WO2019002367A1

WO2019002367A1 - Topical compositions for the treatment of dermatological diseases

Info

Publication number: WO2019002367A1
Application number: PCT/EP2018/067247
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 comprising optionally a half C1-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, a non-volatile organic solvent, a volatile alcohol, 2-(2-ethoxyethoxy)ethanol, a surfactant or mixture of surfactants having an HLB value from 10 to 18. The invention also relates to the use of said compositions in the prevention and/or treatment of psoriasis and dermatitis.

Description

TOPICAL COMPOSITIONS FOR THE TREATMENT OF

DERMATOLOGICAL DISEASES

FIELD OF THE INVENTION

The invention relates to pharmaceutical compositions for topical application, and to their use in medicine, particularly in the prevention and/or treatment of dermatological diseases such as psoriasis and atopic dermatitis. BACKGROUND OF THE INVENTION

The human and animal skin is the outer organ of the body. In humans, it is the largest organ of the body and is composed of three layers: epidermis (which is the outermost layer of skin), dermis (which is beneath the epidermis, contains tough connective tissue, hair follicles and sweat glands) and hypodermis (which is the deeper subcutaneous tissue and is made of fat and connective tissue). Since the skin interfaces with the environment, it plays a key role in protecting the body against pathogens. The range of known skin or dermatological diseases is broad. Psoriasis and dermatitis are amongst the most common ones.

Psoriasis is a chronic, non-infectious, inflammatory disease of the skin. Psoriasis occurs when skin cells quickly rise from their origin below the surface of the skin and pile up on the surface before they have a chance to mature. Usually this movement (also called turnover) takes about a month, but in psoriasis it may occur in only a few days. It is characterized by the presence of sharply bounded plaques with a silvery-white scaling. The clinical picture of psoriasis is very broad, reaching from mild alterations of the skin to life-threatening systemic conditions. In over a third of the affected patients, a genetic predisposition can be determined. The disease can further be provoked or aggravated by factors such as trauma, infections, exposure to UV radiation, stress, artificial food products, alcohol, smoking or various medicaments. Sometimes, psoriasis is accompanied by joint disorders or autoimmune conditions. Treatment of psoriasis commonly uses topical medicaments such as tar preparations, dithranol, corticosteroids, vitamin D analogues or salicylic acid. More severe forms of the disease often have to be treated systemically using photochemical therapies, retinoids, methotrexate, hydroxyurea, azathioprine or cyclosporine. However, these treatments have severe side- effects and/or are not effective in some patients. In summary, treatments of more severe forms of psoriasis are costly, often show undesirable side-effects and have a varying efficacy.

Dermatitis, also known as eczema, is a group of diseases that results in inflammation of the skin. These diseases are characterized by itchiness, red skin and a rash. In cases of short duration there may be small blisters, while in long-term cases the skin may become thickened. The most common types of dermatitis include atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

Atopic dermatitis is more common in children, but can occur at any age. It is characterized by areas of severe itching, redness, scaling and loss of the surface of the skin. Atopic dermatitis is frequently associated with other allergic disorders, especially asthma and hay fever. In infants, eczema usually appears as tiny bumps on the cheeks. Older children and adults often experience rashes on the knees or elbows (often in the folds of the joints), on the backs of hands or on the scalp. Symptoms of atopic dermatitis (eczema) include: patches of skin that are red or brownish, itchy skin, especially at night, and dry cracked or scaly skin. Treatment of atopic dermatitis typically involves the use of topical steroids, immunomodulators, interleukin inhibitors and moisturizers; antibiotics may be required if there are signs of skin infection.

Contact dermatitis refers to an inflammation of the skin resulting from direct contact of a substance with the surface of the skin. Unlike atopic dermatitis, there is not necessarily a pre-disposition to allergic disease. Symptoms of contact dermatitis include red rash, bumps or a burn-like rash on the skin, itchy, painful or burning skin, blisters and draining fluid. There are two types of contact dermatitis: irritant contact dermatitis and allergic contact dermatitis. Irritant contact dermatitis is the most common form and is caused when substances such as solvents or other chemicals irritate the skin. The exposure produces red, often more painful than itchy, patches on the involved skin areas. Allergic contact dermatitis occurs when a substance triggers an immune response. Nickel, perfumes, dyes, rubber (latex) products, topical medications and cosmetics frequently cause allergic contact dermatitis. Contact dermatitis is typically treated with corticosteroids and antihistamines. Dermatological diseases, such as psoriasis and dermatitis, pose a serious and often chronic impairment of the quality of life of the affected subjects. These skin diseases also account for high costs in medical treatments and emotional suffering of patients. Current treatments involve the use of immunosuppressant drugs, antibiotics and other active ingredients. However, the use of these drugs has several drawbacks such as an in increased microbial resistance of the bacteria responsible for various skin diseases and severe side effects. Moreover, many patients do not comply with the often complex and tedious treatment protocols their practitioners prescribe. Therefore, alternative therapies for treating skin disorders that are safe, effective, easy to use and have a reduced cost are urgently needed, in particular the treatment of psoriasis and dermatitis (including atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis).

SUMMARY OF THE INVENTION

The inventors have surprisingly found that compositions comprising optionally a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, a non- volatile organic solvent, a volatile alcohol, 2-(2- ethoxyethoxy)ethanol, a surfactant or mixture of surfactants having an HLB value from 10 to 18, and optionally a medium chain triglyceride and triacetin are effective in the prevention and/or treatment of dermatological diseases such as psoriasis and dermatitis (in particular atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis), even when said compositions are devoid of any drug known in the art to be effective for the treatment of this type of diseases, such as cyclosporine A and other immunomodulators, antibiotics and steroids including corticosteroids. Thus, the compositions of the invention either do not contain any active ingredient or contain only minor amounts (less than 0.1 %w/w) of cyclosporine A as the sole active ingredient. These compositions are stable and suitable for topical application.

The compositions of the invention have several advantages over other formulations of the prior art such as high tolerance (on account of the fact that they elicit less or no side effects), skin bioadhesive properties, physical and chemical stability, percutaneous absorption, spontaneous formation, ease of manufacturing and scale-up, and suitability for preparing formulations suitable for spraying. Said compositions are capable of solving all or some of the drawbacks related to known treatments and formulations, for example, side effects, low long-term stability, low encapsulation efficacy, low percutaneous absorption, systemic absorption, high costs and complex production processes which require the use of toxic organic solvents or complex techniques.

The examples of the present invention shown that the compositions of the invention have high stability under accelerated storage conditions and are effective in the treatment of dermatological diseases, in particular of allergic contact dermatitis.

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

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

(b) a volatile alcohol, such as ethanol,

(c) 2-(2-ethoxyethoxy)ethanol,

(d) a surfactant or surfactant mixture having an HLB value from 10 to 18, such as polysorbate 80,

(e) less than 0.1%w/w of cyclosporine A relative to the total weight of the composition, preferably no cyclosporine A,

(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, and

(h) optionally triacetin.

In a second 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 third 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 and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

In a fourth aspect, the invention related 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 and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

In a fifth aspect the present invention relates to a method of preventing and/or treating a disease selected from the group consisting of psoriasis and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis, which method comprises administering to a patient in need thereof a therapeutically amount of a 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) a non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, such as propylene glycol

(b) a volatile alcohol, such as ethanol

(c) 2-(2-ethoxyethoxy)ethanol,

(d) a surfactant or surfactant mixture having an HLB value from 10 to 18, such as polysorbate 80

(e) less than 0.1%w/w of cyclosporine A relative to the total weight of the composition, preferably no cyclosporine A

(g) optionally a medium chain triglyceride, and

(h) optionally triacetin.

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 compositions.

Component (f) in the pharmaceutical compositions of the present invention is a half Ci-4-alkyl ester of a poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer. Preferably, said component is present in the compositions of the invention.

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 Ci-4-alkyl ester of a poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer" or "half d-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 preferred 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 about 0.05% w/w. The term "w/w", in the context of the present invention, refers to the weight of each component relative to the total weight of the composition, unless otherwise stated.

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.

In the pharmaceutical compositions of the invention the half Ci-4-alkylalkyl ester of a PVM/MA copolymer 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 a) of the composition of the invention.

The presence of the copolymer (component (f)) in the composition increases the stability of the composition and provides adhesive properties to the product, therefore enhancing its adhesion to the skin.

Preferably, the compositions of the invention are in the form of micro emulsions.

A "microemulsion" refers to a isotropic, thermodynamically stable transparent system made of droplets (i.e. the disperse phase), generally spherical droplets, this disperse phase being surrounded by the copolymer (component (f)) and with an average diameter of the disperse phase between 1 nm and 200 nm, preferably between 10 nm and 100 nm.

The term "average diameter" or "mean diameter", as used herein, relates to the average diameter of a population of droplets forming the disperse phase. The average size of these systems can be measured by standard processes known by persons skilled in the art such as Dynamic light scattering (DLS or photon correlation spectroscopy, PCS), that has been described as an appropriate method for measuring droplet size in microemulsions [Goddereris C. et al, International Journal of Pharmaceutics, 2006, 312, 187-195] and is well known to the skilled person.

When the compositions of the present invention are in the form of a microemulsion, it is believed that the disperse phase of said microemulsions contains part or all of the non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, component (a), and, when present, the medium chain triglyceride and cyclosporine A. Said disperse phase is surrounded by the PVM/MA copolymer. The non- volatile organic solvent other than 2- (2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, component (a), may be located in the disperse phase or both in the disperse phase and continuous phase. The polymer (component (f)) is located in the interphase between the disperse phase and the continuous phase of the microemulsion. The continuous phase of the microemulsions contains the remaining components.

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 and surfactants having an HLB value from 10 to 18. The nonvolatile organic solvents other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin useful in the present invention are preferably capable of solubilizing 10 mg of the half Ci-4-alkylalkyl ester of a PVM/MA copolymer per mL of solvent, in particular, when said copolymer is present in the compositions of the invention. 2-(2-ethoxyethoxy)ethanol and some surfactants having an HLB value from 10 to 18 are also capable of solubilizing the copolymer, but the compositions of the present invention need an organic solvent different from these. Thus, 2-(2- ethoxyethoxy)ethanol and some surfactants having an HLB value from 10 to 18 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 (a)). Exemplary non-volatile organic solvents other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, which are capable of solubilizing a half Ci-4-alkylalkyl ester of a PVM/MA copolymer, 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 (a), 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 compositions of the invention comprises from 5% w/w to 25% 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 10%> w/w to 16%> w/w, more preferably about 13.1% w/w.

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 25%o w/w of propylene glycol, preferably from 10%> w/w to 16%> w/w of propylene glycol, more preferably about 13.1% w/w of propylene glycol.

Component (b) 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 110 °C. The volatile alcohols useful in the present invention are capable of solubilizing 10 mg of the half Ci- 4-alkylalkyl ester of a PVM/MA copolymer per mL of volatile alcohol. 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 15%o w/w of a volatile alcohol, preferably from 10%> w/w to 16%> w/w of a volatile alcohol, more preferably about 9.85%> w/w.

In a preferred embodiment the volatile alcohol is ethanol.

In a particular embodiment the composition of the invention comprises from 5% w/w to 15%o w/w of ethanol, preferably from 10%> w/w to 16%> w/w of ethanol, more preferably about 9.85%> w/w of ethanol.

Component (c) in the pharmaceutical composition 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 20%> w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol, more preferably about 24% w/w of 2-(2- ethoxyethoxy)ethanol.

Component (d) 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. Pubhlished 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 fo llo wing equation ( 1 )) .

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

wherein W; 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 5% w/w to 25% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18, preferably from 10% w/w to 16% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18, more preferably about 13.7% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18.

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 5% w/w to 25%o w/w of polysorbate 80, preferably from 10%> w/w to 16%> w/w polysorbate 80, more preferably about 13.7% w/w of polysorbate 80.

Component (g) in the pharmaceutical compositions of the present invention is a medium chain triglyceride. 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).

The MCT is an optional component of the compositions of the invention, i.e. it may be present or absent. The presence of a MCT in the composition of the invention is particularly advantageous since it may contribute to the stability of the formulations. Thus, in a preferred embodiment, the compositions of the invention comprise a medium chain triglyceride, i.e. triacetin is present.

In a particular embodiment the composition of the invention comprises from 10% w/w to 30% w/w of a MCT, preferably from 18% w/w to 25% w/w of a MCT, more preferably about 21.9% 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 10%) w/w to 30%) w/w of caprylic/capric acid triglyceride, preferably from 18% w/w to 25%o w/w of caprylic/capric acid triglyceride, more preferably about 21.9% w/w of caprylic/capric acid triglyceride.

Component (h) is an optional component of the compositions of the invention, i.e. it may be present or absent.

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:

Preferably, triacetin is present in the compositions of the invention. In a particular embodiment the composition of the invention comprises from 10% w/w to 30%) w/w of triacetin, preferably from 15% w/w to 20%> w/w of triacetin, more preferably about 17.5% w/w of triacetin.

The compositions of the invention may comprise cyclosporine A in an amount of less than 0.1% w/w, preferably in an amount of less than 0.01% w/w. Less than the specified amount means that the corresponding component may be absent, i.e. 0% w/w. Thus, less than 0.1 % w/w of cyclosporine A means from 0%> w/w (i.e. cyclosporine is absent) to less than 0.1% w/w of cyclosporine A. In a particularly preferred embodiment, the compositions of the invention are devoid of 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, 8,11,14, 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. 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 dermatological diseases. In this regard, Amor et al. [J. Am. Acad. Dermatol, 2010, 63, 925-946], Kovalik et al. [The Veterinary Journal, 2012, 193, 317-325] and Palmeiro [Vet. Clin. Small Anim., 2013, 43, 154-171] disclosed that cyclosporine A successfully treated atopic dermatitis and allergic dermatitis.

The compositions of the invention may comprise further ingredients other than those mentioned above. In particular the compositions of the invention may comprise water, for example, more than 10% w/w of water or from 15% w/w to 25%> w/w of water. However, the compositions of the invention are preferably water-free.

The term "water- free" when characterizing the composition of the invention refers compositions substantially free from water. Nevertheless, the water-free compositions of the invention may contain non-significant quantities of water coming from the rest of the components of the formulation. Particularly, the water-free compositions of the invention does not comprise more than 2% w/w of water. The water-free compositions 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. In a preferred embodiment, the compositions of the invention comprise the medium chain triglyceride (preferably a caprylic/capric triglyceride) and/or triacetin, preferably both. In another preferred embodiment, the compositions of the invention comprise the medium chain triglyceride (preferably a caprylic/capric triglyceride) and triacetin, and are devoid of cyclosporine A. In a more preferred embodiment, the compositions of the invention comprise the medium chain triglyceride (preferably a caprylic/capric triglyceride) and triacetin, and are devoid of cyclosporine A and water (water-free compositions).

In a preferred embodiment, the composition of the present invention comprises: (a) from 5% w/w to 25% 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,

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

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

(d) from 5% w/w to 25% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(e) less than 0.1%w/w of cyclosporine A relative to the total weight of the composition,

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

(g) from 10%) w/w to 30%) w/w of a medium chain triglyceride, and

(h) from 10%) w/w to 30%> w/w of triacetin,

wherein w/w is the weight of each component relative to the total weight of the composition. Preferably, said composition is devoid of cyclosporine A, is water-free or is both water-free and devoid of cyclosporine A.

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

(a) from 10% w/w to 16% 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,

(b) from 7%o w/w to 12% w/w of a volatile alcohol,

(c) from 20%) w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol,

(d) from 10% w/w to 16% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18, (e) less than 0.1%w/w of cyclosporine A relative to the total weight of the composition,

(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,

(g) from 18% w/w to 25% w/w of a medium chain triglyceride, and

(h) from 15%) w/w to 20%> w/w of triacetin,

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

(a) from 12% w/w to 14% 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,

(b) from 9%) w/w to 10%> w/w of a volatile alcohol,

(c) from 23%) w/w to 25 %> w/w of 2-(2-ethoxyethoxy)ethanol,

(d) from 13% w/w to 14% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18,

(f) from 0.04% w/w to 0.06% w/w of a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer,

(g) from 21%) w/w to 23% w/w of a medium chain triglyceride, and

(h) from 17%) w/w to 18% w/w of triacetin,

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

(a) from 5% w/w to 25% w/w of propylene glycol,

(b) from 5%) w/w to 15% w/w of ethanol,

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

(d) from 5%) w/w to 25% w/w of polysorbate 80, (e) less than 0.1%w/w of cyclosporine A relative to the total weight of the composition,

(f) from 0.01% w/w to 5% w/w of the half n-butyl ester of a PVM/MA copolymer,

(g) from 10% w/w to 30%> w/w of caprylic/capric acid triglyceride, and

(h) from 10%) w/w to 30%) w/w of triacetin,

In a particular embodiment, the composition of the present invention comprises: (a) from 10%> w/w to 16%> w/w of propylene glycol,

(b) from 7%) w/w to 12% w/w of ethanol,

(c) from 20%o w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol,

(d) from 10%) w/w to 16%> w/w of polysorbate 80,

(f) from 0.01%) w/w to 1 % w/w of the half n-butyl ester of a PVM/MA copolymer,

(g) from 18%o w/w to 25% w/w of caprylic/capric acid triglyceride, and

(h) from 15%o w/w to 20% w/w of triacetin,

(a) from 12% w/w to 14% w/w of propylene glycol,

(b) from 9% w/w to 10% w/w of ethanol,

(c) from 23%o w/w to 25% w/w of 2-(2-ethoxyethoxy)ethanol,

(d) from 13%) w/w to 14% w/w of polysorbate 80,

(f) from 0.04% w/w to 0.06% w/w of the half n-butyl ester of a PVM/MA copolymer,

(g) from 21%) w/w to 23% w/w of caprylic/capric acid triglyceride, and

(h) from 17%) w/w to 18% w/w of triacetin, wherein w/w is the weight of each component relative to the total weight of the composition. Preferably, said composition is devoid of cyclosporine A, is water-free or is both water-free and devoid of cyclosporine A.

In a particular embodiment, the compositions consist 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, phenoxyethanol, 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 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. Said excipients are particularly useful in the production of microemulsions and, when the compositions of the invention are in the form of a microemulsion, they may be found in the disperse phase of said microemulsion.

The compositions of the invention are preferably devoid of any compound known in the art for the treatment and/or prevention of psoriasis and dermatitis, such as calcineurin inhibitors (e.g. cyclosporine A, voclosporine, pimecrolimus and tacrolimus), phosphodiesterase 4 (PDE4) inhibitors (e.g. apremilast, crisaborole, cilomilast, diazepam, ibudilast, luteolin, mesembrenone, piclamilast, foflumilast and rolipram), Janus kinase (JAK) inhibitors (e.g. tofacitinib, peficitinib, ruxolitinib, ocalcitinib and PF-04965842), tar, dithranol, corticosteroids (hydrocortisone, prednisone, prednisolone and betamethasone), vitamin D analogues (e.g. calcipotriene, maxacalcitol, tacalcitol and calcitriol), salicylic acid, retinoids (e.g. acitretin and tazarotene), immunosuppressive agents (e.g. methotrexate, azathioprine, mycophenolate mofetil and cyclophosphamide), hydroxyurea, interleukin 31 (IL-31) inhibitors (e.g. nemolizumab and lokivetmab) and antihistamines (e.g. diphenhydramine, hydroxyzine, cyproheptadine, cetirizine and loratadine).

In a particular embodiment, the compositions of the invention are devoid of cyclosporine A, voclosporine, pimecrolimus, tacrolimus, apremilast, crisaborole, cilomilast, diazepam, ibudilast, luteolin, mesembrenone, piclamilast, foflumilast rolipram, tofacitinib, peficitinib, ruxolitinib, ocalcitinib, PF-04965842, tar, dithranol, hydrocortisone, prednisone, prednisolone, betamethasone, calcipotriene, maxacalcitol, tacalcitol, calcitriol, salicylic acid, acitretin, tazarotene, methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, hydroxyurea, nemolizumab, lokivetmab, diphenhydramine, hydroxyzine, cyproheptadine, cetirizine and loratadine.

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 and on the presence or absence of cyclosporine A.

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 and cyclosporine A may be prepared by a process comprising the following steps: (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-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

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

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).

A topical pharmaceutical composition as defined in the first aspect which comprises cyclosporine A but is devoid of the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, may be prepared by a process comprising the following steps:

(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.

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).

A topical pharmaceutical composition as defined in the first aspect which comprises the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer but is devoid of cyclosporine A, may be prepared by a process comprising the following steps:

(i) preparing an homogeneous solution comprising the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, 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;

(ii) adding optionally the medium chain triglyceride, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18, and optionally triacetin to the solution obtained in step (i) and stirring until a homogeneous solution is obtained, and

Step (i) comprises mixing the half Ci-4-alkyl ester of a poly(methyl vinyl ether- co-maleic anhydride) (PVM/MA) copolymer, 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 stir until the copolymer is completely dissolved, preferably at room temperature (20-25°C).

Step (ii) comprises adding the medium chain triglyceride (when present in the composition), 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18, and triacetin (when present in the composition) to the copolymer solution obtained in step (i) and stirring until a homogeneous solution is obtained, preferably at room temperature (20-25°C). 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, which indicates that the composition has been formed.

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

The compositions of the invention which are devoid of the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer A and of cyclosporine A, may be prepared by a process comprising the following steps:

(i) 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, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin until a homogeneous solution is obtained, and

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

Step (i) 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, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin 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 (i), a clear solution is obtained.

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

All the specific embodiments disclosed in the context of the compositions of the invention are applicable to the process of the invention.

Medical uses of the pharmaceutical compositions

The pharmaceutical compositions of the invention can be applied for the treatment of psoriasis and dermatitis.

Thus, in a further 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 another 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 and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis; preferably psoriasis, atopic dermatitis or allergic contact 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 and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis; preferably psoriasis, atopic dermatitis or allergic contact 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 and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis; preferably psoriasis, atopic dermatitis or allergic contact 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 dermatitis.

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 contact 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 pharmaceutical composition of the invention 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. Application of the pharmaceutical composition of the invention by spraying is particularly 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 and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis, preferably psoriasis, atopic dermatitis or allergic contact dermatitis, 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

Caprylic/capric acid triglyceride (MCT), propylene glycol, polysorbate 80 (Tween^® 80) was 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. Composition for topical application

The following composition was 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. 12 kg of the composition described above were manufactured according to the following process:

- Polymer solution: Ethanol and propylene glycol were mixed with GES425 under stirring until the polymer was completely dissolved. - To the previously prepared polymer solution, MCT, 2-(2- ethoxyethoxy)ethanol, tween 80 and triacetine were added. The mixture was stirred at room temperature until a clear and homogeneous solution was obtained

This formulation showed appropriate properties to be administered by spraying.

4. Stability studies

The composition described above (50 mL) was kept at 25 °C and 60% RH and at 40 °C and 75% RH. The composition remained stable after 6 months at 40 °C and 75% RH and after 1 year at 25 °C and 60% RH, by macroscopical examination (i.e. the formulations remained transparent) .

5. Biological activity studies

The biological activity of the composition prepared above, 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 contact dermatitis). As reference formulation a 0.1% tacrolimus commercially available formulation (Protopic O. P/o) was used.

Test animals

3 female (not siblings) pigs (Landrance x Large White from Prolabor) 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 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 20μΙ_^ 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 treatment corresponding to the test formulation were applied randomly in the application sites of all the animals. The three animals of the study were treated with the reference formulation and the composition of the invention prepared above. 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:

Score Intensity Extension Consistency

0 No erythema No erythema Normal findings

1 Barely perceptible Macules of pinhead size Nodules of pinhead size 2 Slight Lentil-sized macules Doughy, lentil- sized nodules

3 Moderate Confluent macules Confluent firm nodules

4 Severe Diffuse Diffuse hard lesions

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 criterion (intensity, extension and consistency) was calculated for each treatment group using the following formula:

(Mean global score) _control - {Mean global score)_treatment

%Inhibition = xlOO

(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 (composition of the invention prepared above and the reference treatment with Protopic 0.1%) with respect to the control treatment are gathered in the table below:

Treatment Intensity (%) Extension (%) Consistency (%) I+E+C^" (%)

Composition of

55 59 77 63 the invention

Protopic 0.1% 52 54 60 56

Control 0 0 0 0 The composition of the invention showed good inhibitory response against the reaction induced by the application of DNFB. The following particular embodiments are also described:

Embodiment 1. A topical pharmaceutical composition comprising:

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

(b) a volatile alcohol,

(c) 2-(2-ethoxyethoxy)ethanol,

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

(g) optionally a medium chain triglyceride, and

(h) optionally triacetin. Embodiment 2. The composition according to embodiment 1, wherein a half C1-4- alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer is present.

Embodiment 3. The composition according to any one of embodiments 1 to 2, wherein component (f) is the half n-butyl ester of a PVM/MA copolymer.

Embodiment 4. The composition according to any one of the embodiments 1 to 3, wherein component (a) is propylene glycol. Embodiment 5. The composition according to any one of embodiments 1 to 4, wherein component (b) is ethanol. Embodiment 6. The composition according to any one of embodiments 1 to 5, wherein component (d) is polysorbate 80.

Embodiment 7. The composition according to any one of embodiments 1 to 6, wherein component (g) is caprylic/capric acid triglyceride.

Embodiment 8. The composition according to any one of embodiments 1 to 7, which does not comprise cyclosporine A.

Embodiment 9. The composition according to any one of embodiments 1 to 8, wherein triacetin is present.

Embodiment 10. The composition according to any one of embodiments 1 to 9, wherein the medium chain triglyceride is present.

Embodiment 1 1. The composition according to any one of embodiments 1 to 10, comprising:

(a) from 5% w/w to 25% 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,

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

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

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

(g) from 10%) w/w to 30%> w/w of a medium chain triglyceride, and

(h) from 10%) w/w to 30%> 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 is devoid of cyclosporine A. Embodiment 12. The composition according to any one of embodiments 1 to 11, comprising:

(a) from 10% w/w to 16% w/w of propylene glycol,

(b) from 7% w/w to 12% w/w of ethanol,

(c) from 20%) w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol,

(d) from 10%) w/w to 16%> w/w of polysorbate 80,

(f) from 0.01%) w/w to 1 % w/w of the half n-butyl ester of a PVM/MA copolymer,

(g) from 18%) w/w to 25% w/w of caprylic/capric acid triglyceride, and

(h) from 15%) 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.

Embodiment 13. The composition according to any one of emboidments 1 to 12, which is water-free.

Embodiment 14. A topical pharmaceutical composition as defined in any one of embodiments 1 to 13 for use as a human or veterinary medicament.

Embodiment 15. A topical pharmaceutical composition as defined in any one of embodiments 1 to 13 for use in the prevention and/or treatment of a disease selected from the group consisting of psoriasis and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

Claims

1. A topical pharmaceutical composition comprising:

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

(j) a volatile alcohol, which is ethanol,

(k) 2-(2-ethoxyethoxy)ethanol,

(1) a surfactant or surfactant mixture having an HLB value from 10 to 18, which is polysorbate 80,

(m) less than 0.1%w/w of cyclosporine A relative to the total weight of the composition,

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

(o) optionally a medium chain triglyceride,

(p) optionally triacetin, and wherein the composition does not comprise cyclosporine A.

2. The composition according to any one of the preceding claims, wherein component

(f) is the half n-butyl ester of a PVM/MA copolymer.

3. The composition according to any one of the preceding claims, wherein component

(g) is caprylic/capric acid triglyceride.

4. The composition according to any one of the preceding claims, wherein triacetin is present.

5. The composition according to any one of the preceding claims, wherein the medium chain triglyceride is present.

6. The composition according to any one of the preceding claims, comprising: (i) from 5% w/w to 25% 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, which is propylene glycol,

(j) from 5% w/w to 15% w/w of a volatile alcohol, which is ethanol,

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

(1) from 5% w/w to 25% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18, which is polysorbate 80,

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

(0) from 10%) w/w to 30%> w/w of a medium chain triglyceride, and

(p) from 10%) w/w to 30%> 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 is devoid of cyclosporine A.

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

(h) from 10%) w/w to 16%> w/w of propylene glycol,

(1) from 7%) w/w to 12% w/w of ethanol,

(j) from 20%> w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol,

(k) from 10%) w/w to 16% w/w of polysorbate 80,

(1) less than 0.1%w/w of cyclosporine A relative to the total weight of the composition,

(m) from 0.01% w/w to 1% w/w of the half n-butyl ester of a PVM/MA copolymer, (n) from 18% w/w to 25% w/w of caprylic/capric acid triglyceride, and

(i) from 15%) w/w to 20% w/w of triacetin,

8. The composition according to any one of the preceding claims, which is water-free.

9. A topical pharmaceutical composition as defined in any one of claims 1 to 8 for use as a human or veterinary medicament.

10. A topical pharmaceutical composition as defined in any one of claims 1 to 8 for use in the prevention and/or treatment of a disease selected from the group consisting of psoriasis and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

11. Use of a topical pharmaceutical composition as defined in any one of claims 1 to 8 for the manufacture of a medicament for the prevention and/or treatment of a disease selected from the group consisting of psoriasis and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

12. Method of preventing and/or treating a disease selected from the group consisting of psoriasis and dermatitis, such as atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis, which method comprises administering to a patient in need thereof a therapeutically amount of a composition as defined in any one of claims 1 to 8.