WO2019002362A1

WO2019002362A1 - Cyclosporine a topical compositions

Info

Publication number: WO2019002362A1
Application number: PCT/EP2018/067237
Authority: WO
Inventors: Maria Isabel BERGES FRAILE; Nuria LLUCH LAFUENTE; Benjamín SANTOS LOBO
Original assignee: Spherium Biomed, S.L.
Priority date: 2017-06-28
Filing date: 2018-06-27
Publication date: 2019-01-03

Abstract

The present invention relates to topical pharmaceutical compositions of cyclosporine A comprising at least a volatile alcohol, 2-(2-ethoxyethoxy)ethanol, a surfactant or surfactant mixture having an HLB value from 10 to 18, and a non-volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, the surfactants having an HLB value from 10 to 18 and triacetin. The invention also relates to a process for the preparation of said compositions and to their use in the prevention and/or treatment of several diseases, particularly psoriasis and atopic dermatitis.

Description

CYCLOSPORINE A TOPICAL COMPOSITIONS

FIELD OF THE INVENTION The invention relates to pharmaceutical compositions of cyclosporine A for topical application, to a process for the production of said compositions and to their use in medicine, particularly in the prevention and/or treatment of psoriasis or atopic dermatitis. BACKGROUND OF THE INVENTION

Cyclosporine A was discovered in 1972 while searching for novel antifungal agents. It is a cyclic polypeptide consisting of 11 amino acids and is produced as a metabolite by the fungus species Beauveria nivea. Although cyclosporine A was initially noted to have only a narrow antifungal spectrum, it was subsequently found to be a potent immunosuppressive drug in 1976.

Cyclosporine A was the first immunosuppressive drug found to act selectively on T cells. The helper T cell is the main target, but the T suppressor cell may also be affected. Cyclosporine A forms a complex with cyclophilin, an intracellular immunophilin, and inhibits the activity of calcineurin phosphatase, a calcium/calmodulin-dependent serine-threonine phosphatase. As a result, calcineurin phosphatase is unable to phosphorylate nuclear factor of activated T cells (NFAT), a transcription factor. NFAT requires phosphorylation before transportation to the nucleus for transcription of genes encoding interleukin-2 (IL-2), a cytokine that is necessary for full activation of the T-cell pathway, interferon-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Cyclosporine A depletes lymphocytes and macrophages in the epidermis and dermis and inhibits the activation of T cells, natural killer cells, and antigen-presenting cells. Cyclosporine A also inhibits keratinocyte hyperproliferation, inhibits the release of histamine from mast cells, and downregulates the expression of cellular adhesion molecules on dermal capillary endothelium [Amor et al, J. Am. Acad. Dermatol, 2010, 63, 925-946]. In 1978, cyclosporine A was found to be successful in preventing rejection in renal transplant patients who received mismatched cadaver kidneys. In 1979 it was observed that cyclosporine A improved psoriasis. In fact, cyclosporine A was approved by the FDA for the treatment of this disease in 1997. More recent reports, have disclosed that cyclosporine A is useful for the treatment of a variety of dermato logical diseases. In this regard, Amor et al. [J. Am. Acad. Dermatol, 2010, 63, 925-946] disclosed that cyclosporine A successfully treated atopic dermatitis, pyoderma gangrenosum and refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, epidermolysis bullosa acquisita, photodermatoses (such as chronic actinic dermatitis, polymorphic light eruption and solar urticaria), lichen planus, prurigo nodularis, alopecia areata, benign familiar pemphigus, eosinophilic pustular folliculitis, hidradenitis suppurativa and scleroderma. Cyclosporine A has also been used in veterinary dermatology; in particular, it has been reported [Kovalik et al, The Veterinary Journal, 2012, 193, 317- 325] to be useful for the treatment of atopic dermatitis, sebaceous adenitis, pemphigus foliaceus and erythematosus, vesicular cutaneous lupus erythematosus, and cutaneous reactive histiocytosis, in cats and dogs. Further dermatologic indications of cyclosporine A in veterinary have been reported by Palmeiro [Vet. Clin. Small Anim., 2013, 43, 154- 171], namely allergic dermatitis, eosinophilic granuloma complex, atopic dermatitis, perianal fistulas, sebaceous adenitis, pemphigus foliaceus and erythematosus, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, granulomatous folliculitis and furunculosis, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, mular folliculitis, alopecia areata, psudopelade, cutaneous reactive hitiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy, in cats and dogs. Cyclosporine A can also be used for the treatment of vitiligo due to its immunosuppressant activity, in particular due to its activity as calcineurin inhibitor, a class of drugs which have shown promising results in repigmentation of affected areas in patients with vitiligo [Caridi et al, Topical Calcineurin Inhibitors in the Treatment of Vitiligo in Bitiligo - Management and Therapy, Dr. Kelly KyunHwa Park Ed., 2001]. Cyclosporine A exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms were been developed for oral administration and for injection, such as Sandimmune^® and Neoral^® (Novartis Pharmaceuticals). However, systemic therapies, such as oral and intravenous administrations, have the drawback of producing significant side effects.

Thus, it is desirable to have topical cyclosporine A formulations suitable for topical administration of cyclosporine A, in particular to permit site specific delivery to the skin. The key challenges for topical delivery of this drug are its poor water solubility, high molecular weight and limited cutaneous permeation.

Ophthalmic emulsions containing cyclosporine A, glycerin, castor oil, polysorbate 80, carbomer copolymer A, and water, have been disclosed [US 8,642,556 B2; US 8,629,111 B2; US 8,618,064 B2; US 8,633,162 B2; US 8,648,048 B2; and US 8,685,930 B2], one of them being marketed under the trademark Restasis^®. However, the concentration of cyclosporine A in these emulsions is not greater than 0.1% by weight.

Topical compositions comprising higher concentrations of cyclosporine A, from 0.1 to 10%) by weight, can be formulated by using a polyalkyl ester of polycarboxylic acid, such as adipic, pimelic, azelaic, sebacic and phthalic dialkyl esters, as disclosed in US 5,891,846. However, manufacturing these formulations requires the use of complex equipment and/or processes.

Therefore, there is a need in the art to develop further topical compositions comprising cyclosporine A, in particular that allow the local delivery of cyclosporine A to skin compartment, capable of containing high concentrations of cyclosporine A, having high stability. It is also desirable that the preparation of these compositions avoid the use of toxic organic solvents or complex techniques.

SUMMARY OF THE INVENTION

The inventors have surprisingly found that compositions comprising a volatile alcohol, 2-(2-ethoxyethoxy)ethanol, a non- volatile organic solvent and a surfactant or mixture of surfactants having an HLB value from 10 to 18 and optionally a half C_1-4- alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, triacetin, water and/or a medium chain triglyceride, are capable of containing high concentrations of cyclosporine A. These compositions are stable and suitable for topical application.

The compositions of the invention have one or several advantages over other formulations of the prior art such as improved drug solubilization, skin bioadhesive properties, physical and chemical stability, percutaneous absorption, spontaneous formation, ease of manufacturing and scale-up and/or suitability for preparing formulations suitable for spraying. Said compositions are capable of solving all or some of the drawbacks related to other compositions of cyclosporine A, for example, low long-term stability, low encapsulation efficacy, poor drug solubilization, low percutaneous absorption, systemic absorption, high cost and complex production process which requires the use of toxic organic solvents or complex techniques.

The examples of the present invention show that the compositions of the invention have high stability under accelerated storage conditions both in terms of physical stability of the composition and chemical stability (in particular avoiding degradation of cyclosporine A) and are effective in the treatment of dermatological conditions.

In a first aspect, the invention relates to a topical pharmaceutical compositions comprising:

(a) from 0.1% w/w to 10%w/w of cyclosporine A relative to the total weight of the composition,

(b) a non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin,

(c) a volatile alcohol,

(d) 2-(2-ethoxyethoxy)ethanol,

(e) a surfactant or surfactant mixture having an HLB value from 10 to 18,

(f) optionally a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer,

(g) optionally a medium chain triglyceride,

(h) optionally water, and

(i) optionally triacetin; with the proviso that, when the composition comprises the half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.

In a second aspect, the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect comprising the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:

(i) providing cyclosporine A optionally in a mixture with a medium chain triglyceride and/ or triacetin,

(ii) preparing an homogeneous solution comprising the volatile alcohol and the nonvolatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, and the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer;

(iii) adding the solution obtained in step (ii) to the product of step (i) under stirring,

(iv) adding 2-(2-ethoxyethoxy)ethanol and the surfactant or surfactant mixture having an HLB value from 10 to 18to the mixture obtained in step (iii) and stirring until a homogeneous solution is obtained, and

(v) optionally adding water to the mixture obtained in step (iv) and stirring until a homogeneous solution is obtained.

In a third aspect, the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect which does not comprise the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:

(i) providing cyclosporine A optionally in a mixture with a medium chain triglyceride,

(ii) adding the volatile alcohol and the non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin to the product obtained in step (i) and stirring until a homogeneous solution is obtained, and

(iii) optionally adding water to the mixture obtained in step (ii) and stirring until a homogeneous solution is obtained. In a fourth aspect, the invention relates to a topical pharmaceutical composition as defined in the first aspect for use as a medicament, in particular a medicament for human or veterinary use.

In a fifth aspect, the invention relates to a topical pharmaceutical composition as defined in the first aspect for use in the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigonodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy.

In a sixth aspect, the invention relates to the use of a topical pharmaceutical composition as defined in the first aspect for the manufacture of a medicament for the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy; preferably selected from the group consisting of psoriasis, atopic dermatitis and allergic dermatitis.

In a seventh aspect, the invention relates to a method of prevention and/or treatment of a subject suffering from a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy, preferably a disease selected from the group consisting of psoriasis, atopic dermatitis and allergic dermatitis, comprising the administration to said subject of a topical pharmaceutical composition as defined in the first aspect.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical compositions

In a first aspect, the invention relates to a topical pharmaceutical composition comprising:

(a) from 0.1%w/w to 10% w/w of cyclosporine A relative to the total weight of the composition,

(c) a volatile alcohol,

(d) 2-(2-ethoxyethoxy)ethanol,

(e) a surfactant or surfactant mixture having an HLB value from 10 to 18, (f) optionally a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer,

(g) optionally a medium chain triglyceride,

(h) optionally water, and

(i) optionally triacetin;

with the proviso that, when the composition comprises the half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.

The compositions of the invention are suitable for topical application. The term

"topical" is used herein to designate application in the exterior of the body such as, without limitation, the skin, scalp and nails; and also the application to mucosae such as, without limitation, buccal, nasal or rectal mucosae.

The term "pharmaceutical", as used herein, means that the compositions of the invention are pharmaceutically acceptable to the patient (such as a mammal) from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view, due to the identity of the components forming the composition.

The term "w/w", in the context of the present invention, relates to the weight of each component relative to the total weight of the composition, unless otherwise stated.

Component (a) in the pharmaceutical compositions of the present invention is cyclosporine A.

The term "cyclosporine A", as used herein, refers to a cyclic undecapeptide compound with chemical name (3S,6S,9S, 12iU5S, 18S,21S,24S,30S,33S)-30-ethyl-33- [( 1R,2R,4E)- 1 -hydroxy-2-methyl-4-hexen- 1 -yl]-6,9, 18,24-tetraisobutyl-3 ,21 - diisopropyl-1 ,4,7, 10, 12, 15, 19,25, 28-nonamethyl- 1 ,4,7, 10, 13, 16, 19,22,25,28,31- undecaazacyclotritriacontane-2, 5, 8, 1 1 ,14, 17,20,23,26,29, 32-undecone or cyclo[[(E)- (25',3i?,4i?)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl-N- methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N- methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] and having the chemical formula:

Cyclosporine A is a calcineurin phosphatase inhibitor, having potent immunosuppressive activity.

The compositions of the invention comprise from 0.1% w/w to 10% w/w by weight of cyclosporine A relative to the total weight of the composition, preferably from 0.1%) w/w to 7% w/w, more preferably from 0.1 % w/w to 5% w/w, still more preferably from 1% w/w to 7% w/w, still more preferably from 1% w/w to 5% w/w, even more preferably from 3% w/w to 5% w/w, even more preferably about 5% w/w.

In the context of the present invention, the term "about" refers to the indicated value ± 5% of said value, preferably to the indicated value ± 1% of said value.

Component (f) in the pharmaceutical composition of the present invention is a half Ci-4-alkyl ester of a poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer. This component may be present or absent. When present, it provides adhesive properties to the product, therefore enhancing its adhesion to the skin. When component (f) is present, the composition of the invention does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.

As used herein, the term "Ci-4-alkyl" refers to a linear or branched saturated monovalent hydrocarbon chain containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

The terms "half C₁-₄-alkyl ester of a poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer" or "half C₁-₄-alkyl ester of a PVM/MA copolymer" are used interchangeably here and refer to water-insoluble copolymers that are water- soluble when neutralized by bases in aqueous solution and having a structure of formula

wherein R is a Ci-4-alkyl, i.e. PVM/MA copolymer ester in which only one of the two carboxyl groups is esterified. These half esters include the half ester form of PVM/MA with different alkyl chain lengths (such as monoethyl ester, wherein R is ethyl; monobutyl ester, wherein R is butyl; and isopropyl ester, wherein R is isopropyl). Said copolymers are commercialized by International Specialty Products (ISP) under trademark Gantrez® ES and include Gantrez® ES 225 (monoethyl ester), Gantrez® ES 425 (monobutyl ester) and Gantrez® ES335I (isopropyl ester) and are supplied as alcoholic solutions, for example, in ethanolic solutions [50% (w/v)].

In a particular embodiment, the half Ci-4-alkylalkyl ester of a PVM/MA copolymer is selected from the group consisting of ethyl ester of a PVM/MA copolymer, isopropyl ester of a PVM/MA copolymer and n-butyl ester of a PVM/MA copolymer; more preferably n-butyl ester of a PVM/MA copolymer.

In a particular embodiment, the composition of the invention comprises from

0.01 to 5% w/w of a half Ci-4-alkyl alkyl ester of a PVM/MA copolymer, preferably from 0.01 to 1% w/w, more preferably from 0.05 to 0.2% w/w.

When the half Ci-4-alkylalkyl ester of a PVM/MA copolymer is present in the compositions of the invention, it is dissolved in a volatile alcohol, in a non-volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, or in a mixture of one or several volatile alcohol and one or several non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, i.e. in components (b) and (c) of the composition of the invention.

The term "non-volatile organic solvent", as used herein, refers to an organic liquid that does not evaporate easily or evaporates very slowly at room temperature, i.e. that has vapor pressure lower than 1 kPa at 25 °C and boiling point higher than 1 10 °C at standard atmospheric pressure (101.325 kPa), but which does not include 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin. Thus, 2-(2-ethoxyethoxy)ethanol, some surfactants having an HLB value from 10 to 18 and triacetin are not considered within the scope of non-volatile organic solvent in the compositions of the present invention and, therefore, they are explicitly excluded from this category (component (b)). Exemplary non- volatile organic solvents other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, that can be used in the present invention include, without limitation, propylene glycol and polyethylene glycol. Preferably, the non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, i.e. component (b), is propylene glycol. The non-volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, also encompasses a mixture of one or more non-volatile organic solvents as herein defined, such as a mixture of one, two or three non-volatile organic solvents as herein defined, preferably only one non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin.

In a particular embodiment the composition of the invention comprises from 5% w/w to 20% w/w of a non-volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin; preferably from 7% w/w to 17% w/w when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer, or alternatively from 10% w/w to 20% w/w when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 10%> w/w to 15%> w/w when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 13% w/w to 18% w/w when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.

In a preferred embodiment the non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin is propylene glycol. The term "propylene glycol", refers to propane- 1 ,2-diol.

In a particular embodiment the composition of the invention comprises from 5% w/w to 20%) w/w of is propylene glycol; preferably from 7%> w/w to 17%> w/w of propylene glycol when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer, or alternatively from 10% w/w to 20% w/w of propylene glycol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 10% w/w to 15% w/w of propylene glycol when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 13% w/w to 18% w/w of propylene glycol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.

Component (c) in the pharmaceutical compositions of the present invention is a volatile alcohol.

A "volatile alcohol", as used herein, refers to a liquid alcohol that vaporizes/evaporates easily at room temperature; a volatile alcohol usually has a vapor pressure higher than 1 kPa at 25 °C and a boiling point lower than 1 10 °C. The term "alcohol" refers to a linear or branched saturated monovalent hydrocarbon chain containing the indicated number of carbon atoms, typically from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, said hydrocarbon chain being linked to an OH group. Examples of volatile alcohols are methanol, ethanol, isopropanol, isobutanol, etc.

In a particular embodiment the composition of the invention comprises from 5% w/w to 20%) w/w of a volatile alcohol; preferably from 5% w/w to 15% w/w of a volatile alcohol when the composition does not comprise the half C₁-₄-alkylalkyl ester of a PVM/MA copolymer or alternatively from 7% w/w to 17% w/w of a volatile alcohol when the composition contains the half C₁-₄-alkylalkyl ester of a PVM/MA copolymer; more preferably from 7% w/w to 1 1% w/w of a volatile alcohol when the composition does not comprise the half C₁-₄-alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 14% w/w of a volatile alcohol when the composition contains the half C₁-₄-alkylalkyl ester of a PVM/MA copolymer.

In a preferred embodiment the volatile alcohol is ethanol.

In a particular embodiment the composition of the invention comprises from 5% w/w to 20%) w/w of ethanol; preferably from 5% w/w to 15% w/w of ethanol when the composition does not comprise the half C₁-₄-alkylalkyl ester of a PVM/MA copolymer or alternatively from 7% w/w to 17% w/w of ethanol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 7% w/w to 1 1% w/w of ethanol when the composition does not comprise the half C₁-₄-alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 14% w/w of ethanol when the composition contains the half C₁-₄-alkylalkyl ester of a PVM/MA copolymer Component (d) in the pharmaceutical compositions of the present invention is 2- (2-ethoxyethoxy)ethanol .

2-(2-Ethoxyethoxy)ethanol is commercialized under the name transcutol.

In a particular embodiment the composition of the invention comprises from 15% w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol; preferably from 18% w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol when the composition does not comprise the half Ci- 4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 25% w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 20% w/w to 25% w/w of 2-(2- ethoxyethoxy)ethanol when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 25% w/w to 32% w/w of 2-(2- ethoxyethoxy)ethanol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.

Component (g) in the pharmaceutical compositions of the present invention is a medium chain triglyceride. This component may be present or absent. When present, the composition of the invention does not comprise a half Ci-4-alkylalkyl ester of a PVM/MA copolymer.

The term "medium-chain triglyceride" or "MCT", as used herein, refers to triglycerides triesters of glycerol and 6-12 carbon fatty acid. The fatty acids found in medium-chain triglycerides are called medium-chain fatty acids. Like all triglycerides (fats and oils), medium-chain triglycerides are composed of a glycerol backbone and three fatty acids. In the case of medium-chain triglycerides, 2 or 3 of the fatty acid chains attached to glycerol are medium-chain in length. The three fatty acids of the MCT can be the same or different, preferably there are two different fatty acids. Examples of medium fatty acids are caproic or hexanoic acid (C6:0), caprylic or octanoic acid (C8:0), capric or decanoic acid (C10:0) and lauric or dodecanoic acid (C12:0).

In a particular embodiment the composition of the invention comprises from 15% w/w to 25% w/w of a MCT, preferably from 19% w/w to 23% w/w of a MCT.

In a preferred embodiment, the medium chain triglyceride is caprylic/capric acid triglyceride. In a particular embodiment the composition of the invention comprises from 15% w/w to 25% w/w of caprylic/capric acid triglyceride, preferably from 19%> w/w to 23%o w/w of caprylic/capric acid triglyceride.

Component (e) in the pharmaceutical compositions of the present invention is a surfactant or surfactant mixture having an HLB value from 10 to 18.

The term "surfactant", as used herein, refers to a compound that lowers the surface tension or interfacial tension between two liquids or between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming agents and dispersants.

The term "HLB" refers to the hydrophilic- lipophilic balance and is a measure of the degree to which a surfactant is hydrophilic or lipophilic. The HLB values of surfactants are widely reported in the literature [see for example Griffin, Journal of the Society of Cosmetic Chemists, 1949, 1, 31 1-326; Raymond C Rowe, Poul, J. Sheskey, Marian E Quinn (Eds). Handbook of pharmaceutical excipients. Published by the Pharmaceutical Press and the American Pharmacists Association. Sixth edition, 2009]. When two or more surfactants are present in the composition of the invention, the total HLB_t value of the mixture of said two or more nonionic surfactants is calculated as the weight average of the HLB values of the two or more nonionic surfactants (see following equation (1)).

HLB_t = (∑Wi -HLB_t) / (∑Wi) Equation (1)

wherein Wi and HLBi indicate the weight and the HLB value of the i-th nonionic surfactant, respectively

Surfactants having an HLB value from 10 to 18 that can be used in the present invention are, among others, polysorbates and poloxamers.

Polysorbates refer to esters of sorbitan with fatty acids such as lauric acid, palmitic acid, stearic acid and oleic acid. The number following the polysorbate part is related to the type of fatty acid associated with the polyoxyethylene sorbitan part of the molecule. Monolaurate is indicated by 20, monopalmitate is indicated by 40, monostearate by 60 and monooleate by 80. Non-limiting examples of polysorbates having an HLB value from 10 to 18 that can be used in the present invention arepolysorbate-20, polysorbate-21 , polysorbate-40, polysorbate-60, polysorbate-65, polysorbate-80 and polysorbate-81. Poloxamers refer to polyoxyethylene-polyoxypropylene copolymers. Non- limiting examples of poloxamers having an HLB value from 10 to 18 that can be used in the present invention are poloxamer 184 and poloxamer 185. The particular poloxamers are followed by a number, the first two digits of which, when multiplied by 100, correspond to the approximate average molecular weight of the polyoxypropylene portion of the copolymer, and the third digit, when multiplied by 10, corresponds to the percentage by weight of the polyoxyethylene portion.

Mixtures of surfactants can also be used.

In a particular embodiment the composition of the invention comprises from 8% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18; preferably from 8% w/w to 18% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18 when the composition does not comprise the half Ci-₄- alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18 when the composition contains the half Ci-₄-alkylalkyl ester of a PVM/MA copolymer; more preferably from 10% w/w to 15% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18 when the composition does not comprise the half Ci-₄- alkylalkyl ester of a PVM/MA copolymer or alternatively from 15% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18 when the composition contains the half Ci-₄-alkylalkyl ester of a PVM/MA copolymer.

In a preferred embodiment, the surfactant is polysorbate 80. The term "polysorbate 80", also known as Tween 80, refers to a nonionic surfactant and emulsifier often used in foods and cosmetics. The synthetic compound is a viscous, water-soluble yellow liquid derived from polyethoxylated sorbitan and oleic acid. Its full chemical name is polyoxyethylene (20) sorbitan monooleate or (x)-sorbitan mono- 9-octadecenoate poly(oxy-l ,2-ethanediyl). Its chemical formula is:

In a particular embodiment the composition of the invention comprises from 8% w/w to 20% w/w of polysorbate 80; preferably from 8% w/w to 18% w/w of polysorbate 80 when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 20% w/w of polysorbate 80 when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 10% w/w to 15% w/w of polysorbate 80 when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 15% w/w to 20% w/w of polysorbate 80 when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.

Component (h), i.e. water, is optionally present in the pharmaceutical compositions of the present invention.

In one embodiment water is present in the compositions of the invention. In another embodiment, the composition of the invention is water-free.

The term "water- free" when characterizing the composition of the invention refers compositions substantially free from water. However, the water-free composition of the invention may contain non-significant quantities of water coming from the rest of the components of the formulation. Particularly, the water-free composition of the invention does not comprise more than 2% w/w of water. The water-free composition of the invention may comprise between 0% w/w and 2% w/w of water. In particular, unless explicit reference is made to the presence of water, the compositions of the invention are substantially free from water, i.e. do not comprise more than 2% w/w of water. The water-free compositions of the invention have particularly advantageous organoleptic properties and extensibility on the skin. Thus, preferably the compositions of the invention are water-free.

Component (i) is optionally present in the pharmaceutical compositions of the present invention and is triacetin. Preferably, the compositions of the invention comprise triacetin.

The term "triacetin", as used herein, is the triglyceride 1 ,2,3-triacetoxypropane and is also known as glycerin triacetate or l ,3-diacetyloxypropan-2-yl-acetate and its chemical formula is the following:

In one embodiment triacetin is present in the composition of the invention. In a particular embodiment the composition of the invention comprises from 10% w/w to 25% w/w of triacetin; preferably from 10% w/w to 20% w/w of triacetin when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 15% w/w to 25% w/w of triacetin when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 15% w/w to 19% w/w of triacetin when the composition does not comprise the half C₁-4- alkylalkyl ester of a PVM/MA copolymer or alternatively from 20% w/w to 23% w/w of triacetin when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.

In a preferred embodiment, the compositions of the invention comprise either component (f) (i.e. the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer) or component (g) (i.e. the medium chain triglyceride).

In a particular embodiment, the composition of the present invention comprises:

(a) from 0.1 %> w/w to 10%> w/w of cyclosporine A,

(b) from 5% w/w to 20% w/w of a non-volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin,

(c) from 5% w/w to 20%> w/w of a volatile alcohol,

(d) from 15%) w/w to 35%> w/w of 2-(2-ethoxyethoxy)ethanol,

(e) from 8% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(f) optionally from 0.01% w/w to 5% w/w of a half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer,

(g) optionally from 15 > w/w to 25% w/w of a medium chain triglyceride,

(h) optionally water, and

(i) optionally from 10%> w/w to 25% w/w of triacetin, wherein w/w is the weight of each component relative to the total weight of the composition, and with the proviso that, when the composition comprises the half C1-4- alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medicum chain triglyceride and isopropyl myristate.

In a particular embodiment, the composition of the invention is as described in the paragraph above but being water- free and comprising triacetin.

In another particular embodiment, the composition of the present invention comprises:

(a) from 1% w/w to 7% w/w of cyclosporine A,

(c) from 5%> w/w to 20%> w/w of a volatile alcohol,

(d) from 15%) w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol,

(g) optionally from 15%> w/w to 25 %> w/w of a medium chain triglyceride,

(h) optionally water, and

(i) optionally from 10%> w/w to 25 %> w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition, and with the proviso that, when the composition comprises the half C1-4- alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medicum chain triglyceride and isopropyl myristate.

(a) from 1%> w/w to 5%> w/w of cyclosporine A, (b) from 5% w/w to 20% w/w of a non-volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin,

(c) from 5%> w/w to 20%> w/w of a volatile alcohol,

(d) from 15%) w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol,

(g) optionally from 15% w/w to 25% w/w of a medium chain triglyceride,

(h) optionally water, and

(i) optionally from 10%> w/w to 25% w/w of triacetin,

In a preferred embodiment, the composition of the present invention comprises: (a) from 1% w/w to 7% w/w of cyclosporine A,

(b) from 7% w/w to 17% w/w of a non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin,

(c) from 5%> w/w to 15% w/w of a volatile alcohol,

(d) from 18% w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol,

(e) from 8% w/w to 18% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18, and

(g) optionally from 15% w/w to 25% w/w of a medium chain triglyceride, and

(i) from 10%) w/w to 25% w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer. In a particular embodiment, the composition of the invention described in the paragraph above is water-free.

In a particular embodiment, the composition of the present invention comprises: (a) from 1% w/w to 5% w/w of cyclosporine A,

(c) from 5%> w/w to 15% w/w of a volatile alcohol,

(d) from 18% w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol,

(e) from 8% w/w to 18% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(g) optionally from 15% w/w to 25% w/w of a medium chain triglyceride, and

(i) from 10%) w/w to 25% w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.

In a particular embodiment, the composition of the invention described in the paragraph above is water-free.

In a particular embodiment, the composition of the present invention comprises: (a) from 1% w/w to 7% w/w of cyclosporine A,

(b) from 10% w/w to 15% w/w of a non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin,

(c) from 7%) w/w to 1 1% w/w of a volatile alcohol,

(d) from 20%) w/w to 25% w/w of 2-(2-ethoxyethoxy)ethanol,

(e) from 10% w/w to 15% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(g) optionally from 19% w/w to 23% w/w of a medium chain triglyceride, and

(i) from 15%) w/w to 19% w/w of triacetin,

In a particular embodiment, the composition of the invention described in the paragraph above is water-free. In a particular embodiment, the composition of the present invention comprises:

(a) from 1% w/w to 5% w/w of cyclosporine A,

(b) from 10% w/w to 15% w/w of a non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, (c) from 7% w/w to 1 1% w/w of a volatile alcohol,

(d) from 20%) w/w to 25% w/w of 2-(2-ethoxyethoxy)ethanol,

(g) optionally from 19%> w/w to 23% w/w of a medium chain triglyceride, and

(i) from 15% w/w to 19% w/w of triacetin,

In a particular embodiment, the composition of the invention described in the paragraph above is water- free.

In a preferred embodiment, the composition of the present invention comprises:

(a) from 1% w/w to 7% w/w of cyclosporine A,

(b) from 10% w/w to 20% w/w of a non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, (c) from 7% w/w to 17% w/w of a volatile alcohol,

(d) from 25% w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol,

(e) from 10% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(f) from 0.01% w/w to 1% w/w of a half Ci-4-alkyl ester of a poly(methyl vinyl ether- co-maleic anhydride) (PVM/MA) copolymer, and

(i) from 15%) w/w to 25% w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.

In a particular embodiment, the composition of the invention described in the paragraph above is water-free. In a preferred embodiment, the composition of the present invention comprises:

(a) from 1% w/w to 5% w/w of cyclosporine A,

(d) from 25% w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol,

(i) from 15%) w/w to 25% w/w of triacetin,

(b) from 13% w/w to 18% w/w of a non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin,

(c) from 10%) w/w to 14% w/w of a volatile alcohol,

(d) from 25%) w/w to 32% w/w of 2-(2-ethoxyethoxy)ethanol,

(e) from 15% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(f) from 0.05% w/w to 0.2% w/w of a half C₁-₄-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, and

(i) from 20%) w/w to 23% w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate. In a particular embodiment, the composition of the invention described in the paragraph above is water-free.

(c) from 10%) w/w to 14% w/w of a volatile alcohol,

(d) from 25%) w/w to 32% w/w of 2-(2-ethoxyethoxy)ethanol,

(f) from 0.05% w/w to 0.2% w/w of a half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, and

(i) from 20%) w/w to 23% w/w of triacetin,

In the particular and preferred embodiments described above, preferably the half

Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer (component (f)), when present in the composition, is the half n-butyl ester of a PVM/MA copolymer, the non- volatile organic solvent capable other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin (component (b)) is propylene glycol, the volatile alcohol (component (c)) is ethanol, the medium chain triglyceride (component (g)), when present in the composition, is caprylic/capric acid triglyceride, and the surfactant having and HLB value from 10 to 18 (component (e)) is polysorbate 80.

The particular and preferred compositions described above may also comprise other amounts of cyclosporine A, such as from 0.1 % w/w to 7% w/w by weight of cyclosporine A relative to the total weight of the composition, from 0.1% w/w to 5% w/w, from 3%) w/w to 5% w/w, or about 5% w/w, in particular when the half C₁-₄-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer (component (f)), when present in the composition, is the half n-butyl ester of a PVM/MA copolymer, the non- volatile organic solvent capable other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin (component (b)) is propylene glycol, the volatile alcohol (component (c)) is ethanol, the medium chain triglyceride (component (g)), when present in the composition, is caprylic/capric acid triglyceride, and the surfactant having and HLB value from 10 to 18 (component (e)) is polysorbate 80.

In a particular embodiment, the composition of the invention does not comprise neither component (f) (i.e. the half Ci-4-alkylester of a poly(methyl vinyl ether-co- maleic anhydride) (PVM/MA) copolymer) nor component (g) (i.e. the medium chain triglyceride).

In a particular embodiment, the composition consists of the ingredients explicitly mentioned with respect to any of the embodiments described herein, i.e. they do not comprise ingredients other than those explicitly mentioned.

The compositions of the invention do not require the use of preservatives. Therefore, in another embodiment, the composition does not contain additional preservatives. By "additional preservatives", as used herein, is understood as substances added to pharmaceutical products to prevent decomposition by microbial growth or by undesirable chemical changes. Additional preservatives include antimicrobial additives and antioxidants.

Although it is not required to add additional preservatives, the compositions of the invention may contain preservatives. Exemplary preservatives that can be used in the compositions of the invention include, without limitation, potassium sorbate, sodium benzoate, phenoxy ethanol, sorbic acid, thimerosal, benzalkonium chloride, parabens, etc.

In another embodiment, the composition does not contain oleic acid.

In another embodiment, the composition does not contain additional preservatives and oleic acid.

The compositions of the present invention are stable and allow formulating high concentrations of cyclosporine A, without the use of a polyalkyl ester of polycarboxylic acid, such as adipic, pimelic, azelaic, sebacic and phthalic dialkyl esters. The term "polyalkyl ester of polycarboxylic acid", as used herein, refers to the polyalkyl ester of polycarboxylic acids disclosed in US 5,891,846 (which is incorporated by reference with respect to their definition), and are defined as those which are liquid at ordinary temperature. The esters having a total carbon atom number of 10 to 25 are preferable and the esters having polycarboxylic acids having at least two carboxyl groups and linear or branched alcohols, in which the carboxyl group may be an aliphatic group, aromatic aliphatic group, or aromatic group having the carboxyl groups bonded aliphatically or aromatically are preferable. Partial ester compounds may also be used. These esters may be used alone or in a mixture of two kinds or more. Specific examples include adipic dialkyl esters of a total of 12 to 22 carbon atoms, pimelic dialkyl esters having a total of 13 to 23 carbon atoms, sebacic dialkyl esters having a total of 14 to 22 carbon atoms, phthalic dialkyl esters having a total of 14 to 24 carbon atoms (these alkyl groups may be straight or branched and the alkyl portion of the dialkyl may be the same or different). Preferable examples are dibutyl phthalate, diethyl phthalate, diiso butyl phthalate, dibutyl sebacate, diethyl sebacate, diisopropyl azelate, diisopropyl adipate, dibutyl adipate, and diisobutyl adipate.

Thus, in a particular embodiment, the composition of the present invention does not contain a polyalkyl ester of polycarboxylic acid. In another particular embodiment, the composition does not contain additional preservatives and a polyalkyl ester of polycarboxylic acid.

The composition of the invention may contain excipients. The term "excipient", as used herein, refers to an inactive substance that can be liquid, solid or semisolid, used as a medium or carrier for the active ingredients of a composition. Illustrative, non- limitative examples of excipients are butyl hydroxytoluene (BHT), liquid paraffin or melted lipids such as wax, cotton oil, hydrogenated vegetable oil, canola oil, coconut oil, etc. Thickening agents, i.e. substances that increase the viscosity of the compositions, may also be added to the compositions of the invention.

The person skilled in the art knows that the compositions of the invention may be administered in the form of pharmaceutical compositions comprising cyclosporine A as a sole active ingredient or in combinations with other active ingredients.

The pharmaceutical compositions of the invention can be administered by different topical routes such as, without limitation, cutaneous, buccal, nasal or rectal route. In a preferred embodiment they are applied on the skin, i.e. cutaneous route, preferably by spraying. More preferably they are applied by massage.

Process for producing the pharmaceutical compositions

The process used for the preparation of the pharmaceutical compositions of the invention depends on the presence of absence of the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.

In the second aspect, the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect comprising the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:

(i) providing cyclosporine A optionally in a mixture with a medium chain triglyceride and/or triacetin,

(ii) preparing an homogeneous solution comprising the volatile alcohol and the non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an

HLB value from 10 to 18 and triacetin, and the half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer;

(iii) adding the solution obtained in step (ii) to the product obtained in step (i) under stirring,

(iv) adding 2-(2-ethoxyethoxy)ethanol and the surfactant or surfactant mixture having an HLB value from 10 to 18 to the mixture obtained in step (iii) and stirring until a homogeneous solution is obtained, and

Step (i) comprises providing cyclosporine A, optionally in a mixture with the medium chain triglyceride and/or triacetin. When the medium chain triglyceride and/or triacetin is present, the cyclosporine A and medium chain triglyceride and/or triacetin mixture is stirred until complete dissolution of cyclosporine A or until an homogeneous suspension is obtained, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least three hours.

Step (ii) comprises mixing the volatile alcohol and the non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, and the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, and stirring until the copolymer is completely dissolved, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least one hour.

Step (iii) comprises adding the solution obtained in step (ii) to the cyclosporine

A product obtained in step (i) under stirring, preferably at room temperature (20-25°C).

Step (iv) comprises adding 2-(2-ethoxyethoxy)ethanol and the surfactant or surfactant mixture having an HLB value from 10 to 18 to the mixture obtained in step

(iii) and stirring until a homogeneous solution is obtained, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least five hours. If other excipients are present in the composition of the invention, they are added at this step. At the end of step (iv), a clear solution is obtained.

Finally, for those compositions of the invention comprising water, step (v) is performed. This step comprises adding water to the mixture obtained in step (iv) and stirring until a homogeneous solution is obtained, preferably at room temperature (20-

25°C).

In the third aspect, the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect which does not comprise the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:

(iii) optionally adding water to the mixture obtained in step (ii) and stirring until a homogeneous solution is obtained.

Step (i) comprises providing cyclosporine A, optionally in a mixture with the medium chain triglyceride. When the medium chain triglyceride is present, the cyclosporine A and medium chain triglyceride mixture is stirred until complete dissolution of cyclosporine A or until an homogeneous suspension is obtained, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least three hours.

Step (ii) comprises adding the volatile alcohol and the non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin to the product obtained in step (i) and stirring until a homogeneous solution is obtained. In particular the stirring is carried out for at least five hours. If other excipients are present in the composition of the invention, they are added at this step. At the end of step (ii), a clear solution is obtained.

Finally, for those compositions of the invention comprising water, step (iii) is performed. This step comprises adding water to the mixture obtained in step (ii) and stirring until a homogeneous solution is obtained, preferably at room temperature (20- 25°C).

Medical uses of the pharmaceutical compositions

The pharmaceutical compositions of the invention can be applied for the treatment of all diseases that can be topically treated with cyclosporine A, said diseases being disclosed in the background section of the present document.

Thus, in the fourth aspect, the invention relates to a topical pharmaceutical composition of the invention for use as a medicament, in particular a medicament for human or veterinary use.

In a fifth aspect, the invention relates to a topical pharmaceutical composition as defined in the first aspect for use in the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy; preferably psoriasis, atopic dermatitis or allergic dermatitis.

In another aspect, the invention relates to the use of a topical pharmaceutical composition of the invention for the manufacture of a medicament for the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy; preferably psoriasis, atopic dermatitis or allergic dermatitis.

In another aspect, the invention relates to a method of prevention and/or treatment of a subject suffering from a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy, preferably psoriasis, atopic dermatitis or allergic dermatitis, comprising the administration to said subject of a topical pharmaceutical composition of the invention.

In one particular embodiment of the aspects defined above, the disease is psoriasis.

In another particular embodiment of the aspects defined above, the disease is atopic dermatitis.

In another particular embodiment of the aspects defined above, the disease is allergic dermatitis.

In another particular embodiment of the aspects defined above, the disease is psoriasis or atopic dermatitis.

The term "prevention", as used herein, refers to the administration of the composition of the invention in an initial or early stage of a disease, or to also prevent its onset.

The term "treatment" is used to designate the administration of the composition of the invention to control disorder progression before or after the clinical signs had appeared. By control of the disorder progression it is meant to designate beneficial or desired clinical results including, but not limited to, reduction of symptoms, reduction of the length of the disorder, stabilization pathological state (specifically avoidance of further deterioration), delay in the disorder's progression, improvement of the pathological state and remission (both partial and total). In a particular embodiment of the invention the composition of the invention is used to control the disorder progression once at least one of the disorder's clinical signs has appeared.

The term "medicament", as used herein, refers to a pharmaceutical composition of the invention comprising cyclosporine A. The medicament may be administered by any suitable topical route. It is prepared by conventional means with pharmaceutically acceptable excipients. Formulations for application on the skin are preferred.

The term "subject", as used herein, refers to any animal or human that is suffering from one of the diseases disclosed above. Preferably, the subject is a mammal. The term "mammal", as used herein, refers to any mammalian species, including but not being limited to domestic and farm animals (cows, horses, pigs, sheep, goats, dogs, cats or rodents), primates, and humans. Preferably, the mammal is selected from a human being, a dog, a cat and a horse. In the context of the present invention, the mammal is suffering from a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy, preferably psoriasis, or in risk of suffering from one of said diseases.

All the embodiments disclosed in the context of the compositions of the invention are applicable to the medical uses of the pharmaceutical compositions of the invention.

The invention is described below by means of several examples which do not limit, but rather illustrate the invention.

Examples

1. Materials

Cyclosporine A was purchased from Concorde Biothech Ltd. Caprylic/capric acid triglyceride (MCT), propylene glycol, and polysorbate 80 (Tween^® 80), were purchased from Guinama. Gantrez^®ES (poly(methyl vinyl ether-maleic acid monobutyl ester) (GES 425) was purchased from Sigma-Aldrich. 2-(2-ethoxyethoxy)ethanol P^® was purchased from Fagron. Triacetin and ethanol absolute were purchased from Panreac. Acetonitrile HPLC grade was purchased from Merck. 2. Equipment

- Biological and cytostatic safety cabinet. Telstar, Cytostar, 29045.

- Analytical balance. Mettler Toledo, XA 204 Delta Range.

- Analytical balance. OHAUS, PA114C.

- Ultrasonic bath. Bandelin, Sonorex Digitec DT100H.

- Heating Stove. INDELAB, IDL-CD-120.

- Climatic chambers MEMMERT, HPP 108.

- Water purification system. Millipore, Direct Q 3UV.

- Autoclave. Raypa, AH-21N2.

3. Cyclosporine A compositions for topical application

The following compositions were prepared:

* GES425 refers to the commercial Gantrez® ES (poly(methyl vinyl ether- maleic acid monobutyl ester) which is a solution of said polymer 50% w/w in ethanol.

20 g of compositions 1 and 3 were manufactured according to the following process:

- Cyclosporine A was weighed and MCT was added. This solution was kept under magnetic stirring at room temperature for at least three hours. - To the previously described drug solution, the rest of the components were added in this order: ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, tween 80 and triacetin. The mixture was kept under vigorous magnetic stirring at room temperature for at least five hours until a clear and homogeneous solution was obtained.

20 g of compositions 2 and 4 were manufactured according to the following process:

- The necessary amount of Cyclosporine A was weighed and triacetin was added. This solution was kept under magnetic stirring at room temperature for at least three hours.

- Ethanol, propylene glycol and GES425 (in this order) were mixed and kept under stirring for at least one hour.

- To the previously prepared drug solution and under constant magnetic stirring, the previously prepared GES425 solution, 2-(2-ethoxyethoxy)ethanol and tween 80 were added (in this order). The mixture was kept under stirring for at least five hours at room temperature until a clear and homogeneous solution was obtained.

Compositions 1-4 showed appropriate properties to be administered by spraying.

4. Stability studies

Physical stability

The cyclosporine A- loaded topical compositions 1-4 described previously (5-7 mL) were kept for one week at 40 °C and 75% RH. Then they were subjected to stress conditions, i.e. three freezing cycles of 15 hours at -20 °C followed by 2 h at 80 °C. All the formulations were stable by macroscopical examination (i.e. the formulations remained transparent).

The cyclosporine A- loaded topical compositions 1-4 described previously (5-7 g) were kept at 25 °C and 60% RH and at 40 °C and 75% RH. The compositions remained stable after 3 months by macroscopical examination (i.e. the formulations remained transparent). Chemical stability

The cyclosporine A- loaded topical compositions 1-4 described previously (5-7 g) were kept at 25 °C and 60% RH at 40 °C and 75% RH for three months. The formulations were analyzed by HPLC chromatography before and after the three month storage.

HPLC chromatographic conditions of formulations 1 and 2:

- analytical column: Agilent Zorbax SB-C18 (250 x 4.6 mm) 5 μιη, 100 A with the following guard-column: Zorbax SB-18 (12.5 x 4.6 mm)

- column temperature: 70 °C,

- mobile phase: ACN:H₂0 (75:25),

- flow: 2 mL/min,

- injection volume: 5 followed by a needle wash with mobile phase,

- detection wavelength: 210 nm

- flow cell: optical path length 60 mm.

The determination of cyclosporine A content was measured in triplicate by weighing 100 mg of each formulation into 10 mL volumetric flasks and then filling to the mark with acetonitrile for analysis.

HPLC chromatographic conditions of formulations 3 and 4:

- analytical column: Zorbax SB-Aq (150 x 4.6 mm) 5 μιη, 100 A with the following guard-column: Zorbax SB-Aq (12.5 x 4.6 mm)

- column temperature: 70 °C,

- mobile phase: ACN:H₂0 (65:35),

- flow: 2 mL/min,

- injection volume: 5 μΐ, followed by a needle wash with mobile phase,

- detection wavelength: 210 nm

- flow cell: optical path length 60 mm.

The determination of cyclosporine A content was measured in triplicate by weighing 200 mg of each formulation into 5 mL volumetric flasks and then filling to the mark with acetonitrile for analysis.

The relative error was calculated for each formulation as the concentration of cyclosporine A before storage with respect to the concentration after the period of storage and expressed as %. Formulations having a relative error of less than 5% were considered as chemically stable. Formulations having a relative error of 5% or more were considered as chemically unstable.

Compositions 1-4 remained stable after 3 months of storage. 5. Biological activity studies

The biological activity of compositions 1 and 2 described previously, applied topically, was assessed on the inflammation reaction produced by the induction of an allergic contact dermatitis on farm pigs' skin (a validated model of allergic dermatitis). As reference formulation a 0.1% tacrolimus commercially available formulation (Protopic 0.1%) was used.

Test animals

3 female (not siblings) pigs (Landrance x Large White from Pro labor) having a mean body weight of 16.6-20.6 kg were used. The animals were kept under standard laboratory conditions and received standard porcine feed and tap water ad libitum.

Administration route and volume

The treatments were applied topically to circular areas approximately 2 cm in diameter (3.14 cm² surface), on the back of the animals. The amount of the test formulation to be applied for each treatment was 30 μΐ on each application site.

Activity on allergic contact dermatitis

After an acclimatization period of 10 days, the sensitization started on what was considered day 1 of the study by means of topical administration of 100

of 10% difluoronitrobenzene (DNFB, Sigma Aldrich) on the ears (medial aspects) and groins of the animals. On day 4 of the study, 100

of DNFB was administered at a concentration of 2% on the ears of each animal, avoiding the application site of day 1. The application of DNFB on days 1 and 4 was performed by spreading the formulation on the cited areas. Four days before the challenge test, the animals were shaved to assure the correct application of the treatments. On day 12 of the study, the challenge was induced by means of the topical application of 20

of 1% DNFB on six application sites (2 cm in diameter) on each side of the back of the animals (12 application sites in total). The application sites were located in a dorsal position, avoiding the flexor area of the neck of the animals. The first application sites, with respect to a craniocaudal position, were reserved for the control (no treatment). The rest of treatments (including the treatment with the reference formulation) were applied after the control treatment position. Both the reference formulation treatment and the treatments corresponding to the test compositions were applied randomly in the application sites of all the animals. The three animals of the study were treated with the reference formulation and compositions 1 and 2. The assigned treatments were applied on the aforementioned sensitized areas 0.5 and 6 hours after the induction of the challenge. The application were applied and then massaged until they were absorbed. Before the application of the treatments at 6 h, the remainder of the test formulations was removed with gauze moistened with physiological saline. Each treatment was administered on two of the application sites on each animal (one application on each side of the back of the animal). No treatment was applied to the control sites. Twenty- four hours after the induction of the challenge, the remainder of the test formulations was removed with a gauze moistened with physiological saline and approximately four minutes later, the areas of the skin where the treatments were applied were evaluated.

Evaluation of results

The intensity and extension of the erythema and the consistency of the lesions was assessed on a scale of 0-4 according to the following criteria:

The means of the scores obtained were calculated for the different parameters to be evaluated, both per animal and per treatment group. The mean, standard error (SE), and the standard error of the mean (SEM) were calculated for each treatment group. The percentage of inhibition for each criteria (intensity, extension and consistency) was calculated for each treatment group using the following formula:

. _ (Mean global score) _control - (Mean global score) _treatment

(Mean global score)_control The values obtained for each animal were only accepted for the test when the score for the consistency lesion induced in the control treatment application site was greater than or equal to 2.

The criteria for the classification of the activity against the inflammation induced by the application of DNFB were the following:

Results

The percentage of inhibition of the different treatments (compositions 1 and 2 described previously and the reference treatment with Protopic 0.1%) with respect to the control treatment are gathered in the table below:

I=Intensity, E=Extension, C=Consistency

Compositions 1 and 2 showed good inhibitory response against the reaction induced by the application of DNFB.

Claims

1. A topical pharmaceutical composition comprising:

(c) a volatile alcohol,

(d) 2-(2-ethoxyethoxy)ethanol,

(e) a surfactant or surfactant mixture having an HLB value from 10 to 18,

(g) optionally a medium chain triglyceride,

(h) optionally water, and

(i) optionally triacetin;

2. The pharmaceutical composition according to claim 1 , wherein either component (f) or component (g) is present.

3. The pharmaceutical composition according to claim 1 or 2, wherein component (f) is the half n-butyl ester of a PVM/MA copolymer.

4. The pharmaceutical composition according to any one of the preceding claims, wherein component (b) is propylene glycol.

5. The pharmaceutical composition according to any one of the preceding claims, wherein component (c) is ethanol.

6. The pharmaceutical composition according to any one of the preceding claims, wherein component (g) is caprylic/capric acid triglyceride.

7. The pharmaceutical composition according to any one of the preceding claims, wherein component (e) is polysorbate 80.

8. The pharmaceutical composition according any one of the preceding claims, wherein component (a) is present in a concentration of 1% w/w to 7% w/w relative to the total weight of the composition, preferably in a concentration of 1% w/w to 5% w/w, more preferably in a concentration of about 5% w/w.

9. The pharmaceutical composition according to any one of the preceding claims, comprising:

(a) from 1% w/w to 7% w/w of cyclosporine A,

(b)from 7% w/w to 17% w/w of a non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin,

(c) from 5% w/w to 15% w/w of a volatile alcohol,

(d) from 18%) w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol,

(e)from 8% w/w to 18% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(f) from 15%) w/w to 25% w/w of a medium chain triglyceride, and

(i) from 10%) w/w to 20%> w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition and wherein the composition does not comprise a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.

10. The pharmaceutical composition according to any one of claims 1 to 8, comprising:

(a) from 1% w/w to 7% w/w of cyclosporine A,

(b)from 10% w/w to 20% w/w of a non-volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, (c) from 7% w/w to 17% w/w of a volatile alcohol,

(d) from 25% w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol,

(f) from 0.01% w/w to 1% w/w of a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, and

(i) from 15%) w/w to 25% w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition and wherein the composition does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.

1 1. The pharmaceutical composition according to any one of the preceding claims, which is water-free and wherein triacetin is present.

12. A process for producing a topical pharmaceutical composition as defined in any one of claims 1 to 1 1 comprising the half Ci-4-alkyl ester of a poly(methyl vinyl ether- co-maleic anhydride) (PVM/MA) copolymer, the process comprising:

(ii) preparing an homogeneous solution comprising the volatile alcohol and the nonvolatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, and the half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer;

13. A process for producing a topical pharmaceutical composition as defined in any one of claims 1 to 1 1 which does not comprise the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:

(i) providing cyclosporine A optionally in a mixture with a medium chain triglyceride, (ii) adding the volatile alcohol and the non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin to the product obtained in step (i) and stirring until a homogeneous solution is obtained, and

14. A topical pharmaceutical composition as defined in any one of claims 1 to 1 1 for use as a human or veterinary medicament.

15. A topical pharmaceutical composition as defined in any one of claims 1 to 1 1 for use in the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigonodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy, preferably selected from the group consisting of psoriasis, atopic dermatitis and allergic dermatitis.

16. Use of a topical pharmaceutical composition as defined in any one of claims 1 to 1 1 for the manufacture of a medicament for the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy; preferably selected from the group consisting of psoriasis, atopic dermatitis and allergic dermatitis.

17. Method of prevention and/or treatment of a subject suffering from a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo, eosinophilic granuloma complex, perianal fistulas, sebaceous adenitis, juvenile cellulitis, vesicular cutaneous lupus erythematosus, erythema multiforme, discoid lupus erythematosus, sterile nodular panniculitis, metatarsal fistulae, nasal arteritis, ulcerative dermatosis of nasal philtrum, facial dermatitis, sterile granuloma or pyogranuloma syndrome, pseudopelade, cutaneous reactive histiocytosis, feline plasma cell pododermatitis, vasculitis and ischemic dermatopathy, preferably a disease selected from the group consisting of psoriasis, atopic dermatitis and allergic dermatitis, comprising the administration to said subject of a topical pharmaceutical composition as defined in any one of claims 1 to 11.