WO2020049086A1 - A pharmaceutical aerosol composition - Google Patents

Abstract

The present invention relates to a pharmaceutical aerosol composition comprising tacrolimus as the active ingredient and the use of the composition in the treatment of inflammatory dermal diseases. The aerosol composition comprise a propellant mixture and further a pharmaceutically acceptable hydrophobic carrier solubilized or suspended in said propellant mixture.

Description

A PHARMACEUTICAL AEROSOL COMPOSITION

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical aerosol composition comprising tacrolimus as the active ingredient and the use of the composition in the treatment of inflammatory dermal diseases.

BACKGROUND OF THE INVENTION

Tacrolimus and pimecrolimus are immunosuppressive macrolide lactones which have been approved as drug substances. The drugs inhibit calcineurin leading to suppression of antigen-specific T-cell activation and inhibition of inflammatory cytokine release.

Tacrolimus has been approved for a number of indications such as treatment of transplant rejections, rheumatoid arthritis, ulcerative colitis, allergic conjunctivitis as well as for the treatment of a number of orphan indications. Furthermore, tacrolimus has been approved for treatment of atopic dermatitis.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease with a high prevalence in infancy as it affects 10-20% of all children (Katoh, J. Dermatol. 36, 2009, pp. 367-376). For many years, the first line treatment of AD has been topical

corticosteroids which display a wide anti-inflammatory and immunosuppressive effect. It is recommended, however, that corticosteroids are used only intermittently as chronic use may lead to adverse side effects such as skin atrophy, striae, acneiform eruptions, perioral dermatitis, overgrowth of skin fungus and bacteria, hypopigmentation of pigmented skin and rosacea.

Tacrolimus has been marketed for several years as an 0.03% and 0.1% ointment (Protopic^®) for the topical treatment of AD. Several clinical studies have stablished that tacrolimus is a fast-onset and efficacious treatment of moderate to severe AD in adults and children.

Protopic^® ointment has also attracted interest in the treatment of vitiligo. Vitiligo is an autoimmune skin disease which is characterized by the progressive disappearance of melanocytes, resulting in depigmentation of the skin. Topical corticosteroids are often used to treat vitiligo, however as mentioned above there are concerns over side effects due to long term use. As an alternative to corticosteroids there are reports of off-label use of the calcineurin inhibitors tacrolimus and pimecrolimus in the treatment of vitiligo (Wong et. al, Int. J. Dermatology, (2013), 52, 491-96; Sisti et. al, An. Bras. Dermatol., (2016), 91(2), 187-95).

Development of topical formulations of tacrolimus is not straightforward. Permeation of tacrolimus into skin is difficult due to the large size (804 Da) of the drug substance. Furthermore, tacrolimus is a complex, highly functionalized molecule which renders the molecule sensitive towards degradation by reaction with pharmaceutical excipients or contaminants or with water, thus making the development of a chemically stable formulations of tacrolimus a challenge. The commercially available Protopic^® ointment contains propylene carbonate as a solvent and penetration enhancer for tacrolimus. The bioavailability of tacrolimus from the ointment has been found to be high for a topically applied drug of the given molecular weight and lipophilicity (Potts et. al._r Pharm.

Res. (1992), 9(5), 663-9). A large macrocyclic compound such as tacrolimus would not be expected to penetrate well into the skin in the absence of a penetration enhancer.

SUMMARY OF THE INVENTION

In spite of the pronounced clinical benefits observed with treatment with tacrolimus, patients have expressed preference for a cream vehicle (pimecrolimus cream) over an ointment vehicle (tacrolimus ointment) among other things because it is perceived as easier to apply, more quickly absorbed and less greasy (cf. Onumah et al., J. Drugs. Dermatol. 22(10), 2013, pp. 1145-1148). Application of an ointment which is very viscous and consequently difficult to spread over large areas of skin may be perceived as profoundly irritating or even painful if applied on sensitive skin. Furthermore, a possible side effect of application of tacrolimus ointment is a sensation of stinging, burning and pruritus (Protopic 0.03% Ointment; Summary of Product Characteristics; EMA), which potentially may lead to patients discontinuing the treatment.

It is an object of the present invention to provide a patient-friendly composition which is less viscous and consequently more easily spreadable on application while resulting in approximately the same level of skin penetration as application of the commercial tacrolimus ointment (Protopic^®).

It is another object of the invention to provide a composition which does not include excipients which may cause skin irritation, such as propylene carbonate which is present in the commercial tacrolimus ointment as a solvent and penetration enhancer (Draelos, Clinics in Dermatology (2014), 32, 809-812).

It is a further object of the invention to provide an aerosol composition from which the spray rate is adjusted to ensure that the number of droplets ejected from the aerosol container with a droplet size of 10 pm or less does not exceed about 5% of the total number of droplets so as to reduce systemic exposure to tacrolimus resulting from inhalation.

It is a still further object of the invention to provide a composition in which tacrolimus is chemically stable during storage and which composition is physically stable.

Accordingly, the present invention relates to a storage stable topical pharmaceutical aerosol composition, the composition comprising a therapeutically effective amount of tacrolimus dissolved in a propellant, wherein the composition further comprises a pharmaceutically acceptable hydrophobic carrier solubilized or suspended in said propellant, wherein said hydrophobic carrier comprises hydrocarbons.

The invention furthermore relates to said composition for use in the treatment of inflammatory dermal diseases and conditions.

It has been found that tacrolimus in a therapeutically effective concentration is soluble in propellant mixtures composed of dimethyl ether or methylethyl ether, and alkanes such as for example propane, butane and pentane, or fluoroalkenes.

Consequently, it is not required to add any other solvent to the composition and the inclusion of potentially irritative components such as propylene carbonate may therefore be avoided.

On evaporation of the propellant mixture, tacrolimus forms a supersaturated solution in the hydrophobic carrier, driving the penetration of tacrolimus into the skin. It has been found that the penetration of tacrolimus into the skin is generally best facilitated when no other excipients capable of dissolving tacrolimus are present in the hydrophobic carrier, that is when tacrolimus is substantially solely dissolved in the propellants prior to application of the composition and evaporation of the propellant mixture. The aerosol composition forms a lightly foaming layer on the skin on evaporation of the propellant mixture. The foam is easily spreadable due to its unique viscoelastic properties as it is much less viscous than the commercial Protopic ® ointment.

Furthermore, it provides a transient cooling sensation when the propellants evaporate that may help relieve any application-related stinging and burning sensation.

In specific embodiments, the flow point of the present aerosol compositions is in the range of 10-25 Pa. By way of contrast, the commercial tacrolimus ointment (Protropic ® ointment ) exhibits a shear stress value at the cross-over point (= flow point) in the range of 150-210 Pa under the same conditions. The lower flow point of the aerosol compositions of the invention makes them more easily spreadable than the commercial ointment.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. la is a graph showing the relationship between the amount of dimethyl ether in the propellant mixture and the vapor pressure inside the aerosol container.

Fig. lb is a graph showing the relationship between the vapor pressure inside the aerosol container and the number of droplets with a size below 10 pm expelled from the container.

Fig. 2 is a graph showing the value of the shear stress (Tau) at the cross-over point (G' = G") determined for an aerosol composition of the invention ("Foam") and the commercial ointment ("Ointment") when subjected to an oscillation amplitude sweep test as described in Example 5.

Fig. 3 is a graph showing a comparison of the XRPD pattern of crystalline tacrolimus API (solid line) the 0.1% foam of table 2 (dotted line) with the corresponding 0.1 % ointment without the propellants (dashed line). It can be seen that peaks for the 0,1 % ointment are identical to the peaks for crystalline Tacrolimus API but not for the 0.1 % foam. DETAILED DESCRIPTION OF THE INVENTION

Definitions In the present context, the term "tacrolimus" is intended to indicate a macrolide compound (CAS No. 104987-11-3) produced by Streptomyces tsukubaensis, which in older literature is also designated FK506. The term is intended to include tacrolimus monohydrate (CAS No. 109581-93-3).

Tacrolimus (CAS No. 104987-11-3)

The term "substantially non-aqueous" is intended to indicate that the content of water in the composition is less than 3% by weight, preferably less than 2% or 1% by weight, in particular less than 0.5%, 0.3%, 0.1% or 0.05% weight of the composition.

The term 'storage stable' or 'storage stability' is intended to indicate that the

composition exhibits chemical stability that permit the storage of the composition for a sufficient period of time at room temperature to make the composition commercially viable, such as at least 12 months, in particular at least 18 months, and preferably at least 2 years.

The term "chemical stability" or "chemically stable" is intended to mean that no more than 10%, preferably no more than 5% and more preferably no more than 3%, of the active ingredient degrades over the shelf-life of the product, typically 2 years, at room temperature. An approximation of chemical stability at room temperature is obtained by subjecting the composition to accelerated stability studies at 40°C / 75% RH (Relative Humidity) where the composition is placed in a dark heating cupboard at 40°C / 75% RH and samples are taken at 1 and 3 months and tested for the presence of degradation products by HPLC. If less than about 3% of the active ingredient has degraded after 3 months at 40°C, this is usually taken to correspond to a shelf-life of 2 years at room temperature, wherein less than 5% of the active ingredient degrades in 2 years. (D. G. Pope, Drug & Cosmetic Industry (1980), 127(6), 48-66 and 110-116). More specifically, "chemical stability" of tacrolimus usually indicates that tacrolimus does not degrade significantly over the shelf-life of the composition to 8-epi-tacrolimus (CAS No. 129212- 35-7), iso-tacrolimus (CAS No. 134590-88-8) or other degradation products of tacrolimus.

The term "physical stability" or "physically stable" is intended to mean that tacrolimus does not precipitate from the propellant or vehicle phases over the shelf life of the composition and that the vehicle is homogenously admixed with the propellants or, if phase separation of the propellants and vehicle occurs on standing, the vehicle is easy to distribute homogenously in the propellants when shaken.

The term "occlusive" is intended to indicate the provision of a lipid layer on the skin surface which forms a hydration barrier sufficient to result in reduction of transepidermal water loss, resulting in skin hydration.

The term "skin penetration" is intended to mean the diffusion of the active ingredient into anyone of the different layers of the skin, i.e. the stratum corneum, epidermis or dermis.

The term "skin permeation" is intended to mean the diffusion of the active ingredient through the different layers of the skin (stratum corneum, epidermis and dermis) and into the receptor fluid or blood.

The term "spray rate" is intended to indicate the rate at which the composition is expelled from the aerosol container when the actuator is pressed. The spray rate is a function of the vapour pressure inside the container. The spray rate is measured as the amount of composition in grams per second sprayed from the aerosol container. The term "EDTA" is an abbreviation of ethylene diamine tetraacetic acid (also known as edetic acid). The term is intended to include sodium salts and/or calcium salts of edetic acid, such as for example mono-, di-, tri- or tetra-sodium salts of edetic acid, or edetate calcium disodium.

The term "supersaturated solution" is intended to indicate that, after application of the composition and evaporation of the propellant mixture, tacrolimus is dissolved in the remaining composition vehicle at a concentration which is above the concentration of tacrolimus calculated as soluble in that composition vehicle without propellants. I.e. tacrolimus is not present as an amorphous or crystalline solid at a concentration which is above the concentration of tacrolimus calculated as soluble in that composition vehicle without propellants for at least 48 hours, such as 36 h, 24 h, 12 h, lOh, 6 h, 5h, 4 h, 3h, 2h, 1 h, 0.5 h or 0.25h after application of the composition and evaporation of the propellants. Evaporation of propellants takes place approximately within one minute of application of the composition.

In the present context, the phrase "without propellants" in association with percentage concentration values is intended to indicate that the calculations of concentrations is performed excluding the weight contribution of the propellants.

The term "practically insoluble" is intended to indicate that, for a given solute, more than 10000 ml of solvent is required to dissolve 1 g of the solute at about 20°C.

The term "topical aerosol composition" is intended to indicate a pharmaceutical aerosol composition to be used on skin, such as human skin, that is, the topical aerosol composition is not an aerosol for inhalation.

The term "pharmaceutical aerosol composition" is intended to indicate a composition comprising vehicle or carrier, API and propellant, the propellant providing the force that expels vehicle or carrier and API from a container.

The term " topical pharmaceutical aerosol composition" is intended to indicate a composition to be used on skin, such as human skin, comprising vehicle or carrier, API and propellant, the propellant providing the force that expels vehicle or carrier and API from a container. The term C3-5-alkane includes straight chained and branched C3-5-alkane, such as n- butane, iso-butane, propane and pentane.

Embodiments of the invention

In the course of research leading to the present invention, it was found that when dimethyl ether was used as a propellant, tacrolimus could be dissolved in the

compositions without requiring the addition of a co-solvent, whilst maintaining chemical stability. However, as shown in Fig. la , there is a linear relationship between the amount of dimethyl ether included in the composition and the vapor pressure inside the aerosol container and ultimately the number of droplets with a size of 10 pm or less. It has been found that for instance when the amount of dimethyl ether is 10 ml in a composition further comprising 60 ml butane and 30 g of the hydrophobic carrier or the amount of dimethyl ether is 20 ml in a composition further comprising 50 ml butane and 30 g of the hydrophobic carrier, it is possible on the one hand to obtain complete dissolution of tacrolimus in the composition and on the other hand to adjust the spray rate with which the composition is expelled from the container so as to avoid the formation of a high number of aerosol droplets with a size of 10 pm or less, such that fewer than 5% of the droplets have a size of 10 pm or less. It is generally believed that 50% of the particles in air with an aerodynamic diameter of 10 pm belong to the thoracic fraction (the mass fraction of the inhaled particles that pass the larynx); and that 50% of particles in the air with an aerodynamic diameter of 4 pm belong to the respirable fraction (the mass fraction of the inhaled particles that reach the alveoli) (European Chemicals Agency (ECHA), Guidance on Information Requirements and Chemical Safety Assessment; Chapter R.7a: Endpoint specific guidance, p. 140, v. 6.0, July 2017).

For the reasons indicated above, it is preferred to include as little dimethyl ether as possible to obtain dissolution of tacrolimus as this will result in formation of fewer droplets of a size of 10 pm or less.

On the other hand the liquid propellant also serves to dissolve or suspend the

hydrophobic carrier and has to be present in relatively high concentration otherwise the viscosity of the formulation inside the spray can will be too high and it will be impossible to spray out the formulation.

It has been found that increasing the relative amount of C3-Cs-alkane or C3-C5- fluoroalkene compared to dimethyl ether allows for a reduction of pressure inside the can and thereby control of the droplet size and at the same time have a sufficiently high amount of C₃-C₅ - alkane or C₃-C₅- fluoroalkene so as to maintain the viscosity of the aerosol composition at a level where it is sprayable.

Suitably the propellant is composed of dimethyl ether and C3-Cs-alkane with a weight ratio in the range 1 :20 - 10: 1 (w/w), 1 : 18 - 2: 1 (w/w), 1 : 15 - 4:3 (w/w), 1 : 10 -1 : 1 (w/w), 1 :8 - 1 :2 (w/w), or 1 :6 - 1 :3 (w/w).

In a preferred embodiment the ratio of dimethyl ether to butane in the propellant mixture is 10:60 (v/v); a preferred composition comprises 10 ml dimethyl ether and 60 ml butane per 30 g of the hydrophobic carrier. This amount of dimethyl ether relative to butane is sufficient to dissolve the tacrolimus included in the composition (0.3-1 mg/g of the composition calculated without propellants) while resulting in the formation of about 2.5% of droplets with a size of 10 pm or less.

The composition comprising 10 ml dimethyl ether and 60 ml butane per 30 g of the hydrophobic carrier corresponds to a formulation comprising of 58 mg propellant mixture and 42 mg of the hydrophobic carrier where the weight ratio of dimethyl ether to butane in the propellant mixture is 10: 52 (w/w).

In another preferred embodiment the ratio of dimethyl ether to butane in the propellant mixture is 15: 55 (v/v); a preferred composition comprises 15 ml dimethyl ether and 55 ml butane per 30 g of the hydrophobic carrier. This amount of dimethyl ether relative to butane is sufficient to dissolve the tacrolimus included in the composition (0.3-1 mg/g of the composition calculated without propellants)

The composition comprising 15 ml dimethyl ether and 55 ml butane per 30 g of the hydrophobic carrier corresponds to a formulation comprising 58 mg propellant mixture and 42 mg of the hydrophobic carrier where the weight ratio of dimethyl ether to butane in the propellant mixture is 10:32 (w/w).

It has surprisingly been found that when the propellant mixture evaporates after application of the composition, tacrolimus remains as a supersaturated solution, i.e. it does not precipitate or crystallize on the skin within the period of time required for spreading the composition. No immediate precipitation of tacrolimus was observed after evaporation of the propellants. It has been observed that the penetration of tacrolimus into the skin is facilitated from a supersaturated solution and that the degree of supersaturation is important for the penetration. Generally, the degree of supersaturation is higher if the vehicle (without propellants) is one in which tacrolimus is practically insoluble; i.e. if the vehicle does not contain co-solvents.

The hydrophobic carrier in which tacrolimus is practically insoluble and which can be homogeneously distributed in the propellants upon shaking may suitably be a

hydrocarbon or mixture of hydrocarbons with chain lengths ranging from approximately Cio to Cioo- The hydrocarbons may comprise straight chain, branched or cyclic hydrocarbons. A frequently used ointment carrier is white petrolatum, which may be composed of hydrocarbons of different chain lengths peaking at about C40-44, or a mixture of white petrolatum and liquid paraffin (liquid paraffin may be composed of hydrocarbons of different chain lengths peaking at C28-40) . White petrolatum provides occlusion of the treated skin surface, reducing transepidermal water loss and

potentiating the therapeutic effect of the active ingredient in the composition. It is also an option to employ paraffins consisting of hydrocarbons of a somewhat lower chain length, such as paraffins consisting of hydrocarbons with chain lengths peaking at C14-18, C18-22, C18-24, C20-22 or C20-26 or mixtures thereof (the hydrocarbon composition of the paraffins is determined by gas chromatography). Suitable paraffins of this type are termed light liquid paraffin. When the hydrophobic carrier in the composition is liquid paraffin or light liquid paraffin, it may suitably include a hydrophobic viscosity-increasing ingredient capable of imparting to the hydrophobic carrier the property of forming an occlusive layer on skin after application and evaporation of the propellant mixture. The hydrophobic viscosity-increasing ingredient may suitably be a petroleum wax composed of a mixture of high molecular weight hydrocarbons, e.g. saturated C30-90 alkanes, such as microcrystalline wax. Alternatively, the viscosity of the hydrophobic carrier may be increased by including white petrolatum.

Alternatively, the hydrocarbons of the hydrophobic carrier may be characterised by their specific gravity, melting range and consistency and/or viscosity.

According to US Pharmacopeia white petrolatum is characterised by a specific gravity of 0.815 - 0.880 at 60°C; a melting range of 38 °- 60 °C and a consistency of 100 - 300 dmm.

A preferred white petrolatum of the invention is characterized by a specific gravity of 0.815 - 0.880 at 60°C; a melting range of 38° - 51.6°C and a consistency of 240 - 300 dmm. Liquid paraffin and light liquid paraffin are characterised by a viscosity of 110 - 230 mPa-s and 25 - 80 mPa-s respectively.

The specific gravity is measured according to the United States Pharmacopeia 41 <841 > which is incorporated herein by reference. The specific gravity is measured by use of a pycnometer. The pycnometer is filled with melted petrolatum and the temperature is adjusted to 60°C. Excess liquid is removed. The filled pycnometer is cooled and weighed. The tara weight of the pycnometer is subtracted from the filled weight. The specific gravity of the liquid is the quotient obtained by dividing the weight of the white petrolatum contained in the pycnometer by the weight of water contained in it at 25°C.

The melting range or melting point is defined at the points of temperature within which the first detectable drop is formed to the temperature at which no solid substance is apparent. The melting range is measured according to the United States Pharmacopeia 41 <741> Class III; which is incorporated herein by reference. The melting range is measured by melting a quantity of the white petrolatum to a temperature of 90°-92°C. The molten substance is cooled to a temperature of 8°-10°C above the expected melting point. A thermometer is cooled and dipped it into the molten white petrolatum The thermometer is withdrawn and held until the wax surface dulls, then it is dipped into a water bath. The thermometer is fixed in a test tube. The test tube is suspended in a water bath at about 16°C, and the temperature of the bath is raised at the rate of about 2°C/min to 30°C, then at a rate of about l°C/min. The temperature at which the first drop of melted substance leaves the thermometer to the temperature at which no solid substance is apparent is the melting point or melting range.

The consistency is measured according to the United States Pharmacopeia 41, p. 3249- 3250, which is incorporated herein by reference. The consistency is measured by use of a penetrometer fitted with a cone-shaped metal plunger weighing 150 g, The containers for the test are flat-bottomed metal cylinders. White petrolatum is brought to a temperature of about 82 °C. The white petrolatum is poured into a container and cooled to 25 °C. The containers are placed in a water bath at 25 °C. The container is placed on the penetrometer table, and the cone is lowered until the tip just touches the top surface of the test substance. The plunger is released and the total penetration is measured. A penetration of 10 mm corresponds to a consistency value of 100 dmm; and a penetration of 30 mm corresponds to a consistency value of 300 dmm. Viscosity can be measured by use of a suspended-level (Ubbelohde-type) capillary viscometer as described in the European Pharmacopoeia 9^th Edition 2017 (9.0) 2.2.9 Capillary viscometer method 01/2008:20209; which is incorporated herein by reference.

The present composition may further comprise an oily component in which tacrolimus is soluble or partly soluble. The oily component may be selected from the group consisting of triglycerides of C6-22 fatty acids and isopropyl esters of straight or branched Cio-ie fatty acids, or mixtures thereof. The oily component may act as an emollient. The triglycerides of C6-22 fatty acids are preferably selected from the group consisting of medium chain triglycerides (caprylic/capric triglycerides) and long chain triglycerides such as safflower oil, sunflower oil or mixtures thereof. The isopropyl ester of Cio-ie fatty acids is preferably selected from the group consisting of isopropyl myristate, isopropyl palmitate and isostearyl isostearate. It has been found that if such an oily component is included in a concentration that results in dissolution of (some of) the tacrolimus, this leads to lower penetration of tacrolimus into the skin than that obtained after application of Protopic^® ointment. The concentration of the oily component should therefore preferably be less than the concentration at which tacrolimus is dissolved . In a preferred embodiment the amount of oily component is less than 10 % (w/w) of the composition calculated without propellants, such as less than 5, 3, 1 %(w/w). In a particularly preferred embodiment the composition does not comprise said oily components.

The viscoelastic properties of the present compositions were determined by a rheological method involving oscillation amplitude sweep substantially as disclosed in T.G. Mezger, "Applied Rheology", 1st Ed. 2015, Anton Paar GmbH, Austria, Chapter 15 (pp. 101-112). According to this method, when a composition is solid or semi-solid the elastic part of the viscoelastic behavior (G', termed "storage modulus" in Example 4 below) dominates over the viscous part of the viscoelastic behavior (G", termed "loss modulus" in Example 4 below) in the linear viscoelastic region (which is the range in which the test can be carried out without destroying the structure of the sample composition) (in other words, the composition is more solid than liquid). The value of the shear stress (Tau) at the cross-over point (G' = G") is the flow point of the composition, i.e. the point where a solid or semi-solid composition starts to become liquid. As determined by the method, the aerosol composition of the invention exhibits a shear stress value at the cross-over point in the range of 5-50 Pa when subjected to an oscillation amplitude sweep at 25°C and an angular frequency of 10 rad/s within about 3 minutes after spraying onto a 50 mm sandblasted parallel plate of a rheometer (e.g. Physica MCR300 manufactured by Anton Paar GmbH). Therefore, in an embodiment the composition is characterized by a flow point of 5-50 Pa when subjected to an oscillation amplitude sweep at 25°C and an angular frequency of 10 rad/s within about 3 minutes after spraying onto a 50 mm sandblasted parallel plate of a rheometer operating in the oscillation mode. In specific embodiments, the flow point of the present aerosol compositions is in the range of 10-25 Pa.

If necessary, improved chemical stability of tacrolimus during manufacture of the composition may be obtained by adding a chelating agent during the preparation of the composition. Suitable chelating agents for stabilizing tacrolimus are various organic acids such as citric acid, tartaric acid, oxalic acid and EDTA. EDTA may be added in an amount of 0.01-0.5 mg/g, such as 0.1 mg/g, of the composition calculated without propellants.

Furthermore, the composition may comprise suitable stabilisers such as antioxidants, such as tocopherol, alpha-tocopherol, BHT (butylated hydroxytoluene) or BHA (butylated hydroxyanisole).

Tacrolimus exerts its immunomodulatory and anti-inflammatory activity by binding to the FK-binding protein (FKBP). The tacrolimus-FKBP complex then binds to calcineurin which is only active when bound to calcium and calmodulin. The ability of calcineurin to dephosphorylate the nuclear factor of activated T-cells (NFAT) is inhibited. NFAT is a transcription factor which activates the promoter region of the gene for a number of inflammatory cytokines that are believed to participate in the pathogenesis of AD (cf.

J.C. Pascual et al., Skin Therapy Letter 9, 2004; J.R. Azzi et al., J. Immunol. 191, 2013, pp. 5785-5791).

Accordingly, the present invention further relates to a composition as disclosed herein for use in the treatment of inflammatory dermal diseases and conditions. Examples of dermal diseases and conditions to be treated using the present compositions are atopic dermatitis, eczema, contact dermatitis, psoriasis, vitiligo, rosacea, alopecia, acne, urticaria or pruritus. The present composition may be particularly useful in the treatment of atopic dermatitis and vitiligo.

The amount of tacrolimus may suitably be in the range of 0.05 - 3 mg/g of the composition without the propellants, such as 0.1 - 2 mg/g, such as 0.2 - 1.5 mg/g, such as 0.3 - 1 mg/g , such as 0.3 mg/g or 1.0 mg/g of the composition without the propellants. In a specific embodiment, the present composition comprises tacrolimus dissolved in a propellant mixture of about 10 ml dimethyl ether and about 60 ml butane per about 30 g of a hydrocarbon carrier with or without EDTA as the stabiliser.

In another specific embodiment, the present composition comprises tacrolimus dissolved in a propellant mixture of about 15 ml dimethyl ether and about 55 ml butane per about 30 g of a hydrocarbon carrier with or without EDTA as the stabilizer.

In another specific embodiment, the present composition comprises tacrolimus dissolved in a propellant mixture of about 94 mg dimethyl ether and about 486 mg butane per about 420 g of a hydrocarbon carrier with or without EDTA as the stabilizer (ratio of dimethyl ether to butane is 10: 52 (w/w)).

In another specific embodiment, the present composition comprises tacrolimus dissolved in a propellant mixture of about 140 mg dimethyl ether and about 443 mg butane per about 417 mg of a hydrocarbon carrier with or without EDTA as the stabilizer (ratio of dimethyl ether to butane is 10:32 (w/w).

The hydrocarbon carrier may favorably be selected from white petrolatum or a mixture of white petrolatum and liquid paraffin.

The compositions according to the invention may be dispensed from aerosol containers, typically of the type comprising a container body and valve assembly. The container body may, for instance, comprise a metal body, preferably lined with a chemically inert coating material to avoid degradation of the composition due to interaction between the body and the composition and/or to avoid corrosion of the metal body due to

components in the composition.

The valve assembly may comprise a valve cup, sometimes referred to as a mounting cup, a valve body or housing (possibly containing a ball) provided with a valve stem, a spring, a dip tube and an actuator. An inner gasket typically seals one or more holes in the valve stem, but when the actuator is operated the valve stem is shifted so that the holes are uncovered. Once exposed, the pressure exerted by the propellant mixture in the container body forces the composition to flow through the holes into the dip tube and the valve stem and out through the actuator. As will be understood, when the actuator is released the valve spring returns the valve stem to the position where the holes are once again sealed. The valve stem and actuator each contain one or more holes (orifices) and channels, the number, size and shape of which are determined in conjunction with the physical properties of the particular composition formulation so as to control both the flow rate through the valve and the characteristics of the spray that emerges from the actuator.

The spray pattern and spray rate may be controlled by means of a separate insert fitted into the outlet orifice of the actuator and which provides the terminal orifice for the actuator assembly. The channel through the insert leading to the outlet typically includes a portion narrower in diameter than the channel in the body of the actuator so that fluid emerging from the actuator channel into the insert channel is caused to swirl and break up into droplets. The insert may be profiled, for example it may be stepped, so that the composition is forced forwards and out of the terminal orifice in a forward motion, rather than the more usual rotational motion. This results in a homogeneous or solid spray pattern and hence enabling a user better to focus the composition on the area of skin being treated.

Since inhalation of the composition according to the invention is not desirable, it is preferred that the dimensions of the fluid channels, orifices, inserts, etc are selected to avoid production of a fine mist on expulsion.

The valve assembly may comprise a metering valve to permit only a metered quantity of the composition to be dispensed with each actuation of the actuator.

For storage, safety and/or hygiene reasons, the actuator may be provided with a protective hood or overcap, separate or integral therewith. The overcap may be moveable from a first position in which the terminal orifice is enclosed to a second position where the orifice is exposed; in the second position, the cover may also function as a directing nozzle by limiting the spray area. The actuator itself may comprise a simple button actuator, or may for example be fitted with a lever or operated by squeezing the side(s) of the cap. In another arrangement, an overcap having an integral finger actuator may be secured to the container and cover an underlying actuator button. The underside of the overcap may include for example a plurality of projections for contacting the actuator button upon movement due to finger pressure of the operator and triggering the valve to open.

Alternatively, or in addition thereto, the actuator may be moveable between a first position in which the valve is prevented from being intentionally or accidentally operated and a second operative position. For example, part of the valve assembly may be rotatable about the valve stem such that in one rotary position the actuator is operable to dispense the product while in another rotary position the actuator aligns with projections or abutments on the container to prevent actuation. Such a "twist and spray" mechanism may include tactile or audible indications of the open and closed positions.

The inclusion of a tamper-evidence tab, which has to be broken before first use of the aerosol container, is desirable. The present invention is further described in the following examples which are not in any way intended to limit the scope of the invention as claimed.

EXAMPLES Example 1

Compositions of the invention

Composition A

Composition B

Composition C

Composition D

Composition E

Composition F

Composition G

Composition H

Composition

Composition J

Composition K

Composition L (60:10)

Composition M : (55:15)

(*) Tacrolimus is added as tacrolimus monohydrate. The amount in table give the amount of the corresponding anhydrate. a specific gravity 0.815 - 0.880 at 60°C; melting range 38° - 51.6°C; consistency 240 - 300dmm b specific gravity 0.815 - 0.880 at 60°C; melting range of 38 °- 60 °C, consistency 100 - 300dmm

c mg/g of the composition calculated without the propellants. To prepare compositions A-G and K, edetic acid and tacrolimus monohydrate were suspended in the white petrolatum by mixing. 30 g portions of the mixture were transferred to aluminium spray containers provided with a polyamide-polyimide inner lacquer after which a valve cup was fastened to the container body by crimping. The requisite amount of propellant mixture was added through the valve, after which the container was shaken for 5 minutes for complete dissolution of the tacrolimus monohydrate.

To prepare composition H, white petrolatum was melted at 80°C and mixed with paraffin liquid. Upon cooling to 30-35°C, edetic acid and tacrolimus monohydrate were suspended in the vehicle by mixing. 30 g portions of the mixture were transferred to aluminium spray containers provided with a polyamide-polyimide inner lacquer after which a valve cup was fastened to the container body by crimping. The requisite amount of propellant mixture was added through the valve, after which the container was shaken for 5 minutes for complete dissolution of the tacrolimus monohydrate.

To prepare compositions I and J, tacrolimus monohydrate was suspended in the white petrolatum by mixing. 30 g portions of the mixture were transferred to aluminium spray containers provided with a polyamide-polyimide inner lacquer after which a valve cup was fastened to the container body by crimping. The requisite amount of propellant mixture was added through the valve , after which the container was shaken for 5 minutes for complete dissolution of the tacrolimus monohydrate.

To prepare composition L white soft paraffin was melted at approximately 80°C. Parts of the melted white soft paraffin were withdrawn and cooled to 65 - 70°C. Edetic acid and Tacrolimus monohydrate were dispersed in this part of the melted white soft paraffin using a magnetic stirrer followed by homogenization. The mixture was transferred to the remaining part of the melted white soft paraffin. To obtain a homogeneous dispersion this mixture was stirred and homogenized followed by cooling to < 25°C while stirring and homogenization. 60 g portions of the mixture were transferred to aluminium spray containers provided with a polyamide-polyimide inner lacquer after which a valve cup was fastened to the container body by crimping. The requisite amount of propellant mixture was added through the valve, after which the container was shaken for complete dissolution of the tacrolimus monohydrate.

To prepare composition M a small part of white soft paraffin was melted at 60 - 70°C. Tacrolimus monohydrate was dispersed in the melt using homogenizer. The remaining part of white soft paraffin was melted at 65 - 70°C and cooled 60 - 65°C. The tacrolimus dispersion was transferred into the main melt while homogenizing. To obtain a homogeneous dispersion this mixture was stirred and homogenized followed by cooling to below 25°C while stirring and homogenization. 25 g portions of the mixture were transferred to aluminium spray containers provided with a polyamide-polyimide inner lacquer after which a valve cup was fastened to the container body by crimping. The requisite amount of propellant mixture was added through the valve, after which the container was shaken for complete dissolution of the tacrolimus monohydrate. Example 2

The chemical stability of tacrolimus in compositions A-I was tested and provided the following results. Composition A

Composition B

Composition C

Composition D

Composition E

Composition F

Composition G

Composition H

Composition

Composition J

Composition K

Example 3

Effect of spray rate on droplet size

The spray performance of Composition G of Example 1 (containing 20 ml dimethyl ether and 50 ml butane as the propellant mixture) was compared to that of Composition E (containing 10 ml dimethyl ether and 60 ml butane as the propellant mixture), F

(containing 30 ml dimethyl ether, 30 ml butane and 10 ml pentane as the propellant mixture) and K (containing 10 ml dimethyl ether, 50 ml butane and 10 ml pentane as the propellant mixture). The amount of composition in grams per second sprayed from aerosol containers containing Composition G, E, F and K (i.e. the spray rate) was determined as follows:

Aerosol containers containing the compositions were shaken for 10 seconds at 20°C ± 0.5°C and actuated for about 5 seconds. The containers were weighed before and after spraying. The procedure was repeated twice, and the average of the three

determinations was calculated. On average, 3.22 g of Composition G was sprayed in 5 seconds, i.e. the spray rate was 0.64 g/s. On average, 2.87 g of Composition E was sprayed in 5 seconds, i.e. the spray rate was 0.57 g/s. On average, 3.21 g of Composition F was sprayed in 5 seconds, i.e. the spray rate was 0.64 g/s. On average, 2.88 g of Composition K was sprayed in 5 seconds, i.e. the spray rate was 0.58 g/s. Thus, there appears to be a trend that the amount of dimethyl ether included in the propellant mixture affects the spray rate.

To determine the vapour pressure inside the containers, they were shaken vigorously and left standing in a water bath at 20°C ± 0.5°C for at least 30 minutes. The containers were then shaken again and the pressure inside them was determined as an average of three measurements.

The pressure inside the container with Composition G was 3.52 bar.

The pressure inside the container with Composition E was 3.01 bar.

The pressure inside the container with Composition F was 3.86 bar.

The pressure inside the container with Composition K was 2.64 bar.

Thus, it appears that the amount of dimethyl ether in the propellant mixture affects the pressure inside the containers, cf. Fig. la. The pressure, in turn, affects the spray rate.

The size of the droplets expelled from the containers when the actuator is pressed is also affected by the pressure inside the container and consequently by the amount of dimethyl ether in the propellant mixture. As shown in Fig. lb, increasing pressure generates a larger number of droplets of a size below 10 pm. It appears from Fig. lb that a pressure of about 3.5 bar, corresponding to an amount of 20 ml dimethyl ether in the Composition G container, results in 4.5% of droplets below 10 pm. A pressure of about 3 bar, corresponding to an amount of 10 ml dimethyl ether in the Composition E container, results in about 2.5% of droplets below 10 pm. A pressure of about 4.7 bar, corresponding to an amount of 30 ml dimethyl ether in the Composition F container, results in about 4.7% of droplets below 10 pm. A pressure of about 2.6 bar,

corresponding to an amount of 10 ml dimethyl ether in the Composition K container, results in about 1.7% of droplets below 10 pm.

Example 4

Permeation studies Intact skin

Dermatomed human skin obtained from three donors undergoing abdominoplasty was used. The skin was kept frozen at -18°C until use. On the day of the experiment, the skin was thawed at room temperature. The individual skin pieces for Franz diffusion cells were prepared by using a 38 mm skin punch. The used PermeGear® diffusion cells were made of clear glass, in which the donor and receptor chambers were separated by a diffusion membrane and held together by a pinch clamp. For each skin donor 2 diffusion cells were used for each test item. The cells had an available diffusion area of 3.14 cm² and an average receptor volume of 11.9 ml. The membrane was placed over a support with an orifice of 2 cm in diameter and the cells were placed in a cell warmer connected with a Haake®-DC10 circulating bath programmed to 38 °C, resulting in a temperature on the membrane surface of 32 °C. To ensure adequate stirring, the cells were placed on a magnetic stirrer (500 rpm). After mounting the skin, receptor buffer (0.04 M isotonic phosphate buffer pH 7.4 containing 4 % (W/V) bovine serum albumin, fraction V) was filled into the receptor chamber for hydration of the skin for one hour. Formulations were applied at t=0. At t= 16.5, 18, 19.5, 21, 22.5 and 24h 500pL receptor buffer was collected and replaced accordingly with fresh buffer.

15 pi of each formulation (Compositions E, J and H of Example 1 as well as Protopic® ointment 1 mg/g) were applied topically. The aerosol formulations were sprayed out in weighing boats and left to degas for 30 minutes prior to application. All formulations were applied to the skin using a Gilson Microman M25 pipette.

As shown in Table 1, skin permeation of tacrolimus across intact skin expressed either as flux (ng/(cm2*h) or total amount in receptor phase at 24h (% of dose) is similar for all tested formulations with no significant differences between formulations; I.e. the skin permeation of the compositions of the invention is on par with that of Protopic® ointment.

Table 1 : * Only 2 observations, therefore no

SD (Standard Deviation) Example 5

Rheological characterization by amplitude sweep

The storage modulus (G') and the flow point (T) of Composition C and Protopic^® ointment were determined using a Physica MCR300 rheometer (Anton Paar, GmbH) operating in the oscillation mode. An amplitude sweep test was performed with controlled shear stress using the parallel plate system, with a sandblasted parallel upper plate (PP50/P) (diameter 50mm, gap size 1mm). The angular frequency was 10 rad/s and all samples were evaluated at 25°C. The sample was sprayed directly onto the bottom rheometer plate using an actuator with tube and a glass funnel (0.04L)

(Composition C) or gently placed on the bottom rheometer plate using a spoon

(ointment). An equilibration step (180 sec) was included before the shear stress was applied. The storage modulus was read in the linear viscoelastic range and the flow point was read as the cross-over point between the storage modulus (G') and the loss modulus (G"). As shown in Fig.2, the elastic behaviour dominates the viscous behaviour for both products, as G' > G" in the linear viscoelastic range, but the storage modulus of tacrolimus foam is smaller than the storage modulus of Protopic® Ointment, which correlates to a softer feeling of the foam during application. The flow point of

Composition C is lower than the flow point of Protopic^® ointment, cf. Fig. 2, which explains the more easy spreadability of Composition C compared to the ointment.

Example 6

XRPD analysis

Composition L of example 1 were subjected to X-ray powder diffraction (XRPD) analysis to determine the presence of crystalline tacrolimus therein after spraying/application and subsequent evaporation of the propellant mixture from the aerosol composition. For purposes of comparison, ointment composition corresponding to the aerosol

composition, but without any propellant was also subjected to XRPD.

XRPD was carried out by placing aapproximately 210 mg of formulation in affixed volume sample holder with a diameter of 1.5 cm. XRPD patterns were collected from 0.5 hrs after application with a PANalytical Empyrean diffractometer using an incident Cu Ka radiation and operating at 45 kV and 40 mA. The XRPD patterns were collected in the 2 theta range from 9.8 to 14.5° with a step size of 0.013°, counting time of 1499.1 s and 71 repetitions in transition geometry to a total duration of the experiment of 71 hrs and 22 min for the foam sample and 24 repetitions and a total experimental time of 24 hrs and 13 min. In the incident beam path an elliptically graded multilayer mirror together with a 10 mm fixed mask, fixed anti-scatter slit 1° and fixed divergence slits of Vi° was placed to line focus the Cu Ka X-rays through the sample and onto the detector. At the diffracted beam path a long antiscatter extension and antiscatter slit of 2 mm were placed to minimize the background generated by air. Furthermore Soller slits of 0.02 rad were placed on both the incident and diffracted beam paths to minimize broadening from axial divergence and the sample was spun to ensure better particle statistics. The diffraction patterns were collected using a PIXel 3D- Medipix3 lxl detector with active length of 3.347° and located 240 mm from the sample.

The repetitions belonging together where summed and background subtraction was done using the parameters in highscore 4.8: Bending factor = 0 and Granularity = 21, and last smooth with a factor of 2.

Peaks showing the presence of crystalline tacrolimus were present in both ointment samples.

No peaks were observed showing the presence of crystalline tacrolimus in the aerosol composition sample in this experiment indicating that the active ingredients remained in solution after evaporation of the propellant or propellant mixture (see Figure 3). The XRPD results support the hypothesis that fully dissolved, supersaturated active ingredients remain in the aerosol compositions after application and evaporation of the propellant or propellant mixture.

Example 7

Composition M of the invention and Protopic® ointment was tested in 24 healty volunteers.

The systemic exposure after 14 days application composition to 35% body surface area twice daily was assessed. C_max was 112.3 ng/l and AUCo-i2_h was 1269.1 h*ng/l.

The safety and tolerability of tacrolimus foam was similar to that of Protopic® ointment, except that there were no reports of skin burning for composition M, whereas application site burning is a frequently reported adverse effect for Protopic ® in atopic dermatitis. Embodiments

The following are further embodiments of the invention

Embodiment 1.

A storage stable topical pharmaceutical aerosol composition, the composition comprising a therapeutically effective amount of tacrolimus dissolved in a propellant mixture comprising a first propellant selected from dimethyl ether and methylethyl ether and a second propellant selected from C3-C5 alkanes, C3-C5 fluoroalkenes and mixtures thereof, wherein the composition further comprises a pharmaceutically acceptable hydrophobic carrier solubilized or suspended in said propellant mixture, wherein said hydrophobic carrier comprises hydrocarbons, and wherein a supersaturated solution of tacrolimus is formed on the skin after application of the composition and evaporation of the propellant mixture.

Embodiment 2.

The composition according to the embodiment above, the composition without propellants comprising more than 90%(w/w), 91% (w/w), 92% (w/w), 93% (w/w), 94% (w/w), 95% (w/w), 95% (w/w), 97% (w/w), 98% (w/w), 98.5% (w/w), 99% (w/w) or 99.9% (w/w) of hydrocarbons.

Embodiment 3. The composition according to any one of the embodiments above, the composition without propellants comprising more than 90% (w/w) of (C10- Cioo)hydrocarbons, such as more than 91% (w/w), 92% (w/w), 93% (w/w), 94% (w/w), 95% (w/w), 96% (w/w), 97% (w/w), 98% (w/w), 99% (w/w) or more than 99.5% (w/w) of (Cio-Cioo)hydrocarbons.

Embodiment 4.

The composition according to the embodiment above, wherein upon application of the composition to skin and evaporation of the propellant mixture, the hydrocarbons are present in an amount of more than 90% (w/w), 91% (w/w), 92% (w/w), 93% (w/w), 94% (w/w), 95% (w/w), 95% (w/w), 97% (w/w), 98% (w/w), 98.5% (w/w), 99%

(w/w) or 99.9% (w/w) of the composition.

Embodiment 5. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, the (Cio-Cioo)hydrocarbons are present in an amount of more 90% (w/w), such as more than 91% (w/w), 92% (w/w), 93% (w/w), 94% (w/w), 95% (w/w), 96%

(w/w), 97% (w/w), 98% (w/w), 99% (w/w) or more than 99.5% (w/w) of the composition.

Embodiment 6.

The composition according to the embodiment above, the hydrophobic carrier comprising more than 90% (w/w), 91% (w/w), 92% (w/w), 93% (w/w), 94% (w/w), 95% (w/w), 96% (w/w), 97% (w/w), 98% (w/w), 98.5% (w/w), 99% (w/w) or 99.5% (w/w) of hydrocarbons.

Embodiment 7. The composition according to any one of the embodiments above, the hydrophobic carrier comprising more than 90% (w/w) of (Cio-Cioo )hydrocarbons, such as more than 91% (w/w), 92% (w/w), 93% (w/w), 94% (w/w), 95% (w/w), 96%

(w/w), 97% (w/w), 98% (w/w), 99% (w/w) or more than 99.5% (w/w) of (Cio-Cioo )hydrocarbons.

Embodiment 8. The composition according to any one of the embodiments above, the chain lengths of the hydrocarbons peaking at Ci_4-i6, C18-22, C18-24, C18-30, C18-34, C20-22, C20- 26, C28-40 or C40-44, or a mixture of two or more of such hydrocarbons.

Embodiment 9. The composition according to any one of the embodiments above, the hydrophobic carrier comprising hydrocarbons selected from white petrolatum, liquid paraffin, light liquid paraffin and mixtures thereof.

Embodiment 10. The composition according to any one of the embodiments above, wherein the hydrocarbons have a melting range of about 30°C - 70°C, 36°C - 62°C, 38°C - 60°C, 35°C - 55°C, 37°C - 53°C, 38°C - 52°C or 38°C - 51.6°C.

Embodiment 11. The composition according to any one of the embodiments above, wherein the hydrocarbons have a consistency of about 50-400dmm, 90-310dmm, 100- 300dmm, 170-320dmm, 230-310dmm or 240-300dmm.

Embodiment 12. The composition according to any one of the embodiments above, wherein the hydrocarbons have a melting range of 30°C - 70°C and a consistency of 50- 400dmm, such as 36°C - 62°C and 90-310dmm, such as 38°C - 60°C and 90-310dmm, such as 38°C - 60°C and 100-300dmm, such as 35°C - 55°C and 230-320dmm, such as 37°C - 53°C and 230-310dmm or such as 38°C - 51.6°C and 240-300dmm. Embodiment 13. The composition according to any one of the embodiments above, wherein tacrolimus is practically insoluble in the hydrophobic carrier.

Embodiment 14. The composition according to any one of the embodiments above, wherein tacrolimus is the sole active pharmaceutical ingredient.

Embodiment 15. The composition according to any one of the embodiments above, wherein the hydrophobic carrier comprises hydrocarbons which form an occlusive layer on the skin after application of the composition and evaporation of the propellant mixture.

Embodiment 16. The composition according to any one of the embodiments above, wherein at least 10000 ml of hydrophobic carrier is required to dissolve 1 g of tacrolimus at about 20°C.

Embodiment 17. The composition according to any one of the embodiments above, wherein at least 10000 ml of hydrophobic carrier is required to dissolve 2 g of tacrolimus at about 20°C °C.

Embodiment 18. The composition according to any one of the embodiments above, wherein tacrolimus is practically insoluble in the composition without propellants.

Embodiment 19. The composition according to any one of the embodiments above, wherein at least 10000 ml of composition without propellants is required to dissolve 1 g of tacrolimus at about 20°C.

Embodiment 20. The composition according to any one of the embodiments above, wherein at least 10000 ml of composition without propellants is required to dissolve 2 g of tacrolimus at about 20°C.

Embodiment 21. The composition according to any one of the embodiments above, wherein at least 10000 ml of the composition prior to addition of propellants is required to dissolve 1 g of tacrolimus at about 20°C.

Embodiment 22. The composition according to any one of the embodiments above, wherein at least 10000 ml of the composition prior to addition of propellants is required to dissolve 2 g of tacrolimus at about 20°C. Embodiment 23. The composition according to any one of the embodiments above, wherein the content of water does not exceed about 3% (w/w), such as 2% (w/w), such as 1% (w/w), such as 0.5% (w/w), such as 0.3% (w/w) or such as 0.1% (w/w) of the composition.

Embodiment 24. The composition according to any one of the embodiments above, wherein the composition is substantially anhydrous.

Embodiment 25. The composition according to any one of the embodiments above, wherein the composition is physically stable.

Embodiment 26. The composition according to any one of the embodiments above, wherein tacrolimus does not precipitate from the propellant during storage of the composition for at least 12 months at 25 °C.

Embodiment 27. The composition according to any one of the embodiments above, wherein no more than about 10% of tacrolimus degrades during storage of the composition at 40 ⁰ C for at least two months.

Embodiment 28. The composition according to any one of the embodiments above, wherein no more than about 10% of tacrolimus degrades during storage of the composition at 40 ⁰ C for three months.

Embodiment 29. The composition according to any one of the embodiments above, wherein no more than about 6 % of tacrolimus degrades during storage of the composition at 40 ⁰ C for three months.

Embodiment 30. The composition according to any one of the embodiments above, wherein no more than about 3% of tacrolimus degrades during storage of the composition at 40 °C for three months.

Embodiment 31. The composition according to any one of the embodiments above, wherein tacrolimus does not precipitate during storage of the composition for at least 12 months at 25 °C.

Embodiment 32. The composition according to any one of the embodiments above, further comprising a chelating agent. Embodiment 33. The composition according to any one of the embodiments above, wherein the amount of the chelating agent is 0.01-0.5 mg/g, such as 0.1 mg/g of the composition without propellants.

Embodiment 34. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, the amount of the chelating agent is 0.01-0.5 mg/g, such as 0.1 mg/g of the composition.

Embodiment 35. The composition according to any one of the embodiments above, wherein the chelating agent is EDTA.

Embodiment 36. The composition according to any one of the embodiments above, wherein the first propellant is dimethyl ether.

Embodiment 37. The composition according to any one of the embodiments above, wherein the second propellant is selected from propane, butane and pentane and mixtures thereof.

Embodiment 38. The composition according to any one of the embodiments above, wherein the second propellant is selected from propane, n-butane, iso-butane, n- pentane and iso-pentane and mixtures thereof.

Embodiment 39. The composition according to any one of the embodiments above, wherein the second propellant is butane.

Embodiment 40. The composition according to any one of the embodiments above, wherein the first propellant is dimethyl ether and the second propellant is n-butane.

Embodiment 41. The composition according to any one of the embodiments above, wherein the ratio of the first propellant to the second propellant is 1 :20 - 10: 1 (v/v), such as 1 : 18 - 2: 1, 1 : 15 - 4:3, 1 : 15 - 3 :4, 1 : 15-2:5, 1 : 14 - 1 : 1, 1 : 13 - 3 :4 or 1 : 13- 2: 5 (v/v).

Embodiment 42. The composition according to any one of the embodiments above, wherein the propellant mixture is composed of dimethyl ether and one or more C3-C5 alkanes in a ratio in the range of 1:20 - 10:1 (v/v), such as 1:18 - 2:1, 1:15 - 4:3,

1:15 - 3:4, 1:15-2:5, 1:14 - 1:1, 1:13 - 3:4 or 1:13-2:5 (v/v).

Embodiment 43. The composition according to any one of the embodiments above, wherein the propellant mixture is composed of dimethyl ether and butane in a ratio in the range of 1:20 - 10:1 (v/v), such as 1:18 - 2:1, 1:15 - 4:3, 1:15 - 3:4, 1:15-2:5, 1:14 - 1:1, 1:13 - 3:4 or 1:13-2:5 (v/v).

Embodiment 44. The composition according to any one of the embodiments above, wherein the propellant mixture is present in an amount from 40% to 95% (w/w), such as 45% to 80% (w/w), 50% to 75% (w/w) or 50% to 65% (w/w) of the composition.

Embodiment 45. The composition according to any one of the embodiments above, wherein dimethyl ether is present in an amount of 1 to 40% (w/w), such as 2 to 30%, 2 to 20% or 2 to 15% (w/w) of the composition.

Embodiment 46. The composition according to any one of the embodiments above, wherein more than 85% (w/w), such as more than 90%, 93%, 95%, 96%, 97%, 98% or 99% (w/w) of tacrolimus is dissolved in the propellant mixture.

Embodiment 47. The composition according to any one of the embodiments above, wherein said composition does not comprise a penetration enhancer.

Embodiment 48. The composition according to any one of the embodiments above, wherein said composition does not comprise propylene carbonate.

Embodiment 49. The composition according to any one of the embodiments above, wherein said composition comprises an antioxidant.

Embodiment 50. The composition according to any one of the embodiments above, wherein said composition comprises tocopherol and butylated hydroxytoluene.

Embodiment 51. The composition according to any one of the embodiments above, wherein said composition does not comprise a release enhancing agent.

Embodiment 52. The composition according to any one of the embodiments above, wherein said composition does not comprise a co-solvent. Embodiment 53. The composition according to any one of the embodiments above, wherein said composition does not comprise an animal wax or a plant wax.

Embodiment 54. The composition according to any one of the embodiments above, the composition without propellants comprising less than 10 % (w/w), such as less than 5%, 3% or 1% (w/w) of co-solvent.

Embodiment 55. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, the co-solvent is present in an amount of less than 10 % (w/w), such as less than 5%, 3% or 1% (w/w) of the composition.

Embodiment 56. The composition according to any one of the embodiments above, the hydrophobic carrier comprising less than 10 % (w/w), such as less than 5%, 3% or 1% (w/w) of co-solvent.

Embodiment 57. The composition according to any one of the embodiments above, the composition having a flow point of 5-50 Pa when subjected to an oscillation amplitude sweep at 25°C and an angular frequency of 10 rad/s within about 3 minutes after spraying onto a 50 mm sandblasted parallel plate of a rheometer operating in the oscillation mode.

Embodiment 58. The composition according to the embodiments above, the composition having a flow point of 10-25 Pa.

Embodiment 59. The composition according to any one of the embodiments above, comprising tacrolimus 0.01 - 0.2% (w/w) or 0.02 - 0.15% (w/w) without propellants.

Embodiment 60. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, tacrolimus is present in an amount of 0.01 - 0.2% (w/w) or 0.02 - 0.15% (w/w) of the composition.

Embodiment 61. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, the co-solvent is present in an amount of less than 10 % (w/w), such as less than 5%, 3% or 1% (w/w) of the composition. Embodiment 62. The composition according to any one of the embodiments above, comprising tacrolimus 1 mg/g or 0.3 mg/g without propellants.

Embodiment 63. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, tacrolimus is present in an amount 1 mg/g or 0.3 mg/g of the composition.

Embodiment 64. The composition according to any one of the embodiments above, comprising

tacrolimus 0.01 - 0.1% (w/w),

Hydrophobic carrier 30-50% (w/w),

dimethyl ether 3 - 30 % (w/w),

one or more C3-C5 alkanes 20 - 60 % (w/w),

and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Embodiment 65. The composition according to any one of the embodiments above, comprising

tacrolimus 0.01 - 0.1% (w/w),

(Cio-Cioo)Hydrocarbons 30-50% (w/w),

dimethyl ether 3 - 30 % (w/w),

one or more C3-C5 alkanes 20 - 60 % (w/w),

and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Embodiment 66. The composition according to any one of the embodiments above, consisting of

tacrolimus 0.01 - 0.1% (w/w),

(Cio-Cioo)Hydrocarbons 30-50% (w/w),

dimethyl ether 3 - 30 % (w/w),

one or more C3-C5 alkanes 20 - 60 % (w/w),

and optionally EDTA 0.0001 - 0.001 % (w/w).

Embodiment 67. The composition according to any one of the embodiments above, comprising

tacrolimus 0.01 - 0.1% (w/w),

white petrolatum 30-50% (w/w),

dimethyl ether 3 - 30 % (w/w),

butane 20 - 60 % (w/w), and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Embodiment 68. The composition according to any one of the embodiments above, comprising

tacrolimus 0.01 - 0.06% (w/w),

white petrolatum 35-55% (w/w),

dimethyl ether 3 - 15 % (w/w),

butane 30 - 60 % (w/w),

and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Embodiment 69. The composition according to any one of the embodiments above, comprising

tacrolimus 0.01 - 0.06% (w/w),

white petrolatum 35-50% (w/w),

dimethyl ether 3 - 15 % (w/w),

n-butane 35 - 60 % (w/w),

and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Embodiment 70. The composition according to any one of the embodiments , comprising

tacrolimus 0.01 - 0.06% (w/w),

white petrolatum 38-46% (w/w),

dimethyl ether 5 - 13 % (w/w),

n-butane 44 - 52 % (w/w),

and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Embodiment 71. The composition according to any one of the embodiments above, comprising

tacrolimus 0.04% (w/w),

white petrolatum 42% (w/w),

dimethyl ether 9% (w/w),

n-butane 48% (w/w),

EDTA 0.004% (w/w).

Embodiment 72. The composition according to any one of the embodiments above, comprising

tacrolimus 1 mg/g, white petrolatum 998.9 mg/g,

EDTA 0.1 mg/g,

without propellants.

Embodiment 73. The composition according to any one of the embodiments above, comprising

tacrolimus 1 mg/g,

white petrolatum 998 mg/g,

EDTA 0.1 mg/g,

without propellants.

Embodiment 74. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, the composition comprises

tacrolimus 1 mg/g,

white petrolatum 998.9 mg/g,

EDTA 0.1 mg/g.

Embodiment 75. The composition according to any one of the embodiments above, wherein upon application of the composition to skin and evaporation of the propellant mixture, the composition comprises

tacrolimus 1 mg/g,

white petrolatum 998 mg/g,

EDTA 0.1 mg/g,

Embodiment 76. The composition according to any one of the embodiments above, wherein tacrolimus is added to the formulation as as tacrolimus monohydrate.

Embodiment 77. The composition according to any one of the embodiments above, wherein the hydrophobic carrier comprises anti-oxidant(s).

Embodiment 78. The composition according to any one of the embodiments above, wherein the hydrophobic carrier comprises anti-oxidant(s) and stabilizer.

Embodiment 79. A process for preparation of a composition according to any one of the embodiments above, comprising the steps of

(a) Suspending tacrolimus and optionally a stabilizer in a hydrophobic carrier (b) Adding propellants to the suspension from step (a).

Embodiment 80. The process for preparation of the composition according to any one of the embodiments above, comprising the steps of

(a) Suspending tacrolimus and optionally a stabilizer in a hydrophobic carrier

(b) Adding propellants to the suspension from step (a)

(c) Dissolution of tacrolimus in the propellants.

Embodiment 81. The process for preparation of the composition according to any one of the embodiments above, comprising the steps of

(a) Suspending tacrolimus and optionally a stabilizer in a hydrophobic carrier

(b) Adding propellants to the suspension from step (a)

(c) Dissolution of tacrolimus and the hydrophobic carrier in the propellants.

Embodiment 82. The process for preparation of the composition according to any one of the embodiments above, comprising the steps of

(a) Suspending tacrolimus and optionally a stabilizer and optionally one or more antioxidant(s) in a hydrophobic carrier

(b) Adding propellants to the suspension from step (a)

(c) Dissolution of tacrolimus in the propellants.

Embodiment 83. A composition according to any one of the embodiments above, for use in the treatment of inflammatory dermal diseases and conditions.

Embodiment 84. The composition for use according to the embodiments above, wherein the dermal disease or condition is selected from the group consisting of atopic dermatitis, eczema, contact dermatitis, psoriasis, vitiligo, rosacea, alopecia, acne, urticaria and pruritus.

Embodiment 85. The composition for use according to the embodiments above, wherein the dermal disease or condition is atopic dermatitis.

Embodiment 86. The composition for use according to the embodiments above, wherein in the dermal disease or condition is vitiligo. Embodiment 87. The composition for use according to the embodiments above, wherein the treated subject is human.

Embodiment 88. The composition according to any of the embodiments above, comprising

Tacrolimus 0.038-0.046 % (w/w),

White petrolatum 38-46% (w/w),

Dimethyl ether 12-15 % (w/w),

Butane 39-49% (w/w).

Embodiment 89. The composition according to any of the embodiments above, comprising

Tacrolimus 0.038-0.046 % (w/w),

White petrolatum 38-46 % (w/w),

Dimethyl ether 8-10 % (w/w),

Butane 44-53 (w/w).

Embodiment 90. The composition according to the embodiments above,

comprising

tacrolimus 0.1 % (w/w) without the weight contribution of the propellant,

white petrolatum in an amount above 95 % (w/w) without the weight contribution of the propellant, and a propellant in an amount between 40 to 80 % (w/w) of the total composition wherein the propellant comprises dimethyl ether and C3-C5 alkane wherein the ratio of dimethyl ether to C3-C5 alkane is 10:20 (w/w) to 10:70 (w/w).

Embodiment 91. The composition according to the embodiments above,

comprising

tacrolimus 0.03 % (w/w) without the weight contribution of the propellant,

white petrolatum in an amount above 95 % (w/w) without the weight contribution of the propellant, and a propellant in an amount between 40 to 90 % (w/w) of the total composition wherein the propellant comprises dimethyl ether and C3-C5 alkane wherein the ratio of dimethyl ether to C3-C5 alkane is 10:20 (w/w) to 10:70 (w/w).

Embodiment 92 The composition according to the embodiments above, wherein the amount of propellant is 50 to 70 % w/w of the total composition Embodiment 93. The composition according to the embodiments above where the ratio of dimethyl ether to C3-C5 alkane is 10:30 (w/w) or 10: 55 (w/w).

Embodiment 94. The composition according to the embodiments above wherein the C3- C5 alkane is butane, isobutane or a mixture of butane and propane.

Claims

Claim 1. A storage stable topical pharmaceutical aerosol composition, the composition comprising a therapeutically effective amount of tacrolimus dissolved in a propellant, wherein the composition further comprises a pharmaceutically acceptable hydrophobic carrier solubilized or suspended in said propellant, wherein said hydrophobic carrier comprises hydrocarbons.

Claim 2. The composition according to claim 1, wherein the propellant comprises dimethyl ether and/or methylethyl ether.

Claim 3. The composition according to claim 2 wherein the propellant is a propellant comprises a first propellant selected from dimethyl ether and methylethyl ether and a second propellant selected from C3-C5 alkanes, C3-C5 fluoroalkenes and mixtures thereof.

Claim 4. The composition according to any one of claims 1-3, wherein the composition without propellants comprises more than 95% (w/w) of hydrocarbons.

Claim 5. The composition according to any one of claims 1 to 4, wherein upon

application of the composition to skin and evaporation of the propellant, the

hydrocarbons are present in an amount of more than 95% (w/w) of the composition.

Claim 6. The composition according to any one of claims 1-5, wherein the hydrocarbons have a melting range of about 37°C - 53°C.

Claim 7. The composition according to any one of claims 1-6, wherein the hydrocarbons have a consistency of about 230-310dmm.

Claim 8. The composition according to any one of claims 1-7, wherein tacrolimus is practically insoluble in the hydrophobic carrier.

Claim 9. The composition according to any one of claims 1-8, wherein the content of water does not exceed about 2% (w/w) of the composition.

Claim 10. The composition according to any one of claims 1-9, wherein the composition has a flow point of 5-50 Pa when subjected to an oscillation amplitude sweep at 25°C and an angular frequency of 10 rad/s within about 3 minutes after spraying onto a 50 mm sandblasted parallel plate of a rheometer operating in the oscillation mode.

Claim 11. The composition according to any one of claims 1-10, wherein the composition is physically stable.

Claim 12. The composition according to any one of claims 1-11, wherein tacrolimus is the sole active pharmaceutical ingredient.

Claim 13. The composition according to any one of claims 1-12, wherein the hydrophobic carrier comprises hydrocarbons which form an occlusive layer on the skin after application of the composition and evaporation of the propellant mixture.

Claim 14. The composition according to any one of claims 1-13, further comprising a chelating agent.

Claim 15. The composition according to any one of claims 1-14, wherein the propellant comprises dimethyl ether.

Claim 16. The composition according to claim 15, wherein the propellant is composed of dimethyl ether and C3-Cs-alkane in a ratio in the range 1 : 1 -1 : 10 (w/w), 1 :2 - 1 :8 (w/w), or 1 :3 - 1 :6 (w/w) .

Claim 17. The composition according to claim 16 wherein the C3-Cs-alkane is n-butane or a mixture of n-butane and propane.

Claim 18. The composition according to claim 17, wherein the C3-Cs-alkane is n-butane.

Claim 19. The composition according to any one of claims 1-18, wherein the propellant is present in an amount from 40% to 95% (w/w), such as 45% to 80% (w/w), 50% to 75% (w/w) or 50% to 65% (w/w) of the composition.

Claim 20. The composition according to any one of claims 1-19, wherein said

composition does not comprise a penetration enhancer.

Claim 21. The composition according to any one of claims 1-20, wherein said

composition does not comprise a co-solvent.

Claim 22. The composition according to any one of claims 1-5, comprising tacrolimus 0.01 - 0.1% (w/w),

(Cio-Cioo)-hydrocarbons 30-50% (w/w),

dimethyl ether 3 - 30 % (w/w),

one or more C3-C5 alkanes 20 - 60 % (w/w),

and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Claim 23. The composition according to any one of claims 1- 5, comprising

tacrolimus 0.01 - 0.06% (w/w),

white petrolatum 38-46% (w/w),

dimethyl ether 5 - 13 % (w/w),

n-butane 44 - 52 % (w/w),

and optionally comprising EDTA 0.0001 - 0.001 % (w/w).

Claim 24. The composition according to any one of claims 1-5, comprising

Tacrolimus 0.038-0.046 % (w/w),

White petrolatum 38-46% (w/w),

Dimethyl ether 12-15 % (w/w),

Butane 39-49% (w/w).

Claim 25. The composition according to any one of claims 1-5, comprising

Tacrolimus 0.038-0.046 % (w/w),

White petrolatum 38-46 % (w/w),

Dimethyl ether 8-10 % (w/w),

Butane 44-53 (w/w).

Claim 26. The composition according to any one of claims 1-5,

comprising

tacrolimus 0.1 % (w/w) without the weight contribution of the propellant,

white petrolatum in an amount above 95 % (w/w) without the weight contribution of the propellant, and a propellant in an amount between 40 to 90 % (w/w) of the total composition wherein the propellant comprises dimethyl ether and C3-C5 alkane wherein the ratio of dimethyl ether to C3-C5 alkane is 1 :2 (w/w) to 1 :7 (w/w).

Claim 27. The composition according to any one of claims 1-5, comprising

tacrolimus 0.03 % (w/w) without the weight contribution of the propellant, white petrolatum in an amount above 95 % (w/w) without the weight contribution of the propellant, and a propellant in an amount between 40 to 90 % (w/w) of the total composition wherein the propellant comprises dimethyl ether and C3-C5 alkane wherein the ratio of dimethyl ether to C3-C5 alkane is 1 :2 (w/w) to 1 :7 (w/w).

Claim 28. The composition according to any one of claims 26-27 wherein the amount of propellant is 50 to 70 % w/w of the total composition

Claim 29. The composition according to any one of claims 26 to 28 wherein the ratio of dimethyl ether to C3-C5 alkane is 10:30 (w/w) to 10: 55 (w/w).

Claim 30. The composition according to any one of claims 26 to 29 wherein the C3-C5 alkane is n-butane or a mixture of n-butane and propane.

Claim 31. The composition according to any one of claims 1-5, comprising

tacrolimus 0.04% (w/w),

white petrolatum 42% (w/w),

dimethyl ether 14 % (w/w),

n-butane 44 % (w/w),

optionally EDTA 0.004% (w/w).

Claim 32. The composition according to any one of claims 1-31, wherein the hydrophobic carrier comprises one or more anti-oxidants.

Claim 33. A process for preparation of the composition according to any one of claims 1- 32, comprising the steps of

(a) Suspending tacrolimus and optionally a stabilizer in a hydrophobic carrier

(b) Adding propellants to the suspension from step (a)

(c) Dissolution of tacrolimus in the propellants.

Claim 34. A composition according to any one of claims 1-32 for use in the treatment of inflammatory dermal diseases and conditions.

Claim 35. The composition for use according to claim 34, wherein the dermal disease or condition is atopic dermatitis.

Claim 36. The composition for use according to claim 34, wherein in the dermal disease or condition is vitiligo.