated for 24 and 72 hours at 37 ° C, shaking at 50 rpm in order to encourage the growth of the biofilm. Biofilm treatment
    [0187] [00187] After 24 hours and 72 hours, the test coupons were removed from the CDC reactor and washed 3 times in sterile phosphate buffered saline (PBS) in order to remove planktonic bacteria. The washed coupons were then treated by sandwiching each coupon between two pieces of wound dressing material. The dressings were activated before the test by adding 350 µl of PBS containing 1% TSB. Control coupons were submerged in 2 ml of PBS containing 1% TSB. After the 24-hour treatment period, the coupons were placed in 2 ml of neutralizer and sonicated for 15 minutes to recover the remaining fixed bacteria. Serial dilutions were performed in the resulting recovery broth and drip plates were used to quantify the recovered bacteria. All samples were tested in triplicate.
    [0188] [00188] The results are shown in Figures 7 to 10.
    [0189] [00189] Figure 7 shows the amount of viable Pseudomonas aeruginosa recovered from preformed biofilms 24 hours after 24 hour treatment with the sample wound dressings. Controls were treated with PBS + 1% TSB.
    [0190] [00190] Figure 8 shows the amount of viable Pseudomonas aeruginosa recovered from preformed biofilms 72 hours after 24 hour treatment with the sample wound dressings. Controls were treated with PBS + 1% TSB.
    [0191] [00191] Figure 9 shows the amount of viable Staphylococcus aureus recovered from preformed biofilms 24 hours after 24 hour treatment with the sample wound dressings. Controls were treated with PBS + 1% TSB.
    [0192] [00192] Figure 10 shows the amount of viable Staphylococcus aureus recovered from preformed biofilms 72 hours after 24 hour treatment with the sample wound dressings. Controls were treated with PBS + 1% TSB.
    [0193] [00193] It is evident from the graphs shown in Figures 7 to 10 that Samples L, M and N of the present invention are effective against both microorganisms tested. While Samples Q and P were effective against Staphylococcus aureus, they were less effective against Pseudomonas aeruginosa ATCC 10434. MBEC assay 2 Test microorganism Staphylococcus aureus NCTC 8325 Tested agents
    [0194] [00194] All test agents were prepared by coating chitosan granules having a degree of deacetylation> 75% with the specified acid (s) using a non-aqueous solvent. This formed a solid chitosan salt in the form of a granule. The granules were then mixed in a gel formulation using deionized water with the gel containing between 5-10% of chitosan salt. MBEC assay
    [0195] [00195] The biofilm of S. aureus was grown in pin cover projections of a microtiter plate for 24 hours and 72 hours at 37 ° C. After 24 hours and 72 hours, the pin caps were removed, washed briefly in sterile phosphate buffered saline (PBS) to remove planktonic bacteria and then placed on the agent's challenge plate for 24 hours. For the preparation of the challenge plate, an amount of each gel formulation was placed in the wells of a microtiter plate. The positive and negative projections of the control pin cover were placed in PBS + 1% TSB. After treatment, the pin cover projections were washed twice in PBS and then placed in a neutralizer. The plates were sonicated. Serial dilutions were performed in the resulting recovery broth and drip plates were used to quantify the recovered bacteria. All samples were tested in triplicate. Twenty-four hour biofilm
    [0196] [00196] All agents successfully tested reduced the number of viable bacteria recovered from the preformed 24-hour biofilms of S. aureus after treatment for 24 hours at 37 ° C, as shown in Figure 11. This represented a reduction logarithmic rate of 5.84 ± 0.53 in viable bacteria compared to untreated controls. Seventy-two hour biofilm
    [0197] [00197] All agents tested successfully reduced the number of viable bacteria recovered from the preformed 72 hour biofilms of S. aureus after treatment for 24 hours at 37 ° C, as shown in Figure 12. For each agent, this represented a logarithmic reduction of 5.52 ± 0.22 in viable bacteria compared to untreated controls.
    [0198] [00198] Of course, it should be understood that the present invention is not intended to be limited by the above examples, which are described by way of example only.
    权利要求:
    Claims (15)
    [0001]
    Composition characterized by the fact that it comprises a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and any combination thereof; at least one triprotic acid and at least one solubilizing acid, where the triprotic acid is present in an amount of at least 10% of the first component, and where the solubilizing acid is a monoprotic acid.
    [0002]
    Composition according to claim 1, characterized by the fact that the first component is non-antimicrobial.
    [0003]
    Composition according to claim 1 or claim 2, characterized in that the ratio of the first component to the at least one triprotic acid is at least 2: 1; and / or where the ratio of at least one triprotic acid to at least one solubilizing acid is at least 1: 1.
    [0004]
    Composition according to any one of the preceding claims, characterized by the fact that the first component is chitosan; and / or in which the triprotic acid is citric acid.
    [0005]
    Composition according to claim 4, characterized by the fact that the first component has a degree of deacetylation greater than 70%; and / or where the first component has a viscosity greater than 150cps in a 1% acetic acid solution.
    [0006]
    Composition according to any one of the preceding claims, characterized by the fact that the first component is in the form of fibers, granules, flakes, powder, sheet, or any combination thereof; and / or in which the composition is a solid, optionally in the form of granules, flakes, fibers, powder, non-woven cloth or knitted textile.
    [0007]
    Composition according to any one of the preceding claims, characterized by the fact that the triprotic acid is present in an amount around 25 to 60% of the first component.
    [0008]
    Composition according to any one of the preceding claims, characterized in that the solubilizing acid is selected from the group consisting of lactic acid, formic acid, acetic acid, hydrochloric acid, succinic acid and mixtures thereof.
    [0009]
    Composition according to any one of the preceding claims, characterized in that the triprotic acid and the solubilizing acid are coated on the first component; and / or in which the triprotic acid and / or the solubilizing acid is coated on a carrier material.
    [0010]
    Composition according to any one of the preceding claims, characterized in that the solubilizing acid is present in an amount of 2-50% of the first component, and optionally in which the solubilizing acid is present in an amount of 15-20% of the first component.
    [0011]
    Composition according to any one of the preceding claims, characterized by the fact that it still comprises an additional component selected from the group consisting of antimicrobial agents; pharmaceutical agents; chelating agents; wetting agents; growth factors; cytokines; agents that absorb agents that delay healing, such as MMP’s (matrix metalloproteinases) and elastase; calcium; vitamin K; fibrinogen; thrombin; factor VII; factor VIII; clays; oxidized regenerated cellulose; gelatine; and collagen.
    [0012]
    Wound dressing, characterized by the fact that it comprises a composition as defined in any of the preceding claims.
    [0013]
    Composition according to any one of claims 1-11, characterized in that it is for use as a therapeutic agent.
    [0014]
    Composition according to any one of claims 1-11, characterized in that it is for use in the treatment of wounds; or for use in bacterial rupture and death in a biofilm; or for use in preventing the formation of a biofilm.
    [0015]
    Method of making a composition comprising a first component selected from the group consisting of chitosan, chitin, chitosan derivatives, chitin derivatives, and combinations thereof; at least one triprotic acid and at least one solubilizing acid, in which the triprotic acid is present in an amount of at least 10% of the first component, and in which the solubilizing acid is a monoprotic acid, the method characterized by the fact that it comprises the steps of: The. coating at least a portion of the first component with a mixture comprising at least one triprotic acid and at least one solubilizing acid; and / or B. absorbing at least a portion of the first component a mixture comprising at least one triprotic acid and at least one solubilizing acid.
    类似技术:
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    同族专利:
    公开号 | 公开日
    RU2017129872A3|2019-08-13|
    WO2016120621A1|2016-08-04|
    GB2537009A|2016-10-05|
    ES2896474T3|2022-02-24|
    EP3250244B8|2021-09-22|
    DK3250244T3|2021-11-15|
    AU2016210992B2|2020-03-26|
    KR20170107012A|2017-09-22|
    JP6974177B2|2021-12-01|
    US20200197225A1|2020-06-25|
    BR112017016072A2|2018-04-03|
    CN107530470A|2018-01-02|
    SA517381998B1|2021-12-23|
    RU2748184C2|2021-05-20|
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    法律状态:
    2019-10-15| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-01-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-03-23| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/01/2016, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    GBGB1501333.7A|GB201501333D0|2015-01-27|2015-01-27|Composition for a wound dressing|
    GB1501333.7|2015-01-27|
    PCT/GB2016/050179|WO2016120621A1|2015-01-27|2016-01-27|Composition for a wound dressing|
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