WO2001015750A1 - Pansement aux hydrogels, contenant un agent therapeutique encapsule dans des liposomes - Google Patents

Pansement aux hydrogels, contenant un agent therapeutique encapsule dans des liposomes Download PDF

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Publication number
WO2001015750A1
WO2001015750A1 PCT/CA2000/000991 CA0000991W WO0115750A1 WO 2001015750 A1 WO2001015750 A1 WO 2001015750A1 CA 0000991 W CA0000991 W CA 0000991W WO 0115750 A1 WO0115750 A1 WO 0115750A1
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WIPO (PCT)
Prior art keywords
wound dressing
cross
wound
hydrogel matrix
liposomes
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PCT/CA2000/000991
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English (en)
Inventor
Lucie Martineau
Pang Shek
Valerio Ditizio
Frank Dicosmo
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Department Of National Defence
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Application filed by Department Of National Defence filed Critical Department Of National Defence
Priority to CA002345779A priority Critical patent/CA2345779A1/fr
Priority to AU66794/00A priority patent/AU6679400A/en
Priority to EP00954243A priority patent/EP1124587A1/fr
Priority to JP2001520161A priority patent/JP2003508127A/ja
Publication of WO2001015750A1 publication Critical patent/WO2001015750A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/44Medicaments
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406Antibiotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/626Liposomes, micelles, vesicles

Definitions

  • the present invention is directed to a multi-layer wound dressing that releases an effective amount of a therapeutic agent over a prolonged period of time.
  • the multilayer wound dressing of the present invention comprises: an outer layer; a cross- linked hydrogel matrix layer, with an optional support material confined within the hydrogel matrix; a liposome-encapsulated therapeutic agent incorporated in the hydrogel layer; and, optionally, a protective release sheet.
  • the present invention further provides means for treating or alleviating cutaneous wound infections.
  • the present invention also provides a method of manufacture of the wound dressing product.
  • Dressings to be applied to various types of wounds including burns, surgical incisions and inflicted wounds, ideally promote healing, provide protection against infection, and prevent pooling of wound exudate.
  • the dressings should be as comfortable as possible and should not cause or contribute to ancillary problems, such as bed sores.
  • the dressings should be translucent so that the wound may be easily visualized and monitored.
  • Hydrogels are complex formulations of hydrophilic cross-linked polymers (e.g., polyethylene oxide, polyacrylamides, and polyvinylpyrroiidone). Despite their high water content (up to 96%), hydrogels can absorb a slight to moderate amount of wound exudate, thereby preventing pooling of wound exudate. They are particularly useful as dressings for many partial-thickness skin defects (e.g., shallow abrasions, superficial wounds), blisters, decubitus ulcers, second-degree burns, and healthy, granulating tissue. Hydrogels are available as amorphous gels, as well as in a wafer or sheet form.
  • the hydrogel sheets may include an adhesive border or be secured by applying a secondary dressing (e.g., stretch gauze, tubular bandage, and large film dressing).
  • a secondary dressing e.g., stretch gauze, tubular bandage, and large film dressing.
  • commercially available hydrogel sheets include: GelipermTM (Geistlich- Pharma/Fougera), GelipermTM (Geistlich-Pharma/Fougera), VigilonTM (Bard), Bard Absorption DressingTM (Bard), Cutinova GelfilmTM (Biersdorf), Elasto-gelTM (Southwest Technologies), AQUASORBTM (DeRoyal), CarraDresTM (Carrington Laboratories Inc.), 2 nd SkinTM (Spenco Medical Ltd), Derma-GelTM (Medline Industries), FLEXDERMTM (Dow Hickman Pharmaceuticals Inc.), AcryDermTM (AcryMed), THINSite TransorbentTM (B. Braun), ClearSiteTM (Conmed
  • U.S. Patent No. 5,064,655 describes a liposomal gel composition suitable for topical application.
  • U.S. Patent No. 5,094,819 is directed to fluorophore- containing liposomes immobilized in a hydrogel.
  • U.S. Patent No.5, 843, 647 discloses a stent coated with a hydrogel which optionally comprises liposomes containing DNA.
  • U.S. Patent No. 5,879,713 is directed to enhanced delivery of biologically active molecules using a hydrogel to immobilize the bioactive molecules at the site of release.
  • U.S. Patent No. 6,048,546 discloses a method of preparing a lipid-bilayer material, such as polymerized liposomes, wherein the lipid-bilayer material is encapsulated in a gel.
  • U.S. Patent No. 4,897,269 describes a pharmaceutical composition containing liposomes, which encapsulate an active compound, dispersed in a gel for topical application.
  • none of these referenced patents disclose or suggest a wound dressing which comprises a gel comprising liposomes.
  • Topical application of a hydrogel comprising liposomes results in the gel rapidly drying up, and thus long-term release of the drug is not obtained.
  • a liposomal hydrogel wound dressing that does not dry out and will release a therapeutic agent at a controlled rate over an extended period of time.
  • silver-coated antimicrobial barrier dressings were developed for the treatment of burn wounds, graft and donor sites, chronic wounds (including pressure ulcers, diabetic ulcers, etc.), and post-surgical wounds (ActicoatTM, Westaim Biomedical Corp.; AerglaesTM, Maersk).
  • wound dressings are also impregnated with antibiotics or antibacterial agents.
  • some gauze dressings are impregnated with chlorhexidine (BactigrasTM,
  • hydrogel wound dressing sheets comprising within the hydrogel matrix a therapeutic agent.
  • an antimicrobial agent be applied under the hydrogel dressing or blended with the amorphous hydrogel. While this method ensures some control of bacterial growth, it is not always practical as it introduces another step in the wound care management.
  • Therapeutic substances have been added to gel pads or bandages to provide additional bacterial control and other therapeutic effects. Examples of medicated hydrogel products are disclosed in U.S. Patent No. 5,753,257 (burn dressing), U.S. Patent No. 5,260,066 (cryogel bandage containing therapeutic agent), U.S. Patent No. 5,695,777 (absorptive wound dressing for wound healing promotion), U.S. Patent No. 4,552,138 (dressing material based on a hydrogel, and a process for its production), and in W.O. Patent No. 9820916A1 (antimicrobial-coated hydrogel-forming absorbent polymers).
  • Wachol-Drewek et al, Biomaterials 17:1733-1738 (1996) disclose the use of collagen implants of various structures and a gelatin sponge which were placed in antibiotic solutions and allowed to absorb the compounds. They concluded: "If an implant that has a protective effect against wound infections over a period of 24-48 h is required, the materials described here are suitable. However, where treatment in infected areas should ensure antibiotic cover for 5-10 d[days] neither collagen materials immersed in antibiotics nor collagen sponges containing gentamicin are suitable.”
  • the therapeutic agents contained in the aforementioned wound dressings are not immobilized within the hydrogel matrix.
  • the drug in the presence of wound exudate, the drug is thus rapidly released at the injured site, so that a long-lasting local therapeutic effect cannot be achieved.
  • liposomes have been increasingly explored as novel drug delivery systems that alleviate this problem.
  • Liposomes are microscopic spheres that are produced when a phospholipid thin film is hydrated under particular conditions. Conditions of high shear, produced during extrusion of the lipid solution through 100 nm pore size membranes, typically yield liposomes of 100 nm diameter. Liposomes have been used as drug delivery systems for many years, because they are biocompatible; non-immunogenic; non- toxic; allow encapsulation of water soluble and hydrophobic drugs equally well; allow solubilization of recalcitrant drugs; reduce toxicity of certain drugs; and, allow a slow, continuous release of their contents over a relatively long period of time. Typically, liposomes can release their drug content over a 7-14 day period, or even longer if required.
  • Liposomes can be custom-designed by varying the lipid type, lipid and cholesterol ratio, the surface charge, surface charge density, size and mode of production. Careful attention must be given to the formulation and drug encapsulation efficiency of liposomes in order to produce a slow-release drug reservoir. In essence, liposomes are an excellent drug delivery vehicle. Furthermore, one study described the use of a topical liposomal povidone- iodine hydrogel combined with moisturizer for antiseptic treatment of wounds [Reimer, K., er a/., Povidone-iodine liposomes-an overview. Dermatology, 1997. 195(Suppl 2): p. 93-9]. U.S. Pat.
  • hydrogel wound dressing As discussed above, the advantage of a hydrogel wound dressing is that it allows for hydration of the wound site, while simultaneously removing excess moisture and providing for a barrier from outside contaminants.
  • the prior art has not disclosed hydrogel wound dressing sheets that deliver, in a uniform and controlled manner, a therapeutically effective amount of one or more therapeutic agents entrapped in a plurality of liposomes dispersed throughout the hydrogel.
  • the advantage of having a therapeutic agent delivered to the wound site is that the therapeutic agent can further promote wound healing and prevent infection.
  • a hydrogel wound dressing which effectively keeps a wound hydrated, while simultaneously removing excess moisture from the wound, wherein the hydrogel wound dressing releases a therapeutic agent to the wound site over a period of time to promote wound healing and prevent infection.
  • the invention provides a therapeutic wound dressing which comprises an outer layer; a cross-linked hydrogel matrix layer; an optional hydrogel-supporting material confined within the hydrogel matrix; a liposome-encapsulated therapeutic agent incorporated in the hydrogel matrix; and an optional protective release sheet.
  • the hydrogel matrix material is preferably cross-linked with polyethylene glycol or carbodiimide, and is positioned under the outer layer for placement on the wound.
  • the cross-linked hydrogel matrix is biocompatible and biodegradable (i.e. does not release potentially toxic degradation products), and will ensure protection of the liposomes from membrane-disrupting shear forces that are encountered during handling of the wound dressing, and from rapid degradation of the liposome in vivo.
  • By adjusting the amount of cross-linking within the hydrogel matrix it is possible to control the rate of release of the therapeutic agent. For example, with higher levels of cross-linking, one gets slower release of the therapeutic agent. With reduced cross- linking, one gets a quicker release of the therapeutic agent.
  • the containment of the liposomes within the hydrogel matrix creates an opportunity to control drug diffusion rates.
  • the liposomes used in the present invention may be unilamellar or multilamellar.
  • Liposomes, microspheres, nanospheres, biodegradable polymers, and other systems are excellent drug delivery vehicles, and the methods of preparation and drug loading procedures for liposomes and the others are well known in the art (see, for example, U.S. Patent Application Serial No. 08/843,342 by DiCosmo et al).
  • Liposomes can store both polar and non-polar compounds via interactions with the biocompatible and biodegradable lipid bilayer, or compartmentation within the aqueous core, respectively.
  • the liposomal hydrogel of the present invention includes a variety of gel drug combinations. Generally, the selection or pairing of the hydrogel and drug is determined only by the desired application and relevant indication. That is, any active agent that can be compounded into liposomes, microspheres, nanospheres, or other suitable encapsulation vehicle can be confined within the hydrogel matrices of the present invention, which are then used to create the wound dressings of the present invention.
  • the hydrogel matrix thus constitutes a vehicle for the containment of high concentrations of therapeutic agent such as one or more antibiotics, antiseptic agents, hormones, steroids, growth factors, antihistamines, colony stimulating factors, interleukins, and the like, and/or combinations thereof.
  • therapeutic agent such as one or more antibiotics, antiseptic agents, hormones, steroids, growth factors, antihistamines, colony stimulating factors, interleukins, and the like, and/or combinations thereof.
  • the therapeutic hydrogels of the present invention can be used in wound dressings for the management of wound infection and to promote wound healing.
  • the liposomes which are incorporated within the hydrogel and encapsulate the therapeutic agent, act as controlled drug delivery depots by releasing the drug over several days.
  • the hydrogel wound dressings of the present invention are applied to a wound and the drug is then released by diffusion from the hydrogel to the wound site onto which the hydrogel wound dressing is applied.
  • the hydrogel matrix can be a conventional hydrogel (e.g., gelatin, pectin, etc.), a protein (e.g. collagen, etc.), or other adjuvant.
  • the hydrogel matrix of the present invention is cross-linked and preferably will have some structural support to impart resistance to shear forces. As discussed above, by adjusting the amount of cross- linking within the hydrogel matrix, one can effectively control the rate of drug diffusion.
  • a preferred hydrogel is gelatin cross-linked with polyethylene glycol as by reacting gelatin with nitrophenylcarbonate- or disuccinimidylcarbonate-PEG. Another preferred hydrogel is gelatin cross-linked with carbodiimide.
  • the therapeutic hydrogels of the present invention serve as support material for a variety of liposomal therapeutics.
  • Any therapeutic agent suitable for encapsulation in a liposome, microsphere, nanosphere or the like can be utilized in the present invention.
  • therapeutic agents useful in the present invention include antibiotics, antiseptic agents, antihistamines, hormones, steroids, therapeutic proteins, and the like.
  • the desired concentration of therapeutic agent within a hydrogel will vary depending upon the characteristics of the chosen therapeutic agent. For example, as between an antibiotic and a therapeutic protein, the required concentration of antibiotic, which are generally active in the microgram range, will likely be higher than the concentration of a therapeutic protein, many of which are active in the nanogram range.
  • the present invention provides a multi-layer wound dressing comprising: an outer layer; a cross-linked hydrogel matrix layer, with an optional support material confined within the hydrogel matrix; at least one liposome-encapsulated therapeutic agent incorporated in the cross-linked hydrogel matrix; and optionally a protective release sheet.
  • the present invention further provides a multi-layer wound dressing which provides for the long term, stable release of a therapeuticaliy effective amount of at least one therapeutic agent, wherein said wound dressing comprises: an outer layer, a cross-linked hydrogel matrix layer, and a therapeutic agent encapsulated in liposomes and incorporated in said hydrogel matrix layer.
  • stable release is meant the release of a stable therapeutic agent over a period of at least about 24 hours, and preferably up to about 14 days.
  • therapeuticaliy effective amount of a therapeutic agent it is meant an amount suitable to achieve the desired therapeutic effect, depending on the agent employed.
  • a therapeuticaliy effective amount of an antibiotic is that which is capable of reducing the bacterial counts in the wound significantly below the threshold considered to be a clinical infection (i.e., 10 5 colony forming units per g of tissue). It will be appreciated that the therapeuticaliy effective amount of the therapeutic agent will vary depending on the agent employed and the conditions requiring treatment. One of ordinary skill in the art relying on established medical principles will be able to readily determine the appropriate agent and the therapeuticaliy effective amount required.
  • the present invention also provides a multi-layer wound dressing which provides for the effective distribution of a therapeutic agent, wherein said wound dressing comprises: an outer layer, a cross-linked hydrogel matrix layer, and a therapeutic agent encapsulated in liposomes and incorporated in said hydrogel matrix layer.
  • the present invention also provides methods for formulating such a multi-layer wound dressing.
  • the present invention also provides means for treating or alleviating cutaneous wound infections.
  • the type of therapeutic agent encapsulated in the liposome is not restricted to any single therapeutic agent.
  • Therapeutic agents which can be used in the present invention include, but are not limited to, antibiotics, hormones, growth factors and other factors that are beneficial for the condition under management, in accordance with sound medical judgment.
  • the present invention also provides a method of treating wounds comprising applying a wound dressing of the present invention to a wound.
  • a preferred embodiment of the present invention is a wound dressing comprised of a gelatin hydrogel cross-linked with polyethylene glycol (PEG), wherein dispersed within the hydrogel is a liposomal antibiotic or a liposomal antiseptic.
  • PEG polyethylene glycol
  • hydrogel or gel any material forming, to various degrees, a jelly like product when suspended in a solvent, typically water or polar solvents.
  • a solvent typically water or polar solvents.
  • These gels can be proteins such as collagen or hemoglobin, or more conventional hydrogels such as gelatin, pectin, and fractions and derivatives thereof.
  • liposomal therapeutic agents any physical structure surrounding or encapsulating a therapeutic agent such as a drug.
  • liposomal therapeutic agents will include various drugs or biologically active agents such as antibiotics, antiseptic agents, antihistamines, hormones, steroids, growth factors, colony stimulating factors, interleukins, and the like confined or encapsulated within a structure such as a liposome, whether of unilamellar or bilayer structure, or microspheres or nanospheres or the like.
  • Figure 1 A cross-sectional view of the preferred wound dressing of the present invention illustrating the three layers that form the wound dressing.
  • Figure 2. An enlarged view of the hydrogel matrix layer (2) illustrated in Figure 1.
  • Figure 3. A cross-sectional view illustrating the two layers that form a second preferred embodiment of the hydrogel wound dressing product.
  • FIG. 4 A bar graph representing the effectiveness of liposomal ciprofloxacin-loaded hydrogel wound dressings in treating a full-thickness wound infection in rats. Wounds were covered with either a plain liposome hydrogel wound dressing (black bars) or a liposomal ciprofloxacin hydrogel wound dressing (dashed bars). Number of animals in each experimental group is indicated in parenthesis. Data are means ⁇ SEM.
  • FIG. 5 A bar graph representing the effectiveness of liposomal ciprofloxacin-loaded hydrogel wound dressings in preventing the progression of infection in contaminated full-thickness wounds in rats. Wounds were covered with either a plain liposome hydrogel wound dressing (black bars) or a liposomal ciprofloxacin hydrogel wound dressing (dashed bars). Number of animals in each experimental group is indicated in parenthesis. Data are means ⁇ SEM.
  • Figure 6 A bar graph comparing the bactericidal efficacies of liposomal ciprofloxacin-loaded hydrogel wound dressings and commercially available silver-coated barrier wound dressings in a rat model of contaminated full-thickness burn wounds. Wounds were excised after 30 min (dashed bars) or 120 min (black bars). Number of wounds excised in each experimental group is indicated in parenthesis. Data are means ⁇ SEM.
  • FIG. 7 A bar graph representing the effectiveness of liposomal ciprofloxacin-loaded hydrogel wound dressings in treating an infection in a superficial muscle in rats. Wounds were covered with a plain liposome hydrogel wound dressing (black bars), a free ciprofloxacin hydrogel wound dressing (empty bars) or a liposomal ciprofloxacin hydrogel wound dressing (dashed bars). Number of animals in each experimental group is indicated in parenthesis. Data are means ⁇ SEM.
  • FIG. 8 A bar graph representing the effectiveness of liposomal ciprofloxacin-loaded hydrogel wound dressings in treating an infection in a deep muscle in rats. Wounds were covered with a plain liposome hydrogel wound dressing (black bars), a free ciprofloxacin hydrogel wound dressing (empty bars) or a liposomal ciprofloxacin hydrogel wound dressing (dashed bars). Number of animals in each experimental group is indicated in parenthesis. Data are means ⁇ SEM.
  • a major object of the present invention is to provide a therapeutic wound dressing, characterized in that the wound dressing comprises an outer layer; a cross- linked hydrogel matrix layer; an optional gel-supporting material confined within the hydrogel matrix; a liposome-encapsulated therapeutic agent incorporated in the hydrogel matrix; and an optional protective release sheet.
  • the hydrogel matrix of the present invention can be hydrogel (e.g. gelatin, pectin, etc.), a protein (e.g. collagen, hemoglobin, etc.), or other adjuvant.
  • the wound dressing of the present invention is optionally translucent.
  • the outer layer of the wound dressing optionally is coated with a medical-grade adhesive, to facilitate binding of the hydrogel matrix to the outer layer. Additionally, the outer layer may optionally be perforated, vapor permeable, and/or waterproof.
  • a further object of the present invention is a method of treating a wound by applying the hydrogel wound dressing of the present invention.
  • the hydrogel wound dressing of the present invention provides an improved level of wound management for a wide range of applications, including burn wounds and full thickness wounds.
  • the rate of release of the therapeutic agent it is possible to modulate the rate of release of the therapeutic agent. For instance, by increasing the amount of crosslinking, one can slow down the rate of release of the therapeutic agent. Conversely, by decreasing the amount of crosslinking, one can speed up the rate of release of the therapeutic agent.
  • Another means of controlling the release of the therapeutic agent is by selection of the appropriate liposome. Different therapeutic agents have different properties, and one of skill in the art would know how to match particular therapeutic agents with particular liposomes to arrive at desired properties, such as rate of release of a therapeutic agent. Thus, by adjusting the amount of crosslinking in the hydrogel matrix and the type of liposome used, one can effectively control the rate of release of the therapeutic agent.
  • the inventors discovered that one can extend the period of time the therapeutic agent is released. This is because without the outer layer, the hydrogel matrix quickly dried up and once this occurred, the liposomes no longer released the therapeutic agent.
  • the outer layer used in the present invention prevents the hydrogel matrix from drying up (while simultaneously releasing excess moisture from the hydrogel matrix) thereby allowing for extended release of the therapeutic agent.
  • a gelatin hydrogel matrix (b), cross-linked with polyethylene glycol or carbodiimide (c) in which a drug encapsulated by a liposome (d) is dispersed is made to form a thin, flexible sheet by procedures known in the art and disclosed herein.
  • the hydrogel sheet (2) is positioned in the center portion of a larger diameter adhesive outer layer (1 ).
  • the thin-film outer layer (1 ) is preferably selected from a group of materials including, but not limited to, polyurethane, polyethylene, vinyl, polyvinylchloride, or other suitable material.
  • the perimeter portion of the outer layer (1 ) is coated with a medical-grade adhesive, and is preferably perforated to allow the skin of the patient to breath.
  • a medical-grade adhesive e.g., a methyl methacrylate copolymer
  • this outer layer (1 ) is required to maintain an adequate hydration level of the hydrogel matrix, as well as to prevent maceration of the wound by allowing release of excess moisture.
  • the outer layer (1 ) and hydrogel sheet (2) optionally are translucent and optionally the outer layer (1 ) has a grid pattern transposed thereon to allow for easy measurement and viewing of the wound.
  • the medicated hydrogel sheet can be manufactured to any shape and size.
  • the release sheets can be made of, for example, non-adherent, plasticized material.
  • Each release sheet (3) is attached to the adhesive perimeter portion of the outer layer (1 ), and extends towards the center of the dressing to cover half of the hydrogel matrix (2).
  • the free edge of one of the release sheets (3) is folded at the center of the dressing, while the free edge of the other release sheet (3) lies flat on top of the folded edge.
  • the hydrogel wound matrix (2) located in the center of the dressing is placed in contact with the wound, followed by the adhesive portion of the outer layer (1 ).
  • this release system preserves sterility of the wound dressing by minimizing contact with the hydrogel matrix (2) per se.
  • the ready-to-use wound dressings can then be sealed preferably in pouches that are impermeable to water vapor, and sterilized (e.g., by ⁇ -irradiation).
  • the drug incorporated in the liposomes is preferably selected from a group of drugs including, but not limited to antibiotics, antimicrobials, antipathogenic peptides, antiseptic, antibacterial and antifungal agents, anti- inflammatory drugs, local anesthetics, central nervous system acting agents, and wound-healing promoting agents (e.g., growth factors).
  • antibiotics antibiotics
  • antimicrobials antipathogenic peptides
  • antiseptic antiseptic
  • antibacterial and antifungal agents anti- inflammatory drugs
  • local anesthetics e.g., central nervous system acting agents
  • wound-healing promoting agents e.g., growth factors
  • composition e.g., lipid type, lipid and cholesterol ratio, surface charge, etc.
  • the composition can be customized depending on the drug encapsulated to produce an appropriate slow- release drug reservoir.
  • polyethylene glycol cross-linked gels containing dipalmitoylphosphatidyicholine/ dipalmitoylphosphatidylethanolamine- polyethylene glycol/cholesterol or dipalmitoylphosphatidylcholine/cholesterol liposomes constitute the optimum formulation with respect to gel matrix stability, liposome efflux, and drug loading efficiency.
  • a wound dressing that includes an adhesive border is not necessarily suitable for covering very large (e.g., entire torso or back) or irregular surface areas.
  • a proprietary hydrogel matrix (2) that incorporates a liposomal drug is made to form a thin, flexible sheet by pouring a fluid hydrogel mixture into an appropriate mold.
  • An adhesive outer layer (1 ) is then applied to the hydrogel matrix sheet (2) to fit its dimensions.
  • the thin-film outer layer (1 ) is preferably selected from a group of materials including, but not limited to polyurethane, polyethylene, vinyl, polyvinylchloride, or other suitable material.
  • the hydrogel wound dressing sheet is secured to the wound using secondary dressings (e.g., bandages, tubular dressings).
  • secondary dressings e.g., bandages, tubular dressings.
  • a large hydrogel sheet may require inclusion of a support material to facilitate its handling and reduce risks of tear of the hydrogel matrix.
  • an optional support material (3) is included in the dressing to confer strength to the hydrogel matrix layer (2).
  • the permeable nature of the support material allows the hydrogel matrix to completely impregnate the material, so that the hydrogel matrix is entirely exposed at the outer edges of the support material. In this way, the support material does not adhere to the wound.
  • the support material may be selected from the group of materials consisting of strands of natural fibers, strands of synthetic fibers, knitted fabrics, woven medical- grade fabrics or meshes, non-woven medical-grade fabrics or meshes, or any combination thereof.
  • Liposomes that are incorporated into the hydrogels may be composed of a variety of lipids.
  • dipalmitoyl phosphatidyl choline (DPPC)/cholesterol (1 :1 ) is used.
  • DPPC dipalmitoyl phosphatidyl choline
  • the formulation to be used is not limiting, and any number of lipid-to- other-constituents ratios may be used to effectively achieve the embodiments of this invention.
  • the usual procedure for liposome synthesis begins by dissolving the resulting lipid in a small volume of chloroform (i.e.
  • Therapeutic agent was encorporated in the liposomes according to the remote- loading technique described in Y.K. Oh et al, "Formulation and efficacy of liposome- encapsulated antibiotics for therapy of intracellular Mycobacte ⁇ um avium infection," Antimicrob. Agents Chemother. 39:2104-2111 (1995).
  • chlorhexidine-containing liposomes can be immediately mixed with PEG and gelatin to initiate hydrogel formation.
  • Ammonium sulfate liposomes can be loaded with ciprofloxacin after incorporation within the hydrogel matrix, by incubation of the iiposome-hydrogel in a solution of antibiotic, typically 2-10 mg/mL, for 1 hr at 50°C.
  • the hydrogel matrix when cross-linked with PEG consists of 10% gelatin, 6%NPC-PEG and 10% sucrose at pH4.0, and self cross-linked hydrogel (SelfXL) contains 10% w/v gelatin.
  • Both formulations of hydrogels can be prepared by dissolving the components in a suspension of 100 nm liposomes at 45°C for approximately 15 min.
  • the hydrogels are kept at 4°X for at least 10 min prior to cross-link initiation, that involves immersion of the gels into a 200 mM, pH 9, borate buffer solution.
  • self cross-linked gels must first be activated by reaction with water soluble carbodiimide (5 mg/mL) for 1 h.
  • Cross-linking excipients are removed form the gels by continual washing with buffer for 24 h. If liposomes were required, they were added from a pure liposome suspension. The concentration of liposomes in PEG-geiatin solutions was 15 mM with respect to DPPC. All solutions were heated at
  • Drugs may be incorporated in liposomes by either of two general drug-loading strategies, often referred to as active and passive loading.
  • Weak amines such as ciprofloxacin
  • ciprofloxacin can be actively loaded into pre-formed liposomes at high concentrations through the generation of a trans-bilayer pH gradient (acidic inside) that traps the protonated compound within the liposome core.
  • Many other compounds, especially lipophilic ones become associated with liposomes as they form, either through their co-formulation with lipids dissolved in organic solvent or by their inclusion in the medium used to hydrate the lipid film.
  • the choice of loading strategy is usually dictated by the chemical properties of the target compound, and in the case of ciprofloxacin either strategy may be used.
  • BACTERIAL CHALLENGE A clinical isolate of Pseudomonas aeruginosa was used to infect the wounds. A bacterial suspension was obtained using standard microbiological procedures, and diluted to approximately 1x10 8 colony forming units per mL. This bacterial dose was selected because the clinical definition of wound infection pertains to at least 1x10 5 organisms/g tissue.
  • HYDROGEL WOUND DRESSINGS Liposomal ciprofloxacin-loaded hydrogel wound dressings or plain liposome-loaded hydrogel wound dressings were supplied in individual vials (2-cm disks, 1.25 mm thick). Sterility of the hydrogel dressings of a given batch was assessed two days prior to their application on the wounds.
  • Each dressing was then covered with a TegadermTM (3M) semi-permeable membrane; a gauze pad was applied to ensure a good contact between the dressing and the wound; and a piece of tubular elastic dressing retainer as well as a rat tether jacket were fitted to each rat.
  • All animals were sacrificed 24 h after application of the dressing and muscle tissues were excised and processed as previously described.
  • a 5-log reduction in bacterial counts measured in the panniculus carnosus muscle was observed after application of the liposomal ciprofloxacin hydrogel dressings for 24 h compared to the control dressings (Fig. 4).
  • a gauze pad was then applied to ensure a good contact between the dressing and the wound, and a piece of self-adherent elastic bandage was used to securely wrap the dressing around each rat.
  • All animals were sacrificed 24 h after application of the dressing and muscle tissues were excised and processed as previously described. All hydrogel wound dressings recovered were intact (i.e., no apparent dehydration). Assessment of bacterial counts in the panniculus carnosus and the spinotrapezius muscles revealed approximately 7-log and 3-log reductions, respectively, in the number of bacteria recovered in these tissues after application of the liposomal ciprofloxacin hydrogel dressings for 24 h compared to that of the control dressings (Fig. 5).
  • This study was designed to compare the bactericidal efficacy of liposomal ciprofloxacin-loaded hydrogel dressings to that of a commercially available silver- coated antibacterial barrier wound dressing.
  • a modified Walker-Mason burn wound model was used. Briefly, four male, Sprague-Dawley rats were anesthetized. Their dorsum was shaved and cleansed using standard procedures. Six 2 cm x 2 cm burn wounds were made on the back of each animal by applying a heated brass rod for 40 s on the skin, to induce a full-thickness, non-lethal burn. Three 2 cm x 2 cm pieces of sterile gauze and three 2 cm x 2 cm silver-coated wound dressings were applied to cover the wounds in two rats.
  • a mixture of Ps. aeruginosa Utah strain (approximately 10 7 CFU in 200 ⁇ l) was then applied to each of the dressings.
  • Each dressing was then covered with a small sterile piece of gauze, and an ElastoplastTM adhesive tape. A gauze pad was then applied to ensure a good contact between the dressing and the wound, and a piece of self- adherent elastic bandage was used to securely wrap the dressing around each rat. Animals were sacrificed after 1 , 3 or 7 days following application of the experimental wound dressing. Muscle tissues were excised and processed as previously described.

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Abstract

Cette invention se rapporte à un pansement aux hydrogels, qui libère efficacement un agent thérapeutique sur une période prolongée. Des agents thérapeutiques liposomiques, tels que des antibiotiques et des antiseptiques, sont incorporés dans les hydrogels et la matrice hydrogels/liposomes est produite sous la forme d'une feuille. Cette feuille hydrogels/liposomes est placée sur une couche extérieure (éventuellement recouverte d'un adhésif de qualité médicale) et appliquée ensuite sur la plaie. Cette invention sert particulièrement à traiter et à prévenir les infections des plaies.
PCT/CA2000/000991 1999-08-27 2000-08-25 Pansement aux hydrogels, contenant un agent therapeutique encapsule dans des liposomes WO2001015750A1 (fr)

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CA002345779A CA2345779A1 (fr) 1999-08-27 2000-08-25 Pansement aux hydrogels, contenant un agent therapeutique encapsule dans des liposomes
AU66794/00A AU6679400A (en) 1999-08-27 2000-08-25 Hydrogel wound dressing containing liposome-encapsulated therapeutic agent
EP00954243A EP1124587A1 (fr) 1999-08-27 2000-08-25 Pansement aux hydrogels, contenant un agent therapeutique encapsule dans des liposomes
JP2001520161A JP2003508127A (ja) 1999-08-27 2000-08-25 リポソームで被包された治療薬を含むヒドロゲル傷被覆用品

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WO2003047643A1 (fr) * 2001-12-06 2003-06-12 Johnson & Johnson Medical Limited Pansements therapeutiques a liberation controlee
WO2005035012A1 (fr) * 2003-10-10 2005-04-21 Coloplast A/S Pansement
WO2007110767A2 (fr) * 2006-03-24 2007-10-04 Universita' Degli Studi Di Pavia Pansements interactifs pour le traitement de maladies dermatologiques
DE102006015271A1 (de) * 2006-04-01 2007-10-11 Lohmann & Rauscher Gmbh & Co. Kg Biguanidhaltige Liposomen
WO2011095353A1 (fr) * 2010-02-05 2011-08-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Compositions antimicrobiennes actives, revêtements et méthodes de lutte contre les bactéries pathogènes
US8071135B2 (en) 2006-10-04 2011-12-06 Anthrogenesis Corporation Placental tissue compositions
CN102309448A (zh) * 2010-06-29 2012-01-11 中国人民解放军军事医学科学院毒物药物研究所 一种肺部给药的环丙沙星药用组合物及其制备方法
US8105634B2 (en) 2006-08-15 2012-01-31 Anthrogenesis Corporation Umbilical cord biomaterial for medical use
US20120064146A1 (en) * 2003-06-19 2012-03-15 Coloplast A/S Wound care device
US20130023544A1 (en) * 2011-07-07 2013-01-24 Sanofi CARBOXYLIC ACID DERIVATIVES HAVING AN OXAZOLO[5,4-d]PYRIMIDINE RING
WO2013058996A1 (fr) * 2011-10-19 2013-04-25 R.P. Scherer Technologies, Llc Système d'administration pharmaceutique à deux phases
US8821857B2 (en) 2006-10-06 2014-09-02 Anthrogenesis Corporation Human placental collagen compositions and methods of making and using the same
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
US9017664B2 (en) 2006-12-15 2015-04-28 Lifebond Ltd. Gelatin-transglutaminase hemostatic dressings and sealants
US9044456B2 (en) 2008-06-18 2015-06-02 Lifebond Ltd. Cross-linked compositions
CN105536031A (zh) * 2016-02-03 2016-05-04 常州市奥普泰科光电有限公司 一种茶树油脂质体抗炎抑菌医用敷料的制备方法
US9499852B2 (en) 2012-01-12 2016-11-22 The University Of Bath Wound dressing
US9877871B2 (en) 2010-09-17 2018-01-30 Teikoku Seiyaku Co., Ltd. Method for using hydrogel sheet for treating wound
US9901660B2 (en) 2013-07-04 2018-02-27 Yeda Research And Development Co. Ltd. Low friction hydrogels and hydrogel-containing composite materials
US10202585B2 (en) 2009-12-22 2019-02-12 Lifebond Ltd Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
CN114767620A (zh) * 2022-03-16 2022-07-22 四川省医学科学院·四川省人民医院 一种负载藤黄酸的多级响应可注射水凝胶及其用途
CN116271179A (zh) * 2023-03-23 2023-06-23 南通大学 一种伤口敷料及其制备方法
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices

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US20050214376A1 (en) * 2003-10-21 2005-09-29 Marie-Pierre Faure Hydrogel-containing medical articles and methods of using and making the same
DE102005063375A1 (de) * 2005-09-15 2007-04-19 Schülke & Mayr GmbH Antimikrobielle Zubereitungen mit einem Gehalt an Octenidindihydrochlorid verkapselt in Liposomen
EP1815877B1 (fr) * 2006-02-02 2009-11-25 Euro-Celtique S.A. Hydrogel pour le traitment de blessures
JP2011051966A (ja) * 2009-09-03 2011-03-17 Daiya Seiyaku Kk 爪白癬治療用貼付剤
DE102012011422A1 (de) * 2012-06-08 2013-12-12 Gottlieb Binder Gmbh & Co. Kg Medizinprodukt zur Versorgung eines Individuums
JP6522387B2 (ja) * 2015-03-27 2019-05-29 株式会社キレートジャパン ハイドロゲル含有化粧料
CN106309150B (zh) * 2015-06-29 2020-10-30 烟台蓝创生物技术有限公司 一种医用胶原蛋白敷料及其制备方法和应用

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US7732655B2 (en) 2001-12-06 2010-06-08 Systagenix Wound Management (Us), Inc. Controlled release therapeutic wound dressings
WO2003047643A1 (fr) * 2001-12-06 2003-06-12 Johnson & Johnson Medical Limited Pansements therapeutiques a liberation controlee
US8409610B2 (en) * 2003-06-19 2013-04-02 Coloplast A/S Wound care device
US20120064146A1 (en) * 2003-06-19 2012-03-15 Coloplast A/S Wound care device
WO2005035012A1 (fr) * 2003-10-10 2005-04-21 Coloplast A/S Pansement
WO2007110767A2 (fr) * 2006-03-24 2007-10-04 Universita' Degli Studi Di Pavia Pansements interactifs pour le traitement de maladies dermatologiques
WO2007110767A3 (fr) * 2006-03-24 2008-02-07 Univ Pavia Pansements interactifs pour le traitement de maladies dermatologiques
DE102006015271A1 (de) * 2006-04-01 2007-10-11 Lohmann & Rauscher Gmbh & Co. Kg Biguanidhaltige Liposomen
US8105634B2 (en) 2006-08-15 2012-01-31 Anthrogenesis Corporation Umbilical cord biomaterial for medical use
US8071135B2 (en) 2006-10-04 2011-12-06 Anthrogenesis Corporation Placental tissue compositions
US9770488B2 (en) 2006-10-06 2017-09-26 Anthrogenesis Corporation Human placental collagen compositions, and methods of making and using the same
US9775886B2 (en) 2006-10-06 2017-10-03 Celularity, Inc. Human placental collagen compositions, and methods of making and using the same
US9974840B2 (en) 2006-10-06 2018-05-22 Celularity, Inc. Human placental collagen compositions, and methods of making and using the same
US8821857B2 (en) 2006-10-06 2014-09-02 Anthrogenesis Corporation Human placental collagen compositions and methods of making and using the same
US8877180B2 (en) 2006-10-06 2014-11-04 Anthrogenesis Corporation Human placental collagen compositions, and methods of making and using the same
US9017664B2 (en) 2006-12-15 2015-04-28 Lifebond Ltd. Gelatin-transglutaminase hemostatic dressings and sealants
US9655988B2 (en) 2006-12-15 2017-05-23 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US9636433B2 (en) 2006-12-15 2017-05-02 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US9044456B2 (en) 2008-06-18 2015-06-02 Lifebond Ltd. Cross-linked compositions
US10202585B2 (en) 2009-12-22 2019-02-12 Lifebond Ltd Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
WO2011095353A1 (fr) * 2010-02-05 2011-08-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Compositions antimicrobiennes actives, revêtements et méthodes de lutte contre les bactéries pathogènes
EP2361502A1 (fr) * 2010-02-05 2011-08-31 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Compositions antimicrobiennes actives, revêtements et procédés de contrôle des bactéries pathogènes
CN102309448B (zh) * 2010-06-29 2014-07-09 中国人民解放军军事医学科学院毒物药物研究所 一种肺部给药的环丙沙星药用组合物及其制备方法
CN102309448A (zh) * 2010-06-29 2012-01-11 中国人民解放军军事医学科学院毒物药物研究所 一种肺部给药的环丙沙星药用组合物及其制备方法
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
US9877871B2 (en) 2010-09-17 2018-01-30 Teikoku Seiyaku Co., Ltd. Method for using hydrogel sheet for treating wound
US9321787B2 (en) * 2011-07-07 2016-04-26 Sanofi Carboxylic acid derivatives having an oxazolo[5,4-d]pyrimidine ring
US20130023544A1 (en) * 2011-07-07 2013-01-24 Sanofi CARBOXYLIC ACID DERIVATIVES HAVING AN OXAZOLO[5,4-d]PYRIMIDINE RING
US9314441B2 (en) 2011-10-19 2016-04-19 R.P. Scherer Technologies, Llc Two phase pharmaceutical delivery system
WO2013058996A1 (fr) * 2011-10-19 2013-04-25 R.P. Scherer Technologies, Llc Système d'administration pharmaceutique à deux phases
US9499852B2 (en) 2012-01-12 2016-11-22 The University Of Bath Wound dressing
US9901660B2 (en) 2013-07-04 2018-02-27 Yeda Research And Development Co. Ltd. Low friction hydrogels and hydrogel-containing composite materials
US10314946B2 (en) 2013-07-04 2019-06-11 Yeda Research And Development Co. Ltd. Low friction hydrogels and hydrogel-containing composite materials
US10799619B2 (en) 2013-07-04 2020-10-13 Yeda Research And Development Co. Ltd. Low friction hydrogels and hydrogel-containing composite materials
CN105536031B (zh) * 2016-02-03 2018-12-11 浙江康诚工业产品设计有限公司 一种茶树油脂质体抗炎抑菌医用敷料的制备方法
CN105536031A (zh) * 2016-02-03 2016-05-04 常州市奥普泰科光电有限公司 一种茶树油脂质体抗炎抑菌医用敷料的制备方法
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices
CN114767620A (zh) * 2022-03-16 2022-07-22 四川省医学科学院·四川省人民医院 一种负载藤黄酸的多级响应可注射水凝胶及其用途
CN114767620B (zh) * 2022-03-16 2023-06-27 四川省医学科学院·四川省人民医院 一种负载藤黄酸的多级响应可注射水凝胶及其用途
CN116271179A (zh) * 2023-03-23 2023-06-23 南通大学 一种伤口敷料及其制备方法

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