Pharmaceutical Compounds and Methods of Use

Abstract

The present invention relates to pharmaceutical compositions for topical use comprising a corticosteroid and an insecticide selected from pyrethrin or synthetic pyrethroid insecticides. Methods for the use of the compositions of the present invention in animals in the treatment of allergic dermatitis, particularly insect bite hypersensitivity.

Description

[Technical Field]

[0001] This application claims priority to Australian Provisional Application No. 2019903522, entitled "Pharmaceutical Compositions and Methods of Use," filed on September 23, 2019, the contents of which are incorporated herein by reference in their entirety. The present invention relates to pharmaceutical compositions for topical use comprising a corticosteroid and an insecticide selected from pyrethrin or synthetic pyrethroid insecticides. Methods for their use in treating allergic dermatitis, particularly lesions and pruritus associated with insect bite hypersensitivity, in animals using the compositions of the invention are also described. [Background technology]

[0002] Allergic dermatitis due to insect bites (insect bite allergic dermatitis) is a common condition in animals. It occurs in all parts of the world where animals and their respective parasites coexist, and is particularly prevalent in warm climates. Allergic dermatitis due to insect bites can affect domestic animals such as sheep, cattle, pigs, horses, and dogs. It is particularly common in horses and dogs, and is by far the most common cause of skin disease in domestic horses and dogs.

[0003] Allergy is a hypersensitivity or altered state of the immune system that results in self-injury. Within a group of animals, only a small proportion may be affected. There are four types of immune responses to allergens. The common type, and the type primarily responsible for the clinical syndrome of insect bite hypersensitivity, is the type I IgE-mediated immune response, although type III and type IV cell-mediated immune pathogenesis can also occur.

[0004] In type I immunopathogenesis, allergen-specific IgE binds to antigens on mast cells, triggering their degranulation and subsequent release of histamine, serotonin, eotaxin, and other cytokines. This leads to inflammation and attracts other inflammatory cells. For insect bite hypersensitivity, allergens are primarily salivary gland antigens, including 11 salivary gland proteins of Culicoides species (midge) identified as allergens for insect bite hypersensitivity (IBH) in horses (Schaffartzik et al., Veterinary Immunology and Immunopathology 147 (2012) 113-126) and numerous Ctenocephalides felis (cat flea) salivary proteins identified as allergens in dogs (Lee et al., Veterinary Immunology and Immunopathology 69 (1999) 229-237).

[0005] The degree of stimulation of the IgE response depends on the characteristics of the individual antigen affected and genetic factors. Insect models demonstrate both the protective and potentially destructive nature of immune system responses. Irritation from an insect bite can cause the host to flake or kill the insect, and under normal circumstances, the immune response can be altered to anergy, i.e., hyporesponsiveness. Alternatively, if an individual is genetically predisposed, hypersensitivity can develop, leading to persistent inflammation, which is enhanced and sustained by self-trauma through rubbing, biting, or scratching. Furthermore, the release of other inflammatory factors, such as histamine and eicosanoids, increases vascular blood flow and permeability at the site of the reaction, resulting in an itch response and further epidermal damage via self-trauma. This cycle of itch, scratching, skin damage, and more itch results in ongoing tissue damage and animal suffering.

[0006] This abnormal, long-lasting hypersensitivity is thought to have a genetic basis in horses. For example, a study of Warmblood horses in the Czech Republic showed significant differences in prevalence, ranging from 10% to 75%, among the offspring of specific stallions (Raskova et al., J. Equine Vet. Sci. 2013; 33(6):427-432), supporting a genetic predilection model. Conversely, no genetic association has been established, and no breed predilection has been identified (Miller et al., Muller & Kirk's Small Animal Dermatology, 7th ed. St. Louis, MO: Elsevier / Mosby, 2013; 407).

[0007] Horses commonly suffer from IBH caused by Culicoides species (stable flies). The disease is known as Queensland Itch in Australia and Sweet Itch in the Northern Hemisphere. Culicoides species are the most commonly involved parasites, but Tabanus and Chrysops species (horse flies), Stomoxys species (stable flies), Simulium species (blow flies), and Musca species (house flies), as well as wasps and wasps, can all cause epidermal lesions and hypersensitivity reactions in horses.

[0008] In dogs, the most common form of insect-induced allergic dermatitis is flea allergy dermatitis (FAD). Ctenocephalides felis ("cat flea") is the primary parasite involved, but C. canis may also be present. The terms "summer itch" or "summer eczema / dermatitis" are also used colloquially to refer to the disease in horses and dogs, as both are seasonal in the summer.

[0009] Clinical signs vary between species, but there are similarities in dorsal distribution and intense pruritus. In horses, Culicoides species feed on the dorsal surface, primarily along the mane and tail regions, and around the face and ears. Even in non-hypersensitive animals, the bite of Culicoides midge can be particularly painful, due to the biting mouthparts.

[0010] In dogs, clinical signs associated with FAD include pruritic papular dermatitis of the buttocks, dorsal chest, flanks, tank, and perineum. In severe cases, a generalized distribution may occur. Some dogs may develop severe acute lesions such as acrolic granulomas or suppurative traumatic dermatitis on the buttocks or lateral face.

[0011] Horses or dogs whose irritation progresses to a hypersensitive state show signs ranging from hair or coat thinning, papules and wheals to alopecia, crusting, excoriation, depigmentation and lichenification. The pruritus is often exacerbated by secondary infection of the epidermis. These secondary infections are often associated with staphylococcal isolates.

[0012] Both IBH and FAD are known to cause significant distress and suffering in affected animals worldwide. Numerous treatments have been developed for the disease, with varying degrees of success and, in some cases, adverse consequences. In theory, eliminating all stinging insects to which the animal is allergic (i.e., environmental control) would eliminate the dermatitis, but in most cases, this is difficult or impossible to achieve. Therefore, treatment should include both minimizing insect bites and managing the pruritus resulting from the allergic reaction. To date, no single treatment addresses both of these requirements, nor is there a formulation with a practical and reasonable dosing interval. Current dosing and treatment methods have several drawbacks.

[0013] Environmental control of Culicoides species is difficult. Their life cycle is poorly understood, making environmental management challenging. Development from eggs to adults takes several weeks during the summer. Like fleas, some larvae and pupae overwinter in protected breeding sites and continue development in warmer climates. These midges breed in moist conditions in a variety of habitats, particularly in damp, muddy areas, feces, and vegetable matter. Adults typically live for about 20 days, but can live for over 90 days depending on environmental conditions. Adults fly in swarms to mate. Like fleas, female midges require a blood meal for egg maturation. 100 to 200 eggs are typically laid in an area with specific humidity and abundant organic material. Development from eggs to adults typically takes about 15 days, but can take up to seven months during the overwintering period. Modification of these areas by removing organic matter and draining muddy areas forms an important part of the control strategy for Culicoides species bleeding, but complete control remains difficult to achieve.

[0014] Environmental control of fleas is easy because all breeding stages occur within the house and yard. Good results can be achieved by flea bombing, vacuuming the house, and treating all livestock.

[0015] Prevention of exposure to biting insects is the cornerstone of current treatment protocols. For example, stableing horses at dawn and dusk and using fans during these times can reduce the number of Culicoides midge parasites accessing the animals. If fans are not available, hanging mosquito nets over windows and around doors in the stable area can be helpful. During the summer months, stables are typically required between 4:00 PM and 8:00 AM. In temperate climates such as subtropical to tropical Australia, enclosed stables are not readily available, as horses may be stabled most of the time in temperate climates such as Europe. Many Australian horses are routinely kept on pasture year-round, relying only on shade trees and other open structures for shelter. The use of rags ("rigging") is often used to prevent exposure to midges, but rags are inappropriate under hot summer conditions. Additionally, rag damage caused by horses rubbing against fences and trees necessitates frequent and expensive repairs and replacements.

[0016] It is often impractical or impossible to completely eliminate insects from the environment or to physically protect against fleas and midges. Chemical insect repellents can be used to prevent insect bites. A natural pyrethrin insect repellent was extracted from the flowers of certain chrysanthemum species, Chrysanthemum cinerariifolium.

[0017] Synthetic pyrethroid insect control products are commonly used for their repellent activity in both dogs and horses. These synthetic pyrethroids are potent, low-odor, long-lasting, and can be used in lower concentrations than natural pyrethrins (see, for example, the Chemical WATCH fact sheet: https: / / www.beyondpesticides.org / assets / media / documents / mosquito / documents / SyntheticPyrethroids.pdf).

[0018] Type I pyrethroids include allethrin, bifenthrin, permethrin, fenothrin, resmethrin, tefluthrin, and teramethrin. Type II pyrethroids include cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, flucrinate, flumethrin, fluvalinate, and tralomethrin.

[0019] A drawback of synthetic pyrethroids is that chemical modifications to the natural pyrethrin structure to increase stability and insect control efficacy often result in increased irritation. Those with a cyano group tend to be more irritating. This is particularly evident in second-generation pyrethroids such as permethrin. To avoid irritation, the concentration of permethrin can be reduced, but this negatively impacts efficacy. As a result of the need to reduce or avoid irritation, insect control products often do not contain high enough concentrations of permethrin to be effective as repellents. Alternatively, products containing first-generation pyrethrin compounds are used, which are approximately four times less effective and less stable than permethrin.

[0020] Commonly available insecticide treatments for horses include permethrin 87 g / L, diluted to 2% as a spray or rinse, administered daily or as a weekly pour-on application, or permethrin 40 g / L as a spray or rinse twice daily to twice weekly. A combination of piperonyl butoxide and permethrin is applied to horses or dogs as a spray or rinse twice daily to twice weekly. These treatments have drawbacks, including frequent application and / or skin irritation. Injecting 200 g / L of fenvalerate into horses once weekly can cause injury. Citronella oil 89 g / L and N,N-diethyl-M-toluamide 51 g / L applied twice daily to dogs or horses has low efficacy against fleas and Culicoides and a short duration of action. Alternating daily applications of a permethrin / citronella combination spray or rinse to dogs or horses results in a very short activation period. Benzoyl benzoate / bronopol formulations applied twice daily as sprays or rinses are used to treat secondary skin infections in dogs or horses. They are less effective against fleas and gnats, and bronopol is known to cause allergic dermatitis.

[0021] Several products are available for treating dogs, but not horses, to kill fleas as soon as they enter the animal. This reduces the feeding time, thereby preventing or reducing exposure to saliva allergens. These products include topical treatments containing permethrin, fipronil, or indoxacarb. Typically, these are applied to the back of the animal's neck and then allowed to spread via epidermal lipids. These products, often referred to as "spot-on" treatments, require frequent application and avoid bathing for several days before and after application. In some cases, the effectiveness of these products may decrease as fleas develop resistance.

[0022] Systemic products for treating dogs are also commercially available. These usually come in the form of monthly or three-monthly chewable tablets containing active ingredients such as spinosad, afoxolaner, or fluralaner. In common with topical spot-on treatments, they do not act as repellents; fleas must be fed to the dog for ingestion and death by the active form. However, the kill time is relatively fast. These products have the disadvantage of being relatively expensive (Pucheu-Haston et al., Practical Parasitology: The Flea Infested Pet: Overview of Current Products. Today's Vet. Pract. 7: 90-95).

[0023] To treat the allergic component of this disease, both topical and systemic glucocorticoids are used in dogs. Topical polypharmacy creams are typically used. These typically contain a corticosteroid, a local anesthetic, and an antibiotic. These polypharmacy compositions have the disadvantage of containing antibiotic components that may not be needed, potentially resulting in inappropriate dosing, which can exacerbate the development of resistance.

[0024] Corticosteroid spray products are also available that contain hydrocortisone aceponate or similar in an alcohol base. After application of the corticosteroid spray, the carrier evaporates, leaving the active ingredient in the epidermis. This can be damaging to the epidermis and should be used judiciously to avoid further animal suffering.

[0025] Oral prednisolone is commonly used in dogs while flea control is effective. A typical dose is approximately 1 mg / kg / day, after which the dose is gradually tapered. Common side effects of oral prednisolone include bruising, lethargy, increased dry mouth and urination, and increased appetite, all of which can cause concern for the animal and its owner. Long-term use of oral prednisolone can lead to symptoms of hypercortisolism, including abnormalities in fat metabolism, hair loss, and thinning of the epidermis.

[0026] Systemic corticosteroids used in horses to address the allergic component of this disease include short courses (1–2 weeks) of oral prednisolone at a dose of 1 mg / kg / day. Alternatively, convenient but potentially dangerous long-acting injectable corticosteroids may be administered in conjunction with other management methods until the pruritus is blocked or relieved. These long-acting injectable corticosteroids, such as triamcinolone acetonide, dexamethasone, and methylprednisolone acetate, typically induce increased side effects and continued suppression of the pituitary-hypothalamic-adrenal axis. Furthermore, all systemic corticosteroids are contraindicated in pregnant mares, horses with a history of laminitis, horses with equine Cushing's syndrome or equine metabolic disease, and horses with other visceral complications.

[0027] H1-antihistamines are used to relieve symptoms of insect bite allergic dermatitis, but their effectiveness in reducing pruritus is limited, making them less advantageous than glucocorticoids. Furthermore, H1-antihistamines may induce mild sedation and behavioral or personality changes.

[0028] Alternative treatments, such as immunotherapy-based desensitization, have been attempted, but this appears to induce poor responses in both horses and dogs (Ginel, et al., Vet. Dermatol. 2014; 25:29-e 10).

[0029] Recent approaches using blocking analogs or monoclonal antibodies to inactivate proinflammatory cytokines have shown promise in horses and have proven effective in dogs against flea allergies (Michaels, et al., Vet. Dermatol. 2016;27:478-e 129). Their true value in insect bite allergies remains to be evaluated. However, given the research input required, this is expected to be an expensive approach in horses, similar to the current commercially available cytokine blockers for dogs. Furthermore, the long-term effects of blocking this pathway in the immune system are unknown.

[0030] Popular and relatively accessible treatments, such as shampooing animals with oatmeal preparations, have been used to provide some relief, and the application of other "natural" or accessible treatments, such as calamine lotion, have all been suggested, although none are effective as stand-alone treatments and their benefits are minimal. The use of dietary supplements, for example with essential fatty acids, has increased in recent years, but there is limited data supporting their effectiveness. Similarly, traditional or natural remedies, such as garlic supplementation in the diet, have been suggested for both flea control and inflammation management, but there is insufficient data to support any real benefit. Summary of the Invention

[0031] The complexity of allergic dermatitis due to insect bites, the worldwide prevalence of parasites, and the resulting suffering and impaired quality of life for affected animals, along with the concern and expense to owners, clearly justify the development of more effective treatments that address one or more of the shortcomings of currently available treatments. In particular, there is a need for treatments that are more effective, easier to use, have convenient application intervals, are readily accessible, or are cost-effective.

[0032] Advantageously, the inventors have discovered that compositions for topical application comprising a corticosteroid in combination with a pyrethrin or pyrethroid insecticide find use in the treatment of insect bite allergic dermatitis or insect bite hypersensitivity in mammals. In a preferred embodiment, the composition further comprises one or more silicone excipients.

[0033] Topical formulations avoid systemic administration of corticosteroids. Therefore, these compositions are considered safe for use, with minimal systemic toxicity or side effects. The formulations are convenient and easy to use. Furthermore, the formulations are fast-acting, providing rapid relief to animals suffering from allergic reactions.

[0034] Thus, in a first aspect, there is provided a pharmaceutical composition for topical application comprising, or consisting essentially of: a corticosteroid; an insecticide selected from pyrethrin and pyrethroid insecticides; and a pharmaceutically acceptable carrier.

[0035] Preferably, the composition is for application to the skin and / or coat of an animal. In a preferred embodiment, the composition further comprises one or more silicones.

[0036] In another aspect, a method of treating insect bite allergic dermatitis in a mammal is provided, comprising topically administering to a mammal in need thereof an effective amount of a composition consisting of, consisting essentially of, or comprising a corticosteroid and an insecticide selected from a pyrethrin and a pyrethroid insecticide.

[0037] In yet another aspect, there is provided a topical composition consisting of, or consisting essentially of, a corticosteroid and an insecticide selected from pyrethrin and pyrethroid insecticides for use in treating insect bite allergic dermatitis.

[0038] In a still further aspect, there is provided the use of a topical composition consisting of, or consisting essentially of, a corticosteroid and an insecticide selected from pyrethrin and pyrethroid insecticides in the manufacture of a medicament for the treatment of insect bite allergic dermatitis.

[0039] In some embodiments, the corticosteroid is budesonide.

[0040] In some embodiments, the insecticide is permethrin.

[0041] In some embodiments, the composition comprises budesonide in an amount of about 0.2 g / L to about 1 g / L, e.g., about 0.25 g / L, and permethrin in an amount of about 20 g / L to about 80 g / L, e.g., about 40 g / L.

[0042] The composition is preferably formulated in a base that includes one or more conditioning excipients, such as one or more silicones.

[0043] In some embodiments, the composition comprises one or more silicons totaling about 25 g / L to about 150 g / L of the composition, for example, about 75 g / L of the composition.

[0044] In some embodiments, the pharmaceutical composition is a conditioner, a leave-in (or leave-on) conditioner, a lotion, a spray, a cream, an ointment, or a pour-on formulation.

[0045] In some embodiments, the pharmaceutical formulation is suitable for application by pouring or spraying, preferably onto the skin, coat, or hair of the animal, hi some embodiments, the composition is formulated for application by smoothing onto the animal's coat.

[0046] In some embodiments, the mammal is a horse or a dog.

[0047] In yet another aspect, there is provided a pharmaceutical composition formulated for topical administration comprising, consisting essentially of, or consisting essentially of: corticosteroids in amounts of about 0.025 g / L to about 1 g / L, or 0.15 g / L to about 1 g / L; Pyrethrin or pyrethroid insecticides in an amount of about 0.5 g / L to about 50 g / L; one or more silicons in an amount of about 25 g / L to about 150 g / L; at least one pharmaceutically acceptable excipient; and Pharmaceutically acceptable aqueous carrier

[0048] In yet another aspect, there is provided a pharmaceutical composition formulated as a leave-in (or leave-on) conditioner for topical administration, comprising, consisting of, or consisting essentially of: budesonide in an amount of approximately 0.25 g / L; Permethrin approximately 40g / L; one or more silicons in a total amount of about 75 g / L; thickener in an amount of about 30 g / L; one or more pharmaceutically acceptable excipients selected from solubilizing agents, chelating agents, antioxidants, and pH adjusting agents; and A pharmaceutically acceptable aqueous carrier, preferably purified water.

[0049] Preferably, the composition is formulated or adapted for application to the skin, coat, or hair of an animal.

[0050] Also provided is a method of treating insect bite allergic dermatitis in a mammal by topically applying to a mammal in need thereof, preferably to the skin, coat, or hair of the mammal, a pharmaceutical composition described herein. [Brief explanation of the drawings]

[0051] [Figure 1]Figure 1 is a graph showing the comparative mean lesion scores and standard deviations for each treatment group in a randomized, controlled clinical trial of permethrin and budesonide formulations for the topical treatment of horses suffering from Culicoides (stable fly) allergy. Lesion scores for all treatment groups are shown on days 0, 21, and 42. [Figure 2] Figure 2 is a graph showing pruritus scores for each treatment group in a clinical trial of a formulation of permethrin and budesonide for the topical treatment of horses suffering from Culicoides allergy. Itch scores were measured daily for 42 days using an itch visual analogue scale. [Figure 3] Figure 3 is a graph summarizing the overall response to treatment in each treatment group of the clinical trial, as assessed by veterinarians on days 21 and 42 using a 4-point scale ranging from 1 (poor) to 4 (excellent) as a measure of overall improvement. DETAILED DESCRIPTION OF THE INVENTION

[0052] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For purposes of the present invention, the following terms are defined below.

[0053] The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0054] "About" means a reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies relative to the reference amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length to the extent of 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%. The term "approximately" should be interpreted similarly.

[0055] As used herein, the terms "% w / w," "% w / v," and "% v / v" refer to weight-to-weight, weight-to-volume, and volume-to-volume percentages, respectively. Amounts listed as "g / L" refer to grams of ingredient per liter of composition.

[0056] As used herein, the term "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

[0057] Unless the context requires otherwise, throughout this specification and the claims that follow, the words "comprise," and variations such as "comprises" and "comprising," are understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of other integers or steps or group of integers or steps. Thus, use of the term "comprise," etc., indicates that the recited integers are required or required, but that other integers are optional and may or may not be present. "Consisting of" means including and limited to what follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are required or necessary, and that no other elements may be present. "Consisting essentially of" means including any elements listed after the phrase, and is limited to other elements that do not interfere with or contribute to the activity or operations specified in the disclosure for the recited elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are essential or required, but that other elements are optional and may or may not be present depending on whether they affect the operation or activity of the listed elements.

[0058] As used herein, the term "topical," when used in terms such as "topical application," "topical administration," "topical medication," "topical formulation," etc., refers to the application of a composition or formulation to a body surface of an animal, such as the epidermis, hair, coat, or mucous membrane. In some preferred embodiments, the body surface is the skin, hair, or coat of an animal.

[0059] As used herein, the term "corticosteroid" refers to a steroid anti-inflammatory agent. Suitably, the corticosteroid is adapted for topical application. Preferably, the corticosteroid is a glucocorticoid. Suitably, the glucocorticoid is an approved or registered veterinary drug selected from, but not limited to, alclometasone; amcinonide; betamethasone; budesonide; clobetasol; clobetasone; desonide; desoximetasone; diflucortolone; diflucinolone; fluocinonide; flurandrenolide; fluticasone; halcinonide; halobetasol; halometasone; hydrocortisone; mometasone; methylprednisolone; triamcinolone; and / or any one of their salts, solvates and / or derivatives. In some embodiments, the glucocorticoid is hydrocortisone or budesonide.

[0060] In one embodiment, the glucocorticoid is alclometasone dipropionate; amcinonide; betamethasone dipropionate; betamethasone valerate; budesonide; clobetasol propionate; clobetasone butyrate; desonide; desoximetasone; diflucortolone valerate; diflorasone diacetate; fluocinolone acetonide; fluocinonide; fludroxycortide; fluticasone propionate; halcinonide; halobetasol propionate; halometasone; hydrocortisone; hydrocortisone aceponate; hydrocortisone butyrate; hydrocortisone 17-butyrate; hydrocortisone valerate; mometasone furoate; methylprednisolone aceponate; or triamcinolone acetonide.In some embodiments, the glucocorticoid is budesonide.

[0061] As used herein, the term "pyrethrin" or "pyrethrin insecticide" refers to a natural pyrethrin compound extracted from the flowers of certain chrysanthemum species, particularly Chrysanthemum cinerariifolium (silver lace). The potent insecticidal activity of pyrethrins is achieved through their effects on the insect's nervous system. However, those skilled in the art will understand that the effectiveness of pyrethrin insecticides may be due to their insecticidal and / or insect repellent properties. Both the insecticidal and insect repellent (repellent) effects of pyrethrins are encompassed herein. Examples of natural pyrethrins include pyrethrin I, pyrethrin II, cinerin I, cinerin II, jasmolin I, and jasmolin II. Natural pyrethrins can be used individually or in combinations of two or more natural pyrethrins.

[0062] As used herein, the term "pyrethroid" or "pyrethroid insecticide" refers to synthetic pyrethroid compounds. Pyrethroids are synthetic versions of the natural pyrethrin structure, which undergo chemical modifications to enhance stability and insect repellent and / or insecticidal efficacy. Pyrethroid compounds include, but are not limited to, allethrin I, allethrin II, bioallethrin, bifenthrin, permethrin, fenothrin, resmethrin, tefluthrin, and tetramethrin, including cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, flucythrinate, flumethrin, fluvalinate, and tralomethrin. In some embodiments, the pyrethroid insecticide is permethrin.

[0063] As used herein, the term "silicone excipient" or "silicone" refers to siloxanes, including siloxanes such as cyclosiloxanes and polysiloxanes. Silicones are well known in the art and readily available from commercial sources such as The Dow Chemical Co. Silicones are widely used in the formulation of pharmaceutical compositions, cosmetics, and personal care products. Examples of silicones include, but are not limited to, at least one cyclosiloxane selected from cyclopentasiloxane and cyclotetrasiloxane, or a mixture thereof; and hydroxy-terminated polydimethylsiloxane. In some embodiments, a combination of two or more silicones can be incorporated into the composition of the present invention to impart desired physical properties to the composition. For example, hydroxy-terminated polydimethylsiloxane (dimethiconol, poly[oxy(dimethyl-silylene)], α-hydro-ω-hydroxy-) is a high-viscosity siloxane that has emollient properties and can impart a soft, silky feel and conditioning to animal coats, hair, or skin. Cyclosiloxanes, such as mixtures of cyclopentasiloxane and cyclotetrasiloxane, provide spreading and lubricating properties. When used in the compositions described herein, the silicone mixtures can provide conditioning benefits to the skin, coat, or hair of animals.

[0064] The term "insect bite allergic dermatitis" encompasses a hypersensitive reaction of an animal's skin to insect bites due to specific protein allergens in the insect's saliva. Insect bite allergic dermatitis is sometimes referred to as insect bite hypersensitivity (IBH). This condition is typically found in warmer climates and can affect many species of mammals, such as domestic mammals, including dogs and horses. Typically, the insect may be a midge or flea, although it will be understood that the type of insect is not so limited. Typical biting insects include, for example, Culicoides species (stable flies) and Ctenocephalides species (dog fleas), such as C. felis or C. canis. Other examples of biting insects include Forcipomyia species, such as Forcipomyia taiwana. It will be understood that the species of biting insects will vary depending on factors such as the particular geographic region and climate.

[0065] Insect bite allergic dermatitis in horses is usually caused by Culicoides species and is commonly known as Culicoides hypersensitivity allergic reaction. It is also known as seasonal relapsing dermatitis, Queensland itch, or sweet itch. The allergic reaction typically affects the animal's epidermis at sites where the insect feeds, such as the mane, tail, and dorsal midline. Abdominal involvement may also occur. Epidermal lesions around the ears, face, and head are also common.

[0066] In dogs, typical symptoms of insect bite allergic dermatitis include a pruritic papular dermatitis on the animal's buttocks, dorsal chest, flanks, tank, or perineum. Severe lesions include acrolic lick granulomas or pyotraumatic dermatitis.

[0067] Symptoms of insect bite allergic dermatitis include, but are not limited to, one or more of the following: dry, cracked, or scaly skin; rash; redness; itching, including intense itching; swelling; burning; tenderness; sensitivity; lesions; papules or wheals that may be oozing or crusting; hair loss; excoriation; depigmentation; or lichenification. A particularly troublesome symptom for animals is the intensely itchy skin lesions. This often leads to aggressive rubbing, resulting in significant self-trauma. The coat may become damaged, appear severely mottled, or the epidermis may break and bleed. Secondary infections, such as bacterial and fungal infections, especially skin infections, may also occur. Common secondary bacterial infections include staphylococcal infections.

[0068] As used herein, the term "derivative" includes chemical modifications introduced into the structure of a corticosteroid molecule. Typical derivatives of corticosteroids include derivatives of steroid hydroxy substituents, such as esters, ethers, and ketals, e.g., cyclic ketals such as acetonides. For example, hydrocortisone can be derivatized to form esters such as hydrocortisone aceponate, hydrocortisone butyrate, hydrocortisone 17-butyrate, or hydrocortisone valerate. The corticosteroid molecule may be derivatized at one or more positions.

[0069] Ester derivatives of corticosteroids are well known in the art. Typical ester derivatives of steroid hydroxy groups, particularly 17- or 21-hydroxy groups, include acetate, propionate, butyrate, valerate, pivalate, succinate, benzoate, salicylate, and 2-furoate. When a corticosteroid has two ester derivatives, examples include diacetate, dipropionate, diphosphate, valeroacetate, acetate / propionate (aceponate), and butyrate and propionate (butyrate).

[0070] Cyclic ketal derivatives such as acetonides can be formed via two adjacent hydroxy groups on the steroid structure, for example, the 16- and 17-hydroxy substituents.

[0071] As used herein, the terms "salt" and "solvate" include any pharmaceutically acceptable salt or solvate of an active pharmaceutical ingredient. Pharmaceutically acceptable salts are well known in the art.

[0072] Salts of corticosteroids include sodium salts, including the sodium salts of derivatives such as sodium succinate.

[0073] Pharmaceutically acceptable solvates are known in the art and include hydrates and alcoholates. Suitably, pharmaceutically acceptable solvates include hydrates, for example, monohydrates, dihydrates and trihydrates.

[0074] The preparation of salts, derivatives and solvates can be carried out using methods well known in the art.

[0075] The chemical structure of the corticosteroid or insecticide used in accordance with the present invention may contain asymmetric centers, such as asymmetric carbon atoms. It will be understood that isomers arising from such asymmetry (e.g., all enantiomers, stereoisomers, diastereomers, rotamers, or racemates) are included within the scope of the present invention. When stereochemistry is not specified, it will be understood that the structure is intended to encompass any stereoisomer and all mixtures thereof. For example, the corticosteroid budesonide [11β,21-dihydroxy-16α,17α-(butylidenebis(oxy))pregna-1,4-diene-3,20-dione, or 1β,21-dihydroxy-16α,17α-[butane-1,1-diylbis(oxy)]pregna-1,4-diene-3,20-dione] can have either the (22R)- or (22S)-configuration.

[0076] The chemical structures of the corticosteroids or insecticides used in accordance with the present invention may include geometric isomers, for example, due to the presence of carbon-carbon double bonds. It will be understood that all geometric isomers, such as cis / trans geometric isomers, are included within the scope of the present invention unless otherwise specified. It will be understood that if the stereochemistry is not specified, the structure is intended to encompass any geometric isomer and all mixtures thereof. Permethrin may exist as either cis- or trans-isomers, or as a mixture thereof; for example, permethrin may be a 25:75 cis:trans mixture.

[0077] The terms "subject," "individual," "mammal," or "animal," as used herein, refer to a mammalian subject for whom treatment or prevention is desired. In certain embodiments, the subject is a livestock mammal, such as equines, including but not limited to horses, ponies, donkeys, asses, and mules; camelids, including but not limited to camels, llamas, and alpacas; dogs, sheep, cattle, pigs, and goats. Preferably, the mammal is selected from cattle, pigs, sheep, dogs, or horses. In some embodiments, the mammal is selected from cattle, pigs, sheep, goats, dogs, or horses. In some embodiments, the mammal is a dog. In some embodiments, the mammal is an equine, such as a horse or pony. In some embodiments, the mammal is a goat.

[0078] As used herein, the terms "alleviate," "treat," "treating," "inhibiting," or "treatment" cover the treatment of insect bite allergic dermatitis and / or the symptoms of insect bite allergic dermatitis and include suppressing the symptoms, i.e., arresting their development, alleviating the symptoms, i.e., causing regression of the symptoms, or alleviating the symptoms resulting from the symptoms without addressing the underlying disease or condition.

[0079] Each embodiment described herein applies mutatis mutandis to each embodiment and each embodiment unless otherwise specified. Composition of the Invention

[0080] The compositions of the present invention find use in treating or inhibiting insect bite allergic dermatitis or symptoms associated with insect bite allergic dermatitis.

[0081] The present invention is based on the surprising discovery that a pharmaceutical composition formulated for topical application comprising a corticosteroid; an insecticide selected from a pyrethrin or a pyrethroid; and a pharmaceutically acceptable carrier provides access to an effective and convenient treatment for insect bite allergic dermatitis.

[0082] The pharmaceutical compositions described herein comprise a combination of an insecticide or insect repellent and a corticosteroid anti-inflammatory agent. These components are readily available and provide a cost-effective treatment for insect bite allergic dermatitis. In a preferred embodiment, the composition includes a topical corticosteroid, such as hydrocortisone or budesonide. These topical corticosteroids are largely metabolized in the epidermis and achieve systemic release at approximately 0.4-0.7% of their concentration, minimizing the potential for systemic side effects typically encountered with systemic corticosteroids. In some embodiments, the topical steroid is a "soft" or "dissociable" steroid. These steroids are androstene-derived steroids that exhibit anti-inflammatory effects similar to conventional corticosteroids but without the potentially serious systemic side effects associated with some conventional steroids.

[0083] In preferred embodiments, the corticosteroid is a glucocorticoid suitable for topical application. In some embodiments, the glucocorticoid is selected from glucocorticoids that are not substantially systemically absorbed when applied to mammalian skin. Preferred glucocorticoids are those that are substantially metabolized in the epidermis, thus reducing or minimizing undesirable systemic effects. Examples of suitable glucocorticoids are well known in the art. In some embodiments, the glucocorticoid is selected from alclometasone, amcinonide, betamethasone, budesonide, clobetasol, clobetasone, desonide, desoximetasone, diflucortolone, diflorasone, fluocinolone, fluocinonide, fludroxycortide, fluticasone, halcinonide, halobetasol, halometasone, hydrocortisone, mometasone, methylprednisolone, triamcinolone, and / or any one of their salts, solvates, and / or derivatives. In some embodiments, the corticosteroid is hydrocortisone or a salt and / or solvate and / or derivative thereof, such as hydrocortisone aceponate. In some particular embodiments, the corticosteroid is budesonide or a salt and / or solvate and / or derivative thereof.

[0084] In some embodiments, the insecticide is a natural pyrethrin insecticide, such as pyrethrin I, pyrethrin II, cinerin I, cinerin II, jasmolin I, or jasmolin II, or a mixture of two or more of the foregoing. Pyrethrins are extracted from the dried flowers of certain chrysanthemum species, particularly Chrysanthemum cinerariifolium (silver lace), which is commercially grown in Kenya. Isolated pyrethrins are readily available from commercial sources.

[0085] In some embodiments, the insecticide is a synthetic pyrethroid insecticide. Synthetic pyrethroid insecticides are well known in the art and are commercially available. It will be understood that the pyrethroid compound is suitable for application to the skin of animals. Pyrethroid insecticides include: Examples of suitable pyrethroid insecticides include, but are not limited to, allethrin I, allethrin II, bioallethrin, bifenthrin, permethrin, phenothrin, resmethrin, tefluthrin, and tetramethrin, including cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, flucythrinate, flumethrin, fluvalinate, and tralomethrin. In some embodiments, the pyrethroid insecticide is permethrin. Permethrin exists in the form of cis- and trans-geometric isomers. In the compositions described herein, permethrin may include a single geometric isomer or may include both isomers as a mixture. In some embodiments, permethrin is a mixture of cis- and trans-isomers in a ratio of about 25:75.

[0086] The amount of corticosteroid present in the composition will vary depending on the type of formulation and its method of application. For example, typically, ointments, creams, lotions, conditioners, leave-in (or leave-on) conditioners, pour-on, or spray formulations will have a concentration of from about 0.025 g / L to about 0.5 g / L, or from about 0.025 g / L to about 1 g / L; from about 0.05 g / L to about 0.5 g / L, or from about 0.05 g / L to about 1 g / L; or from about 0.1 g / L to about 0.5 g / L, or from about 0.05 g / L to about 1 g / L; e.g., from about 0.05 g / L to about 0.6 or 0.8 g / L, or from about 0.1 g / L to about 0.5 g / L; from about 0.15 g / L to about 0.5 g / L; or from about 0.1 g / L to about 0.5 g / L. The corticosteroid may be present in an amount of from 15 g / L to about 0.4 g / L; from about 0.2 g / L to about 0.4 g / L; from about 0.1 g / L to about 0.3 g / L; from about 0.15 g / L to about 0.5 g / L; from about 0.2 g / L to about 0.5 g / L; from about 0.15 g / L to about 0.35 g / L; from about 0.15 g / L to about 0.45 g / L; from about 0.2 g / L to about 0.4 g / L; from about 0.25 g / L to about 0.5 g / L; from about 0.25 g / L to about 0.4 g / L; from about 0.2 g / L to about 0.3 g / L, particularly about 0.25 g / L. It will be appreciated that if application of the composition involves a rinse, such as a shampoo or cleaning formulation, this will require a higher concentration of corticosteroid.

[0087] The amount of insecticide present in the composition depends on the type of formulation and application method. Typically, the formulation may contain pyrethrin or pyrethroid insecticide in an amount of about 0.5 g / L to about 60 g / L, about 0.5 g / L to about 50 g / L, or about 1 g / L to about 50 g / L; for example, about 5 g / L to about 50 g / L, about 10 g / L to about 45 g / L, about 20 g / L to about 40 g / L, about 30 g / L to about 45 g / L, or about 35 g / L to about 45 g / L, particularly about 40 g / L. In some embodiments, the composition contains pyrethrin or pyrethroid insecticide in an amount of up to 10, 15, 20, 25, 30, 35, 40, or 45 g / L. In some embodiments, the composition comprises a pyrethrin or pyrethroid insecticide in an amount of at least 5, 10, 15, 20, 25, 30, or 35 g / L. It will be appreciated that if application of the composition comprises a rinse, such as a shampoo or cleaning formulation, this will require a greater concentration of insecticide.

[0088] In some embodiments, the corticosteroid is present in the compositions of the present invention in an amount of about 0.0025% to about 0.1% w / w, about 0.005% to about 0.1% w / w, about 0.0075% to about 0.1% w / w, about 0.01% to about 0.075% w / w, about 0.01% to about 0.05% w / w, about 0.02% to about 0.04% w / w, about 0.02% to about 0.3% w / w, or about 0.025% w / w. In some embodiments, the corticosteroid is present at about 0.015% w / w to about 0.05% w / w; about 0.02% w / w to about 0.05% w / w; about 0.015% w / w to about 0.035% w / w; about 0.015% w / w to about 0.045% w / w; about 0.02% w / w to about 0.04% w / w; about 0.025% w / w to about 0.05% w / w; about 0.025% w / w to about 0.04% w / w; about 0.02% w / w to about 0.03% w / w; particularly about 0.025% w / w.

[0089] In some embodiments, the insecticide is present in the compositions of the present invention in an amount of about 0.05% to about 5.0% w / w, about 0.1% to about 4.5% w / w, about 0.15% to about 4% w / w, about 0.2% to about 4% w / w, about 0.5% to about 4.5% w / w, about 1% to about 4% w / w, 2% to about 4.5% w / w, or about 4% w / w.

[0090] In some embodiments, the ratio of corticosteroid to pyrethrin or pyrethroid insecticide is about 1:100 to about 1:200 by weight, e.g., about 1:125 to about 1:175 by weight, or about 1:140 to about 1:170 by weight. In some embodiments, the ratio of corticosteroid to pyrethrin or pyrethroid insecticide is about 1:160 by weight.

[0091] It will be understood that when the compositions of the present invention include one or more silicones, the amount of silicone component present will depend on the type of formulation and how it is applied. In some compositions as described herein, such as lotions or leave-in conditioners, the ratio of API (insecticide and corticosteroid) to the combined amount of silicone is about 1:2 to 2:1 or about 1:2 to 3:2, for example, about 40:70 or 41:75.

[0092] In its simplest form, the composition of the present invention may comprise a corticosteroid, an insecticide selected from pyrethrin and pyrethroid insecticides, and a pharmaceutically acceptable carrier. Those skilled in the art will also understand that the composition may comprise other pharmaceutically acceptable additives, such as surfactants, emulsifiers, rheology or viscosity modifiers, solvents or solubilizers, buffers, pH adjusters, diluents, dispersants, chelating agents, preservatives, antioxidants, stabilizers, tonicity agents, wetting agents, thickeners, and excipients.

[0093] The composition preferably includes one or more silicones as modifying excipients.

[0094] The inventors have discovered that compositions of the present invention further comprising one or more silicones are particularly advantageous. Silicones provide properties such as film-forming properties, wash-off resistance, and spreading properties to the composition. Silicones can also provide soothing and emollient properties, and thus can provide a soothing effect on the skin or conditioning of the skin, coat, or hair of animals. In some embodiments, the presence of one or more silicones in the compositions of the present invention provides an emollient effect. This emollient effect may be due to the formation of a residual layer or film of silicone on the animal's skin, which forms a water-repellent barrier (see, for example, https: / / luisafanzani.com / what-is-dimethicone / ).

[0095] Thus, in a further aspect, the present invention advantageously provides a pharmaceutical composition for topical application comprising, consisting of, or consisting essentially of: corticosteroids, pyrethrin or pyrethroid insecticides, 1 or more silicon, a pharmaceutically acceptable aqueous carrier, and optionally one or more pharmaceutically acceptable excipients.

[0096] In some embodiments, one or more silicons are present in the composition in an amount of about 25 g / L to about 150 g / L, e.g., about 50 g / L to about 100 g / L, about 60 g / L to about 90 g / L, about 70 g / L to about 80 g / L, or about 75 g / L.

[0097] In some preferred embodiments, silicon-containing composition is formulated as conditioner, leave-in conditioner or lotion.Suitably, composition is packaged in a pump dispenser, which is adapted to deliver a predetermined amount of composition per actuation.In some embodiments, the composition of the present invention is a leave-in conditioner formulation, which is also called leave-on conditioner, for applying to animal skin, coat or hair, and contains one or more silicones.

[0098] Those skilled in the art will understand that the physical properties of silicone vary according to its chemical structure, and can appropriately select silicone according to the desired final physical properties of the composition.Suitable silicones are well known in the art, and one or more silicones can be selected to impart properties such as increasing or decreasing viscosity, film-forming properties, wash-off resistance, diffusibility, volatility or permeability to the composition.The amount and type of silicone present in the composition of the present invention can be adjusted according to the needs of animals, and depend on the species, for example, dog or horse.It will be understood that factors such as the type of animal, pathology and chronicity, coat length, oiliness, and general condition of skin or hair can be taken into consideration when formulating the composition.

[0099] In some embodiments, the composition includes one or more silicones selected from cyclopentasiloxane, cyclotetrasiloxane, and hydroxyl-terminated polydimethylsiloxane. In some embodiments, a combination of two or more silicones can be incorporated into the composition to impart desired physical properties. In some examples, the composition includes cyclopentasiloxane, cyclotetrasiloxane, and hydroxyl-terminated polydimethylsiloxane. Suitable silicones and silicone blends are readily available from commercial sources, such as Xiameter® PMX-344 or Xiameter® PMX-1401, available from The Dow Chemical Company. Xiameter® PMX-344 is a cyclosiloxane blend containing cyclopentasiloxane and cyclotetrasiloxane. This silicone blend can act as a base fluid and has good spreading and lubricating properties, as well as unique volatility characteristics. Xiameter® PMX-1401 is a 13% aqueous solution of cyclopentasiloxane and cyclotetrasiloxane formulated with dimethiconol (a hydroxyl-terminated polydimethylsiloxane). The hydroxyl-terminated polydimethylsiloxane can act as an emollient, thus providing a soft feel to the skin and improving the condition of the hair and coat.

[0100] Dimethiconol is a high viscosity polysiloxane silicone. In some embodiments of the present invention, dimethiconol is present in the compositions of the present invention in an amount of about 0.5 g / L to 3 g / L, e.g., about 1 g / L to 2.5 g / L, or about 2 g / L, or about 1.95 g / L.

[0101] Cyclosiloxanes, including mixtures of cyclopentasiloxane and cyclotetrasiloxane, may be present in the composition in an amount of from about 25 g / L to about 125 g / L; e.g., from about 50 g / L to about 100 g / L; 60 g / L to about 80 g / L; or from about 70 g / L to 75 g / L; e.g., about 73%.

[0102] In yet another aspect, there is provided a pharmaceutical composition formulated for topical administration comprising, consisting essentially of, or consisting essentially of: 1. a corticosteroid in an amount of about 0.025 g / L to about 1 g / L; 2. Pyrethrin or pyrethroid insecticides in an amount of about 0.5 g / L to about 50 g / L; 3. One or more cyclosiloxanes in an amount of about 25 g / L to about 150 g / L, for example, about 50 g / L to about 100 g / L; 4. At least one polysiloxane, such as dimethiconol, in an amount of about 1 g / L to about 3 g / L, for example, about 2 g / L. 5. at least one pharmaceutically acceptable excipient; and 6. A pharmaceutically acceptable aqueous carrier.

[0103] Topical administration according to the present invention can be in any formulation suitable for delivering active ingredients to the skin or coat of an animal.Topical formulations are well known in the art and are described, for example, in Ueda et al., Topical and Transdermal Drug Products, Pharmacopeial Forum, Vol. 35(3), 2009; Buhse et al., Topical Drug Classification, International Journal of Pharmaceutics, 2005, 295, 101-112.Suitable formulations include, but are not limited to, liquids, aerosols, creams, ointments, lotions, mousses, gels, shampoos, conditioners, and leave-in conditioners.In some embodiments, the pharmaceutically acceptable carrier is an aqueous carrier, for example, water, such as purified water.

[0104] In some embodiments, the composition is a liquid, such as an aqueous liquid or an aqueous solution. The liquid can be applied to the animal's coat or skin by any suitable means, such as, for example, washing, drench, dip, spray, aerosol, pour-on, or backliner. The liquid may be a ready-to-use formulation or may be supplied as a concentrate to be diluted with an aqueous diluent, such as water, before application. The concentration of the composition depends on the intended method of administration. For example, a composition for spraying, dip, drench, washing, or pour-over may be a more dilute composition than a composition applied as a pour-on or spray onto a backliner. A backliner is a ready-to-use liquid formulation that can be applied to an animal, such as a cow, sheep, pig, or horse, by pouring it along the backline from the neck to the tail. In some embodiments, the composition can be formulated as a spray-on for administration by spraying, such as delivered by a trigger spray bottle. Other suitable application means are known in the art, such as moistened gauze, swabs, cotton, foams, sponges, or cloths. In some examples, the composition may be applied manually to the skin or coat.

[0105] In some embodiments, the composition of the present invention is a cream or lotion. Creams are semi-solid multi-phase compositions containing active agents, in this case a corticosteroid and an insecticide, each dissolved in a suitable base. Creams contain water-in-oil or oil-in-water emulsions, or aqueous microcrystalline dispersions of long-chain fatty acids or alcohols, and generally have a relatively soft, spreadable consistency.

[0106] In some preferred embodiments, the composition is in the form of a lotion. Lotions share many characteristics with creams and are typically viscous emulsions, solutions, or suspensions. Typically, they contain an aqueous vehicle and greater than 50% water and volatile materials. Lotions are easy to apply and, if water-based, easy to remove. They have emollient properties and may leave a cooling or soothing sensation on the animal's skin.

[0107] In some embodiments, the composition is applied topically to hair-bearing skin, and the composition may be in the form of a shampoo or conditioner.Conditioners, such as hair conditioners, are well known for hair care.Such conditioner formulations are particularly useful for application to parts of the body of hair-bearing animals.

[0108] The inventors have discovered that conditioning compositions are useful formulations for the compositions of the present invention. The inventors have also identified that compositions of the present invention formulated as leave-in (also referred to as leave-on) conditioners are particularly advantageous. Leave-in conditioners are conditioning products that can be applied to the hair, skin, or coat of animals. Leave-in conditioners generally contain silicone. The bases and excipients for such conditioner formulations are well known and are described, for example, in Barel et al., Handbook of Cosmetic Science and Technology, Third Edition, 2009. CRC Press, page 687.

[0109] The presence of silicone in the leave-in conditioners of the present invention provides conditioning and emollient benefits by providing water repellency by forming a residual film or barrier on the animal's coat. The leave-in conditioner allows penetration of the pleage and coats the hair with a residual film of the medicinal agent. The leave-in conditioners of the present invention offer several advantages over other forms of topical application. For example, application of a spray formulation can frighten or stress an already distressed animal, particularly a horse. Semi-solid dosage forms, such as creams, require massage to penetrate the coat. Massaging sensitive skin is generally opposed by animals, and the massaging action can cause matting of the coat and prevent proper spreading and application of the cream.

[0110] Leave-in conditioner formulations are lighter and less viscous than standard conditioners, providing a thin, residual layer of the formulation on the animal's coat, hair, or skin. In their simplest form, leave-in conditioners can be used to restore lost moisture to the skin or hair. In addition to treating the symptoms of IBH in the compositions of the present invention, leave-in conditioners provide conditioning and / or emollient benefits due to the residual film that can provide water repellency. This is advantageous because exposure of skin lesions to water can exacerbate the animal's suffering. The conditioner can be applied to the animal's coat at any time, but it is preferable to apply it to a freshly washed animal's coat. The coat may be dry, damp, or wet, but preferably the animal's coat is wet.

[0111] The leave-in conditioner formulations of the present invention are easy and quick to apply, limiting the amount of discomfort or stress to the animal. They provide rapid relief. They are cost-effective and long-lasting, eliminating the need for frequent reapplication.

[0112] Lotions and leave-in conditioners are suitably dispensed from pump dispensers that may be adapted to dispense a predetermined dose or amount of the composition, hi some embodiments, the pump is adapted to dispense about 1.6 mL or 1.5 g of lotion or leave-in conditioner per actuation.

[0113] The compositions of the present invention can be prepared by conventional methods known in the art. Typically, the desired ingredients are measured by weight or volume as appropriate and blended in a suitable container using blending techniques such as milling, blending, shear blending, or homogenization to form a substantially homogeneous blend. Those skilled in the art can determine the optimal blending technique and container depending on the batch size and physical form of the starting materials and the final composition. Preferably, the API, carrier, and excipients are combined in a homogenizer. The selection of additional excipients, if desired or necessary, is within the knowledge of those skilled in the art and depends on considerations such as the type and physical form of the required composition.

[0114] The composition is formulated as a composition adapted or suitable for topical administration. Preferably, the pharmaceutical composition is an aqueous formulation. It will be understood that any carriers and excipients used must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient. In some embodiments, the aqueous carrier is purified water. It will also be understood that compositions for topical application preferably have a physiologically acceptable pH. Preferably, the final pH of the composition is 3.5 to 4.5.

[0115] The pharmaceutical compositions of the present invention or the compositions used in the methods of the present invention can be formulated and administered using methods well known in the art.Techniques for formulation and administration can be found, for example, in Remington: The Science and Practice of Pharmacy, Loyd V. Allen, Jr (Ed), The Pharmaceutical Press, London, 22nd Edition, September 2012.

[0116] It will be appreciated that incorporating one or more pharmaceutically acceptable excipients into the composition may be useful. Excipients for aqueous compositions include, but are not limited to, buffers, stabilizers, chelating agents, tonicity agents, humectants, antioxidants, thickeners, solubilizers, viscosity adjusters, rheology adjusters, and preservatives. Suitable excipients are well known in the art and readily available from commercial sources. Preferably, the excipients are pharmaceutical grade, for example, USP or BP grade. Pharmaceutical excipients are described, for example, in Handbook of Pharmaceutical Excipients, Paul J. Sheskey et al., The Pharmaceutical Press, London, Eighth Edition, August 2017. It will be appreciated that determining whether a particular class of excipient is needed and selecting an appropriate excipient are within the skill and knowledge of those skilled in the art. It will also be recognized that the excipient must be chemically inert to other components in the composition. The concentration of any particular excipient will vary according to its identity, and one of ordinary skill in the art will be able to readily select an appropriate excipient and determine the amount required without undue burden or inventive input.

[0117] For example, the excipient may contain one or more pH adjusting agents or buffering agents to adjust or maintain the pH of the composition at a physiologically acceptable pH.Suitable buffering agents are well known in the art.Suitable pH adjusting agents include acids such as hydrochloric acid, or bases or alkalis such as sodium hydroxide or potassium hydroxide.

[0118] In some embodiments, it may be beneficial to solubilize certain ingredients when preparing the compositions described herein. For example, it may be useful to solubilize a corticosteroid or pesticide in a non-aqueous solvent prior to or simultaneously with its introduction into the aqueous base during preparation of the pharmaceutical compositions described herein. Suitable solvents, cosolvents, or solubilizers for organic APIs such as corticosteroids and pesticides are well known in the art. Those skilled in the art can readily determine whether the use of a solvent / solubilizer is desirable or necessary. The selection of a particular solubilizer or solvent, or class of solubilizer or solvent, and the determination of the amount of solubilizer or solvent, are within the skill and knowledge of those skilled in the art. In some embodiments, the solubilizer comprises oleoyl macrogel-6 glyceride. In some embodiments, the solubilizer comprises N-methylpyrrolidone (NMP), propylene glycol, or 2-(2-ethoxyethoxy)ethanol. It will be understood that the amount and selection of solubilizer required will depend on the solubility characteristics of the API and its concentration in the aqueous composition. A person skilled in the art can easily determine this without input of the invention, based on general knowledge and the examples herein. The solubilizer may be present in the compositions of the present invention in an amount of, for example, about 100 g / L to about 200 g / L, or about 150 g / L or about 130 g / L.

[0119] Surfactants, such as nonionic water-dispersible surfactants, are well known in the art of pharmaceutical formulations. They can solubilize poorly water-soluble active pharmaceutical ingredients (APIs) and increase their bioavailability. They can also act as co-emulsifiers in topical formulations to improve emulsion stability. An example of a nonionic water-dispersible surfactant is oleoyl macrogel-6 glyceride, available as Labrafil® M1944. Such surfactants can be present in the compositions of the present invention in an amount of about 10 g / L to about 30 g / L, e.g., about 20 g / L.

[0120] Those skilled in the art will also understand that thickeners, rheology adjusters or viscosity modifiers can be incorporated into the composition to adjust viscosity or rheological properties to the requirements of topical application.Suitable thickeners are well known in the art and include cellulose derivatives such as hydroxypropylmethylcellulose, carboxymethylcellulose; natural gums such as sodium alginate, xanthan, agar or carrageenan; pectin; and gelatin.If present, the amount of thickener in the composition of the present invention depends on the desired consistency (concentration / density / viscosity).

[0121] Thickeners, stabilizers, and emulsifiers or excipients for products formulated as lotions or leave-in conditioners are well known in the art. These excipients are useful because they can provide an advantageous base for the compositions of the present invention, which can condition animal coats or condition and soothe animal skin. In a preferred embodiment, the compositions of the present invention contain one or more excipients selected from thickeners, stabilizers, and emulsifiers. Suitable excipients for the formulation of cosmetics, hair care, personal care, and pharmaceutical compositions are well known. One of the excipients is polyquaternium-37, propylene glycol, commercially available from BASF as Salcare® SC96. Dicaprylate / Zicaplateand PPG-1 Trideceth-6. In some preferred embodiments, the composition includes one or more conditioning excipients. In some embodiments, the thickener / stabilizer / emulsifier is present in an amount of about 10 g / L to about 60 g / L, e.g., about 20 g / L to about 40 g / L, or about 30 g / L.

[0122] In some embodiments, the composition comprises a corticosteroid in an amount of about 0.025 g / L to about 1 g / L; an insecticide selected from a pyrethrin or a pyrethroid in an amount of about 0.5 g / L to about 60 g / L; and a total of about 10 g / L to about 60 g / L of thickeners, stabilizers, and emulsifiers; a pharmaceutically acceptable carrier; and optionally, a total of about 25 g / L to about 150 g / L of one or more silicones.

[0123] In preferred embodiments, the composition comprises one or more silicones and one or more thickeners. In some embodiments, the ratio of silicone to thickener is about 4:1 to 3:2, or 3:1 to 2:1, e.g., about 75:30. The combined amount of thickener and silicone in the composition typically forms about 10-12% by weight of the formulation. In some embodiments, the total amount of silicone and thickener present in the formulation is 100 g / L to 200 g / L.

[0124] Those skilled in the art will recognize that the compositions of the present invention are susceptible to microbial contamination or physical or chemical deterioration, and therefore, preservatives can be incorporated into the compositions to reduce or prevent their degradation or alteration. Suitable preservatives and antioxidants are well known to those skilled in the art, and the selection of a particular preservative or antioxidant and the determination of the necessary amount are well within the skill and knowledge of those skilled in the art. In some embodiments, the antioxidant is butylated hydroxytoluene in an amount of about 0.2 g / L to about 1 g / L, such as 0.5 g / L. Preservatives are well known in the art and include one or more of propylene glycol, diazolidinyl urea, and parabens, such as methylparaben and propylparaben. Typical amounts of preservatives in compositions such as those described herein are about 5 g / L to about 15 g / L, e.g., about 10 g / L. Preservatives for pharmaceuticals and personal care formulations are commercially available. For example, a mixture of propylene glycol, diazolidinyl urea, methylparaben, and propylparaben, commercially available as Germaben II®, is used.

[0125] The compositions of the present invention may also contain one or more stabilizers. Examples of stabilizers include chelating agents such as ethylenedinitrilotetraacetic acid disodium salt dihydrate. The amount of stabilizer used will depend on the circumstances, and may range from about 0.5 g / L to about 2 g / L, for example, about 1 g / L.

[0126] In certain embodiments, the present invention provides a leave-in conditioner formulation comprising, consisting of, or consisting essentially of: Budesonide: approximately 0.25 g / L; Permethrin: approximately 40 g / L; silicones, such as one or more of cyclopentasiloxane, cyclotetrasiloxane, and hydroxyl-terminated polydimethylsiloxane, in a total amount of about 75 g / L; A thickening agent, such as polyquaternium-37 / propylene glycol in an amount of about 30 g / L. Dicaprylate / Zicaplate / PPG-1 Trideceth-6 mixture; Approximately 20 g / L of oleoyl macrogel-6 glyceride:; N-methylpyrrolidone: approximately 50 g / L; Propylene glycol: approximately 30 g / L; 2-(2-ethoxyethoxy)ethanol: approximately 50 g / L; one or more pharmaceutically acceptable excipients selected from chelating agents, stabilizers, antioxidants, preservatives, and pH adjusters; and Purified water (1000mL).

[0127] In some preferred embodiments, the silicone comprises one or more of cyclosiloxanes, such as cyclopentasiloxane and cyclotetrasiloxane, in an amount of about 73 g / L, and hydroxyl-terminated polydimethylsiloxane in a total amount of about 2 g / L or 1.95 g / L.

[0128] If necessary, the composition of the present invention can further comprise one or more bioactive agents.Preferably, any additional bioactive agent can be formulated as a topical formulation.Additional therapeutic active ingredients can include antibiotics.Other therapeutic active ingredients include analgesics, anti-inflammatory or antipyretics. Method of Invention

[0129] The above compositions find use in methods for treating insect bite allergic dermatitis.

[0130] Accordingly, there is also provided a method of treating insect bite allergic dermatitis or symptoms thereof in a mammal, comprising administering to the mammal an effective amount of a pharmaceutical composition described herein.

[0131] Preferably, the mammal is selected from cows, pigs, sheep, dogs, and horses. In some embodiments, the mammal is a dog. In some embodiments, the mammal is an equine, such as a horse or pony. In some embodiments, the mammal is a goat.

[0132] In a further embodiment, the pharmaceutical composition described herein is provided for use in treating insect bite allergic dermatitis or its symptoms.The pharmaceutical composition described herein is also provided for use in treatment.The pharmaceutical composition described herein can also be used to manufacture a medicament for treating insect bite allergic dermatitis or its symptoms.

[0133] Although other modes of administration may be contemplated, the compositions of the present invention are primarily intended for topical administration to the skin, coat or hair of an animal. In the methods or uses described herein, the compositions of the present invention are delivered topically.

[0134] It will be appreciated that the compositions of the present invention are most effective when applied to contact the epidermis, particularly those areas typically affected by insect bite allergic epidermitis. Queensland Itch lesions correspond to horses' preferred feeding locations, and the compositions are typically applied to the coat or skin of the horse in one or more of the backline, mane, tail, ears, head, dorsal midline, or ventral areas as needed. In some embodiments, the compositions are suitably applied to one or more dorsal areas, such as the forehead, poll, ears, neck, crest, withers, shoulders, or rump, as needed. In the case of dogs, the compositions are typically applied to one or more of the dog's rump, dorsal chest, flank, tank, or perineum.

[0135] In some embodiments, the compositions of the present invention are spread by hand onto the animal's coat, preferably using a circular motion.

[0136] It will be appreciated that the compositions described herein are likely to be more effective if applied to a clean animal coat. In the case of leave-in conditioner, pour-on, spray or lotion formulations, preferably the animal's coat is freshly washed and moistened.

[0137] It will be understood that there will be variability in how well a dose of the composition spreads on an animal. When spread on the coat, a formulation as described herein may disperse significantly into the hair before reaching the epidermis. This will vary depending on the animal species, e.g., dog, horse. It will also vary depending on factors such as hair length, hair density, hair texture (coarse / fine), the amount of sebum / scale present on the skin surface, and the oiliness of the skin. Furthermore, coat density varies across parts of the body, with coats tending to be finer on the shoulders and denser on the rump, tail, and mane. Therefore, it will be understood that depending on the situation, the product may be diluted depending on the method of application. It will be understood that it may be necessary to adjust the amount and type of excipients, as well as the amount of carrier present in the formulation, to enable optimal delivery to the animal's skin. For example, spray applications can be diluted with water.

[0138] The compositions of the present invention can be used in any amount effective for suppressing or treating insect bite allergic dermatitis. As used herein, the term "effective amount" refers to the amount of a composition that, when administered according to a desired dosing schedule, provides the desired therapeutic activity for the condition. Typically, administration occurs at intervals of several hours, days, weeks, or months. Weekly application of the compositions of the present invention is considered appropriate. A therapeutically effective amount or therapeutically effective amount is an amount of a composition that, when administered according to a desired dosing schedule, is sufficient to at least partially achieve the desired therapeutic effect, or to delay the onset of the condition, or inhibit, stop, or partially or completely inhibit the onset or progression of the condition. A prophylactically effective amount of a composition, when administered according to a desired dosing schedule, is sufficient to at least partially prevent the onset of the condition.

[0139] The dosage and frequency of administration of the composition will depend on the requirements of the particular mammal being treated. The appropriate dosage and administration schedule can be determined by a veterinarian and can depend on the general age, health and weight of the mammal being treated, as well as the severity of the condition.

[0140] In some embodiments, a lotion or leave-in conditioner according to the present invention may be applied at about 1 g or about 1.5 g (about 1.5 mL, e.g., 1.6 mL) to cover about 0.025 to 0.03 m² of mammalian epidermis. In some embodiments, the pump is configured to dispense about 1.6 mL of lotion or leave-in conditioner, which typically covers about 0.025 m² (approximately a handspan) when spread manually on an animal's coat. In some embodiments of the present invention, this may contain about 0.0004 g of corticosteroid, 0.064 g of insecticide, or about 0.0004 g of corticosteroid, 0.064 g of insecticide, and 0.12 g of silicone.

[0141] In some embodiments of the present invention, the composition is applied about once a week.

[0142] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described, and the invention is to be understood as including all such variations and modifications within its spirit and scope.

[0143] In order that the present invention may be readily understood and put into practical practice, certain preferred embodiments will now be described by way of the following non-limiting examples. Example

[0144] The compositions of the present invention can be prepared from commercially available active pharmaceutical ingredients, carriers, and excipients. The compositions can be prepared using conventional mixing equipment, such as a blender, mixer, or homogenizer, and using conventional routes for preparing pharmaceutical formulations. Example 1 Preparation of Pharmaceutical Composition (IVP)

[0145] The following commercially available ingredients were combined by mixing in a homogenizer: budesonide [corticosteroid, 0.25 g]; Permethrin [insecticide, 25:75 cis:trans, 40g]; Cyclotetrasiloxane / cyclopentasiloxane mixture (Xiameter® PMX-344) [silicone excipient / conditioner, 60 g]; 13% solution of hydroxy-terminated polydimethylsiloxanes cyclopentasiloxane and cyclotetrasiloxane (Xiameter® PMX-1401) [viscous silicone conditioner, 15 g]; Polyquaternium-37 / Propylene Glycol Dicaprylate / Zicaplate / PPG-1 Trideceth-6 (Salcare® SC96) [thickener, 30 g]; oleoyl macrogel-6 glyceride (Labrafil® M 1944) [solubilizer, surfactant, 20 g]; Ethylenedinitrilotetraacetic acid disodium salt, dehydrate [chelating agent, 1 g]; N-methylpyrrolidone [solubilizer, 50 g]; Propylene glycol [solubilizer, 30 g]; 2-(2-ethoxyethoxy)ethanol [solubilizer, 50 g]; butylated hydroxytoluene [antioxidant, 0.5 g]; Propylene glycol / diazolidinyl urea / methylparaben / propylparaben (germaben II) [preservative, 10g]; Purified water [1000g]; pH adjuster (hydrochloric acid, sodium hydroxide) for pH 3.5 to 4.5

[0146] The formulated composition, referred to as CP or Example 1 Formula, is suitable as a residue in a conditioner. It is introduced into a pump-action dispenser adapted to dispense a predetermined volume of the composition per actuation. The pump typically dispenses 1.5 g or approximately 1.6 mL per actuation. Example 2 Efficacy Testing

[0147] A clinical trial was conducted using the formulation of Example 1 in horses suffering from Queensland Itch. These Culicoides-allergic horses were treated topically in a blinded trial conducted to Good Clinical Practice standards, in accordance with the GCP International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) Guideline 9, dated June 15, 2000. This randomized, placebo-controlled study investigated the efficacy of the leave-on conditioner of Example 1 (CP), containing budesonide and permethrin, for the treatment of equine stable fly hypersensitivity (Queensland itch, sweet itch, or QI). CP contains two active ingredients: budesonide (a steroid that relieves itch and inflammation) and permethrin (an insect repellent). Horses were treated with the commercial product (CP), placebo (control, vehicle only, PL), and three comparison products with varying levels of the active ingredients. Low budesonide (LB) contained 50% less budesonide than CP, but the same amount of permethrin. Budesonide only (BO) and permethrin only (PO) contained the same amount of a single active ingredient as CP, demonstrating the efficacy of that activity alone.

[0148] Data were collected and analyzed from 51 horses with spontaneous Queensland itch (10 horses per group, excluding 11 horses receiving budesonide only). Each horse received 40 pumps (approximately 60 g) of the drug percutaneously weekly for 6 weeks. Each dose was administered by a veterinarian to areas where QI commonly occurs: the face, head, neck, flank, and back. Veterinarians assessed the horses on days 0, 21, and 42, and owners measured itch and quality of life scores. Statistical analysis was performed using GraphPad Prism 8 software. A nonparametric one-way ANOVA (Kruskal-Wallis test with Dunn's multiple comparisons) was used.

[0149] Lesion scores were calculated based on four different components: excoriation, scaling (crusting / flaking skin), crusting, alopecia, and papules. These are the most common lesion types in horses affected by QI. Scores were calculated for eight different areas of the horse's body. For each of the eight areas, the severity of each sign was graded from 0 (none) to 5 (severe). A total lesion score was then calculated by multiplying the severity by the number of signs by the area, with a maximum possible score of 160. Each horse was assigned a score on days 0, 21, and 42. The lesion scores for all treatment groups on days 0, 21, and 42, which were the endpoints of the study, are shown in Figure 1.

[0150] Total lesion scores (maximum score 160) were similar between groups at baseline (p=0.6259). CP alone at day 21 (p=0.0012) and CP and PO at day 42 were significantly different from placebo (p=0.0003 and p=0.0366, respectively). Multiple comparisons revealed no other differences between treatment groups.

[0151] Itch scores: Pruritus scores were measured daily by the owners on a scale of 0 to 10 for 42 days using an itch visual analog scale, whereby an itch score of 1 to 10 was assigned based on various indicators of the horse's itch. On Day 0, no differences were observed between treatment groups (p=0.3360). On Day 42, only CP was statistically significantly different from placebo (p=0.0483). Results are shown in Figure 2.

[0152] Overall response to treatment: The overall treatment effectiveness score, a 4-point scale ranging from 1 (poor) to 4 (excellent), was used as a measure of overall improvement assessed by veterinarians on days 21 and 42. A total of 70% of horses in the CP group demonstrated an excellent response to treatment on days 21 and 42. Only CP demonstrated statistically significant differences (p=0.0019) from the placebo control on days 21 and 42 (Figure 3).

[0153] Summary: The table below (Table 1) shows the results of all major outcome measures, namely lesion score, itch score, quality of life, and overall effect of treatment (treatment efficacy).

[0154] [Table 1]

[0155] These data show that CP is the only treatment that shows a statistically significant difference in the outcome measures of this study compared to placebo. These data demonstrate that the formulation of Example 1 (CP) significantly reduces lesion scores, itch scores, and overall response to treatment, and increases quality of life.

[0156] Sleep data was collected using a horse activity tracker to track their movement. Sleep data was calculated from the time (in minutes) that the horse remained motionless. Horses in the CP treatment group were observed to generally rest longer than horses in other treatment groups. Horses in the placebo / control treatment group rested the least. These data support the hypothesis that horses treated with the CP composition were less restless and more likely to sleep or rest.

[0157] After the initial study, 42 horse owners chose to continue with the Phase 2 study, which involved using the product as needed for one year. Most owners used the product only occasionally, much less than the full dose. No significant side effects were observed under these conditions.

[0158] Animal safety studies were conducted on healthy horses using 1x (single dose), 3x, and 5x the recommended doses for 6 weeks, and 1x for 12 weeks. No abnormalities were detected in the blood or epidermis (biopsy) at either the 6-week full dose or the 5x full dose. Therefore, this product was considered safe for use.

[0159] These data demonstrate that the formulation of the present invention can be used to treat the symptoms of IBH or Queensland itch. Rapid relief of at least one symptom, including peeling, scaling and crusting, alopecia, and papules, was observed, and the overall therapeutic effect is considered beneficial. In general, a significant reduction in horse itching and pain was observed. The welfare of affected animals was observed to improve with no or minimal side effects. This is considered useful as an effective and safe treatment that works within a reasonable timeframe. Only weekly application is required, and the common complications of systemic corticosteroids are not present. Therefore, the formulation of the present invention is believed to find use in treating animals suffering from IBH, a particularly cruel, painful, and distressing disease.

[0160] The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

[0161] Citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.

[0162] Throughout the specification, the objective has been to describe preferred embodiments of the invention without limiting the invention to any one embodiment or particular collection of features. Accordingly, those skilled in the art will understand that various modifications and changes can be made in the particular embodiments illustrated without departing from the scope of the invention. All such variations and changes are intended to be included within the scope of the appended claims.

Claims

1. A pharmaceutical composition for topical application, comprising: A composition for treating insect bite allergic dermatitis in a mammal, comprising budesonide, permethrin, a silicone excipient, and a pharmaceutically acceptable carrier.

2. 10. The composition of claim 1, wherein the silicone excipient is selected from one or more of cyclopentasiloxane, cyclotetrasiloxane, and dimethiconol.

3. 3. The composition of claim 1 or 2, wherein budesonide is in an amount of about 0.05 g / L to about 1 g / L, preferably about 0.25 g / L.

4. A composition described in any one of claims 1 to 3, wherein permethrin is present in an amount of about 10 g / L to about 60 g / L, preferably about 40 g / L.

5. A composition described in any one of claims 1 to 4, wherein the ratio of budesonide to permethrin is approximately 1:

160.

6. The composition of any one of claims 1 to 5, wherein the silicone excipient is present in an amount of about 25 g / L to about 150 g / L, preferably about 75 g / L.

7. The composition comprises: budesonide in an amount of about 0.05 g / L to about 1 g / L; permethrin in an amount of about 10 g / L to about 60 g / L; one or more silicone excipients in an amount of about 25 g / L to about 150 g / L; a pharmaceutically acceptable aqueous carrier, and optionally one or more excipients selected from thickening agents, solubilizing agents, chelating agents, antioxidants, preservatives, and pH adjusters; The composition of claim 1 comprising:

8. The composition comprises: budesonide in an amount of about 0.25 g / L; Permethrin in an amount of about 40 g / L; one or more silicone excipients in an amount of about 75 g / L; a thickener in an amount of about 30 g / L; one or more excipients selected from solubilizing agents, chelating agents, antioxidants, preservatives, and pH adjusters; 1L of purified water, The composition of claim 1 comprising:

9. 9. The composition of claim 8, wherein the silicone is one or more of cyclopentasiloxane, cyclotetrasiloxane, and dimethiconol.

10. 10. The composition of claim 8 or claim 9, wherein the thickening agent is a mixture of Polyquaternium-37, Propylene Glycol Dicaprylate / Dicaprate and PPG-1 Trideceth-6.

11. The composition according to any one of claims 1 to 10, wherein the composition is in the form of a conditioner, a leave-in conditioner, a lotion, a spray, a cream, an ointment or a pour-on formulation.

12. The composition according to any one of claims 1 to 11, wherein the composition is in the form of a leave-in conditioner.

13. The composition according to any one of claims 1 to 11, wherein the composition is suitable for application by pouring or spraying.

14. The composition of any one of claims 1 to 13, wherein the mammal is selected from cattle, pigs, sheep, dogs or horses, preferably the mammal is an equine such as a dog or a horse.

15. 15. The composition of any one of claims 1 to 14, wherein the composition is applied to the coat or skin of the backline, mane area, tail area, midline, ears, head or belly area of ​​an equine animal.

16. The composition of any one of claims 1 to 14, wherein the composition is applied to the rump, dorsal chest, flank, ear, head or perineum of a dog.

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