WO2022162640A1 - Gestion de la douleur post-opératoire - Google Patents

Gestion de la douleur post-opératoire Download PDF

Info

Publication number
WO2022162640A1
WO2022162640A1 PCT/IB2022/050834 IB2022050834W WO2022162640A1 WO 2022162640 A1 WO2022162640 A1 WO 2022162640A1 IB 2022050834 W IB2022050834 W IB 2022050834W WO 2022162640 A1 WO2022162640 A1 WO 2022162640A1
Authority
WO
WIPO (PCT)
Prior art keywords
nanocomposite
hcl
collagen
wound
nanoparticles
Prior art date
Application number
PCT/IB2022/050834
Other languages
English (en)
Inventor
Paul Chambers
Kavitha KONGARA
Sujay PRABAKAR
Farzin SAHEBJAM
Preet Singh
Yi Zhang
Original Assignee
Massey University
Nz Leather & Shoe Research Association Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2021900209A external-priority patent/AU2021900209A0/en
Application filed by Massey University, Nz Leather & Shoe Research Association Inc filed Critical Massey University
Priority to AU2022213016A priority Critical patent/AU2022213016A1/en
Publication of WO2022162640A1 publication Critical patent/WO2022162640A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A61L15/325—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0033—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0052—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0095—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • This invention relates generally to a nanocomposite comprising collagen, nanoparticles and two or more different active agents.
  • the active agents can be drugs.
  • the invention also relates generally to the use of a nanocomposite comprising collagen, nanoparticles and two or more active agents for pain relief such as post-operative pain relief in livestock.
  • BACKGROUND Velvet deer antler is highly valued, particularly within Asian cultures, where it has been used in traditional medicines for more than 2000 years. Velvet antler has been very popular in the modern era too.
  • analgesia Code of Welfare for Deer, page 43, Std no 15 Pre-Transport Selection
  • the DeerQA Transport Programme The production of antler velvet requires the removal of the developing antler from the pedicle of young male deer under local anaesthetic.
  • the antler from animals in the family Cervidae differs from that of other species in that it is highly vascularised and innervated. Consequently, its removal is a painful procedure, thus represents an animal welfare issue (Kawtikwar et al., 2010).
  • Velvet antlers can be removed by either veterinarians or trained personnel acting under veterinary supervision and following the Velveting Code of Practice.
  • lidocaine HCL injected as a ring block does not provide long-term pain relief after antler removal in deer (Webster and Matthews, 2006). There is thus a need to find a method of producing longer acting postoperative analgesia.
  • An alternative harvest method for velvet antlers in deer utilises NaturO rings, which provide some local desensitization and control of bleeding (Woodbury et al., 2002).
  • Dehorning can cause several problems including profuse bleeding, exposure of the frontal sinus (a cavity in the skull), increased risk of sinusitis, prolonged wound healing, infection, and pain and distress. It is a legal requirement in New Zealand to provide pain relief for dehorning. Lidocaine hydrochloride (2%), the commonly used local anaesthetic for dehorning can provide pain relief for about 1.5 hours following the procedure (Stafford and Mellor, 2011). Behavioural, physiological, and neuroendocrine responses suggest that animals feel pain for several hours to days following dehorning (Stafford and Mellor, 2005). The wound healing following dehorning can take up to 3 months or more. There appears to have been no major advances in reducing bleeding and accelerating wound healing in dehorned cattle.
  • a composition for use for post-operative pain management in deer following antler removal and/or to provide a composition for use for post- operative pain management in cattle following dehorning and/or a method of managing post-operative pain in deer following antler removal and/or a method of managing post-operative pain in cattle following dehorning and/or to at least provide the public with a useful choice.
  • the present invention relates to a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and bupivacaine HCL.
  • PVP polyvinylpyrrolidone
  • ZnO/PVP nanoparticles zinc oxide nanoparticles
  • lidocaine HCL and bupivacaine HCL a nanocomposite comprising collagen, ZnO/PVP nanoparticles, lidocaine HCL and bupivacaine HCL for use in treating pain.
  • the invention in another aspect relates to a method of treating pain in a mammal comprising contacting an open wound with a nanocomposite of the invention.
  • a method of treating pain in a mammal comprising contacting an open wound with a nanocomposite of the invention.
  • Figure 1 The collagen/drug/nanoparticle wafer preparation process.
  • Figure 2 Locations around the antler measured by pressure algometry for measurement of pain sensation in deer.
  • the labelled sites indicate the order in which the mechanical nociceptor thresholds (MNT) were measured.
  • Figure 5 Pain threshold values (N) at different time points in control (solid circles), T125% nanoparticles (squares), T25% nanoparticles (triangles pointing up), and T3 no nanoparticles (triangles pointing down).
  • FIG. 6 Representative images of dehorned wounds of cattle from each treatment group: 6a) Group 1 (control) – image shows the wound and exposed frontal following dehorning; 6b) Group 2 (topical collagen wafers) – image of dehorned wound following the application of collagen wafers; 6c) Group 3 (topical local anaesthetic gel) – image shows the dehorned wound following the application topical local anaesthetic gel, Tri-Solfen.
  • Figure 7 Representative images of dehorned wounds of cattle from each treatment group: 7a) Group 1 (Control) – image shows the dehorned wound was not completely healed (scabs can be seen) 90 days following dehorning; 7b) Group 2 (topical collagen wafers) – image shows the dehorned wound was completely healed 65 days following dehorning; 7c) Group 3 (topical local anaesthetic gel) – image shows the dehorned wound was completely healed 85 days following dehorning.
  • Group 1 Control
  • Group 2 topical collagen wafers
  • Group 3 topical local anaesthetic gel
  • nanocomposite means a composite material containing at least one material that is a nanomaterial.
  • nanomaterial refers to a material with any external dimension in the nanoscale or having internal structure or surface structure in the nanoscale, with nanoscale defined as the length range approximately from 1 nm to 100 nm.
  • the invention provides a nanocomposite for effective post-operative pain management in deer following antler removal and in cattle following dehorning.
  • the nanocomposite of the invention has many applications that will be readily apparent to them based on the examples detailed in the present specification. Such applications are contemplated herein as part of the present invention.
  • Pain management in deer Deer antler is a highly vascularized tissue.
  • Another branch of the superficial temporal artery connects both the lateral and medial arteries, thus forming a vascular ring at the base of the pedicle.
  • This ring gives off several branches from distal to the proximal end of the antler.
  • the venous return is by the superficial temporal vein formed by converging lateral and medial veins draining the tip of the antler.
  • the bony structure in the middle of the antlers also contains blood vessels, and they are prone to bleed after antler removal.
  • the innervation to the antler is mainly from the infratrochlear and zygomaticotemporal branches of the ophthalmic branch of the trigeminal nerve (CNV).
  • CNV trigeminal nerve
  • the fast-growing horns of the male deer are termed as velvet antlers due to the covering skin, which looks like velvet. This condition occurs when the antler is in the growing stage, and they are not yet calcified. Eventually, the deer antler becomes calcified to form “hard antler” and after the mating period casts naturally; however, since these antlers lack the velvet covering, the market has no interest in purchasing them. Therefore, harvesting practices in the deer velvet industry focus on antler removal during their growing stage (Kawtikwar et al., 2010). As described previously herein, there are several products and methods currently in use for the removal of velvet antlers. The current industry standard is to use local anaesthesia to abolish the sensation of pain during the procedure.
  • Lidocaine HCL is favoured because it is very short- acting, and thus minimises the contamination of harvested products with drug residues that are destined for human consumption.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • opioids are well known to cause dependence in humans (albeit they are poorly studied in livestock).
  • dehorning can cause several problems including profuse bleeding, exposure of the frontal sinus (a cavity in the skull) leading to increased risk of infection, increased risk of sinusitis, prolonged wound healing, pain and distress. It is a legal requirement in New Zealand to provide pain relief for dehorning. Lidocaine hydrochloride (2%), the commonly used local anaesthetic for dehorning provides only short term pain relief; i.e., about 1.5 hours following the dehorning procedure. However, behavioural, physiological, and neuroendocrine responses suggest that animals feel pain for several hours to days following dehorning. Moreover, the wound healing following dehorning can take up to 3 months or more. There appears to have been no major advances in reducing bleeding and accelerating wound healing in dehorned cattle.
  • a nanocomposite comprising a combination of collagen, ZnO/PVP nanoparticles, bupivacaine HCL and lidocaine HCL can be used to provide sustained pain relief to deer following velvet antler removal and dehorning in cattle.
  • sustained pain relief and increased wound healing can be provided by a nanocomposite comprising a combination of collagen, ZnO/PVP nanoparticles, lidocaine HCL and optionally bupivacaine.
  • a nanocomposite as described herein, preferably comprising Type I collagen is surprisingly effective at mediating the sustained release of various anaesthetics when applied to a wound.
  • the nanocomposite comprises a novel combination of the local anaesthetics, bupivacaine HCL and lidocaine HCL.
  • sustained release was found to be particularly effective when these anaesthetics were combined in a collagen wafer containing ZnO/PVP nanoparticles.
  • Local anaesthetic compounds incorporated into collagen wafers comprising nanoparticles were released more gradually as compared to control treatment wafers without ZnO/PVP nanoparticles.
  • the inventors believe that the addition of nanoparticles during collagen wafer formation alters the architecture of the collagen fibre matrix, providing reinforcement and possibly facilitating adherence of the drugs within the collagen structure.
  • the nanocomposites described also have the advantage of low antigenicity. Collagen structure and uses in drug delivery Collagen, which was discovered by Payen in 1838, is one of the most animal abundant proteins.
  • collagenous More than 30 percent of the structural proteins in animals are collagenous, which is present in tissues, including skin, bone, tendon, cartilage, and cornea.
  • the various functions of collagen in these tissues are related to the different collagen types and structures.
  • Collagen as a vehicle in drug delivery is exceptionally biocompatible and biodegradable, and its abundance has made it unique in terms of accessibility.
  • Collagen matrices can be used in various forms including pads, gels, hydrogels and sprays.
  • Type I collagen is composed of three left-handed polypeptide alpha chains right hand twisted into a triple helical structure.
  • the polypeptide has a repeating amino acid sequence Gly-Xaa- Yaa., where Xaa and Yaa represent arbitrary amino acid residues.
  • Collagen which is used for biomedical purposes, can be extracted from various sources such as cattle skin and tendon, pig skin, avian skin, fish skin, and rat tail (Chattopadhyay and Raines, 2014). According to Zhang et al. and Li, collagen can be extracted from limed bovine split wastes, using various techniques such as acetic acid and pepsin extraction methods (Zhang et al., 2006, Li, 2003). Each extraction method can result in a different structure and functionality of collagen (Zhang et al., 2006, Li, 2003). Collagen yield is also related to the method of extraction (Li et al., 2008). In a particular embodiment, the Type I collagen is produced by pepsin extraction from cattle skin.
  • Nanoparticles are ultrafine particles which have a size between 1-100 nm (Scenihr, 2007).
  • the use of nanoparticles to form nanocomposites with collagen polymers is believed to be known in the art.
  • various nanoparticles which may be used to form nanocomposites as described herein including zinc oxide (ZnO), titanium oxide, gold (Au), and silver.
  • ZnO zinc oxide
  • Ti titanium oxide
  • Au gold
  • silver silver
  • a nanocomposite comprising collagen and 25% by weight of ZnO/PVP nanoparticles could be used to mediate the sustained release of bupivacaine HCL and/or lidocaine HCL, preferably both combined, and provide extended pain relief.
  • extended pain relief was up to 10 hours.
  • the incorporation of ZnO/PVP nanoparticles into the nanocomposite as described herein also resulted in an increase in the adherence of the nanocomposite to a treated wound. Without wishing to be bound by theory, the inventors believe that this process enhances wound healing by reducing cellular dehydration and facilitating cellular migration which is crucial for wound repair and/or tissue regeneration.
  • nanocomposite of the invention as described herein can take many forms.
  • the nanocomposite is in the form of a hydrogel.
  • a hydrogel is a crosslinked network of hydrophilic polymers which results in a three- dimensional structure dispersed in water.
  • Crosslinks can be either physical, such as hydrogen bonds, hydrophobic interactions, and physical entanglement of polymer chains, or chemical, i.e., covalent bonds.
  • hydrogel form it is believed that it is within the skill of a person in the art to convert the hydrogel into various different forms for use as described herein including powders, gels, films, wafers, pads, patches, sponges, sprays and adhesives.
  • the hydrogel can be moulded into a wafer or pad and lyophilized for application to a wound as described herein.
  • application is topical application.
  • the first aspect of the invention relates to a nanocomposite comprising collagen, ZnO/PVP nanoparticles, lidocaine HCL and bupivacaine HCL.
  • the nanocomposite consists essentially of collagen, ZnO/PVP nanoparticles, lidocaine HCL and bupivacaine HCL.
  • the nanocomposite consists of collagen, ZnO/PVP nanoparticles, lidocaine HCL, bupivacaine HCL and a carrier, diluent or excipient.
  • the nanocomposite is a slow release drug delivery device.
  • the collagen is Type I collagen.
  • the nanocomposite comprises about 6 to about 10 mg/ml collagen, preferably about 8 mg/ml collagen.
  • the nanocomposite comprises 6 to 10 mg/ml collagen, preferably 8.33 mg/ml.
  • the bupivacaine HCL and lidocaine HCL are associated with, and have a substantially homogenous distribution throughout, the polymeric matrix.
  • the ratio of bupivacaine HCL to lidocaine HCL is about 0.1:1 or 0.25:1 or 0.5:1 or 0.75:1 or about 1:1. In one embodiment the ratio of bupivacaine HCL to lidocaine HCL is 0.1:1 or 0.25:1 or 0.5:1 or 0.75:1 or 1:1.
  • the ZnO/PVP nanoparticles nanoparticles are replaced with a nanoparticle selected from the group consisting of titanium dioxide, gold (Au) and silver nanoparticles, and nanoparticles of organic compounds. In one embodiment the nanoparticles are monodispersed. In one embodiment the nanoparticles range in size from 20 to 100 nm.
  • the nanocomposite comprises Type I collagen, ZnO/PVP nanoparticles, bupivacaine HCL and lidocaine HCl. In one embodiment the nanocomposite consists essentially of Type I collagen, ZnO/PVP nanoparticles, bupivacaine HCL and lidocaine HCL. In one embodiment the nanocomposite consists of Type I collagen, ZnO/PVP nanoparticles, bupivacaine HCL, lidocaine HCL and a carrier, diluent or excipient.
  • the nanocomposite comprises about 0.1% to about 30% (wt/wt) nanoparticles, preferably about 1% to about 25%, preferably about 5% to about 25%, preferably about 5%, about 10%, about 15%, about 20%, preferably about 25% nanoparticles. In one embodiment the nanocomposite comprises 0.1% to 30% (wt/wt) nanoparticles, preferably 1% to 25%, preferably 5% to 25%, preferably 5%, 10%, 15%, 20%, preferably 25% nanoparticles. In one embodiment the nanocomposite comprises 0.1% to about 30% nanoparticles, preferably about 1% to 25%, about 5% to 25%, preferably about 10% to 25% nanoparticles.
  • the nanocomposite comprises 0.1% to 30% nanoparticles, preferably 1% to 25%, 5% to 25%, preferably 10% to 25% nanoparticles. In one embodiment the nanocomposite comprises a sufficient amount of bupivacaine HCL and lidocaine HCL to provide sustained pain relief. In one embodiment the nanocomposite comprises a sufficient amount of lidocaine HCL and optionally bupivacaine HCL to provide sustained pain relief. In one embodiment sustained pain relief is relief for about 4, 5, 6, 7, 8, 9, 10, 11 or about 12 hours, preferably for about 7, 8, 9, 10 or about 11 hours, preferably for about 8, 9 or 10 hours, preferably for about 10 hours.
  • sustained pain relief is relief for 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours, preferably for 7, 8, 9, 10 or 11 hours, preferably for 8, 9 or 10 hours, preferably for 10 hours.
  • the nanocomposite comprises about 1 to about 30 mg/ml bupivacaine HCL, preferably about 5 to about 25 mg/ml, about 10 to about 20 mg/ml, about 12 to about 16 mg/ml, about 13 to about 15 mg/ml, about 14 mg/ml.
  • the nanocomposite comprises 1 to 30 mg/ml bupivacaine HCL, preferably 5 to 25 mg/ml, 10 to 20 mg/ml, 12 to 16 mg/ml, 13 to 15 mg/ml, 14 mg/ml.
  • the nanocomposite comprises about 1 to about 30 mg/ml lidocaine HCL, preferably about 5 to about 25 mg/ml, about 10 to about 20 mg/ml, about 12 to about 16 mg/ml, about 13 to about 15 mg/ml, about 14 mg/ml. In one embodiment the nanocomposite comprises 1 to 30 mg/ml lidocaine HCL, preferably 5 to 25 mg/ml, 10 to 20 mg/ml, 12 to 16 mg/ml, 13 to 15 mg/ml, 14 mg/ml.
  • the release rate of bupivacaine HCL from the nanocomposite is about 32000 ng.mL- 1 .min -1 or less, preferably about 30000 ng.mL -1 .min -1 or less, about 27000 ng.mL -1 .min -1 or less, preferably about 15000 ng.mL -1 .min -1 or less. In one embodiment the release rate of bupivacaine HCL is about 12300 ng.mL -1 .min -1 or less. In one embodiment the release rate of bupivacaine HCL from the nanocomposite is about as shown in Table 1 (ng.mL -1 .min -1 ) or less.
  • the release rate of bupivacaine HCL from the nanocomposite is 32000 ng.mL -1 .min -1 or less, preferably 30000 ng.mL -1 .min -1 or less, 27000 ng.mL -1 .min -1 or less, preferably 15000 ng.mL- 1 .min -1 or less.
  • the release rate of bupivacaine HCL is 12300 ng.mL -1 .min -1 or less.
  • the release rate of bupivacaine HCL from the nanocomposite is as shown in Table 1 (ng.mL -1 .min -1 ) or less.
  • the release rate of lidocaine HCL from the nanocomposite is about 47000 ng.mL- 1 .min -1 or less, preferably about 37000 ng.mL -1 .min -1 or less, about 27000 ng.mL -1 .min -1 or less, preferably about 15000 ng.mL -1 .min -1 or less. In one embodiment the release rate of lidocaine HCL from the nanocomposite is about 12750 ng.mL -1 .min -1 or less. In one embodiment the release rate of lidocaine HCL from the nanocomposite is about as shown in Table 1 (units given are in ng.mL -1 .min -1 ) or less.
  • the release rate of lidocaine HCL from the nanocomposite is 47000 ng.mL -1 .min -1 or less, preferably 37000 ng.mL -1 .min -1 or less, 27000 ng.mL -1 .min -1 or less, preferably 15000 ng.mL -1 .min -1 or less. In one embodiment the release rate of lidocaine HCL from the nanocomposite is 12750 ng.mL- 1 .min -1 or less. In one embodiment the release rate of lidocaine HCL from the nanocomposite is as shown in Table 1 (units given are in ng.mL -1 .min -1 ) or less.
  • the nanocomposite is in the form of a gel, hydrogel, powder or spray. In one embodiment the nanocomposite is a solid or semi-solid. In one embodiment the solid or semi-solid is in the form of a film, sheet, wafer, patch, pad, powder, foam, paste, spray, aerosol spray or cream, preferably a wafer or pad. Preferably the nanocomposite is in the form of a wafer. In one embodiment the nanocomposite is formed as a wound dressing. In another aspect, the invention relates to a nanocomposite comprising collagen, ZnO/PVP nanoparticles, lidocaine HCL and optionally bupivacaine HCL.
  • the invention relates to a nanocomposite comprising collagen, lidocaine HCL and bupivacaine HCL for use in treating pain.
  • the nanocomposite comprises ZnO/PVP nanoparticles, lidocaine HCL and bupivacaine HCL.
  • the nanocomposite consists essentially of collagen, ZnO/PVP nanoparticles, lidocaine HCL and bupivacaine HCL.
  • the nanocomposite consists of collagen, ZnO/PVP nanoparticles, lidocaine HCL, bupivacaine HCL and a carrier, diluent or excipient.
  • the invention relates to a nanocomposite comprising collagen, lidocaine HCL and optionally bupivacaine HCL for use in treating pain.
  • the nanocomposite comprises collagen, ZnO/PVP nanoparticles, lidocaine HCL and optionally bupivacaine HCL.
  • the nanocomposite consists essentially of collagen, ZnO/PVP nanoparticles, lidocaine HCL and optionally bupivacaine HCL.
  • the nanocomposite consists of collagen, ZnO/PVP nanoparticles, lidocaine HCL, optionally bupivacaine HCL and a carrier, diluent or excipient.
  • the collagen is Type I collagen.
  • the nanocomposite is for use in treating pain in an animal.
  • the animal is a mammal.
  • the mammal is a non-human mammal.
  • the non-human mammal is a livestock animal.
  • the non-human mammal is of the family Cervidae.
  • the cervid is Cervus elaphus, Cervus canadensis, or Cervus nippon, preferably Cervus elaphus.
  • the non-human mammal is of the family Bovidae.
  • the bovid is of the genus Bos.
  • the bovid is Bos taurus or Bos indicus.
  • the use comprises application of the nanocomposite to the surface of an open wound on the non-human mammal.
  • the open wound is an internal or external wound or combination thereof.
  • the open wound is an external wound.
  • the open wound is an internal wound.
  • the open wound is a vascularized wound.
  • the vascularized wound is one that was created by removing an antler or horn, preferably antler, preferably horn, from the non-human mammal.
  • the nanocomposite comprises a coating, film, wafer or pad.
  • the nanocomposite comprises or is in the form of a wafer.
  • the nanocomposite is for use to alleviate pain due to antler or horn, preferably antler, preferably horn, removal from the non-human animal.
  • pain is alleviated for at least 4, preferably at least 5, 6, 7, 8, 9, 10, 11 or preferably at least 12 hours from contact.
  • the alleviation of pain is determined mechanical nociceptor threshold (MNT) testing.
  • the invention relates to a method of treating pain in a mammal comprising contacting an open wound of the mammal with a nanocomposite as described herein.
  • the mammal is a non-human mammal.
  • the non-human mammal is a livestock animal.
  • the non-human mammal is of the family Cervidae.
  • the cervid is Cervus elaphus, Cervus canadensis, or Cervus nippon, preferably Cervus elaphus.
  • the non-human mammal is of the family Bovidae.
  • the bovid is of the genus Bos.
  • the bovid is Bos taurus or Bos indicus.
  • the open wound is an internal or external wound or combination thereof. In one embodiment the open wound is an external wound. In one embodiment the open wound is an internal wound. In one embodiment contacting is for about 10 hours. In one embodiment contacting is for at least 10 hours. In one embodiment contacting is for at least one day, preferably at least two, three, four, five, six, preferably at least seven days. In one embodiment contacting is for at least one week, preferably for at least two, three, four, five, six, seven, eight, nine, ten, eleven, preferably at least twelve weeks. In one embodiment contacting is for about one day, preferably about two, three, four, five, six, preferably about seven days.
  • contacting is for about one week, preferably for about two, three, four, five, six, seven, eight, nine, ten, eleven, preferably about twelve weeks. In one embodiment contacting is for one day, preferably two, three, four, five, six, preferably seven days. In one embodiment contacting is for one week, preferably for two, three, four, five, six, seven, eight, nine, ten, eleven, preferably twelve weeks.
  • contacting comprises contacting with a nanocomposite according to the invention having a release rate of bupivacaine HCL of about 32000 ng.mL -1 .min -1 or less, preferably about 30000 ng.mL -1 .min -1 or less, about 27000 ng.mL -1 .min -1 or less, preferably about 15000 ng.mL -1 .min -1 or less.
  • the release rate of bupivacaine HCL is about 12300 ng.mL -1 .min -1 or less.
  • the release rate of bupivacaine HCL from the nanocomposite is about as shown in Table 1 (units given are in ng.mL -1 .min -1 ) or less.
  • contacting comprises contacting with a nanocomposite according to the invention having a release rate of lidocaine HCL of about 47000 ng.mL -1 .min -1 or less, preferably about 37000 ng.mL -1 .min -1 or less, about 27000 ng.mL -1 .min -1 or less, preferably about 15000 ng.mL -1 .min -1 or less.
  • the release rate of lidocaine HCL from the nanocomposite is about 12750 ng.mL- 1 .min -1 or less. In one embodiment the release rate of lidocaine HCL from the nanocomposite is about as shown in Table 1 (units given are in ng.mL -1 .min -1 ) or less.
  • contacting comprises contacting with a nanocomposite according to the invention having a release rate of bupivacaine HCL of 32000 ng.mL -1 .min -1 or less, preferably 30000 ng.mL -1 .min -1 or less, 27000 ng.mL -1 .min -1 or less, preferably 15000 ng.mL -1 .min -1 or less.
  • the release rate of bupivacaine HCL is 12300 ng.mL -1 .min -1 or less.
  • the release rate of bupivacaine HCL from the nanocomposite is as shown in Table 1 (units given are in ng.mL -1 .min -1 ) or less.
  • contacting comprises contacting with a nanocomposite according to the invention having a release rate of lidocaine HCL of 47000 ng.mL -1 .min -1 or less, preferably 37000 ng.mL -1 .min -1 or less, 27000 ng.mL -1 .min -1 or less, preferably 15000 ng.mL -1 .min -1 or less.
  • the release rate of lidocaine HCL from the nanocomposite is 12750 ng.mL -1 .min -1 or less.
  • the release rate of lidocaine HCL from the nanocomposite is as shown in Table 1 (units given are in ng.mL -1 .min -1 ) or less.
  • treating pain comprises alleviating pain for about 4, preferably about 5, 6, 7, 8, 9, 10, 11 or preferably about 12 hours. In one embodiment treating pain comprises alleviating pain for 4, preferably 5, 6, 7, 8, 9, 10, 11 or preferably 12 hours. In one embodiment the alleviation of pain is determined mechanical nociceptor threshold (MNT) testing. Additionally, and specifically contemplated as embodiments of this method aspect of the invention are all of the embodiments relating to the aspects of the invention that are nanocomposites and nanocomposites for use as described previously herein. In another aspect the invention relates to a method of increasing the rate of mammalian wound healing comprising contacting an open wound of the mammal with a nanocomposite as described herein. In one embodiment the non-human mammal is a livestock animal.
  • MNT mechanical nociceptor threshold
  • the non-human mammal is of the family Cervidae.
  • the cervid is Cervus elaphus, Cervus canadensis, or Cervus nippon, preferably Cervus elaphus.
  • the non-human mammal is of the family Bovidae.
  • the bovid is of the genus Bos.
  • the bovid is Bos taurus or Bos indicus.
  • the open wound is an internal or external wound or combination thereof.
  • the open wound is an external wound.
  • the open wound is an internal wound.
  • the composition comprises a coating, film, wafer, or pad. In one embodiment the composition is a wafer.
  • the wafer is a collagen wafer.
  • the wafer comprises about 1% to about 10% lidocaine HCL, preferably about 2% to about 8%, about 3% to about 6%, about 4% to about 5%, preferably about 4% lidocaine HCL.
  • the collagen wafer comprises 1% to 10% lidocaine HCL, preferably 2% to 8%, 3% to 6%, 4% to 5%, preferably 4% lidocaine HCL.
  • contacting is for at least one, preferably at least two, three, four, five, six, seven, eight, nine, ten, eleven or twelve days.
  • contacting is for at least one, preferably at least two, three, four, five, six, seven, eight, nine, ten, eleven or twelve weeks. In one embodiment contacting is contacting until the wound is at least 70% healed, preferably at least 75%, 80%, 85%, 90%, 95%, at least 99% healed, preferably completely healed.
  • the open wound site is a wound site created by physical dehorning of the bovid.
  • the rate of wound healing is increased by about 10%, preferably by about 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 25%, 25%, 26%, 27%, 28%, 29%, preferably about 30% or more as compared to an untreated control wound. In one embodiment the rate of wound healing is increased by 10%, preferably by 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 25%, 25%, 26%, 27%, 28%, 29%, preferably 30% as compared to an untreated control wound.
  • the rate of wound healing is increased by at least 10%, preferably by at least 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 25%, 25%, 26%, 27%, 28%, 29% or at least 30% as compared to an untreated control wound.
  • the physical dehorning is cutting or sawing.
  • the open wound is the result of dehorning.
  • contacting is for at least one day, preferably at least two, three, four, five, six, preferably at least seven days. In one embodiment contacting is for at least one week, preferably for at least two, three, four, five, six, seven, eight, nine, ten, eleven, preferably at least twelve weeks.
  • contacting is for about one day, preferably about two, three, four, five, six, preferably about seven days. In one embodiment contacting is for about one week, preferably for about two, three, four, five, six, seven, eight, nine, ten, eleven, preferably about twelve weeks. In one embodiment contacting is for one day, preferably two, three, four, five, six, preferably seven days. In one embodiment contacting is for one week, preferably for two, three, four, five, six, seven, eight, nine, ten, eleven, preferably twelve weeks. Specifically contemplated as embodiments of these method aspects of the invention are all of the embodiments relating to the nanocomposite, method and use aspects of the invention previously described herein.
  • the invention in another aspect relates to a method of controlling or preventing mammalian infection comprising contacting an open wound on and/or in the mammal with a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and bupivacaine HCL.
  • a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and bupivacaine HCL.
  • the invention in another aspect relates to a method of controlling or preventing mammalian infection comprising contacting an open wound on and/or in the mammal with a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and optionally bupivacaine HCL.
  • a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and optionally bupivacaine HCL.
  • the invention in another aspect relates to a method of reducing mammalian wound hemorrhaging comprising contacting an open wound on and/or in the mammal with a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and bupivacaine HCL.
  • a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and bupivacaine HCL.
  • the invention in another aspect relates to a method of reducing mammalian wound hemorrhaging comprising contacting an open wound on and/or in the mammal with a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and optionally bupivacaine HCL.
  • a nanocomposite comprising collagen, polyvinylpyrrolidone (PVP) capped zinc oxide (ZnO) nanoparticles (ZnO/PVP nanoparticles), lidocaine HCL and optionally bupivacaine HCL.
  • each wafer was 3.8 cm (area of 9.5 cm2), and the thickness was 0.5 cm, and all the wafers contained 136 mg of each drug (bupivacaine HCL and lidocaine HCL) in their structure (Fig. 1).
  • Each Franz diffusion cell has two separate chambers, the donor and the receptor (Fig. 2). Initially, the magnetic stirrers were placed in the recipient chambers, and the previously cut and weighed dialysis membranes were carefully placed in between the recipient and donor chambers. Then, the stainless- steel clamps were used to keep the dialysis membranes steady in the place and prevent leaking. Each receptor chamber of the diffusion cells was carefully filled with 8 mL of Phosphate-Buffered saline (PBS) (pH 7.45).
  • PBS Phosphate-Buffered saline
  • 0.5ml aliquots were sampled with 23G needles attached to a 2.5 mL syringe. These samples were placed into individual 2 ml microtubes. Samples were drawn from the placed PVS tubes in the sampling ports, starting from time zero (t0), every 15 minutes for the first hour (until t60 min), then at t120 min and eventually every 2 hours until 12 hours had elapsed. The cells were refilled to 8ml with PBS solution after each sampling. The Franz diffusion cells were maintained at 38 o C throughout this experiment. Before placement of the controls and treatments on the membranes on the donor chambers, four drops of deer plasma (weighing ⁇ 247 mg) were added with disposable Pasteur pipette to the donor side to have a condition similar to the wound.
  • control group contained 20 mg lidocaine HCL and 20 mg bupivacaine HCL in a solution form (1 ml drawn from 20 mg/ml lidocaine HCL and bupivacaine HCL solution and squirted in the donor chamber of Franz diffusion cell). All the treatments contained 20.4 mg of each drug in them; however, the concentrations of ZnO/PVP nanoparticles varied. Treatment 1 had 25%, treatment 2 had 10%, treatment 3 had 5%, and treatment 4 had zero or no nanoparticles in collagen composite.
  • Sample preparation The sample aliquots from the Franz diffusion cells were centrifuged at 14000X for 10 minutes, and after transferring to the HPLC vials for analysis.
  • Sample analysis HPLC instrumentation The HPLC system consisted of LC-20AD pumps (Shimadzu, Japan), an SIL-20AC HT auto-injector (Shimadzu, Japan), a diode array (DA) detector SPD-M20A (Shimadzu, Japan), a CTO-20A column oven (Shimadzu, Japan) and DGU-20A3 degasser (Shimadzu, Japan). All chromatograms were analysed by LC solution software (Shimadzu, Japan).
  • the mobile phase preparation consisted of 75% buffer consist of potassium phosphate 30 mM and 0.016% triethylamine (pH was adjusted on 4.9 with orthophosphoric acid and NaOH 1N), and the organic solvent was 25% acetonitrile.
  • the buffer was made using HPLC grade with milli-Q water (Milli-Q PFplus system; Millipore Corporation). The flow rate was determined 1 mL/min.
  • the separation was achieved using Phenomenex C18A (Luna® 5 ⁇ m C18100 ⁇ , LC column 150 x 4.6 mm internal diameter, 5 ⁇ m particle size) column maintained under isocratic conditions at 40°C.
  • the DA (Diode Array) detector was set at 210 nm wavelength.
  • Lowest Limit Quantification and Lowest Limit of Quantification The lower limit of quantification (LLQ) in the mobile phase was measured by running a series of low concentrations of bupivacaine HCL and Lidocaine HCL and mixed bupivacaine HCL and lidocaine HCL standard (1000, 500, 250, 125, 62.5 and 31.25 and 16.12 ng/mL) diluted in the mobile phase.
  • the LLQ was set at the lowest concentration showing a signal to noise ratio of 10.
  • Accuracy The linearity of the measurements was checked by running duplicate runs of five different concentrations (1000, 500, 250, 125, 62.5 ng/mL) three times in the mobile phase, every day for six consecutive days, and they were linear with the R square of more than 0.99.
  • the inter-day variation (RSD) for this method in water ranged from 2.27 to 5.18 percent, and the and intra-day variation (RSD) ranged from 1.57 to 12.93 percent.
  • the inter-day variation (RSD) for this method in water ranged from 0.41 to 2.56 percent.
  • intra-day variation (RSD) ranged from 1.56 to 7.48 percent.
  • Franz diffusion cell and drug release In total, 600 tests were performed, which resulted in drug concentrations of 15572.34 ng/ml and 6713296 ng/ml as the minimum and maximum. The values only in treatment groups (25NP, 10NP, 5NP, and 0NP) were normally distributed.
  • the overall bupivacaine HCL and lidocaine HCL least-squares means ( ⁇ SEM) of concentration were 392205.67 ⁇ 37495.14 and 555847.08 ⁇ 37495.14 (ng/ml), respectively.
  • the least-squares means ( ⁇ SEM) of bupivacaine HCL concentration (ng/ml) in groups control, 0NP, 5NP, 10NP, 25NP were 660791.26 ⁇ 83841.68, 386862.63 ⁇ 83841.68, 366694.9 ⁇ 83841.68, 306399.13 ⁇ 83841.68, 240280.44 ⁇ 83841.68, respectively.
  • the least-squares means ( ⁇ SEM) of lidocaine HCL concentration (ng/ml) in groups control, 0NP, 5NP, 10NP, 25NP were 700510.12 ⁇ 83841.68, 690838.96 ⁇ 83841.68, 605253.04 ⁇ 83841.68, 494928.64 ⁇ 83841.68, 287704.68 ⁇ 83841.68, respectively.
  • Normality of value distribution of the overall drug concentration in the in vitro groups For Bupivacaine HCL, the Kolmogorov-Smirnov test showed normality in the value distribution of the drug concentrations in total among all the treatment groups with p-values of >0.1000. However, the control group values were not normally distributed with the p-value of 0.0322.
  • the Kolmogorov-Smirnov test showed normality in the value distribution of the drug concentrations in total among all the treatment groups with p-values of >0.1000. However, the control group values were not normally distributed with the p-value of 0.0157. Differences between least-squares means Summing up the values from all groups, the least-squares means of bupivacaine HCL and lidocaine HCL concentrations (ng/ml) were significantly different from each other (P ⁇ 0.0001). For bupivacaine HCL, no significant difference was seen among the groups. However, for lidocaine HCL, significant differences were seen in groups 0NP vs 10NP (P ⁇ 0.05), 0NP vs.
  • the treatment collagen wafers crosslinked with 25% nanoparticles showed the lowest concentrations of lidocaine HCL and bupivacaine HCL sampled from the receptor chamber of Franz Cells compared to collagen wavers crosslinked with 10%, 5% and 0% nanoparticles, indicating that that less drug had passed through the membrane.
  • the treatment group involving non-crosslinked wafers (0% nanoparticles) showed more drug passage through the membrane compared to the other groups, meaning that drug release was the fastest.
  • Drug release rates by the log of concentration The release rate was calculated by transforming the ⁇ axis values (concentration in ng/ml) to their log (log ng.mL -1 .min -1 ).
  • the calculated slopes ( ⁇ SEM) for bupivacaine HCL were; 0.00483 ⁇ 0.00037, 0.00289 ⁇ 0.00037, 0.00296 ⁇ 0.00037, 0.00296 ⁇ 0.00037 and 0.00152 ⁇ 0.00037 for control, 0NP, 5NP, 10NP and 25NP, respectively.
  • the calculated slopes ( ⁇ SEM) for lidocaine HCL were; 0.00456 ⁇ 0.00029, 0.00298 ⁇ 0.00030, 0.00288 ⁇ 0.00028, 0.00281 ⁇ 0.00028 and 0.00139 ⁇ 0.00028 for control, 0NP, 5NP, 10NP and 25NP, respectively.
  • the active drugs incorporated in the matrices diffuse through the denatured collagen matrix and are taken up by the underlying tissue.
  • the drug can exist either linked to the polymeric chains or as free drug within the matrix.
  • the free drug molecules reside in the partially open porous structure are freely available for a rapid uptake via desorption phenomenon.
  • the majority of the bound drugs are only released after enzymatic degradation, thus providing a source of drug over an extended period.
  • a nanocomposite of the invention particularly in the form of a treatment pad as described herein, provides the unexpected advantage of providing sustained release of a short acting anaesthetic to a healing wound.
  • Example 2 Animal study - Deer Materials and Methods Animals This study was approved by the Massey University (New Zealand) Animal Ethics Committee (19/70). Forty male deer weighing 116.6 ⁇ 11.38 kg were used in this experiment. Animals were kept in paddocks throughout the study period and had free access to pasture and water. On the study days, all the deer were mustered indoors in the hold pens, and two deer were guided carefully in the hydraulic crush with closed curtains to reduce their exposure to stressors as much as possible. While indoors, they had access to water and multi fed nuts (Sharpes Stock Feeds, Carterton, New Zealand). At the end of the day, all the animals were let out back on the pasture.
  • the animal study group comprised 40 total animals. The animals in were divided into four groups, ten animals each, for subsequent comparative treatments. The four groups were made up of three treatment groups (25%NP or T1, 5%NP or T2, 0%NO or T3) and a control group. The control group followed current industry protocol.
  • a tourniquet was applied at the base of the antlers. All the groups received articaine HCL ring block injections (subcutaneous (SC) injections in every 1 cm antler circumference) at the base of the antlers below the tourniquet.
  • the antlers were removed after testing the efficacy of the local anaesthetic using a saw.
  • treatment and control wafers were placed immediately on the open stump wounds after the antler removal procedure. For better adherence, the hair around the edges of the removed antler was clipped using an electrical clipper. All the tourniquets were removed after two hours.
  • Pain assessments Pain assessments were carried out by a trained assessor using a handheld algometer (FPX 25, Wagner Instruments, Greenwich, CT, USA) with a 2-mm-diameter round stainless-steel tip. The pain measurement was performed in three alternate days in one week for inter-day assessment. Four sites, including cranial, medial, caudal, and lateral aspects of each antler (Fig.
  • Blood for the pharmacokinetic analysis was collected from right and left jugular veins before the administration of local anaesthetics (t0) followed by 2, 4, 8, and 24 hours after the application of collagen wafers.
  • a 7 mL blood sample was collected using a 21G vacutainer needle. The vacutainers were immediately centrifuged at 4500 RPM for 5 minutes. The plasma was harvested and stored at -20 °C in aliquots of 2mL Eppendorf tubes.
  • SPE positive pressure solid-phase extraction
  • the supernatant was separated and loaded into the SPE cartridge conditioned with 1 ml of acetonitrile, followed by equilibrating with 1 ml of milli-Q water.
  • the SPE tubes were then washed with 1 mL methanol: water of (20:80) followed by drying under high pressure for 10 min.
  • the elution was made with 1 ml acetonitrile into glass tubes.
  • the samples were evaporated to dryness using a Speedvac (Thermo Scientific) for 1 hour, followed by reconstitution with 200 ⁇ l of milli-Q water. After a final centrifugation (13000 RPM, 5 min), the samples were transferred to the autosampler of the Liquid-Chromatography Mass Spectrometry system.
  • LC-MS Liquid-Chromatography-Mass-Spectrophotometry
  • the mobile phase consisted of 0.1% formic acid and acetonitrile (75:25, v/v) and was delivered at a flow rate of 0.3 mL/minute.
  • Mass spectrometric detection was performed on a hybrid quadrupole-orbitrap mass spectrometer (Q Exactive Focus Hybrid Quadrupole-Orbitrap Mass Spectrometer; Thermo Scientific, Bremen, Germany) with an electrospray- ionization interface, positive ion mode.
  • the precursor ions of lidocaine HCL (235.18 g/mol), bupivacaine HCL (288.43 g/mol), and procainamide (235.32 g/mol) were included in the target list.
  • the linearity of the LC-MS method was determined by linear regression analysis of the samples, which were prepared by dilution of bupivacaine HCL, lidocaine HCL, and both in blank deer plasma. Procainamide was used as an Internal Standard (IS) in all the samples. Calibration curves were constructed using three replicates of bupivacaine HCL, lidocaine HCL, and both in LC- MS water with concentrations between 3.12 to 100 ng/ml. Intra-day and inter-day precision and accuracy of the method were determined by processing three replicates. Specificity and Recovery Blank plasma from 10 different red deer was extracted and analysed to assess the specificity of the SPE and LC-MS method.
  • the extraction recovery was assessed by comparing the pre- and post-spiked samples with bupivacaine HCL and lidocaine HCL and procainamide as an internal standard.
  • Wound healing For comparison of the wound healing process and antler regrowth in animals treated according to the invention compared to control animals, images were taken with Huawei P20 Pro, Leica lens and were stored at google drive. A steel ruler (in centimetre unit) was used in the pictures to be able to calibrate the measurements after transferring the images to ImageJ software (version 1.52r, Wayne Rasband, National Institute of Health, USA). The scale was determined by the allocated ruler next to the wound in each photo and calibrating the measurements using millimetre as the unit.
  • the surface area of the wounds was manually selected in the software by one person, and the area measurement was obtained using mm2 unit. All the measurements were transferred to Microsoft Excel sheet for further analysis.
  • Adherence of the treatment wafers to the wound site The adherence of the treatment wafers was defined as the duration of time the wafers were intact and sticking to the wound. Time in days or hours was recorded when a treatment wafer was lost. Data analysis Statistical analyses were performed in SAS (version 9.4) and GraphPad Prism LLC, version 8.3.0. The dependent variable, which was drug concentration in ng/ml was analysed with the MIXED procedure using a linear mixed model for repeated measures.
  • the Kolmogorov-Smirnov test indicated that the data followed a normal distribution, and data were analysed in the nominal scale without a numerical transformation.
  • the model included the fixed effects; time of measurement 15, 30, 45, 60, 120, 240, 360, 480, 600, and 720 minutes as covariates.
  • the model included the fixed effects; time in minutes (t0, t10, t120, t240, t360, t480 and t600) and for pain assessment and day of measurement (1, 3, 7, 14, 21, 30, 60) for wound healing, antler (right or left), antler site within antler (cranial, medial, caudal and lateral) and as covariates, and the random effect of deer (between-animal variation; ⁇ a ) and residual (within-animal variation; ⁇ e ).
  • the repeated measures on the same deer were modelled with a compound symmetry error structure.
  • the lowest level of detection (LLD) for both bupivacaine HCL and lidocaine HCL was 10 ng/ml.
  • the lowest level of quantification (LLQ) was 62.5 ng/ml, and.
  • the correlation coefficient was more than 0.999 for the standard curves.
  • bupivacaine HCL the inter-day variation for this method in deer plasma ranged from 4.17 to 19.72 percent, and the and intra-day variation ranged from 1.48 to 19.32 percent.
  • lidocaine HCL the inter-day variation for this method in water ranged from 3.63 to 8.61 percent, and the intra-day variation ranged from 3.71 to 10.54 percent.
  • the extraction recovery rate was 73 percent for bupivacaine HCL and 82% for lidocaine HCL.
  • the relative standard deviation for internal standard (procainamide HCL) was 8.74 percent.
  • Adherence of the collagen wafers All forty animals were healthy in the first days of experiments. However, one animal was euthanized on day 14 of the assessments due to an accident to the hind limb. Another deer also lost an antler on the third day because of severe trauma to the right antler. The majority of the treatment wafers in all the study groups remained intact until the end of the study, which lasted two months.
  • T3 (0% NP) (wafers with no crosslinked collagen) showed more fragility and had the least adherence of treatment wafers to wounds compared to the treatment groups in which treatment wafers containing crosslinked collagen were used.
  • the adherence of the wafers was as follows: T1 (25% NP): 18 wafers out of 20 adhered on the antlers (90% adherence) T2 (5% NP): 14 wafers out of 20 adhered on the antlers (70% adherence) T3 (0% NP or no crosslinking): 9 wafers out of 20 adhered on the antlers (45% adherence)
  • the least-squares means ( ⁇ SEM) of the overall period of wafer adherence for 4 study groups were 46.27 ⁇ 6.24, 50.13 ⁇ 6.24, and 35.13 ⁇ 6.24 days in T1, T2, and T3, respectively.
  • the least-squares means ( ⁇ standard errors) of pain thresholds determined in control, treatments 1 (25% NP), 2 (5% NP), and 3 (0% NP) were 26.93 ⁇ 1.56 Newtons, 40.83 ⁇ 1.37 Newtons, 43.21 ⁇ 1.37, 41.39 ⁇ 1.37 Newtons, respectively (Fig. 11).
  • the differences in least-squares means and slopes A significant difference (P ⁇ 0.05) was seen among the study groups.
  • the comparison of the least- squares means showed a significant difference in treatment 2 (NP 5%) compared to treatment 1 (NP 25%), and 3 (NP 0%) (P ⁇ 0.0001).
  • the trendline between the groups is shown in Figure 12.
  • the measurements across all the groups rise to cut-off point of 50 (N) force, approximately 10 minutes after the application of the 4% articaine hydrochloride ring block in response to the onset of analgesia.
  • the control showed a faster trend in returning to the baseline values of pain assessment compared to the treatment groups (Fig. 13).
  • the treatment wafers used in this study provided all the characteristics of a modern wound dressing in addition to sustained analgesia including preventing cellular dehydration and thus enhancing healing.
  • the inventors also found that in this study the crosslinked treatment wafers (5%NP and 25%NP) possessed better flexibility, integrity, and wound adherence compared to the un-crosslinked wafers.
  • the non-crosslinked treatment wafers were typically lost due to erratic animal movements.
  • the inventors believe that the greater adherence of crosslinked treatment wafers to wound sites was due to the porous structure of the wafers. This structure avoided accumulation of wound exudate under the wafer and absorbed a considerable amount of bleeding.
  • an additional advantage of this greater absorption is an increased adsorption of the treatment wafer to the wound surface, i.e., it sticks better.
  • the treatment wafers as described herein comprise at least some haemostatic properties. The inventors believe, that based on the results presented herein, a person skilled in the art will immediately appreciate the advantages of a nanocomposite as described herein that provides to a wounded animal, an anaesthetic drug, for a sufficient time, and in a sufficient amount, to provide an unanticipated therapeutic effect (i.e., prolonged pain relief via the use of a short acting anaesthetic).
  • cornual nerve block was performed by injecting 2% lidocaine hydrochloride (10 mL) subcutaneously around the left cornual nerves (halfway between the horn and the lateral corner of the eye, below the frontal crest) using an 18-gauge 2.5 cm needle. After testing the effect of the nerve block using a nick test (see below), the left horn of each animal was removed by sawing with an embryotomy wire. Major blood vessels were clamped using artery forceps to arrest bleeding.
  • Head shaking Head moves right and left at least once in a successive rapid motion. There must be 1 second between successive rapid side-to-side movements to count as a new head shake.
  • Ear flicking Animal rapidly moves one or both ears to the front and back independent of a head shake. Each time movement constitutes an ear flick.
  • Lying Lateral recumbency and sternal recumbency Pain assessments for cattle treated after dehorning were carried out substantially as set forth in Example 1. Results: No adverse effects were seen following the application of any of the topical materials.
  • the wound diameter ranged from 6.2 to 8.0 cm (average 7.1 ⁇ 0.68 cm). Collagen wafers adhered well to the wound surface after application whereas the topical local anaesthetic gel, Tri-Solfen did not stick well to the dehorned wound surface. No dislodgement of collagen wafers was observed in any of the animals during the observation period. Less haemorrhage was observed in animals that received the topical materials (groups 2 and 3) than control animals (group 1). Infection of dehorned wound was observed in two of the animals that received Tri-Solfen and one of the animals in control group. Purulent (pus) discharge was seen two weeks following dehorning in those animals. No infection was seen in animals that received collagen wafers.
  • Table 4 shows the total number of days required for complete healing of dehorned wound.
  • Figure 7 shows the images of dehorned wounds of cattle from each treatment group.
  • Collagen wafers assisted in clot formation in minor blood vessels as less haemorrhage was observed following the application of these topical materials compared to control group. No significant differences in the pain related behaviours were observed between treatment groups. Only one animal per group was used for behaviour comparison, which is a limitation of the study. Future studies in a larger population of animals are required to investigate the pain relief properties of collagen wafers.
  • One of the major findings of this study is that application of collagen wafers on dehorning wounds can accelerate wound healing. The average number of days required for complete wound healing following the application of collagen (69.83 ⁇ 5.49 days) wafers was significantly less than the control (94.16 ⁇ 17.44 days) and Tri-Solfen (99.66 ⁇ 26.18 days) groups.
  • Nanoparticle cross- linked collagen shields for sustained delivery of pilocarpine hydrochloride International Journal of Pharmaceutics, 501(1-2), 96-101.
  • ZnO/PVP nanoparticles induce gelation in type I collagen. European Polymer Journal, 75, 399- 405.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Materials Engineering (AREA)
  • Anesthesiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Nanotechnology (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medical Informatics (AREA)
  • Composite Materials (AREA)
  • General Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biotechnology (AREA)
  • Electrotherapy Devices (AREA)
  • Measuring And Recording Apparatus For Diagnosis (AREA)
  • Exchange Systems With Centralized Control (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne de manière générale un nanocomposite comprenant du collagène, des nanoparticules et au moins un agent actif, des utilisations dudit nanocomposite pour soulager la douleur causée par une plaie, et des méthodes de traitement de la douleur causée par une plaie qui font appel audit nanocomposite.
PCT/IB2022/050834 2021-02-01 2022-01-31 Gestion de la douleur post-opératoire WO2022162640A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2022213016A AU2022213016A1 (en) 2021-02-01 2022-01-31 Post-operative pain management

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2021900209 2021-02-01
AU2021900209A AU2021900209A0 (en) 2021-02-01 Post-operative pain management

Publications (1)

Publication Number Publication Date
WO2022162640A1 true WO2022162640A1 (fr) 2022-08-04

Family

ID=82653964

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/050834 WO2022162640A1 (fr) 2021-02-01 2022-01-31 Gestion de la douleur post-opératoire

Country Status (2)

Country Link
AU (1) AU2022213016A1 (fr)
WO (1) WO2022162640A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060029654A1 (en) * 2004-08-04 2006-02-09 Cassel R D Analgesic patch for sports injury rehabilitation medicine and method to alleviate pain
WO2008117268A2 (fr) * 2007-03-28 2008-10-02 Innocoll Technologies Limited Dispositif d'administration de médicament pour assurer une analgésie locale, une anesthésie locale ou un blocage nerveux
WO2017199181A1 (fr) * 2016-05-17 2017-11-23 Alberta Veterinary Laboratories Ltd Composition topique pour lutter contre la douleur chez les animaux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060029654A1 (en) * 2004-08-04 2006-02-09 Cassel R D Analgesic patch for sports injury rehabilitation medicine and method to alleviate pain
WO2008117268A2 (fr) * 2007-03-28 2008-10-02 Innocoll Technologies Limited Dispositif d'administration de médicament pour assurer une analgésie locale, une anesthésie locale ou un blocage nerveux
WO2017199181A1 (fr) * 2016-05-17 2017-11-23 Alberta Veterinary Laboratories Ltd Composition topique pour lutter contre la douleur chez les animaux

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AGBAN Y ET AL.: "Nanoparticle cross-linked collagen shields for sustained delivery of pilocarpine hydrochloride", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 501, 2016, pages 96 - 101, XP029435836, DOI: 10.1016/j.ijpharm. 2016.01.06 9 *
AGBAN YOSRA, MUGISHO ODUNAYO O., THAKUR SACHIN S., RUPENTHAL ILVA D.: "Characterization of Zinc Oxide Nanoparticle Cross-Linked Collagen Hydrogels", GELS, vol. 6, no. 4, 22 October 2020 (2020-10-22), pages 37, XP055960541, DOI: 10.3390/gels6040037 *
LIAN J. ET AL.: "ZnO/PVP nanoparticles induce gelation in type I collagen", EUROPEAN POLYMER JOURNAL, vol. 75, 2016, XP029398894, DOI: 10.1016/j.eurpolymj. 2016.01.00 9 *
SAHEBJAM FARZ1N: "Efficacy of Sustained-Release Novel Bupivacaine Formulations in Sheep, Master's Thesis", MASTER'S THESIS. INSTITUTE OF VETERINARY, ANIMAL AND BIOMEDICAL SCIENCES, NEW ZEALAND, 1 June 2017 (2017-06-01), New Zealand, XP055960539, Retrieved from the Internet <URL:https://mro.massey.ac.nz/handle/10179/12484> [retrieved on 20220913] *
WOODBURY MURRAY R., NIGEL A. CAULKETT, PETER R. WILSON: "Comparison of lidocaine and compression for velvet antler analgesia in wapiti", THE CANADIAN VETERINARY JOURNAL, vol. 43, no. 11, 1 November 2002 (2002-11-01), pages 869 - 875, XP055960502 *

Also Published As

Publication number Publication date
AU2022213016A1 (en) 2023-08-24

Similar Documents

Publication Publication Date Title
Baron et al. Optimal support of wound healing: New Insights
Amin et al. Accelerated wound healing and anti-inflammatory effects of physically cross linked polyvinyl alcohol–chitosan hydrogel containing honey bee venom in diabetic rats
TWI672155B (zh) 膠原蛋白海綿
Leoci et al. A dose-finding, long-term study on the use of calcium chloride in saline solution as a method of nonsurgical sterilization in dogs: evaluation of the most effective concentration with the lowest risk
JP6663351B2 (ja) 温度感受性ヒドロゲル−コラゲナーゼ製剤
CN112533676A (zh) 用于抑制cgrp的神经毒素
Feng et al. Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord
AU2019200630B2 (en) Modulation of heparin-binding epidermal growth factor activity for tympanic membrane healing
Poranki et al. Assessment of deep partial thickness burn treatment with keratin biomaterial hydrogels in a swine model
DE60212143T2 (de) Verwendung von thrombin-peptidderivaten zur behandlung von chronischen hautulcera
Andrews et al. A comparison of buprenorphine, sustained release buprenorphine, and high concentration buprenorphine in male New Zealand white rabbits
US20160250202A1 (en) Mast Cell Stabilizers to Prevent or Treat Laminitis
EP2424527B1 (fr) Stabilisateurs de mastocytes utilisés pour prévenir ou traiter la fourbure
BRPI0619975A2 (pt) formulações de osteopontina bovina para o aperfeiçoamento do processo de cicatrização de ferida
Varasano et al. Exuberant granulation tissue in a horse: successful treatment by the intralesional injection of 4% formaldehyde solution.
WO2022162640A1 (fr) Gestion de la douleur post-opératoire
Catapano et al. N-acetylcysteine prevents retrograde motor neuron death after neonatal peripheral nerve injury
JP6056064B2 (ja) 卵殻膜成分を含むインスリン抵抗性改善剤ならびにそれを用いた組成物
Schoiswohl et al. Comparison of alternative methods for thermal disbudding in calves
JP2023515181A (ja) 架橋ヒアルロン酸を利用した薬物送達組成物およびその製造方法
Venkatachalam et al. Pharmacokinetics and efficacy of a novel long-acting bupivacaine formulation for cornual nerve block in calves
Chen et al. Vanadate ingestion enhances the organization and collagen fibril diameters of rat healing medical collateral ligaments
Sahebjam Novel collagen-based wafers as a drug delivery method for local analgesia in deer antlers: a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Sciences at Massey University, Manawatu, New Zealand
KR20220115589A (ko) 조직 재생 다중-약물 칵테일 및 이를 전달하기 위한 장치
KR20120140453A (ko) 동물용 복합 항생제 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22745492

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022213016

Country of ref document: AU

Date of ref document: 20220131

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22745492

Country of ref document: EP

Kind code of ref document: A1