Foam Compositions, Foam Matrices and Methods

Abstract

Disclosed herein are matrices, compositions, and methods for making the matrices. The matrices include biomolecules, and the matrices are dry, cross-linked foams. The matrices are not freeze-dried. The method includes foaming the composition, cross-linking the composition, and drying the composition. The matrices disclosed herein are useful as wound dressings and for treating wounds.

Description

[Technical field]

[0001] The present invention relates to matrices. More specifically, the present invention relates in aspects to foamed matrices and related compositions, methods of making and using same. [Background technology]

[0002] Gelatin and collagen-based materials have hemostatic ability, and therefore gelatin and collagen sponges have been used as effective tools to control wound bleeding. Typically, gelatin-based materials are stabilized in some way so that they are durable when applied to human skin or tissue. Methods for stabilizing gelatin-based materials include chemical treatment, heat treatment, and crosslinking methods.

[0003] US Pat. No. 2,465,357 describes a liquid-permeable, water-insoluble gelatin sponge which has the general physical characteristics of a sponge but which is absorbable by an animal body.

[0004] U.S. Pat. No. 4,703,108 describes a method for preparing a biodegradable collagen-based matrix in sponge or sheet form, in which a collagen-based material is freeze-dried to form a collagen-based sponge, which is contacted with a cross-linking agent to form an intermediate collagen-based matrix, which is subsequently subjected to severe dehydration conditions to form a collagen-based matrix in sponge or sheet form.

[0005] US Patent No. 8,361,501 describes a substantially non-adhesive elastic gelatin matrix. The matrix is ​​non-adhesive to wounds, tissues and organs, and is also elastic so as to be flexible. The matrix is ​​a freeze-dried mixture of proteins, polymers, crosslinkers and optional plasticizers. A method for making the non-adhesive elastic gelatin matrix is ​​also described.

[0006] There is a need for alternative matrices and compositions to overcome or alleviate at least some of the shortcomings of the prior art, or to provide a useful alternative. Summary of the Invention

[0007] According to one aspect, a matrix comprising a biomolecule is provided, the matrix being a dry cross-linked foam.

[0008] In an embodiment, the matrix is ​​not lyophilized.

[0009] In an embodiment, the biomolecule is selected from the group consisting of gelatin, collagen, elastin, and combinations thereof.

[0010] In embodiments, the biomolecule is present at about 40% to about 80% (w / w).

[0011] In embodiments, the matrices described herein further comprise at least two layers.

[0012] In embodiments, each layer is independently homogeneous or non-homogeneous.

[0013] In embodiments, at least two layers are substantially identical in terms of biomolecule content and / or amount of crosslinking relative to adjacent foam layers.

[0014] In embodiments, at least two layers differ with respect to biomolecule content and / or amount of crosslinking relative to adjacent foam layers.

[0015] In embodiments, the matrix does not include a hardened and / or compressed "skin" on the surface of the matrix.

[0016] In embodiments, the matrices described herein further comprise at least one biocompatible polymer.

[0017] In embodiments, the biocompatible polymer is selected from the group consisting of polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose, and mixtures thereof.

[0018] In embodiments, the biocompatible polymer is present at about 0.4% to about 25% (w / w).

[0019] In an embodiment, the matrix has a pore size ranging from about 100 μm to about 750 μm.

[0020] In an embodiment, the matrix has an absorptive capacity of from about 20 to about 50 times the dry weight of the dried crosslinked foam matrix.

[0021] In an embodiment, the matrix has a thickness of at least 1 mm.

[0022] In an embodiment, the matrix further comprises an active agent.

[0023] In embodiments, the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

[0024] In embodiments, the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, active chlorine compounds, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

[0025] In an embodiment, the antimicrobial agent comprises silver ions.

[0026] In embodiments, the silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

[0027] In embodiments, the active agent is present at about 0.1%-30% (w / w).

[0028] In embodiments, the active agent is present in and / or on one of the at least two layers.

[0029] In embodiments, the active agent is present in and / or on both of the at least two layers.

[0030] In embodiments, the active agent, biomolecule and / or biocompatible polymer is uniformly distributed in and / or on both of the at least two layers.

[0031] In embodiments, the active agent, biomolecule and / or biocompatible polymer is non-uniformly distributed in and / or on both of the at least two layers.

[0032] In an embodiment, the matrix is ​​crosslinked using a crosslinking agent.

[0033] In an embodiment, the cross-linking agent is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), and mixtures thereof.

[0034] In an embodiment, the crosslinker is present at about 0.5% to about 5% (w / w).

[0035] In an embodiment, the matrix is ​​prepared as a coating.

[0036] In an embodiment, the covering is selected from the group consisting of a wound barrier, a wound dressing, a hemostatic dressing, a vascular wrap, a sponge, a gauze, a bandage, a film, a sheet, a tube, and combinations thereof.

[0037] In aspects, the matrix is ​​for use as a wound barrier, a wound dressing, a hemostatic dressing, a vascular wrap, a sponge, a gauze, a bandage, a film, a sheet, a tube, and combinations thereof.

[0038] In an embodiment, the matrix is ​​for use in delivering an active agent to a surface.

[0039] In an embodiment, the matrix is ​​for use in treating a wound.

[0040] According to another aspect, a composition for forming a foamed cross-linked non-lyophilized matrix is ​​provided, the composition comprising a biomolecule, the composition being foamable, and the biomolecule being cross-linkable.

[0041] In an aspect, the compositions described herein further comprise a pharma- ceutically acceptable excipient.

[0042] In embodiments, the pharma- ceutically acceptable excipient is selected from the group consisting of diluents, disintegrants, glidants, binders, lubricants, antioxidants, preservatives, colorants, flavoring agents, emulsifiers, suspending agents, pharmaceutical solvents, and combinations thereof.

[0043] In an embodiment, the biomolecule is selected from the group consisting of gelatin, collagen, elastin, and combinations thereof.

[0044] In embodiments, the biomolecule is present at about 40% to about 80% (w / w).

[0045] In aspects, the compositions described herein further comprise an active agent.

[0046] In embodiments, the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

[0047] In embodiments, the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, active chlorine compounds, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

[0048] In an embodiment, the antimicrobial agent comprises silver ions.

[0049] In embodiments, the silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

[0050] In embodiments, the active agent is present at about 0.1%-30% (w / w).

[0051] In an embodiment, the composition further comprises a crosslinker.

[0052] In an embodiment, the cross-linking agent is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), and mixtures thereof.

[0053] In an embodiment, the crosslinker is present at about 0.5% to about 5% (w / w).

[0054] In an embodiment, the composition further comprises at least one biocompatible polymer.

[0055] In embodiments, the biocompatible polymer is selected from the group consisting of polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose, and mixtures thereof.

[0056] In embodiments, the biocompatible polymer is present at about 0.4% to about 25% (w / w).

[0057] According to another aspect, there is provided a use of a matrix as described herein for reducing microbial growth on a surface.

[0058] In embodiments, the microorganism is selected from the group consisting of Candida albicans, Escherichia coli, and antibiotic-resistant Enterococcus.

[0059] In embodiments, the surface is skin or a medical device.

[0060] According to another aspect there is provided the use of a matrix as described herein as a wound dressing, bandage or sponge.

[0061] According to yet another aspect, there is provided a use of a composition as described herein to form a foamed cross-linked non-lyophilized matrix for reducing microbial growth on a surface.

[0062] In embodiments, the microorganism is selected from the group consisting of Candida albicans, Escherichia coli, and antibiotic-resistant Enterococcus.

[0063] In embodiments, the surface is skin or a medical device.

[0064] According to yet another aspect, there is provided a method of treating a wound comprising applying to the wound a matrix as described herein.

[0065] According to a further aspect, there is provided a use of the matrix described herein for treating a wound.

[0066] According to yet a further aspect, a method of making a matrix is ​​provided, the method comprising foaming a composition comprising a biomolecule, crosslinking the composition, and drying the composition.

[0067] In an aspect, the compositions described herein further comprise a pharma- ceutically acceptable excipient.

[0068] In embodiments, the pharma- ceutically acceptable excipient is selected from the group consisting of diluents, disintegrants, glidants, binders, lubricants, antioxidants, preservatives, colorants, flavoring agents, emulsifiers, suspending agents, pharmaceutical solvents, and combinations thereof.

[0069] In an embodiment, the biomolecule is selected from the group consisting of gelatin, elastin, collagen, and combinations thereof.

[0070] In an embodiment, crosslinking occurs after foaming.

[0071] In an embodiment, crosslinking is performed while foaming.

[0072] In an aspect, the cross-linking comprises adding a cross-linking agent.

[0073] In an embodiment, the cross-linking agent is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), and mixtures thereof.

[0074] In an embodiment, the addition is done dropwise.

[0075] In embodiments, the compositions described herein further comprise at least one biocompatible polymer.

[0076] In embodiments, the at least one biocompatible polymer is selected from the group consisting of polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose, and mixtures thereof.

[0077] In aspects, the compositions described herein further comprise an active agent.

[0078] In an embodiment, the activator does not substantially affect foaming.

[0079] In aspects, the methods described herein further comprise the step of depositing an active agent onto the matrix.

[0080] In embodiments, the active agent is in powder or concentrated liquid form.

[0081] In embodiments, the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

[0082] In embodiments, the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, active chlorine compounds, polyhexamethylene biguanide, copper, zinc, silver, chlorine, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

[0083] In an embodiment, the antimicrobial agent comprises silver ions.

[0084] In embodiments, the silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

[0085] In aspects, the methods described herein further comprise the step of heating the composition.

[0086] In an embodiment, the heating occurs prior to foaming.

[0087] In an embodiment, the heating is at about 50°C.

[0088] In aspects, the methods described herein further comprise cooling the composition.

[0089] In an embodiment, cooling occurs prior to foaming.

[0090] In an embodiment, cooling is performed to about 25°C to about 28°C.

[0091] In an embodiment, cooling is to about 26°C.

[0092] In an embodiment, the cooling is performed while continuously stirring the composition.

[0093] In aspects, the methods described herein further comprise the step of transferring the matrix to a tray or mold.

[0094] In an embodiment, the transfer occurs before drying.

[0095] In an embodiment, the tray or mold is lined with a hydrophobic film.

[0096] In an embodiment, the transferring step comprises spreading the matrix in a tray or mold.

[0097] In an embodiment, the drying step comprises air drying.

[0098] In embodiments, air drying is performed at ambient pressure and temperature.

[0099] In an embodiment, air drying is performed at about 40°C.

[0100] In an embodiment, drying ensures efficient air circulation around the matrix.

[0101] In an embodiment, drying is for up to 48 hours.

[0102] In an embodiment, the drying is not freeze-drying.

[0103] In embodiments, the matrix does not include a cured and / or compressed skin on a surface of the matrix.

[0104] According to yet another aspect, there is provided a wound dressing comprising the matrix described herein.

[0105] According to yet another aspect, there is provided a matrix produced by the methods described herein. Although overlapping with other descriptions, various aspects of the present invention are described below. However, the present invention is not limited to the following. [1] A matrix comprising biomolecules, the matrix being a dry crosslinked foam. [2] The matrix according to [1], wherein the matrix is ​​not freeze-dried. [3] The matrix according to [1] or [2], wherein the biomolecule is selected from the group consisting of gelatin, collagen, elastin, and combinations thereof. [4] The matrix according to any one of [1] to [3], wherein the biomolecule is present in an amount of about 40% to about 80% (w / w). [5] The matrix according to any one of [1] to [4], further comprising at least two layers. [6] 6. The matrix of claim 5, wherein the at least two layers are substantially identical in terms of the biomolecule content and / or amount of crosslinking relative to adjacent foam layers. [7] [5] The matrix of [5], wherein the at least two layers differ with respect to the biomolecule content and / or the amount of crosslinking relative to adjacent foam layers. [8] 13. The matrix according to any one of [1] to [7], wherein the matrix does not contain a hardened and / or compressed "skin" on the surface of the matrix. [9] The matrix according to any one of [1] to [8], further comprising at least one biocompatible polymer.

[10] The matrix according to [9], wherein the biocompatible polymer is selected from the group consisting of polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose, and mixtures thereof.

[11] The matrix according to [9] or

[10] , wherein the biocompatible polymer is present at about 0.4% to about 25% (w / w).

[12] The matrix according to any one of [1] to

[11] , having a pore size in the range of about 100 μm to about 750 μm.

[13] The matrix according to any one of [1] to

[12] , having an absorption capacity of about 20 to about 50 times the dry weight of the dried crosslinked foam matrix.

[14] 13. A matrix according to any one of claims 1 to 13, having a thickness of at least 1 mm.

[15] The matrix according to any one of [1] to

[14] , further comprising an active agent.

[16] 15. The matrix according to claim 14, wherein the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

[17] 16. The matrix of claim 15, wherein the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, active chlorine compounds, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

[18] The matrix according to

[16] or

[17] , wherein the antimicrobial agent comprises silver ions.

[19]

[18] The matrix according to

[18] , wherein the silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

[20] The matrix according to any one of

[15] to

[19] , wherein the active agent is present at about 0.1% to 30% (w / w).

[21] The matrix according to any one of

[15] to

[20] , wherein the active agent is present in and / or on one of the at least two layers.

[22] The matrix according to any one of

[15] to

[20] , wherein the active agent is present in and / or on both of the at least two layers.

[23] The matrix according to any of

[15] to

[22] , wherein the active agent, the biomolecule and / or the biocompatible polymer are uniformly distributed in and / or on both of the at least two layers.

[24] The matrix according to any of

[15] to

[22] , wherein the active agent, the biomolecule and / or the biocompatible polymer are distributed heterogeneously in and / or on both of the at least two layers.

[25] The matrix according to any one of [1] to

[24] , wherein the matrix is ​​crosslinked using a crosslinking agent.

[26] The matrix according to

[25] , wherein the cross-linking agent is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS) and mixtures thereof.

[27] The composition according to

[25] or

[26] , wherein the crosslinking agent is present at about 0.5% to about 5% (w / w).

[28] The matrix according to any one of [1] to

[27] , wherein the matrix is ​​produced as a coating.

[29] 28. The matrix according to claim 27, wherein the covering is selected from the group consisting of wound barriers, wound dressings, hemostatic dressings, vascular wraps, sponges, gauze, bandages, films, sheets, tubes and combinations thereof.

[30] 27. The matrix according to any of [1] to

[27] for use as a wound barrier, wound dressing, hemostatic dressing, vascular wrap, sponge, gauze, bandage, film, sheet, tube and combinations thereof.

[31] 27. A matrix according to any one of claims 1 to 27 for use in delivering an active agent to a surface.

[32] A matrix according to any one of [1] to

[27] for use in treating a wound.

[33] 1. A composition for forming a foamed cross-linked non-lyophilized matrix, said composition comprising a biomolecule, said composition being foamable, and said biomolecule being cross-linkable.

[34] The composition described in

[33] , further comprising a pharma- ceutically acceptable excipient.

[35] The composition of claim 34, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of diluents, disintegrants, glidants, binders, lubricants, antioxidants, preservatives, colorants, flavoring agents, emulsifiers, suspending agents, pharmaceutical solvents, and combinations thereof.

[36] The matrix according to any one of

[33] to

[35] , wherein the biomolecule is selected from the group consisting of gelatin, collagen, elastin, and combinations thereof.

[37] The matrix according to any one of

[33] to

[36] , wherein the biomolecule is present at about 40% to about 80% (w / w).

[38] The composition according to any one of

[33] to

[37] , further comprising an active agent.

[39] 38. The composition of claim 37, wherein the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

[40] The composition of

[39] , wherein the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, active chlorine compounds, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

[41] The composition described in

[39] or

[40] , wherein the antimicrobial agent comprises silver ions.

[42]

[41] The composition of claim 41, wherein the silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

[43] The composition according to any one of

[38] to

[31] , wherein the active agent is present at about 0.1% to 30% (w / w).

[44] The composition according to any one of

[33] to

[43] , further comprising a crosslinking agent.

[45] The composition according to

[44] , wherein the crosslinking agent is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), and mixtures thereof.

[46] The composition according to

[44] or

[45] , wherein the crosslinking agent is present at about 0.5% to about 5% (w / w).

[47] The composition described in any of

[33] to

[46] , further comprising at least one biocompatible polymer.

[48] The composition described in

[47] , wherein the biocompatible polymer is selected from the group consisting of polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose, and mixtures thereof.

[49] The composition according to

[47] or

[48] , wherein the biocompatible polymer is present at about 0.4% to about 25% (w / w).

[50] 20. Use of a matrix according to any of claims 1 to 27 for reducing microbial growth on a surface.

[51] The use according to

[50] , wherein the microorganism is selected from the group consisting of Candida albicans, Escherichia coli, and antibiotic-resistant Enterococcus.

[52] The use according to

[50] or

[51] , wherein the surface is skin or a medical device.

[53] 20. Use of a matrix according to any one of [1] to

[27] as a wound dressing, bandage or sponge.

[54] 2. Use of a composition according to any one of

[33] to

[49] for forming a foamed cross-linked non-lyophilized matrix for reducing microbial growth on a surface.

[55] The use according to

[54] , wherein the microorganism is selected from the group consisting of Candida albicans, Escherichia coli, and antibiotic-resistant Enterococcus.

[56] The use according to

[54] or

[55] , wherein the surface is skin or a medical device.

[57] A method of treating a wound comprising the step of applying a matrix according to any one of [1] to

[27] to the wound.

[58] 20. Use of a matrix according to any one of [1] to

[27] for treating a wound.

[59] 1. A method of making a matrix, comprising the steps of: foaming a composition comprising a biomolecule; crosslinking the composition; and The method comprises the step of drying the composition.

[60] The method according to

[59] , wherein the composition further comprises a pharma- ceutically acceptable excipient.

[61] 60. The method of claim 60, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of diluents, disintegrants, glidants, binders, lubricants, antioxidants, preservatives, colorants, flavoring agents, emulsifiers, suspending agents, pharmaceutical solvents, and combinations thereof.

[62] The method according to any of

[59] to

[61] , wherein the biological molecule is selected from the group consisting of gelatin, elastin, collagen, and combinations thereof.

[63] The method according to any one of

[59] to

[62] , wherein the crosslinking is carried out after foaming.

[64] The method according to any one of

[59] to

[62] , wherein the crosslinking is carried out while foaming.

[65] The method according to

[63] or

[64] , wherein the cross-linking comprises adding a cross-linking agent.

[66] The method according to

[65] , wherein the cross-linking agent is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS) and mixtures thereof.

[67] The method according to

[65] or

[66] , wherein the addition is carried out dropwise.

[68] The method according to any of

[59] to

[67] , wherein the composition further comprises at least one biocompatible polymer.

[69] 68. The method according to claim 68, wherein the at least one biocompatible polymer is selected from the group consisting of polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose, and mixtures thereof.

[70] The method according to any one of

[59] to

[69] , wherein the composition further comprises an active agent.

[71] 70. The method of claim 70, wherein the activator does not substantially affect the foaming.

[72] The method according to any of

[59] to

[69] , further comprising the step of depositing an active agent on the matrix.

[73] The method according to

[72] , wherein the active agent is in powder or concentrated liquid form.

[74] The method of any of

[70] to

[73] , wherein the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents and combinations thereof.

[75] 74. The method of claim 74, wherein the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, active chlorine compounds, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

[76] The matrix according to

[74] or

[75] , wherein the antimicrobial agent comprises silver ions.

[77] 8. The matrix according to

[76] , wherein the silver ions are derived from a silver salt selected from the group consisting of silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

[78] The method of any of

[59] to

[77] , further comprising the step of heating the composition.

[79] The method according to

[78] , wherein the heating is carried out before foaming.

[80] The method according to

[78] or

[79] , wherein the heating is carried out at about 50°C.

[81] The method of any of

[59] to

[80] , further comprising a step of cooling the composition.

[82]

[81] The method according to

[81] , wherein the cooling is carried out before foaming.

[83] The method according to

[81] or

[82] , wherein the cooling is performed at about 25°C to about 28°C.

[84] The method according to

[82] or

[83] , wherein the cooling is performed at about 26°C.

[85] The method according to any one of

[82] to

[84] , wherein the cooling is carried out while continuously stirring the composition.

[86] The method of any of

[59] to

[85] , further comprising the step of transferring the matrix to a tray or mold.

[87] The method according to

[86] , wherein the transferring is carried out before drying.

[88] The method of

[86] or

[87] , wherein the tray or mould is lined with a hydrophobic film.

[89] The method according to any of

[86] to

[88] , wherein the transferring step comprises a step of spreading the matrix in the tray or mold.

[90] The method of any of

[59] to

[89] , wherein the drying step comprises air drying.

[91] The method according to

[90] , wherein the air drying is carried out at ambient pressure and temperature.

[92] The method according to

[90] , wherein the air drying is carried out at about 40°C.

[93] The method according to any of

[90] to

[92] , wherein the drying ensures efficient air circulation around the matrix.

[94] The method according to any one of

[90] to

[93] , wherein the drying is for up to 48 hours.

[95] The method according to any one of

[59] to

[89] , wherein the drying is not freeze-drying.

[96] The method according to any of

[59] to

[95] , wherein the matrix does not contain a hardened and / or compressed skin on a surface of the matrix.

[97] A wound dressing material comprising a matrix according to any one of [1] to

[27] .

[98] Matrices prepared by the methods described in any of

[59] to

[97] .

[0106] Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from the said detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] Described herein, in embodiments, are matrices, compositions for forming matrices, and methods for forming matrices from the compositions. In embodiments, the methods described herein utilize foaming and air drying techniques that are easy to use and produce the matrices described herein without undesirable surface layers that must be removed by further processing techniques as further described below.

[0108] definition As used herein, a "foamed matrix" or "foam" is formed from a mass of small air bubbles formed on or in a liquid, typically by agitation. The process of "foaming" involves the generation of a mass of small air bubbles, similar to the formation of a foam. For example, a foam can be made by whipping a composition described herein, like whipping cream. A foam can also be made by bubbling air through a composition described herein.

[0109] As used herein, "bandage" means a piece of fabric or other material used to bind or encase diseased or damaged parts of the body. Bandages are placed directly against a wound or used to bind a wound dressing to a wound.

[0110] As used herein, "wound dressing," "hemostatic dressing," "vascular wrap," "sponge" or "gauze" means a piece of cloth or material that is placed directly against a wound to serve the purposes of protecting the wound, stopping or reducing bleeding, promoting healing, and / or providing, retaining or removing moisture, and is optionally held in place with a bandage.

[0111] As used herein, "active chlorine compounds" refers to compounds that contain active chlorine (chlorine with oxidizing properties similar to elemental chlorine). Such compounds usually contain chlorine atoms bonded to oxygen or nitrogen atoms. Compounds of this type are useful in industrial textile bleaching, as germicides, as components of bleaching, disinfecting and detergent compositions, and for other purposes. Active chlorine compounds include, but are not limited to, sodium and potassium dichloroisocyanurates, di- and trichlorocyanuric acid, trichloromelamine, chloramine T (sodium N-chloro-p-toluene-sulfonamide), dichlorodimethylhydantoin, sodium, calcium and lithium hypochlorite, and the like.

[0112] As used herein, the term "antineoplastic agent" refers to a chemotherapeutic agent that partially, substantially, or completely eliminates a tumor. Exemplary antineoplastic agents include nitrogen mustard, nitromine, chlorambucil, cyclophosphamide, melphalan, uracil mustard, mannomustine, dopan, BCNU, triethylenemelamine, thiotepa, azetepa, slenimone, improquon, busulfan, dimethylmylan, piposulfan, etoglucide, epoxypropidine, epoxypiperazine, hexamethylmelamine, dibromomannitol, pipobroman, CCNU, Alkylating agents such as methyl-CCNU, chlorozotocin, GANU, MCNU, ACNU, TA-077 and fosamide, folic acid, aminopterin, methotrexate, guanine, 8-azaguanine, 6-mercaptopurine, azathioprine, uracil, 5-fluorouracil, cytarabine, azaserine, diazamycin, BHAC, SM108, cisplatam, cytosine arabinoside, tegafur, HCFU, 5'DFUR, TK-117 and cyclotidine; antibiotics such as actinomycin D, cyclomycin, mitomycin C, daunomycin, bleomycin, chromomycin, carzinophilin, macrocinomycin, neothramycin, tallysomycin, sporamycin, saframycin, ansamitocin, DON, macromomycin, nogalomycin, 7-o-methylnogalol-4'-epidriamycin, streptozotocin, 4-demethoxydaunorubicin and mitoxantrone; synthetic agents such as 5-HP and IQ-1; thiotepa, cyclophosphamide, doxorubicin, daunorubicin, neocarzinosteine, and botanicals such as Hg-hematoporphyrin, Co-protoporphyrin, stilbestrol, hydroxyurea, procarbazine, methylglyoxal bis-guanylhydrazone, L-asparaginase and TNF.

[0113] As used herein, the term "antiproliferative drugs" refers to antimetabolites that act by inhibiting key metabolic processes and are commonly used to treat diseases involving abnormal cell proliferation, such as tumors. The above-mentioned antitumor drugs are also considered antiproliferative drugs in some cases.

[0114] As used herein, the term "analgesic" refers to a substance that has a pain relieving effect. Analgesic includes, but is not limited to, non-opioid analgesics such as acetaminophen acetylsalicylate, paracetamol, ibuprofen, ketoprofen, ketoconazole, indomethacin, diflunisole, naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefamanic acid, dextromethorphan, other nonsteroidal anti-inflammatory drugs including salicylates, their pharmaceutically acceptable salts and mixtures thereof, or opioid analgesics such as codeine, morphine, hydromorphine, levophanol, meperidine, meptazinol, propoxyphene, propiram, buprenorphine, pentazocine, nalbuphine, butorphanol, tramadol, hydrocodone, oxycodone, methadone, their pharmaceutically acceptable salts and mixtures thereof. Such pharma- ceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, phosphate, sulfate, acetate, succinate, ascorbate, tartrate, gluconate, benzoate, malate, fumarate, and the like.

[0115] As used herein, the term "anti-adhesion compound" refers to a compound (or polymer in film or liquid form) that can be used to prevent post-operative adhesion (e.g., scar) formation. Exemplary anti-adhesion compounds include, but are not limited to, polylactic acid, polyethylene glycol berberine solution (PEG), sodium hyaluronate, and chitosan.

[0116] As used herein, the term "chelating agent" refers to a substance that can capture or remove free ions or promote their removal from target tissue, thus impairing their catalytic activity and protecting skin.Exemplary chelating agents include, but are not limited to, desferrioxamine, diethylenetriaminepentaacetic acid, N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid, 1,2-dimethyl-3-hydroxypyridin-4-one and 1,2-dimethyl-3-hydroxyl-3-hydroxypyridin-4-one.

[0117] As used herein, the term "antimicrobial agent" refers to any agent capable of partially, substantially, or completely eliminating a microorganism. Examples of antimicrobial agents include the antibacterial agents, antiviral agents, antifungal agents, and innate immune peptides or proteins described herein.

[0118] As used herein, the term "pharmaceutical acceptable" means that a compound or combination of compounds is compatible with the other ingredients of a formulation or composition for pharmaceutical use and is generally safe for administration to humans according to established government standards, including those promulgated by the U.S. Food and Drug Administration.

[0119] As used herein, the term "excipient" refers to a non-active ingredient that can be added to a composition or matrix described herein. Examples of excipients will be understood by those of skill in the art, and some examples are provided in the description below.

[0120] As used herein, the term "air drying" encompasses any drying method carried out above freezing temperatures. For example, the matrices described herein are dried at ambient temperature and pressure after a wet foam is created. Drying in this manner may or may not be carried out under vacuum to remove trace solvents (e.g., if the matrix is ​​dried at room temperature, the sample may be dried in a vacuum desiccator, or if the matrix is ​​dried above room temperature, the matrix may be dried in a vacuum drying oven).

[0121] The term "lyophilization" encompasses the removal of water droplets from a matrix after it has been frozen and placed under vacuum (leaving holes in the matrix), thereby allowing the ice to change directly from a solid to a vapor under low temperature and pressure without passing through a liquid phase. In this way, the product (e.g., matrix) is never exposed to temperatures above freezing during the drying process. Lyophilization and freeze-drying are used interchangeably herein.

[0122] Matrices produced by these two different processes (air-drying and freeze-drying) tend to have different structural properties, and therefore are not necessarily the same product. For example, air-dried products tend to be more compact and durable (e.g., resistant to collapse), whereas freeze-dried products tend to be less compact and more fragile (e.g., easily crushed). Despite this, the air-dried matrices described herein perform at least as well as freeze-dried products, as exemplified herein. Thus, the methods described herein can produce durable foam matrices (e.g., sponges) suitable as compact wound dressings.

[0123] In understanding the scope of this application, the articles "a," "an," "the," and "said" are intended to mean that there are one or more elements. Furthermore, as used herein, the term "comprises" and its derivatives are intended to be open-ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. The above also applies to words having similar meanings, such as the terms "comprises," "having," and their derivatives.

[0124] Any embodiment described as "comprising" a particular component can also be "consist of" or "consist essentially of" (or vice versa), with "consisting of" having a limited or restrictive meaning and "consisting essentially of" being understood to mean including the specified component, but excluding other components, except for materials present as impurities, unavoidable materials present as a result of the process used to provide the component, and components added for purposes other than achieving the technical effect described herein. For example, a composition defined using the phrase "consisting essentially of" encompasses any known pharma- ceutically acceptable additives, excipients, diluents, carriers, and the like. Typically, a composition consisting essentially of a set of components contains less than 5% by weight, typically less than 3% by weight, and more typically less than 1% by weight of an unspecified component.

[0125] It will be understood that any component defined as included herein may be expressly excluded by a condition or negative limitation, such as any particular compound or method step, whether implicitly or explicitly defined herein. For example, in aspects, methods involving lyophilization are expressly excluded from the methods described herein. Similarly, in aspects, the matrices described herein are not lyophilized.

[0126] Moreover, all ranges given herein include the range endpoints and any intermediate range points, whether or not expressly stated.

[0127] Finally, terms of degree, such as "substantially," "about," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified term such that the end result is not significantly altered. These terms of degree should be construed to include a deviation of at least ±5% of the modified term if this deviation does not negate the meaning of the word it modifies.

[0128] matrix Described herein are matrices that include biomolecules, which are dry cross-linked foams. Advantageously, the matrices described herein do not require lyophilization. Rather, they can simply be air-dried, for example, under ambient conditions.

[0129] The biomolecules may be dry components that are biocompatible and can be crosslinked to form a three-dimensional matrix. The biomolecules are typically biodegradable and, once formed into a matrix, can absorb fluids. In embodiments, the absorption of fluids reaches several times the weight of the matrices described herein. In typical embodiments, the biomolecule is selected from gelatin, collagen, elastin, and combinations thereof. Typically, the biomolecule is gelatin.

[0130] The matrices described herein may be formed as a single layer or multiple layers. When the matrix comprises multiple layers, the layers may be bonded together to form an integral composite.

[0131] In an embodiment, the matrix comprises at least two layers.In an embodiment, the at least two layers can be substantially identical in terms of biomolecule content and / or crosslinking amount with respect to adjacent foam layers.For example, when the matrix has two layers, both layers have a similar amount (e.g., concentration) of biomolecule, or both layers have a similar degree of crosslinking.

[0132] In an embodiment, the biomolecule content and / or crosslinking amount for adjacent foam layers are different.For example, if the matrix has two layers, one layer can have a higher proportion (e.g., concentration) of biomolecule than the second layer.Similarly, one layer can have an increased degree of crosslinking compared to the other layer.

[0133] It will be appreciated that the amount and / or degree of crosslinking of the biomolecules of the layers of the matrix can be varied, for example, by increasing the amount of the biomolecules and / or crosslinking agents when forming the layers of the matrix. In this way, each layer or a single layer of the matrices described herein can have different physicochemical properties. For example, differences in the degree of crosslinking or concentration of the biomolecules within a layer of the matrix can affect the absorption properties of the matrices described herein. For example, the absorption capacity of the matrix (e.g., the amount of fluid that can be retained by the matrix when applied to the skin) can be increased by increasing the amount of biomolecules in a layer of the matrix, particularly the layer closest to the skin. Additionally or alternatively, the degree of crosslinking of the biomolecules described herein can affect the tensile strength or elongation properties of the matrix, thereby affecting its effectiveness as a wound dressing. Thus, these factors can be taken into consideration when manufacturing the matrix by the methods described herein.

[0134] When a conventional composition is freeze-dried to make a matrix, it is typically a liquid composition that is poured into a mold and then freeze-dried. This liquid may have a tendency to form a hardened or compressed skin on the surface as it dries. Because the compositions and matrices described herein are foamed and not in liquid form, they do not tend to form a similar skin as they dry. Thus, in an embodiment, the matrices described herein do not include a hardened and / or compressed "skin" on the surface of the matrix. This "skin" is similar to a film that can form on the surface of the matrix. Typically, the surface is the surface that contacts the drying equipment during the air drying process described herein (i.e., the drying vessel contact surface). Because the matrices made by the methods described herein do not include this "skin", the matrices described herein do not require further processing to remove the "skin", which is typical of other matrices.

[0135] In an embodiment, the matrix described herein further comprises at least one biocompatible polymer.Typically, the biocompatible polymer is selected from, but not limited to, polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose and mixtures thereof.Typically, the biocompatible polymer is alginic acid or carboxymethylcellulose.

[0136] The matrices described herein are porous. In an embodiment, the matrices described herein have a pore size ranging from about 100 μm to about 750 μm. The pore size can be 90 μm, 95 μm, 100 μm, 110 μm, 150 μm, 175 μm, 200 μm, 250 μm, 300 μm, 400 μm, 450 μm, 500 μm, 600 μm, 650 μm, 700 μm, 750 μm, or 800 μm (or any value therebetween).

[0137] Typically, the matrices described herein are absorbent. In embodiments, the matrices described herein have an absorption capacity of about 20 times to about 50 times the dry weight of the matrix formed by the methods described herein. For example, the absorption capacity can be 15, 20, 25, 30, 35, 40, 45, 50, or 55 times the dry weight of the matrix formed by the methods described herein. This absorption capacity contributes to the ability of the matrices described herein to function, for example, as wound dressings and / or hemostatic dressings.

[0138] In a typical embodiment, the matrix described herein has a thickness of at least 1 mm. It is understood that the thickness of the matrix can be changed, for example, by adjusting the amount of foam injected into the mold or by increasing the number of layers. Changing the thickness of the matrix can be appropriate, for example, to increase the volume of the matrix to the extent that it can be filled with fluid (e.g., blood or wound exudate) or fluid can be absorbed by the matrix.

[0139] The matrices described herein are dried by any known method. Typically, the drying method excludes freeze-drying. In typical embodiments, the matrices are air-dried, for example, under ambient conditions. For example, the matrices can be dried at room temperature and pressure. This is a simple and inexpensive method for drying the matrices, and no specialized equipment is required. In embodiments, a ventilation device is used to ensure efficient air circulation around the matrix (e.g., no wet spots remain around the matrix as it dries). In this way, the foamed matrices produced by the methods described herein are no longer wet foams and can absorb fluids when placed in contact. As mentioned above, the air-drying technique used to produce the matrices described herein advantageously simplifies the methods described herein for producing the matrices, but also eliminates the creation of a hardened or compressed skin on the surface of the matrix.

[0140] In aspects, the matrices described herein further comprise an active agent, including, but not limited to, antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

[0141] The active agent, in embodiments, is an antimicrobial agent, including one or more antimicrobial agents, and / or one or more antifungal agents, and / or one or more antiviral agents, and / or one or more preservatives, and / or combinations thereof.

[0142] In a typical embodiment, the antimicrobial agent is an antibacterial agent. Any antibacterial agent described herein can be used in the compositions described herein, but some non-limiting exemplary antibacterial agents include those classified as aminoglycosides, beta-lactams, quinolones or fluoroquinolones, macrolides, sulfonamides, sulfamethoxozole, tetracyclines, streptogramins, oxazolidinones (such as linezolid), clindamycin, lincomycin, rifamycin, glycopeptides, polymaxines, lipopeptide antibiotics, metal salts, and pharmacologically acceptable sodium salts, pharmacologically acceptable calcium salts, pharmacologically acceptable potassium salts, lipid formulations, derivatives and / or analogs of the above.

[0143] In other embodiments, the antimicrobial agent comprises an antifungal agent. Some exemplary classes of antifungal agents include imidazoles or triazoles such as clotrimazole, miconazole, ketoconazole, econazole, butoconazole, omoconazole, oxiconazole, terconazole, itraconazole, fluconazole, voriconazole (UK 109,496), posaconazole, ravuconazole or flutrimazole, polyene antifungals such as amphotericin B, liposomal amphotericin B, natamycin, nystatin and nystatin lipid formulations, cell wall active cyclic lipopeptide antifungals including echinocandins such as caspofungin, micafungin, anidolfungin, cilofungin, and the arylamine group of antifungals such as LY121019, LY303366, terbinafine. Further non-limiting examples of antifungal agents include naftifine, tolnaftate, mediocidin, candicidin, trichomycin, hamycin, aurefungin, ascosin, ifatin, azacortin, trichomycin, levorin, heptamycin, candimycin, griseofulvin, BF-796, MTCH24, BTG-137586, pradimicin (MNS18184), benamycin, ambisome, nikkamycin Z, flucytosine, or perimycin.

[0144] In yet other embodiments, the antimicrobial agent comprises an antiviral agent, non-limiting examples of which include cidofovir, amantadine, rimantadine, acyclovir, ganciclovir, penciclovir, famciclovir, foscarnet, ribavirin, or valciclovir.

[0145] In some embodiments, the antimicrobial agent is an innate immune peptide or protein. Some exemplary classes of innate peptides or proteins are transferrin, lactoferrin, defensins, phospholipases, lysozymes, cathelicidins, serprocidins, bactericidal permeability-increasing proteins, amphipathic alpha-helical peptides, and other synthetic antimicrobial amino acids, peptides, or proteins.

[0146] When the active agent is an antimicrobial agent, the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, active chlorine compounds such as, but not limited to, sodium hypochlorite, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

[0147] In typical embodiments, the antimicrobial agent comprises silver ions, hi embodiments, the silver ions are derived from silver salts, such as, but not limited to, silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

[0148] When the matrices described herein include more than one layer, the one or more active agents can be present in and / or on any one or more of the layers. In a similar embodiment, when the matrices described herein include more than one layer, the one or more active agents can be present in and / or on all of the layers.

[0149] In further embodiments, when the matrix described herein comprises two or more layers, the active agent described herein, the biomolecule described herein and / or the biocompatible polymer described herein are typically uniformly distributed in and / or on some or all of the layers. By "uniform" distribution is meant that the layers have a uniform composition (i.e., no portion of a layer has a substantially higher concentration or proportion of the biomolecule, the active agent and / or the biocompatible polymer than another portion of the same and / or adjacent layer). For example, when the matrix comprises two layers, the concentration of the biomolecule may be uniformly distributed in a single layer or may be uniformly distributed in both layers. In this way, there are no "pockets" of space or portions of the first layer with an increased amount (e.g., concentration) of the biomolecule compared to another portion of the first layer or, for example, compared to the second layer.

[0150] In further embodiments, the biomolecules described herein and / or the biocompatible polymers described herein are distributed non-uniformly in and / or on some or all of the layers. By "non-uniform" distribution, it is meant that one or more layers have at least a portion of the layer that has a different (e.g., increased or decreased) concentration or proportion of the biomolecules, active agents and / or biocompatible polymers described herein compared to a different layer and / or another portion of the same layer. For example, if the matrix includes two layers, the biocompatible polymer may have an increased proportion (e.g., concentration) in one portion of the first layer compared to another portion of the first layer, or compared to, for example, a portion or the entirety of the second layer. In this way, a portion of the first layer or the entirety of the first layer may have a different biomolecule concentration, for example, than a portion or the entirety of the second layer. Varying the amount of biomolecules within a layer may be advantageous, for example, to create a highly crosslinked matrix layer with increased absorbency, for contact with a wound.

[0151] It is understood that a "uniform" or "non-uniform" distribution of biomolecules and / or biocompatible polymers can be varied, for example, by having the same amount of biomolecules and / or biocompatible polymers in each layer, or, for example, by increasing or decreasing the amount of biomolecules and / or biocompatible polymers in one layer compared to another layer.

[0152] Although two layers have been described, it is understood that a single layer foam matrix or a foam matrix having more than two layers is within the scope of the present invention.

[0153] Furthermore, when the matrices described herein are layered, temporal and / or spatial separation of the therapeutic effect can be achieved. For example, when the matrix has two layers of foam and the active agent is disposed in and / or on the layer of the matrix furthest from the skin, the active agent is temporally and spatially separated from the skin so as to delay the contact time between the active agent and the skin. Conversely, when the active agent is disposed in the skin-contacting foam layer, the contact time between the active agent and the skin is reduced (especially when the active agent is disposed on the surface of the layer and thus in direct contact with the skin). It is also contemplated that when the matrices described herein include layers, the variety of therapeutic agents that can be included in the matrices described herein can be greatly increased. For example, different active agents having different concentrations can be disposed in and / or on different layers. As long as the active agent does not interfere with the foaming and / or stability of the matrices described herein, it is considered that the active agent is within the scope of the invention described herein.

[0154] The matrices described herein are crosslinked. The matrices are crosslinked using a crosslinking agent. Typically, the crosslinking agent is a fast crosslinking agent.

[0155] In an exemplary embodiment, the cross-linking agent is selected from, but is not limited to, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), and mixtures thereof.

[0156] In certain aspects, the matrices described herein are manufactured as coatings, which can be, but are not limited to, wound barriers, wound dressings, hemostatic dressings, vascular wraps, sponges, gauze, bandages, films, sheets, tubes, and combinations thereof.

[0157] The matrices described herein are crosslinked, absorbent sponges, and when produced by the methods described herein, lack the presence of undesirable surface characteristics (e.g., the aforementioned "skin") that are known to affect air-dried gelatin sponge materials. Furthermore, the porosity of the matrices described herein allows them to absorb many times their weight in fluid, while at the same time remaining stable under physiological conditions.

[0158] composition The matrix may be formed from a composition as described herein, the composition including a biomolecule as described above, the biomolecule being crosslinkable, and the composition being foamable according to the instructions provided herein.

[0159] The composition comprises at least one biodegradable biomolecule. In an exemplary embodiment, the biomolecule is gelatin.

[0160] It will be understood that the biomolecule may be present in any amount in the matrices and / or compositions described herein, typically from about 40% to about 80% (by weight), such as from about 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% to about 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% (by weight).

[0161] In an embodiment, the composition further comprises a biocompatible polymer as described herein. In an exemplary embodiment, the biocompatible polymer is alginate or carboxymethylcellulose.

[0162] It will be understood that the biocompatible polymer can be present in the matrices and / or compositions described herein in any amount, typically from about 0.4% to about 25% (by weight), such as from about 0.4%, 1%, 5%, 10%, 15% or 20% to about 1%, 5%, 10%, 15%, 20% or 25% (by weight).

[0163] In certain embodiments, the composition may include excipients, as will be understood by those skilled in the art.Non-limiting examples of such excipients include diluents, disintegrants, glidants, binders, lubricants, antioxidants, preservatives, coloring and flavoring agents, emulsifiers and suspending agents, and pharmaceutical solvents.The use of excipients is understood by those skilled in the art, and an exemplary list of such excipients can be found, for example, in Osol et al., Remington's Pharmaceutical Sciences (16th Edition), 1980, 1225-1267 and 1367, and Liberman et al., Pharmaceutical Dosage Forms: Tablets (Vol. 1), 1989, ISBN: 0-8247-8044-2, both of which are incorporated herein by reference.

[0164] It will be appreciated that the excipients may be present in the composition in any amount, typically from 1% to 50% (by weight), for example from about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% (by weight).

[0165] If an additional therapeutic effect is desired, for example, in addition to providing a matrix that acts as a hemostatic agent (e.g., wound dressing) to stop, restrict, block, prevent or impede blood flow from a wound, the composition may further include an active agent that contributes to the above-mentioned control of blood flow, or provides soothing, for example, to relieve pain associated with a wound. In a typical embodiment, when the composition further includes an active agent as described herein, the active agent is integral with the foam matrix (e.g., in and / or on the foam layer). It will be understood that when the foam is made using the composition described herein, if it is desired that the active agent is on the surface of the foam made by the method described below, the active agent can be applied to the dried foam by brushing a liquid concentrate of the active agent on the surface of the foam or by spreading a powder form of the active agent on the surface of the foam. Alternatively and / or additionally, the active agent can be spread on a tray or mold used to dry the foam, and the surface of the foam comes into contact with the active agent when the foam is spread on the tray or mold. Thus, when the matrix is ​​applied to a wound as a wound dressing, the active agent is in direct contact with the skin surface or wound to provide an additional therapeutic benefit (eg, in addition to the matrix providing a hemostatic function).

[0166] It will be understood that the active agent may be present in the matrices and / or compositions described herein in any amount, typically from about 0.1% to about 30% (by weight), such as from about 0.1%, 1%, 5%, 10%, 15%, 20%, or 25% to about 1%, 5%, 10%, 15%, 20%, 25%, or 30% (by weight).

[0167] In alternative or additional aspects, the compositions described herein further comprise a cross-linking agent as described herein. The matrices and / or compositions described herein are substantially free of cross-linking agents, which advantageously contribute to a lower toxicity profile of the matrices and / or compositions.

[0168] It will be understood that the crosslinker can be present in the matrices and / or compositions described herein in any amount, typically from about 0.5% to about 5% (by weight), for example, from about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, or 4.5% to about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, or 4.5%, or 5% (by weight).

[0169] The compositions described herein are useful for making the dried crosslinked foam matrices described herein.

[0170] Methods for preparing matrices and uses thereof Described herein is a method of forming the matrices described herein, the method comprising foaming a composition comprising the biomolecules described above, crosslinking the composition, and drying the composition.

[0171] The method utilizes foaming and crosslinking steps. Typically, crosslinking occurs during foaming. In embodiments, crosslinking occurs after foaming.

[0172] In an embodiment, the biomolecule is selected from gelatin, collagen, elastin, and combinations thereof. Typically, the biomolecule is gelatin. To create a solution of the biomolecule, in an embodiment, the water is stirred to create a small vortex into which the biomolecule is added. Typically, the biomolecule is added slowly to allow for uniform dispersion in the water. In an embodiment, the solution is heated with continuous stirring until the biomolecule is completely dissolved. In an embodiment, the heating is performed at a temperature of about 50°C. That is, the temperature is 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, or 55°C.

[0173] The solution may be a combination of a biomolecule and a biocompatible polymer. Thus, in an embodiment, the composition further comprises a biocompatible polymer as described herein. In a typical embodiment, the biocompatible polymer is alginic acid or carboxymethylcellulose. When the composition comprises both a biomolecule and a biocompatible polymer, a solution of the biocompatible polymer (e.g., alginic acid) is similarly prepared, for example, by swirling water to create a small vortex and adding the biocompatible polymer or a salt thereof (e.g., sodium alginate) to the water. In an embodiment, the biocompatible polymer or a salt thereof is added slowly to minimize clumping.

[0174] Typically, the solution is heated with continuous stirring until the biocompatible polymer is completely dissolved. In an embodiment, the heating is performed at a temperature of about 50° C., i.e., the temperature is 45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C. or 55° C. In this way, a solution of biomolecules or a biocompatible solution is created.

[0175] If an antimicrobial foam is desired, in embodiments, an active agent such as silver (in the form of a salt, e.g., silver lactate) is added to water and stirred to form a homogenous mixture. The silver lactate solution is then added to the biomolecule solution, and the solution is heated to about 60° C. with continuous stirring to ensure that the biomolecule has completely dissolved. At this point, another salt (such as sodium chloride) is added to initiate the formation of silver chloride in the solution.

[0176] Heating the solutions described herein ensures the creation of homogenous solutions of biomolecules or biocompatible polymers.

[0177] If a combination of a biomolecule solution and a biocompatible polymer solution is desired, the biocompatible polymer solution (e.g., alginate) is added to the biomolecule solution (e.g., gelatin) after heating each solution. Typically, this addition is done slowly to ensure thorough mixing. For example, a homogenous mixture (solution) of biomolecule and biocompatible polymer is produced.

[0178] If only biomolecule solution is desired, after heating, a crosslinker as described herein is added to the solution. Typically, the crosslinker is a fast crosslinker. Typically, the crosslinker is EDC and / or NHS. In an embodiment, a combination of crosslinkers can be prepared and added to the biomolecule or biomolecule-biocompatible polymer solution as described herein. In an embodiment, the solution is stirred until the crosslinker is completely dissolved in the biomolecule solution. For example, a homogeneous mixture of crosslinker and biomolecule is created.

[0179] When preparing a biomolecule and biocompatible polymer solution (e.g., alginate or carboxymethylcellulose) by adding a biocompatible polymer solution to a biomolecule solution, in an embodiment, the temperature of the solution is adjusted to about 30°C to about 40°C.

[0180] In embodiments, additional agents are added to the biomolecule biocompatible polymer solution, such as, but not limited to, a chelating agent (e.g., EDTA) or a lipid (e.g., glycerol). One of skill in the art will appreciate that different additional agents may be added to the solution, for example, to aid in the dissolution of the components of the solution.

[0181] In a typical embodiment, a separate cross-linking agent (e.g., NHS or EDC, depending on which was not used as described above) is prepared prior to addition to the above solution (e.g., gelatin solution or gelatin-alginate solution).

[0182] Typically, the temperature of the biomolecule biocompatible polymer solution is cooled to about 25°C to about 28°C to initiate the foaming process. In embodiments, the solution is cooled to 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C. Reducing the temperature of the mixture is advantageous to ensure chemical activity of the crosslinking agents (e.g., EDC and NHS) as well as provide a suitable viscosity for foaming as described herein. Typically, cooling is performed with continuous stirring to generate a foaming solution. After cooling, the foaming solution is transferred to a bowl in a stand mixer for foaming. In embodiments, the solution is mixed or foamed at maximum speed for about 4 minutes. In embodiments, the mixing time is 3 minutes, 4 minutes, or 5 minutes. In a typical embodiment, the mixing speed is 495 RPM. Typically, other crosslinking agents are added to the foaming solution while mixing is taking place. For example, the addition of the crosslinking agent is performed in combination with foaming. In embodiments, the addition of the crosslinking agent is performed slowly within a period of time. In embodiments, the period is about 30 seconds. In embodiments, the period is 20 seconds, 25 seconds, 30 seconds, or 35 seconds (or any value therebetween).

[0183] The addition of the crosslinker can be done in any manner. For example, the crosslinker can be prepared as a separate solution and added completely during the foaming process. For example, the crosslinker can be prepared as a separate solution and added (completely) to the above solution of biomolecules and biocompatible polymers after the foaming process. Typically, the addition of the other crosslinker is done in a drop-wise manner (e.g., by using a serological pipette) so that all of the solution is dispensed within a short period of time. The drop-wise addition of the other crosslinker allows the other crosslinker to be evenly distributed within the solution of biomolecules and biocompatible polymers during the foaming process. For example, the dissolution time of the other crosslinker is faster because there is less volume of the other crosslinker per unit time that mixes with the total volume of the solution being added. In an embodiment, the short period is about 30 seconds. In an embodiment, the period is 20 seconds, 25 seconds, 30 seconds, or 35 seconds (or any value therebetween).

[0184] Typically, once all of the other crosslinkers (e.g., NHS or EDC) have been mixed into the foaming solution, the foaming solution is continuously mixed for another period of time. The continuous mixing aids in the foaming process and increases (expands) the volume of the foam as described below. Typically, this period is about 10 seconds. In embodiments, the period is 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11 seconds, or 12 seconds.

[0185] In embodiments, mixing is continued until a foam volume increases. In other words, mixing is continued until a foam is formed with a total volume expansion of about 3 times to about 10 times the initial solution volume. In embodiments, the volume increase is about 2 L. In embodiments, the volume increase is 1 L, 1.5 L, 2 L, or 2.5 L (or any value therebetween). In embodiments, the foam volume increase occurs in about 5 minutes.

[0186] After the foam is made, it is removed from the bowl and dispensed and spread on a tray or mold. In an embodiment, the tray or mold has a pre-applied layer of the activator described herein. For example, the activator described herein may be spread on the surface of the tray or mold such that when the foam is placed on the surface of the tray or mold and thus in contact with the activator, the activator may be laminated on the surface of the matrix that contacts the tray or mold. It is believed that this lamination process may be uniform or non-uniform, depending, for example, on the spread of the activator on the surface of the tray or mold, the adhesive properties of the surface of the matrix that contacts the activator, and / or the length of time that the matrix remains in contact with the surface of the tray or mold.

[0187] In an embodiment, the tray or mold is lined with a hydrophobic film, for example to provide a non-stick surface on the tray or mold for application of the foams described herein.

[0188] The time for removing the foam from the bowl and spreading it in the tray or mold can vary, for example, the foam can be removed and spread within 10 seconds of the foam's formation, or the foam can be removed and spread within 60 seconds of the foam's formation. In embodiments, the foam is removed from the bowl in less than 15 seconds. In embodiments, the foam is spread in 60 seconds or less. Once the foam is spread on the tray or mold, it is dried. In typical embodiments, the foam is air dried so that moisture is removed from the foam. Typically, the foam is then allowed to dry for a period of time. In embodiments, the period is up to 48 hours. In embodiments, the period is 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 16 hours, 20 hours, 30 hours, 40 hours, or 48 hours (or any period in between).

[0189] As mentioned above, the matrices described herein are not freeze-dried, but are instead air-dried. Typically, air-drying is performed at ambient pressure and temperature (e.g., 25C (298.15K) and 101.325kPa pressure), although other temperatures are considered within the scope of the present invention, as described below. In a typical embodiment, drying is performed using a ventilation device to ensure efficient air circulation around the foam. By providing efficient air circulation around the foam, the drying process can ensure that there are no "wet spots" on the foam. Typically, the foams made by the drying methods described herein are not wet foams. In an embodiment, the foam has substantially no moisture, such that the foam is substantially dry (e.g., at least about 90% dry).

[0190] Once the foam is dry, the dried sponge (e.g., gelatin sponge or gelatin-alginate sponge) is removed from the tray and cut to the desired size. The size of the sponge will depend on the needs of the user. It will be appreciated that the size and / or shape of the sponge can be varied, for example, by cutting the sponge to size or shape, by changing the shape or size of the tray or mold, or by varying the amount of foam applied to the tray or mold.

[0191] In typical embodiments, drying and cutting is performed at a temperature of about 40° C. or less and a relative humidity of about 35%. In embodiments, the temperature is about 20° C., about 25° C., about 30° C., about 35° C., or about 40° C. (or any value therebetween). In embodiments, the relative humidity is about 33%, about 34%, about 35%, about 36% or about 37%. One of skill in the art will understand how to cut a sponge produced by the methods described herein.

[0192] Additionally, the compositions used to make the matrices described herein according to the methods described herein may also include an activator as described herein. Typically, the activator does not substantially affect the foaming as described herein. In an embodiment, instead of a composition including an activator as described herein, an activator as described herein may be layered onto the foam produced by the methods described herein (e.g., an activator as described herein is layered onto the top layer of the foam). As also described herein, the activator may be applied to the surface of a tray or mold, and when the foam is applied (e.g., spread) onto the tray or mold, the activator may adhere to the surface of the foam and / or pores. In an embodiment, the activator is in powder or concentrated liquid form. For example, a pre-applied layer of powdered activator may be applied to the tray or mold, whereby contact between the foam and the tray or mold results in the powdered activator on the surface of the foam. Alternatively, an activator in liquid form may be applied to the dried foam after or subsequent to removal of the dried foam from the tray or mold. It is understood that the addition of the activator can be varied as described above so long as the activator does not substantially affect the foaming described herein and / or the stability of the foam so produced.

[0193] The foam produced by the methods described herein may consist of a single layer (e.g., the methods described herein may be performed and the resulting dried foam may be used as a wound dressing), or the foam may include two or more layers. If the foam includes multiple layers (e.g., at least two layers), the methods described herein may be repeated and each layer bonded to each other to form an integral composite. In an embodiment, the foam produced by the methods described herein includes at least two layers. In an embodiment, the active agent may be layered on or in at least one of the at least two layers. For example, layering the active agent onto a layer (i.e., single or multiple) may be performed by applying the active agent directly onto the surface of the foam, or, for example, by applying the active agent onto a tray or mold and contacting the foam during spreading. Alternatively or additionally, the active agent may be placed into a composition described herein, such that the active agent is a component of the interior portion of the foam layer. These examples may advantageously allow for temporal and / or spatial separation of potential therapeutic effects and may broaden the variety of active agents that may be used with the invention described herein. For example, if one active agent is placed on the surface of the foam that contacts the skin and another (e.g., the same or a different active agent) is placed within the foam layer, the active agent closest to the skin will have an immediate or rapid therapeutic effect, while the active agent in the foam layer will be temporally controlled (e.g., the active agent permeates through the porous foam) to provide a benefit to the user at a later time.

[0194] The above methods may be fully manual, fully automated, or partially automated.

[0195] The advantage of the methods described herein for making the matrices described herein is that the methods described herein allow for almost instantaneous crosslinking of the foamed (e.g., gelatin) solution followed by an air-drying process, typically carried out at ambient pressure and temperature, without forming a hardened and / or compressed "skin" or film-like material on the surface of the sponge in contact with the drying container. Thus, further processing of the matrices described herein to remove the presence of undesirable surface layers (e.g., the aforementioned "skin") is avoided. Furthermore, since the methods described herein do not require freeze-drying, the need for large and expensive equipment to obtain a porous matrix by freeze-drying is also avoided. In this way, the procedure for making the foam matrices of the present invention is greatly simplified, producing a product without physical anomalies such as the hardened or compressed skins described herein.

[0196] Further, methods and uses of the compositions and matrices are described herein. As described herein, the matrices and compositions for making the matrices described herein can be used to reduce microbial growth on a surface (see also Examples 3 and 5). In this regard, the above solution of biomolecules and biocompatible polymers further comprises an active agent, for example, silver. As described herein, the active agent) may be included on the surface of the foam layer or may be an integral part of the foam layer. In an embodiment, the microorganism is selected from, but is not limited to, Candida albicans, Escherichia coli, and antibiotic-resistant Enterococcus.

[0197] To use the sponge made by the method described herein for antimicrobial activity, the sponge is applied (e.g., placed and adhered) to a surface. The surface is suspected to have one or more microorganisms or has been confirmed to have one or more microorganisms. The application, e.g., placing or adhering, of the sponge to a surface is a method of controlling the growth and / or spread of one or more microorganisms. In an embodiment, the surface is a skin surface. In an embodiment, the surface is an inanimate surface such as, but not limited to, a table, chair, or countertop. In an embodiment, the surface is a surface of a medical device. In this manner, the matrix described herein can be used to clean (e.g., sterilize) medical devices and other inanimate objects.

[0198] A medical device is typically a device for use inside or outside a wound, for example. Thus, in certain embodiments, the medical device is selected from the group consisting of a dressing, a scaffold, a fracture fixation device, a catheter, a stent, an implant, tubing, a rod, a prosthesis, an endoscope, a heart valve, a pacemaker, a dental implant, and a surgical, medical or dental instrument.

[0199] In an embodiment, the matrix described herein is used as a wound dressing, bandage, or sponge. Typically, the matrix is ​​an effective hemostatic agent useful for treating a wound or injury. Typically, the wound or injury is to a skin surface. Also described herein is a method of treating a wound or injury, which includes applying a matrix described herein to a wound or injury site. The application can be, for example, placing the matrix on the skin or wound (e.g., covering the skin or wound with the matrix), inserting the matrix into the wound (e.g., to fill the wound with the matrix), or adhering the matrix to the skin or wound (e.g., the adhering can be by applying a medical grade adhesive to the surface of the wound and then applying the matrix to the adhesive, or applying a medical grade adhesive to the matrix and then applying the matrix to the wound). In this way, the use of the matrix described herein is contemplated to treat a wound or injury site. For example, application of the matrix described herein can treat a wound or injury site by stopping, slowing, or preventing further bleeding. For example, application of the matrix to a wound or injury site can prevent other objects from entering the wound or injury site. In a further example, application of the matrix allows delivery of active agents, contributes to wound repair and / or provides soothing pain relief. In a typical embodiment, the wound or injury site is to a skin surface.

[0200] Thus, the matrices described herein have a variety of uses, including but not limited to wound dressings and barriers, surgical dressings, hemostatic dressings, and delivery of therapeutic and / or chemical agents. For example, it is contemplated that application of an active agent described herein to the surface of a matrix described herein, followed by application of the matrix to, for example, the skin, is not only useful for treating wounds, but also allows delivery of the active agent to the wound or skin, as described above, thereby providing additional and / or alternative therapeutic benefits.

[0201] The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific examples. These examples are set forth merely for illustrative purposes and are not intended to limit the scope of the present invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or indicate to be expedient. Although specific terms are used herein, such terms are intended in a descriptive sense and not for purposes of limitation. EXAMPLES

[0202] Example 1 – Gelatin sponge A gelatin sponge within the scope of the invention described herein was formed as follows. Purified water (500 mL) was added to a 1 L flask or container. The water was swirled to create a small vortex and 36 g of porcine gelatin was added to the water. The gelatin was added slowly to evenly disperse it in the liquid. The flask or container was covered and heated to 50°C with continuous stirring until the gelatin was completely dissolved. 0.52 g of NHS was then added and the solution was stirred until completely dissolved.

[0203] Purified water (10 mL) was added to a 50 mL Falcon tube or container. The EDC solution was prepared immediately before use by adding 2.8 g of EDC to the water and stirring the solution until completely dissolved.

[0204] The gelatin / NHS mixture was cooled (with continuous stirring) to 25-28°C to create the foaming solution. The foaming solution was transferred to the bowl of a stand mixer. The solution was then mixed / foamed at maximum speed for 1 minute. While continuing to mix, a 20 mL serological pipette was used to drop the EDC solution into the bowl such that all of the solution was dispensed within 30 seconds. The added EDC droplets were immediately mixed into the solution. After all the EDC solution was dispensed, mixing was continued for an additional 10 seconds.

[0205] The foam was then immediately dispensed and spread onto the tray.

[0206] The foams were then allowed to dry for up to 48 hours. A ventilation system was used to ensure efficient air circulation around the foams. Once dry, the gelatin sponges were removed from the trays and directly cut to the desired size for final packaging and processing.

[0207] Example 2 – Gelatin-alginate sponge A gelatin-alginate sponge within the scope of the invention described herein was formed as follows. Gelatin Solution Purified water (500 mL) was added to a 1 L flask or container. The water was swirled to create a small vortex, then 36 g of fish gelatin was added. The gelatin was added slowly to ensure it was evenly dispersed in the liquid. The flask or container was covered and heated to 50°C with continuous stirring until the gelatin was completely dissolved.

[0208] Alginate solution Purified water (490 mL) was added to a 1 L flask or container. The water was swirled and 0.25 g of sodium hydroxide was added and mixed for 3-5 minutes until visually dissolved. The mixing speed was increased to create a small vortex and 40 g of sodium alginate was added slowly to minimize clumping. The flask or container was covered and heated to 50 °C with continuous stirring until the alginate was completely dissolved.

[0209] Gelatin / alginate / glycerol / NHS solution The alginate solution was slowly added to the gelatin solution to ensure thorough mixing. The temperature of the gelatin / alginate solution was reduced to 30° C. 2.0 g of glycerol (1.59±0.03 mL) was then added and stirred until thoroughly mixed. 0.52 g of NHS was then added and stirred until completely dissolved.

[0210] EDC solution Purified water (10 mL) was added to a 50 mL Falcon tube or container. The EDC solution was prepared immediately before use by adding 2.8 g of EDC to the water and stirring the solution until completely dissolved.

[0211] Foaming The gelatin / alginate / glycerol / NHS mixture was cooled (with continuous stirring) to 25-28 °C to create the foaming solution. The foaming solution was transferred to the bowl of a stand mixer. The foaming solution was then mixed / foamed at maximum speed for 4 minutes. While mixing continued, a 20 mL serological pipette was used to drop the EDC solution into the bowl such that all of the solution was dispensed within 30 seconds. The added EDC droplets were immediately mixed into the solution. After all the EDC solution was dispensed, mixing was continued for an additional 10 seconds.

[0212] The foam was then immediately dispensed and spread onto the tray.

[0213] Drying and Sizing The foams were allowed to dry for up to 48 hours. A ventilation system was used to ensure efficient air circulation around the foams. The dried gelatin-alginate sponges were removed from the trays and directly cut to the desired size for final packaging and processing.

[0214] Example 3 – Antimicrobial gelatin-CMC sponge An antimicrobial gelatin-CMC sponge within the scope of the invention described herein was formed as follows. Gelatin Solution Purified water (245 mL) was added to a 1 L flask or container. The water was stirred and 1.90 g of silver lactate was added. The solution was mixed until the silver lactate was dissolved (approximately 5-10 minutes). A small vortex was created by increasing the mixing speed and 12.0 g of gelatin was added to the solution. The gelatin was added slowly to disperse evenly in the liquid. The flask or container was covered and heated to 60°C with continuous stirring until the gelatin was completely dissolved. Sodium chloride (0.56 g) was added slowly to initiate the formation of silver chloride.

[0215] CMC solution Purified water (250 mL) was added to a 2 L flask or container. Then, 0.10 g of sodium hydroxide was added and mixed for 3-5 minutes until visually dissolved. The mixing speed was increased to create a small vortex and 2.85 g of CMC was added to minimize clumping. The flask or container was covered and heated to 60 °C with continuous stirring until the CMC was completely dissolved.

[0216] Gelatin / CMC solution The gelatin solution was slowly added to the CMC solution to ensure thorough mixing (stirred for approximately 1 hour). The temperature of the gelatin / CMC solution was reduced to 25°C.

[0217] EDTA solution EDTA (calcium disodium salt) (2 g) was placed in a 50 mL falcon tube and 5 mL of water was added to the falcon tube. The solution was mixed by shaking until the EDTA was dissolved. This solution was added to the gelatin / CMC solution and mixed for at least 5 minutes.

[0218] EDC / NHS solution (prepared immediately before use) EDC (0.65 g) and NHS (0.10 g) were transferred to a 50 ml Falcon tube. 2.5 mL of water was then added to the Falcon tube containing EDC / NHS. The solution was mixed with shaking until the EDC / NHS was dissolved (did not exceed 15 min mixing time before use).

[0219] Foaming The mixture (0.5 L) was transferred to a mixing bowl. The mixture was then mixed (blended) at maximum speed until the foam volume increased to approximately 2 L (approximately 5 minutes). The EDC / NHS crosslinker was then slowly added to the foam within 30 seconds. Foaming was then continued for an additional 10 seconds.

[0220] The foam was then immediately dispensed and spread onto a tray.

[0221] Drying and Sizing The foams were allowed to dry for up to 48 hours. A ventilation system was used to ensure efficient air circulation around the foams. The dried gelatin-CMC sponges were then removed from the trays and directly cut into desired sizes for final packaging and processing.

[0222] Example 4 - Antimicrobial activity The antimicrobial activity of the samples prepared according to Example 3 above was tested in a growth inhibition assay using the microorganisms Escherichia coli (ATCC 8739), vancomycin-resistant enterococcus (ATCC 51575) and Candida albicans (ATCC 10231).

[0223] [Table 1]

[0224] Example 5 – Comparative freeze-dried sponges A freeze-dried gelatin sponge was prepared as follows. Silver lactate (0.965 g) was added to 600 mL of water at 50 °C and the solution was mixed until complete dissolution of the silver salt was achieved. Afterwards, 0.289 g of silver chloride was added to the silver solution to form a suspension of silver chloride. Gelatin (275 bloom, 5.778 g) was then added to the silver chloride suspension and the mixture was stirred until the gelatin was dissolved. In a separate container, 1.133 g of CMC was added to 400 mL of alkaline water (pH 9.0) at 50 °C and the mixture was stirred until all of the CMC was dissolved. The gelatin / silver chloride suspension and the CMC solution were mixed and 1.0 g of sodium EDTA was added and stirred until the EDTA was completely dissolved. In a final step, 0.909 g of EDC and 0.140 g of NHS were added to the biopolymer mixture and stirred until dissolved. After mixing for an additional 15 min, aliquots of the biopolymer mixture were poured into plastic trays and lyophilized for 24 h to obtain gelatin / CMC sponges containing silver.

[0225] Example 6 - Silver Leaching An antimicrobial sponge (gelatin / CMC containing silver) prepared according to Example 3 above was compared with a gelatin / CMC containing silver sponge prepared according to Example 5 above in terms of silver elution profile.

[0226] Briefly, samples of each type of antimicrobial sponge were incubated with agitation in saline maintained at 37°C. At selected intervals, aliquots of the eluate were removed for analysis of silver content by atomic absorption spectrometry. The results of the silver elution assay are shown in Table 2. [Table 2]

[0227] As noted above, silver release from the two antimicrobial sponges was essentially identical, indicating similar characteristics of the final products with respect to silver elution, despite the different methods used to prepare the sponges (i.e., air drying according to the present invention versus freeze drying).

[0228] Example 7 - Physical properties Sponge samples prepared according to Examples 1, 2 and 3 and Comparative Example 5 were characterized for their degree of cross-linking, thermal stability and water absorption. The water absorption of the gelatin matrix was measured according to a procedure that involved measuring the weight difference of the sample before and after incubation in water at 37°C for 1 hour. At this point, the thermal stability of the sample was also evaluated. The degree of cross-linking was determined similarly, except that the sample was incubated in water at 37°C for 16 hours and then dried before measuring the sample weight after incubation.

[0229] The degree of crosslinking, thermal stability, and water absorption (expressed as grams of water absorbed per gram of material) of each test sample are shown in Table 3.

[0230] [Table 3]

[0231] The above disclosure generally describes the present invention. Although specific terms have been used herein, such terms are intended in a descriptive sense and not for purposes of limitation.

[0232] All publications, patents, and patent applications cited above are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0233] Although preferred embodiments of the invention have been described in detail herein, those skilled in the art will recognize that variations are possible without departing from the spirit of the invention or the scope of the appended claims.

Claims

1. 1. A matrix comprising: (i) a biomolecule selected from the group consisting of gelatin, collagen, elastin, and combinations thereof; (ii) a biocompatible polymer selected from the group consisting of polyethylene glycol, poly-L-lysine, alginic acid, chitosan, hyaluronic acid, chondroitin sulfate, pectin, cellulose, carboxymethylcellulose, and mixtures thereof; and (iii) an active agent, wherein the biomolecule and biocompatible polymer are uniformly distributed throughout the matrix, the matrix is ​​a dry crosslinked foam, the biomolecule is present at 40%-80% (w / w) of the weight of the matrix, and the matrix is ​​not lyophilized and has an absorptive capacity of 20-50 times the dry weight of the matrix.

2. The matrix of claim 1 , wherein the biomolecule is gelatin.

3. The matrix of claim 1 further comprising at least two layers.

4. The matrix of claim 1 , wherein the matrix does not include a hardened and / or compressed skin on a surface of the matrix.

5. The matrix of claim 1, wherein the biocompatible polymer is present at 0.4% to 25% (w / w).

6. The matrix according to claim 1, having a pore size in the range of 100 μm to 750 μm and / or a thickness of at least 1 mm.

7. 10. The matrix of claim 1, wherein the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

8. 8. The matrix of claim 7, wherein the antimicrobial agent is selected from the group consisting of chlorhexidine, octenidine, benzalkonium chloride, benzethonium chloride, polyhexamethylene biguanide, copper, zinc, silver, chlorine, active chlorine compounds, fluoroquinolones, b-lactams, macrolides, aminoglycosides, tetracyclines, and combinations thereof.

9. 8. The matrix of claim 7, wherein the antimicrobial agent comprises silver ions derived from a silver salt selected from the group consisting of silver phosphate, silver sulfate, silver citrate, silver lactate, silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodide, silver iodate, silver nitrate, silver laurate, silver sulfadiazine, silver palmitate, and mixtures thereof.

10. 2. The matrix of claim 1, wherein the matrix is ​​crosslinked using a crosslinker selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS) and mixtures thereof, present at 0.5% to 5% (w / w).

11. 10. The matrix of claim 1, wherein the matrix is ​​selected from the group consisting of a wound barrier, a wound dressing, a hemostatic dressing, a vascular wrap, a sponge, a gauze, a bandage, a film, a sheet, a tube, and combinations thereof.

12. The matrix according to claim 1 for treating a wound.

13. The matrix of claim 12 , wherein the treatment comprises applying the matrix to a wound.

14. 13. A method for making the matrix of claim 1, comprising: foaming a composition comprising a biomolecule; crosslinking the composition; and The method comprises the step of drying the composition.

15. The method of claim 14, wherein the biomolecule is gelatin.

16. 15. The method of claim 14, wherein the crosslinking is performed during or after foaming with a crosslinking agent selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), and mixtures thereof.

17. The method of claim 14 , wherein the biocompatible polymer is carboxymethylcellulose.

18. 15. The method of claim 14, wherein the active agent is selected from the group consisting of antimicrobial agents, analgesics, anti-adhesion compounds, anti-tumor agents, anti-proliferative agents, chelating agents, and combinations thereof.

19. 20. The method of claim 18, wherein the drying step comprises air drying and does not comprise freeze drying.

20. 20. The method of claim 19, wherein the air drying is at ambient pressure and temperature.

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