WO2016096797A1

WO2016096797A1 - Compound of the avermectin family in combination with an other active compound for treating and/or preventing inflammatory dermatoses

Info

Publication number: WO2016096797A1
Application number: PCT/EP2015/079709
Authority: WO
Inventors: Jean JACOVELLA
Original assignee: Galderma Sa
Priority date: 2014-12-15
Filing date: 2015-12-15
Publication date: 2016-06-23

Abstract

The present invention relates to the use of a compound of the avermectin family preferably ivermectin, in the treatment and/or prevention of inflammatory dermatoses especially neutrophilic dermatoses, in combination with at least one other active compound.

Description

COMPOUND OF THE AVERMECTIN FAMILY IN COMBINATION WITH AN OTHER ACTIVE COMPOUND FOR TREATING AND/OR PREVENTING INFLAMMATORY

DERMATOSES The present invention relates to a compound of the avermectin family in combination with at least one other active compound, which are suitable for the treatment and/or prevention of inflammatory dermatoses, especially neutrophilic dermatoses.

Inflammatory dermatoses refer to any cutaneous abnormality or eruption accompanied by an inflammatory component. Inflammatory dermatoses are classified in several specific and distinct types of dermatoses according to the localization, causes and symptoms thereof. They are very common skin disorders and comprise a wide and complex variety of clinical conditions. The diagnosis of cutaneous inflammatory diseases can be confusing, even for the most experienced pathologist. This is because the immune system within the skin has limited ways in which it reacts and responds to an antigenic stimulus, and many inflammatory diseases do not show specific clinicopathological features.

Inflammatory dermatoses can be classified in two different classes: acute and chronic inflammatory dermatoses. In general, acute lesions last from days to weeks and are characterized by inflammatory infiltrates (usually composed of lymphocytes and macrophages), edema, and variable degrees of epidermal, vascular, or subcutaneous injury. Chronic lesions, on the other hand, persist for months to years and are often associated with changes in epidermal growth (atrophy or hyperplasia) or dermal fibrosis. The skin surface in some chronic inflammatory dermatoses is roughened as a result of excessive or abnormal scale formation and shedding.

Among the inflammatory dermatoses, the compounds of the present invention are especially directed to the treatment and/or prevention of the neutrophilic dermatoses. The neutrophilic dermatoses are a group of disorders characterized by skin lesions for which histologic examination reveals intense epidermal and/or dermal inflammatory infiltrates composed primarily of neutrophils with no evidence of infection. Classification of the neutrophilic dermatoses is based upon the recognition of clinical and pathologic features, as well as the identification of associated diseases. Cutaneous findings in neutrophilic dermatoses are variable, and can include vesiculopustules, plaques, nodules, or ulcerations. Depending on the disorder, lesions may be localized or widespread. The pathogenesis of neutrophilic dermatoses is unknown. It is believed that these disorders represent a state of altered immunologic reactivity. Several authors have proposed pharmaceutical or dermatological compositions in order to treat inflammatory dermatoses and neutrophilic dermatoses. The most widely prescribed drugs to treat dermatologic diseases are corticosteroids, also known as glucocorticosteroids or glucocorticoids. Although systemic corticosteroids are often required in some severe dermatologic diseases, a topical treatment using corticosteroids can be associated in most responsive cases because it causes fewer systemic adverse effects. However even if some topical steroids are efficacious in some inflammatory dermatoses and neutrophilic dermatoses, a long term use of steroids is associated with serious local side effects. These include skin atrophy (thinning, telangiectasia, striae) and a prompt rebound flare when the steroid is stopped. Treatment of large areas of skin and use of occlusive dressings can also increase the potential for adverse effects. This is especially the case in children.

Topical retinoids such as tretinoin (all-trans- retinoic acid or Vitamin A acid) have been used by dermatologists for almost twenty years to treat inflammatory dermatoses. Topical retinoids in combination with systemic retinoids or other systemic active compounds such as corticosteroids or dapsone, have been used effectively in the treatment of various inflammatory dermatoses and especially neutrophilic dermatoses. A number of topical retinoid formulations are commercially available. However the available topical dosage forms have been reported to produce skin irritation (dermatitis) which may be characterized by erythema, scaling, peeling, drying, pruritus, and sensations similar to sunburn. This problem is described in U.S. Patent No. 4,888,342. Other side effects have also been reported with topical retinoids like itching, stinging or burning. Rarely edema, and blistering or crusting of skin may occur. Temporary hypopigmentation or hyperpigmentation has been reported in a few individuals treated with tretinoin. Temporary depigmentation in non-caucasians is possible.

Dapsone, (4,4'-diaminodiphenyl sulfone) is an antibacterial commonly used as one of the medicinal agents used in the treatment of leprosy. Dapsone is also useful as an antiinflammatory agent. It has been used to treat skin diseases characterized by the abnormal infiltration of neutrophils, such as dermatitis herpetiformis, linear IgA dermatosis, pustular psoriasis, pyoderma gangrenosum, acne vulgaris, and Sweet's Syndrome. Use of topical compositions of dapsone alone or in combination with other active compounds such as corticosteroids has already been tested but remain most of the time problematic. Indeed, topical compositions of dapsone induce several skin side effects since they may act as drying agents for the skin. They remove essential oils and natural skin softeners from the skin thus causing it to be dry, itch and crack. Moreover, no topical formulation of Dapsone is commercially available for local treatment of skin disease and references describing topical administration of Dapsone are not common. The main reason is that Dapsone and derivatives are practically insoluble in water and in oils such as petroleum gel, wax and vegetable oils.

According to the complexity of the pathophysiology of inflammatory dermatoses, especially neutrophilic dermatoses and the side effects of the current treatments of these inflammatory skin diseases, there is a need for developing compounds for use in the treatment and/or the prevention of neutrophilic dermatoses.

More specifically there is a need for developing compounds and a pharmaceutical composition comprising these compounds for use in the treatment and/or the prevention of inflammatory dermatoses such as neutrophilic dermatoses, able to be used by topical route with less or no side effect.

In this context, inventors have surprisingly found that a combination of a compound of the avermectin family, particularly ivermectin even at low dose, and at least one other active compound can be effectively used in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses with less or no side effect.

They especially found that the topical administration of a combination of a compound of the avermectin family with at least one other active compound, allowed to treat and/or to prevent inflammatory dermatoses and neutrophilic dermatoses with less or no side effect. More specifically the inventors have surprisingly identified that a combination of ivermectin with a compound chosen in the corticosteroid family, for a topical application presents a therapeutic interest for treating and/or preventing inflammatory dermatoses and especially neutrophilic dermatoses. The present invention relates to the use of a compound of the avermectin family, preferably ivermectin, in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses, in combination with at least one other active compound. The present invention relates to a compound of the avermectin family, preferably ivermectin, in combination with at least one other active compound, for use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses.

In a particular embodiment, the compound of the avermectin family is chosen from the group consisting of ivermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin, aversectin B, AB or C, emamectin Bla, emamectin Bib and their derivatives. More preferably, the compound of the avermectin family is ivermectin.

In a particular embodiment, the other active compound is chosen from the group comprising antibiotics, antibacterial, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergic agents, retinoids, free-radical scavengers, anti-pruriginous, the keratolytic agents, antiseborrheic, antihistaminic, sulfides, immunosuppressant products and antiproliferative agents, corticosteroids, intravenous immunoglobulin, anti- angiogenic, anti-inflammatory and/or a mixture thereof. More preferably the other active compound is chosen in the corticosteroid family.

The inflammatory dermatoses which may be treated according to the present invention are well known in the art. They include chronic, as well as acute, afflictions of the skin. Non exhaustive examples of inflammatory skin disorders treated and/or prevented by the present invention are: Sneddon- Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, infantile acropustulosis, lupus miliaris disseminatus faciei, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, pityriasis rosea, Hailey-Hailey disease or familial benign chronic pemphigus, Jessner-Kanof syndrome, Kaposi's sarcoma, psoriasis, pustular psoriasis, Hallopeau's disease, erosive lichen planus, lichen planus, lichen ruber pemphigoids, mucous membrane pemphigoid, granulomatous rosacea, bullous pemphigoid, cicatricial pemphigoid, Behcet's disease, recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome, dermatitis herpetiformis, linear IgA dermatosis, IgA pemphigus, pemphigus vulgaris, relapsing polychondritis, leukocytoclastic vasculitis, urtical vasculitis, eosinophil folliculitis, cutaneous lupus erythematosus, alopecia aerata, urticurial pressure.

Among the previous list of inflammatory dermatoses, those which preferably can be treated and/or prevented by the present invention are selected in the group of: Sneddon- Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, infantile acropustulosis, lupus miliaris disseminatus faciei, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, pityriasis rosea, Hailey-Hailey disease or familial benign chronic pemphigus, Jessner-Kanof syndrome, Kaposi's sarcoma, psoriasis, pustular psoriasis, Hallopeau's disease, erosive lichen planus, lichen planus, lichen ruber pemphigoids, mucous membrane pemphigoid, granulomatous rosacea, bullous pemphigoid, cicatricial pemphigoid, Behcet's disease, recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome. More specifically inflammatory dermatoses which can be treated and/or prevented by the present invention: recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome.

More preferably inflammatory dermatoses which can be treated and/or prevented by the present invention are neutrophilic dermatoses which are inflammatory dermatoses with a neutrophilic component.

A non-exhaustive example list of neutrophilic dermatoses which may be treated and/or prevented by the present invention are: Sneddon- Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, infantile acropustulosis, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, Hailey-Hailey disease or familial benign chronic pemphigus, Hallopeau's disease, Kaposi's sarcoma, psoriasis, pustular psoriasis, erosive lichen planus, lichen planus, lichen ruber pemphigoids, mucous membrane pemphigoid, granulomatous rosacea, bullous pemphigoid, cicatricial pemphigoid, Behcet's disease, recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome.

On a more specific and preferred embodiment, the neutrophilic dermatoses which may be treated and/or prevented by the combination of the present invention are: mucous membrane pemphigoid, erosive lichen planus, lichen planus, lichen ruber pemphigoids, pustular psoriasis.

The inventors have surprisingly identified that a compound of the avermectin family, preferably ivermectin, in combination with at least one other active compound presents a therapeutic interest for treating and/or preventing inflammatory dermatoses, especially neutrophilic dermatoses. Preferably the compounds are present in a pharmaceutical composition for a topical application. More specifically the inventors have surprisingly identified that ivermectin in combination with at least one other active compound preferably chosen in the corticosteroid family, presents a therapeutic interest for treating and/or preventing inflammatory dermatoses, especially neutrophilic dermatoses. In a particular embodiment, it is provided a pharmaceutical composition comprising a compound of the avermectin family, wherein the composition optionally further comprises the other active compound.

According to the invention, the composition comprises from 0.001 to 10%, by weight of a compound of the avermectin family, preferably of ivermectin, relative to the total weight of the composition, more preferably from 0.001 to 8%, preferably from 0.001 to 5%, more preferably from 0.1 to 3%, and even more preferably 1%.

The composition of the invention comprises from 0.001 to 10%, by weight the other active compound relative to the total weight of the composition. Preferably, the composition comprises from 0.001 to 5% by weight of the other active compound relative to the total weight of the composition. More preferably, the composition comprises from 0.1 to 3% by weight of the other active compound relative to the total weight of the composition. The choice of the concentration of the avermectin family compound, preferably ivermectin and/or of the other active compound but also the form of the pharmaceutical composition for treatment of a particular condition of the above-referenced inflammatory dermatoses can be made depending on the type and severity of the diseases, location of the affected area, and form of the pharmaceutical composition. A person of ordinary skill in the art will be able to determine these different parameters.

Therefore, the present invention relates to a compound of the avermectin family, preferably ivermectin, in combination with at least one other compound for use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses.

The present invention relates also to a composition for a topical application, comprising a compound of the avermectin family, preferably ivermectin, in combination with at least one other compound in a pharmaceutically acceptable carrier, for use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses.

Advantageously, the avermectin family compound, preferably ivermectin, in combination with the other active compound, may be in the same composition to be administered concurrently, or in different compositions to be administered simultaneously but separately, sequentially. Preferably, the avermectin compound, and the other active compound are in the same composition.

The present invention also relates to a method for treating and/or preventing inflammatory dermatoses, comprising administering to a subject suffering of inflammatory dermatoses and especially neutrophilic dermatoses, an effective amount of a topical composition comprising a compound of the avermectin family, preferably ivermectin, and at least one other active compound in a pharmaceutically carrier. In another embodiment, the invention relates to simultaneous or subsequent administration of separate compositions, one comprising the compound of the avermectin family, the other comprising at least one other active compound in a pharmaceutically acceptable carrier, for use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses.

In another embodiment, the invention concerns a compound of the avermectin family, preferably ivermectin, in combination with at least one other active compound in a pharmaceutically acceptable carrier for simultaneous or sequential use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses. The present invention also concerns the use of a compound of the avermectin family, preferably ivermectin and at least one other active compound in a pharmaceutically acceptable carrier for the preparation of a drug for treating and/or preventing inflammatory dermatoses and especially neutrophilic dermatoses.

In an additional embodiment, the present invention further relates to a pharmaceutical kit for treating inflammatory dermatoses and especially neutrophilic dermatoses. The kit includes a pharmaceutical composition comprising a compound of the avermectin family in combination with at least one other active compound in a pharmaceutically acceptable carrier in a container, and an insert, on or inside of said container, with instructions on how to use the dermatological composition for treating the above mentioned inflammatory dermatoses.

In another embodiment, the kit according to the present invention comprises a first container comprising a pharmaceutical composition comprising the compound of the avermectin family, preferably ivermectin, and a second container comprising a pharmaceutical composition comprising a pharmaceutical composition comprising the other active compound.

In a particular embodiment, the compound of the avermectin family is chosen from the group consisting of ivermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin, aversectin B, AB or C, emamectin B la, emamectin B ib and their derivatives.

Avermectin derivatives according to the present invention refers to compounds produced by avermectin derivatization, generally obtained by exploiting the reactive centers of molecules, since these groups in turn are totally responsible for stability profile as well as anthelmintic activities of avermectin compounds.

More preferably, the compound of the avermectin family is ivermectin.

Ivermectin is a mixture of two compounds belonging to the avermectin class, 5-O-demethyl- 22,23-dihydroavermectin A_la and 5-0-demethyl-22,23-dihydroavermectin Art.. They are also known as 22,23-dihydroavermectin Bi_a and 22,23-dihydroavermectin Bib. Ivermectin contains at least 80% of 22,23-dihydroavermectin Bi_a and less than 20% of 22,23- dihydroavermectin Bib. This active agent is part of the avermectin class, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis. In the middle of the 1980s, ivermectin was presented as a broad- spectrum antiparasitic medicinal product for veterinary use (Campbell et al.: Science, 1983, 221, 823-828). Ivermectin is effective against most common intestinal worms, except tapeworms, most acarids and some lice. In particular, it exhibits considerable affinity for the glutamate- dependent chloride channels present in invertebrate nerve cells and muscle cells. Its binding to these channels promotes an increase in membrane permeability to chloride ions, resulting in hyperpolarization of the nerve or muscle cell. Neuromuscular paralysis which can lead to the death of certain parasites results therefrom. Ivermectin also interacts with other ligand- dependant chloride channels, such as those involving the neuromediator GABA (gamma- aminobutyric acid).

Ivermectin is more particularly disclosed as an anthelmintic used in humans for the treatment of river blindness caused by Onchocerca volvulus, of gastrointestinal strongyloidiasis (anguillulosis) (product Stromectol®), and of human scabies (Meinking et al., N. Engl. J. Med., 1995, 333, 26-30).

Manetta and Watkins (WO 2004/093886) have suggested the use of ivermectin for producing a topical pharmaceutical composition for the treatment of rosacea and other dermatologic conditions.

However, an avermectin family compound, especially ivermectin in combination with at least one other active compound have never been disclosed or suggested to treat and/or prevent inflammatory dermatoses and especially of the neutrophilic dermatoses referenced above. The present invention therefore relates to an avermectin family compound in combination with at least one other active ingredient, for use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses. The preferred compound of the avermectin family according to the present invention is ivermectin. Although the applicants are not bound by any theoretical explanation as to why the present invention is effective in treating and/or preventing inflammatory dermatoses and especially neutrophilic dermatoses, presentation of certain theoretical understanding may be of value. Based on clinical observations by the inventors, it is believed that the efficacy of the avermectin family compounds in combination with at least one other active ingredient, the pharmaceutical composition and the method of the present invention in topical treatment of inflammatory dermatoses and especially neutrophilic dermatoses is due in part to the antiinflammatory property of avermectin family compounds and especially ivermectin, along with its antiseptic properties. It is believed that ivermectin is an effective anti-inflammatory agent, which blocks certain mediators of inflammation, therefore, diminishes symptoms caused by inflammation. Moreover, in view of the effect of ivermectin on neural system, it may also have some direct effects on the neural receptors in the skin, which may contribute to the rapid pain relief observed clinically. The other active ingredient, which is combined to the compound to the avermectin family in the same or in a separate composition, is preferably selected from the group comprising antibiotics, antibacterial, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergic agents, retinoids, free-radical scavengers, anti-pruriginous, the keratolytic agents, antiseborrheic, antihistaminic, sulfides, immunosuppressant products and antiproliferative agents, corticosteroids, intravenous immunoglobulin, anti- angiogenic, anti-inflammatory and/or a mixture thereof.

In one embodiment, the preferred other active compound is chosen in the corticosteroid family.

Corticosteroids are a class of chemicals that includes the steroid hormones that are produced in the adrenal cortex of vertebrates, and synthetic analogues of these hormones. Corticosteroids are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Synthetic pharmaceutical drugs with corticosteroid-like effects are used in a variety of health conditions but are most of the time associated with side effects especially by topical route.

Among the corticosteroids, exemplary are clobetasone and esters thereof such as the 17- butyrate, clobetasol and esters thereof such as the 17-propionate, hydrocortisone and esters thereof such as the 17-butyrate, cortisone and esters thereof such as the 21-acetate, prednisolone and esters thereof such as pivalate, miconazole, prednisone, triamcinolone and esters and ethers thereof such as triamcinolone acetonide, methylprednisolone, fluometholone, fluocinolone and esters and ethers thereof such as fluocinolone acetonide, desonite, betamethasone and esters thereof such as the 21-acetate, the 17-adamantoate, the 17-benzoate, the 17-valerate and the 17,21-di [rho]ropionate, and dexamethasone, and mixtures and derivatives thereof. The term "corticosteroid derivatives" is intended in particular to mean their pharmaceutically acceptable salts with a base, such as the disodium phosphate salts.

In one embodiment, the term "treatment" or "treating" refers to an improvement, the prophylaxis of a disease or disorder, or at least one symptom can be discerned therefrom. In another embodiment, "treatment" or "treating" means an improvement, prevention of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily discernible in the subject. In another further embodiment "treatment" or "treating" refers to inhibiting or slowing the progression of a disease or disorder, physically, eg, stabilization of a discernible symptom, physiologically, for example, stabilization of a physical parameter, or both. In another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder. In some embodiments, compounds of interest are administered as a preventive measure. In this context, "prevention" or "preventing" refers to a reduction in the risk of acquiring a disease or disorder specified.

In another embodiment, the term "pharmaceutical composition" refers preferably to a dermatological composition which can be topically applied. "Topical application" refers to the skin, the mucous membranes and/or the ocular area.

The present invention is directed to any mammal, particularly humans, male or female.

According to the invention, the pharmaceutical composition is formulated in a pharmaceutically acceptable carrier meaning that the pharmaceutical composition comprises ivermectin, optionally in combination with at least one other active ingredient in a pharmaceutically acceptable carrier. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. Particularly, in the context of the invention, the carrier is compatible with human skin, mucous membranes and ocular area.

Suitable examples of carrier or base include, but are not limited to, water, glycols, alcohols, lotions, creams, gels, emulsions, and sprays. The composition for use in the context of the invention is administered by topical application, preferably in the form of an emulsion, a cream, a lotion type, a gel, an ointment, or a solution.

The pharmaceutical composition can also comprise an additive, preferably selected from the group consisting of sequestering agents, chelating agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, conventional acids, or bases, organic or inorganic, perfumes, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, soothing and protective agents of the skin, penetrating agents, emulsifiers, gelling agents and a mixture thereof.

The pharmaceutical composition is advantageously administered by topical application and, therefore, is in a form suitable for topical application to the skin. For example, it may be in the form of an optionally gelled, oily solution, an optionally two-phase dispersion of the lotion type, an emulsion obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa (W/O), or a triple emulsion (W/O/W or 0/W/O) or a vesicular dispersion of ionic and/or non-ionic type. This topical composition may be in anhydrous form, in aqueous form or in the form of an emulsion. These compositions are prepared according to the usual methods. According to this invention, a composition in the form of an emulsion obtained by dispersion of a fatty phase in an aqueous phase (O/W) is preferably used.

This composition may be more or less fluid and may be in the form of salves, emulsions, creams, milks, ointments, impregnated pads, syndets, solutions, gels, sprays or aerosols, foams, suspensions, lotions or sticks. Preferably, the composition used in the present invention is in the form of an emulsion, of a cream, of a lotion type, of a gel, or of a solution, and more preferably in the form of an emulsion.

To treat most patients diagnosed with one of the above-mentioned dermatoses, a lotion containing about 0.05% to 0.2% of ivermectin can be used. In the case of treating acute conditions, a more potent composition containing higher concentration of ivermectin can be used. On the other hand, for prolonged maintenance of certain conditions, a low concentration such as from about 0.05% to about 0.1% is preferred. Further, a low concentration of ivermectin should be used for pediatric patients. It is known that in some of the diseases such as inflammatory dermatoses, the skin on the eyelids can be affected. To treat eyelids, a high concentration of the medicine should be avoided to prevent irritation of the eyes. It is found that a 0.075% ivermectin lotion does not cause eye irritation when it is used on the face, around the eyes, or directly on the eyelids.

In the form of shampoo, soap, facial cleanser, and facial mask the concentration of ivermectin is higher, such as about 2% to about 8%, because the medicine is not retained on the skin after rinsing, and treatment time is short. On the contrary, in the forms of topic dressing, medicated tape, and dermal patch the medicine stays on the treated area longer than other forms, therefore, the concentration of ivermectin can be lower.

In one exemplary embodiment, the pharmaceutical composition is in a form of lotion having substantially neutral pH from about 6 to about 7. A commercially available moisturizing lotion manufactured by Galderma Laboratories, Inc. under the trade name Cetaphil^® moisturizing lotion is used as the medium for ivermectin to form the pharmaceutical composition. Cetaphil^® moisturizing lotion contains purified water, glycerin, hydrogenated polyisobutene, cetearyl alcohol and ceteareth-20, macadamia nut oil, dimethicone, tocopheryl acetate, stearoxytrimethylsilane and stearyl alcohol, panthenol, farnesol, benzyl alcohol, phenoxyethanol, acrylates/C 10-30 alkyl acrylate crosspolymer, sodium hydroxide, and citric acid.

In some embodiments, the pharmaceutical composition is an emulsion with one or more avermectin family compounds in combination with at least one other active compounds therein. More specifically, the pharmaceutical composition comprises one or more avermectin compounds, preferably also one or more other active compound, as well as one or more solvents for the active agent, an oily phase, one or more surfactants as emulsifier, and water. The method of preparing an emulsion is known to those skilled in the art. The emulsion can be formulated into a solution, lotion, or cream. The emulsion can also be sprayable. The pharmaceutical composition in the form of ointments can be prepared using either an oleaginous base or medium or an absorbent base. The oleaginous base comprises fixed oils or hydrocarbons, such as white petrolatum or mineral oil. The absorbent base comprises an anhydrous substance or substances which can absorb water, for example anhydrous lanolin. Following formation of the base, the avermectin compound, and optionally the other active compound, are added to an amount affording the desired concentration to form the pharmaceutical composition.

In some embodiments, the composition is in the form of a hydrogel. The water content in the gel has hydrating and cooling effect of the inflamed tissue. In some embodiments, the composition is in the form of liquid.

In some embodiments, the pharmaceutical composition is in the form of suppository. Typically, suppository includes one or more lipophilic agents. Suitable examples of lipophilic agents include, but not limited to, hydrogenated vegetable oils, cocoa butter, glycerinated gelatin, polyethylene glycols of different molecular weights, and fatty acid esters of polyethylene glycols.

By vaginal route the compositions according to the present invention can be applied using ova.

By oropharyngeal route, nasal route or auricular route the pharmaceutical composition is in the form of liquid compositions such as suspension or lotions. By parenteral route, the pharmaceutical compositions according to the present invention can be applied subcutaneously or intradermal route. By enteral route, the pharmaceutical compositions according to the present invention can be used in form of tablets, capsules, syrups, suspensions, solutions, powders, emulsions, microspheres, nanosphere, lipid or polymeric vesicles, or of polymeric patches and of hydrogels for controlled release.

By ocular route, the pharmaceutical composition is in the form of eyewash.

The composition useful in the invention comprises from 0.001 to 10%, by weight of a compound of the avermectin family relative to the total weight of the composition. Preferably, the composition comprises from 0.001 to 5% by weight of a compound of the avermectin family relative to the total weight of the composition. More preferably, the composition comprises from 0.1 to 2% by weight of a compound of the avermectin family relative to the total weight of the composition. Advantageously, the composition comprises 1% by weight of a compound of the avermectin family relative to the total weight of the composition. The compound of the avermectin family is preferably ivermectin.

The composition useful in the invention comprises from 0.001 to 10%, by weight of the other active compound relative to the total weight of the composition. Preferably, the composition comprises from 0.001 to 5% by weight of the other active compound relative to the total weight of the composition. More preferably, the composition comprises from 0.1 to 3% by weight of the other active compound relative to the total weight of the composition. The preferred other active compound is chosen in the corticosteroid family.

The treatment method using the combination described herein, for each of these dermatoses is quite similar. Preferably, in an initial treatment of these dermatoses the pharmaceutical composition(s) can be applied topically from one to several times daily for a period of from about one week to several weeks, to substantially control the condition and clear the lesions. The initial dosage, including frequency of the topical application of the pharmaceutical composition(s), the avermectin family compound and the other active compound concentrations in the pharmaceutical composition(s), and the length of the initial treatment period can be determined depending on a specific disease, severity of the disease, and the response of the patient to the medication.

According to the invention, the treatment method can be done by a simultaneous or a sequential topical application.

The term "sequential" means an application with separated steps of avermectin family compound, preferably ivermectin and of the other active compound. The user will thus successively applying avermectin family compound, preferably ivermectin and then the other active compound, in a few seconds or after several hours in the same day including in a range of from 1 hour to 3 days. According to an alternative, the avermectin family compound, preferably ivermectin is administered in the first place and the other active compound is secondly administered.

According to another alternative, the other active compound is administered in the first place and avermectin family compound, preferably ivermectin is secondly administered. In one embodiment, administration of the avermectin family compound may be carried out sequentially or simultaneously administering the other active compound. More preferably the administration of the pharmaceutical composition comprising avermectin compound, preferably iveremctin in combination with at least one other active compound is done simultaneously.

The choice of the avermectin family compound and of the other active compound concentrations, of the pharmaceutical composition form and of the type of treatment method, for the treatment and/or prevention of a particular condition of the above-referenced dermatoses can be made depending on the type and severity of the diseases, location of the affected area.

Claims

1. Compound of the avermectin family in combination with at least one other active compound, for use in the treatment and/or prevention of inflammatory dermatoses.

2. Compound of the avermectin family in combination with at least one other active compound for use according to the claim 1, wherein inflammatory dermatoses are selected in the group of:

Sneddon- Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, infantile acropustulosis, lupus miliaris disseminatus faciei, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, pityriasis rosea, Hailey- Hailey disease or familial benign chronic pemphigus, Jessner-Kanof syndrome, Kaposi's sarcoma, psoriasis, pustular psoriasis, Hallopeau's disease, erosive lichen planus, lichen planus, lichen ruber pemphigoids, mucous membrane pemphigoid, granulomatous rosacea, bullous pemphigoid, cicatricial pemphigoid, Behcet's disease, recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome, dermatitis herpetiformis, linear IgA dermatosis, IgA pemphigus, pemphigus vulgaris, relapsing polychondritis, leukocytoclastic vasculitis, urtical vasculitis, eosinophil folliculitis, cutaneous lupus erythematosus, alopecia aerata, urticurial pressure.

3. Compound of the avermectin family in combination with at least one other active compound for use according to the claim 2, wherein the inflammatory dermatoses are selected in the group of:

Sneddon- Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, infantile acropustulosis, lupus miliaris disseminatus faciei, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, pityriasis rosea, Hailey- Hailey disease or familial benign chronic pemphigus, Jessner-Kanof syndrome, Kaposi's sarcoma, psoriasis, pustular psoriasis, Hallopeau's disease, erosive lichen planus, lichen planus, lichen ruber pemphigoids, mucous membrane pemphigoid, granulomatous rosacea, bullous pemphigoid, cicatricial pemphigoid, Behcet's disease, recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome.

4. Compound of the avermectin family in combination with at least one other active compound for use according to the claim 3, wherein the inflammatory dermatoses are selected in the group of: recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome.

5. Compound of the avermectin family in combination with at least one other active compound for use according to the claim 1, wherein the inflammatory dermatoses are neutrophilic dermatoses.

6. Compound of the avermectin family in combination with at least one other active compound for use according to the claim 5, wherein the neutrophilic dermatoses are selected in the group of: Sneddon-Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, infantile acropustulosis, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, Hailey-Hailey disease or familial benign chronic pemphigus, Hallopeau' s disease, Kaposi's sarcoma, psoriasis, pustular psoriasis, erosive lichen planus, lichen planus, lichen ruber pemphigoids, mucous membrane pemphigoid, granulomatous rosacea, bullous pemphigoid, cicatricial pemphigoid, Behcet's disease, recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome.

7. Compound of the avermectin family in combination with at least one other active compound for use according to the claim 6 wherein, the neutrophilic dermatoses are selected in the group of: recurrent neutrophilic dermatosis of the dorsal hands, pyoderma gangrenosum, mucinosis follicularis, reticular erythematous mucinosis syndrome.

8. Compound of the avermectin family in combination with at least one other active compound for use according to the claim 5 wherein, the neutrophilic dermatoses are selected in the group of: mucous membrane pemphigoid, erosive lichen planus, lichen planus, lichen ruber pemphigoids, pustular psoriasis.

9. Compound of the avermectin family in combination with at least one other active compound for use according to any one of the preceding claims, wherein the compound of the avermectin family is chosen from the group consisting of ivermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin, aversectin B, AB or C, emamectin Bla, emamectin Bib and their derivatives.

10. Compound of the avermectin family in combination with at least one other active compound for use according to any one of the preceding claims, wherein the compound of the avermectin family is ivermectin.

11. Compound of the avermectin family in combination with at least one other active compound for use according to any one of the preceding claims, wherein the other active compound is chosen from the group comprising antibiotics, antibacterial, antivrirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergic agents, retinoids, free -radical scavengers, anti-pruriginous, the keratolytic agents, antiseborrheic, antihistaminic, sulfides, immunosuppressant products and antiproliferative agents, corticosteroids, intravenous immunoglobulin, anti- angiogenic, anti-inflammatory and/or a mixture thereof.

12. Compound of the avermectin family in combination with at least one other active compound for use according to claim 11, wherein the other active compound is chosen from the corticoisteroid family compounds.

13. Compound of the avermectin family in combination with at least one other active compound for use according to any of claims 1 to 12, wherein the compounds are in the form of a pharmaceutical composition, or separate pharmaceutical compositions for administration in combination.

14. Compound of the avermectin family in combination with at least one other active compound for use according to claim 13, wherein the composition(s) are for topical administration.

15. Compound of the avermectin family in combination with at least one other active compound for use according to claim 14, wherein the compounds are in the form of a pharmaceutical composition that is an emulsion, a cream, a lotion type, a gel, a solution, or an ointment.

16. Compound of the avermectin family in combination with at least one other active compound for use according to claim 15, wherein the compounds are in the form of a pharmaceutical composition comprising from 0.001 to 10%, preferably from 0.001 to 8%, more preferably from 0.001 to 5%, and even more preferably from 0.1 to 3% by weight of a compound of the avermectin family relative to the total weight of the composition.

17. Compound of the avermectin family in combination with at least one other active compound for use according to claim 15, wherein the compounds are in the form of a pharmaceutical composition comprising 1% by weight of a compound of the avermectin family relative to the total weight of the composition.

18. Compound of the avermectin family in combination with at least one other active compound for use according to claim 15, wherein the compounds are in the form of a pharmaceutical composition comprising from 0.001 to 10%, preferably from 0.001 to

5%, more preferably from 0.1 to 3% by weight of the other active compound relative to the total weight of the composition.

19. Compound of the avermectin family in combination with at least one other active compound for use according to claim 15, wherein the compounds are in the form of a pharmaceutical composition, comprising one or more avermectin family compounds, one or more other active compound, one or more solvents for the active agent, an oily phase, one or more surfactants as emulsifier, and water.