Porcine collagen compositions and methods of using same

Abstract

The present disclosure provides compositions and methods for wound management. The compositions include a micronized extracellular matrix and, optionally, one or more antimicrobial agents. In some embodiments, the extracellular matrix is ​​composed of porcine purified collagen wound matrix (CWM) and polyhexamethylene biguanide (PHMB). The compositions can be formulated as a powder and applied to the wound as a powder, or can be hydrated and applied to the wound as a paste or slurry.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 224,209, filed July 21, 2021, the contents of which are incorporated by reference in their entirety herein.

[0002] The present disclosure relates to micronized porcine collagen compositions for use in wound management. [Background technology]

[0003] Wounds present a common clinical challenge to both medical and veterinarians. Broadly defined, wounds consist of acute injuries (e.g., trauma, burns, surgical wounds, radiation injuries) and chronic processes (e.g., ulcers, diabetic ulcers, venous stasis ulcers, pressure ulcers, abscesses), as well as irregularly shaped and tunneling wounds.

[0004] Extracellular matrix (ECM) derived products are widely used to support wound management and are widely known to be well tolerated as a wound management modality. Extracellular matrices can be derived from either animals or humans and can contain cellular components or can be decellularized. Currently, ECMs consisting of placenta-based matrices, porcine intestinal collagen wound matrix (CWM), porcine bladder matrix, among others, are clinically utilized to support wound repair and healing. Collagen is a key protein of the extracellular matrix and is known to play a role in connective tissue healing, both structurally and functionally.

[0005] Irregularly shaped wounds and tunnel wounds are difficult to manage using standard available (most often delivered in sheets) wound management modalities. Micronizing the ECM to form an ECM powder offers unique clinical advantages, allowing the powder to be applied to ensure direct contact of the product with the wound bed. Additionally, the powder can be hydrated and delivered in the form of a paste or slurry.

[0006] Bacterial colonization and biofilms are known to be major contributors to wound chronicity. In one or more of the embodiments, to address the microbes, bacterial load, or biofilm present within the wound bed, the ECM powder is designed to include an antimicrobial component that delivers both the benefits of the ECM and an antimicrobial agent. Summary of the Invention

[0007] The present disclosure provides a micronized collagen composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, the composition comprising greater than 95% by weight (w / w) porcine collagen.

[0008] The present disclosure provides and includes a method for managing a wound in a subject in need thereof, comprising cleaning the wound of debris and necrotic tissue and applying a micronized collagen composition to the entire area of ​​the wound, the composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, the composition comprising greater than 95% by weight (w / w) porcine collagen.

[0009] The present disclosure provides and includes a micronized collagen composition for use in the manufacture of a medicament for wound management, the composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, the composition comprising greater than 95% by weight (w / w) native porcine type I collagen, less than 0.7% by weight (w / w) lipids, less than 1.0% by weight (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA, the native porcine type I collagen is free of cells and cellular debris, and the wound is selected from the group consisting of partial thickness wounds, full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, undermined wounds, surgical wounds, wound dehiscence, traumatic wounds, second degree burns, and draining wounds.

[0010] The present disclosure provides and includes a micronized collagen composition comprising particles of collagen wound matrix (CWM) having a particle size of 10-1200 micrometers (μm) in diameter, a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml), wherein the composition comprises greater than 95% by weight (w / w) porcine collagen. [Brief description of the drawings]

[0011] [Figure 1A] 1 is a plot of particle size distribution of a micronized collagen composition prepared according to one embodiment according to Example 6. FIG 2 is a plot of particle size distribution of Wet Sample A. [Figure 1B] 1 is a plot of particle size distribution of a micronized collagen composition prepared according to one embodiment from Example 6. FIG 2 is a plot of particle size distribution of dried Sample A. [Figure 1C] 1 is a plot of particle size distribution of a micronized collagen composition prepared according to one embodiment from Example 6. FIG 2 is a plot of particle size distribution of dried Sample B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] A. Compositions and Methods

[0013] This disclosure relates to a diameter of 10 to 1200 × 10 -6 The present invention provides and includes compositions comprising micronized particles of collagen wound matrix (CWM) having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml). In an embodiment, the CWM comprises porcine collagen. In an embodiment, the porcine collagen is free of cells and cell debris. In a further embodiment, the CWM comprises porcine type I collagen. In an embodiment, the CWM comprises native porcine type I collagen.

[0014] Micronized particles of CWM according to the present disclosure include particles having a size of 10-1200 μm in diameter as determined using Laser Light Scattering Particle Size Analysis (LLSPSA). The present disclosure further provides micronized particles of CWM having an average size of 200-300 μm. In certain embodiments, the micronized particles include less than 0.5% particles having a diameter of greater than 1000 μm as determined by LLSPSA. In embodiments of the present disclosure, the particles include flakes.

[0015] In an embodiment of the present disclosure, micronized particles of CWM are prepared from an intestinal collagen layer (ICL). In one embodiment, the particles are prepared from a CWM comprising one or more layers of ICL prior to micronization. In one embodiment, the CWM is prepared from a sheet of ICL comprising two layers. In one embodiment, the CWM is prepared from a sheet of ICL comprising three layers. In one embodiment, the CWM is prepared from a sheet of ICL comprising four layers. In one embodiment, the CWM is prepared from a sheet of ICL comprising five layers. In one embodiment, one or more layers of the ICL are crosslinked prior to micronization. In one embodiment, the CWM comprises PURAPLY®, PURAPLY AM®, PURAPLY MZ®, or PURAPLY AM-XT®.

[0016] The present disclosure provides and includes compositions that are primarily composed of natural porcine type I collagen. In embodiments, the compositions include greater than 90% (w / w) natural porcine type I collagen. In embodiments, the compositions include greater than 95% (w / w) natural porcine type I collagen.

[0017] The present disclosure provides and includes compositions having low levels of lipids. In an embodiment of the present disclosure, the composition comprises less than 1.0% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises less than 0.9% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises less than 0.% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises less than 0.7% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises less than 0.6% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises less than 0.5% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises between 0.5% (w / w) and 1.0% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises between 0.6% (w / w) and 0.8% (w / w) lipid by weight. In an embodiment of the present disclosure, the composition comprises about 0.7% (w / w) lipid by weight.

[0018] The present disclosure provides and includes compositions having low or undetectable levels of glycosaminoglycans. In an embodiment of the present disclosure, the composition comprises less than 1.0% (w / w) glycosaminoglycans. In an embodiment of the present disclosure, the composition comprises less than 0.8% (w / w) glycosaminoglycans. In an embodiment of the present disclosure, the composition comprises less than 0.6% (w / w) glycosaminoglycans. In an embodiment of the present disclosure, the composition comprises less than 0.4% (w / w) glycosaminoglycans. In an embodiment of the present disclosure, the composition comprises less than 0.2% (w / w) glycosaminoglycans. In an embodiment of the present disclosure, the composition comprises about 1.0% (w / w) glycosaminoglycans. In an embodiment of the present disclosure, the level of glycosaminoglycans in the composition is undetectable.

[0019] The present disclosure provides and includes compositions having low or undetectable levels of DNA. In an embodiment of the present disclosure, the composition comprises less than 0.5 nanograms per milliliter (ng / ml) of DNA. In an embodiment of the present disclosure, the composition comprises less than 0.25 nanograms per milliliter (ng / ml) of DNA. In an embodiment of the present disclosure, the composition comprises less than 0.1 nanograms per milliliter (ng / ml) of DNA. In an embodiment of the present disclosure, the composition comprises about 0.1 nanograms per milliliter (ng / ml) of DNA. In an embodiment of the present disclosure, the level of DNA in the composition is undetectable.

[0020] The present disclosure also provides and includes micronized particles of CWM further comprising an antimicrobial agent selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polyhexanide biguanide (polyhexanide, polyhexamethylene biguanide, polyhexamethylene guanide, poly(iminoimidocarbonyl-iminoimidocarbonyliminohexamethylene), poly(hexamethylene biguanide), polyaminopropyl biguanide), and salts or combinations thereof. In one embodiment, the antimicrobial agent is a cationic antimicrobial agent that is a quaternary ammonium compound, a bisbiguanide, or a polymeric biguanide. In one embodiment, the antimicrobial agent is a polyhexamethylene biguanide (PHMB) coating. In an embodiment, the concentration of PHMB is less than 0.05% by weight (w / w). In some embodiments, the concentration of PHMB is between 0.001% (w / w) and 0.045% (w / w). In some embodiments, the concentration of PHMB is between 0.01% (w / w) and 0.02% (w / w).

[0021] In an embodiment according to the present disclosure, the antimicrobial agent is applied to the surface of the sheet of ICL. In an embodiment, the sheet of ICL comprises one or more layers with or without the antimicrobial agent. As provided herein, the antimicrobial agent is applied to the surface of the ICL and allowed to dry prior to micronization.

[0022] The present disclosure provides and includes compositions that are sterilized (e.g., pathogen inactivated). The sterilization process inactivates microorganisms within the composition. In embodiments, the compositions are sterilized by irradiation. In further embodiments, the compositions are sterilized by gamma irradiation. In other further embodiments, the compositions are sterilized by X-ray irradiation.

[0023] This disclosure relates to a diameter of 10 to 1200 × 10 -6 The present invention provides and includes compositions comprising micronized particles of CWM having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml), and further comprising polyhexamethylene biguanide (PHMB) at a concentration of 0.001% by weight (w / w) to 0.045% by weight (w / w). In certain embodiments, the concentration of PHMB is 0.01% by weight (w / w) to 0.02% by weight (w / w). In embodiments, the CWM comprises porcine collagen. In further embodiments, the CWM comprises porcine type I collagen. In embodiments, the CWM comprises native porcine type I collagen.

[0024] The present disclosure provides and includes a composition comprising micronized particles of CWM having an average particle diameter of 1000 micrometers (μm) or less, the composition comprising greater than 95% by weight (w / w) native porcine type I collagen, less than 0.7% by weight (w / w) lipids, less than 1.0% by weight (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA. In a further aspect, the native porcine type I collagen is free of cells and cell debris.

[0025] The present disclosure also provides and includes a gamma irradiated composition comprising micronized particles of CWM having an average particle diameter of 1000 micrometers (μm) or less, the composition comprising greater than 95% by weight (w / w) native porcine type I collagen, less than 0.7% by weight (w / w) lipids, less than 1.0% by weight (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA. In a further aspect, the native porcine type I collagen is free of cells and cell debris.

[0026] Also included and provided in this disclosure are 10 to 1200×10 -6 The paste comprises micronized particles of CWM having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml). In embodiments, the paste is an aqueous paste. In other embodiments, the paste is a non-aqueous paste.

[0027] In an embodiment, the paste of the present disclosure is a water-based paste. As provided herein, the water-based paste is an isotonic paste (e.g., about 0.15M salt equivalent). In one embodiment, the paste contains 10 mM PO4 3- , 137 mM NaCl, and 2.7 mM KCl. As provided herein, the paste has a viscosity of at least 1.5 Newton seconds per square meter (N s / m 2 ) or Pascal seconds (P·s). In embodiments, the viscosity is at least 10 P·s. In other embodiments, the paste is between 10 and 1000 P·s. As provided herein, pastes can be prepared from dry powders of the CWM at the point of use.

[0028] In aspects, the pastes of the present disclosure are derived from blood. As provided herein, the blood used to form the pastes can be whole blood or platelet-rich plasma.

[0029] The present disclosure relates to a method for producing 10 to 1200×10 granules of 10- ... -6 The hemostatic paste of the present disclosure includes a hemostatic paste comprising micronized particles of CWM having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml). As provided herein, the hemostatic paste of the present disclosure can be prepared at the point of use from a dry powder of CWM.

[0030] Also included and provided are preparations that are free of bacterial endotoxins as determined using the USP Bacterial Endotoxins Test Method for Medical Devices. -6 Micronized particles of CWM having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml) have less than 25 endotoxin units (EU) per 100 milligrams of micronized particles. Also included and provided are micronized particles of CWM having less than 10 endotoxin units (EU) per 100 milligrams. In other aspects, micronized particles of CWM have less than 5 endotoxin units (EU) per 100 milligrams. In further aspects, micronized particles have undetectable levels of endotoxin per 100 milligrams.

[0031] The present disclosure provides a method for managing a wound in a subject in need thereof, comprising: clearing the wound of debris and necrotic tissue; -6and applying to the entire area of ​​the wound a micronized collagen composition comprising particles of CWM having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml). In an embodiment, the method of managing a wound further comprises debriding the wound to ensure that the wound edges contain viable tissue. In an embodiment, the CWM comprises porcine collagen. In a further embodiment, the CWM comprises porcine type I collagen. In an embodiment, the CWM comprises native porcine type I collagen. In an embodiment, the CWM particles are flakes.

[0032] Also included and provided in the method for managing a wound in a subject in need thereof is to apply a suitable non-adherent secondary dressing to maintain a moist wound environment according to methods known to those skilled in the art. The optimal secondary dressing is determined by the location, size, depth, and user preference of the wound, and according to practices known to physicians and other skilled practitioners. The secondary dressing is changed as needed to maintain a moist, clean wound area. The frequency of secondary dressing changes will depend on the amount of exudate produced and the type of dressing used.

[0033] In an embodiment of the present disclosure, as healing occurs, a portion of the micronized collagen composition containing particles of CWM may gradually slough off and may be removed during dressing changes, but is not forcibly removed. In an embodiment, the micronized CWM may form a gel, which may be rinsed off with gentle irrigation and replaced by additional micronized CWM according to the present disclosure to ensure continuous and complete coverage of the wound during healing. As provided herein, the method further includes assessing the wound at least weekly and reapplying the micronized CWM to ensure complete coverage of the wound.

[0034] As provided herein, a subject in need thereof is either a human or an animal having a wound. In an embodiment, the subject in need thereof is a human.

[0035] In an aspect, a method for managing a wound in a subject in need thereof includes a subject having a wound selected from the group consisting of partial thickness wounds, full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, pocket wounds, surgical wounds, traumatic wounds, second degree burns, and draining wounds.

[0036] In an embodiment, the method for managing a wound in a subject in need thereof includes a subject having a surgical wound selected from the group consisting of a donor site wound, a graft wound, a post-Mohs surgery wound, a post-laser surgery wound, or a podiatric wound, or a wound dehiscence, hi other embodiments, the wound is selected from an abrasion, a laceration, or a skin laceration.

[0037] In an embodiment, a method for managing a wound in a subject in need thereof includes administering a wound treatment solution having a diameter of 10 to 1200×10 -6 The method includes applying to the entire area of ​​the wound a crosslinked micronized collagen composition comprising particles of collagen wound matrix (CWM) having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml). In an embodiment, the CWM particles are flakes.

[0038] In an embodiment, a method for managing a wound in a subject in need thereof includes administering a wound treatment solution having a diameter of 10 to 1200×10 -6The method includes applying a micronized collagen composition to the entire area of ​​the wound, the micronized collagen composition comprising particles of CWM having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml), the particles of CWM further comprising an antimicrobial agent. In one embodiment, the antimicrobial agent is a cationic antimicrobial agent. In another embodiment, the antimicrobial agent is a quaternary ammonium compound, a bisbiguanide, or a polymeric biguanide. In other embodiments, the antimicrobial agent is a cationic antimicrobial agent selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polyhexanide biguanide (polyhexanide, polyhexamethylene biguanide, polyhexamethylene guanide, poly(iminoimidocarbonyl-iminoimidocarbonyliminohexamethylene), poly(hexamethylene biguanide), polyaminopropyl biguanide), and salts or combinations thereof. In certain embodiments, the CWM particles are prepared from crosslinked CWM.

[0039] In an embodiment, a method for managing a wound in a subject in need thereof includes administering a wound treatment solution having a diameter of 10 to 1200×10 -6 The method includes applying a micronized collagen composition to the entire area of ​​the wound, the micronized collagen composition comprising particles of CWM having a particle size of 1 meter (micrometer, micron, or μm), a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml), the particles of CWM further comprising polyhexamethylene biguanide (PHMB). In one embodiment, the PHMB is present at a concentration of less than 0.05% by weight (w / w) of the dried particles. In another embodiment, the method provides for the PHMB to be present at a concentration of 0.001% by weight (w / w) to 0.045% by weight (w / w). In a further embodiment, the method provides for the PHMB to be present at a concentration of 0.01% by weight (w / w) to 0.02% by weight (w / w). The method further provides for particles of collagen wound matrix having less than 25 endotoxin units (EU) per 100 milligrams of dry powder.

[0040] The present disclosure provides and includes the use of a composition comprising a micronized collagen composition comprising particles of CWM having a particle size of 10-1200 μm in diameter, a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml) for use in the manufacture of a medicament for the management of a wound selected from the group consisting of partial thickness wounds, full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, pocket wounds, surgical wounds, wound dehiscence, traumatic wounds, second degree burns, and draining wounds. In an embodiment, the surgical wound is a donor site wound, a graft wound, a post-Mohs surgery wound, a post-laser surgery wound, a foot wound, or a wound dehiscence. In certain embodiments, the traumatic wound is selected from an abrasion, a laceration, or a skin laceration.

[0041] B. Definition

[0042] The term "and / or," when used in the context of a list of two or more items, means that any one of the listed items may be used by itself or in combination with any one or more of the listed items. For example, the phrase "A and / or B" is intended to mean either or both of A and B, i.e., A alone, B alone, or a combination of A and B. The phrase "A, B, and / or C" is intended to mean A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0043] As used herein, the singular and singular terms "a," "an," and "the," for example, include plural references unless the content clearly dictates otherwise.

[0044] When a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, and any other stated or intervening value in that stated range, is encompassed in the disclosure. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges, which are also encompassed in the disclosure, subject to any specifically excluded limits in the stated ranges. Where a stated range includes one or both of the upper and lower limits, ranges excluding either or both of those included upper and lower limits are also included in the disclosure. Whenever the term "comprising" is used, variations such as "consisting essentially of" and "consisting of" are also contemplated.

[0045] Unless otherwise defined herein, terms are to be understood according to conventional usage by those skilled in the relevant art. When a term is described in the singular, the inventors also contemplate aspects of the present disclosure described by the plural of that term. In the event of a discrepancy in terms and definitions used in references incorporated by reference, the terms used in this application shall have the definitions given herein. Other technical terms used have their ordinary meanings in the art in which they are used, as exemplified by various art-specific dictionaries, such as "The American Heritage® Science Dictionary" (Editors of the American Heritage Dictionaries, 2011, Houghton Mifflin Harcourt, Boston and New York), or "McGraw-Hill Dictionary of Scientific and Technical Terms" (6th edition, 2002, McGraw-Hill, New York).

[0046] As used herein, the term "matrix" refers to the material or tissue between eukaryotic cells, and the term "extracellular matrix" or "ECM" refers to the structure of extracellular macromolecules and minerals that provide structural and biochemical support between and around cells and serve as a scaffold for tissues and organs throughout the body. The main components of the extracellular matrix are collagen fibers, which organize and strengthen the matrix, and elastin fibers, which provide elasticity and resilience to the matrix. The extracellular matrix includes the interstitial matrix (i.e., the matrix present in the intracellular space) and the basement membrane (i.e., the sheet-like deposits in which various epithelial cells reside). The extracellular matrix serves a wide range of functions, including providing physical support, isolating tissue types, regulating cell-cell communication, and regulating the dynamic behavior of cells. The extracellular matrix can also sequester or store cell growth factors, which upon release allow for rapid and localized growth factor-mediated activation of cell functions. Formation of the extracellular matrix is ​​essential for processes such as growth, wound healing, and fibrosis, and it has been found to cause regrowth and healing of injured tissue by (1) preventing the immune system from responding to injury with inflammation and scar tissue, and (2) promoting the repair of damaged tissue by surrounding cells at the site of injury rather than scar tissue formation.

[0047] As used herein, the term "wound matrix" refers to an extracellular matrix that is applied to a wound or injury site. As used herein, the term "collagen wound matrix" or "CWM" refers to a wound matrix that contains collagen as its primary component.

[0048] As used herein, "wound management" refers to passively supporting the patient's ability to heal by providing a suitable environment for the wound to heal.

[0049] As used herein, "micronization" refers to reducing the average size of the particles of a solid material to very fine particles. Processes for micronization include crushing, grinding, pounding, and comminution.

[0050] As used herein, the term "salt" refers to the combination of a compound with a counterion to form a neutral complex. For a discussion of suitable salts and pharma- ceutically acceptable salts suitable for use herein, see Berge et al., "Pharmaceutical salts," J.Pharm.Sci.66(1):1-19 (1997), and "Handbook of Pharmaceutical Salts: Properties, selection and use", PH Stahl, PG Vermuth, IUPAC, Wiley-VCH (2002), each of which is incorporated herein by reference in its entirety for all purposes.

[0051] As used herein, the term "porosity" refers to the amount of void ("empty") space within a material or composition. Porosity can be expressed as a ratio of void volume to total volume or as a percentage. Porosity can be measured by a variety of techniques, including nitrogen adsorption, thermoporometry, scanning electron microscopy (SEM), atomic force microscopy, confocal laser scanning microscopy, nuclear magnetic resonance (NMR), X-ray computed tomography (CT), and terahertz time-domain spectroscopy (THz-TDS).

[0052] As used herein, the "density" of a substance is its mass per unit volume. Density is calculated by d=M / V, where d is density, M is mass, and V is volume.

[0053] As used herein, a "hemostatic dressing" is a substance for application to a wound that promotes hemostasis and reduces the clotting time of blood. Types of hemostatic dressings include bandages, dry powders, and pastes.

[0054] Having generally described the present disclosure, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to limit the disclosure, unless otherwise specified.

[0055] Each journal, patent, and other document or reference cited herein is incorporated herein by reference in its entirety.

[0056] C. Embodiment

[0057] Embodiment 1. A micronized collagen composition comprising particles of collagen wound matrix (CWM) having a particle size range of 10-1200 micrometers (μm) in diameter, a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml).

[0058] Embodiment 2. The composition of embodiment 1, wherein the CWM comprises porcine type I collagen.

[0059] Embodiment 3. The composition of embodiment 2, wherein the CWM comprises native porcine type I collagen.

[0060] Embodiment 4. The composition of embodiment 3, wherein the native porcine type I collagen is free of cells and cell debris.

[0061] Embodiment 5. The composition of embodiment 3 or embodiment 4, wherein the CWM comprising native porcine type I collagen has a denaturation temperature of 45° C. or greater, as determined by differential scanning calorimetry (DSC).

[0062] Embodiment 6. A composition according to any one of embodiments 3 to 5, wherein the composition comprises more than 95% by weight (w / w) native porcine type I collagen.

[0063] Embodiment 7. The composition of any one of embodiments 1-6, wherein the CWM is crosslinked.

[0064] Embodiment 8. A composition according to any one of embodiments 1 to 7, wherein the particles are flakes.

[0065] Embodiment 9. The composition of any one of embodiments 1-8, wherein the composition is gamma irradiated.

[0066] Embodiment 10. A composition according to any one of embodiments 1 to 9, wherein the composition comprises less than 0.7% by weight (w / w) lipid.

[0067] Embodiment 11. A composition according to any one of embodiments 1 to 10, wherein the composition comprises less than 1.0% by weight (w / w) glycosaminoglycan.

[0068] Embodiment 12. The composition of any one of embodiments 1 to 11, wherein the composition comprises less than 0.1 nanograms per microliter (ng / μL) of DNA.

[0069] Embodiment 13. The composition of any one of embodiments 1 to 12, wherein the composition further comprises an antibacterial agent.

[0070] Embodiment 14. The composition of embodiment 13, wherein the antibacterial agent is a cationic antibacterial agent selected from the group consisting of quaternary ammonium compounds, bisbiguanides, and polymeric biguanides.

[0071] Embodiment 15. The composition of embodiment 14, wherein the cationic antibacterial agent is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polyhexanide biguanide (polyhexanide, polyhexamethylene biguanide, polyhexamethylene guanide, poly(iminoimidocarbonyl-iminoimidocarbonyliminohexamethylene), poly(hexamethylene biguanide), polyaminopropyl biguanide), and salts or combinations thereof.

[0072] Embodiment 16. The composition of any one of embodiments 1 to 15, wherein the particles further comprise a polyaminopropyl biguanide coating.

[0073] Embodiment 17. The composition of embodiment 16, wherein the polyaminopropyl biguanide coating comprises polyhexamethylene biguanide (PHMB).

[0074] Embodiment 18. The composition of embodiment 17, wherein PHMB is added prior to micronization.

[0075] Embodiment 19. A composition according to embodiment 17 or embodiment 18, wherein PHMB is present at a concentration of less than 0.05% by weight (w / w) of the dry particles.

[0076] Embodiment 20. The composition of embodiment 19, wherein PHMB is present in a concentration of 0.001% by weight (w / w) to 0.045% by weight (w / w).

[0077] Embodiment 21. The composition of embodiment 20, wherein PHMB is present in a concentration of 0.01% by weight (w / w) to 0.02% by weight (w / w).

[0078] Embodiment 22. A composition according to any one of embodiments 1 to 21, wherein less than 0.5% of the particles are greater than 1000 μm in diameter.

[0079] Embodiment 23. A composition according to any one of embodiments 1 to 22, wherein the particles are wet particles and the composition further comprises a sterile solution.

[0080] Embodiment 24. The composition of embodiment 23, wherein the sterile solution is sterile saline.

[0081] Embodiment 25. The composition of embodiment 23 or embodiment 24, wherein the wet particles are formulated as a hemostatic paste.

[0082] Embodiment 26. The composition of any one of embodiments 1 to 25, wherein the composition contains less than 25 endotoxin units (EU) per 100 milligrams (mg).

[0083] Embodiment 27. The composition of any one of embodiments 1 to 26, wherein the composition further comprises petrolatum or an oil-based carrier.

[0084] Embodiment 28. A micronized collagen composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, the composition comprising porcine collagen.

[0085] Embodiment 29. The composition of embodiment 28, wherein the composition comprises more than 95% by weight (w / w) porcine collagen.

[0086] Embodiment 30. The composition of embodiment 28 or embodiment 29, wherein the CWM comprises porcine type I collagen.

[0087] Embodiment 31 The composition of embodiment 30, wherein the CWM comprises native porcine type I collagen.

[0088] Embodiment 32. The composition of embodiment 31, wherein the native porcine type I collagen is free of cells and cell debris.

[0089] Embodiment 33. The composition of embodiment 31 or embodiment 32, wherein the CWM comprising native porcine type I collagen has a denaturation temperature of 45° C. or higher, as determined by differential scanning calorimetry (DSC).

[0090] Embodiment 34. A composition according to any one of embodiments 28 to 33, wherein the composition comprises less than 0.7% by weight (w / w) lipid.

[0091] Embodiment 35. A composition according to any one of embodiments 28 to 34, wherein the composition comprises less than 1.0% by weight (w / w) of glycosaminoglycan.

[0092] Embodiment 36. The composition of any one of embodiments 28 to 35, wherein the composition contains less than 0.1 nanograms per milliliter (ng / ml) of DNA.

[0093] Embodiment 37. The composition of any one of embodiments 28 to 36, wherein the composition is gamma irradiated.

[0094] Embodiment 38 The composition of any one of embodiments 28-37, wherein the CWM is crosslinked.

[0095] Embodiment 39. A composition according to any one of embodiments 28 to 38, wherein the particles are flakes.

[0096] Embodiment 40. The composition of any one of embodiments 28 to 39, wherein the composition further comprises an antibacterial agent.

[0097] Embodiment 41. The composition of embodiment 40, wherein the antibacterial agent is a cationic antibacterial agent selected from the group consisting of quaternary ammonium compounds, bisbiguanides, and polymeric biguanides.

[0098] Embodiment 42. The composition of embodiment 41, wherein the cationic antibacterial agent is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polyhexanide biguanide (polyhexanide, polyhexamethylene biguanide, polyhexamethylene guanide, poly(iminoimidocarbonyl-iminoimidocarbonyliminohexamethylene), poly(hexamethylene biguanide), polyaminopropyl biguanide), and salts or combinations thereof.

[0099] Embodiment 43. The composition of any one of embodiments 28 to 42, wherein the particles further comprise a polyaminopropyl biguanide coating.

[0100] Embodiment 44. The composition of embodiment 43, wherein the polyaminopropyl biguanide coating comprises polyhexamethylene biguanide (PHMB).

[0101] Embodiment 45. The composition of embodiment 44, wherein PHMB is added prior to micronization.

[0102] Embodiment 46. A composition described in embodiment 44 or embodiment 45, wherein PHMB is present at a concentration of less than 0.05% by weight (w / w) of the dry particles.

[0103] Embodiment 47. The composition of embodiment 46, wherein PHMB is present in a concentration of 0.001% by weight (w / w) to 0.045% by weight (w / w).

[0104] Embodiment 48. The composition of embodiment 47, wherein PHMB is present in a concentration of 0.01% by weight (w / w) to 0.02% by weight (w / w).

[0105] Embodiment 49. A composition described in any one of embodiments 28 to 48, wherein the particles are wet particles and the composition further comprises a sterile solution.

[0106] Embodiment 50. The composition of embodiment 49, wherein the sterile solution is sterile saline.

[0107] Embodiment 51. A composition described in embodiment 49 or embodiment 50, wherein the wet particles are prepared as a hemostatic paste.

[0108] Embodiment 52. The composition of any one of embodiments 28 to 51, wherein the composition contains less than 25 endotoxin units (EU) per 100 milligrams (mg).

[0109] Embodiment 53. The composition of any one of embodiments 28 to 52, wherein the composition further comprises a petrolatum or oil-based carrier.

[0110] Embodiment 54. A method for managing a wound in a subject in need thereof, comprising: cleaning the wound of debris and necrotic tissue; and applying to the entire area of ​​the wound a micronized collagen composition comprising particles of collagen wound matrix (CWM) having a particle size range of 10-1200 micrometers (μm) in diameter, a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml).

[0111] Embodiment 55. The method of embodiment 54, further comprising debridement of the wound to ensure that the wound edges contain viable tissue.

[0112] Embodiment 56. The method of embodiment 54 or embodiment 55, further comprising hydrating the composition with sterile saline or a biological fluid selected from amniotic fluid, blood, bone marrow aspirate, or platelet rich plasma to form a paste.

[0113] Embodiment 57. The method of any one of embodiments 54-56, further comprising applying to the wound one or more secondary dressings appropriate to the type and stage of the wound.

[0114] Embodiment 58. The method of any one of embodiments 54-57, wherein the micronized collagen composition is applied to the wound weekly until the wound is healed.

[0115] Embodiment 59. The method of any one of embodiments 54-58, wherein the wound is selected from the group consisting of partial thickness wounds, full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, pocket wounds, surgical wounds, wound dehiscence, traumatic wounds, second degree burns, and draining wounds.

[0116] Embodiment 60. The method of embodiment 59, wherein the surgical wound is a donor site wound, a graft wound, a post-Mohs surgery wound, a post-laser surgery wound, a foot wound, or a wound dehiscence.

[0117] Embodiment 61 The method of embodiment 59, wherein the traumatic wound is selected from an abrasion, a laceration, or a skin laceration.

[0118] Embodiment 63. The method of any one of embodiments 54 to 61, wherein the CWM comprises porcine type I collagen.

[0119] Embodiment 64 The method of embodiment 63, wherein the CWM comprises native porcine type I collagen.

[0120] Embodiment 65. The method of embodiment 64, wherein the CWM comprising native porcine type I collagen has a denaturation temperature of 45° C. or greater, as determined by differential scanning calorimetry (DSC).

[0121] Embodiment 66. The method of any one of embodiments 63 to 65, wherein the composition comprises more than 95% by weight (w / w) natural porcine type I collagen.

[0122] Embodiment 67 The method of any one of embodiments 54 to 66, wherein the CWM is crosslinked.

[0123] Embodiment 68 The method of any one of embodiments 54 to 67, wherein the CWM particles are flakes.

[0124] Embodiment 69. The method of any one of embodiments 54 to 68, wherein the composition has been gamma irradiated.

[0125] Embodiment 70. The method of any one of embodiments 54 to 69, wherein the composition comprises less than 0.7% by weight (w / w) lipid.

[0126] Embodiment 71. The method of any one of embodiments 54 to 70, wherein the composition comprises less than 1.0% by weight (w / w) glycosaminoglycan.

[0127] Embodiment 72. The method of any one of embodiments 54 to 71, wherein the composition comprises less than 0.1 nanograms per microliter (ng / μL) of DNA.

[0128] Embodiment 73. The method of any one of embodiments 54 to 72, wherein the composition further comprises an antibacterial agent.

[0129] Embodiment 74. The method of embodiment 73, wherein the antibacterial agent is a cationic antibacterial agent selected from the group consisting of a quaternary ammonium compound, a bisbiguanide, or a polymeric biguanide.

[0130] Embodiment 75. The method of embodiment 74, wherein the cationic antibacterial agent is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polyhexanide biguanide (polyhexanide, polyhexamethylene biguanide, polyhexamethylene guanide, poly(iminoimidocarbonyl-iminoimidocarbonyliminohexamethylene), poly(hexamethylene biguanide), polyaminopropyl biguanide), and salts or combinations thereof.

[0131] Embodiment 76. The method of any one of embodiments 54 to 75, wherein the particles further comprise a polyaminopropyl biguanide coating.

[0132] Embodiment 77. The method of embodiment 76, wherein the polyaminopropyl biguanide coating comprises polyhexamethylene biguanide (PHMB).

[0133] Embodiment 78. The method of embodiment 76 or embodiment 77, wherein PHMB is present at a concentration of less than 0.05% by weight (w / w) of the dry particles.

[0134] Embodiment 79. The method of embodiment 78, wherein PHMB is present in a concentration of 0.001% by weight (w / w) to 0.045% by weight (w / w).

[0135] Embodiment 80. The method of embodiment 79, wherein PHMB is present in a concentration of 0.01% by weight (w / w) to 0.02% by weight (w / w).

[0136] Embodiment 81. The method of any one of embodiments 54 to 80, wherein less than 0.5% of the particles are greater than 1000 μm in diameter.

[0137] Embodiment 82. The method of any one of embodiments 54 to 81, wherein the composition contains less than 25 endotoxin units (EU) per 100 milligrams (mg).

[0138] Embodiment 83. A method for managing a wound in a subject in need thereof, comprising cleaning the wound of debris and necrotic tissue and applying a micronized collagen composition to the entire area of ​​the wound, wherein the composition comprises particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, and wherein the composition comprises more than 95% by weight (w / w) porcine collagen.

[0139] Embodiment 84 The method of embodiment 83, further comprising debridement of the wound to ensure that the edges of the wound contain viable tissue.

[0140] Embodiment 85. The method of embodiment 83 or embodiment 84, further comprising hydrating the composition with sterile saline or a biological fluid selected from amniotic fluid, blood, bone marrow aspirate, or platelet rich plasma to form a paste.

[0141] Embodiment 86. The method of any one of embodiments 83-85, further comprising applying to the wound one or more secondary dressings appropriate to the type and stage of the wound.

[0142] Embodiment 87. The method of any one of embodiments 83-86, wherein the micronized collagen composition is applied to the wound weekly until the wound is healed.

[0143] Embodiment 88. The method of any one of embodiments 83-87, wherein the wound is selected from the group consisting of partial thickness wounds, full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, pocket wounds, surgical wounds, wound dehiscence, traumatic wounds, second degree burns, and draining wounds.

[0144] Embodiment 89. The method of embodiment 88, wherein the surgical wound is a donor site wound, a graft wound, a post-Mohs surgery wound, a post-laser surgery wound, a foot wound, or a wound dehiscence.

[0145] Embodiment 90. The method of embodiment 88, wherein the traumatic wound is selected from an abrasion, a laceration, or a skin laceration.

[0146] Embodiment 91. The method of any one of embodiments 83 to 89, wherein the CWM comprises porcine type I collagen.

[0147] Embodiment 92. The method of embodiment 91, wherein the CWM comprises native porcine type I collagen.

[0148] Embodiment 93. The method of embodiment 92, wherein the native porcine type I collagen is free of cells and cell debris.

[0149] Embodiment 94. The method of embodiment 92 or embodiment 93, wherein the CWM comprising native porcine type I collagen has a denaturation temperature of 45° C. or higher, as determined by differential scanning calorimetry (DSC).

[0150] Embodiment 95. The method of any one of embodiments 92 to 94, wherein the composition comprises more than 95% by weight (w / w) natural porcine type I collagen.

[0151] Embodiment 96 The method of any one of embodiments 83 to 95, wherein the CWM is crosslinked.

[0152] Embodiment 97. The method of any one of embodiments 83 to 96, wherein the CWM particles are flakes.

[0153] Embodiment 98. The method of any one of embodiments 83 to 97, wherein the composition has been gamma irradiated.

[0154] Embodiment 99. The method of any one of embodiments 83 to 98, wherein the composition comprises less than 0.7% by weight (w / w) lipid.

[0155] Embodiment 100. The method of any one of embodiments 83 to 99, wherein the composition comprises less than 1.0% by weight (w / w) glycosaminoglycan.

[0156] Embodiment 101. The method of any one of embodiments 83 to 100, wherein the composition contains less than 0.1 nanograms per microliter (ng / μL) of DNA.

[0157] Embodiment 102. The method of any one of embodiments 93 to 101, wherein the composition further comprises an antibacterial agent.

[0158] Embodiment 103. The method of embodiment 102, wherein the antibacterial agent is a cationic antibacterial agent selected from the group consisting of a quaternary ammonium compound, a bisbiguanide, or a polymeric biguanide.

[0159] Embodiment 104. The method of embodiment 103, wherein the cationic antibacterial agent is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polyhexanide biguanide (polyhexanide, polyhexamethylene biguanide, polyhexamethylene guanide, poly(iminoimidocarbonyl-iminoimidocarbonyliminohexamethylene), poly(hexamethylene biguanide), polyaminopropyl biguanide), and salts or combinations thereof.

[0160] Embodiment 105. The method of any one of embodiments 83 to 104, wherein the particles further comprise a polyaminopropyl biguanide coating.

[0161] Embodiment 106 The method of embodiment 105, wherein the polyaminopropyl biguanide coating comprises polyhexamethylene biguanide (PHMB).

[0162] Embodiment 107. The method of embodiment 106, wherein PHMB is present at a concentration of less than 0.05% by weight (w / w) of the dry particles.

[0163] Embodiment 108. The method of embodiment 107, wherein PHMB is present in a concentration of 0.001% by weight (w / w) to 0.045% by weight (w / w).

[0164] Embodiment 109. The method of embodiment 108, wherein PHMB is present in a concentration of 0.01% by weight (w / w) to 0.02% by weight (w / w).

[0165] Embodiment 110. The method of any one of embodiments 83 to 109, wherein the composition contains less than 25 endotoxin units (EU) per 100 milligrams (mg).

[0166] Embodiment 111. A micronized collagen composition comprising particles of collagen wound matrix (CWM) having a particle size of 10 to 1200 micrometers (μm) in diameter, a porosity of 55 to 95%, and a density of 0.4 to 1.4 grams per milliliter (g / ml), for use in the manufacture of a medicament for the management of a wound selected from the group consisting of partial thickness wounds, full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, pocket wounds, surgical wounds, wound dehiscence, traumatic wounds, second degree burns, and draining wounds.

[0167] Embodiment 112. The composition for use according to embodiment 111, wherein the surgical wound is a donor site wound, a graft wound, a post-Mohs surgery wound, a post-laser surgery wound, a foot wound, or a wound dehiscence.

[0168] Embodiment 113. A composition for use according to embodiment 111, wherein the traumatic wound is selected from an abrasion, a laceration, or a skin laceration.

[0169] Embodiment 114. A micronized collagen composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter for use in the manufacture of a medicament for the management of a wound selected from the group consisting of partial thickness wounds, full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, pocket wounds, surgical wounds, wound dehiscence, traumatic wounds, second degree burns, and draining wounds, wherein the composition comprises more than 95% (w / w) natural porcine type I collagen, less than 0.7% (w / w) lipids, less than 1.0% (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA.

[0170] Embodiment 115. A composition for use according to embodiment 114, wherein the native porcine type I collagen is free of cells and cell debris.

[0171] Embodiment 116. The composition for use according to embodiment 114 or embodiment 115, wherein the surgical wound is a donor site wound, a graft wound, a post-Mohs surgery wound, a post-laser surgery wound, a foot wound, or a wound dehiscence.

[0172] Embodiment 117. A composition for use according to embodiment 114 or embodiment 115, wherein the traumatic wound is selected from an abrasion, a laceration, or a skin laceration.

[0173] Embodiment 118. A method of producing a micronized collagen composition comprising particles of collagen wound matrix (CWM), comprising: producing an intestinal collagen layer (ICL) from a porcine small intestine; chemically cleaning the ICL to produce a chemically cleaned ICL; drying the chemically cleaned ICL to produce a dried chemically cleaned ICL; and milling the dried chemically cleaned ICL to produce a micronized collagen composition comprising particles of collagen wound matrix (CWM) having a particle size range of 10-1200 microns (μm) in diameter, a porosity of 55-95%, and a density of 0.4-1.4 grams per milliliter (g / ml).

[0174] Embodiment 119. The method of embodiment 118, further comprising irradiating the composition with gamma radiation.

[0175] Embodiment 120. The method of embodiment 118 or embodiment 119, wherein generating an ICL comprises arranging the small intestine into intestinal sheets and mechanically removing the inner and outer mucosal layers from the intestinal sheets to form an intestinal collagen layer (ICL).

[0176] Embodiment 121. The method of any one of embodiments 118-120, wherein the chemically cleaning comprises incubating the intestinal collagen layer (ICL) at a pH of 11-12, followed by incubation at a pH of 0-1, followed by incubation in phosphate buffered saline (PBS) at a pH of 7-7.4.

[0177] Embodiment 122. The method of any one of embodiments 118 to 121, further comprising packaging the composition into one or more single-use packages.

[0178] Embodiment 123. The method of embodiment 122, wherein each of the one or more single-use packages contains 100 milligrams (mg), 500 mg, or 1000 mg of the composition.

[0179] Embodiment 124. The method of embodiment 122 or embodiment 123, further comprising storing one or more single-use packages for up to 8 months prior to use.

[0180] Embodiment 125. A method of producing a micronized collagen composition comprising particles of collagen wound matrix (CWM), comprising: producing an intestinal collagen layer (ICL) from a porcine small intestine; chemically cleaning the ICL to produce a chemically cleaned ICL; drying the chemically cleaned ICL to produce a dried chemically cleaned ICL; and grinding the dried chemically cleaned ICL to produce a micronized collagen composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, wherein the composition comprises more than 95% (w / w) porcine collagen, less than 0.7% (w / w) lipids, less than 1.0% (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA.

[0181] Embodiment 126. The method of embodiment 125, wherein the porcine collagen is native porcine type I collagen free of cells and cell debris.

[0182] Embodiment 127. The method of embodiment 125 or embodiment 126, further comprising irradiating the composition with gamma radiation.

[0183] Embodiment 128. The method of any one of embodiments 125 to 127, wherein generating an ICL comprises arranging the small intestine into intestinal sheets and mechanically removing the inner and outer mucosal layers from the intestinal sheets to form an intestinal collagen layer (ICL).

[0184] Embodiment 129. The method of any one of embodiments 125-128, wherein the chemically cleaning comprises incubating the intestinal collagen layer (ICL) at a pH of 11-12, followed by incubation at a pH of 0-1, followed by incubation in phosphate buffered saline (PBS) at a pH of 7-7.4.

[0185] Embodiment 130. The method of any one of embodiments 125-129, further comprising packaging the composition into one or more single-use packages.

[0186] Embodiment 131. The method of embodiment 130, wherein each of the one or more single-use packages contains 100 milligrams (mg), 500 mg, or 1000 mg of the composition.

[0187] Embodiment 132. The method of embodiment 130 or embodiment 131, further comprising storing one or more single-use packages for up to 8 months prior to use.

[0188] Embodiment 133. A micronized collagen composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, the composition comprising greater than 95% by weight (w / w) native porcine type I collagen, less than 0.7% by weight (w / w) lipids, less than 1.0% by weight (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA, wherein the native porcine type I collagen is free of cells and cell debris.

[0189] Embodiment 134. The composition of embodiment 133, wherein the composition is gamma irradiated.

[0190] Embodiment 135. A micronized collagen composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, the composition comprising greater than 95% by weight (w / w) native porcine type I collagen, less than 0.7% by weight (w / w) lipids, less than 1.0% by weight (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA, the native porcine type I collagen being free of cells and cell debris, and the particles further comprising a polyaminopropyl biguanide coating comprising polyhexamethylene biguanide (PHMB).

[0191] Embodiment 136. The composition of embodiment 135, wherein the composition is gamma irradiated.

[0192] Embodiment 137. A micronized collagen composition comprising particles of collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter for use in the manufacture of a medicament for the management of a wound selected from the group consisting of partial thickness wounds, full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel wounds, pocket wounds, surgical wounds, wound dehiscence, traumatic wounds, second degree burns, and draining wounds, wherein the composition comprises greater than 95% by weight (w / w) native porcine type I collagen, less than 0.7% by weight (w / w) lipids, less than 1.0% by weight (w / w) glycosaminoglycans, and less than 0.1 nanograms per milliliter (ng / ml) DNA, wherein the native porcine type I collagen is free of cells and cellular debris, and the particles further comprise a polyaminopropyl biguanide coating comprising polyhexamethylene biguanide (PHMB).

[0193] Embodiment 138. The composition for use of embodiment 137, wherein the composition is gamma irradiated. EXAMPLES

[0194] Example 1: Preparation of Intestinal Collagen Layer (ICL)

[0195] Porcine intestinal collagen is prepared essentially as described in U.S. Patent No. 5,993,844. Briefly, porcine small intestines are harvested, trimmed into sheets, mechanically stripped, and cleaned to thin and separate the tunica submucosa by mechanically squeezing the material between opposing rollers and washing with water. The tunica submucosa of the small intestine is relatively tough and rigid compared to the surrounding tissue, and the rollers squeeze the softer components from the submucosa. The intestine is cut longitudinally downward to the lumen and then cut into 15 cm sections. The material is weighed and placed in a container with a ratio of approximately 100:1 v / v of solution to intestinal material.

[0196] The resulting intestinal material is then treated with 1 liter of filter-sterilized 100 mM ethylenediaminetetraacetic acid tetrasodium salt (EDTA) / 10 mM sodium hydroxide (NaOH) solution in a ratio of up to 1.5 m intestine / 1 L and placed on a shaker table at approximately 200 rpm for approximately 18 hours. After shaking, the EDTA / NaOH solution is removed from each container. Approximately 1 liter of filter-sterilized 1 M hydrochloric acid (HCl) / 1 M sodium chloride (NaCl) solution is added to each container, which is then placed on a shaker table at approximately 200 rpm for approximately 6-8 hours. After shaking, the HCl / NaCl solution is removed from each container and replaced with approximately 1 liter of 0.22 mm filter-sterilized 1 M sodium chloride (NaCl) / 10 mM phosphate buffered saline (PBS) solution. The containers are placed on a shaker table at 200 rpm for approximately 18 hours. After shaking, the NaCl / PBS solution is removed from each container and replaced with approximately 1 liter of filter-sterilized 10 mM PBS. The containers are then placed on a shaker table at 200 rpm for approximately 2 hours. After shaking, the phosphate buffered saline is removed from each container and replaced with approximately 1 liter of 0.22 mm filter-sterilized water. The containers are placed on a shaker table at 200 rpm for approximately 1 hour. After shaking, the water is then removed from each container and the resulting intestinal collagen layer (ICL) is allowed to dry. The processed samples are free of cells and cell debris. The ICLs may be used fresh or frozen for later use.

[0197] Example 2: Chemical Cleaning of the Intestinal Collagen Layer (ICL)

[0198] As described in U.S. Patent No. 6,893,653, ICLs prepared as described in Example 1 are chemically cleaned to remove non-collagenous components from the tissue matrix by treatment with alkaline agents, chelating agents, acids, and salts, with controlled amounts of swelling and collapse, so that the resulting collagen matrix retains its structural organization, integrity, and bioremodeling properties. Briefly, ICLs are used fresh or thawed at temperatures below 55°C, cut longitudinally, and placed in purified water USP. All solutions are filter sterilized (0.2 μm filter) before use.

[0199] The cut ICLs are placed in cleaning solution (100 mM EDTA / 10 mM NaOH) for 16-20 hours. The cleaned ICLs are transferred to a second cleaning solution (1 M HCl / 1 M NaCl) and agitated for 6-8 hours, then rinsed with 1 M NaCl / 1×PBS and agitated for 16-20 hours. A second rinse in 1×PBS is performed for 2-8 hours with agitation, followed by a final rinse in purified water for 2-8 hours with agitation. The washed and processed samples contain less than 0.016 μg / mg DNA. The mechanically and chemically cleaned ICLs may be used fresh or frozen for later use.

[0200] Example 3: Effect of humidity on grinding

[0201] The effect of storage humidity on grinding of porcine collagen wound matrix (CWM) is determined by storing unground CWM intermediates under the humidity conditions for each experimental group as shown in Table 1 for at least 2 hours prior to grinding. The dried samples are placed in a drying chamber with fresh desiccant and sealed. The high humidity samples are placed in an incubator set at the desired humidity percent and room temperature. The samples are ground at 25 Hz for 5 minutes and sieved at less than 1000 μm into a 15 mL conical tube. The samples are observed for changes in appearance.

[0202] [Table 1]

[0203] The results show that humidity above 65% reduces the grindability of the CWM, affects the color, and leads to clumping and loss of material during sieving.

[0204] Example 4: Effect of ICL shape on ICL drying and grinding

[0205] The effect of drying intestinal collagen layers (ICLs) on particle size, static electricity, and reproducibility is investigated. Layered ICLs are prepared as described in Example 1. Three different forms of ICLs are evaluated and compared to layered cross-linked ICLs containing PHMB (e.g., PuraPly® AM): 1. Control layered, cut, ICL; 2. Layered ICL, folded but not cut; 3. Elongated ICL (non-layered, noodle shape), and 4. Molded ICL (formed in grinding cup, nuggets). Elongated ICLs are prepared by stretching but not spreading ICLs on a drying tray. ICLs in the shape of a grinding cup (nuggets) are made by placing ICLs in a grinding cup and transferring them to a drying tray without changing their shape. After molding, the ICLs are dried for 24 hours in a drying cabinet with air flow. The dried ICLs are removed and stored before grinding.

[0206] The dried ICLs are milled using a Reich Ball Mill MM400 at room temperature for 5 minutes at 25 Hz. The control ICLs are cut into pieces the size of the grinding cup and filled with about one third of the grinding cup or about 1 gram of material. The folded ICLs are not cut but folded to fit into the grinding cup. One ICL fits into a single grinding cup. The noodles are cut into strips approximately 2 cm long with scissors and about 0.5 to 2 noodles per cup are placed in the grinding cup. Individual nuggets are placed in a single grinding cup. All samples are passed through a stainless steel sieve with pore sizes less than 1000 μm to remove larger particles and collect particles less than 1000 μm after grinding. The samples are then filled into vials.

[0207] The control ICL produced a powder as expected, yielding 1329.68 mg of powder; however, the resulting powder suffered from a high static charge making it difficult to work with.

[0208] The folded ICL is not ground properly, leaving a noticeable amount of material that is not able to pass through the sieve. The noodles are ground well and produce an off-white powder that passes through the sieve. The powder appears fluffier than the control powder. Two noodles ground in one grinding cup produce 1262.45 mg of powder, and one noodle ground in one cup produces 737.57 mg of powder. One of the four nuggets is not ground properly, producing a gray powder and leaving a noticeable amount of material that does not pass through the sieve. The remaining three nuggets are ground well and produce an off-white powder.

[0209] Dried ICL noodles produce a satisfactory powder, reduce labor, and increase the efficiency of the micronization process. Dried ICL nuggets do not consistently produce an acceptable powder and are less ideal than dried ICL noodles for producing micronized ICL.

[0210] Example 5: Effect of sample loading

[0211] The loading of the canister with CWM affects the yield of micronized powder. The effect of the canister loading is evaluated under three conditions as shown in Table 2.

[0212] [Table 2]

[0213] The dried ICL strips are cut to a size of approximately 2 cm, weighed, and loaded into canisters according to experimental group. The samples are ground at 25 Hz for 5 minutes, and then sieved into weighing boats with a cutoff of less than 1000 μm. The weight of the micronized powder is recorded. The particles that do not pass through the sieve are also placed in weighing boats and weighed.

[0214] [Table 3]

[0215] The moderately loaded condition produced the sample that was micronized into the highest percentage of product, while the heavily loaded condition produced the greatest amount of powder retained on the sieve.

[0216] Example 6: Particle size characterization of micronized preparations

[0217] Micronized, dried ICLs are prepared as described above, and then particle size is assessed by laser light scattering particle size analysis using a Microtrac S3500 tri-laser system. The average results of three experiments with no delay between tests are provided below. The flow rate is 55% and three degassing cycles are performed before testing the wet samples. The dry samples are analyzed using a turbotrac feeder system.

[0218] Starting with 1 gram of each sample, the bulk powder is evaluated for particle size characteristics and porosity. For sample A, the micronized sample is tested directly. For sample B, the bulk powder is passed through a 700-800 μm sieve. For each sample, the following values ​​are collected: MV = Mean Volume Mean Diameter, MN = Mean Number Mean Diameter, MA = Mean Area Mean Diameter, CS = Surface Area calculated based on an assumed spherical geometry, SD = Standard Deviation, Mz = Graphical Mean Particle Size, σι = Inclusive Graphic Standard Deviation, Ski = Inclusive Graphical Skewness, and Kg = Kurtosis (peakedness) of the distribution.

[0219] For the wetting analysis, approximately 0.625 ml of thoroughly mixed sample is wetted with 0.25 ml of 2% Triton X100 surfactant. 60 ml of deionized water is added and the solution is stirred with an overhead stir bar while a 1 ml aliquot is removed for sampling.

[0220] The particles are further characterized using scanning electron microscopy (SEM) and are observed to contain flat flakes with individual collagen fibers that retain their native collagen structure throughout the process.

[0221] [Table 4]

[0222] [Table 5]

[0223] [Table 6]

[0224] [Table 7]

[0225] Example 7: Porosity characterization of micronized preparations

[0226] Mercury intrusion / extrusion is used to investigate the porosity of the particulates of Sample A above. Mercury intrusion / extrusion is based on forcing mercury (a non-wetting liquid) into a porous structure under tightly controlled pressure, allowing pores from 900 μm to 3 nm to be measured. In this method, mercury, which is non-wetting to most substances, is forced into voids in the sample by applying an external pressure. The pressure required to fill the voids is inversely proportional to the size of the pores. Mercury intrusion / extrusion allows the calculation of total pore volume, total pore area, median pore diameter, bulk density, skeletal density, and percent porosity. The results are presented in Table 8.

[0227] [Table 8]

[0228] Example 8: Preparation of collagen paste

[0229] A collagen paste is prepared as described in U.S. Patent No. 4,891,359 using the micronized porcine collagen wound matrix (CWM) described in Example 4. The collagen paste is useful for managing irregularly shaped or tunnel wounds, as well as being useful as a hemostatic agent.

[0230] Two paste consistencies are prepared: a thin paste with a high liquid percentage and a dough-like paste with a low liquid percentage. In addition, pastes are made using two different mesh sizes of micronized porcine collagen wound matrix (CWM) and phosphate buffered saline as provided in Table 9.

[0231] [Table 9]

[0232] One gram of ground micronized CWM is prepared as provided in Example 6 and PBS is added as provided in Table 10. The sample is mixed to a homogenous consistency for less than one minute.

[0233] [Table 10]

[0234] Condition 1 results in a very thin paste that has more liquid than powder and does not stick to the skin. Condition 2 results in a thick doughy paste that can be molded and does not stick to the skin. Condition 3 paste is thicker than condition 1 paste but is still thin and does not stick to the skin. Condition 4 results in a very thick doughy paste that can be easily molded. Condition 4 paste sticks to the skin.

[0235] Example 10: Micronized Porcine Collagen Wound Matrix Powder Device

[0236] The micronized porcine collagen wound matrix (CWM) described in Example 4 is provided as a sterile single-use powder device for wound management. It is a dry, absorbent, white to off-white / light yellow powder with a particle size distribution of 1000 μm or less. The micronized powder device consists primarily of purified porcine type I collagen in its native form (>95%), with less than 0.7% lipids, and undetectable levels of glycosaminoglycans (1.0%) and DNA (0.1 ng / μl), and the porcine intestinal collagen is free of cells and cell debris. The micronized powder device is provided in the following sizes: 100 mg, 500 mg, and 1000 mg.

[0237] The micronized powder device helps to create and maintain a moist wound environment for the identified wound. The device is applied as a dry powder and then hydrated by absorbing exudate. Alternatively, the micronized powder device may be hydrated prior to application of an appropriate sterile solution, such as sterile saline. The micronized form of the device allows it to conform to uneven or irregularly shaped wounds, including tunnel wounds, while the collagen matrix absorbs and retains fluid, forming a paste or gel depending on the amount of fluid absorbed. The mixing ratio between the device and the exudate, or between the device and the sterile solution, can be adjusted to provide a wound management environment appropriate for the type of wound being managed. The device does not affect the acidity / alkalinity level of the fluid being hydrated (measured in terms of the pH of the mixture). These features facilitate achieving the intended effect of maintaining a moist wound environment.

[0238] Important parameters of the micronized powder device are provided in Table 11.

[0239] [Table 11]

[0240] Example 11: Preparation of a Micronized Porcine Collagen Wound Matrix Powder Device

[0241] The micronized porcine CWM powder device of Example 10 is prepared as follows: Porcine intestinal tissue from the small intestine of approximately 450 lb or larger large pigs that are deemed healthy is obtained according to a defined procedure that specifies the health status and age of the animals from which tissue can be collected. The small intestine is manually removed of mesenteric fat and membranes. The small intestine is then rinsed in hot water (40-49° C. [105-120° F.]) and mechanically processed through a series of rollers to remove the inner mucosal layer and outer muscle layer, leaving the collagenous submucosa behind. The mechanically cleaned submucosa is frozen until further processing.

[0242] The mechanically cleaned submucosa is thawed at a temperature of 45-55°C (113-131°F) for 15-45 minutes. The submucosal tracts are then cut open longitudinally between the lymphatic tags to yield sheets. The tissue is then further purified using two separate chemical cleansing steps. The chemical cleansing process removes cells, cellular debris, lipids, DNA, glycosaminoglycans, and epithelial basement membrane components while also inactivating viruses. The process yields purified collagen sheets.

[0243] The chemical cleaning process consisted of: (1) incubation for 16-20 hours in 100 mM ethylenediaminetetraacetic acid (EDTA) in stirred 10 mM sodium hydroxide (NaOH) at a pH of 11-12 at a ratio of up to 1.5 m / 1 L, (2) incubation for 6-8 hours in 1 M sodium hydrochloride (HCl) in stirred 1 M sodium chloride (NaCl) at a ratio of up to 1.5 m / 1 L at a pH of 0-1, (3) incubation for 16-20 hours in 1 M NaCl in 10 mM phosphate buffered saline (PBS) at a pH of 7-7.4, (4) incubation for 2-8 hours in 10 mM PBS alone at a pH of 7-7.4, and (5) two successive rinses for 2-8 hours each in sterile water that meets or exceeds the USP standard for water for injection. The chemically cleaned intestinal collagen material is frozen at -20°C in sealed bags until further processing.

[0244] Further processing is carried out in a controlled clean room environment. The chemically cleaned intestinal collagen is thawed for 10-20 minutes at a temperature of 45-55°C (113-131°F). The collagen sheet is flattened, inspected for excess material, and dried at ambient humidity. The dried collagen serves as the base biomaterial for the micronized porcine CWM powder device. To generate the micronized porcine CWM powder device, the dried collagen is milled, packaged, and sterilized by gamma irradiation.

[0245] Example 12: Viral inactivation validation of micronized porcine collagen wound matrix powder devices

[0246] Two of the chemical cleaning steps described in Example 11 above, (1) a NaOH / EDTA alkaline chelating solution (pH 11-12) incubation step, and (2) an HCl / NaCl acid salt solution (pH 0-1) incubation step, are tested for virus inactivation against four relevant model viruses. The four model viruses were selected based on the source porcine material and represent a wide range of physicochemical properties, DNA-based enveloped and non-enveloped viruses, and RNA-based enveloped and non-enveloped viruses. The viruses tested are pseudorabies virus (PRV), bovine viral diarrhea virus (BVDV), reovirus-3 (Reo-3), and porcine parvovirus (PPV).

[0247] As shown in Table 12, the cumulative viral inactivation of the two chemical cleaning steps was 10% for all four model viruses. 6 The data demonstrate that the chemical cleanup procedure is a robust and effective process that maintains its inactivation potential for a wide variety of viral agents.

[0248] [Table 12]

[0249] Example 13: Wound Management Using a Micronized Porcine Collagen Wound Matrix Powder Device

[0250] The micronized porcine CWM powder device of Example 10 is used as a single-use device for the management of wounds. The micronized porcine CWM powder device is applied weekly from development through the life of the wound and handled using aseptic technique according to the following five steps:

[0251] First, the wound area is prepared using standard methods to ensure that the wound is free of debris and necrotic tissue. If necessary, the wound is surgically debridement to ensure that the wound edges contain viable tissue.

[0252] Second, the device is gently applied over the desired wound area, and multiple devices are applied if the wound is larger than a single device can cover. Alternatively, if applying a dry powder is difficult due to the location and / or shape of the wound, the micronized porcine CWM powder is hydrated with a sterile solution to form a paste to aid in the application of the device. Hydration is performed by transferring the product to an appropriately sized sterile container and slowly adding the sterile solution until the desired consistency is achieved. The hydrated device is then applied directly to the wound bed.

[0253] Third, a non-adherent dressing is applied to the wound undergoing wound management.

[0254] Fourth, a secondary dressing appropriate for the type and stage of the wound is applied over the non-adhesive dressing. The non-adhesive secondary dressing maintains a moist wound environment and is selected based on the location, size, depth of the wound, and patient preference. The secondary dressing is changed as needed to maintain a moist, clean wound area. The frequency of secondary dressing changes depends on the volume of exudate produced and the type of secondary dressing used.

[0255] Fifth, reassess the wound weekly to assess wound healing. If necessary, apply additional micronized porcine CWM powder devices to the wound weekly. Also, if the applied device no longer covers the wound at any point during the healing process, apply at least one additional micronized porcine CWM powder device to the wound at that time. As wound healing progresses, parts of the applied device may gradually peel off, and if necessary, gently remove the flakes during dressing change. Alternatively, as wound healing progresses, the applied device may turn into a caramel-colored gel, and if necessary, the gel is rinsed off by gentle irrigation.

[0256] According to the five-step procedure described above, weekly application of the micronized porcine CWM powder device is tested to achieve complete or near-complete wound healing for more than 95% of all wounds. Wounds are of the following types: partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunnel / pocket wounds, surgical wounds (e.g., donor sites / grafts, post-Mohs surgery wounds, post-laser surgery wounds, podiatric wounds, and wound dehiscence), traumatic wounds (e.g., abrasions, lacerations, and skin tears), partial thickness burns, and draining wounds. Wound healing is assessed by visual skin inspection of wounds undergoing wound management, which is performed weekly before reapplication of the micronized porcine CWM powder device, if necessary. Wound healing is divided into four phases: (a) hemostasis, (b) inflammation, (c) proliferation, and (d) remodeling, and managed wounds are determined to be completely healed when visual assessment indicates that the remodeling phase is complete.

Claims

1. A collagen composition for use in wound management, wherein the composition is sterilized and micronized, the composition contains micronized particles of a collagen wound matrix (CWM) having an average particle size with a diameter of 1000 micrometers (μm) or less, the composition contains more than 95% by weight (w / w) of native porcine type I collagen, the micronized particles contain flakes, the composition.

2. (i) the native porcine type I collagen does not contain cells and cell debris, (ii) the collagen wound matrix (CWM) has a denaturation temperature of 45 °C or higher as determined by differential scanning calorimetry (DSC), or (iii) both of the above (i) and (ii), the composition according to claim 1.

3. the composition contains less than 0.7% by weight (w / w) of lipid, less than 1.0% by weight (w / w) of glycosaminoglycan, and less than 0.1 nanogram per milliliter (ng / ml) of DNA per milliliter, the composition according to claim 1.

4. the composition is sterilized by gamma-ray irradiation, the composition according to claim 1.

5. the collagen wound matrix (CWM) is crosslinked, the composition according to claim 1.

6. the composition further contains an antibacterial agent, optionally, the antibacterial agent is a cationic antibacterial agent selected from the group consisting of quaternary ammonium compounds, bisbiguanides, and polymeric biguanides, the composition according to claim 1.

7. the cationic antibacterial agent is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polyhexanide biguanide (polyhexanide, polyhexamethylene biguanide, polyhexamethylene guanide, poly(iminocarbonyl-iminocarbonyliminohexamethylene), poly(hexamethylene biguanide), polyaminopropyl biguanide), salts thereof, and any combination thereof, the composition according to claim 6.

8. the micronized particles further contain a polyaminopropyl biguanide coating, optionally, the polyaminopropyl biguanide coating contains polyhexamethylene biguanide (PHMB), The composition according to claim 1, wherein the polyhexamethylene biguanide (PHMB) is present at a concentration selected from the group consisting of less than 0.05% by weight (w / w), from 0.001% by weight (w / w) to 0.045% by weight (w / w), and from 0.01% by weight (w / w) to 0.02% by weight (w / w).

9. The micronized particles are wet particles, The composition further comprises a sterile solution, Optionally, the sterile solution is sterile physiological saline, the composition according to claim 1.

10. The composition according to claim 1, wherein the composition contains less than 25 endotoxin units (EU) per 100 milligrams (mg) of the micronized particles.

11. The composition according to claim 1, wherein the composition further comprises petrolatum or an oil-based carrier.

12. A collagen composition for use in wound management in a subject in need thereof, The composition is sterilized and micronized, The wound management is, Cleaning the wound debris and necrotic tissue, Applying the composition to the entire area of the wound, and The composition comprises micronized particles of a collagen wound matrix (CWM) having an average particle size of 1000 micrometers (μm) or less in diameter, The composition contains more than 95% by weight (w / w) of natural porcine type I collagen, The micronized particles contain flakes, the composition.

13. The wound management is, (i) Debriding the wound so as to ensure that the edges of the wound contain viable tissue, (ii) Applying to the wound one or more secondary dressing materials appropriate for the type and stage of the wound, or (iii) Further comprising both (i) and (ii) above, the composition according to claim 12.

14. The wound management is, Further comprising hydrating the composition with a sterile physiological saline or a biological fluid selected from amniotic fluid, blood, bone marrow aspirate, or platelet-rich plasma to form a paste, the composition according to claim 12.

15. The composition according to claim 12, wherein the composition is applied to the wound weekly until the wound heals.

16. The wound is selected from the group consisting of an intermediate layer wound, a full-thickness wound, a pressure ulcer, a venous ulcer, a diabetic ulcer, a chronic vascular ulcer, a tunnel wound, a pocket wound, a surgical wound, wound dehiscence, a traumatic wound, a second-degree burn, and a draining wound, Optionally, the surgical wound is a donor site wound, a graft wound, a wound after Mohs surgery, a wound after laser surgery, a foot wound, or wound dehiscence, Optionally, the traumatic wound is an abrasion, a laceration, or a skin tear, The composition according to claim 12.

17. (i) The natural porcine type I collagen does not contain cells and cell debris, (ii) The composition contains less than 0.7% by weight (w / w) of lipids, less than 1.0% by weight (w / w) of glycosaminoglycans, and less than 0.1 nanogram per microliter (ng / μL) of DNA, or, (iii) Both (i) and (ii) above, The composition according to claim 12.

18. The composition according to claim 12, wherein the composition is sterilized by gamma irradiation.

19. A collagen composition for use in the manufacture of a medicament for wound management, The composition is sterilized and micronized, The composition contains micronized particles of a collagen wound matrix (CWM) having an average particle size with a diameter of 1000 micrometers (μm) or less, The composition contains more than 95% by weight (w / w) of natural porcine type I collagen, less than 0.7% by weight (w / w) of lipids, less than 1.0% by weight (w / w) of glycosaminoglycans, and less than 0.1 nanogram per milliliter (ng / ml) of DNA, The natural porcine type I collagen does not contain cells and cell debris, The micronized particles contain flakes, The composition is applied to a wound, The wound is selected from the group consisting of an intermediate layer wound, a full-thickness wound, a pressure ulcer, a venous ulcer, a diabetic ulcer, a chronic vascular ulcer, a tunnel wound, a pocket wound, a surgical wound, wound dehiscence, a traumatic wound, a second-degree burn, and a draining wound, A composition.

20. The composition according to claim 19, wherein the composition is sterilized by gamma irradiation.

21. The wound is an irregularly shaped wound or a tunnel wound, The composition according to claim 1, wherein the micronized size of the composition enables direct contact with the entire wound bed.

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