AU2007221941B2

AU2007221941B2 - A topical anaesthetic composition

Info

Publication number: AU2007221941B2
Application number: AU2007221941A
Authority: AU
Inventors: Allan Giffard; Charles Robert Olsson; Meredith Sheil
Original assignee: Animal Ethics Pty Ltd
Current assignee: Animal Ethics Pty Ltd
Priority date: 2005-03-15
Filing date: 2007-10-11
Publication date: 2012-08-23
Anticipated expiration: 2026-03-15
Also published as: AU2007221941A1

Abstract

A method for providing anaesthesia to a subject having a wound, such as a laceration, a surgical incision, an ulcer, an abrasion or a bum, said method comprising the step of applying topically to the wound a composition comprising: at least one local anaesthetic agent; a hydrophilic or 5 hydroalcoholic gelling agent; an antiseptic agent; a vasoconstrictor; and a detectable marker such as a food dye, wherein when the composition is topically applied to the wound of the subject the presence of the anaesthetic agent on the subject is indicated by the detectable marker. The method has been developed primarily for anaesthetising open wounds of animals, particularly those caused by husbandry procedures.

Description

A ustralian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title: A topical anaesthetic composition The following statement is a full description of this invention, including the best method of performing it known to me: P/00/0 I I A Topical Anaesthetic Composition TECHNICAL FIELD This invention relates to a composition comprising a local anaesthetic agent in combination 5 with a detectable marker. In particular, the invention concerns a composition for topical application to a subject and the presence of the anaesthetic agent on the subject is indicated by the detectable marker. This invention has been developed primarily for anaesthetising open wounds of animals, particularly those caused by husbandry procedures, and will therefore be described in this context. o It is to be appreciated, however, that the invention may have general use in anaesthetising open wounds (including lacerations, surgical incisions, abrasions, ulcers and bums) of animals and humans alike. BACKGROUNDART Local anaesthetics used in animal husbandry procedures are usually in the form of 5 injectable compositions. Injectable compositions have disadvantages in that they cause pain to the animal during administration and pose risks to the animal due to inadvertent injury or toxicity if incorrectly applied. They can be difficult or dangerous to administer. They can increase animal stress by prolonging handling times. They can increase the risk of injury to the handler due to needle stick or prolonged handling times. In addition, they are single use and are not convenient 0 for administration to a large number of animals at the one time. They may require administration by a veterinarian, and it may be difficult to determine whether administration has been carried out correctly. It is for these reasons that most husbandry procedures (eg. mulesing, shearing, castration, tail docking, ear tagging, de-horning, branding and marking) are performed without anaesthesia. 25 It is an object of the present invention to provide a topical anaesthetic composition, or a method of administering a topical anaesthetic composition, which minimises or ameliorates at least one of the disadvantages referred to above, or to provide the public with a useful or commercial choice. DISCLOSURE OF INVENTION 30 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

CNWRPoM OMCC 5]3m7L3J .DOC-MO In Z 2 According to a first aspect of the invention there is provided a topical anaesthetic composition for topical use on an open wound of a subject, comprising: an effective amount of a first local anaesthetic agent having a rapid onset of action and an effective amount of a second local anaesthetic agent having a long duration of action; a vasoconstrictor in an amount effective to reduce bleeding from the open wound and to decrease the rate of vascular absorption of the local anaesthetic agents so as to reduce the risk of systemic toxicity; a detectable marker in the form of a colourant for indicating the presence of the anaesthetic agent on the open wound; and a polyhydric alcohol in combination with a cellulosic preparation as gelling agents, wherein said composition is in the form of a visibly coloured, sticky, viscous gel capable of remaining sticky when coating a said open wound. According to a second aspect of the invention there is provided a method for anaesthetising an open wound of a subject, the method comprising applying topically to the wound a composition of the first aspect. Also disclosed herein is a topical anaesthetic composition comprising at least one local anaesthetic agent and a detectable marker, wherein when the composition is topically applied to a subject the presence of the anaesthetic agent on the subject is indicated by the detectable marker. Also disclosed herein is a method for anaesthetising a subject, said method comprising the step of applying topically to the subject a composition comprising at least one local anaesthetic agent and a detectable marker, wherein the presence of the anaesthetic agent on the subject is indicated by the detectable marker. Also disclosed herein is the use of a composition comprising at least one local anaesthetic agent and a detectable marker in the preparation of a topical medicament for providing anaesthesia to a subject, wherein the presence of the anaesthetic agent on the subject is indicated by the detectable marker.

mnaf b Wt t L p~,;-I I ( (_lpJ z 2a Also disclosed herein is a method for preparing a topical anaesthetic composition for use on a subject, wherein said method comprises the step of combining at least one local anaesthetic agent together with a detectable marker, whereby the presence of the anaesthetic agent on the subject is indicated by the detectable marker. Any suitable type of anaesthetic agent or combination of agents can be used. Lignocaine, chloroprocaine, mepivacaine, bupivacaine, articaine, etidocaine, levobupivacaine, tetracaine, prilocaine, benzocaine, ropivacaine, cocaine, oxyprocaine, hexylcaine, dibucaine, piperocaine and procaine and pharmaceutically acceptable acids, bases and salts thereof, for instance, may be suitable anaesthetic agents. Other potential anaesthetic agents include: butamben, butambenpicrate, dimethisoquin hydrochloride, diperodon, diphenhydramine, dyclonine, ketamine, methapyriline, p-buthylaminobenzoic acid, 2- (die-ethylamino) ethyl ester hydrochloride, pramoxine and tripelennamine. The anaesthetic composition preferably provides maximum anaesthesia with minimal risk of toxicity. The formulation of the composition can be varied, as required, for potency, speed of onset and duration of anaesthetic action. The composition may comprise at least one local anaesthetic agent having a rapid onset of action and at least one local anaesthetic agent having a long duration of action. Anaesthetic agents that usually have a rapid onset of action (usually between about 5-10 minutes) include lignocaine, prilocaine, amethocaine and cocaine. Anaesthetic agents that usually have a much slower onset of action but a much greater duration of action (usually between about 4-12 hours of anaesthesia) include bupivacaine 3 amethocaine / tetracaine. Bupivacaine may typically provide up to about 6-12 hours of anaesthesia, depending on the method of administration. Any suitable amount of lignocaine can be used in the composition but preferably about 1 10 weight/volume % lignocaine is used. About 2-8 weight/volume % lignocaine may be used as 5 the anaesthetic agent in those situations where a rapid onset of action is required. In one embodiment, about 5% lignocaine is used. The composition may further comprise any suitable amount of bupivacaine if, for example, lignocaine has an inadequate duration of action. The composition may comprise about 0.1-5 weight/volume % bupivacaine, or about 0.5% bupivacaine. 0 Preferably, the composition is used for anaesthetising an open wound, preferably an open skin wound, such as a laceration, surgical incision, abrasion, ulcer or burn of the subject. Such a wound may actively bleed or weep. The term "open skin wound" is to be understood as excluding a mucous membrane wound of the alimentary and respiratory tracts and eyes, but including a skin laceration, surgical incision, ulcer, abrasion or burn and exposed underlying tissues. However, the 5 composition may be applied to a sutured skin wound and the like - whenever anaesthesia of a skin wound is required. The composition may further include a vasoconstrictor to decrease the rate of vascular absorption of the anaesthetic agent, so to improve the depth and duration of anaesthesia, to reduce bleeding from an open wound of the subject, as well as to reduce systemic toxicity. Any suitable '0 type of vasoconstrictor can be used. Suitable vasoconstrictors include, for instance, adrenaline (epinephrine), noradrenalin (norepinephrine) and fenylpressin. In an embodiment the composition includes about 1:1000-1:80,000 adrenalin, or about 1:2,000 adrenalin. The composition may include one or more other active ingredients. An active ingredient, as defined herein, is a compound that provides benefit to the subject. The active ingredient can be, for 25 instance, an antibody, analgesic, anticoagulant, antiproliferative, anti-.inflammatory, cytokine, cytotoxin, growth factor, interferon, haemostatic agent, hormone, lipid, demineralized bone or bone morphogenetic protein, cartilage inducing factor, oligonucleotide, polymer, polysaccharide, polypeptide, protease inhibitor, vitamin, mineral, antiseptic agent, insecticide or insect repellent, antibiotic or antifungal agent. 30 Potential analgesic anti-inflammatory agents include the following: acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, I-menthol, camphor, mefenamic acid, fluphenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxene, pranoprofen, fenoprofen, sulindac, fenbufen, clidanac, flurbiprofen, indoprofen, protizidic acid, fentiazac, tolmetin, tiaprofenic acid, bendazac, bufexemacpiroxicam, 4 phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone, medrysone, prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone, fludrocortisone, corticosterone, paramethasone, betamethasone, ibuprophen, naproxen, fenoprofen, fenbufen, flurbiprofen. indoprofen, ketoprofen, 5 suprofen, indomethacin, piroxicam, aspirin, salicylic acid, diflunisal, methyl salicylate, phenylbutazone, sulindac, mefenamic acid, meclofenamate sodium, and tolmetin. The composition preferably also includes an antiseptic agent to, amongst other things, minimize wound contamination and infection. Any suitable type of antiseptic agent may be used. Suitable antiseptic agents include cetrimide, povidone-iodine, chlorhexidine, iodine, benzalkonium 0 chloride, benzoic acid, nitrofurazone, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol and cetylpynidinium chloride. It is possible that a strongly coloured antiseptic such as iodine can also be the detectable marker. The composition may also include an insecticide or insect repellent to stop insects from infesting a wound of the subject. Any suitable type of insecticide or insect repellent may be used. 5 Examples of suitable insecticides include: trichlorfon, triflumeron., fenthion, bendiocarb, cyromazine, dislubenzuron, dicyclanil, fluazuron, amitraz, deltamethrin, cypermethnin, chlorfenbinphos, flumethrin, ivermectin, abermectin, avermectin, doramectin, moxidectin, zeti cypermethrin, diazinon, spinosad, imidacloprid, nitenpyran, pyriproxysen, sipronil, cythioate, lufenuron, selamectin, milbemycin oxime, chlorpyrifos, coumaphos. propetamphos, alpha 0 cypermethrin, high cis cypermethrin, ivermectin, diflubenzuron, cyclodiene, carbamate and benzoyl urea. Any suitable type of detectable marker may be used. The marker may be, for instance, visible to the eye or visible under UV light. The detectable marker is typically a visual marker and can be visible before the composition is applied to the subject and/or after the composition is 25 applied to the subject. The detectable marker may be a colourant. The colourant may be a pigment and/or dye. Suitable colourants include, for example, common food dyes or the ORCODERM@, ORCOBRITE@ and ORCOFUR@ lines of pigments and dyes sold by the Organic Dyestuffs Corporation. Typically, the detectable marker is non-toxic and will not permanently stain the skin or animal hide or surrounding hair, fur or wool. 30 The subject may be a human. The subject may be an animal such as a sheep, horse, cow, goat, pig, dog or cat. The subject may be another type of animal. The composition may be used for an animal husbandry procedure. The procedure may be, for example, mulesing, shearing, castration, tail docking, ear tagging, de-horning, branding, 5 marking, or treating an open wound, eg. caused by shearing. In one embodiment, the composition is used for mulesing which is performed so as to prevent flystrike. The composition may be applied to the subject in any suitable form. The composition may be, for example, in form of an ointment, gel, lotion, creme, cream, stick, emulsion, powder, paste, 5 solution, suspension, spray-solution, spray-on gel, creme, foam or aerosol. The composition may be in a sustained-release form, whereby actives are slowly released over an extended period of time. The composition can be incorporated into a bandage or plaster. Preferably, the composition is applied to the subject as a spray-on gel, emulsion, powder, solution, creme, suspension or foam, so as to disturb a wound of the subject as little as possible. 0 Preferably, the composition is applied as a metered dose. The composition may be applied to the subject as a spray-on get so as to minimise pain related to touching or handling a wound (caused by mulesing, for example), minimise the risk of infection from skin contamination and so that the wound need not be disturbed more than necessary. Alternatively, the composition can be applied as a gel by hand, or squeezed from a tube 5 to fill a wound caused, say, during a de-horning procedure. According to a fifth aspect of the present invention, there is provided a method for anaesthetising a large number of animals for a husbandry procedure in a short period of time, said method comprising the steps of: creating an open skin wound on each animal in accordance with the husbandry procedure; .0 and spraying onto the skin wound of each animal a composition comprising: a local anaesthetic agent; at least one ingredient for making the composition viscous and adhere to the skin wound; a vasoconstrictor; and 25 a detectable marker, wherein when the composition is sprayed onto the skin wound the presence of the local anaesthetic agent is indicated by the detectable marker. The animal husbandry procedure may be selected from the group consisting of mulesing, shearing, castration, tail docking, ear tagging, de-horning, branding and marking. 30 Such a method allows for the high throughput of animals due to the unique properties of the composition; namely, it can be sprayed on rather than needle-injected, it is wound-adherent and its application to the wound can be easily detected. Depending on the form of the composition, the composition may include one or more of the following types of ingredients: aqueous or oily diluent, carrier, excipient or base; buffer; bittering 6 agent (i.e. foul-tasting agent); suspending agent; emulsifier; emollient; humectant; stabilising agent; dispersing agent; solubiliser; skin conditioning agent; skin protectant; skin penetration enhancer; fragrance; preservative; propellant; sunscreen agent; surfactant; textural modifier; and waterproofing agent. 5 Suitable oily or aqueous bases, carriers, diluents and excipients are inert and physiologically acceptable and include, for example: bacteriostatic saline (saline containing benzyl alcohol), cetomacrogol, cetyl alcohol, glycerine, lanolin, petrolatum based creams, gels, hydrogels, saline, short chain alcohols and glycols (e.g. ethyl alcohol and propylene glycol), and water. Either water in oil or oil in water emulsions may be used. Examples of suitable surfactants 0 and emulsifying agents include: non-ionic ethoxylated and non-ethoxylated surfactants, abietic acid, almond oil PEG, beeswax, butylglucoside caprate, C1 8

-C

36 acid glycol ester, C 9 -Ci 5 alkyl phosphate, caprylic/capric triglyceride PEG-4 esters, cetomacrogol, ceteareth-7, cetereth-20, cetyl phosphate, cetyl stearyl alcohol, corn oil PEG esters, DEA-cetyl phosphate, dextrin laurate, dilaureth-7 citrate, dimyristyl phosphate, glycereth-17 cocoate, glyceryl erucate, glycerol, glyceryl 5 laurate, G.M.S. acid stable, hydrogenated castor oil PEG esters, isosteareth-l I carboxylic acid, lecithin, lysolecithin, nonoxynol-9, octyldodeceth-20, palm glyceride, PEG diisostearate, PEG stearamine, poloxamines, polyglyceryls, potassium linoleate, PPGs, raffinose myristate, sodium caproyl lactylate, sodium caprylate, sodium cocoate, sodium isostearate, sodium tocopheryl phosphate, steareths, TEA-C1 2

-CI

3 pareth-3 sulfate, tri-C 12

-CI

5 pareth-6 phosphate, and trideceths. 0 The composition may include one or more types of preservative. A suitable preservative, for example, can be: benzalkonium chloride, benzoic acid, benzothonium chloride, benzyl alcohol, 2-bromo-2-nitropropane-1,3-diol, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butyl paraben, chlorophene, chlorphenesin, diazolidinyl urea, DMDM hydantoin, ethyl paraben, formaldehyde-releasing preservative, hydroquinone, iodopropynyl butylcarbamate, imidazolidinyl 25 urea, methyldibromo glutaronitrile, methylhydroquinone, methylisothiazolinone, methyl paraben, nitrosamines, o-cymen-5-ol, phenoxyethanol, propyl paraben, quatemium-15, sodium benzoate, sodium dehydroacetate, sodium hydroxymethylglycinate, sodium metabisulfite, and sodium sulfite. Preferably, the composition includes the reducing agent sodium metabisulfite so as to enhance the stability of the vasoconstrictor. 30 A skin conditioning agent, as defined herein, improves dry or damaged skin. Such agents, for example, include: acetyl cysteine, N-acetyl dihydrosphingosine, acrylates/behenyl acrylate/dimethicone acrylate copolymer, adenosine, adenosine cyclic phosphate, adensosine phosphate, adenosine triphosphate, alanine, albumen, algae extract, allantoin and deriviatives, aloe barbadensis extracts, aluminum PCA, amyloglucosidase, arbutin, arginine, azulene, bromelain, 7 buttermilk powder, butylene glycol, caffeine, calcium gluconate, capsaicin, carbocysteine, carnosine, beta-carotene, casein, catalase, cephalins, ceramides, chamomilla recutita (matricaria) flower extract, cholecalciferol, cholesteryl esters, coco-betaine, coenzyme A, corn starch modified, crystallins, cycloethoxymethicone, cysteine DNA, cytochrome C, danitoside, dextran sulfate, 5 dimethicone copolyols, dimethylsilanol hyaluronate, DNA, elastin, elastin amino acids, epidermal growth factor, ergocalciferol, ergosterol, ethylhexyl PCA, fibronectin, folic acid, gelatin, gliadin, beta-glucan, glucose, glycine, glycogen, glycolipids, glycoproteins, glycosaminoglycans, glycosphingolipids, horseradish peroxidase, hydrogenated proteins, hydrolyzed proteins, jojoba oil, keratin, keratin amino acids, kinetin, lactoferrin, lanosterol, lauryl PCA, lecithin, linoleic acid, 0 linolenic acid, lipase, lysine, lysozyme, malt extract, maltodextrin, melanin, methionine, mineral salts, niacin, niacinamide, oat amino acids, oryzanol, palmitoyl hydrolyzed proteins, pancreatin, papain, PEG, pepsin, phospholipids, phytosterols, placental enzymes, placental lipids, pyridoxal 5 phosphate, quercetin, resorcinol acetate, riboflavin, RNA, saccharomyces lysate extract, silk amino acids, sorbitol, sphingolipids, stearamidopropyl betaine, stearyl palmitate, tocopherol, tocopheryl 5 acetate, tocopheryl linoleate, ubiquinone, vitis vinifera (grape) seed oil, wheat amino acids, xanthan gum, and zinc gluconate. The composition may include a skin penetration enhancer for enhancing the penetration of active ingredients, such as the anaesthetic agent. Any suitable type of enhancer may be used. Examples of suitable enhancers may include solvents, detergents or low carbon alcohols such as 0 dimethylsulfoxide, oleyl alcohol, propylene glycol, methyl pyrrolidone and dodecylazyl cycloheptan 2-one. Examples of thickening or viscosity increasing agents include: acrylamides copolymer, agarose, amylopectin, bentonite, calcium alginate, calcium carboxymethyl cellulose, carbomer, carboxymethyl chitin, castor oil derivatives, cellulose gum, cellulosic preparation, cetyl alcohol, 25 cetostearyl alcohol, coconut oil, dextrin, gelatin, hydrogenated tallow, hydroxy cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxpropyl starch. inorganic thixotrope, magnesium alginate, methylcellulose, microcrystalline cellulose, modified clays, paraffin, pectin, various PEG's, polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, quaternium ammonium compound of bentonite or zinc stearate, shea butter, sorbitol, various PPG's, sodium acrylates 30 copolymer, sodium carrageenan, silicon dioxide, xanthum gum, and yeast beta-glucan. Powders may incorporate a conventional powder base, such as kaolin, lactose, starch or talc. The propellant may be, for example, a fluorochlorohydrocarbon such as dichlorodifluoromethane, difluoroethane or trichlorofluoromethane.

8 In a particular embodiment the composition is in the form of a sticky, viscous gel. For example, the composition may be in the form of a spray-on gel that can coat a wound of the subject and can maximise delivery of the active ingredients to the wound by way of staying moist and viscous (ie. "sticky"). 5 The composition may comprise a hydrophilic or hydroalcoholic gelling agent. The composition may comprise about 1 to 20 g per litre of at least one type of gum or cellulosic preparation. More typically, the composition may comprise a polyhydric alcohol in combination with a cellulosic preparation. Even more typically, the composition may comprise about 5 mg/mL hydroxy cellulose in combination with about 100 mg/mL non-crystallising liquid sorbitol (70%). 0 In particular, the composition may comprise one or more of the following adhesives, thickening agents, gelling agents and/or viscosity increasing agents: acrylamides copolymer, agarose, amylopectin, calcium alginate, calcium carboxymethyl cellulose, carbomer, carboxymethyl chitin, castor oil derivatives, cellulose gum, cellulosic preparation, cetyl alcohol, cetostearyl alcohol, dextrin, gelatin, hydroxy cellulose, hydroxyethylcellulose, 5 hydroxypropylcellulose, hydroxpropyl starch, inert sugar, magnesium alginate, methylcellulose, microcrystalline cellulose, pectin, PEG's, polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, quaternium ammonium compound of bentonite or zinc stearate, sorbitol, PPG's, sodium acrylates copolymer, sodium carrageenan, xanthum gum, and yeast beta-glucan. In an embodiment the composition comprises: .0 about 100 mg/mL non-crystallising liquid sorbitol (70%); about 50.0 mg/mL lignocaine HCI; about 5.0 mg/mL bupivacaine HCI; about 1.5 mg/mL sodium metabisulfite; 0 mg/mL to about 5.0 mg/mL cetrimide; 25 about 45.0 pg/mL adrenaline tartrate; about 5.0 mg/mL hydroxy cellulose; and dye. In a further embodiment the composition comprises: about 100 mg/mL non-crystallising liquid sorbitol (70%); 30 about 40.0 mg/mL lignocaine HCI; about 1.5 mg/mL sodium metabisulfite; 0 mg/mL to about 5.0 mg/mL cetrimide; about 36.0 pg/mL adrenaline tartrate; about 5.0 mg/mL hydroxy cellulose; and 9 dye. When the composition is used on animals, such as for mulesing, the composition typically includes an insecticide or insect repellent. If used for castration or tail docking, for example, the composition may include a penetration enhancer. 5 The active ingredient may also include, for instance, a defleecing agent or skin scarring agent that causes temporary or permanent defleecing / wool or hair follicle destruction / skin scarring at the site of application (hereafter referred to as a "wounding agent"). The composition containing the wounding agent may be used for any suitable type of procedure (including surgical procedures) in which wool, fur or hair removal is required. The 0 procedure may be, for example, chemical mulesing or chemical branding of animals. In a particular embodiment the composition is used for chemical mulesing. According to a sixth aspect of the present invention, there is provided a topical anaesthetic composition sprayable onto a skin wound such as a laceration, a surgical incision, an ulcer, an abrasion or a burn, said composition comprising: 5 a local anaesthetic agent having a rapid onset of action; at least one ingredient for making the composition viscous and adhere to the skin wound; a vasoconstrictor; and a detectable marker, 0 wherein when the composition is sprayed onto the skin wound, the presence of the local anaesthetic agent is indicated by the detectable marker. According to a seventh aspect of the present invention, there is provided a method for anaesthetising a skin wound of a subject, wherein said skin wound is selected from the group consisting of a laceration, a surgical incision, an ulcer, an abrasion and a burn, said method 25 comprising the step of applying topically to the skin wound of the subject a composition comprising at least one local anaesthetic agent and a detectable marker, wherein the presence of the anaesthetic agent on the wound is indicated by the detectable marker. According to an eighth aspect of the present invention, there is provided a method for anaesthetising a skin wound of a subject, wherein said skin wound is selected from the group 30 consisting of a laceration, a surgical incision, an ulcer, an abrasion and a burn, said method comprising the step of spraying onto the skin wound of the subject a composition comprising: a local anaesthetic agent having a rapid onset of action; at least one ingredient for making the composition viscous and adhere to the skin wound; 10 a vasoconstrictor; and a detectable marker, wherein when the composition is sprayed onto the skin wound, the presence of the local anaesthetic agent is indicated by the detectable marker. 5 According to a ninth aspect of the present invention, there is provided a method for providing anaesthesia to a subject having a skin wound such as a laceration, a surgical incision, an ulcer, an abrasion or a burn, said method comprising the step of spraying onto the skin wound a composition comprising: at least one local anaesthetic agent; 0 a hydrophilic or hydroalcoholic gelling agent for making the composition viscous and adhere to the skin wound; optionally an antiseptic agent; a vasoconstrictor; and a detectable marker, 5 wherein when the composition is sprayed onto the wound of the subject the presence of the anaesthetic agent on the wound is indicated by the detectable marker. According to a tenth aspect of the present invention, there is provided a method for providing anaesthesia to a subject having a wound caused by castration, mulesing, tail docking or dehorning, said method comprising the step of spraying onto the wound of the subject a 0 composition comprising: a local anaesthetic agent having a rapid onset of action; at least one ingredient for making the composition viscous and adhere to the wound; a vasoconstrictor; and a detectable marker, 25 wherein when the composition is sprayed onto the wound, the presence of the local anaesthetic agent is indicated by the detectable marker. According to an eleventh aspect of the present invention, there is provided a topical composition for both creating a wound on a subject and for alleviating pain due to the wound, said composition comprising: at least one wounding agent for creating a wound; at least one 30 local anaesthetic agent; and, a detectable marker, wherein the presence of the anaesthetic agent on the subject is indicated by the detectable marker. According to a twelfth aspect of the present invention, there is provided a method for both creating a wound on a subject and for alleviating pain due to Ihe wound, said method 11 comprising the step of applying topically to the subject a composition comprising: at least one wounding agent for creating a wound; at least one local anaesthetic agent for anaesthetising the wound; and a detectable marker, wherein the presence of the anaesthetic agent on the subject is indicated by the detectable marker. 5 Any suitable type of wounding agent can be used. The wounding agent may comprise, for instance, one or more of the following: phenol; and, a cationic quaternary ammonium compound having the formula R,

H

3 C N-0O wherein R, and R 2 are alkyl having 8-10 carbon atoms, 0 didecylmethylamine oxide, didecyldimethylammonium chloride, dioctyldimethylammonium chloride, octyldecyldimethylammonium chloride, didecyldimethylammonium chloride, didecylmethylethylammonium chloride, didecylmethylpropylammonium chloride, didecylethylpropylammonium chloride, nonyltrimethylammonium bromide, tricapryl(trioctyl)methylammonium chloride, trioctylpropylammonium bromide, and Adogen 464 5 trimethyl C 8

-C

10 quaternaryammonium chloride. Further wounding agents are described in the specifications of Australian Patent No. 524658 to ICI Australia Limited and No. 647784 to Commonwealth Scientific and Industrial Research Organisation - the entire contents of which are hereby incorporated by reference. Any suitable quantity of wounding agent or agents may be used. If the composition 20 contains phenol, then it may comprise about 25-80 % weight/volume of that compound. The phenol may be phenol, resorcinol or cresol, or a mixture of those compounds. The composition may include other ingredients as described in the specification of No. 524658. If the composition contains a cationic quaternary ammonium compound, then it may comprise about 15-25 % weight/weight of that compound. The composition may include other 25 ingredients as described in the specification of No. 647784. The composition may comprise other ingredients as described in respect of the other aspects of the invention. It will be readily appreciated by those skilled in the art that compositions in accordance 30 with the present invention as herein described and exemplified can be used to reduce or minimise 12 pain in a large variety of animal husbandry procedures in which anaesthetic agents are not currently used by virtue of being too impractical, dangerous, complex or costly. Compositions in accordance with embodiments of the invention can also be used on human wounds for effective pain relief. In animal husbandry procedures any reduction in pain is likely to be of significant benefit 5 to the animal. There is minimal risk of toxicity to the animal using compositions of the invention. Such compositions can be conveniently and safely applied to animals without the added pain and risk of injury associated with invasive methods of anaesthetic delivery, and without increasing animal stress due to prolonged handling times. Preliminary studies in lambs have demonstrated a significant reduction in pain related behaviour and a marked improvement in feeding and 0 prevention of weight loss in treated lambs undergoing surgical mulesing. Compositions of the invention also offer benefits to animal handlers in that they provide a simple, practical and convenient method for reducing pain that animals may experience. This is of advantage to the handler for moral and ethical reasons and because reducing animal pain can result in improved growth, handling and health outcomes for animals. Compositions of the invention also 5 offer benefits over invasive methods of anaesthetic delivery because they can be quickly and easily administered to a large numbers of animals, even in remote locations with minimal additional cost and/or animal handling times. Simplicity of application, low risk of toxicity and ready visualisation of the adequate wound covering is advantageous to the handler as successful application of the anaesthetic can be readily achieved and monitored without risk of needle stick injury, without ,0 compromising animal breathing, mobility and/or recovery, and without the need for a veterinarian to administer the composition. Additional benefits of the present invention may be found in the applicant's co-pending Australian patent application no. 2006202528 (also published as WO 2006/096914) the contents of which are hereby incorporated by reference in their entirety. 25 The present invention will now be described with reference to the following specific examples which should be construed as in any way limiting the scope of the invention. EXAMPLES 30 Example 1 - Formulation of a Topical Anaesthetic Gel This example describes the preparation of a topical anaesthetic composition in the form of a spray-on gel. The composition has the following formulation: - Purified water Sorbitol Liquid 70% Non-Crystallising 100.0 mg/mL 13 - Lignocaine HCI 40.0 mg/mL (4%) - Sodium Metabisulfite 1.5 mig/mL - Cetrimide 0 - 5.0 mg/mL - Adrenaline Tartrate 36.0 pg/mL (1:2000) 5 - Hydroxy Cellulose Quantity to suit (q.s.) - Food Dye (e.g. blue) q.s. - Purified water to 1 mL The composition is prepared by combining the above ingredients to achieve the required 0 colour and consistency as required. The composition is then placed within a suitable spray-on applicator. The composition is viscous and, when applied, is in the form of a "sticky" gel. Sorbitol functions as a thickener and a humectant and keeps the gel "sticky" after application. Sodium metabisulfite prevents oxidation of the adrenalin. Cetrimide is an antiseptic as well as a surfactant and humectant. Hydroxy cellulose functions as a thickener. 5 The hydroxy cellulose and sorbitol are primarily responsible for the gelatinous nature of the composition. Although typically the composition will comprise about 5 rng/mL hydroxy cellulose in combination with about 100 mg/mL non-crystallising liquid sorbitol (70%), the composition can comprise anywhere from about 1 to 20 g per litre of at least one type of gum or cellulosic preparation. Typically, the composition will comprise a polyhydric alcohol in combination with a .0 cellulosic preparation. If desired, the composition can further comprise an anti-inflammatory agent (e.g. isoflupredone acetate), and/or an insecticide/insect repellent such as diazinon, cyromazine or spinosad (at about lmg/mL), and/or a skin penetrating enhancer, and/or a bittering agent. Example 2 - Formulation of a Topical Anaesthetic Gel 25 Having a Long Duration of Action This example describes the preparation of another topical anaesthetic composition in the form of a spray-on gel and potentially having a longer duration of action than the composition of Example 1. The composition has the following formulation: 30 - Purified water Sorbitol Liquid 70% Non-Crystallising 100.0 mg/mL - Lignocaine HCI 50.0 mg/mL (5%) - Bupivacaine HCI 5.0 mg/mL (0.5%) - Sodium Metabisulfite 1.5 mg/mL - Cetrimide 0 - 5.0 mg/mL 35 - Adrenaline Tartrate 45.0 ptg/mL - Food Dye (e.g. brilliant blue) q.s. - Hydroxy Cellulose q.s. - Purified water to 1 mL 14 The composition is prepared by combining the above ingredients to achieve the required colour and consistency as required. The composition is then placed within a suitable spray-on applicator. Again, the composition is in the form of a "sticky" gel. If desired, the composition can further comprise an anti-inflammatory agent, and/or an 5 insecticide/insect repellent, and/or a skin penetrating enhancer, and/or a bittering agent. Example 3 - Formulation of a Topical Anaesthetic Creme Having a Long Duration of Action This example describes the preparation of another topical anaesthetic composition in the form of a spray-on creme. The composition has the following formulation: 0 - Cetyl Alcohol 78.00 mg/mL - Paraffin Wax 135.00 mg/mL - Glycerol 75.00 mg/mL - Lauryl Sulfate 10.00 mg/Ml 5 - Dye q.s. - Lignocaine HCl 50.00 mg/mL - Bupivacaine HCI 5.00 mg/mL - Sodium Metabisulfite 1.50 mg/mL - Cetrimide 0 - 5.0 mg/mL 0 - Hydrochloric Acid 25% q.s. - Adrenaline Acid Tartare 0.045 mg/mL - Purified Water to 1 mL The composition is prepared by combining the above ingredients to achieve the required 5 colour and consistency as required. The composition is then placed within a suitable spray-on applicator. The composition is in the form of a "sticky" creme. If desired, the composition can further comprise an anti-inflammatory agent, and/or an insecticide/insect repellent, and/or a skin penetrating enhancer, and/or a bittering agent. Example 4 - Formulation of a Topical Anaesthetic Gel 30 Having a Long Duration of Action This example describes the preparation of another topical anaesthetic composition in the form of a spray-on gel having a gum base. The composition has the following formulation: - Xanthum Gum 10.00 mg/mL 35 - Gum Arabic 1.00 mg/mL - Sorbitol Liquid 100.00 mg/mL - Dye q.s - Lignocaine HCI 50.00 mg/mL - Bupivacaine HCI 5.00 mg/mL 40 - Sodium Metabisulfite 1.50 mg/mL 15 - Cetrimide 0 - 5.0 mg/mL - Hydrochloric Acid 25% q.s. - Adrenaline Acid Tartare 0.045 mg/mL - Purified Water to I mL 5 The composition is prepared by combining the above ingredients to achieve the required colour and consistency as required. The composition is then placed within a suitable spray-on applicator. The composition is in the form of a "sticky" gel. If desired, the composition can further comprise an anti-inflammatory agent, and/or an 0 insecticide/insect repellent, and/or a skin penetrating enhancer, and/or a biltering agent. Example 5 - Formulation of a Topical Anaesthetic Gel Having a Long Duration of Action This example describes the preparation of another topical anaesthetic composition in the form of a spray-on gel having a polyacrylic acid base. The composition has the following 5 formulation: - Polyacrylic Acid 10.00 mg/mL - Sodium Hydroxide q.s. - Polyhydrogenated Castor Oil 10.00 mg/mL .0 - Sorbitol Liquid 100.00 mg/mL - Dye q.s. - Lignocaine HCI 50.00 mg/mL - Bupivacaine HCI 5.00 mg/mL - Sodium Metabisulfite 1.50 mg/mL 5 - Cetrimide 0 - 5.0 mg/mL - Hydrochloric Acid 25% q.s. - Adrenaline Acid Tartare 0.045 mg/mL - Purified Water to 1 mL 30 The composition is prepared by combining the above ingredients to achieve the required colour and consistency as required. The composition is then placed within a suitable spray-on applicator. The composition is in the form of a "sticky" gel. If desired, the composition can further comprise an anti-inflammatory agent, and/or an insecticide/insect repellent, and/or a skin penetrating enhancer, and/or a bittering agent. 35 16 Example 6 - Formulation of a Topical Anaesthetic Gel Having an Insecticide and a Skin Penetrating Enhancer This example describes the preparation of another topical anaesthetic composition in the form of a spray-on gel having an insecticide (spinosad) as well as a skin penetrating enhancer 5 (propylene glycol). The composition has the following formulation: - Cellulose 5.00 mg/mL - Spinosad 1.25 mg/mL - Propylene Glycol 100.00 mg/mL 0 - Sorbitol Liquid 50.00 mg/mL - Dye q.s. - Lignocaine HCl 50.00 mg/mL - Bupivacaine HCl 5.00 mg/mL - Sodium Metabisulfite 1.50 mg/mL 5 - Cetrimide 0 - 5.0 mg/mL - Hydrochloric Acid 25% q.s. - Adrenaline Acid Tartare 0.045 mg/mL - Purified Water to 1 mL 0 The composition is prepared by combining the above ingredients to achieve the required colour and consistency as required. The composition is then placed within a suitable spray-on applicator. The composition is in the form of a "sticky" gel. If desired, the composition can further comprise an anti-inflammatory agent and/or a bittering agent. 5 Example 7 - Use of a Topical Anaesthetic Composition in Mulesing This example describes the use of the composition of Example 1 or Example 2 in mulesing. It is to be appreciated that the compositions as described in the other examples could equally be used in a mulesing procedure. If necessary, the breech area of the sheep is crutched of wool. Mulesing is then performed. 30 This involves removing strips of skin from either side of the perineum and from the dorsal surface of the tail. The tail may be docked at the same time. The composition is .:hen immediately applied to the surgical wound as a coloured gel by a metered dose spray-on pump pack or trigger spray bottle. About 5-15 mLs of the composition is applied, depending on the size of the wound and the animal. 35 The lignocaine/bupivacaine/adrenaline combination in a sustained release gel base provides rapid as well as prolonged pain relief for a period of at least 8 hours. The dye indicates the area of the sheep that has been anaesthetised. The antiseptic cetrimide helps minimise contamination of 17 the wound with bacteria. The insecticide, if present, can repel insects such as blowflies and prevent flystrike. The gel remains as a "sticky" coat on the wound protecting it and maximising extended delivery of the active ingredients to the wound. Moreover, preliminary experiments on lambs undergoing mulesing indicate that the fact that the gel coats the wound (i.e. nerve endings), 5 numbing of pain occurs after about 4 hours independently of the anaesthetic agent/s; this therefore contributes to and enhances the anaesthetic effect of the formulation. If the composition contains an insecticide (eg. the composition as described in Example 6), then it can be further applied onto the woollen skin surrounding the wound/cut skin edges for a distance of about 2-10 cm. 0 Example 8 - Use of a Topical Anaesthetic Composition for Castration This example describes the use of the composition of any one of Examples 1-6, but preferably Example 6, for animal castration. The animal should be held firmly and securely in a cradle or restraint designed for routine surgical castration. An incision is made in the scrotal sac and the testes and chordal tissue exposed 5 as per routine surgical castration. The composition is then sprayed onto the chordal tissue so as to fully coat it, particularly at the site of intended incision and along the length of chordal tissue that will remain and retract into the scrotal sac after the testes are excised. Depending on the size of the animal, approximately 0.5 - 2 mLs of spray-on composition is used. The testes are then excised by cutting through the chordal tissue at the level where the composition has been applied, using ,0 routine surgical castration technique. The empty scrotal sac and edges of the skin incision are then sprayed with an additional dose of the composition so as to fill the sac and coat the cut skin edges. Depending on the size of the animal, approximately 1-4 mLs of spray-on composition is used. Example 9 - Use of a Topical Anaesthetic Composition for Shearing Cuts, Skin Lacerations and Superficial Burns 25 This example describes the use of the composition of any one of Examples 1-6 for shearing cuts, skin lacerations and superficial burns. Where a significant skin laceration or superficial (1st or second degree) bum occurs, such as during shearing or branding, the composition may be sprayed directly onto the wound so as to coat the wound and cover the cut skin edges. The spray is applied by metered dose. The volume 30 applied will vary depending on the size of the wound and animal. For instance, a total dose of 50 mg/kg of lignocaine should not be exceeded for sheep.

18 Example 10 - Use of a Topical Anaesthetic Composition for Dehorning This example describes the use of the composition of any one of Examples 1-6 for dehorning. Where dehorning of animals is carried out leaving a raw, bleeding bed of tissue, the 5 composition may be applied directly to the raw tissue bed immediately following dehorning either by metered spray, or by metered squeeze application of the composition in a thick gel, creme or paste so as to cover the entire exposed tissue bed and remain in contact with it. Estimated volumes required are 1-3 mLs per dehorned tissue bed depending on the size of the wound. The total dose applied should not exceed safety limits of mg/kg lignocaine (topically applied) for the animal 0 species involved. Example II - Use of a Topical Anaesthetic Composition for Treating Flystrike Wounds This example describes the use of a topical anaesthetic composition containing an insecticide, such as the composition described in Example 6, for treating wounds resulting from flystrike. 5 Flystrike wounds are very painful for sheep. Current practices involve cutting away all wool in the flystruck area and then spraying or applying an insecticide to kill the maggots and eggs. Pain is not addressed. A combination agent of a maggot killing insecticide plus an anaesthetic agent, such as the composition described in Example 6, may be applied to kill maggots and relieve pain and aid in wound healing. .0 The method entails cutting wool away from an affected area and scraping maggots off as per routine flystrike management. The composition is sprayed by metered dose to cover the affected area. The volume applied will vary depending on the size of the wound and animal. For instance, a total dose of 50 mg/kg of lignocaine should not be exceeded for sheep. In cases of large flystrike wounds where it is anticipated that an excessive volume of the composition is required to 25 cover the wound (eg >1 ml / kg /sheep), a lower concentration composition should be used containing, for example, I or 2% lignocaine with insecticide. Example 12 - Formulation of Topical Anaesthetic Compositions for Chemical Mulesing or Branding This example describes various compositions for use in chemical rnulesing or branding. 30 Each composition for use in chemical mulesing or branding includes a wounding agent, such as a cationic quaternary ammonium compound, in combination with one or more anaesthetic agents as described in the above examples.

19 Various formulations are given below: 1. Dimethyl Ammonium Chlorides with Emollients - Dimethyl Ammonium Chlorides 250.00 mg/mL - Propylene Glycol 150.00 mg/mL 5 - Sorbitol Liquid 100.00 mg/mL - Dye q.s. - Glycerol 400.00 mg/mL - Purified Water to 1 mL This mixture is then admixed with, say, the composition of Example 1 or 2. 0 2. Dimethyl Ammonium Chlorides in a Creme Base - Dimethyl Ammonium Chlorides 250.00 mg/mL - Cetyl Alcohol 80.00 mg/mL - Propylene Glycol 100.00 mg/mL - Dye q.s. 5 - Purified Water to 1 mL This mixture is then admixed with, say, the composition of Example 1 or 2. 3. Dimethyl Ammonium Chlorides in Polyacrylic Acid base - Dimethyl Ammonium Chlorides 250.00 mg/mL 0 - Polyacrylic Acid 10.00 mg/mL - Sodium Hydroxide q.s. - Propylene Glycol 100.00 mg/mL - Dye q.s. - Purified Water to I mL 5 This mixture is then admixed with, say, the composition of Example 1 or 2. Each chemical mulesing/branding composition is prepared by combining the above ingredients to achieve the required colour and consistency as required. The composition is then applied against the skin with a squeeze-on applicator which is combed through the wool or fur over the intended wound area. The composition is viscous and, when applied, is in the form of a 30 "sticky" base. The ammonium compound, where applied, creates a wound, and shortly thereafter the wound is anaesthetised as described in Example 7. If desired, the composition can further comprise an insecticide/insect repellent such as cyromazine or spinosad (at about Img/mL) and/or a skin penetrating enhancer. 35 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or 20 admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. It will be appreciated by one of skill in the art that many changes can be made to the 5 composition and uses exemplified above without departing from the broad ambit and scope of the invention.

Claims

1. A topical anaesthetic composition for topical use on an open wound of a subject, comprising: an effective amount of a first local anaesthetic agent having a rapid onset of action and an effective amount of a second local anaesthetic agent having a long duration of action; a vasoconstrictor in an amount effective to reduce bleeding from the open wound and to decrease the rate of vascular absorption of the local anaesthetic agents so as to reduce the risk of systemic toxicity; a detectable marker in the form of a colourant for indicating the presence of the anaesthetic agent on the open wound; and a polyhydric alcohol in combination with a cellulosic preparation as gelling agents, wherein said composition is in the form of a visibly coloured, sticky, viscous gel capable of remaining sticky when coating a said open wound.

2. The composition of claim 1, wherein the gelling agents comprise about 100 mg/rnL non-crystallising liquid sorbitol (70%) in combination with about 5 mg/mL hydroxy cellulose.

3, The composition of claim 1 or claim 2, wherein the composition further comprises one or more ingredients selected from the group consisting of an antiseptic agent, an insecticide, an insect repellent and a skin penetrating enhancer.

4. The composition of any one of claims I to 3, wherein the first local anaesthetic agent is selected from the group consisting of of lignocaine, prilocaine, amethocaine and cocaine.

5. The composition of any one of claims 1 to 4, wherein the second local anaesthetic agent is selected from the group consisting of bupivacaine and amethocaine.

6. The composition of any one of claims 1 to 5, wherein the vasoconstrictor comprises adrenalin.

7. The composition of claim 3, wherein the antiseptic agent is cetrimide.

8. The composition of any one of claims 1 to 7, wherein the composition is sprayable onto the open wound. C:M~~oM 0CC\ 3- Wm_.OC-6/MrA LZ 22

9. The composition of claim 1, comprising: non-erystallising liquid sorbitol (70%), lignocaine HCi, bupivacaine HCl, sodium metabisulfite, cetrimide, adrenaline tartrate, hydroxy cellulose, and dye.

10. The composition of claim 9, comprising: about 100 mg/mL non-crystallising liquid sorbitol (70%); about 50.0 mg/mL lignocaine HC; about 5.0 mg/mL bupivacaine HCl; about 1.5 mg/mL sodium metabisulfite; about 5.0 mg/mL cetrimide; about 45.0 pg/mL adrenaline tartrate; about 5.0 mg/mL hydroxy cellulose; and dye.

11. The composition of any one of claims 1 to 10, wherein the open wound is a laceration, a surgical incision, an ulcer, an abrasion or a burn.

12. The composition of any one of claims I to 11, wherein the subject is an animal undergoing a husbandry procedure selected from the group consisting of mulesing, shearing, castration, tail docking, ear tagging, de-horning, branding and marking.

13. The composition of any one of claims I to 12, wherein the composition further comprises an analgesic agent.

14. The composition of claim 13, wherein the analgesic agent is an anti inflammatory agent.

15. A method for anaesthetising an open wound of a subject, the method comprising applying topically to the wound a composition as claimed in any one of claims 1 to 14.

16. The method of claim 15, wherein the subject is a non-human animal.

17. The method of claim 16, wherein the animal is a sheep.

18. A composition as claimed in claim 1, substantially as herein described with reference to the examples. EDITORIAL NOTE APPLICATION NUMBER - 2007221941 It should be noted that the next page is 25.