Technical Field

[0001 ] The present invention relates to topical formulations comprising methanol, and methods of using the same for the treatment of pain and or inflammation associated with a skin condition. The skin condition includes, but is not limited to, stings and/or bites from animals, insects and plants, dermatitis, burns, urticaria and rash.

Background

[0002] Despite recent advances in the treatment of pain and/or inflammation associated with skin conditions many people complain that current treatments and methodologies are insufficient in treating significant pain and/or inflammation, for example, pain and/or inflammation associated with a number of common skin conditions, such as, stings and/or bites from animals, insects and plants, dermatitis, burns, urticaria and rash. General inflammation initiated from skin damage or skin irritations result in heat, pain, redness, swelling, itching and dilation of blood vessels which increases blood flow, leakage and increased vascular permeability. However, there remains a need for effective and timely treatments for pain and/or inflammation associated with such common skin conditions.

[0003] Menthol and other remedies on the market possess some soothing effects on skin and have anti-inflammatory effects. However, the amount of menthol required to treat pain and inflammation can cause further rashes, and difficulties breathing in young children.

[0004] There are numerous venomous flora and fauna in the world, some of which possess venom that causes significant medical problems when a human or an animal is exposed to the venom. Invenomation by such a plant or animal can cause both systemic and local reactions. The severity of the reaction is dependent on a variety of factors including the source of the venom, the amount of venom injected, the location of the bite or sting (e.g. arm, thigh), and prior exposure to the venom.

[0005] Jellyfish, or coelenterates, are marine invertebrates belonging to the Scyphozoan class, and in turn the phylum Cnida a. They are related to corals, hydra and sea anemones. The body of an adult jellyfish is composed of a bell-shaped, jellylike substance enclosing its internal structure, from which the creature's tentacles suspend. Each tentacle is covered with stinging cells (cnidocytes) that can sting or kill other animals: most jellyfish use them to secure prey or as a defense mechanism. Most jellyfish have tentacles or oral arms coated with thousands of the stinging cells called cnidocytes containing a microscopic, toxin-filled harpoon, a nematocysts. Generally, each nematocyst has a "trigger" (cnidocil) paired with a capsule containing a coiled stinging filament, as well as barbs on the exterior. Upon contact, the filament will swiftly unwind, launch into the target, and inject toxins. It can then pull the victim into its mouth, if appropriate. In addition to discharging toxin, the nematocysts activate the surrounding cnidocytes to increase the total volume of venom injected. Importantly, the nematocysts are still able to function when separated from the jellyfish.

[0006] There are several types of coelenterate toxins, but all consist of a complex mixture of proteins and enzymes. The most severe invenomations can occasionally induce systemic responses such as nausea, headache, and chills and even more rarely can induce severe systemic reactions such as cardiac arrhythmia, respiratory dysfunction, psychosis, and muscular spasm. Yet the major feature of most stings is the rash and associated pain, which is caused by a combination of several elements of the venom. Most invenomations result in pain that can be severe, but is usually self-limited. The duration of the symptoms of minor stings ranges from a few minutes to several hours, weeks, or longer depending upon the jellyfish species, the extent of the sting, the presenting symptoms, and the physiology of the individual. Most of the effects, both mild and severe, are caused by the actions of the venom, not an allergic reaction. The local reaction to most jellyfish invenomations includes local reactions such as pain, pruritus, paresthesias such as numbness, burning, or throbbing, inflammatory rash, blistering, and swelling.

[0007] Common anecdotal treatment of an invenomation is the liberal application of acetic acid (household vinegar) to the affected areas. The acetic acid is supposed to deactivate any non-discharged nematocysts, however may actually trigger firing of additional nematocysts. Additionally, the nematocysts of certain species of jellyfish may not be effectively deactivated by vinegar. Other topical decontaminants such as baking soda, isopropyl alcohol, a paste of meat tenderizer or papaya, concentrated citrus juice, olive oil and quarter strength household ammonia are often recommended, but have varying or little effectiveness.

[0008] However, most of these traditional or "home" remedies prove slow-acting and/or ineffective at best, and at worst, some of the above remedies can result in the release of more toxin and an increase in pain. Meanwhile, the patient continues to experience pain and other symptoms of the sting for several hours or days. [0009] No commercial preparations for the treatment of jellyfish stings appear to exist, and topical preparations for other skin conditions such as sunburn prove ineffective. While the above-described traditional remedies, such as vinegar, may have limited deactivating properties, such formulations still lack an effective pain relief, particularly in the short term. Thus, presently a formulation that adequately and quickly treats the pain and swelling associated with jellyfish stings, and other animal stings and skin conditions is not available and would be desirable.

Summary of Invention

[0010] The present invention is broadly directed to treatment of pain and/or inflammation associated with a skin condition. In work leading up to the present invention, the inventors sought to develop a formulation that adequately and quickly treats pain and swelling associated with jellyfish stings. The inventors have found that surprisingly, a topical formulation comprising menthol in combination with an acidifier is effective at treating pain and/or inflammation associated with a skin condition, e.g., invenomation by bluebottle stings and is further useful in the treatment of a number of other skin conditions.

[001 1 ] In a first aspect, the present invention provides a topical formulation comprising an effective amount of menthol in combination with an acidifier to treat pain and/or inflammation associated with a skin condition, wherein the topical formulation has a pH from about 1 to 3.

[0012] In second aspect, the present invention provides a method of treating pain and/or inflammation associated with a skin condition comprising administering a topical formulation according to the first aspect to the skin condition.

[0013] In a third aspect, the present invention provides a use of the topical formulation of the first aspect in the treatment of pain and/or inflammation associated with a skin condition.

[0014] In a fourth aspect, the present invention provides a use of the topical formulation of the first aspect in the manufacture of a medicament for the treatment of pain and/or inflammation associated with a skin condition.

[0015] The topical formulation of the invention can treat pain and/or inflammation associated with a number of common skin conditions that are experienced by a large number of individuals on a day-to-day basis. For example, the topical formulation relieves pain, redness, swelling, reduces rash and/or itching relating to skin conditions, such as, but not limited to, any kind of invenomation from stings and/or bites from animals, insects and plants in addition to contact dermatitis, burns, urticaria, rash and other forms of dermatitis. The insects may include ants, bees, wasps, mosquitoes, sandflies, spiders, and sea lice. The animals may include mammals, rodents, reptiles, or marine animals. In a preferred embodiment, the animal is a jelly-like marine invertebrate and/or jellyfish. The topical formulation of the invention is particularly useful for treating pain and/or inflammation associated with the jelly-like marine invertebrate Physalia physalis, also known as, bluebottle jelly fish, or Portuguese Man-of-War.

[0016] In another example, the skin condition is any kind of irritation including any plant that irritates skin including, but not limited to, vines, nettles, poison ivy, poison oak, and poison sumac.

[0017] Without being bound by any particular theory, the treatment of pain and/or inflammation may include activation and/or stimulation and/or blocking and/or reducing the activity of one or more pain receptors to thereby treat the pain and/or inflammation. For example, the one or more pain receptors may be TRPM8, TRPV1 and/or Kappa Opiod receptors.

[0018] A topical formulation having an acidifier that adjusts and/or maintains the pH of the formulation low between about 1 to about 3 permits the use of a lower effective amount of menthol to treat pain and/or inflammation associated with skin conditions. In one example, the effective amount of menthol is about 0.1 % w/w to about 1 % w/w. In another example, the effective amount of menthol is about 0.25% w/w to about 0.5% w/w. In a preferred example, the effective amount of menthol is about 0.35% w/w. It will also be appreciated by persons skilled in the art, that the menthol can be of substantial purity, and the menthol may be synthesized and/or extracted from peppermint and/or obtained commercially. For example, the menthol may be from Liquid Menthol, Menthol Crystals or peppermint oil, but is not limited to such forms. In a preferred example, the peppermint oil is high-menthol peppermint oil (Mentha Piperita). In this example, the peppermint oil contains at least 70% menthol. The peppermint oil is about 0.15% w/w to about 1 % w/w of the formulation or about 0.3% w/w to about 0.7% w/w. Preferably, the peppermint oil is about 0.5% w/w.

[0019] It will also be understood that the acidifier can lower the pH of the formulation of any aspect and/or example described herein, thus any typical biocompatile acid may be used for this purpose such that the pH of the topical formulation is adjusted to and/or maintained at about 1 .5 to about 3. Preferably, the pH is adjusted to and/or maintained at about 2 to 2.5. It is thought that the lower pH and the action of the acid aids in the treatment of pain and/or inflammation by denaturing proteins at the site of the skin condition being treated, e.g., the venom and/or other inflammatory proteins released by e.g., skin trauma, and/or skin irritation such as, but not limited to, stings, and/or bites from an animal, insect, plant, or a rash, the onset of urticaria, contact dermatitis, or any other dermatitis. In one example, the acidifier may be acetic acid, citric acid, tartaric acid or a mixture thereof. Typically, the acidifier is at about 1 .0% w/w. In one example, the acidifier is a mixture of glacial acetic acid, anhydrous citric acid, and tartaric acid. In this example, the mixture may be about 0.5% w/w glacial acetic acid, 0.25% w/w anhydrous citric acid and 0.25% w/w tartaric acid.

[0020] The topical formulation of any aspect and/or example described herein may further comprise any known excipient and/or preservative and/or constituent suitable for topical formulation e.g., the formulation further comprises an emulsifier. The emulsifier may be at about 1 to 10%. Preferably, the emulsifier is about 5% w/w. Any typical emulsifier known to a skilled person may be used. In one example, the emulsifier is Laureth-9. The topical formulation of the invention may further comprise an alcohol. The alcohol is thought to act as a preservative, which also acts as a carrier to increase the penetration of menthol, and provides a secondary local anaesthetic effect. It will be understood that any known additive that acts as a preservative, and/or carrier, and/or other anaesthetic alone or in combination known in the art to be suitable for a topical formulation may be used. Any typical alcohol useful in topical formulations may be used. A preferred alcohol is benzyl alcohol.

[0021 ] The topical formulation of any aspect and/or example described herein may further comprise an essential oil. It will be understood that any essential oil known in the art to be suitable for a topical formulation may be used. Preferably, the essential oil has further effects on the pain receptors, to thereby enhance the pain-relief and/or other analgesic properties. The essential oil may also have one or more other properties, for example, but not limited to, anti-inflammatory antiseptic, antibiotic, anti-infectious, anti-neuralgic, or bactericidal properties. In one example, the topical formulation according to any aspect and/or example described herein comprises about 0.1 % w/w to about 1 % w/w of 100% pure essential oil, or about 0.5% of 100% pure essential oil. The 100% pure essential oil may be 100% chamomile oil, German chamo, Manuka, eucalyptus, lavender, myrrh, roman chamo, rosemary, spikenard, tea tree, thyme linalool, calendula, Palma Rosa, Niaouli, laurel, myrtle, rosewood, helichrysum, St. John's Wort infusion, carrot seed, Cistus, galbanum, clary, angelica, yarrow, Witch hazel, Chamomile Hydrosols, Jasmine, heli, and/or lavendar, or a mixture thereof. In one example, the essential oil is chamomile oil. The chamomile oil may be Roman or German blue chamomile. In a preferred example, the 100% pure essential chamomile oil is from Matricaria recutica.

[0022] Topical formulations according to any aspect and/or example as described herein may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. When formulated in an ointment, the effective amount of menthol and acidifier may be employed with either a paraffinic or a water-miscible ointment base.

Alternatively, the effective amount of menthol and acidifier may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. (See, generally, Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Co., Pa., 1985). Such formulations can be prepared by any method known in the art of pharmacy, for example by bringing into association the effective amount of menthol and acidifier with the carrier(s), diluent(s) or excipient(s).

[0023] To prepare topical formulations, the effective amount of menthol and acidifier is mixed with a pharmaceutically acceptable carrier or excipient for example, by mixing with physiologically acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions, or suspensions (see, e.g., Hardman, et al. (2001 ) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms:

Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.).

[0024] The topical formulation of the invention may also comprise other functional ingredients. It will be apparent to the skilled artisan what functional ingredients are to be included, and is dependent upon the symptoms of skin condition that are being treated.

[0025] In one example, the formulation further comprises sun-block with an SPF rating to block UVB rays and/or compounds such as for example, titanium dioxide, zinc oxide and/or avobenzone, which helps protect against UVA rays. [0026] In another example, the formulation further comprises anti-allergic agents such as for example, any known blocker of histamine release in skin.

[0027] In another example, the formulation further comprises a known compound that is useful for wound-healing such as, but not limited to a MMP inhibitor, or any ligand or modulator of the signalling pathways of growth factors belonging to the TGF-β superfamily of ligands.

[0028] In another example, the formulation further comprises anti-inflammatory agents such as for example, alclometason, amcinonide, benzoyl peroxide, betamethasone, clobetasol, cortisone, hydrocortisone, desonide, desoximetasone, diflorasone, or any agents that treat symptoms associated with dermatitis, including psoriasis, and eczema that may be formulated with an anti-inflammatory agent in a cosmetic base for topical application for local prevention of inflammation and/or tissue damage consequent to inflammation.

[0029] A variety of steroidal and non-steroidal anti-inflammatory agents can be combined with the effective amount of menthol and acidifier. For example, steroidal anti-inflammatory agents, including but not limited to, corticosteroids such as hydrocortisone,

hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate,

beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone,

desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate,

diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, flupreclnisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, eprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof may be used.

[0030] Specific non-steroidal anti-inflammatory agents useful in the topical formulation of the present invention include, but are not limited to: piroxicam, isoxicam, tenoxicam, sudoxicam, CP-14,304, aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, fendosal, diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, aemetacin, fentiazac, zomepirac, clidanac, oxepinac, felbinac, mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic acids, ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, al inoprofen, tiaprofenic, phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone, among others.

[0031 ] Mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically-acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application. Of the nonsteroidal anti-inflammatory agents, ibuprofen, naproxen, flufenamic acid, mefenamic acid, meclofenamic acid, piroxicam and felbinac are preferred and ibuprofen, naproxen, and flufenamic acid are most preferred.

[0032] Emollients may also be included in the topical formulation of the invention.

Particularly useful emollients which provide skin conditioning are glycerol, hexanetriol, butanetriol, lactic acid and its salts, urea, pyrrolidone carboxylic acid and its salts, amino acids, guanidine, diglycerol and triglycerol. Preferred skin conditioning agents are the propoxylated glycerol derivatives.

[0033] Throughout this specification, 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 step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers.

[0034] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0035] Each embodiment described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

[0036] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

[0037] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally- equivalent products, compositions and methods are clearly within the scope of the invention, as described herein.

Detailed Description of Preferred Embodiments

EXAMPLE 1

An aqueous topical formulation for the treatment of pain and/or inflammation associated with skin conditions was prepared as follows.

Step 1 - Acidifier was added to purified water. This was stirred in a 2 litre stainless steel mixing vessel with a stand mounted mixer on slow speed. The acidifier was a solution of vinegar providing a percentage of acetic acid of approximately 17%.

Step 2 - Purified water and emulsifier were combined . Laureth -9, which helps disperse the water insoluble ingredients and has a secondary local anaesthetic effect was added followed by Liquid Menthol which has anti itch properties and thought to possibly act by activating TRPM8, blocking receptor TRPV1 and stimulating Kappa Opiod receptors to relieve pain. Benzyl alcohol was then added to the same mixture, which is a preservative and may act to increase the penetration of the menthol, but also has a secondary local anaesthetic effect. These ingredients were then stirred in a separate vessel until uniform.

Step 3 -Step 2 was mixed into Step 1 with slow mixing until clear.

Step 4 - The pH of the mixture was adjusted to between 2.0 -2.5. It is thought that the low pH may the protein in the skin conditions e.g., venoms and/or inflammatory proteins.

Step 5 - Purified water was added to bring adjust weight/volume and the solution was mixed for a further 10 mins. EXAMPLE 2

An aqueous topical formulation for the treatment of pain and/or inflammation associated with skin conditions was prepared as described in Example 1 with the following changes. a) As vinegar varies has considerable batch and brand variation, the vinegar

component was replaced with a proprietary blend of Standardized Glacial Acetic Acid , Citric Acid Anhydrous and Tartaric Acid as acidifier in step 1 . b) Liquid Menthol was replaced with Menthol Crystals, and further changed to the high menthol peppermint oil {Mentha Piperita). c) The percentage of Benzyl Alcohol was also increased to enhance the local

anaesthetic effect.

EXAMPLE 3

An aqueous topical formulation for the treatment of pain and/or inflammation associated with skin conditions was prepared as described in Example 1 and/or 2, wherein the formulation had the following characteristics and formula.

BATCH SIZE : 300.0 Kgs 297.6 Ltrs Density : 1 .008g/cc

EXAMPLE 4

An aqueous topical formulation for the treatment of pain and/or inflammation associated with skin conditions was prepared as described in Example 1 and/or 2, wherein the formulation had the following characteristics and formula.

BATCH SIZE : 100.7 Kgs 100.0 L.trs Density : 1 .065g/cc

Anal tical Testing - Bulk

EXAMPLE 5

An aqueous topical formulation for the treatment of pain and/or inflammation associated with skin conditions was prepared as described in Example 1 . The formula was then used in a beach-trial, wherein lifeguards on Cronulla's beaches (Sydney Australia) were enlisted to help trial a spray of Example 1 . 800 people were treated for bluebottle stings. The people treated said that they could feel it working, it relieved the pain that the spray quickly eased discomfort caused by blue bottle stings.

EXAMPLE 6

An aqueous topical formulation for the treatment of pain and/or inflammation associated with skin conditions is prepared as described in any one of Examples 2-4. The formula is used in a beach-trial, wherein lifeguards on Australian beaches are enlisted to help trial a spray. A group of 800 people suffering from contact from bluebottles are treated with the spray for bluebottle stings and compared to a control group of 800 people treated with traditional treatment of cold water, and/or ice, and/or vinegar. The time it takes for relief to be achieved is recorded in both groups and compared.