Pharmaceutical compounds and methods of use

Abstract

The present invention relates to a pharmaceutical composition for topical use comprising a corticosteroid and an insecticide selected from pyrethrins or synthetic pyrethroid-based insecticides. Also described are methods of using the compositions of the invention for the treatment of allergic dermatitis, in particular insect bite hypersensitivity, in an animal.

Description

[0001] This application is a divisional application of the Chinese patent application with an application date of September 23, 2020, application number 202080081346.2, and invention name “Drug Compounds and Methods of Use”.

[0002] This application claims priority to Australian Provisional Application No. 2019903522 filed on September 23, 2019, entitled “Pharmaceutical Compositions and Methods of Use”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to a pharmaceutical composition for topical use comprising a corticosteroid and an insecticide selected from the class of pyrethrins or synthetic pyrethroid insecticides. Methods of using the composition of the invention for treating lesions and itching associated with allergic dermatitis, particularly insect bite hypersensitivity reactions, in animals are also described. Background Art

[0004] Allergic dermatitis caused by insect bites is a common disease in animals. It occurs in areas around the world where animals and their respective parasites coexist and is particularly prevalent in warm climates. Insect bite allergic dermatitis can affect livestock such as sheep, cattle, pigs, horses and dogs. It is particularly prevalent in horses and dogs and is by far the most common cause of skin disease in domestic horses and dogs.

[0005] Allergy is a hypersensitivity reaction or altered state of the immune system that results in self-harm. In the animal population, only a minority are affected. There are four different types of immune responses to allergens. The most common type, and the one primarily associated with the clinical syndrome of hypersensitivity to insect bites, is a type I IgE-mediated immune response, although type III and IV cell-mediated immune pathogenesis may also occur.

[0006] In type I immunopathogenesis, allergen-specific IgE binds to the antigen on mast cells to trigger degranulation, and subsequently releases histamine, serotonin, eotaxin and other cytokines. This results in inflammation and the attraction of other inflammatory cells. For insect bite hypersensitivity, the allergen is mainly a salivary antigen, with 11 species of Culicoides spp. (midges) salivary gland proteins identified as allergens of insect bite hypersensitivity (IBH) in horses (Schaffartzik et al., Veterinary Immunology and Immunopathology 147 (2012) 113-126), and a large amount of Ctenocephalides felis (cat flea) salivary gland proteins identified as allergens in dogs (Lee et al., Veterinary Immunology and Immunopathology 69 (1999) 229-237).

[0007] The degree of stimulation of the IgE response depends on the antigenic characteristics and genetic factors of the affected individual. The insect model demonstrates both the protective and potentially destructive nature of the immune system response, the stimulation of an insect bite can cause the host to react and expel or kill the insect, and under normal circumstances, the immune response may be altered, resulting in weakness, i.e., reduced responsiveness. Alternatively, if the individual is genetically susceptible, a hypersensitivity reaction may develop and lead to persistent inflammation, which is exacerbated and perpetuated by self-trauma caused by rubbing, chewing, and scratching. In addition, the release of histamine and other inflammatory factors such as eicosanoids leads to increased blood flow and vascular permeability at the site of the reaction, resulting in an itch reaction and further damage to the skin through self-trauma. This cycle of itching, scratching, skin damage, and further itching leads to persistent tissue damage and animal suffering.

[0008] Abnormal and persistent hypersensitivity in horses is thought to have a genetic basis. For example, a study of Czech Warmblood horses showed significant differences in distress rates in offspring of specific stallions, ranging from 10% to 75% (Raskova et al., J. Equine Vet. Sci. 2013; 33(6): 427-432), which supports the genetic bias model. In contrast, a genetic link has not been established, nor has a breed bias been determined. (Miller et al., Muller & Kirk's Small Animal Dermatology, 7th ed. St. Louis, MO: Elsevier / Mosby, 2013; 4072013).

[0009] Horses are commonly afflicted with IBH from Culicoides (biting midges). The disease is known as Queensland itch in Australia and sweet itch in the northern hemisphere. While Culicoides is the most common parasite of concern; Tabanus spp. and Chrysops spp. (horse flies), Stomoxys spp. (biting flies), Simulium spp. (black flies), and Musca spp. (house flies), as well as bees and wasps, can all cause lesions and hypersensitivity reactions on the skin of horses.

[0010] In dogs, the most common form of allergic dermatitis caused by insects is flea allergy dermatitis (FAD). Ctenocephalides felis (cat flea) is the primary parasite involved, although C. cams may also be present. The terms "summer itch" or "summer eczema / dermatitis" are also colloquially used for the disease in horses and dogs, as both are seasonal in the summer.

[0011] Clinical signs vary between animal species, however there are similarities in their dorsal distribution and intense pruritus. In horses, Culicoides feed on the dorsal surface, primarily along the mane and tail regions, as well as on the face and around the ears. Even in animals without hypersensitivity, Culicoides bites can be particularly painful due to the chewing mouthparts.

[0012] In dogs, clinical signs associated with FAD include a papular, pruritic dermatitis on the buttocks, dorsal thorax, flanks, tanks, and perineal area. In severe cases, a generalized distribution may occur. Some dogs may develop severe acute lesions such as acral lick granulomas or purulent traumatic dermatitis on one side of the buttocks or face.

[0013] Horses or dogs that progress to the hypersensitivity stage of irritation will have signs ranging from thinning of the hair or coat, papules and wheals to hair loss, crusting, abrasions, hypopigmentation and lichenification. Pruritus often worsens when the skin becomes secondarily infected. Staphylococcal isolates are often implicated in these secondary infections.

[0014] It is well known that both IBH and FAD cause severe pain and distress to affected animals worldwide. Many treatments for this disease have been developed with varying degrees of success and in some cases harmful results. In theory, eliminating all biting insects to which the animal is allergic (i.e., environmental control) will resolve the dermatitis, but in most cases, it is difficult or impossible to achieve this. Therefore, treatment should include minimizing insect bites and managing the itching caused by allergic reactions. To date, there is no single treatment that can address these needs, nor is there a formulation with a practical and reasonable application interval. Current management and treatment modes have several disadvantages.

[0015] Environmental control of Culicoides species is difficult. The life cycle is poorly understood, making environmental control challenging. Development from egg to adult takes several weeks in the summer. Similar to fleas, some larvae and pupae overwinter in protected breeding grounds and continue to develop in warmer weather. These midges breed in moist conditions in a variety of habitats, particularly in wet, muddy areas and in feces and vegetation. Adult midges typically live about 20 days, but can live up to 90 days depending on environmental conditions. Adults fly and mate in groups. Like fleas, female midges require a blood meal to mature their eggs. 100 to 200 eggs are usually laid in areas with a certain humidity and sufficient organic matter. Development from egg to adult usually takes about 15 days, but can take up to 7 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 breeding, however, complete control remains difficult to achieve.

[0016] Environmental control of fleas is easier because all breeding stages occur within the house and yard. Flea bombing and indoor dusting, as well as treating all domestic animals, can provide good results.

[0017] Preventing contact with biting insects is the cornerstone of current treatment options. For example, herding horses into stables at dawn and dusk and using fans at these times will reduce the number of Culicoides approaching the animals. If fans cannot be used, mosquito nets on the windows of the enclosed stable area and the surrounding doors may be helpful. In the summer, it is usually necessary to herd horses into stables between 4 pm and 8 am. In warm climates, such as subtropical to tropical Australia, enclosed stables are not as easy to obtain as in Europe with a more mild climate, where horses may stay in stables for longer periods of time. Many Australian horses are kept on pastures all year round, with only sheltering trees and other open structures to serve as shelter. Blankets ("thick velvet blankets") are often used to prevent contact with midges, but blankets are inappropriate under hot summer conditions. In addition, the blankets are damaged due to friction between horses and fences and trees, requiring frequent and expensive repairs and replacements.

[0018] It is often impractical or impossible to completely eliminate insects from the environment or to provide physical protection against fleas or midges. Chemical repellents can be used to try to prevent insect bites. Natural pyrethroid repellents are extracted from the flowers of certain species of chrysanthemums, especially Chrysanthemum cinerariifolium.

[0019] Insect control products based on synthetic pyrethroids are often used on dogs and horses for their insect repellent activity. These synthetic pyrethroids are more effective, have less odor, last longer, and can be used in lower concentrations than natural pyrethroids (see, e.g., Chemistry Watch fact sheet: https: / / www.beyondpesticides.org / assets / media / documents / mosquito / documents / SyntheticPyrethroids.pdf).

[0020] Type I pyrethroids include allethrin, bifenthrin, permethrin, phenothrin, resmethrin, tefluthrin, and tetramethrin. Type II pyrethroids include cyfluthrin, tri-cyhalothrin, cypermethrin, deltamethrin, cypervalerate, cypromethrin, flucythrin, flumethrin, fluvalinate, and tralomethrin.

[0021] One disadvantage of synthetic pyrethroids is that chemical modifications to the natural pyrethrin structure to increase stability and repellent efficacy often result in an increased irritation potential for the product. Those containing a cyano group are more irritating. This is particularly evident with second generation pyrethroids such as permethrin. To avoid irritation, the concentration of permethrin can be reduced, however this has a negative impact on repellent efficacy. As a result of the need to reduce or avoid irritation, insect control products often do not contain permethrin in high enough concentrations to be effective as an insect repellent. Alternatively, products containing first generation pyrethroid compounds are used which are approximately four times less effective than permethrin and have poorer stability.

[0022] Conventional insecticide treatments for horses include daily use of 40 g / L of permethrin diluted to 2% as a spray or rinse or weekly pouring of 87 g / L of permethrin. The combination of piperonyl butanol and permethrin can be applied to horses or dogs as a spray or rinse twice a day or twice a week. These treatments all have disadvantages, such as frequent use and / or skin irritation. Once a week, pouring 200 g / L cypermethrin on horses can cause irritation. Using 89 g / L citronella oil and 51 g / L N,N-diethyl-M-toluamide twice a day on dogs and horses has poor killing effects on fleas and midges and a short duration of effect. Using a permethrin / citronella combination spray or rinse on dogs or horses every other day has a very short duration of effect. Using a spray or rinse of benzoyl benzoate / bronopol formulation twice a day is used to treat secondary skin infections in dogs and horses. It is not very effective against fleas and mosquitoes; in addition, bronopol is known to cause allergic dermatitis.

[0023] There are several products for treating dogs rather than horses that can be used to ensure that fleas die quickly on the animal. This reduces feeding time and therefore prevents or reduces contact with salivary 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 diffused through the epidermal lipids. These products are often referred to as "precision" treatments and require frequent application, with no bathing for several days before or after application. In some cases the effectiveness of these products decreases as fleas develop resistance.

[0024] Systemic products for treating dogs are also available on the market. These are usually in the form of chewable tablets containing an active ingredient such as spinosad, afoxolaner or flurellaner for a one-month or three-month supply. Like topical precision treatments, they do not act as anthelmintics but require fleas to feed on dogs to ingest the active substance and then die. However, the kill time is relatively rapid. The disadvantage of these products is that they are relatively expensive (Pucheu-Haston et al., Practical Parasitology: The Flea Infested Pet: Overview of Current Products. Today's Vet. Pract. 7:90-95).

[0025] To treat the allergic component of the disease, topical and systemic glucocorticoids are used in dogs. Typically, topical multi-drug creams are used. These typically include a corticosteroid, a local anesthetic, and an antibiotic. The disadvantage of these multi-drug compositions is that they contain an antibiotic component that may not be necessary, leading to potentially inappropriate administration, exacerbating drug resistance.

[0026] Corticosteroid spray products containing, for example, hydrocortisone acetonide dissolved in an ethanol phase are also available. After the corticosteroid spray is applied, the carrier evaporates leaving the active ingredient on the skin. This can sting broken skin and requires careful use to avoid further distressing the animal.

[0027] When flea control is effective, oral prednisolone may be given to dogs. The usual dose is about 1 mg / kg / day, followed by a gradual reduction in the dose. Common side effects of oral prednisolone include panting, lethargy, increased thirst and urination, and increased appetite, all of which can cause concern for the animal and owner. Long-term use of oral prednisolone can lead to symptoms of hypercortisolism, such as abnormal fat metabolism, hair loss, and thinning of the skin.

[0028] Systemic corticosteroids used in horses to address the allergic component of the disease include a short-term (1-2 week) course of oral prednisolone at a dose of 1 mg / kg per day. Alternatively, convenient, but potentially dangerous, long-acting injectable corticosteroids can be used in combination with other therapies until the pruritus is blocked or alleviated. These long-acting injectable corticosteroids, such as triamcinolone acetonide, dexamethasone, and prednisolone acepromazine, often cause increased steroid side effects and continued suppression of the pituitary-hypothalamic-adrenal axis. In addition, 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 internal organ complications.

[0029] H1-antihistamines can be used to reduce the symptoms of insect bite allergic dermatitis, however these drugs do not really have an advantage over glucocorticoids because they have limited effect in reducing itching. In addition, H1-antihistamines have the potential to cause mild sedation in animals and changes in behavior or personality.

[0030] Alternative forms of treatment have been tried, such as attempts at desensitization using immunotherapy, however this appears to cause adverse reactions in horses and dogs (Ginel et al., Vet. Dermatol. 2014; 25:29-e 10).

[0031] Recent approaches to inactivate cytokines using blocking analogs or monoclonal antibodies have shown promise in horses and have been shown to be effective in flea allergy in dogs (Michaels et al., Vet. Dermatol. 2016; 27:478-e 129). The true value for insect bite allergy remains to be assessed. However, this is expected to be an expensive approach in horses given the research investment required because only cytokine blockers are currently available for dogs. In addition, the long-term effects of blocking immune system pathways are unknown.

[0032] Popular and relatively readily available remedies such as shampooing the animal with oatmeal preparations have been used to provide some relief, and other "natural" or acceptable remedies such as calamine lotion have been suggested, although none of them are effective as stand-alone treatments and the benefits are minimal. The use of dietary supplements, such as essential fatty acids, has increased in recent years, but there is limited data available to support its effectiveness. Similarly, traditional or natural remedies such as supplementing the diet with garlic have been suggested for flea control and the management of inflammation, but there is insufficient data to support any actual benefit.

[0033] Clearly, the complexity of insect bite allergic dermatitis, the worldwide prevalence of parasites, and the resulting suffering and reduced quality of life experienced by affected animals, along with owner concern and cost, necessitates the development of a more effective treatment that addresses one or more of the shortcomings of currently available treatments. In particular, there is a need for treatments that are more effective, easy to use, have convenient application intervals, are readily available, or are cost-effective. Summary of the invention

[0034] Advantageously, the inventors have found that a topical composition comprising a combination of a corticosteroid and a pyrethrin insecticide or a pyrethroid insecticide can be used to treat mammalian insect bite allergic dermatitis, or insect bite hypersensitivity. In a preferred embodiment, the composition further comprises one or more than one silicone excipient.

[0035] The topical formulations avoid the need for systemic corticosteroids. Therefore, the compositions are considered safe to use because they have minimal systemic toxicity and side effects. The formulations are convenient and easy to use. In addition, the formulations are fast acting and provide rapid relief to animals suffering from allergic reactions.

[0036] Thus, in a first aspect, there is provided a pharmaceutical composition for topical application comprising, consisting of or consisting essentially of a corticosteroid; an insecticide selected from the group consisting of pyrethrin insecticides and pyrethroid insecticides; and a pharmaceutically acceptable carrier.

[0037] Preferably, the composition is for use on the skin and fur of animals.In a preferred embodiment, the composition further comprises one or more than one silicone.

[0038] In another aspect, a method for treating allergic dermatitis to insect bites in mammals is provided, comprising topically administering to a mammal in need thereof an effective amount of a composition comprising, consisting of, or consisting essentially of a corticosteroid and an insecticide selected from the group consisting of pyrethrin insecticides and pyrethroid insecticides.

[0039] In yet another aspect, a topical composition comprising, consisting of, or consisting essentially of a corticosteroid and an insecticide selected from the group consisting of pyrethrin insecticides and pyrethroid insecticides is provided for use in treating allergic dermatitis to insect bites.

[0040] In another aspect, there is provided a use of a topical composition comprising, consisting of or consisting essentially of a corticosteroid and an insecticide selected from the group consisting of pyrethrin insecticides and pyrethroid insecticides in the manufacture of a medicament for treating allergic dermatitis caused by insect bites.

[0041] In some embodiments, the corticosteroid is budesonide.

[0042] In some embodiments, the insecticide is permethrin.

[0043] In some embodiments, the composition includes 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.

[0044] Preferably the composition is formulated in a matrix comprising one or more than one conditioning excipient, for example one or more than one silicone.

[0045] In some embodiments, the composition comprises one or more than one silicone in a total amount of about 25 g / L to about 150 g / L, such as about 75 g / L, in the composition.

[0046] In some embodiments, the pharmaceutical composition is a conditioner, a leave-in conditioner, a lotion, a spray, a cream, an ointment, or a pour-on formulation.

[0047] In some embodiments, the pharmaceutical formulation is suitable for application by pouring or spraying, preferably onto the skin, fur or hair of an animal. In some embodiments, the composition is applied by rubbing onto the fur of an animal.

[0048] In some embodiments, the mammal is an equine or a canine.

[0049] In yet another aspect, a pharmaceutical composition is provided which is formulated for topical administration, the composition comprising, consisting of, or consisting essentially of:

[0050] A corticosteroid in an amount of about 0.025 g / L to about 1 g / L, or 0.15 g / L to about 1 g / L;

[0051] A pyrethrin insecticide or pyrethroid insecticide in an amount of about 0.5 g / L to about 50 g / L;

[0052] One or more silicones in an amount of about 25 g / L to about 150 g / L;

[0053] at least one pharmaceutically acceptable excipient; and

[0054] A pharmaceutically acceptable aqueous carrier.

[0055] In yet another aspect, a pharmaceutical composition is provided which is formulated as a leave-in conditioner for topical application, the pharmaceutical composition comprising, consisting of, or consisting essentially of:

[0056] Budesonide in an amount of about 0.25 g / L;

[0057] Permethrin in an amount of about 40 g / L;

[0058] One or more silicones in a total content of about 75 g / L;

[0059] A thickener in an amount of about 30 g / L;

[0060] One or more than one pharmaceutically acceptable excipient selected from the group consisting of a solubilizer, a chelating agent, an antioxidant, and a pH adjuster; and

[0061] The pharmaceutically acceptable aqueous carrier is preferably purified water.

[0062] Preferably, the composition is formulated for, or suitable for, application to animal skin, fur, or hair.

[0063] Also provided is a method of treating insect bite allergic dermatitis in mammals by topically applying the pharmaceutical composition described herein, preferably topically applying to the skin, fur or hair of the mammal. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 is a graphical representation showing the mean lesion scores and standard deviations comparing treatment groups in a randomized, controlled clinical study using permethrin and budesonide formulations for the topical treatment of horses allergic to Culicoides. Lesion scores for all treatment groups are shown on Days 0, 21, and 42.

[0065] Figure 2 is a graphical representation showing the pruritus scores for each treatment group in a clinical study using a permethrin and budesonide formulation for the topical treatment of horses allergic to Culicoides. The pruritus scores were measured daily for 42 consecutive days using the Pruritus Visual Analogue Scale.

[0066] Figure 3 A graphic representation summarizing the overall treatment response for each treatment group in the clinical study. A 4-point scale ranging from 1 (poor) to 4 (excellent) was used as a measure of overall improvement, as assessed by the veterinarian on days 21 and 42. DETAILED DESCRIPTION

[0067] definition

[0068] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. Although any methods and materials similar or equivalent to the methods and materials described herein can be used in the practice and testing of the present invention, preferred methods and materials are described herein. For purposes of the present invention, the following terms are defined as follows.

[0069] If an element is not preceded by a quantifier, it means one or more than one (ie, at least one). For example, "an element" means one element or more than one element.

[0070] "About" refers to an amount, level, value, quantity, frequency, percentage, dimension, size, content, weight or length that varies by 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% compared to a reference amount, level, value, quantity, frequency, percentage, dimension, size, content, weight or length. The term "approximately" is interpreted similarly.

[0071] The terms "wt / wt%", "wt / vol%" and "vol / vol%" used herein refer to weight / weight, weight / volume, and volume / volume percentages, respectively. For example, the content unit "g / L" refers to the grams of a component per liter of the composition.

[0072] As used herein, the term "and / or" refers to and encompasses any and all possible combinations of one or more than one of the associated listed items, as well as the absence of combinations when interpreted as alternatives (or).

[0073] Throughout the specification and the appended claims, unless the context requires otherwise, the words "comprise", "include", "contain" will be understood to imply the inclusion of integers or steps or combinations of integers or steps, but not the exclusion of any other integers or steps or combinations of integers or steps. Thus, the use of the terms "comprise" and the like indicates that the listed integers are required or mandatory, but other integers are optional and may or may not be present. "Consisting of" and "consisting of" mean including and are limited to whatever follows the phrases "consisting of" and "consisting of". Thus, the phrases "consisting of" and "consisting of" indicate that the listed elements are required or mandatory and no other elements are present. "Consisting essentially of" and "consisting essentially of" mean including any elements following the phrase and are limited to other elements that do not interfere with or contribute to the activity or action specified by the listed elements in the context. Thus, the phrases "consisting essentially of" and "consisting essentially of" indicate that the listed elements are required or mandatory, but other elements are optional and may or may not be present, depending on whether they affect the activity or action of the listed elements.

[0074] As used herein, the term "topical", such as "topical application", "topical application", "topical medication", "topical preparation" and the like, refers to the application of a composition or preparation to an animal's body surface, such as skin, hair, fur or mucous membrane. In some preferred experimental schemes, the body surface is the skin, hair or fur of an animal.

[0075] The term "corticosteroid" as used herein refers to a steroid anti-inflammatory drug. Suitably, the corticosteroid is suitable for topical application. Preferably, the corticosteroid is a glucocorticoid. Suitably, the glucocorticoid is an approved or registered drug suitable for animal use, selected from, but not limited to, alclomethasone; amcinonide; betamethasone; budesonide; clobetasol; clobetasone; desonide; desoximetasone; diflucortolone; diflorasone; fluocinolone acetonide; flurandrenolide; fluticasone; clofloxacin; ulbetasol; halometasone; hydrocortisone; mometasone; methylprednisolone; prednisolone; and or a salt, solvent and / or any one of the derivatives thereof. In some embodiments, the glucocorticoid is hydrocortisone or budesonide.

[0076] In one embodiment, the glucocorticoid is alclometasone dipropionate; amcinonide; betamethasone dipropionate; betamethasone valerate; budesonide; clobetasol propionate; clobetasone butyrate; desonide; desoximetasone; diflucortolone valerate; diflorasone acetate; fluocinolone acetonide; fluocinolone acetate; flurandrenolide; fluticasone propionate; clofloxacin; halobetasol propionate; halometasone; hydrocortisone; hydrocortisone aceproterone; hydrocortisone butyrate; hydrocortisone-17-butyrate; hydrocortisone valerate; mometasone furoate; methylprednisolone aceproterone; or triamcinolone acetonide. In some embodiments, the glucocorticoid is budesonide.

[0077] The term "pyrethrin" or "pyrethrin insecticide" as used herein refers to natural pyrethrin compounds extracted from the flowers of specific varieties of chrysanthemums, particularly pyrethrum flowers. The potent insecticidal activity of pyrethrins is achieved by affecting the nervous system of insects. However, those skilled in the art will appreciate that the effectiveness of pyrethrin insecticides may be due to their insecticidal and / or anthelmintic properties. Both the insecticidal and anthelmintic effects of pyrethrins are included herein. Examples of natural pyrethrins include pyrethrin I, pyrethrin II, cypermethrin I, cypermethrin II, jasmonate I, and jasmonate II. Natural pyrethrins can be used alone or in combination with two or more natural pyrethrins.

[0078] As used herein, the term "pyrethroids" or "pyrethroid insecticide" refers to synthetic pyrethroid compounds. Pyrethroids are synthetic forms of the natural pyrethrin structure that have been chemically modified to increase stability and insect repellent and / or insecticide effectiveness. Pyrethroid compounds include, but are not limited to, allethrin I, allethrin II, bioallethrin, bifenthrin, permethrin, phenothrin, resmethrin, tefluthrin, and tetramethrin, cyfluthrin, tri-cyhalothrin, cypermethrin, deltamethrin, cypermethrin, cypermethrin, cypermethrin, cypermethrin, cypermethrin, cyfluthrin, cypermethrin, cypermethrin, cypermethrin, and tralomethrin. In some embodiments, the pyrethroid insecticide is permethrin.

[0079] The term "silicone excipient" or "silicone" as used herein refers to siloxanes, including, for example, cyclosiloxanes and polysiloxanes. Silicones are well known in the art and can be readily obtained from commercial sources such as Dow Chemical Company. 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 in order to impart the desired physical properties to the composition. For example, hydroxy-terminated polydimethylsiloxane (polydimethylsiloxane alcohol, poly[oxy(dimethylsilene)], α-hydro-ω-hydroxy-) is a high viscosity siloxane that has emollient properties and can provide a soft, silky feel and conditioning effect to animal fur, hair, or skin. Cyclosiloxanes, such as mixtures of cyclopentasiloxane and cyclotetrasiloxane, provide diffusion and lubrication properties. When used in the compositions described herein, the silicone mixture can provide a conditioning benefit to the skin, coat or hair of an animal.

[0080] The term "insect bite allergic dermatitis" includes a hypersensitivity reaction of the animal skin to insect bites due to specific protein allergens in the insect saliva. Insect bite allergic dermatitis also refers to insect bite hypersensitivity (IBH). The symptoms are usually found in warm areas and can affect many mammalian species, such as domestic mammals including dogs and horses. Typically the insect can be a biting midge or a flea, but it should be understood that the type of insect is not limited to this. Typical insects include, for example, Culicoides and Ctenocephalides, such as Ctenocephalides felis or Ctenocephalides canis. Examples of other biting insects include the genus Cleome, such as Cleome formosanus. It should be understood that the type of biting insect will also vary depending on different factors such as a specific geographical region or climate.

[0081] Insect bite allergy dermatitis in equines is usually caused by Culicoides spp. and is commonly known as Culicoides hypersensitivity allergy. It is also known as seasonal recurrent dermatitis, Queensland itch, or sweet itch. Allergic reactions usually occur on the animal's skin in areas where the insects have fed, such as the bristles, tail, and dorsal midline. Ventral symptoms may also occur. Skin lesions around the ears, face, and head are also common.

[0082] In dogs, typical signs of insect bite allergy dermatitis include papular pruritic dermatitis on the animal's buttocks, dorsal chest, flanks, back of chest, or perineal area. Severe lesions include acral lick granulomas or purulent traumatic dermatitis.

[0083] Symptoms of allergic dermatitis to insect bites include, but are not limited to, dry, cracked or scaly skin; rash; redness; itching, including severe itching; swelling; burning; tenderness; sensitivity; lesions; papules or wheals that may be accompanied by oozing or crusting; hair loss; abrasions; hypopigmentation; or one or more of lichenification. A particularly severe symptom for animals is skin lesions with intense itching. This can cause animals to rub violently and often, and the resulting self-trauma is worrisome. This can cause fur damage, bald patches, and broken, bleeding skin. Secondary infections, such as bacterial or fungal infections, particularly skin infections, can also occur. Common secondary bacterial infections include staphylococcal infections.

[0084] As used herein, the term "derivative" includes chemical modifications to the structure of a corticosteroid molecule. Typical corticosteroid derivatives include derivatives of steroid hydroxyl substituents, such as esters, ethers and ketals, such as cyclic ketals such as acetonides. For example, hydrocortisone can be derived to form esters such as hydrocortisone acepromate, hydrocortisone butyrate, hydrocortisone-17-butyrate or hydrocortisone valerate. The corticosteroid molecule can be derived at one or more than one position.

[0085] Ester derivatives of corticosteroids are well known in the art. Typical ester derivatives of steroid hydroxyl groups, particularly 17- or 21-hydroxyl groups, include acetate, propionate, butyrate, valerate, pivalate, succinate, benzoate, and 2-furoate. Where a corticosteroid has two ester derivatives, examples include diacetate, dipropionate, divalerate, valerate acetate, acetate / propionate (acetopropionate), and butyrate and propionate (butyrate).

[0086] Cyclic ketal derivatives, such as acetone, can be formed by two adjacent hydroxyl groups on the steroid structure, such as the 16- and 17-hydroxy substituents.

[0087] As used herein, the terms "salt" and "solvate" include pharmaceutically acceptable salts or solvates of the active pharmaceutical ingredient. Pharmaceutically acceptable salts are well known in the art.

[0088] Salts of corticosteroids include sodium salts, including sodium salts of derivatives, such as sodium succinate.

[0089] Pharmaceutically acceptable solvates are well known in the art and include hydrates and ethanol compounds. Suitably, pharmaceutically acceptable solvates include hydrates, such as monohydrates, dihydrates and trihydrates.

[0090] Salts, derivatives and solvates can be prepared using methods well known in the art.

[0091] The chemical structure of the corticosteroid or insecticide used according to the present invention may contain asymmetric centers, such as asymmetric carbon atoms. It should be understood that isomers caused by such asymmetry (e.g., all enantiomers, stereoisomers, diastereomers, rotamers or racemates) are included in the scope of the present invention. In the case of no specified stereochemistry, it should be understood that the structure is intended to include any stereoisomers and all mixtures thereof. For example, the corticosteroid budesonide [11β, 21-dihydroxy-16α, 17α-(butylenebis(oxy)pregnant-1,4-diene-3,20-dione, or 1β, 21-dihydroxy-16α, 17α-[butane-1,1-diylbis(oxy)]pregnant-1,4-diene-3,20-dione] has a (22R)- or (22S)- configuration.

[0092] The chemical structures of the corticosteroids or insecticides used according to the present invention include geometric isomers resulting from, for example, the presence of carbon-carbon double bonds. It should be understood that all geometric isomers, such as cis / trans geometric isomers, are included within the scope of the present invention unless otherwise specified. If stereochemistry is not specified, it should be understood that the structure is intended to include any stereoisomers and all mixtures thereof. Permethrin exists as cis or trans isomers or mixtures thereof, for example, permethrin is a mixture of cis:trans 25:75.

[0093] As used herein, the terms "subject," "individual," "mammal," or "animal" refer to a mammalian subject in need of treatment or prevention. In particular embodiments, the subject is a domestic mammal, such as equine animals including, but not limited to, horses, ponies, donkeys, ass, mules; camelid animals including, but limited to, camels, llamas, 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 animal, such as a horse or pony. In some embodiments, the mammal is a goat.

[0094] The terms "alleviate," "treat," "inhibit," or "treating" as used herein encompass treatment of insect bite allergic dermatitis and / or symptoms of insect bite allergic dermatitis, including inhibiting the condition, such as inhibiting its development; alleviating symptoms, such as causing regression of symptoms; or alleviating symptoms caused by the condition due to failure to address the underlying disease or symptoms.

[0095] Unless expressly stated otherwise, each embodiment described herein shall apply mutatis mutandis to every embodiment.

[0096] Compositions of the present invention

[0097] The composition of the present invention is used for treating insect bite allergic dermatitis or symptoms associated with insect bite allergic dermatitis.

[0098] The present invention is based on the surprising discovery of a pharmaceutical composition formulated for topical application that provides an effective and convenient treatment for insect bite allergic dermatitis, the pharmaceutical composition comprising a corticosteroid; an insecticide selected from the class of pyrethrins or pyrethroids; and a pharmaceutically acceptable carrier.

[0099] Pharmaceutical compositions described herein include a combination of an insecticide or insect repellent and a corticosteroid anti-inflammatory. The components are readily available and can 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 primarily metabolized on the skin, with only 0.4 to 0.7% systemic metabolism, thus greatly reducing any potential systemic side effects such as those usually caused by taking systemic corticosteroids. In some embodiments, the topical steroid is a "soft" or "dissociated" steroid. These steroids are androstenone derivative steroids, which have anti-inflammatory effects similar to those of conventional corticosteroids but do not have the potential serious systemic side effects associated with conventional steroids.

[0100] In a preferred embodiment, the corticosteroid is a glucocorticoid suitable for topical application. In some embodiments, the glucocorticoid is selected from a glucocorticoid that is not substantially absorbed by the body when applied to mammalian skin. Preferred glucocorticoids are substantially metabolized on the skin, thereby reducing or greatly reducing any unwanted systemic effects. Suitable glucocorticoid examples 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 acetonide; flurandrenolide; fluticasone; clofloxacin; ulbetasol; halometasone; hydrocortisone; mometasone; methylprednisolone; prednisolone; and or any salt, solvent and / or derivative thereof. In some embodiments, the corticosteroid is hydrocortisone or its salt and / or solvent and / or derivative, such as hydrocortisone acepromazine. In some specific embodiments, the corticosteroid is budesonide or a salt and / or solvent and / or derivative thereof.

[0101] In some embodiments, the insecticide is a natural pyrethrin insecticide such as pyrethrin I, pyrethrin II, cypermethrin I, cypermethrin II, jasmonate I or jasmonate II or a mixture of two or more thereof. Pyrethrins are extracted from the dried flowers of a particular variety of chrysanthemum, particularly pyrethrum, which has been commercially grown in countries such as Kenya. Isolated pyrethrins are readily available from commercial sources.

[0102] In some embodiments, the insecticide is a synthetic pyrethroid insecticide. Synthetic pyrethroid insecticides are well known in the art and are commercially available. It should be understood that the pyrethroid compounds are suitable for the skin of animals. Pyrethroid insecticides include, but are not limited to, allethrin I, allethrin II, bio-allethrin, bifenthrin, permethrin, phenothrin, resmethrin, tefluthrin, and tetramethrin, cyfluthrin, tri-cyhalothrin, cypermethrin, deltamethrin, cypervalerate, cypromethrin, flucythrin, flumethrin, fluvalinate, and tralomethrin. In some embodiments, the pyrethroid insecticide is permethrin. Permethrin exists as cis and trans geometric isomers. In the compositions described herein, permethrin includes a single geometric isomer, or includes two isomers as a mixture. In some embodiments, the permethrin is a mixture of cis and trans isomers in a ratio of 25:75.

[0103] The amount of corticosteroid present in the composition will depend on the type of formulation and mode of application. For example, an ointment, cream, lotion, conditioner, leave-on conditioner, pour-on or spray formulation typically contains an amount of about 0.025 g / L to about 0.5 g / L or about 0.025 g / L to about 1 g / L; about 0.05 g / L to about 0.5 g / L or about 0.05 g / L to about 1 g / L; or about 0.1 g / L to about 0.5 g / L or about 0.05 g / L to about 1 g / L; for example, about 0.05 g / L to about 0.6 or 0.8 g / L, or about 0.1 g / L to about 0.5 g / L; or about 0.15 g / L to about 0.5 g / L; about 0.1 g / L or 0.15 g / L to about 0.4 g / L; about 0.2 g / L to about 0.4 g / L; about 0.1 g / L to about 0.3 g / L; about 0.15 g / L to about 0.5 g / L; about 0.2 g / L to about 0.5 g / L; about 0.15 g / L to about 0.35 g / L; about 0.15 g / L to about 0.45 g / L; about 0.2 g / L to about 0.4 g / L; about 0.25 g / L to about 0.5 g / L; about 0.25 g / L to about 0.4 g / L; about 0.2 g / L to about 0.3 g / L; especially about 0.25 g / L of corticosteroid. It should be understood that if the application of the composition involves rinsing, such as a shampoo or cleaning preparation, a higher concentration of corticosteroid may be required.

[0104] The amount of insecticide present in the composition will depend on the type of formulation and the mode of application. The formulation typically contains a 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 a 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 should be understood that if the application of the composition involves rinsing, such as a shampoo or cleaning formulation, a higher concentration of insecticide may be required.

[0105] In some embodiments, the content of the corticosteroid in the composition of the present invention is about 0.0025% w / w to about 0.1% w / w. In some embodiments, the content of the corticosteroid is about 0.005% w / w to about 0.1% w / w; about 0.0075% w / w to about 0.1% w / w; about 0.01% w / w to about 0.075% w / w; about 0.01% w / w to about 0.05% w / w; about 0.02% w / w to about 0.04% w / w; about 0.02% w / w to about 0.3% w / w; or about 0.025% w / w. In some embodiments, the corticosteroid is present in an amount of 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; and particularly about 0.025% w / w.

[0106] In some embodiments, the insecticide content in the composition of the present invention is about 0.05% w / w to about 5.0% w / w. In some embodiments, the corticosteroid content is about 0.1% w / w to about 4.5% w / w; about 0.15% w / w to about 4% w / w; about 0.2% w / w to about 4% w / w; about 0.5% w / w to about 4.5% w / w; about 1% w / w to about 4% w / w; about 2% w / w to about 4.5% w / w; or about 4% w / w.

[0107] In some embodiments, the weight ratio of corticosteroid to pyrethrin or pyrethroid insecticide is about 1:100 to about 1:200, such as about 1:125 to about 1:175 or about 1:140 to about 1:170. In some embodiments, the weight ratio of corticosteroid to pyrethrin or pyrethroid insecticide is 1:160.

[0108] When the composition of the present invention includes one or more than one silicone, it should be understood that the content of the silicone component will depend on the form of the formulation and the mode of application. In some compositions described herein, such as lotions or leave-in conditioners, the total content ratio of API (insecticide and corticosteroid) to silicone is about 1:2 to 2:1 or about 1:2 to 3:2, such as about 40:70 or 41:75.

[0109] In the simplest form, the composition of the present invention comprises a corticosteroid; an insecticide selected from pyrethroid insecticides and pyrethroid insecticides; and a pharmaceutically acceptable carrier. Those skilled in the art will appreciate that the composition may also comprise other pharmaceutically acceptable additives, such as surfactants, emulsifiers, rheology or viscosity modifiers, solvents or solubilizers, buffers, pH modifiers, diluents, dispersants, chelating agents, preservatives, antioxidants, stabilizers, tonicity agents, humectants, thickeners and excipients.

[0110] Preferably the composition comprises one or more than one silicone as conditioning excipient.

[0111] The inventors have found that compositions of the present invention that also include one or more than one silicone are particularly advantageous. Silicones provide properties such as film-forming properties, anti-rinsing and diffusion properties to the composition. Silicones can also provide soothing and emollient properties and can therefore provide a soothing effect on the skin, or provide a conditioning effect on the skin, fur or hair of an animal. In some embodiments, one or more than one silicone present in the composition 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, thereby forming a hydrophobic barrier (e.g., see, https: / / luisafanzani.com / what-is-dimethicone / ).

[0112] Thus, in another aspect, the present invention advantageously provides a pharmaceutical composition for topical application comprising, consisting of or consisting essentially of:

[0113] Corticosteroids;

[0114] Pyrethrin insecticides or pyrethroid insecticides;

[0115] One or more silicones; and

[0116] a pharmaceutically acceptable aqueous carrier; and optionally

[0117] One or more than one pharmaceutically acceptable excipients.

[0118] In some embodiments, the one or more than one silicone is present in the composition in an amount of about 25 g / L to about 150 g / L, such as 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.

[0119] In some preferred embodiments, the composition containing silicone is configured as a conditioner, a leave-in conditioner or a lotion. Suitably, the composition is packaged in a pump dispenser for releasing a predetermined amount of the composition upon each activation. In some embodiments, the composition of the present invention is a leave-in conditioner formulation, also referred to as a leave-in conditioner, applied to the skin, fur or hair of an animal, which contains one or more than one silicone.

[0120] Those skilled in the art will appreciate that the physical properties of silicones will vary depending on their chemical structure and will be able to select a suitable silicone depending on the desired final properties of the composition. Suitable silicones are well known in the art and one or more than one silicone may be selected to impart properties such as increased or decreased viscosity, film-forming properties, resistance to washing, diffusion, volatility or penetration to the composition. The amount and type of silicone present in the composition of the present invention will be adjusted depending on the needs of the animal and will depend on the species, e.g. dog or horse. It will be understood that factors such as the type of animal, the state and duration of the disease, the length of the coat, the oiliness and general condition of the skin or hair may be considered when making the composition.

[0121] In some embodiments, the composition includes one or more than one silicone selected from cyclopentasiloxane, cyclotetrasiloxane and terminal hydroxyl polydimethylsiloxane. In some embodiments, two or more silicones can be incorporated into the composition of the present invention to impart desired physical properties to the composition. In some examples, the composition includes cyclopentasiloxane, cyclotetrasiloxane and terminal hydroxyl polydimethylsiloxane. Suitable silicones and silicone mixtures are readily available from commercial sources. Xiameter silicones include ® PMX-0344 or Xiameter ® An example of PMX-1401 is available from The Dow Chemical Company. ® PMX-0344 is a cyclosiloxane mixture including cyclopentasiloxane and cyclotetrasiloxane. This silicone mixture can be used as a base fluid and has good spreading and lubricating properties as well as unique volatility characteristics. Xiameter ® PMX-1401 is a 13% solution of a blend of dimethiconol (hydroxyl-terminated dimethicone) in cyclopentasiloxane and cyclotetrasiloxane. The hydroxyl-terminated dimethicone acts as an emollient and thus provides a soft feel to the skin and conditions the hair and coat.

[0122] Dimethicone is a high viscosity polysiloxane silicone. In some embodiments of the present invention, dimethicone is present in the composition of the present invention in an amount of about 0.5 g / L to 3 g / L; for example, about 1 g / L to 2.5 g / L; or about 2 g / L; or about 1.95 g / L.

[0123] The cyclosiloxane including the mixture of cyclopentasiloxane and cyclotetrasiloxane is present in the composition in an amount of about 25 g / L to about 125 g / L; for example, about 50 g / L to about 100 g / L; 60 g / L to about 80 g / L; or about 70 g / L to 75 g / L; for example, about 73%.

[0124] In yet another aspect, there is provided a pharmaceutical composition formulated for topical administration comprising, consisting of, or consisting essentially of:

[0125] A corticosteroid in an amount of about 0.025 g / L to about 1 g / L,

[0126] A pyrethrin insecticide or pyrethroid insecticide in an amount of about 0.5 g / L to about 50 g / L;

[0127] The one or more than one corticosteroid is present in an amount of about 25 g / L to about 150 g / L, such as about 50 g / L to about 100 g / L.

[0128] At least one polysiloxane, such as dimethiconol, is present in an amount of about 1 g / L to about 3 g / L, such as about 2 g / L.

[0129] at least one pharmaceutically acceptable excipient; and

[0130] A pharmaceutically acceptable aqueous carrier.

[0131] Topical application of the present invention can be carried out by any formulation suitable for delivering the active ingredient to the skin or fur of an animal. Topical formulations are well known in the art and are described herein, for example, by 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, such as water, such as purified water.

[0132] In some embodiments, the composition is a liquid such as an aqueous liquid or an aqueous solution. The liquid can be applied to the fur or skin of the animal by any suitable method, such as lavage, drenching, soaking, spraying, aerosol, pouring, or backliner. The liquid can be a ready-to-use preparation or can be provided as a concentrated solution to be diluted with an aqueous diluent such as water. The concentration of the composition depends on the target method of application. For example, the composition used for spraying, immersion, drenching, lavage or pouring is lower than the composition concentration of pouring or spraying. Backliner can be a ready-to-use liquid preparation, which is applied to animals, such as cattle, sheep, pigs or horses, by pouring along the midline of the neck to the tail. In some embodiments, the composition can be formulated as a spray for application by spraying, such as delivered by triggering a spray bottle. Other suitable application methods are well known in the art, such as wet gauze, swabs, cotton, foam, sponge or cloth. In some examples, the composition can be applied to the skin or fur by hand.

[0133] In some embodiments, the composition of the present invention is a cream or lotion. Creams are semisolid multiphase compositions containing active ingredients, in this case corticosteroids and insecticides, each dissolved in a suitable matrix. Creams include water-in-oil or oil-in-water emulsions, or aqueous microcrystalline dispersions of long-chain fatty acids or alcohols, and generally have relatively soft, spreadable properties.

[0134] In some preferred embodiments, the composition is in the form of a lotion. Lotions and creams have many common properties and are generally viscous emulsions, solutions or suspensions. Typically they contain an aqueous carrier and more than 50% water and volatile ingredients. Aqueous lotions are easy to use and easy to remove. They can act as an emollient and can leave a cool or soothing feeling on the animal's skin.

[0135] In some embodiments, when the composition is topically applied to the skin having hair, the composition is in the form of a shampoo or hair conditioner. Hair conditioners, such as hair conditioners, are well known in the art of hair care. Such hair conditioner formulations are particularly useful for application to hairy parts of the animal's body.

[0136] The inventors have found that hair care compositions are useful formulations of the compositions of the present invention. The inventors have also found that compositions of the present invention that are formulated as leave-in (no-rinse) conditioners are particularly advantageous. Leave-in conditioners are hair care products that can be applied to animal hair, skin or fur. Leave-in conditioners typically include silicones. Such conditioner formulation bases and excipients are well known and described, for example, in Barel et al., Handbook of Cosmetic Science and Technology, Third Edition, 2009. CRC Press. page 687.

[0137] The silicone present in the leave-in conditioner of the present invention provides a hair care and skin moisturizing effect by providing hydrophobicity by forming a residual film or barrier on the animal's fur. The leave-in conditioner can penetrate the fur and cover the hair with a residual film of the drug. The leave-in conditioner of the present invention exhibits several advantages over other forms of topical application. For example, the application of spray formulations can cause animals, especially horses, who are already suffering, to become frightened or nervous. Semi-solid formulations such as creams require massage to allow the drug to penetrate the fur. Massaging sensitive skin is usually resisted by the animal and the massage action causes the fur to curl and also prevents the proper diffusion and application of the cream.

[0138] Leave-in conditioner formulations are lighter and less viscous than standard conditioners and form a thin residual layer on the animal's coat, hair or skin. In the simplest form, a leave-in conditioner can be used to restore lost moisture to the skin and hair. In the compositions of the present invention, in addition to treating the symptoms of IBH, the leave-in conditioner provides a coat conditioning and / or skin moisturizing effect by providing hydrophobicity. This is advantageous because skin damage exposed to water can increase the pain suffered by the animal. The conditioner can be applied to the animal's coat at any time, but is preferably applied to the animal's coat after it has been freshly cleaned. The coat can be dry, damp or wet, but preferably the animal's coat is damp.

[0139] The leave-in conditioner formulations of the present invention can be easily and quickly applied and reduce the level of discomfort and stress to the animal. They can provide rapid relief. They are cost-effective and long-lasting, so frequent reapplication is not required.

[0140] The lotion and leave-in conditioner are suitable for dispensing from a pump dispenser, which is suitable for dispensing a predetermined dose or amount of the composition. In some examples, the pump dispenses about 1.6 mL or 1.5 g of lotion or leave-in conditioner each time it is activated.

[0141] Compositions of the present invention are prepared by conventional methods well known in the art. Usually the required ingredients are measured by weight or volume as appropriate, and in suitable containers, mixing techniques such as grinding, blending, shear mixing or homogenization are used to form a substantially homogeneous mixture. Those skilled in the art will be able to determine the most suitable mixing techniques and containers according to the batch size and physical form of the starting material and the final composition. Preferably, the pesticide and corticosteroid, carrier and excipient are combined in a homogenizing apparatus. If desired or required, the selection of additional excipients fully belongs to the technical staff's knowledge, and will depend on the type of the required composition and the consideration of physical form.

[0142] The composition is formulated as a composition suitable or adapted for topical application. Preferably, the pharmaceutical composition is an aqueous preparation. It should be understood that any carriers and excipients used must be "acceptable", i.e., compatible with the other ingredients of the composition and harmless to the recipient thereof. In some embodiments, the aqueous carrier is purified water. It should be understood that the composition for topical application should have a physiologically acceptable pH. Preferably, the final pH of the composition is 3.5 to 4.5.

[0143] The pharmaceutical compositions of the present invention, or the compositions used in the methods of the present invention, are prepared and administered using methods well known in the art. The techniques for making and administering can be found in, for example, Remington: The Science and Practice of Pharmacy, Loyd V. Allen, Jr (Ed), The Pharmaceutical Press, London, 22nd Edition, September 2012.

[0144] It should be understood that it may be useful to incorporate one or more than one pharmaceutically acceptable excipient into the composition. Excipients for aqueous compositions include, but are not limited to, buffers, stabilizers, chelating agents, tonicity agents, humectants, antioxidants, thickeners, solubilizers, viscosity modifiers, rheology modifiers, and preservatives. Suitable excipients are well known in the art and readily available from commercial sources. Preferably, pharmaceutical grade excipients, such as USP or BP grade. Pharmaceutical excipients are described in, for example, Handbook of Pharmaceutical Excipients, Paul J. Sheskey et al., The Pharmaceutical Press, London, Eighth Edition, August 2017. It should be understood that determining whether a particular grade of excipient is needed, and selecting an appropriate excipient will be entirely within the skill and knowledge of those skilled in the art. It will also be recognized that the excipient must be chemically inert relative to the other components in the composition. The concentration of any particular excipient will vary depending on its properties and the skilled artisan will be able to readily select the appropriate excipient and determine the necessary content without undue burden or creative effort.

[0145] For example, the excipient includes one or more than one pH adjusting agent or buffer to adjust the pH of the composition to a physiologically acceptable pH or to maintain the pH of the composition at a physiologically acceptable pH. Suitable buffers are well known in the art. Suitable pH adjusting agents include acids, such as hydrochloric acid; or alkalis or alkali metals, such as sodium hydroxide or potassium hydroxide.

[0146] In some embodiments, when preparing compositions as described herein, it is beneficial to dissolve certain components. For example, it should be understood that in the preparation process of pharmaceutical compositions as described herein, it may be useful to dissolve corticosteroids or pesticides in non-aqueous solvents before or at the same time as the non-aqueous solvent is added to the aqueous. Suitable solvents, cosolvents or solubilizers for organic APIs, such as corticosteroids and pesticides are well known in the art. The technician will be able to easily determine whether a solvent / solubilizer is needed or necessary. The selection of a specific solubilizer or solvent, or the grade of a solubilizer or solvent, and the determination of the solubilizer or solvent content are completely within the skill and knowledge of those skilled in the art. In some embodiments, the solubilizer includes oleoyl macrogel-6 glycerides. In some embodiments, the solubilizer includes N-methylpyrrolidone (NMP), propylene glycol, or 2-(2-ethoxyethoxy) ethanol. It should be understood that the content and selection of the required solubilizer will depend on the solubility characteristics of the corticosteroid and the pesticide and their concentration in the aqueous composition. A person skilled in the art can easily determine this without creative investment based on common knowledge and the examples herein. The content of solubilizer present in the composition of the present invention is, for example, from about 100 g / L to about 200 g / L; or about 150 g / L or about 130 g / L.

[0147] Surfactants, such as nonionic water-dispersible surfactants, are well known in the art of pharmaceutical formulations. These are soluble and increase the bioavailability of poorly water-soluble active pharmaceutical ingredients (corticosteroids and insecticides). They can also act as co-emulsifiers in topical formulations to increase the stability of the emulsion. Examples of nonionic water-dispersible surfactants are Labrafil ® Oleic acid macrogol glycerides of M 1944. Such surfactants may be present in the composition of the invention in a concentration of about 10 g / L to about 30 g / L, such as about 20 g / L.

[0148] Those skilled in the art will also recognize that thickeners, rheology modifiers or viscosity modifiers can be incorporated into the composition to adjust the viscosity or rheological properties for topical application. Suitable thickeners are well known in the art and include cellulose derivatives such as hydroxypropyl methylcellulose, carboxymethyl cellulose, natural gums such as sodium alginate, xanthan gum, agar or carrageenan; pectin; and gelatin. If present, the amount of thickener in the composition of the present invention will depend on the desired properties.

[0149] Thickeners, stabilizers and emulsifiers for products formulated as lotions or leave-on conditioners are well known in the art. These excipients are useful because they can provide a favorable matrix for the compositions of the present invention, which can condition animal coats or condition or relieve animal skin. In a preferred embodiment, the compositions of the present invention comprise one or more excipients selected from thickeners, stabilizers and emulsifiers. Excipients for formulation into cosmetics, hair care products, personal care products and pharmaceutical compositions are well known. One such excipient is a commercially available thickener / stabilizer / emulsifier combination, which includes Salcare® as a combination of thickeners / stabilizers and emulsifiers. ® SC96 is commercially available from BASF as polyquaternium-37, propylene glycol dicaprylate and PPG-1 trideceth-6. In some preferred embodiments, the composition comprises one or more than one hair conditioner excipient. In some embodiments, the thickener / stabilizer / emulsifier is present in an amount of about 10 g / L to about 60 g / L, such as about 20 g / L to about 40 g / L, or about 30 g / L.

[0150] 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 the class of pyrethrins or pyrethroids in an amount of about 0.5 g / L to about 60 g / L; and a thickener, stabilizer, and emulsifier in an amount of about 10 g / L to about 60 g / L in total; a pharmaceutically acceptable carrier; and optionally one or more than one silicone in an amount of about 25 g / L to about 150 g / L in total.

[0151] In a preferred embodiment, the composition comprises one or more than one silicone and one or more than one thickener. In some embodiments, the content ratio of silicone to thickener is about 4:1 to 3:2, or 3:1 to 2:1; for example, about 75:30. The total content of thickener and silicone in the composition is generally about 10% to 12% of the total weight of the formulation. In some embodiments, the total content of silicone and thickener in the formulation is 100 g / L to 200 g / L.

[0152] The skilled person will recognize that the compositions of the present invention may be susceptible to microbial contamination or physical or chemical degradation, and therefore a preservative may be incorporated into the composition to reduce or avoid its degradation or alteration. Suitable preservatives and antioxidants are well known in the art, and the selection of a particular preservative or antioxidant and the determination of the desired content are within the skill and knowledge of those skilled in the art. In some embodiments, the antioxidant is butylated hydroxytoluene, for example, in an amount of about 0.2 g / L to about 1 g / L, for example 0.5 g / L. Preservatives are well known in the art and include one or more than one of propylene glycol, diimidazole lidinyl urea, and parabens such as methylparaben and propylparaben. The preservative is typically present in an amount of about 5 g / L to about 15 g / L, for example about 10 g / L, in the compositions as described herein. Preservatives for pharmaceutical and personal care formulations are generally available. An example is Germaben II ® A commercially available mixture of propylene glycol, diazolidinyl urea, methylparaben and propylparaben.

[0153] The composition of the present invention may also include one or more than one stabilizer. Examples of stabilizers include chelating agents such as disodium ethylenediaminetetraacetic acid dihydrate. The amount of stabilizer used will depend on the circumstances, for example, a content of about 0.5 g / L to about 2 g / L, such as about 1 g / L, is contemplated.

[0154] In a specific embodiment, the present invention provides a leave-in conditioner formulation comprising, consisting of, or consisting essentially of:

[0155] Budesonide: about 0.25 g / L;

[0156] Permethrin: about 40 g / L;

[0157] Silicone, for example, one or more than one of cyclopentasiloxane, cyclotetrasiloxane and hydroxy-terminated polydimethylsiloxane in a total content of about 75 g / L.

[0158] Thickeners, such as a mixture of Polyquaternium-37 / propylene glycol dicaprylate / PPG-1 Trideceth-6 at a level of about 30 g / L;

[0159] Oleic acid macrogol glyceride: about 20 g / L;

[0160] N-methylpyrrolidone: about 50 g / L;

[0161] Propylene glycol: about 30g / L

[0162] 2-(2-ethoxyethoxy)ethanol: about 50g / L.

[0163] One or more than one pharmaceutically acceptable excipient selected from chelating agents, stabilizers, antioxidants, preservatives and pH adjusters; and

[0164] Purified water (make up to 1000 mL).

[0165] In some preferred embodiments, the silicone includes cyclosiloxane, for example, one or more of cyclopentasiloxane and cyclotetrasiloxane in an amount of about 73 g / L; and a total amount of about 2 g / L or 1.95 g / L of hydroxy-terminated polydimethylsiloxane.

[0166] If desired, the compositions of the present invention may also include one or more than one physiologically active agent. Preferably, any additional physiologically active agent may be formulated as a topical preparation. Additional therapeutically active ingredients include antibodies. Other therapeutically active ingredients include analgesics, anti-inflammatory or analgesics.

[0167] Invention Method

[0168] The composition is used for treating allergic dermatitis caused by insect bites.

[0169] Thus, provided is a method for treating insect bite allergic dermatitis or symptoms thereof in a mammal, comprising administering to the mammal an effective amount of the composition of the present invention.

[0170] Preferably, the mammal is selected from cattle, pigs, sheep, dogs and equines. In some embodiments, the mammal is a dog. In some embodiments, the mammal is an equine, such as a horse or a pony. In some embodiments, the mammal is a goat.

[0171] In another aspect, provided herein is a pharmaceutical composition for treating allergic dermatitis to insect bites or its symptoms. Also provided is a pharmaceutical composition as described herein for treatment. The pharmaceutical composition as described herein can also be used to prepare a medicament for treating allergic dermatitis to insect bites or its symptoms.

[0172] The compositions of the present invention are primarily intended for topical application to the skin, coat or hair of an animal, although other modes of administration are contemplated. In the methods or uses described herein, the compositions of the present invention are delivered topically.

[0173] It should be understood that the composition of the present invention will be most effective when applied to the skin, especially in areas commonly affected by insect bite allergic dermatitis. Queensland itch lesions are consistent with the sites where insects prefer to feed. For equines, the composition is usually applied to the fur or skin of one or more of the backline, bristle area, tail area, ear, head, dorsal midline or ventral area of ​​the equines as needed. In some examples, the composition is appropriately applied to the back area, such as one or more of the forehead, scalp, ear, neck, cervical spine, withers, shoulders or buttocks as needed. For dogs, the composition is usually applied to the dog's buttocks, dorsal chest, flanks, chest back or perineum.

[0174] In some embodiments, the composition of the present invention is applied to the animal's coat by hand using circular motions.

[0175] It will be appreciated that the compositions as described herein may be more effective if applied to a clean animal coat. When using a leave-in conditioner, pour-on formulation, spray formulation or lotion, preferably the animal's coat is fresh, clean and damp.

[0176] It should be understood that the extent to which a single dose of the composition spreads on an animal is different. When the formulation described herein is applied to the fur, it will disperse in the hair before reaching the skin. Depending on the type of animal, for example, dogs, horses, this degree of spreading is different. The extent of spreading also depends on factors such as hair length; fur density; hair structure (rough / fine); the amount of sebum / scales on the skin surface and the oiliness of the fur. In addition, the fur density is different in different parts of the body, with finer fur at the shoulders and higher fur density in the buttocks, tail and mane areas. Therefore, depending on the situation, it should be understood that the product can be diluted according to the application method. It should be understood that it may be necessary to adjust the amount and type of excipients present in the formulation and the amount of carrier to achieve the optimal skin delivery effect. For example, the spray can be diluted with water.

[0177] The composition of the present invention can use any amount effective for inhibiting or treating allergic dermatitis caused by insect bites. The term "effective amount" used herein refers to a concentration that can provide the desired therapeutic activity for the condition when applied according to the desired application regimen. Usually, the interval between applications is hours, days, weeks or months. It is considered sufficient to use the composition of the present invention once a week. The therapeutically effective amount or the treatment effective amount is the content of the composition, which is a concentration that is sufficient to at least partially achieve the desired therapeutic effect, or delay the onset of the disease or inhibit the progression of the disease, or partially or completely stop the onset or progression of the disease when applied according to the desired application regimen. The preventive concentration of the composition is a concentration that is sufficient to at least partially prevent the onset of the disease when applied according to the desired application regimen.

[0178] The dosage and frequency of administration of the composition will depend on the requirements of the particular mammal in need of treatment. The appropriate dosage and administration regimen is determined by a veterinarian and may depend on the severity of the condition and the general age, health and weight of the mammal in need of treatment.

[0179] In some examples, each about 1 g or about 1.5 g (about 1.5 mL, such as 1.6 mL) of the lotion or leave-in conditioner prepared according to the present invention can cover about 0.025 to 0.03 M 2 mammalian skin. In some embodiments, the pump dispenses about 1.6 mL of lotion or leave-in conditioner per actuation. When applied by hand to the animal's fur, this typically covers 0.025 mL of 2 (About one palm). In some embodiments of the invention, it contains 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.

[0180] In some embodiments of the invention, the composition is applied about once a week.

[0181] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It should be understood that the invention includes all such variations and modifications that fall within the spirit and scope thereof.

[0182] In order that the present invention may be more readily understood and put into practical effect, particularly preferred embodiments will now be described by way of the following non-limiting examples. Example

[0183] The composition of the present invention can be prepared using commercially available active pharmaceutical ingredients, carriers and excipients. The composition can be prepared using conventional methods for preparing pharmaceutical preparations using conventional mixing equipment, such as a blender, mixer or homogenizer.

[0184] Example 1

[0185] Preparation of pharmaceutical compositions (IVP)

[0186] The following commercially available ingredients were mixed in a homogenizer.

[0187] Budesonide [corticosteroid; 0.25 g];

[0188] Permethrin [insecticide; 25:75 cis:trans; 40g];

[0189] Cyclotetrasiloxane / Cyclopentasiloxane Mixture (Xiameter ® PMX-0344) [Silicone excipient / modifier; 60 g];

[0190] 13% solution of hydroxy-terminated polydimethylsiloxane in cyclopentasiloxane and cyclotetrasiloxane (Xiameter ® PMX-1401) [viscous silicone conditioner, 15g];

[0191] Polyquaternium-37 / propylene glycol dicaprylate / PPG-1 trideceth-6 (Salcare ® SC96) [thickener; 30 g];

[0192] Oleic acid macrogol glyceride (Labrafil ® M 1944) [solubilizer, surfactant; 20 g];

[0193] Disodium EDTA dihydrate [chelating agent; 1g];

[0194] N-methylpyrrolidone [solubilizer; 50 g];

[0195] Propylene glycol [solubilizer; 30g];

[0196] 2-(2-ethoxyethoxy)ethanol [solubilizer; 50 g];

[0197] Butylated hydroxytoluene [antioxidant; 0.5 g];

[0198] Propylene glycol / diazolidinyl urea / methylparaben / propylparaben (Germaben II) [preservative, 10 g];

[0199] Purified water [up to 1000 g];

[0200] pH adjuster (hydrochloric acid, sodium hydroxide), adjust to pH 3.5-4.5.

[0201] The formulated composition, referred to as CP or Example 1 formulation, is suitable as a leave-in conditioner formulation. It is added to a pump dispenser and dispenses a predetermined volume of the composition upon each actuation. The pump typically dispenses 1.5 g or about 1.6 mL of the composition upon each actuation.

[0202] Example 2

[0203] Effect research

[0204] Clinical studies were conducted using the formulation of Example 1 in horses suffering from Culicoides pruritus. Therefore, horses suffering from midge allergy were treated topically in a blinded experiment conducted in accordance with the GCP International Cooperation on Technical Requirements for Registration of Veterinary Medicinal Products (VICH) Guidelines of 15 June 20009'. This randomized, placebo-controlled study investigated the efficacy of a leave-in conditioner containing budesonide and permethrin of Example 1 (CP) intended for the treatment of Culicoides hypersensitivity (Queensland itch, sweet itch, QI) in horses. CP has two active ingredients, budesonide (a steroid that relieves pruritus and allergic reactions) and permethrin (an anthelmintic). Horses were treated with a commercial product (CP), a placebo (control, containing only excipients, PL) and three comparator products with different levels of active ingredients. The low budesonide group (LB) contained less budesonide than the commercial product, but the permethrin content was the same. The budesonide only group (BO) and the permethrin only group (PO) contained only a single active ingredient at the same content as CP to show the effect of a single active ingredient.

[0205] Data from 51 horses naturally suffering from Queensland itch (10 horses per group, and the other 11 only using budesonide) were collected and analyzed. The skin of each horse received 40 doses (about 60 grams) of the drug every week for 6 weeks. The veterinarian applied each dose in the area where QI usually occurs, such as the face, head, neck, flanks and back. The veterinarian evaluated the horses on the 0th day, the 21st day and the 42nd day, and the owner measured the itch score and the quality of life score. GraphPadPrism 8 software was used for statistical analysis. Nonparametric one-way analysis of variance (Kruskal-Wallis test with Dunn's multiple comparisons) was used.

[0206] Lesion Scoring: Lesion scores were calculated from four different areas, abrasions, scaling and crusting, hair loss and papules. These are the most common types of lesions in horses suffering from Queensland itch. Scores were calculated at 8 different sites in the horse. At each of the 8 sites, the severity of each symptom was rated from 0 (none) to 5 (severe). The total lesion score was calculated by (severity) x (number of symptoms) x (location), resulting in a maximum possible score of 160. Scores were determined for each horse on Day 0, Day 21 and Day 42. Figure 1 Lesion scores are shown for all treatment groups at Day 0, Day 21, and Day 42 (endpoint of the study).

[0207] Total lesion scores (maximum score of 160) were similar between groups at baseline (p=0.6259). Only the CP group (p=0.0012) and only the CP and PO groups were significantly different from placebo at Day 21 (p values ​​were 0.0003 and 0.0366, respectively) and Day 42. Multiple comparisons revealed no other differences between treatment groups.

[0208] Pruritus Scores: Pruritus scores were measured daily for 42 consecutive days by the owner using the Pruritus Visual Analogue Scale (VAS), which is a scale of 0-10 based on different itch indicators in horses. On Day 0, there was no difference between treatment groups (p=0.3360). On Day 42, only the CP group was statistically significantly different from placebo (p=0.0483). Results are shown in Figure 2 middle.

[0209] Overall Treatment Response: The overall treatment response score was categorized as 1 (poor) to 4 (excellent) and was used as a measure of overall improvement as assessed by the veterinarian on days 21 and 42. A total of 70% of horses in the CP group showed a good response on days 21 and 42. Only the CP group was statistically significantly different from the placebo control group on days 21 and 42 (p=0.0019). Figure 3 ).

[0210] Summary: The following table (Table 1) shows the main outcome measures, namely lesion score, pruritus score, quality of life and overall treatment response (treatment effect).

[0211] Table 1

[0212] .

[0213] These data show that CP was the only treatment that was statistically significantly different from placebo in all measured outcomes. These data indicate that the formulation of Example 1 (CP) significantly reduced lesion scores, pruritus scores, and overall treatment response and improved quality of life.

[0214] Sleep data was collected in the horses using activity trackers to track their activity. Sleep data was calculated from the time the horses remained motionless (in minutes). It was observed that the horses in the CP treatment group generally got more time to rest than the horses in the other treatment groups. The horses in the placebo / control treatment group had the least time to rest. These data support that the horses treated with the CP composition were less restful and got more sleep or rest.

[0215] After the initial study, 42 horse owners continued in a second phase of the trial, where they used the product for a year, as needed. Results showed that most owners used doses far below the full dose and only used it occasionally. No significant side effects were found in these cases.

[0216] Animal safety studies were conducted on healthy horses using 1x, 3x and 5x recommended doses for 6 weeks and 1x dose for 12 weeks. No abnormalities were detected in the blood or skin (biopsy) after using the full dose or 5x full dose for 6 weeks. Therefore, the product is safe to use.

[0217] These data indicate that the formulation of the present invention can be used to treat the symptoms of IBH or Queensland itch. It was observed that at least one symptom (including abrasions, scaling and crusting, hair loss and papules) was rapidly alleviated and the overall treatment effect was considered beneficial. Itching and distress in the horses were significantly reduced. The health of the affected animals was observed to be improved with no or very minor side effects. It is considered to be an effective and safe treatment method that can work within a reasonable time frame. It only needs to be used once a week and there are no complications common to systemic corticosteroids. Therefore, the formulation of the present invention is believed to be useful for treating animals suffering from IBH that are particularly painful, painful and tormented.

[0218] The disclosures of each patent, patent application, and publication cited herein are incorporated by reference in their entirety.

[0219] The citation of any reference herein should not be construed as an admission that such reference is available as "prior art" to the present application.

[0220] The purpose of this specification is to describe the preferred embodiments of the present invention rather than to limit the present invention to any one embodiment or specific feature set. Those skilled in the art will appreciate that, based on this disclosure, various modifications and changes may be made to the specific embodiments of the examples without departing from the scope of the present invention. All such modifications and changes are intended to be included in the appended claims.

Claims

1. Use of budesonide; an insecticide selected from pyrethrin insecticides and pyrethroid insecticides; a silicone excipient and a pharmaceutically acceptable carrier in the preparation of a medicament for treating allergic dermatitis caused by insect bites in mammals, wherein the medicament is for topical application to mammals.

2. The use according to claim 1, wherein the silicone excipient is selected from one or more than one of cyclopentasiloxane, cyclotetrasiloxane and dimethiconol.

3. The use according to claim 1 or 2, wherein the content of the silicone excipient is 25 g / L to 150 g / L.

4. The use according to claim 3, wherein the content of the silicone excipient is 75 g / L.

5. The use according to any one of claims 1 to 4, wherein the insecticide is allethrin, bifenthrin, permethrin, phenothrin, resmethrin, tefluthrin, tetramethrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, cypervalerate, cypromethrin, flucythrin, flumethrin, fluvalinate, or tralomethrin.

6. Use according to any one of claims 1 to 5, wherein the insecticide is permethrin.

7. The use according to any one of claims 1 to 6, wherein the content of budesonide is about 0.05 g / L to about 1 g / L, preferably about 0.25 g / L.

8. The use according to any one of claims 1 to 7, wherein the content of the pesticide is about 10 g / L to about 60 g / L, preferably about 40 g / L.

9. The use according to any one of claims 1 to 8, wherein the weight ratio of budesonide to insecticide is about 1:

160.

10. The use according to claim 1, wherein the medicament comprises: budesonide in an amount of about 0.05 g / L to about 1 g / L; Permethrin in an amount ranging from about 10 g / L to about 60 g / L; One or more than one silicone in an amount from about 25 g / L to about 150 g / L; and a pharmaceutically acceptable aqueous carrier; and optionally One or more than one excipient selected from thickeners, solubilizers, chelating agents, antioxidants, preservatives, and pH adjusters.

11. The use according to claim 1, wherein the medicament comprises: Budesonide in an amount of about 0.25 g / L; Permethrin in an amount of about 40 g / L; One or more silicones in an amount of about 75 g / L; A thickener in an amount of about 30 g / L; one or more excipients selected from solubilizers, chelating agents, antioxidants, preservatives, and pH adjusters; and Make up to 1L with purified water.

12. The use according to claim 11, wherein the silicone is one or more than one of cyclopentasiloxane, cyclotetrasiloxane and dimethiconol.

13. The use according to claim 11 or 12, wherein the thickener is a mixture of polyquaternium-37, propylene glycol dicaprylate dicaprate and PPG-1 trideceth-6.

14. The use according to any one of claims 1 to 13, wherein the medicament is formulated as a hair conditioner, a leave-in hair conditioner, a lotion, a spray, a cream, an ointment or a pour-on preparation.

15. The use according to any one of claims 1 to 14, wherein the medicament is formulated as a leave-in conditioner.

16. The use according to any one of claims 1 to 13, wherein the medicament is for application by pouring or spraying.

17. The use according to any one of claims 1 to 16, wherein the mammal is selected from cattle, pigs, sheep, dogs and equines.

18. The use according to any one of claims 1 to 16, wherein the mammal is a dog or an equine.

19. The use according to any one of claims 1 to 16, wherein the mammal is a horse.

20. The use according to any one of claims 1 to 16, wherein the medicament is for topical application to the fur or skin of the topline, mane region, tail region, dorsal midline, ear, head or ventral region of an equine animal.

21. The use according to any one of claims 1 to 16, wherein the medicament is for topical application to the buttocks, dorsal chest, flanks, ears, head or perineum area of ​​dogs.

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