WO2008125872A1 - Facteur wif-1 utilisé pour accélérer la guérison de plaies - Google Patents

Facteur wif-1 utilisé pour accélérer la guérison de plaies Download PDF

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Publication number
WO2008125872A1
WO2008125872A1 PCT/GB2008/001360 GB2008001360W WO2008125872A1 WO 2008125872 A1 WO2008125872 A1 WO 2008125872A1 GB 2008001360 W GB2008001360 W GB 2008001360W WO 2008125872 A1 WO2008125872 A1 WO 2008125872A1
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WIPO (PCT)
Prior art keywords
wif
wounds
wound
healing
therapeutically effective
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PCT/GB2008/001360
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English (en)
Inventor
Mark William James Ferguson
Hugh Laverty
Nicholas Occleston
Sharon O'kane
Kerry Nield
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Renovo Limited
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Publication of WO2008125872A1 publication Critical patent/WO2008125872A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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

Definitions

  • the present invention relates to the manufacture of medicaments for accelerating the healing of wounds.
  • the invention also relates to methods of treatment for accelerating the healing of wounds.
  • the invention relates to medicaments and methods for the acceleration of healing of skin wounds.
  • the invention relates to medicaments and methods that can increase the rate of re-epithelialisation of wounds.
  • the invention also relates to wound dressings that are able to provide active agents to a wound, and thereby accelerate healing of the wound, and to formulations such as creams or sprays that may be used to accelerate healing.
  • the skin is the most frequently injured of the body's organs. By virtue of its location, the skin is in constant contact with the external environment, and as a result is the organ most frequently exposed to environmental, and other, damage.
  • Wounds such as skin wounds, may arise as a result of many different forms of damage. Such damage may impair or entirely destroy the function of the injured organ or tissue, and the outcome of such damage depends on the nature and role of the tissue or organ affected.
  • the wound healing response is most commonly described with reference to the healing of skin wounds.
  • the response involves a sequence of overlapping reparative processes.
  • the most important of these processes in terms of influencing the rate of wound healing is that of re-epithelialisation.
  • Skin wounds generally re-epithelialise "from the outside in”. Keratinocytes from the unwounded skin surrounding the damaged area proliferate and migrate to cover the tissue at the wound site. This migration of keratinocytes means that the area around the edge of the wound is the first to heal, and the progress of the keratinocytes over the damaged area provides a useful index by which the progress of wound healing may be measured. In cases where epidermal appendages remain intact within the wounded area, for example, in the case of partial thickness wounds, keratinocytes involved in the re-epithelialisation response may also be derived from these structures.
  • Wounding of organs such as the skin gives rise to a number of undesirable effects.
  • One noticeable effect is that the presence of a wound impairs the barrier function of the skin. This increases the rate at which fluids are lost from the wounded area, which can be a particular concern in the case of wounds covering large areas. It is common for burns victims to suffer severe, potentially life-threatening, dehydration as a result of fluid loss through the damaged skin.
  • the loss of the skin's barrier function also increases the risk of ingress and infection by pathogens such as bacteria and fungi.
  • Wounds are painful, even aside from the events associated with their formation, and delays in the healing of wounds may be associated with extended incidences of pain to the sufferer. Wounds can also decrease the mechanical function of the injured area.
  • More advanced therapies known from the prior art include the use of wound management techniques, accelerants for wound closure and skin substitutes for graft augmentation.
  • Debridement is often used for the treatment of chronic wounds to remove non-viable tissue, this usually takes the form of mechanical/surgical or enzymatic removal of the effected tissue.
  • Surgical excision rapidly clears the area of the affected tissue but can be extremely painful, it is also non-specific and can therefore lead to complications induced by the increased injury to the area.
  • Addition of enzymatic agents such as collagenase, papain-urea and bromelain to clear the wound area have yielded mixed efficacy in current studies.
  • a number of targets exist for the acceleration of wound healing include growth factors, oxidised regenerated cellulose/collagen matrices, adenosine A 2A agonists and recombinant lactoferrin. These act in a variety of ways; the collagen matrix acts to inhibit the negative impact of proteases and oxygen free radicals whilst promoting the activity of growth factors within the wound area; while lactoferrin acts to promote IL- 18 up- regulation within the wound.
  • Gene therapy is now being utilised for the treatment of impaired wound healing, with the modulation of growth factors being the primary target.
  • wounds such as split thickness skin graft donor sites (reviewed in Rakel et al. 1998) or sites subject to skin peels, may merely involve leaving the graft donor site exposed and untreated, or may alternatively make use of treatments such as the application of dressings (typically gauze dressings, which may be used alone or impregnated with a variety of anti-infective agents, alginates, hydrocolloids, synthetic composite membranes, transparent films or honey), application of artificial skin (which may be generated from the individuals own epidermis), application of allografts (typically bovine or porcine allografts) or application of ointments (typically ointments containing silver based compounds as anti- infective agents).
  • dressings typically gauze dressings, which may be used alone or impregnated with a variety of anti-infective agents, alginates, hydrocolloids, synthetic composite membranes, transparent films or honey
  • artificial skin which may be generated from the individuals own epidermis
  • WNT Inhibitory Factor- 1 is a secreted glycoprotein, which binds WNT proteins and inhibits their activities. WIF-I inhibits WNT signalling by this direct binding to WNT molecules.
  • WIF-I contains a well defined N- terminal domain, comprising the WIF domain, which binds WNT ligands; five epidermal growth factor (EGF)-like repeats, which appear to be important for cellular localisation; and a hydrophilic domain of 45 amino acids at the carboxy terminus.
  • EGF epidermal growth factor
  • the WIF domain of human WIF-I was as effective as the full-length protein suggesting that the WIF domain is sufficient for WNT binding, and thereby mediates the biological activity of WIF-I (Hsieh et al, 1999).
  • the WIF domain of WIF-I (as defined by Liepinsh et al.) comprises amino acid residues 32 to 181 of Sequence ID No. 1, and the sequence of this domain is also shown in Sequence ID No. 2.
  • Human WIF-I is encoded by the WIF-I gene, a highly conserved gene first identified from the human retina.
  • the sequence of human WIF-I is set out in Sequence ID No. 3 (which has previously been deposited as Accession Number: NM_007191).
  • the invention provides the use of WNT Inhibitory Factor- 1 (WIF-I), or a therapeutically effective fragment or derivative thereof, in the manufacture of a medicament for accelerating the healing of wounds.
  • WIF-I WNT Inhibitory Factor- 1
  • This first aspect of the invention also provides WIF-I, or a therapeutically effective fragment or derivative thereof, for use as a medicament for accelerating the healing of wounds.
  • the invention provides a method of accelerating the healing of a wound, the method comprising providing to a site in need of such accelerated healing a therapeutically effective amount of WIF-I, or a fragment or derivative thereof.
  • a site in need of accelerated healing in accordance with this aspect of the invention may be a wound, or a site where a wound is to be formed.
  • the methods of treatment of the invention may suitably be practiced using the medicaments of the invention. It may generally be preferred that the medicaments or methods of the invention utilise WIF-I, either alone or in combination with a therapeutically effective fragment or derivative. It will be appreciated that the WIF-I to be used will generally be human WIF-I, as set out in Sequence ID No. 1.
  • the invention is based on the inventors' surprising finding that WIF-I (or its therapeutically effective fragments or derivatives) is able to accelerate the healing of wounds to which it is provided. This finding is particularly surprising in the light of the inventors' previous finding that certain WNTs (whose activity may be expected to be neutralised by WIF-I) play a role in accelerating the rate of wound healing.
  • the wounds healing of which is to be accelerated by medicaments or methods of the invention, may be skin wounds.
  • medicaments or methods of the invention may be successfully used to promote accelerated healing in a range of tissues or organs, including the eyes (and particularly the cornea).
  • the acceleration of healing of wounds within the context of the present invention may be understood to encompass any increase in the rate of healing of a treated wound as compared to the rate of healing occurring in a control-treated or untreated wound.
  • the rate of healing of wounds attained in accordance with the invention may readily be compared with that taking place in control-treated or untreated wounds using any suitable model of wound healing known in the art. Suitable models in which the rate of wound healing may be assessed are set out elsewhere in the specification.
  • Accelerated healing of a wound achieved using the medicaments or methods of the invention may preferably lead to a treated wound healing at a rate at least 5% faster than a control wound or untreated wound, preferably at a rate at least 10% faster, more preferably at least 15%, 20% or 25% faster; yet more preferably at least 50% faster, still more preferably at least 75% faster, and most preferably 100% (or more) faster.
  • Suitable methods by which acceleration of the healing of wounds may be quantified to assess improvements in the rate of healing are described elsewhere in the specification.
  • Skin wounds may be acute wounds or chronic wounds.
  • Wound contraction is a normal and necessary part of the wound healing process, and may assist in closure of wounds by reducing their size. Wound contraction is believed to be mediated by contractile proteins, such as alpha-smooth muscle actin. Since wound contraction can help to promote wound closure, the augmenting of wound contraction has been suggested as a method to promote more rapid wound closure. However, some wounds, including skin wounds and injuries to ligaments or tendons, may be subject to excessive wound contraction. This may occur during the healing response, and/or scar resolution and remodelling. Pathological wound contraction of this type is a major concern to both patients and physicians, since it can lead to damaging physical and psychological effects. In extreme cases, pathological contraction of wounds located around joints may result in limb or joint dislocation and/or loss of function.
  • Pathological wound contraction may be particularly problematic in the case of large wounds, such as those associated with grafting procedures (particularly at graft donor sites) or large burns. Accordingly these wounds may gain particular benefit from treatment with the medicaments or methods of the invention, since their healing may be accelerated, without increasing the likelihood of damaging contraction.
  • Other types of wound are prone to detrimental wound contraction by virtue of the tissues injured. Examples of these include strictures of the duodenum following chronic peptic ulcer disease, urethral strictures and strictures of the esophagus after lye burns, and contraction following skin peels (particularly at cosmetically important sites, such as the face). It will be recognized that these wounds may also gain particular advantage through treatment using the medicaments or methods of the invention.
  • the medicaments and methods of the invention may be used to accelerate the healing of acute wounds, or of chronic wounds.
  • Particular acute wounds that may benefit from accelerated healing provided by the medicaments or methods of the invention include surgical wounds (and particularly those associated with cosmetic procedures and/or grafting procedures), wounds resulting from skin peels (or other procedures leading to the production of partial-thickness wounds), and pre-tibial lacerations.
  • Preferred chronic wounds that may be treated with the medicaments or methods of the invention in order to accelerate their healing include ulcers such as diabetic ulcers, decubitus ulcers, and venous ulcers.
  • therapeutically effective fragments or derivatives of WIF-I should be taken (except for where the context requires otherwise) to encompass any fragment or derivative of WIF-I that is able to accelerate wound healing.
  • Therapeutically effective fragments or derivatives of WIF-I may be fragments or derivatives that are able to increase the rate of re-epithelialisation of wounds. Preferred means by which such acceleration of healing and/or increased rate of re-epithelialisation may be assessed are considered elsewhere in the specification.
  • therapeutically effective derivatives suitable for use in accordance with the invention may be derived either from WIF-I itself, or from therapeutically effective fragments of WIF-I.
  • a therapeutically effective fragment or derivative of WIF-I may be a fragment or derivative that is effective to accelerate healing of a treated wound by at least 10% compared to the rate of healing of a comparable untreated or control wound.
  • a therapeutically effective fragment or derivative of WIF-I may be one capable of accelerating healing by at least 20%, more preferably at least 50%, even more preferably at least 75% and yet more preferably of accelerating healing by at least 90% compared to the rate of healing of an untreated or control wound.
  • a most preferred therapeutically effective fragment or derivative of WIF-I may be capable of accelerating the healing of a wound by 100% or more, compared to the rate of healing of an untreated or control wound.
  • a therapeutically effective fragment or derivative of WIF-I may be a fragment or derivative that is effective to increase the rate of re-epithelialisation of a treated wound by at least 10% compared to the rate of re-epithelialisation of a comparable untreated or control wound.
  • a therapeutically effective fragment or derivative of WIF-I may be capable of increasing the rate of re-epithelialisation of a treated wound by at least 20%, more preferably at least 50%, even more preferably at least 75% and yet more preferably by at least 90% compared to the rate of re- epithelialisation of an untreated or control wound.
  • a most preferred therapeutically effective fragment or derivative of WIF-I may be capable of increasing the rate of re- epithelialisation of a treated wound by 100% or more, compared to the rate of re- epithelialisation of an untreated or control wound.
  • a therapeutically effective fragment or derivative of WIF-I may be one that is capable of accelerating the healing of a wound to which the fragment or derivative of WIF-I is added.
  • Suitable therapeutically effective amounts of WIF-I, as well as suitable therapeutically effective fragments or derivatives of WIF-I, are considered elsewhere in the specification.
  • Fragments comprising all or part of the WIF domain of WIF-I represent preferred therapeutically effective fragments for use in the medicaments or methods of the invention.
  • Conditions for the correct refolding of the WIF domain, thereby allowing the generation of stable samples have previously been reported in Liepinsh (2006), and the disclosure of this document as it relates to the preparation of active and stable samples of the WIF domain is incorporated by reference.
  • the detergent Brij-35 dodecylpoly(ethyleneglycolether) 23
  • the NMR structure of the WIF domain of WIF-I has been disclosed, and this structural information may be of use to the skilled person in selecting or generating therapeutically effective fragments of WIF-I comprising the WIF domain.
  • Therapeutically effective fragments of WIF-I suitable for use in accordance with the present invention may comprise 10 or more amino acid residues from Sequence ID No. 2, preferably up to 50 amino acid residues, more preferably up to 90 amino acid residues, and even more preferably up to 125 amino acid residues. Fragments suitable for use in the medicaments and methods of the present invention include those comprising up to 150 amino acids residues of Sequence ID No. 2. Preferred fragments will comprise at least 10 amino acid residues from Sequence ID No. 2.
  • Therapeutically effective fragments of WIF-I suitable for use in accordance with the present invention may comprise 10 or more contiguous amino acid residues from Sequence ID No. 2, preferably up to 50 contiguous amino acid residues, more preferably up to 90 contiguous amino acid residues, and even more preferably up to 125 contiguous amino acid residues. Fragments suitable for use in the medicaments and methods of the present invention include those comprising up to 150 amino acids residues of Sequence ID No. 2.
  • Preferred therapeutically effective fragments or derivatives of WIF-I may be those that are capable of binding to WNTs. Suitable binding may be mediated via the WIF domain of WIF-I . It will be appreciated that binding of the WIF domain of WIF-I to WNTs may arise as a result of the three dimensional structure of the WIF domain. Accordingly, suitable fragments may be selected based upon their ability to assume the requisite three dimensional conformation necessary for binding to WNTs.
  • peptides comprising all or part of WIF-I (as defined by Sequence ID No. 1) represent preferred agents for use in accordance with the present invention, it will be recognised that there are contexts in which the sensitivity of peptides to degradation may be disadvantageous. There are many known techniques by which peptide derivatives may be produced that have greater resistance to degradation than do the original peptides from which they are derived. Such derivatives may represent preferred active agents suitable for use in accordance with the invention.
  • a preferred therapeutically effective derivative for use in the medicaments or methods of the invention may preferably have a half-life in vivo that is at least 10% longer than that of a corresponding peptide (either WIF-I, or a fragment of WIF-I). It may be further preferred that a derivative has a half-life in vivo at least 20% longer than that of a corresponding peptide, more preferably at least 50% longer, even more preferably at least 70% longer, yet more preferably at least 90% longer, and most preferably at least 100% longer.
  • a preferred therapeutically effective derivative for use in the medicaments or methods of the invention may preferably have resistance to proteolytic degradation that is at least 10% longer than that of a corresponding peptide (either WIF-I, or a fragment of WIF-I). It may be further preferred that a derivative has a resistance to proteolytic degradation at least 20% longer than that of a corresponding peptide, more preferably at least 50% longer, even more preferably at least 70% longer, yet more preferably at least 90% longer, and most preferably at least 100% longer.
  • Peptoid derivatives may be expected to have greater resistance to degradation than do peptide agents of the invention, whilst retaining the same ability to accelerate wound healing. Suitable peptoid derivatives may be readily designed from knowledge of WIF- 1 's sequence and structure (and in particular the sequence and structure of the WIF domain). Commercially available software and well-established protocols may be used to develop peptoid derivatives suitable for use in accordance with the invention. It will be appreciated that the therapeutic effectiveness of peptoid and other derivatives may be investigated using the same techniques that allow assessment of therapeutic effectiveness of peptide fragments.
  • Retropeptoids (based on WIF-I or its therapeutically effective fragments) in which all amino acids are replaced by peptoid residues in reversed order may also be used in the medicaments or methods of the invention to accelerate wound healing.
  • a retropeptoid may be expected to bind to its binding partner in the opposite direction to the naturally occurring peptide or a peptoid-peptide hybrid containing one peptoid residue.
  • D-amino acid forms of WIF-I or its therapeutically effective fragments also confer the requisite ability to accelerate wound healing.
  • the order of the amino acid residues comprising the derivative is reversed as compared to those in the original peptide.
  • the preparation of derivatives using D-amino acids rather than L-amino acids greatly decreases any unwanted breakdown of such an agent by normal metabolic processes, decreasing the amounts of agent which need to be administered, along with the frequency of its administration.
  • Derivatives of WIF-I suitable for use in the medicaments or methods of the invention may preferably be based on the WIF domain, either in whole or in part. Knowledge of NMR of this domain may be of benefit in selecting or designing variants that will retain (or even improve upon) the therapeutic effectiveness of WIF-I .
  • derivatives suitable for use in the medicaments and methods of the invention clearly include both those derived from full length WIF-I and those derived from therapeutically effective fragments of WIF-I.
  • Derivatives of WIF-I suitable for use in the medicaments or methods of the invention also include peptide derivatives capable of increasing the rate of the healing of wounds.
  • Such peptide derivatives may be based on WIF-I, or on fragments thereof, but may comprise alterations or substitutions of the naturally occurring amino acid sequence. It will be appreciated that amino acid residues in the WIF domain of WIF-I that are involved in the binding of this domain to WNTs may be retained in peptide derivatives for use in accordance with the invention, but that amino acid residues that are not involved in binding to WNTs may be substituted without adversely effecting the activity of such derivatives.
  • the group of therapeutically effective derivatives of WIF-I also encompasses therapeutically effective small molecule mimics of WIF-I, or its fragments.
  • small molecule mimics of WIF-I encompass any small molecule chemical entities that are able to mimic WIF-I activity, and thereby accelerate wound healing, for example by binding to WNT molecules. It may be preferred that small molecule mimics of WIF-I are organic molecules with a weight less than 33OkDa, and preferably with a weight less than IkDa.
  • Suitable small molecule mimics of WIF-I that may be used in the medicaments or methods of the invention include those that are able to increase the rate of re-epithelialisation of a wound to which they are provided.
  • a therapeutically effective derivative of WIF-I suitable for use in accordance with the present invention may share at least 10% homology with Sequence ID No. 1 (or a fragment thereof), preferably at least 25% homology, more preferably at least 50% homology, and even more preferably at least 75% homology. Particularly preferred derivatives may share at least 80%, 85%, 90%, 95% or greater homology with Sequence ID No. 1 (or a fragment thereof).
  • Therapeutically effective derivatives of WIF-I suitable for use in accordance with the present invention may share at least 10% identity with Sequence ID No. 1 (or a fragment thereof), preferably at least 25% identity, more preferably at least 50% identity, and even more preferably at least 75% identity. Particularly preferred derivatives may share at least 80%, 85%, 90%, 95% or greater identity with Sequence ID No. 1 (or a fragment thereof).
  • a therapeutically effective amount of WIF-I, or a fragment or derivative thereof is any amount of WIF-I, or a therapeutically effective fragment or derivative thereof, which is able to accelerate the healing of a wound.
  • a therapeutically effective amount of WIF-I, or a fragment or derivative thereof is preferably an amount of WIF-I, or a fragment or derivative thereof, which is able to accelerate the healing of a wound to which the WIF-I, or fragment or derivative, is administered.
  • a therapeutically effective amount of WIF-I, or a fragment or derivative thereof may be an amount of WIF-I, or a fragment or derivative thereof, which is able to increase the rate of re-epithelialisation of a wound
  • a therapeutically effective amount of a medicament of the invention is any amount of such a medicament that is able to accelerate the healing of a wound. This acceleration of healing may preferably be achieved in a wound to which the medicament of the invention is administered.
  • a therapeutically effective amount of a medicament of the invention may be an amount of a medicament of the invention capable of increasing the rate of re- epithelialisation of a wound.
  • a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, or a therapeutically effective amount of a medicament of the invention may preferably be an amount that is effective to accelerate healing of a treated wound by at least 10% compared to the rate of healing of a comparable untreated or control wound.
  • a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, or of a medicament of the invention may be an amount capable of accelerating healing by at least 20%, more preferably at least 50%, even more preferably at least 75% and yet more preferably of accelerating healing by at least 90% compared to the rate of healing of an untreated or control wound.
  • a most preferred therapeutically effective amount of WIF-I, or a fragment or derivative thereof, or of a medicament of the invention may be capable of accelerating the healing of a wound by 100% or more, compared to the rate of healing of an untreated or control wound.
  • a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, or a therapeutically effective amount of a medicament of the invention may preferably be an amount that is effective to increase the rate of re-epithelialisation of a treated wound by at least 10% compared to the rate of re-epithelialisation of a comparable untreated or control wound.
  • a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, or of a medicament of the invention may be an amount capable of increasing the rate of re-epithelialisation by at least 20%, more preferably at least 50%, even more preferably at least 75% and yet more preferably of increasing the rate of re- epithelialisation by at least 90% compared to the rate of re-epithelialisation of an untreated or control wound.
  • a most preferred therapeutically effective amount of WIF-I, or a fragment or derivative thereof, or of a medicament of the invention may be capable of increasing the rate of re-epithelialisation of a treated wound by 100% or more, compared to the rate of re-epithelialisation of an untreated or control wound.
  • medicaments of the invention should be taken as encompassing any medicament manufactured in accordance with any aspect or embodiment of the invention.
  • a medicament of the invention will generally constitute a preferred means for putting into practice any method of treatment in accordance with the present invention.
  • Suitable compositions, formulations and routes of delivery that may be used for medicaments of the invention are considered elsewhere in the specification.
  • Medicaments of the invention may preferably be capable of accelerating wound healing by increasing the rate of re- epithelialisation of treated wounds (as compared to the rate of re-epithelialisation occurring in control or untreated wounds).
  • the medicaments of the invention may comprise a liquid medicament, such as an injectable medicament, spray, cream or the like, incorporating WIF-I, or a therapeutically effective fragment or derivative thereof.
  • a liquid medicament such as an injectable medicament, spray, cream or the like, incorporating WIF-I, or a therapeutically effective fragment or derivative thereof.
  • Such liquid medicaments may be administered to the site of a wound the healing of which is to be accelerated.
  • the medicaments of the invention may comprise solid medicaments from which a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, may be released to a wound the healing of which is to be accelerated.
  • a medicament of the invention may comprise a wound dressing capable of providing a therapeutically effective amount of an active agent to a wound to which the dressing has been applied.
  • Active agent for the purposes of the present disclosure, should be taken to be WIF- 1, or any therapeutically effective fragment or derivative thereof. Active agents may also encompass compounds (such as nucleic acid molecules) capable of stimulating the expression of WIF-I, or its therapeutically effective fragments or derivatives.
  • Suitable active agents that may be used in the medicaments or methods of the invention may be selected from the group consisting of: WIF-I itself; therapeutically effective fragments of WIF-I; the WIF domain of WIF-I; therapeutically effective peptide derivatives of WIF-I; therapeutically effective fragments or derivatives comprising or based on the pharmacophore of WIF-I; therapeutically effective peptoid derivatives of WIF-I; therapeutically effective D-amino acid derivatives of WIF-I; therapeutically effective peptidomimetics based on WIF-I or its fragments; therapeutically effective peptide analogues of WIF-I or its fragments; therapeutically effective pseudopeptides based on WIF-I or its fragments; therapeutically effective retro-inverso peptides based on WIF-I or its fragments; therapeutically effective depsipeptide derivatives based on WIF-I or its fragments; therapeutically effective ⁇ -peptide derivatives based on WIF-I or its fragment
  • a “topical medicament”, for the purposes of the present disclosure, is to be construed as a medicament that is applied at a site where it is intended to have its effect. This site may be a wound, or a site where a wound is to be formed.
  • Topical medicaments suitable for use in accordance with the present invention include, but are not limited to, ointments; creams; lotions; gels; sprays; wound dressings capable of releasing active agents to a wound (or site where a wound is to be formed); and injectable solutions administered by local injections (e.g. intradermal injections).
  • a “treated wound” in the context of the present disclosure is any wound that has been provided with a therapeutically effective amount of WIF-I (or a therapeutically effective fragment or derivative thereof). This provision may be by means of a medicament of the invention, or by means of a method of treatment in accordance with the invention.
  • Control-treated wounds and “untreated wounds” in the present context are respectively wounds treated with a relevant control, and wounds that have not been treated before, or during, healing.
  • Control wounds should not be treated with a medicament of the invention, and preferably will not be treated with a therapeutically effective amount of an active agent. That said, wounds treated with medicaments known from the prior art may constitute suitable control wounds for purposes of comparative studies (for example to illustrate increased efficiency or effectiveness of medicaments of the invention as compared to those already known).
  • a "diluent control-treated wound” will be an untreated wound to which a control diluent has been administered, and a “na ⁇ ve control” will be an untreated wound made without administration of an active agent or a suitable control diluent, and left to heal without therapeutic intervention.
  • Assessment of acceleration of wound healing may be made with reference to any suitable index of the healing age of a wound. Such indices may be assessed macroscopically or microscopically as appropriate. It may be preferred that acceleration of wound healing is assessed with reference to the rate at which treated and untreated or control treated wounds re-epithelialise.
  • the rate of re-epithelialisation may be assessed macroscopically or microscopically.
  • Macroscopic assessment of re-epithelialisation may be performed, directly using measurements taken from wounds themselves, or indirectly, using measurements taken from images or tracings of wounds. Techniques such as image analysis may be used for the quantification of such measurements.
  • Microscopic assessment of re-epithelialisation represents a preferred method by which acceleration of wound healing may be assessed. Many suitable protocols by which re- epithelialisation may be microscopically assessed will be well known or apparent to those skilled in the art.
  • a wound may comprise any injury (whether caused by physical, chemical, metabolic or other means) giving rise to a total or partial defect in an epithelial layer. Such wounds may also be termed full thickness or partial thickness wounds respectively. A wound may also involve damage to the connective tissue underlying the wounded epithelium.
  • wounds within the present disclosure should also be taken to encompass sites where wounds are to be formed, since the inventors have found that such sites may benefit from prophylactic treatment using the medicaments or methods of the invention.
  • wounds will primarily be described with reference to skin wounds, which comprise preferred wounds the healing of which may be accelerated in accordance with the present invention.
  • skin wounds which comprise preferred wounds the healing of which may be accelerated in accordance with the present invention.
  • the acceleration of wound healing should not be limited to skin wounds.
  • the inventors believe that wound healing may be accelerated, using the medicaments or methods of the invention, in wounds of all tissues.
  • Skin wounds, the healing of which may be accelerated using the medicaments and methods of the invention include both chronic wounds and acute wounds. Examples of suitable chronic or acute wounds the healing of which may be accelerated in accordance with the invention are set out elsewhere in the specification.
  • the medicaments and methods of the invention may be used to accelerate healing of wounds selected from the group consisting of: abrasions; avulsions; crush wounds; incisional wounds; lacerations; punctures; ulcers, abscesses, and missile wounds, all of which may be suffered by the skin (among other tissues or organs).
  • suitable wounds include surgical wounds; pre-tibial lacerations; graft recipient sites; gastrointestinal ulcers, lung abscesses and wounds associated with myocardial infarction.
  • Preferred chronic wounds that may be treated with the medicaments or methods of the invention in order to accelerate their healing include ulcers such as, diabetic ulcers, decubitus ulcers, and venous ulcers.
  • wounds of the eye examples include, but are not limited to, those selected from the group consisting of: wounds of the eye; wounds of blood vessels; wounds of the peripheral or central nervous system (where increasing the rate of healing of wounds may enhance the capability for neuronal reconnection); wounds of the oral cavity, including the lips and palate; wounds of the internal organs such as the liver, heart, brain and digestive tissues; and wounds in body cavities such as the abdominal cavity, pelvic cavity and thoracic cavity.
  • the medicaments and methods of the invention be used to accelerate healing of skin wounds. This may be through treatment of such wounds themselves and/or the sites where such wounds are to be formed.
  • the medicaments and methods of the invention may be used to accelerate the healing of full thickness or partial thickness wounds (respectively wounds in which the epithelial layer is either totally or partly compromised).
  • Preferred examples of partial thickness wounds the healing of which may be accelerated using the medicaments or methods of the invention include "skin peels” such as “chemical peels” (such as alphahydroxy acid peels, trichloroacetic acid peels or phenol peels) or "laser peels"; wounds associated with dermabrasion; wounds associated with dermaplaning; and wounds associated with laser tattoo removal.
  • wounds of the eye including wounds of the cornea, and acceleration of healing of wounds resulting from eye surgery including treatments such as laser assisted in situ keratomileusis - LASIK, laser assisted sub-epithelial keratectomy - LASEK or photorefractive keratectomy - PRK); wound of blood vessels; wounds of the peripheral or central nervous system (where increasing the rate of healing of wounds may enhance the capability for neuronal reconnection); wounds of tendons, ligaments or muscle; and wounds of the oral cavity, including the lips and palate; wounds of the internal organs such as the liver, heart, brain and digestive tissues; and wounds in body cavities such as the abdominal cavity, pelvic cavity and thoracic cavity.
  • wounds of the eye including wounds of the cornea, and acceleration of healing of wounds resulting from eye surgery including treatments such as laser assisted in situ keratomileusis - LASIK, laser assisted sub-epithelial keratectomy - LASEK or photorefractive keratectomy - PR
  • Preferred wounds the healing of which may be accelerated using the medicaments and methods of the invention, include chronic wounds, pre-tibial lacerations, wounds associated with skin peels (or other procedures producing partial thickness wounds) and wounds of the immunocompromised.
  • medicaments and methods of the invention be used to accelerate the healing of skin wounds.
  • “Acceleration of the healing of wounds”, or “acceleration of wound healing” in the context of the present disclosure should be taken to encompass any increase in the rate at which a treated wound is healed.
  • the rate at which a wound heals may be assessed by comparison of the rate of healing of a treated wound with the rate of healing of control wounds or untreated wounds (i.e. wounds the healing of which has not been accelerated).
  • the medicaments or methods of the invention are able to increase the rate of re-epithelialisation of treated wounds, and an acceleration of wound healing may be most readily demonstrated by an increased rate of re-epithelialisation of a wound.
  • Such an increase in the rate at which the epithelial covering (for example the epidermis, in the case of skin wounds) is repaired or regenerated will indicate that the healing of the wound in question has been accelerated.
  • Methods by which re- epithelialisation may be assessed are described elsewhere in the specification.
  • An increase in the rate of re-epithelialisation of a wound may be distinguished from closure of a wound brought about by wound contraction.
  • Wound contraction is brought about through the action of contractile elements (generally thought to be associated with myofibroblasts) located within and around the periphery of the wound. Wound contraction leads to a reduction in the surface area of the wound, but this may not be associated with an increase in the proportion of the wound surface covered by epithelium.
  • Increases in the rate of re-epithelialisation may also be distinguished from "filling" of wounds that may occur through the generation of granulation tissue. Such a distinction can generally be made through either macroscopic assessment or microscopic assessment (since the cell types involved in granulation tissue formation differ from those contributing to re-epithelialisation).
  • Accelerated healing of a wound in accordance with the present disclosure may preferably lead to a treated wound healing at a rate at least 5% faster than an untreated wound, preferably at a rate at least 10% faster, more preferably at least 15%, 20% or 25% faster; yet more preferably at least 50% faster, still more preferably at least 75% faster, and most preferably 100% (or more) faster.
  • acceleration of wound healing may preferably lead to a treated wound having a rate of re-epithelialisation at least 5% greater than an untreated wound, preferably at least 10% greater, more preferably at least 15%, 20% or 25% greater; yet more preferably at least 50% greater, still more preferably at least 75% greater, and most preferably 100% (or more) greater.
  • Accelerated healing of a wound in accordance with the present disclosure may preferably lead to a treated wound having a "healing age" that is at least a day faster than an untreated wound, preferably at a rate at least five days faster, more preferably at least ten days faster; yet more preferably at least eleven, twelve, thirteen, fourteen of fifteen days faster, still more preferably fifteen or more days faster, and most preferably 20 (or more) days faster.
  • aling age that is at least a day faster than an untreated wound, preferably at a rate at least five days faster, more preferably at least ten days faster; yet more preferably at least eleven, twelve, thirteen, fourteen of fifteen days faster, still more preferably fifteen or more days faster, and most preferably 20 (or more) days faster.
  • a “centimetre of wound”, “wound centimetre” or “centimetre of wounding” in the context of the present disclosure constitutes a unit by which the size of a wound to be treated may be measured. For the present purposes such measurements should also be taken to encompass sites at which wounds are to be formed.
  • a wound centimetre may be taken to comprise any square centimetre of a body surface that is wounded in whole or in part.
  • a wound of two centimetres length and one centimetre width i.e. with a total surface area of two cm 2
  • a wound having a length of two centimetres and a width of two centimetres i.e. a total surface area of four cm 2
  • a linear wound of two centimetres length, but of negligible width i.e. with negligible surface area
  • the size of a wound in wound centimetres should generally be assessed when the wound is in its relaxed state (i.e. when the body site bearing the wounded area is in the position adopted when the body is at rest). In the case of skin wounds, the size of the wound should be assessed when the skin is not subject to external tension.
  • An inch of administered area, or inch of wound may be similarly defined, save that the relevant units of length or area are measured in inches rather than centimetres. It will be appreciated that the quantity of an active agent constituting a therapeutically effective amount for the treatment of an inch of wound may be derived from those quantities provided in respect of centimetres of wound by use of a suitable conversion factor (one inch corresponding to approximately 2.54 centimetres).
  • a centimetre or inch of wounding may thus provide a unit by which the size of a wound to be treated may be measured, and the required amount of a medicament of the invention (or of an active agent administered in accordance with a method of treatment of the invention) may be determined.
  • the skin suffers from more direct, frequent, and damaging encounters with the external environment than any other organ in the body.
  • the skin suffers from more wounds than other organs, and it is therefore highly desirable to be able to accelerate the healing of skin wounds in order to return this organ as rapidly as possible to its maximum functional effectiveness.
  • Acceleration of the healing of skin wounds is a preferred embodiment of the medicaments or methods of the present invention. Accordingly the medicaments and methods of the invention will generally be discussed with reference to their use to accelerate healing of skin wounds, although it will be appreciated that many of the considerations set out here are also applicable to accelerating healing of wounds other than of the skin.
  • Skin wounds susceptible to accelerated healing in accordance with the medicaments or methods of the invention include both "open” wounds, in which the integrity of the skin has been entirely compromised, exposing the underlying tissues, and also "closed” wounds in which the skin, though damaged, is not entirely compromised.
  • Partial thickness wounds, as described elsewhere in the specification (particularly in the context of skin peels and split thickness skin grafts), provide an example of closed wounds that may benefit from accelerated healing as provided by the invention.
  • Accelerating healing of skin wounds is able to hasten the formation of a functioning protective barrier over previously damaged or denuded areas.
  • the accelerated healing helps prevent ingress into, and colonisation of, the underlying tissue by pathogens such as bacteria, fungi and viruses.
  • pathogens such as bacteria, fungi and viruses.
  • Healed skin also acts as a barrier to fluid movement, and is therefore able to prevent desiccation of underlying tissue.
  • accelerated wound healing that may be achieved with the medicaments or methods of the invention may help to prevent or reduce tissue desiccation arising as a result of fluid loss across damaged areas of the skin.
  • the damage caused as a result of fluid loss through wounded skin is particularly harmful in the case of wounds having large surface areas, such as burns or skin peels. Acceleration of the healing of burns wounds, or wounds associated with skin peels, thus represents a preferred use of the methods or medicaments of the invention.
  • the accelerated healing of wounds may be of benefit in circumstances in which the wound healing response is impaired, inhibited, retarded or otherwise defective as compared to the normal rate of healing.
  • the methods and medicaments of the invention may also be used to accelerate the healing of wounds in patients that are not subject to an impaired healing response. Illustrative examples of both contexts are set out below.
  • the wound healing response may also be retarded as a result of the actions of pathogens (such as bacteria, fungi or viruses), chemical insults (such as chemical burns caused by caustic agents, or through the effect of cytotoxic drugs such as those employed in chemotherapy), or as a result of radiation damage (either through particulate radiation or electromagnetic radiation such as gamma radiation, ultraviolet radiation, or the like) such as that occurring in sunburn.
  • pathogens such as bacteria, fungi or viruses
  • chemical insults such as chemical burns caused by caustic agents, or through the effect of cytotoxic drugs such as those employed in chemotherapy
  • radiation damage either through particulate radiation or electromagnetic radiation such as gamma radiation, ultraviolet radiation, or the like
  • Such patients represent a preferred group that may benefit from accelerated wound healing using the methods or medicaments of the invention. Acceleration of wound healing in such patients may help reduce incidences of infections at wound sites (since the promotion of re-epithelialisation can reduce ingress of pathogens), and may decrease incidences of chronic wound formation.
  • the medicaments and methods of the invention may be useful in accelerating healing of wounds in those subject to defective wound healing, it may generally be preferred that the medicaments or methods of the invention may be utilised to accelerate the healing of wounds of patients in whom the wound healing response is not impaired. Acceleration in this way will give rise to a faster wound healing response than would normally be achieved by such "otherwise healthy" patients in the absence of therapeutic acceleration (i.e. give rise to faster healing than in control wounds of such patients). Accordingly the wounds of healthy patients may be induced to heal more rapidly.
  • a chronic wound may be defined as any wound that does not show any healing tendency within eight weeks of formation when subject to appropriate (conventional) therapeutic treatment.
  • Acute wounds may be considered to be any wound other than a chronic wound.
  • Acceleration of the healing of chronic wounds is a preferred embodiment of the invention.
  • Examples of chronic wounds that may benefit from accelerated healing provided by the medicaments or methods of the invention may be selected from the group comprising: leg ulcers; venous ulcers; diabetic ulcers; bed sores; decubitus ulcers; foot ulcers; and pressure ulcers.
  • the medicaments and methods of the invention may be used to reduce the time taken for such chronic wounds to begin to heal, to heal to an extent where they can then be treated surgically, or even to heal completely. It will be appreciated that the long lasting nature of chronic wounds exacerbates many of the disadvantages associated with normal wound healing.
  • the duration of the period over which a patient suffering from a chronic wound will experience pain will generally be far longer than for a patient with an acute wound.
  • the length of time over which desiccation as a result of liquid loss may occur will also be extended. Incidences of wound infection are also much increased in chronic, as opposed to acute, wounds.
  • Chronic wounds are also subject to many disadvantages that are not generally associated with acute wounds. For example, chronic wounds frequently expand beyond the limits of the original wounded area. This may arise as a result of infection (which may increase the damage around the margins of the wound, thereby leading to expansion) or through maceration of the tissue surrounding the wound (typically as a consequence of increased liquid loss through the chronic wound).
  • the propensity for chronic wounds to expand beyond the boundary of the original injury means that such wounds are frequently of great surface area. Since accelerated wound healing utilising the medicaments and methods of the invention primarily occurs from "the outside in”, it will be appreciated that this will act to counter the progression of chronic wounds. Use of the medicaments and methods of the invention may thus be of notable benefit in the treatment of chronic wounds.
  • Pretibial lacerations are acute wounds of the leg that are very frequently slow to heal, and which frequently give rise to the development of leg ulcers.
  • Existing treatments used for pretibial lacerations include the use of surgical procedures (such as the use of skin grafts and flaps) in an attempt to heal the wound before chronic wound development.
  • Pretibial lacerations constitute acute wounds that may particularly benefit from treatment using the medicaments and methods of the invention, in order to accelerate healing and thereby reduce incidences of chronic wound formation.
  • Acute wounds include: abrasions; avulsions; crush wounds; incisional wounds; lacerations; punctures; and missile wounds. All of these types of wounds may be suffered by the skin (among other tissues or organs).
  • Abrasions are also commonly referred to as "scrapes". Abrasions occur as a result of the skin being rubbed away by friction against another rough surface. Common examples of abrasions include rope burns and skinned knees. An abrasion may macroscopically appear as lines of scraped skin, possibly including tiny spots of bleeding. Damage to the epithelial surface is often a relatively major component of abrasions, and hence the ability of the medicaments and methods of the invention to the increase the rate of re- epithelialisation may be particularly advantageous in accelerating the healing of these wounds.
  • Avulsions occur when an entire bodily structure, or a part of such a structure, is forcibly pulled away from its site. Examples of avulsions include the loss of a permanent tooth or an ear lobe. Avulsions may, for example, arise as a result of explosions, gunshots, and animal bites. An avulsion may characteristically exhibit heavy, rapid bleeding, as well as a noticeable absence of tissue.
  • Crush wounds typically occur as a result of a heavy object falling onto an individual (or part of an individual). The force thus generated may split the skin and shatter or tear underlying structures.
  • a crush wound may have irregular margins, similar in appearance to those of a laceration; however, the wound will generally be deeper and trauma to underlying muscle and bone may be apparent
  • Incisional wounds are also commonly referred to as "cuts". Incisional wounds result from incision, or slicing, of a tissue with a sharp instrument, which results in a wound with relatively even edges. Incisional wounds can vary greatly in their severity, from minimal wounds (such as a paper cut) to significant wounds such as those arising as a result of surgical incision. An incisional wound may have little or profuse bleeding depending on the depth and length of the wound, and also on the tissue involved. The even edges of incisional wounds will generally readily line up, which may facilitate closure of such wounds. Acceleration of wound healing using the medicaments and methods of the invention is particularly useful in the treatment of incisional wounds. The increased rate of re-epithelialisation that can be achieved in treated wounds is advantageous in promoting closure of such wounds.
  • Lacerations are also frequently referred to a "tears". These wounds arise as a result of forcible separation of a tissue or organ, which will normally produce a wound having characteristic ragged edges. Lacerations are generally produced by the action of great mechanical forces against the body, either from an internal source as in childbirth, or from an external source like a punch. The laceration arises when the force exerted on a tissue or organ becomes too great for the tissue or organ to bear. A laceration may exhibit little or profuse bleeding, in much the same manner as an incisional wound. In contrast to incisional wounds however, the tissue damage is generally greater and the wound's ragged edges do not line up so readily. As with incisional wounds, the increased rate of re- epithelialisation that can be attained using the medicaments or methods of the invention may be advantageous in promoting closure of laceration wounds.
  • Punctures are deep, narrow wounds. Punctures may typically be produced by sharp objects such as nails, knives, and broken glass being driven into the body.
  • the depth of a puncture wound will generally be greater than its length. As a consequence there is generally little bleeding around the outside of the wound although more bleeding may occur inside the wound. This may lead to discoloration around the puncture wound.
  • Missile wounds are also known as "velocity wounds". Missile wounds are caused by an object entering the body at a high speed, typically a bullet. A missile entry wound may be accompanied by an exit wound, and bleeding may be profuse, depending on the nature of the injury.
  • Incisional wounds constitute preferred acute wounds, the healing of which may be accelerated by the medicaments and methods of the invention.
  • Surgical incisional wounds may constitute a particularly preferred group of acute wounds to be treated in accordance with the invention.
  • surgical wounds may frequently be subject to artificial means by which the wound margins may be held in apposition (such as sutures, staples, or wound glues), the ability of the medicaments or methods of the invention to increase the re-epithelialisation of such wounds, and to accelerate their healing, may still be of notable advantage in re-establishing the epithelial covering of such wounds.
  • tissues other than the skin such as the cornea, may also be subject to wounds of the type described above and elsewhere in the specification. Such wounds may also benefit from the acceleration of healing that is provided by use of medicaments and methods of the invention.
  • Burn wounds are a further class of wounds the healing of which may be accelerated using the medicaments and methods of the invention.
  • burns may, except for where the context requires otherwise, be considered to include tissue damage resulting from exposure to either high or low temperature, chemical agents, or radiation.
  • burns wounds may therefore derive particular benefit from the accelerated wound healing that may be brought about by the medicaments and methods of the invention.
  • Re-epithelialisation that may be promoted by the medicaments or methods of the invention may aid the reconstitution of a functional epidermal barrier, and thereby reduce ingress of pathogens or loss of fluids.
  • Medicaments or methods of the invention may be used to accelerate healing of all types of burns, including superficial thickness burns, in which only the epidermis is damage (otherwise known as "first degree” burns); partial thickness superficial burns, in which the epidermis and papillary dermis are damaged ("second degree” burns); partial thickness deep burns, in which the epidermis and reticular dermis are damaged (also classified as “second degree” burns); and full thickness burns, in which the epidermis, dermis and underlying tissues, such as fascia, muscle or bone, are damaged ("third degree” or "fourth degree” burns).
  • the use of the medicaments and methods of the invention to accelerate the healing of wounds associated with skin grafting procedures represents a preferred embodiment of the invention.
  • the medicaments and methods of the invention may be used to accelerate healing of wounds associated with grafting procedures in the healing impaired, or in otherwise health patients.
  • the medicaments and methods of the invention may advantageously be used to accelerate healing of wounds associated with grafting procedures in patients without an impaired healing response.
  • the accelerated healing conferred by the medicaments and methods of the invention is of benefit at the graft recipient site, and at the graft donor site.
  • the methods and medicaments of the invention may be used to accelerate healing of wounds associated with both full and partial thickness skin grafts.
  • Such skin grafts i.e. either full or partial thickness grafts
  • the accelerated healing provided by the medicaments and methods of the invention is able to improve and accelerate integration of the grafted tissue.
  • the beneficial effects of the medicaments and methods of the invention come about as a result of effects of the active agents on tissue surrounding or underlying the wounded site. It will therefore be appreciated that these advantageous effects may be available not only in the case of grafts utilising skin (where cells in the graft itself can be beneficially influenced), but also in the case of grafts using artificial skin, or skin substitutes (since provision of the active agent to the damaged area may induce keratinocytes from the surrounding unwounded skin to migrate into the wounded area and thereby encourage integration of the graft).
  • the acceleration of wound healing at graft donor sites is able to decrease the time taken to restore a functioning skin barrier layer, and consequently reduces the potential for donor site infection.
  • the accelerated healing also decreases incidences of blistering and tissue breakdown that may otherwise occur at the donor site.
  • wounds treated with the medicaments or methods of the invention are able to heal faster, the period over which a patient experiences pain associated with sites where the skin has been damaged or removed is reduced.
  • the medicaments and methods of the invention it is possible to reduce the pain associated with the taking of skin grafts.
  • a further advantage of accelerated healing of wounds at skin donor sites is that this decreases the time required until re-harvesting of tissue from the donor site can take place.
  • re-harvesting is meant the subsequent removal of further graftable skin from a previously used donor site. This is particularly advantageous in situations where the skin available for harvesting is limited and/or the area of skin required to be harvested is large. Examples of such situations include occasions when it is necessary to take grafts from children and/or patients suffering from burns covering a large percentage of the body surface. In these cases there may be relatively little unwounded skin that may serve as a donor site for graft material, and it may be desirable to obtain multiple donations from the sites available.
  • Skin peels may use chemical agents (such as alphahydroxy acid, trichloroacetic acid, or phenol), or other agents (such as lasers) to remove epidermal cells.
  • chemical agents such as alphahydroxy acid, trichloroacetic acid, or phenol
  • lasers such as lasers
  • Graft donor sites may generally be treated with the methods or medicaments of the invention before the graft tissue is taken. This allows the donor site to be "primed” in advance of wounding. Such priming may further help to accelerate wound healing by avoiding any "lag” that may otherwise occur between the graft being taken and a medicament administered. Prophylactic use in this manner may further help to avoid onset of complications that may otherwise arise at the graft donor site, such as chronic wound development. In general it may be preferred to avoid the prophylactic treatment of wounds associated with skin peels or dermabrasion, since the priming of such wounds may detract from the effect achieved by the procedure in question.
  • the medicaments and methods of the invention may be used prophylactically in situations other than grafting procedures, such as before surgery or when there is a risk of wounding occurring through other means. Prophylactic use in this manner may be of benefit to both healthy and healing-impaired patients. In the case where the individual to be wounded may otherwise be subject to retarded or incomplete wound healing it will generally be preferred that the medicaments or methods of the invention are administered as soon as the risk of a poor rate of wound healing has been recognised.
  • Suitable active agents that may be used in the medicaments or methods of the invention include: WIF-I itself; therapeutically effective fragments of WIF-I; the WIF domain of WIF-I; therapeutically effective peptide derivatives of WIF-I; therapeutically effective fragments or derivatives comprising or based on the pharmacophore of WIF-I; therapeutically effective peptoid derivatives of WIF-I; therapeutically effective D-amino acid derivatives of WIF-I; therapeutically effective peptidomimetics based on WIF-I or its fragments; therapeutically effective peptide analogues of WIF-I or its fragments; therapeutically effective pseudopeptides based on WLF-I or its fragments; therapeutically effective retro-inverso peptides based on WIF-I or its fragments; therapeutically effective depsipeptide derivatives based on WIF-I or its fragments; therapeutically effective depsipeptide derivatives based on WIF-I or its fragments
  • the medicaments of the invention should be taken to encompass any composition, material or device from which an active agent may be provided to a wound in a therapeutically effective quantity (as defined elsewhere in the specification).
  • compositions, materials or devices should also comprise a pharmaceutically acceptable diluent or carrier.
  • suitable materials include: fabrics (such as woven and non-woven materials) including bandages, sticking plasters, patches, swabs, or other wound dressings.
  • wound dressing materials that may be used in the production of medicaments in accordance with the present invention may include dressings in the following broad classes: passive products, interactive products, and bioactive products.
  • Passive products include traditional dressings, such as gauze and tulle dressings, that provide cover over the wound.
  • Gauze dressings include paraffin gauze and woven gauze dressings. These can stick to surface of wounds to which they are applied, and this can disrupt the wound bed when the dressing is removed. Gauze dressings can be used on clean epithelialising wounds with medium to high exudate. However, given their propensity to stick to wound surfaces they are generally only used on minor wounds or as secondary dressings. Tulle dressings do not stick to wound surfaces. They are suitable for use in flat, shallow wounds, and are useful in patients with sensitive skin. Examples of tulle dressings known from the prior art include Jelonet® and Paranet®.
  • Interactive products such as hyaluronic acid, hydrogels, foam dressings and polymeric films, may be permeable to water vapour and oxygen, and non-permeable to bacteria.
  • Hydrogel dressings are composed mainly of water in a complex network or fibres that keep the polymer gel intact. Water is released to keep the wound moist. Hydrogel dressings may be used for necrotic or sloughy wound beds to rehydrate and remove dead tissue. They should not be used for moderate to heavily exudating wounds. Examples known from the prior art include Tegagel® and Intrasite®. Polyurethane or silicone foam dressings are designed to absorb large amounts of exudates, and are suitable for use on granulating wounds.
  • Bioactive products such as hydrocolloids, alginates, collagens and chitosan, are particularly suitable for the delivery of active agents to be used in the medicaments or methods of the invention.
  • Bioactive products constitute preferred examples of materials that may be used in the medicaments of the invention.
  • Hydrocolloid dressings may comprise carboxymethylcellulose, gelatin, pectin, elastomers and adhesives that turn into a gel when exudate is absorbed. This creates a warm, moist environment that promotes debridement and healing.
  • Hydrocolloid dressings may even be used in relatively dry or necrotic wounds.
  • Dressings of this sort are available in many forms (adhesive or non-adhesive pad, paste, powder) but are most commonly provided as self-adhesive pads. Examples known from the prior art include DuoDERM® and Tegasorb®.
  • Alginate dressings are composed of calcium alginate (a seaweed component). When in contact with a wound, calcium in the dressing is exchanged with sodium from the wound fluid and this turns the dressing into a gel that maintains a moist wound environment. These dressings are favoured for use in exudating and/or granulating wounds and help in debridement of sloughing wounds, hi general they should not be used on low exudating wounds as this may lead to dryness and scabbing.
  • Alginate dressing should generally be changed daily. Examples known from the prior art include Kaltostat® and Sorbsan®. Collagen dressings are generally provided in the form of pads, gels or particles. They promote the deposit of newly formed collagen in the wound bed, and absorb exudate and provide a moist environment.
  • Suitable dressings that may be used as, or in, solid medicaments in accordance with the invention include foam or sponge dressings (i.e. foams in which the matrices in which the pores are located are solid, as opposed to liquid foams considered elsewhere in the disclosure).
  • foam or sponge dressings should be capable of providing a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, to a wound to which the dressing is applied.
  • PVA polyvinyl alcohol
  • WIF-I, or its therapeutically effective fragments or derivatives may be incorporated in, or applied to, foams or sponges for use in wound dressings by any suitable technique known in the art.
  • suitable foams or sponges may be coated with WIF-I, or a therapeutically effective fragment or derivative thereof, or impregnated with such compounds. It will be appreciated that the important concern is merely that the WIF-I, or therapeutically effective fragment or derivative be incorporated in, or applied to, the foam or sponge in such a manner that a therapeutically effective amount of the compound is provided to a treated wound.
  • foams or sponges for use in medicaments of the invention may be such that they prevent substantial ingress of cells contributing to the wound healing process (e.g. keratinocytes associated with re-epithelialisation, or cells involved in granulation tissue formation) into the foam or sponge.
  • Foams or sponges to be used in medicaments of the invention may also be subject to surface treatments designed to reduce their adhesion to wounds to which they are applied. This may be advantageous in reducing damage that may otherwise be associated with changing dressings applied to wounds.
  • Foam or sponge pore sizes may be selected such that they facilitate the removal of exudates from the wound area, thus preventing or reducing maceration of the wound.
  • the removal of exudates may be facilitated by the application of negative pressure to treated wounds, or to wound dressings applied to such wounds, and this may have further beneficial effects on the healing response.
  • the medicaments or methods of the invention may make use of a number of different types of wound dressings in which WIF-I, or a therapeutically effective fragment or derivative thereof, are incorporated in a dressing material such that a therapeutically effective amount of the incorporated compound is releasable to a wound.
  • Suitable examples may include: nonresorbable gauze/sponge dressings for external use (typically a sterile or nonsterile device intended for medical purposes, they may be placed directly on a patient's wound to absorb exudate, and are generally made from open woven or nonwoven mesh cotton cellulose or a simple chemical derivative of cellulose); hydrophilic wound dressing (again, may be sterile or nonsterile in form, are intended to cover a wound and to absorb exudate, and are manufactured of nonresorbable materials such as cotton, cotton derivatives, alginates, dextran, and rayon that have hydrophilic properties and are capable of absorbing exudate); occlusive wound dressing (which are nonresorbable, sterile or nonsterile device intended to cover a wound and thus provide or support a moist wound environment, while allowing the exchange of gases such as oxygen and water vapor through the device, and which tend to be manufactured from synthetic polymeric materials, such as polyurethane, with or without an adhesive backing); and hydrogel wound and burn dressing (available in
  • a suitable wound healing dressing to be used on a particular wound may be selected with reference to the type of the wound, size of the wound, and healing progression of the wound. Guidance as to suitable choices may be found in the preceding paragraphs.
  • a medicament of the invention comprising a solid material
  • the medicament be formulated such that a predetermined area of the medicament provides a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, to a wound to which the solid material is applied.
  • a solid medicament may be formulated such that each square centimetre of the medicament provides between about 2finoles and 30pmoles of WIF-I, or a therapeutically effective fragment or derivative thereof, more preferably between 0.02pmoles and 20pmoles, even more preferably between 0.02pmoles and 2pmoles, and most preferably about 0.2pmoles per square centimetre.
  • such a medicament may, therefore, be formulated such that it provides between O.lng and 1500ng of WIF-I per square centimetre of the medicament, more preferably between Ing and lOOOng, even more preferably between Ing and lOOng, and most preferably about IOng of WIF-I.
  • the medicament is administered in sufficient quantity to provide a therapeutically effective amount of WIF- 1, or a fragment or derivative.
  • medicaments of the invention are formulated to provide discrete dosage units capable of providing a specified amount of WIF-I or a therapeutically effective fragment or derivative thereof (this specified amount will generally be a known fraction or multiple of a therapeutically effective amount of WIF-I or the relevant fragment or derivative).
  • Suitable dosage units may be formulated with reference to the size of a wound to be treated. It may be envisioned that medicaments in accordance with this embodiment of the invention will be formulated so that a specified quantity (for instance a specified volume or a specified weight) of the medicament may be administered to a specified size of wound (for instance a specified area of wound or a specified length of wound) in order that a therapeutically effective amount of an active agent may be administered to the wound.
  • a suitable medicament may be formulated so that a specified quantity of the medicament (for example O.lnL to 10OmL of the medicament, or O.lng to 100 grams of the medicament) provides a therapeutically effective amount of WIF-I, or a fragment or derivative thereof. It may be preferred that the specified quantity of the medicament be provided per centimetre of wounding (including per centimetre of a site where a wound is to be formed).
  • Suitable specified quantities of medicaments of the invention may be selected with respect to the nature of the medicament in question.
  • the quantity of an injectable solution medicament of the invention required to administer a therapeutically effective amount of an active agent may be relatively small (for example in the region of 0.05 to 0.5mL).
  • the quantity of a gel, ointment or spray medicament of the invention required to administer a therapeutically effective amount of an active agent may be relatively larger (for example in the region of 0.25 to 2.5mL).
  • the quantity of an irrigation fluid medicament of the invention required to administer a therapeutically effective amount of an active agent may be larger still (for example in the region of 0.5 to 5mL).
  • the concentration of active agents within the different forms of the medicaments of the invention may be selected, for example in accordance with the volumes outlined above, in order to provide suitable medicaments of the invention capable of providing therapeutically effective amounts of an active agent.
  • Medicaments of the invention may be provided in the form of discrete dosage units capable of providing a therapeutically effective amount of an active agent (which is to say capable of providing an amount of a medicament sufficient to provide a therapeutically effective amount of WIF-I, or a fragment or derivative thereof).
  • a suitable dosage unit in accordance with this embodiment of the invention may comprise a sufficient amount of a medicament of the invention to accelerate the healing of a given length or area of a wound.
  • a suitable dosage unit may comprise sufficient of a medicament of the invention to accelerate the healing of one centimetre of a wound.
  • a suitable dosage unit may comprise sufficient of a medicament of the invention to accelerate the healing of one inch of a wound.
  • medicaments of the invention may be formulated to provide single dosage units or to provide multiple dosage units, as required.
  • a medicament of the invention may be packaged to provide one or more dosage units.
  • Each dosage unit may provide a known fraction or multiple of a therapeutically effective amount of WIF-I, or a fragment or derivative thereof.
  • Suitable forms in which such discrete dosage units may be provided can be selected with reference to the nature of the medicament to be administered.
  • medicaments of the invention comprising injectable solutions may be provided in the form of vials or pre-filled syringes comprising one or more dosage units.
  • Other liquid medicaments in accordance with the invention such as gels, creams, ointments, irrigation fluids or the like, may be provided in the form of tubes, sachets, cartons or blister packs comprising one or more dosage units.
  • Solid medicaments of the invention may readily be formulated such that a given area of the solid medicament is capable of providing sufficient of an active agent to heal a matching-sized area of wound.
  • a solid medicament of the invention may be cut to the required size and/or shape to cover a wound, and the medicament will release a therapeutically effective amount of an active agent into the wound area and thereby accelerate the healing of the wound.
  • Solid medicaments of this type may also advantageously be used to provide a therapeutically effective amount of an active agent to undamaged skin surrounding a wound to be treated. The inventors believe that active agents provided to undamaged skin in this manner may help to promote migration of keratinocytes from the undamaged skin into the wounded area, thereby helping to increase the rate of re-epithelialisation.
  • Medicaments of the invention such as solid medicaments, may be applied to a tissue prior to wounding, such that a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, is provided to the tissue to be wounded.
  • Use of the medicaments of the invention in this manner will allow the site where a wound is to be formed to be “primed", prior to wounding, to give rise to accelerated healing.
  • the period of time over which this therapeutically effective amount of WIF-I, or a fragment or derivative thereof, is administered may be selected with reference to the nature of the medicament.
  • medicaments intended to remain in contact with the wound for a protracted period of time such as bandages, sticking plasters, or other dressings
  • medicaments that are intended only to be placed briefly in contact with the wound such as swabs that will generally be used to "wipe down" a wound
  • medicamentswabs that will generally be used to "wipe down" a wound
  • the therapeutically effective amount of an active agent is administered in the relatively short time in which the medicament is in contact with the wound.
  • Suitable formulations may be selected with reference to how readily the active agent is liberated from the solid or semi-solid medicament.
  • the active agent may be incorporated in a matrix in which the interstices are sized such that the agent is released slowly to the wound.
  • the active agent may be incorporated in a formulation from which it will be slowly released into the wound (in response to wound moisture, acidity, enzyme activity, or the like), as considered elsewhere in the specification.
  • WIF-I WIF-I
  • a therapeutically effective fragment or derivative thereof be provided in a liquid carrier that may be released rapidly from the substrate to the wound.
  • the active agent may be formulated in such a way that it is readily "accessible" to the wound. Such formulations may be free from binding partners or other agents that may form complexes with WIF-I, or its therapeutically effective fragments or derivatives, and thereby delay the release of the active agent to the wound.
  • WIF-I, or therapeutically effective fragments or derivatives thereof, for use in medicaments of the invention may be provided as solid or liquid formulations.
  • the active agent will generally be incorporated in a carrier, from which it will be released to a wound in order to exert its therapeutic activity.
  • Solid formulations for use in medicaments of the invention may include excipients such as binders. Suitable binders are well known to those skilled in the art.
  • Solid formulations for use in medicaments of the invention may, or may not, be contained in a containment membrane or coating, microspheres, microgranules or microcapsules.
  • the materials for such containment membranes or coatings may be selected from any of a variety of biodegradable natural or synthetic materials. Suitable materials may provide resistance to diffusion of the active agent.
  • suitable materials for use in containment membranes or coatings be selected such that they allow sustained release of the active agent to the wound. Examples of techniques by which this may be achieved will be well known to those skilled in the art, and will include the use of alternating layers of a suitable containment membrane or coating with layers of a carrier incorporating the active agent.
  • Suitable materials for use in containment membranes or coatings will generally degrade or be broken down over a period of time, thereby exposing the carrier, and allowing therapeutic release of the active agent from the carrier to the wound.
  • the degradation or breakdown of suitable containment membranes or coatings may be caused by prolonged exposure to a wound. Factors that may mediate the degradation of such containment membranes or coatings will generally be the same as those that may cause the release of the active agent from the carrier. These are considered in more detail below, but it will be appreciated that the degradation or breakdown of containment membranes or coatings may typically be caused by moisture associated with the wound or by the activity of enzymes active during wound healing.
  • Suitable solid formulations that may be used in medicaments of the invention may, for example, be selected from: powders; sprays, crystals; microneedles; solid compositions comprising microparticles, nanoparticles or liposomes; biomaterials; stents; sutures; films; artificial skin substances and wound dressings
  • Suitable liquid formulations that may be used in medicaments of the invention may, for example, be selected from: gels: thermosetting gels; creams; ointments; sprays; injectable solutions; irrigation solutions; other solutions of WIF-I or its therapeutically effective fragments or derivatives; and liquid compositions comprising microparticles, nanoparticles or liposomes.
  • suitable solid formulations may be applied throughout the dressing, and particularly to the surface of the dressing that is to be placed into contact with the wound.
  • Solid formulations may be applied as a coating that may be applied to all the material of the dressing, or may be applied to discrete portions of the dressing (for instance the surface of the dressing that is to be placed in contact with the wound).
  • Solid formulations may also be provided as granules, microgranules, microparticles, nanoparticles or liposomes adhered to the material of the dressing. It will be appreciated that solid formulations may be provided in any such suitable form, so long as the active agent is able to be released from the solid formulation in such a way that it can exert a therapeutic effect.
  • release of the active agent from a solid medicament to a wound may be brought about by the dissolution of the carrier, in which the active agent is incorporated, in moisture associated with (e.g. released from) the wound.
  • suitable carriers may include water soluble compositions.
  • release of the active agent may be mediated by enzyme activity present in the wound.
  • various proteloytic enzymes such as plasmin and the Matrix Metalloproteinases (MMPs) are released during the process of wound healing.
  • MMPs Matrix Metalloproteinases
  • the natural proteloytic activity of such enzymes may be used to control release of the active agent to the wound.
  • the carrier in which the active agent is incorporated may be one which is subject to proteloytic degradation by enzymes released during the wound healing response.
  • the active agent in the case of release mediated by the proteloytic enzyme MMP-I, the active agent may be incorporated in a carrier comprising a collagen matrix, wherein degradation of the collagen by MMP-I causes release of the active agent.
  • proteolytic enzymes the expression of which is significantly upregulated one day post-wounding, and which may therefore be used to control release of active agent into a wound, the healing of which is to be accelerated, include cathepsin C, cathepsin L and MMP-9.
  • carriers suitable for use in medicaments of the present invention may be ones in which the decreased pH of the wound to be treated contributes to therapeutic release of the active agent.
  • Suitable materials that may be used in carriers in accordance with this embodiment of the invention will be well known to those skilled in the art.
  • the triggering pH could be adjusted within the range of 7.2-6.6 by incorporation of different amounts of poly(L-lactic acid)-6/oc£-PEO(PLLA-b-PEO).
  • Release of an active agent in this experimental case the anti-cancer drug doxorubicin could be modulated using pH, and it was found that in vitro activity of the doxorubicin- loaded mixed micelles was heavily dependant on concentration.
  • a material (such as a hydrogel, collagen gel or other suitable polymer) containing an active agent in accordance with the invention may be shaped or otherwise treated to provide a wound dressing (or part thereof).
  • material such as an absorbent wound dressing
  • material may be treated with a solution containing an active agent, and the solution allowed to at least partially evaporate, thereby producing a substantially dry wound dressing permeated with the active agent.
  • the active agent may then be released from the dressing material by dissolution in fluids released from the wound.
  • permeation enhancers in the medicaments of the invention.
  • the need for permeation enhancers may arise since the intact skin provides an effective barrier to the uptake of active agents that may be used in accordance with the invention.
  • permeation enhancers are most likely to be of benefit in medicaments or methods that are to be utilised prophylactically (discussed elsewhere, in which medicaments or methods of the invention are administered prior to the formation of a wound in order to "prime" the treated area so a wound formed at that site will benefit from accelerated healing as soon as the wound is formed), since in these cases the active agents of the medicaments will have to pass through the unwounded skin in order to exert their therapeutic effect.
  • the wound In the case of medicaments administered to sites of existing wounds, the wound (whether full thickness or partial thickness) will generally impair the skin's barrier function. As a result, this will normally facilitate the uptake of therapeutically effective amounts of the active agents from medicaments of the invention without the need for permeation enhancers. That said, there may be circumstances in which it will be desirable to use medicaments comprising permeation enhancers at existing wounds, for instance when it is wished to hasten uptake of the active agent from the medicament.
  • uptake of WIF-I, or its therapeutically effective fragments or derivatives, through the epithelium may be increased by the use of various techniques known to those skilled in the art.
  • low-level electrical energy may be used to actively transport drugs through intact skin.
  • Electrical improvement of transdermal uptake in this manner may be used for locally delivery of active agents (such as WIF-I, or its therapeutically effective fragments or derivatives) to a defined area, and with precise control of the amount of the agent delivered.
  • Another technology that may be used to achieve improved uptake of WIF-I, or its therapeutically effective fragments or derivatives, across the skin uses short bursts of electrical pulses to produce focused thermal energy, which is able to create micropores on the surface of the skin. These micropores then facilitate the flow of the selected active agent into the body.
  • the acceleration of wound healing using the medicaments or method of the invention may give rise to a treated wound having a healing time that is faster than that which can be achieved by a control treated or untreated wound.
  • a suitable assessment of healing time may be calculated as the time to allow complete closure (re- epithelialisation) of the wound, or the time taken until the wound is sufficiently healed to allow its closure by other means (e.g. closure by grafting).
  • the time taken to achieve healing may be assessed from formation of the wound, or from the time at which treatment is first provided to the wound.
  • Treated wounds may preferably have healing times 1 day, 2 days, or 3 days faster than that occurring in a control-treated or untreated wound. More preferably accelerated healing in accordance with the invention may give rise to treated wounds having a healing time that is at least 4 days, 5 days or 6 days faster than that occurring in a control-treated or untreated wound. It is even more preferred that accelerated healing may give rise to treated wounds with a healing time that is at least 7 days, 8 days or 9 days faster than that occurring in a control-treated or untreated wound. Most preferably accelerated healing may give rise to treated wounds with a healing time that is at least 10 days or greater than that occurring in a control-treated or untreated wound.
  • the acceleration of healing may give rise to a time to re- harvesting that is 1 day, 2 days, or 3 days faster than that occurring in a control-treated or untreated graft donor sites. More preferably acceleration of the healing of wounds using the medicaments and methods of the invention may give rise to a time to re-harvesting that is at least 4 days, 5 days or 6 days faster than that occurring in a control-treated or untreated graft donor site.
  • accelerated healing of wounds may give rise to a time to re-harvesting that is at least 7 days, 8 days or 9 days faster than that occurring in a control-treated or untreated graft donor site, and most preferably accelerated healing of wounds may give rise to a time to re-harvesting that is at least 10 days or greater than that occurring in a control-treated or untreated graft donor site.
  • the acceleration of wound healing that may be achieved at graft donor sites, or other sites of partial thickness wounds (such as those associated with skin peels or dermabrasion), may help to reduce redness of such sites, and also to reduce moisture loss that may otherwise occur through such wounds.
  • the inventors have found that the medicaments and methods of the invention are able to accelerate healing of wounds when used either prior to the formation of a wound, or when used after a wound has already been formed.
  • the use of the medicaments and methods of the invention prior to formation of a wound (in which case it is believed that the action of the medicament or method is to "prime" the site where wounding will occur so that the healing response is accelerated immediately upon formation of the wound) is referred to as "prophylactic use” for the purposes of the present disclosure.
  • prophylactic use of agents in accordance with the invention to accelerate the healing of wounds is a preferred mode of use in accordance with the invention.
  • the inventors have found that administration of agents in accordance with the invention immediately prior to formation of a wound (e.g. in the hour preceding wounding, or preferably in the forty minutes or thirty minutes preceding wounding, and more preferably in the ten minutes preceding wounding) is highly effective, though administration at earlier times (e.g. up to 24 or 48 hours before wounding) may also beneficially accelerate the healing of wounds.
  • the prophylactic use of methods and medicaments of the invention is a preferred embodiment of the invention, and is particularly preferred for accelerating the healing of skin graft donor and/or recipient sites.
  • the medicaments or methods of the invention may be used both prophylactically (i.e. before a wound is formed) and after wound formation. This approach, with the medicament used both before and after wounding, represents a preferred embodiment of the invention.
  • Injection and particularly intradermal injection, constitutes a preferred manner in which the medicaments of the invention may be administered (or the methods of the invention effected), as considered elsewhere in the specification.
  • a medicament of the invention be administered by intradermal injection to a site where wounding will take place. If the medicament is administered only a short time prior to wound, then intradermal injection of this type will typically lead to the formation of a raised bleb which will remain at the time of wounding. A wound may then be formed through the bleb. Wounds formed in this way will benefit from accelerated healing in accordance with the present invention.
  • blebs formed by intradermal injection of medicaments of the invention may be allowed to resolve before a wound is formed.
  • the medicaments and methods of the invention may also be used to accelerate the healing of wounds once the wound in question has already been formed. This use may be adopted in respect of many wounds, including accidental wounds and those associated with skin peel procedures (as opposed to prophylactic treatment, which may be preferred in the case of wounds associated with surgical procedures).
  • the medicaments or methods of the invention are to be used to accelerate the healing of an existing wound, it is preferred that such use should occur as early as possible after formation of the wound. That said, the medicaments or methods of the invention may help to accelerate healing of a wound if used at any time up until full healing has occurred (for example even if administered to a partially healed wound the medicaments of the invention may accelerate the healing in respect of that portion of the wound that remains as yet unhealed).
  • Factors that may be considered in relation to the "window” in which medicaments or methods of the invention may be beneficially employed such that they are able to accelerate the healing of wounds will include: the nature of the wound in question (for example: is the wound at a site that is generally subject to "fast” or “slow” healing?); the severity of the wound (what is the extent of the damage that has occurred?); and the size of the damaged area.
  • the methods or medicaments of the invention may be still be effective to accelerate the healing of the wound even if administered relatively late in the healing response.
  • the medicaments or methods of the invention may preferably be administered within the first one to 24 hours after formation of an acute wound, beneficial acceleration of healing may also be brought about if administered up to ten, or more, days after the wound is formed. It will be appreciated that in the case of chronic wounds, the period in which the medicaments or methods of the invention may be beneficially employed will be considerably longer. Chronic wounds may persist for many years, and the healing of wounds that may be many years old may be beneficially accelerated using the medicaments or methods of the invention.
  • Acceleration of the healing of wounds may be achieved using only a single administration of the medicaments or methods of the invention. Due to the simplicity of this therapeutic regime it constitutes a preferred use of the medicaments and methods of the invention.
  • medicaments or methods of the invention be used in repeated incidences of therapy.
  • treatment to accelerate healing of a wound may involve administration of medicaments of the invention on more than one occasion. Use in this manner may be preferred in the case of large wounds, or of wounds that are resistant to treatment, or subject to retarded healing (such as chronic wounds).
  • medicaments of the invention may be administered to a wound as required until healing has been achieved.
  • medicaments of the invention may be administered daily (or on multiple occasions within a given day), or may be administered after a delay of multiple days.
  • the medicaments or methods of the invention may be used on a single instance (either before or after formation of a wound), it may be preferred that the medicaments or methods of the invention are utilised both before and after wounding.
  • the medicaments of the invention are administered to a site where they are to have their effect around the time of wounding, or immediately prior to the forming of a wound (for example in the period up to six hours before wounding, and particularly in the period of 10, 20, 40 or 60 minutes prior to wound formation) or the medicaments may be administered at an earlier time before wounding (for example up to 24 hours before a wound is formed).
  • the most preferred times of administration prior to formation of a wound will be determined with reference to a number of factors, including the formulation and route of administration of the selected medicament, the dosage of the medicament to be administered, the size and nature of the wound to be formed, and the biological status of the patient (which may determined with reference to factors such as the patient's age, health, and predisposition to healing complications) and the half-life of the active agent in the body.
  • the methods or medicaments of the invention may be administered both before and after formation of a wound.
  • the inventors believe that administration of the medicaments of the invention immediately prior to the formation of a wound, followed by administration of an active agent for one or more days following wounding, is particularly effective in accelerating healing.
  • the amount of a medicament of the invention that should be provided to a wound, in order that a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, may be administered depends on a number of factors. A number of these are discussed elsewhere in the specification, and include the biological activity and bioavailability of the active agent present in the medicament, which in turn depends, among other factors, on the nature of the agent and the mode of administration of the medicament. Other factors in determining a suitable therapeutic amount of a medicament may include:
  • the specific wound to be treated (for example: is the wound, healing of which is to be accelerated, an acute wound or a chronic wound, is it a full thickness wound or a partial thickness wound?).
  • the frequency of administration will also be influenced by the above-mentioned factors and particularly the half-life of the chosen active agent within the subject being treated.
  • a medicament of the invention should be administered to a target tissue such that the concentration of the agent at a wound is maintained at a level suitable to accelerate wound healing. This may be achieved by a single administration of the medicament or may require administration of the medicament daily or even several times daily.
  • Medicaments of the invention may be administered by any suitable route capable of achieving the desired effect of accelerating wound healing, but it is preferred that the medicaments be administered locally at a wound site or site where a wound is to be formed.
  • Administration and particularly topical administration of the medicaments of the invention may be effected as part of the initial and/or follow up care for the wounded area.
  • the agents of the invention may be provided on a dressing or patch, which may be used to cover a wound the healing of which is to be accelerated. It will be appreciated that such a dressing or patch used to administer an agent of the invention may preferably be provided in a sterile form.
  • the agents of the invention may be released from a device or implant, or may be used to coat such a device e.g. a stent or controlled release device.
  • a vehicle used in a medicament of the invention should be one that is well tolerated by the patient and allows release of an active agent to the wound to which the composition is provided.
  • a vehicle is preferably biodegradable, biocompatible, bioresolveable, bioresorbable and/or non-inflammatory. If the composition is to be applied to an existing wound then the pharmaceutically acceptable vehicle will be one that is relatively "mild”.
  • Medicaments of the invention may be formulated to comprise at least one or more further agents independently selected from the group consisting of: an antiseptic agent; an antibiotic agent; an antibacterial agent; a desloughing agent. Suitable examples of such agents that may be utilised in this manner will be well known to those skilled in the art.
  • Delayed release devices may be particularly useful for patients requiring protracted treatment with the medicaments or methods of the invention, such as those where it is wished to accelerate healing of chronic wounds. Delayed release devices may be particularly advantageous when used for the administration of an agent that would otherwise normally require frequent administration (e.g. at least daily administration by other routes).
  • Daily doses of an active agent may be given as a single administration (e.g. a daily application of a topical formulation or a daily injection).
  • the active agent may require administration twice or more times during a day.
  • Each such administration may provide a therapeutically effective amount of the active agent, or a known fraction of such a therapeutically effective amount.
  • a slow release device may be used to provide optimal doses of an active agent to a patient without the need to administer repeated doses.
  • a dose of a composition comprising agents of the invention may preferably be sufficient to provide a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, in a single administration.
  • each dose need not in itself provide a therapeutically effective amount of the active agent, but that a therapeutically effective amount may instead be built up through repeated administration of suitable doses.
  • compositions for the administration of active agents in accordance with the invention are known for compositions for the administration of active agents in accordance with the invention.
  • a pharmaceutical vehicle for administration of an active agent may be a liquid and a suitable pharmaceutical composition would be in the form of a solution. Such a solution may be administered by injection, or by other routes, such as by a spray.
  • An active agent of the invention may be formulated as part of a cream, gel or ointment.
  • an active agent may be formulated as a part of a pharmaceutically acceptable patch providing delivery of WIF-I, or a therapeutically effective fragment or derivative thereof, to a wound or a site where a wound is to be formed.
  • Liquid vehicles may be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions (sprays).
  • the active agent can be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid vehicle can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid vehicles for parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • oils e.g. fractionated coconut oil and arachis oil.
  • PBS phosphate buffered saline
  • the vehicle can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration.
  • the liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal, intradermal, intrastromal (cornea), intraadventitial (blood vessels) or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the active agent may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium (such as PBS). Vehicles are intended to include necessary and inert binders, suspending agents, lubricants and preservatives.
  • the medicaments or methods of the invention may be used to accelerate healing of "internal" wounds (i.e. wounds occurring within the body, rather than on an external surface of the body). Examples of internal wounds include penetrative wounds that pass through the skin into underlying tissues, and wounds associated with surgical procedures conducted within the body.
  • medicaments or methods of the invention to accelerate the healing of internal wounds will necessitate the use of suitable routes of administration, thereby requiring the formulation of active agents in a manner that allows their delivery to the wound in question.
  • medicaments in accordance with the invention for accelerating the healing of wounds in the lungs or other respiratory tissues may be formulated for inhalation.
  • medicaments in accordance with the invention for accelerating the healing of wounds in the body cavities may be formulated as a lavage, gel or instillate.
  • the amount of WIF-I, or a therapeutically effective fragment or derivative thereof, that may be administered to a wound (or site where a wound is to be formed) in a single incidence of treatment, for example by means of a topical injection may be up to about 30pmoles per wound centimetre, preferably up to about 20pmoles, more preferably up to about 2pmoles, and most preferably is about 0.2pmoles.
  • the preferred amount of WIF-I, or a therapeutically effective fragment or derivative thereof, to be administered to a wound (or a site where a wound is to be formed) over a period of approximately 24 hours may be up to about ⁇ Opmoles per wound centimetre, preferably up to about 40pmoles, more preferably up to about 4pmoles, and most preferably is about 0.4pmoles (if administered by injection).
  • the amount of WIF-I, or a therapeutically effective fragment or derivative thereof, to be administered via topical administration may be altered depending on permeability of the tissue or organ to which the topical composition is administered.
  • tissue or organ to which the topical composition is administered.
  • WIF-I may be administered by way of an injectable solution containing approximately Ing to lOOOng WIF-I per lOO ⁇ L solution, and preferably Ing to IOng WIF-I per lOO ⁇ L, in order to accelerate re-epithelialisation (and thus accelerate wound healing) when administered as an intradermal injection.
  • Medicaments of the invention may be used to accelerate wound healing as a monotherapy (e.g. through use of medicaments of the invention alone).
  • the methods or medicaments of the invention may be used in combination with other compounds or treatments for the acceleration of re-epithelialisation, or other means by which healing of a wound may be accelerated.
  • Suitable compounds that may be used as parts of such combination therapies will be well known to those skilled in the art.
  • the invention provides a method of accelerating wound healing, the method comprising inducing cellular expression of a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, at a site where healing is to be accelerated.
  • a site may be a wound, or a site where a wound is to be formed, or a site where there is a heightened likelihood of wound formation occurring.
  • WIF-I therapeutically effective amounts of WIF-I may be achieved by manipulating naturally occurring expression of this molecule by cells in the region of the wound to be treated.
  • cells in the region of wound (or site where a wound is to be formed) that is to be treated may be induced to express WIF-I , or therapeutically effective fragments or derivatives thereof, by means of the introduction of materials encoding such agents.
  • Suitable materials may typically comprise nucleic acids such as DNA or RNA. Specific examples of such nucleic acids may be devised based upon the sequences referred to in this specification.
  • Nucleic acids for use in this embodiment of the invention may be administered "as is", for example by means of ballistic transfection, or as parts of a larger construct, which may be able to incorporate stably into cells so transfected.
  • Suitable constructs may also contain regulatory elements, by which expression of a therapeutically effective amount of WIF-I, or a fragment or derivative thereof, may be achieved. Such constructs give rise to further aspects of the present invention.
  • the invention also provides a construct encoding WIF-I, or a therapeutically effective fragment or derivative thereof, said construct being capable of expression at a site where wound healing is to be accelerated to give rise to a therapeutically effective amount of the WIF-I, or therapeutically effective fragment or derivative.
  • the invention also provides a method of accelerating wound healing, the method comprising administering a construct (as described above) to a site where wound healing is to be accelerated such that a therapeutically effective amount of WIF-I, or a therapeutically effective fragment or derivative thereof, is expressed.
  • the invention also provides the use of such a construct in the manufacture of a medicament for the acceleration of wound healing.
  • Figure 1 compares percentage re-epithelialisation in day 3 treated excisional wounds, with percentage re-epithelialisation in diluent control wounds. * indicates statistical significance (p ⁇ 0.05) compared to the value obtained from diluent control wounds.
  • the model of wound healing utilised made use of full thickness excisional wounds in experimental rats.
  • wounds were photographed after wounding, prior to re-injection on day 1 and on day of harvest. Wounds were harvested at day 3 post-wounding for assessment of acceleration of wound healing.
  • Wounds prepared and treated as set out above were excised and processed for histology. Histological sections from treated wounds and control treated wounds were studied and the percentage of re-epithelialisation exhibited by the different wounds calculated and compared. All histological assessments of early wound healing events were made using preserved 5 micron-thickness wound sections taken from the widest part of each excised biopsy site. Sections were stained with Haematoxylin and Eosin to aid visualisation of structural features, and measurements made using image analysis software.
  • the distance travelled by the epithelium was derived from two histological measurements: the freehand total wound diameter and the freehand non-epithelialised wound diameter.
  • the non-epithelialised diameter is subtracted from the total wound diameter, to determine the distance that the new epithelium has covered since the time of wounding.
  • Percentage re-epithelialisation for the new epithelium was calculated as a proportion of the total wound diameter.
  • the average percentage re-epithelialisation value was calculated from the wounds of each animal within a specified treatment group. It will be appreciated that the protocol for assessment of re-epithelialisation set out here is also suitable for use in assessing re-epithelialisation brought about by other compounds of interest, such as fragments or derivatives of WIF-I .

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Abstract

La présente invention concerne le facteur WIF-1 ou un fragment ou dérivé de celui-ci thérapeutiquement efficace, utilisé comme médicament pour accélérer la guérison de plaies. Le médicament peut être un médicament topique ou peut être un médicament injectable. Les plaies dont la guérison doit être accélérée peuvent être des plaies cutanées. WIF-1 ou un fragment ou dérivé de celui-ci thérapeutiquement efficace peut être utilisé pour accélérer une ré-épithélialisation de plaies. Cette invention concerne également un procédé permettant d'accélérer la guérison d'une plaie, lequel procédé consiste à administrer une quantité thérapeutiquement efficace de WIF-1 ou d'un fragment ou dérivé de celui-ci, au niveau d'un site où une telle guérison accélérée est nécessaire.
PCT/GB2008/001360 2007-04-17 2008-04-17 Facteur wif-1 utilisé pour accélérer la guérison de plaies WO2008125872A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0707349.7A GB0707349D0 (en) 2007-04-17 2007-04-17 Medicaments and methods for accelerating wound healing
GB0707349.7 2007-04-17

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WO2008125872A1 true WO2008125872A1 (fr) 2008-10-23

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GB (1) GB0707349D0 (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120318262A1 (en) * 2011-03-21 2012-12-20 Ethan Lee Pyrvinium Wound Treatment Methods and Devices
WO2013058578A2 (fr) * 2011-10-18 2013-04-25 (주)아모레퍼시픽 Système pour sélectionner une matière de blanchiment de la peau
EP3508197A1 (fr) * 2009-10-21 2019-07-10 Otonomy, Inc. Modulation de la température de gélification de formulations contenant des poloxamères
US11369566B2 (en) 2008-07-21 2022-06-28 Alk-Abelló, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000074706A1 (fr) * 1999-06-08 2000-12-14 Lorantis Limited Utilisation therapeutique d'un inhibiteur d'un trajet de signalisation du herisson ou apparente au herisson
US20050288226A1 (en) * 2004-05-21 2005-12-29 Regents Of The University Of California; Office Of Technology Transfer Methods for treating and diagnosing cancer with WNT inhibitory Factor-1 (WIF-1)
WO2007027509A2 (fr) * 2005-08-31 2007-03-08 Biogen Idec Ma Inc. Evaluation et traitement de la sclerodermie
WO2007082352A1 (fr) * 2006-01-20 2007-07-26 Child Health Research Institute Inc Méthode de traitement, de prophylaxie et de diagnostic de pathologies osseuses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000074706A1 (fr) * 1999-06-08 2000-12-14 Lorantis Limited Utilisation therapeutique d'un inhibiteur d'un trajet de signalisation du herisson ou apparente au herisson
US20050288226A1 (en) * 2004-05-21 2005-12-29 Regents Of The University Of California; Office Of Technology Transfer Methods for treating and diagnosing cancer with WNT inhibitory Factor-1 (WIF-1)
WO2007027509A2 (fr) * 2005-08-31 2007-03-08 Biogen Idec Ma Inc. Evaluation et traitement de la sclerodermie
WO2007082352A1 (fr) * 2006-01-20 2007-07-26 Child Health Research Institute Inc Méthode de traitement, de prophylaxie et de diagnostic de pathologies osseuses

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11369566B2 (en) 2008-07-21 2022-06-28 Alk-Abelló, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
EP3508197A1 (fr) * 2009-10-21 2019-07-10 Otonomy, Inc. Modulation de la température de gélification de formulations contenant des poloxamères
US20120318262A1 (en) * 2011-03-21 2012-12-20 Ethan Lee Pyrvinium Wound Treatment Methods and Devices
WO2013058578A2 (fr) * 2011-10-18 2013-04-25 (주)아모레퍼시픽 Système pour sélectionner une matière de blanchiment de la peau
WO2013058578A3 (fr) * 2011-10-18 2013-07-04 (주)아모레퍼시픽 Système pour sélectionner une matière de blanchiment de la peau

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