WO2016096795A1

WO2016096795A1 - Compound of the avermectin family for treating and/or preventing inflammatory dermatoses

Info

Publication number: WO2016096795A1
Application number: PCT/EP2015/079707
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 a compound of the avermectin family, preferably ivermectin, for use in the treatment and/or prevention of inflammatory dermatoses especially neutrophilic dermatoses. It also relates to a pharmaceutical composition comprising avermectin family compound, preferably ivermectin, with a pharmaceutical acceptable carrier to treat and/or prevent inflammatory dermatoses and especially neutrophilic dermatoses.

Description

COMPOUND OF THE AVERMECTIN FAMILY FOR TREATING AND/OR

PREVENTING INFLAMMATORY DERMATOSES

The present invention relates to a compound of the avermectin family which is 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 avermectin family compound of the present invention is 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 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 can be problematic. 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 inflammatory dermatoses such as neutrophilic dermatoses.

More specifically there is a need for developing a compound and a pharmaceutical composition comprising this compound 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 compound of the avermectin family, preferably ivermectin, even at low dose, 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 pharmaceutical composition comprising such compound, allowed to treat and/or to prevent inflammatory dermatoses and neutrophilic dermatoses with less or no side effect.

The present invention relates to a compound of the avermectin family for use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses.

In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the avermectin family in a pharmaceutically acceptable carrier, 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.

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: Sneddon- Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, lupus miliaris disseminates faciei, infantile acropustulosis, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, pityriasis rosea, Hailey-Hailey disease or familial benign chronic pemphigus, Hallopeau's disease, Jessner-Kanof syndrome, 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.

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.

More preferably the neutrophilic dermatoses which may be treated and/or prevented by the present invention are selected from 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. On a more specific and preferred embodiment, the neutrophilic dermatoses which may be treated and/or prevented by the present invention are: mucous membrane pemphigoid, erosive lichen planus, lichen planus, lichen ruber pemphigoids, pustular psoriasis. The avermectin family compound for use in the context of the invention are in the form of a pharmaceutical composition directed to a topical application, preferably in the form of an emulsion, a cream, a lotion type, a gel or a solution.

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%.

In a specific embodiment, the pharmaceutical composition according to the present invention comprise one or more avermectin family compounds, one or more solvents for the active agent, an oily phase, one or more surfactants as emulsifier, and water. a preferred embodiment, the composition comprises in water:

- Ivermectin 1.0

- Glycerol 4.0

- Acrylate CI 0-30 alkyl acrylate crosspolymer 0.2

- Methyl para-hydroxybenzoate 0.2

- Disodium EDTA 0.05

- Citric acid monohydrate 0.05

- Isopropyl palmitate 4.0

- Cetyl alcohol 3.5

- Stearyl alcohol 2.5

- Oleyl alcohol 2.0

- Ceteareth-20 3.0

- Sorbitan monostearate 2.0

- Dimethicone 200 20 cs 0.5

- Propyl para-hydroxybenzoate 0.1

- Propylene glycol 2.0

- Phenoxyethanol 1.0

- 10% sodium hydroxide qs pH

as % by weight relative to the total weight of the composition. The choice of the concentration of the avermectin family compound, preferably ivermectin, and 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.

The inventors have surprisingly identified that a compound of the avermectin family for a topical application, presents a therapeutic interest for treating and/or preventing inflammatory dermatoses and especially neutrophilic dermatoses.

Therefore, the present invention relates to a compound of the avermectin family and especially ivermectin, 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 a pharmaceutically acceptable carrier, for use in the treatment and/or prevention of inflammatory dermatoses and especially neutrophilic dermatoses. 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 and preferably ivermectin, in a pharmaceutically carrier. More specifically the present invention also relates to a method for treating and/or preventing neutrophilic dermatoses, comprising administering to a subject suffering of neutrophilic dermatoses, an effective amount of a topical composition comprising a compound of the avermectin family and preferably ivermectin, in a pharmaceutically carrier.

The present invention also concerns the use of a compound of the avermectin family preferably ivermectin, 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 avermectin compound and 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 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 refer 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.

Avermectin family compound of the present invention can be used alone or in association with other avermectin family compounds and/or with other active compound. 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, avermectin family compounds have never been disclosed or suggested for use to treat and/or prevent inflammatory dermatoses and especially the neutrophilic dermatoses referenced above. More specifically ivermectin has never been disclosed or suggested for use to treat and/or prevent inflammatory dermatoses and especially the neutrophilic dermatoses referenced above.

The present invention therefore relates to avermectin family compound, 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.

In another embodiment, the present invention therefore relates to a pharmaceutical composition comprising a compound of the avermectin family in a pharmaceutically acceptable carrier, 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 composition and the method of the present invention are 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, 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 anti- inflammatory property of avermectin family compounds, along with their antiseptic properties. It is believed that avermectin family compounds are effective anti-inflammatory agents, which block certain mediators of inflammation, therefore, diminish symptoms caused by inflammation. Moreover, in view of the effect of avermectin family compounds 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.

Suitable examples of carrier or base include, but not limited to, water, glycols, alcohols, lotions, creams, gels, emulsions, and sprays. Following examples provide various topical pharmaceutical compositions containing an avermectin compound for treatment of the above- referenced dermatoses.

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.

The present pharmaceutical composition is more specifically a dermatological composition directed to a topical application on the skin, mucous membranes, nails, and/or the ocular area.

The present invention is directed to any mammal, particularly humans, male or female. According to the invention, the avermectin family compound, preferably ivermectin is formulated in pharmaceutical composition meaning that the pharmaceutical composition comprises the avermectin family compound, preferably ivermectin with 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, nails, mucous membranes and ocular area.

It is also considered that the pharmaceutical composition according to the present invention can comprise an additional active ingredient or additive. The additional active ingredient 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.

The additive is 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 (OAV) or vice versa (W/O), or a triple emulsion (W/OAV or OAV/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 (OAV) 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 avermectin family compounds and preferably of ivermectin can be used. In the case of treating acute conditions, a more potent composition containing higher concentration of avermectin family compounds and preferably 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 avermectin family compounds and preferably of ivermectin should be used for pediatric patients.

It is known that some of the diseases, 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 lotion containing 0.075% of avermectin family compounds and preferably of ivermectin 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 avermectin family compounds and preferably 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 avermectin family compounds and preferably 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 avermectin family compounds and preferably of 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 therein. More specifically, the pharmaceutical composition comprises one or more avermectin family compounds, 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 is 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. Some formulations are presented at example 1.

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 of 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 treatment method using the pharmaceutical composition according to the present invention, for each of these dermatoses is quite similar. Preferably, in an initial treatment of these dermatoses the avermectin dermatological composition and more specifically the ivermectin dermatological composition 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, avermectin concentration of the dermatological composition, 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.

The choice of the ivermectin concentration, of the pharmaceutical composition form and of the type of treatment method, for the treatment 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. The invention also relates avermectin family compound, preferably ivermectin, in combination with at least one other active compound, for simultaneous or sequential use in the treatment and/or prevention of inflammatory dermatoses and especially of neutrophilic dermatoses. Following examples illustrate further aspect and advantages of the invention which way limiting in nature.

EXAMPLES

Example 1: Compositions of the invention

Example la: Composition 1

Ingredients % by weight relative to the total weight of the composition

Ivermectin 1.00

Glycerol 4.0

Aluminium magnesium silicate 1.0

Methyl para-hydroxybenzoate 0.2

Disodium EDTA 0.05

Citric acid monohydrate 0.05

Isopropyl palmitate 4.0

Glyceryl / PEG 100 stearate 3.0

Self-emulsifiable wax 2.0

Palmitostearic acid 2.5

Steareth-20 3.0

Sorbitan stearate 2.0

Dimethicone 20 0.5

Propyl para-hydroxybenzoate 0.1

Propylene glycol 4.0

Glyceryl triacetate 1.0

Phenoxyethanol 0.5

10% sodium hydroxide qs pH

Water qs 100 Example lb: Composition 2

Ingredients % by weight relative to the total weight of the composition

Ivermectin 1.00

Glycerol 4.0

Steareth-2 1.0

Steareth-21 2.0

Aluminium magnesium 1.0

silicate/titanium dioxide / silica

Methyl para-hydroxybenzoate 0.2

Propyl para-hydroxybenzoate 0.1

Disodium EDTA 0.05

Citric acid monohydrate 0.05

Isopropyl palmitate 4.0

Glyceryl / PEG 100 stearate 2.0

Self-emulsifiable wax 1.0

Palmitostearic acid 2.00

Dimethicone 20-350 cS 0.5

Propylene glycol 4.0

Glyceryl triacetate 1.00

Phenoxyethanol 0.5

10% sodium hydroxide qs pH

Water qs 100

Example lc: Composition 3

Ingredients % by weight relative to the total weight of the composition

Ivermectin 1.00

Glycerol 4.0

Acrylate CI 0-30 alkyl acrylate crosspolymer 0.15

Methyl para-hydroxybenzoate 0.2

Disodium EDTA 0.05

Citric acid monohydrate 0.05 Isopropyl myristate 4.0

Cetyl alcohol 3.0

Stearyl alcohol 2.0

Self-emulsifiable wax 0.8

Palmitostearic acid 0.5

Steareth-20 2.0

Sorbitan palmitate 1.0

Dimethicone 20 0.5

Propyl para-hydroxybenzoate 0.1

Propylene glycol 4.0

Glyceryl triacetate 1.0

Phenoxyethanol 0.5

10% sodium hydroxide qs pH

Water qs 100

Example Id: Composition 4

Ingredients % by weight relative to the total weight of the composition

Ivermectin 1.00

Glycerol 4.0

Aluminium magnesium silicate 1.0

Methyl para-hydroxybenzoate 0.2

Disodium EDTA 0.05

Citric acid monohydrate 0.05

Isopropyl palmitate 4.0

Glyceryl / PEG 100 stearate 3.0

Self-emulsifiable wax 2.0

Palmitostearic acid 3.0

Steareth-20 3.0

Sorbitan palmitate 2.0

Dimethicone 20 0.5

Propyl para-hydroxybenzoate 0.1

Propylene glycol 4.0 Glyceryl triacetate 1.0

Phenoxyethanol 0.5

10% sodium hydroxide qs pH

Water qs 100

Example le: Composition 5

Ingredients % by weight relative to the total weight of the composition

Ivermectin 1.00

Glycerol 4.0

Acrylate CI 0-30 alkyl acrylate crosspolymer 0.2

Methyl para-hydroxybenzoate 0.2

Disodium EDTA 0.05

Citric acid monohydrate 0.05

Isopropyl palmitate 4.0

Cetyl alcohol 3.5

Stearyl alcohol 2.5

Oleyl alcohol 2.0

Ceteareth-20 3.0

Sorbitan monostearate 2.0

Dimethicone 200 20cs 0.5

Propyl para-hydroxybenzoate 0.1

Propylene glycol 2.0

Phenoxyethanol 1.0

10% sodium hydroxide qs pH

Water qs 100

Example If: Composition 6

Ingredients % by weight relative to the total weight of the composition

Ivermectin 1.4

Glycerol 4.0

Acrylate CI 0-30 alkyl acrylate crosspolymer 0.2 Methyl para-hydroxybenzoate 0.2

Disodium EDTA 0.05

Citric acid monohydrate 0.05

Isopropyl palmitate 4.0

Cetyl alcohol 3.5

Stearyl alcohol 2.5

Oleyl alcohol 2.0

Ceteareth-20 3.0

Sorbitan monostearate 2.0

Dimethicone 200 20 cs 0.5

Propyl para-hydroxybenzoate 0.1

Propylene glycol 2.0

Phenoxyethanol 1.0

10% sodium hydroxide qs pH

Water qs 100

Claims

Compound of the avermectin family for use in the treatment and/or prevention of inflammatory dermatoses.

Compound of the avermectin family 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.

Compound of the avermectin family 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 for use according to the claim 3 wherein the inflammatory dermatoses are selected in the group of:

Sneddon- Wilkinson syndrome or subcorneal pustular dermatosis, palmoplantar pustulosis, lupus miliaris disseminates faciei, infantile acropustulosis, erythema elevatum diutinum, prurigo pigmentosa, granuloma faciale, pityriasis rosea, Hailey- Hailey disease or familial benign chronic pemphigus, Hallopeau's disease, Jessner- Kanof syndrome, 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.

5. Compound of the avermectin family for use according to the claim 1 wherein the inflammatory dermatoses are neutrophilic dermatoses.

Compound of the avermectin family 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.

Compound of the avermectin family for use according to the claim 6 wherein the neutrophilic dermatoses are selected in the group of: mucous membrane pemphigoid, erosive lichen planus, lichen planus, lichen ruber pembphigoids, pustular psoriasis.

Compound of the avermectin family 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.

9. Compound of the avermectin family for use according to any one of the preceding claims, wherein the compound of the avermectin family is ivermectin.

10. Compound of the avermectin family for use according to any one of the preceding claims, wherein the compound is in the form of a pharmaceutical composition.

11. Compound of the avermectin family for use according to claim 10, wherein the composition is for topical administration. 12. Compound of the avermectin family for use according to claim 11, wherein the composition is in the form of an emulsion, of a cream, of a lotion type, of a gel, a solution, or an ointment.

13. Compound of the avermectin family for use according to claim 11 or 12, wherein the composition comprises 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.

14. Compound of the avermectin family for use according to any of claims 11 to 13, wherein the composition comprises 1% by weight of a compound of the avermectin family relative to the total weight of the composition.

15. Compound of the avermectin family for use according to any of claims 11 to 14, wherein the composition comprises comprising one or more avermectin family compounds, one or more solvents for the active agent, an oily phase, one or more surfactants as emulsifier, and water.

16. Compound of the avermectin family for use according to any of claims 11 to 15, wherein the composition comprises in water:

- Ivermectin 1.0

- Glycerol 4.0

- Acrylate ClO-30 alkyl acrylate 0.2

- Methyl para-hydroxybenzoate 0.2

- Disodium EDTA 0.05 - Citric acid monohydrate 0.05

- Isopropyl palmitate 4.0

- Cetyl alcohol 3.5

- Stearyl alcohol 2.5

- Oleyl alcohol 2.0

- Ceteareth-20 3.0

- Sorbitan monostearate 2.0

- Dimethicone 200 20 cs 0.5

- Propyl para-hydroxybenzoate 0.1

- Propylene glycol 2.0

- Phenoxyethanol 1.0

- 10% sodium hydroxide qs pH weight relative to the total weight of the composition.