Novel composition for local skin treatment

Abstract

A composition for use in the treatment of corticosteroid responsive dermatoses, wherein the composition is administered topically at least once every 48 h onto a skin area of a subject in need thereof, wherein the skin is thin or considered too sensitive for general topical corticosteroid treatment and / or where the subject is an infant, and wherein the composition is an oil-in-water emulsion or cream composition comprising one or more corticosteroids, water, and one or more glycols, and wherein the one or more corticosteroids is partially dissolved to an extent of 40-70 wt% and in micronized form, and wherein the one or more glycols are present in a concentration of 25 wt%.

Description

[0001] Novel composition for local skin treatment

[0002] Field of the invention

[0003] The present invention provides a novel pharmaceutical composition comprising a corticosteroid or a pharmaceutically acceptable derivate thereof in the form of an oil-in-water emulsion, notably a cream composition. The composition is suitable for topical use in sensitive skin areas, such as e.g., areas where the skin is thin, larger treatment areas, longer treatment duration and for the use in children. In particular, the composition according to the invention is suitable for dermal use, i.e. administration of the composition onto the skin.

[0004] Background of the invention

[0005] Glucocorticoid derivatives are the most effective and widely prescribed compounds for treating inflammatory and autoimmune diseases.

[0006] However, their therapeutic use is limited by the adverse side effect profile that in skin includes e.g., epidermal thinning (atrophy), striae, senil purpura, telangiectasia, perioral dermatitis, acne, rosacea, impaired wound healing, increased skin fragility, and infection risk. Systemic side effects from local dermal treatment are a concern when higher strength glucocorticoids, thinner skin areas, occlusion, large treatment areas and long treatment durations are required. These are similar to the side effects seen with systemic administration of glucocorticoids and include e.g., HPA axis suppression, Cushing syndrome, corticosteroid-related Addison crises and growth retardation. The above adverse effects are similar to symptoms of individuals with abnormally high endogenous production of glucocorticoids (Cushing’s syndrome) as well as in the elderly population (Bigas, J. et al., Cell Death & Disease, 2018, 9(588).).

[0007] Glucocorticoids penetrate the stratum corneum and bind to glucocorticoid receptors in viable epidermis and dermis (Prakash A. et al., Drugs, 1998, 55(1 )., Smith K. et al., Clin Exp Dermatol, 1987, 12(2). and Leiferman KM, et al., J Invest Dermatol, 1983 81 (4).

[0008] British National Formulary states that the skin of children is sensitive, so they are likely to be susceptible to topical steroids, hence they should be avoided in children, or if necessary, used with care and for shorter periods of time. Also, for adults the application of potent corticosteroids to large areas of diseased psoriatic skin results in sufficient systemic absorption to cause not only adrenal suppression but some degree of hypercortisolism with greater frequency and rapidity than has previously been suggested (Garden J.M., Freinkel R.K., Arch Dermatol. 1986 Sep; 122(9))

[0009] Some examples of topical compositions are known in the art.

[0010] US patent No. 4,808,610 (Schering Corp) and US patent No. 7,312,207 (Taro Pharmaceuticals) relate to mometasone containing compositions for topical use, wherein the composition is in the form of a water-in-oil (w / o) emulsion.

[0011] WO 91 / 08733 (Schering Corp) relates to an oil-in-water (o / w) emulsion comprising a lipophilic active drug substance (e.g. mometasone). The examples show the necessity of using N-methyl-2-pyrrolidone in order to enhance the vasoconstrictor effect. In the examples propylene glycol is used in a concentration of 10% w / w.

[0012] WO 2008 / 126076 (Perrigo Israel Pharmaceuticals Ltd.) relates to a low-dose mometasone formulation. Exemplary formulations are creams containing 0.075% mometasone, a polyol, a gelling agent, an oily phase and water. A low-dose mometasone formulation is desired in order to reduce the toxicity of a mometasone formulation. It is believed that a formulation of WO 2008 / 126076 has a relatively low systemic steroid absorption. No in vivo studies are reported. However, none of prior art compositions appear to address the above mentioned problems and consequently, there is still a need for locally acting pharmaceutical skin formulations that are able to provide adequate clinical effect and at the same time being able to overcome the unwanted corticosteroid side-effects, providing an effective and safe treatment suitable for larger skin treatment areas, longer treatment durations and in areas where the skin is thin or for use in treatment of small children i.e. on sensitive skin.

[0013] Description of the invention

[0014] The present invention relates to a composition which may take any form, notably an emulsion, or a cream or cream like composition, such as e.g., an oil-in-water cream composition.

[0015] The composition according to the invention is suitable for topical use on a subject’s skin. Specifically, the composition may be applied topically onto the skin in areas where the skin is thin and therefore more sensitive to corticosteroid side effects as described above. Non-limiting examples of specific sensitive skin areas is skin on the face and notably near the eyearea, e.g., the eye lids. Other examples are armpits, groin area and genital area.

[0016] The composition according to the invention with 0.1 % (w / w) mometasone furoate is also suitable for use on larger skin areas such as more than 20% of the total skin area of an individual but less than or equal to 60% of total skin area for adults, and more than 10% of the total skin area of an individual but less than or equal to 40% of total skin area for children.

[0017] The composition according to the invention is also suitable for use in small children, such as e.g., children of age up to about 6 months or up to about 1 year or up to about 18 months, or up to about 3 years etc. Stratum corneum, the skin barrier, is thinner and more permeable in babies. The stratum corneum is more permeable in younger infant age groups (3-6 months old) and continue to show higher permeation than mature skin through the first year of life [Community Practitioner 2010], As children age, there are significant decreases in permeability and a concomitant decrease in moisture content, plateauing at about 5 years of age [Walters RM, Khanna P, Chu M, Mack MC. Developmental changes in skin barrier and structure during the first 5 years of life. Skin Pharmacol Physiol. 2016;29: 111-118. doi: 10.1159 / 000444805]

[0018] The composition according to the invention may be administered topically about 1 time daily, such as e.g., 1 time every two days (i.e. once every 48h), etc.

[0019] The composition may comprise a glucocorticosteroid or corticosteroid, such as e.g., mometasone or any acceptable pharmaceutical salt or ester thereof.

[0020] The composition according to the invention may further comprise one or more glycols, such as e.g., propylene glycol (propane-1 ,2-diol), or e.g., a butylene glycol (e.g., 1 ,3-butandiol). However, in principle any glycol (dihydroxy hydrocarbons) having two hydroxyl groups on different carbon atoms may be used in the composition according to the invention.

[0021] The concentration of the one or more glycols may be about e.g. 25 % (w / w).

[0022] The composition according to the invention enables the solubility of the corticosteroid to be between about 40% to about 70% (w / w) of the total amount of corticosteroid in the composition. Furthermore, the composition according to the invention comprises e.g. about 30 to about 60% (w / w) of the total amount of corticosteroid in the composition in undissolved form. The undissolved corticosteroid may be in a particulate form such as e.g., a micronized form.

[0023] As is apparent to a person skilled in the art, the amount of dissolved and undissolved corticosteroid taken together is 100% of the total amount of corticosteroid used in the composition according to the invention.

[0024] In one aspect, the invention relates to use of the composition according to the invention, for treatment of skin related inflammatory condition or autoimmune disease.

[0025] The invention also relates to use of the composition according to the invention, for treatment of skin related inflammatory condition or autoimmune disease, wherein the composition is administered topically on skin.

[0026] In a further aspect, the invention relates to use of the composition according to the invention, wherein the composition is administered once daily. In another aspect, the invention relates to use of the composition according to the invention, wherein the composition is administered once every 48h. In yet a further aspect, the invention relates to use of the composition according to the invention for treatment of skin related inflammatory condition or autoimmune disease, where the composition is administered topically onto a skin area where the skin is thin, over large skin areas, for long treatment duration or where the composition is administered topically on the skin to a child.

[0027] Figures Figure 1 illustrates the topical bioavailability of a mometasone furoate composition according to the invention against three relevant commercial comparator GC cream products. Topical bioavailability of corticosteroids can be proven by the vasoconstrictor assay as originally described by McKenzie and Stoughton (McKenzie AW, Stoughton RB Method for comparing percutaneous absorption of steroids. Arch Dermatol 1962; 86). The vasoconstrictor assay has now been used for many years and is accepted by the FDA as a method to establish bioequivalence on topical corticosteroid compositions. Specifically, the figure illustrates the blanching effect from a cream composition according to the invention containing 0.1% Mometasone furoate as compared to three commercial corticosteroid creams, Kenacort-T 0.1 % (Triamcinolone acetonide, lower potency corticosteroid), Elocon 0.1 % (mometasone furoate, same potency corticosteroid and concentration) and Dermovat 0.05 % (Clobetasol propionate, higher potency ).

[0028] Detailed description of the invention

[0029] In one aspect, present invention provides an oil-in-water emulsion (o / w) comprising mometasone furoate as an active drug substance.

[0030] Moreover, the emulsion may comprise a C4 alkane-diol, wherein the two hydroxyl groups are linked to two different carbon atoms and wherein the alkane may be a straight chain or branched. The C4 alkane-diol may be a butane diol (butylene glycol) such as 1 ,3-butane-diol or a C3 alkane-diol such as e.g. propylene glycol (propane-1 ,2-diol). Preferred substance is butylene glycol.

[0031] However, the o / w composition may also comprise propylene glycol.

[0032] Present invention provides for an effective treatment in sensitive skin areas, on larger treatment areas, for longer treatment duration or for treatment of children, where the unwanted systemic corticosteroid side effects may be reduced, or altogether obviated.

[0033] It has been surprisingly discovered that the specific cream formulation according to the invention exhibit specific properties making it suitable for the treatment of thin and sensitive skin in that the invention do not alter the natural skin barrier function of stratum corneum, as determined by skin resistance. When applying a cream on a skin membrane for 12 hours the resistance ratio before / after was 0.16 for a commercial glucocorticoid (GC) cream (Elocon), a more than 6 times reduction in skin barrier resistance equalling a disturbance effect on stratum corneum. This reduction in stratum corneum resistance facilitates the penetration of the active moiety and thereby the risk of systemic effects. No reduction in skin resistance was detected for a GC cream composition of the invention i.e. , a resistance ratio before / after of 1 .14, equalling a non-disturbed stratum corneum.

[0034] It has also been shown that the formulation according to the invention produces a much lower flux of GC (GlucoCorticoid) through skin as compared to commercial GC creams. However, the lower flux, although beneficial when considering possible systemic side effects, could be detrimental for the clinical effect. A blanching study, according to Figure 1 , has shown similarity in blanching, i.e., bioavailability and consequently, the inventors of present invention has surprisingly found that the compositions according to present invention has a lower flux of GC while at the same time is capable of providing a clinically relevant effect.

[0035] As is apparent from the above, the abbreviation “GC” is intended to mean a glucocorticoid, or synonymously glucocorticosteroids. In other aspects, the terminology is intended to mean corticosteroid. The formulation according to the invention shows a surprisingly even GC retentive / accumulative effect in epidermis and dermis, equal in concentration to the commercial GC cream. The GC from the formulation according to the invention passes the stratum corneum more slowly and passes through the epidermis and dermis to a lesser extent as compared to the commercial GC cream by a factor of approximately 14. The accumulation in epidermis and dermis is however equal due to a slower clearance from epidermis and dermis, ensuring equal clinical effect with a slightly different time profile.

[0036] This formulation effect is highly attractive for topical GC formulations in that the clinical effect is maintained and the systemic side effects are reduced.

[0037] It has been surprisingly discovered that the composition according to the invention and novel treatment regimen enables a slower onset of action and a longer duration when compared to the commercial composition Elocon, producing similar AUC (Area Under the Curve), as measured from skin blanching according to Figure 1 , thereby demonstrating bioequivalence.

[0038] The permeability (steady state flux), presented in Table 1 , of mometasone furoate through porcine skin to receptor media from the composition according to the invention shows approximately 14 times lower flux as compared to Elocon, demonstrating a lower permeation of mometasone furoate via stratum corneum though epidermis and dermis to the larger blood vessels in the subcutaneous tissue.

[0039] At the same time, it is observed that the concentration of the corticosteroid in epidermis / dermis is retained for a longer time according to Table 2. The ratios of the mometasone furoate concentration (Elocon / composition according to the invention) in the skin samples are decreasing from 6h to 12h. It is thus observed that the present composition and treatment regimen provides for a slower concentration build up in epidermis and dermis, while at the same time reaching therapeutical levels similar to Elocon. The therapeutic concentration in epidermis and dermis remains over a longer time i.e., shows a lower tendency to migrate further down in dermis and the subcutaneous tissue in accordance with the permeation data i.e. showing a lower tendency to reach further down into the skin layers and getting in contact with the larger blood vessels and thereby being readily available for systemic absorption.

[0040] This ensures an equal efficacy as observed with prior art compositions and prior art treatment and dosage regimens, and consequently, present invention provides for equal efficacy as demonstrated by an equal Area Under the Curve (AUC) as observed for prior art compositions and prior art treatment and dosage regimens.

[0041] The lower permeability through stratum corneum and the higher affinity to epidermis and dermis ensures a lower systemic uptake via the larger blood vessels and thereby reducing the systemic side effects, such as e.g., hypothalamic pituitary adrenal (HPA) axis suppression, Cushing's syndrome, growth retardation in children, hyperglycaemia and glucosuria, cataract, glaucoma, etc.

[0042] As a further consequence of the surprising effect found by the inventors of present invention, the pharmacokinetic profile provides for a reduced application frequency, such as a reduction to administration strictly once daily and as a further result thereof increasing patient compliance.

[0043] Moreover, and as mentioned herein, the observed pharmacodynamics profile makes the composition according to the invention well tolerated in thin skin or areas with thin skin which would normally be very sensitive to corticosteroid treatment. Such areas may be e.g., the face and particularly the eyelids, the scalp, or genital areas, and young children which generally have thinner skin than adult patients. Other areas of the body which may be relevant for the invention, are parts of the body where skin touches skin, i.e. armpits, groin area, and the rectal area or other skin creases.

[0044] In one aspect, the terminology “thin skin” may be intended to mean areas of the body where the thickness of the skin is about 1 .0 mm or less, such as e.g. about 0.5 mm or less.

[0045] In a further aspect, the invention may comprise use of the composition onto skin that is considered sensitive. As mentioned herein, sensitive skin is skin that is normally considered too sensitive for any topical steroid composition, and wherein treatment employing such compositions would be considered to entail unwanted side effects.

[0046] In another aspect, the terminology “thin skin” may be intended to encompass any area of the body where skin is normally considered too sensitive to steroid treatment.

[0047] As mentioned herein, the skin is made up of three main layers, from the outside starting with epidermis then dermis and hypodermis. The outmost layer, epidermis, is divided in fivelayers, starting from the outside with stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum basale. The outermost layer, stratum corneum, functions to form a barrier to protect us from infection, dehydration, chemicals and mechanical stress. Stratum corneum is also the skin barrier for topical pharmaceutical active ingredients to enter the body system.

[0048] Corticosteroids are better absorbed and more permeable in regions of thin epidermis, such as the eyelid, compared to thicker regions of epidermis, such as the sole. The penetration difference between the two varies by 300 fold. Steroid sensitive skin or skin more prone to local and systemic steroid side effects are defined in the literature as thinner and sensitive skin which is the subject of the present invention. Thus the skin of the palms of the hand and the sole of the feet are generally not considered as thin skin.

[0049] As also mentioned herein, the skin barrier, i.e. stratum corneum, in children is thinner and not fully developed until the age of 2 years. This means that children up to the age of two are more susceptible to topical uptake of e.g. steroids and thereby more sensitive to steroid side effects as compared to adults. Therefore, topical steroids of higher potency are not generally recommended to be used in children below the age of two, and use of potency topical steroids in this patient group is only recommended with great caution. However, the present invention may be applied to the patient group of children under the age of e.g. about 2 years.

[0050] In children above two years and adults certain regions of the body where the skin is thinner and more sensitive to systemic side effects e.g. from topical steroids. The thickness of stratum corneum varies in individual and maybe more so depending on body location. However, the present invention is suitable for application in areas which are usually considered as too thin or too sensitive for any steroid treatment (topical administration). The greatest absorption occurs through the thin skin of eyelids, genitals, and skin creases. Thus, usually, the use of a potent topical steroid is best avoided in these areas. As mentioned herein, the inventors of present invention has surprisingly found that the formulations disclosed herein are suitable for use in said areas.

[0051] Thus, in one aspect, the composition according to the invention may be administered to the skin in the face area such as e.g. to the eyelids. It is also observed that skin becomes thinner as a person ages, or as a result of sun damage, medication, or lifestyle factors. Epidermal thickness decreased somewhat faster in men (7.2% of the original value / decade) than in women (5.7%).

[0052] In the table below, the thickness of Stratum Corneum at different body locations is listed and made from measurements from 301 normal individuals.

[0053] 1A corneocyte is approximately 1 pm in thickness.

[0054] As mentioned herein, the invention relates to topical treatment of skin which may be considered as thin skin. Normally, such areas are considered too sensitive for any topical steroid treatment. In one aspect, thin skin is defined as areas wherein the Stratum Corneum is in the range of (estimated thickness of Stratum Corneum) about 4 p.m to about 17 p.m and may comprise e.g. the genital area, face, neck, scalp, and trunk. In another aspect, thin skin may comprise areas of the skin wherein the Stratum Corneum is in range of (estimated thickness of Stratum Corneum) about 4 p.m to about 14 p.m, and may comprise e.g. the genital area, face, neck, and scalp. The composition according to the invention is also suitable for use on larger skin areas such as recommended for treatment up to 60% of total skin area (total body surface area) for adults and up to 40% total body surface for children when a strong corticosteroid (European Class III) is used, such as 0.1 % mometasone furoate.

[0055] Thus, present invention provides for both a clinically effective treatment while at the same time reducing the incidence of unwanted side effects such as e.g., epidermal thinning (atrophy), striae, senile purpura, telangiectasia, perioral dermatitis, acne, rosacea, impaired wound healing, and increased skin fragility, infection risk, HPA axis suppression, Cushing syndrome, corticosteroid-related Addison crises and growth retardation. In one aspect, the invention provides a clinically effective treatment while at the same time reducing the incidence of HPA axis suppression.

[0056] Thus, in one aspect, present invention may provide for topical treatment in the face area for a period longer than e.g. 5 days, when the composition according to the invention is administered at least once daily. Thus, the treatment may be for e.g. 6 days or longer, such as e.g. about 7 days or longer, such as e.g. about 8 days or longer, such as e.g. about 9 days or longer, such as e.g. about 10 days or longer, such as e.g. about 11 days or longer, such as e.g. about 12 days or longer, such as e.g. about 13 days or longer, such as e.g. about 14 days or longer, such as e.g. about 3 weeks or longer, such as e.g. about 4 weeks or longer, such as e.g. about 5 weeks or longer, such as e.g. about 6 weeks or longer, such as e.g. about 7 weeks or longer, such as e.g. about 8 weeks or longer etc.

[0057] In a further aspect, present invention may provide for treatment of infants or treatment in sensitive areas where the skin is thin and otherwise considered too sensitive for treatment for long periods of time. Consequently, in this aspect, the invention may provide for treatment during periods longer than e.g. about 3 weeks, such as e.g. about 4 weeks or longer, such as e.g. about 5 weeks or longer, such as e.g. about 6 weeks or longer, such as e.g. about 7 weeks or longer, such as e.g. about 8 weeks or longer, such as e.g. about

[0058] 9 weeks or longer, such as e.g. about 10 weeks or longer, such as e.g. about 15 weeks or longer, such as e.g. about 20 weeks or longer, such as e.g. about 25 weeks or longer, such as e.g. about up to 30 weeks of treatment. During such prolonged treatment periods, it is envisaged that the composition according to the invention is administered at least once daily.

[0059] In yet a further aspect, present invention also provides for treatment of larger areas of skin. Thus, in one aspect, present invention provides for treatment of skin larger than about 20% of the total area of skin of the body, such as e.g., about 25% or larger, such as e.g., about 30% or larger, such as e.g., about 35% or larger, such as e.g., about 40% or larger, such as e.g., about 45% or larger.

[0060] As it appears from the examples herein, an o / w emulsion of the present invention provides a therapeutic effect of mometasone furoate 0.1 % that is comparable to the marketed w / o emulsion (Elocon® 0.1 % cream) while at the same time reducing the above mentioned unwanted side effects and allowing for treatment of e.g., small children and topical application in areas where skin is thin and sensitive.

[0061] It is to be understood that the abbreviation “% wM’, refers to the weight percentage measured as the weight of an active ingredient or excipient in relation to the weight of the finished composition as a whole, unless otherwise indicated. For example, when it is mentioned that a concentration of e.g. one or more glycols is about e.g. 25 % (w / w), this means that 25% is calculated as the weight ratio between the glycols and the weight of the complete composition comprising i.a. the glycols. Another example is e.g. when it is stated that 30 to about 60% (w / w) of the total amount of corticosteroid in the composition in undissolved form. This is intended to mean that 30-60% of the total amount of corticosteroid is undissolved form whereas the remaining part, 40-70% of the corticosteroid is dissolved in the composition and calculated as the weight ratio between undissolved / dissolved corticosteroid.

[0062] The present inventors have found that using a corticosteroid, such as e.g. mometasone (e.g. mometasone furoate) and a C4 alkane-diol (notably butylene glycol) or a C3 alkane-diol (such as e.g. propylene glycol) in a relatively high concentration (from 15% to 45% w / w) enables the formulation of an o / w emulsion, wherein mometasone is at least partly dissolved in the formulation (as appears from the examples herein, mometasone furoate is partly dissolved in the formulation). Moreover, it seems to be possible to obtain an o / w emulsion with a similar therapeutic effect to that seen with Elocon cream, i.e. , the o / w emulsion only need to be applied strictly once daily. To this end and as indicated by the results reported herein, a suitable weight ratio between alkane diol and water in the o / w emulsion seems to be important for the once daily administration and the observed reduced side effect profile. It seems as if a too large or a too low ratio will not result in the desired effect and / or the desired bioavailability. Another factor that seems to be of importance is the presence of mometasone (e.g., mometasone furoate) in micronized from. Normally, mometasone is not dissolved (or only partly dissolved) in a composition of the invention. The results reported herein indicates the importance of having undissolved mometasone in micronized from. Thus, in general, 100% of the mometasone particles has a particle size of at the most 20 pm, 99% has a particle size of at the most 15 pm, and 80% has a particle size of at the most 5 pm when measured by means of a laser scattering method. When determining the particle size by means of light microscopy (which is the method preferred, when the particle size is measured in the final composition), no particle of mometasone should exceed 40 pm. Most particles (more than 80% and visually evaluated in the microscope) have a size between 10 and 20 pm. Eventual particle growth over time in the composition should not result in any particles exceeding 100 pm, when measured with light microscopy. Other factors may also influence the results such as the nature of the other ingredients employed. However, the two most important factors in compositions of the present invention seem to be the weight ratio and particle size as discussed above.

[0063] For propylene glycol, a suitable weight ratio between propylene glycol and water is from about 1 :1 to about 1 :3. It is contemplated that a similar suitable weight ratio between butylene glycol and water is from about 1 :1 to about 1 :3. Moreover, it is possible to obtain an emulsion with balanced content of mometasone (e.g. mometasone furoate), and a C4 alkane-diol or C3 alkanediol and water that is bioequivalent in the sense that the composition is equipotent with the w / o Elocon cream.

[0064] A composition of the invention contains two phases, an aqueous phase, which is the continuous phase and an oil phase, which is the dispersed phase that is homogeneously distributed in the continuous phase (i.e. , as generally seen in o / w emulsions). Moreover, the active drug substance, e.g., mometasone (e.g., mometasone furoate), is partly dissolved and partly present in the form of fine particles, notably in micronized form.

[0065] In one aspect, present invention relates to an oil-in-water emulsion composition, wherein the composition comprises mometasone or a pharmaceutically acceptable derivative thereof and propylene glycol, or a C4 alkane-diol, which may be linear or branched, and the concentration of the C4 alkane-diol, or propylene glycol is from 20 to 45% w / w.

[0066] More specifically, the present invention provides an oil-in-water emulsion comprising mometasone or a pharmaceutically acceptable derivative thereof and a C4 alkane-diol, which, if relevant, may be linear or branched, and the concentration of the C4 alkane-diol is from 15 to about 45% w / w such as from 20% w / w to 45% w / w, from 15% w / w to 30% w / w or from 20% to 30% w / w. It is contemplated that other alkane-diols as well may be used in combination with butylene glycol. Propylene glycol and butylene glycol are normally regarded as relatively non-toxic substance with minimally irritant effect. Pentylene glycol and hexylene glycol have even lower irritation effects after topical administration and, accordingly, it is contemplated that such substances could be used in higher concentrations than propylene glycol and butylene glycol (i.e., from about 20% w / w to 50% w / w, notably from about 30% w / w to 45% w / w). If pentylene glycol or hexylene glycol is used in combination with butylene glycol the concentration of pentylene glycol or hexylene glycol is from about 1 % w / w to about 20% w / w (notably from about 5% w / w to about 20% w / w).

[0067] Incorporation of the C4 alkane-diol or C3 alkane diol is very important in order to obtain the desired effect, and not only is it the incorporation of any amount of the C4 alkane-diol or C3 alkane diol in the emulsion, but also the concentration of the C4 alkane-diol or C3 alkane diol, either expressed as the concentration in the total emulsion, or, more specific, expressed as a ratio between the C4 alkane-diol or C3 alkane diol and water. When an oil-in- water emulsion of the invention is applied to the skin, the water in the composition is subject to evaporation. Thus, not only the weight ratio between C4 alkane-diol or C3 alkane diol and water in the composition may be important, but also the ratio between the C4 alkane-diol and mometasone or a pharmaceutically acceptable derivative thereof may have impact on the therapeutic result. One or more of these factors are contemplated to be decisive for whether an emulsion can be obtained with suitable properties with respect to therapeutic effect.

[0068] According to present invention, the active pharmaceutical ingredient may be one or more glucocorticosteroid (or synonymously used herein; glucocorticoids) or any ester or pharmaceutically acceptable salt thereof. Non-limiting examples are hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate or the likes.

[0069] In one aspect, the invention relates to the betamethasone type of corticosteroids such as e.g., beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone.

[0070] In the present context, the term "mometasone" includes mometasone or pharmaceutically acceptable derivatives thereof. Thus, the term includes mometasone as such as well as suitable ester derivatives such as esters with organic acid normally used in pharmaceutics including the furoate ester. Moreover, "mometasone or pharmaceutically acceptable derivatives thereof includes any form such as anhydrous form, hydrate forms including the monohydrate, solvates other than hydrates etc., as well as amorphous, polymorph and crystalline forms thereof. In the present context, all calculation relating to "mometasone or pharmaceutically acceptable derivatives thereof is based on mometasone furoate. Accordingly, if another derivative is employed, an equivalent amount of mometasone furoate must be calculated based on the molecular weights of the derivative and the mometasone furoate. The concentration of mometasone or any suitable corticosteroid (calculated as mometasone furoate) in an emulsion or cream composition of the present invention may be from about 0.01 % to 2% w / w, normally from 0.05% to 0.2% w / w, from 0.075% to 0.2% w / w such as about 0.1 % w / w.

[0071] In an emulsion according to the invention, mometasone (mometasone furoate) or any suitable corticosteroid is not fully dissolved. Accordingly, a part of mometasone or a pharmaceutically acceptable derivative thereof is present in undissolved form, typically from about 25 to about 35 % w / w of the total amount of mometasone present in the emulsion.

[0072] In another aspect, the mometasone (mometasone furoate) or any suitable corticosteroid is present in an amount of about 30 to about 60% (w / w) which is in undissolved form in the composition according to the invention and is also present in micronised form in the composition. Conversely, the composition according to the invention allows for the mometasone (mometasone furoate) or any suitable corticosteroid present in the composition to be dissolved in an amount of from about 40% to about 70% (w / w).

[0073] In order to improve the dispersibility of the undissolved mometasone, or any corticosteroid used in the composition, as well as the absorption rate, mometasone should be employed in micronised form. As it appears from the examples herein, mometasone, e.g., mometasone furoate, should be employed in micronised form, wherein 100% has a particle size of at the most 20 pm, 99% has a particle size of at the most 15 pm, and 80% has a particle size of at most 5 pm (when determined by laser scattering method). It is contemplated that during the manufacturing process, mometasone furoate may partly dissolve, but is not fully dissolved. This seems to be of importance in order to control the particle size in the final composition. If mometasone is fully dissolved during the manufacturing method, a risk will occur that the mometasone that precipitates in the composition have a too large particle size which will negatively affect the release of the active substance and will not result in the desired release to the skin. Accordingly, it is envisaged that the mean particle size (and / or particle size distribution) of mometasone furoate employed is important in order to obtain reproducible therapeutic results.

[0074] In one aspect, the C4 alkane-diol is a butylene glycol. A specific example is butane-1 ,3-diol. It is envisaged that other diols in combination with butylene glycol also may be suitable for use in the present context provided that it is suitable and safe for topical use.

[0075] As mentioned above, the concentration of the C4 alkane-diol (abbreviated "alkane-diol" herein) or propylene glycol in an emulsion of the invention is from about 15% to about 45% w / w. As discussed above, the concentration depends on the specific C4 alkane-diol used. In general, the concentration of the C4 alkane-diol, notably butylene glycol, is from about 20% to about 40% w / w such as from about 20% to about 30% w / w.

[0076] In one aspect, the concentration of the C4 alkane-diol (abbreviated "alkane- diol" herein) or propylene glycol in an emulsion of the invention is about 25% (w / w).

[0077] As mentioned above, the weight ratio between the alkane-diol and water seems to be very important in order to achieve the desired therapeutic effect. Moreover, the weight ratio between butylene glycol and mometasone (M) may also be a useful parameter to decide the amount of alkane-diol in an emulsion of the invention. For example, the lower limit is normally not less than 7.5, such as in a range of from 7.5 to 100 and the upper limit is normally 4500 or less such as in a range of from 600 to 4500. Normally, the ratio is 75 or more such as from 75 to 900 or from about 150 to about 450, and M is calculated as mometasone furoate. Specifically, the weight ratio between the alkane- diol and mometasone (M) is from 200 to 300, such as 200, 225, 250, 275 or 300, and M is calculated as mometasone furoate.

[0078] Thus, in one aspect, the invention relates to a composition, which may be an oil-in-water emulsion or cream composition, comprising one or more glucocorticoids, specifically mometasone furoate, one or more glycols, specifically, propylene glycol or a C4 alkane-diol, wherein the corticosteroid is present in an amount of about 0.1 % (w / w) while also being present in an undissolved micronized form of from about 30% to about 60% (w / w) of the total amount of the corticosteroid present in the composition. The one or more glycols may be present in an amount of 25% (w / w) of the composition. The remaining constituents of the composition may be any other suitable excipients or vehicles suitable in any pharmaceutical use, such as e.g., water. As is fully apparent to a person skilled in the art, the sum of all ingredients or constituents of the composition amounts to 100% (w / w).

[0079] The composition according to the invention may further comprise an array of suitable vehicles or excipients.

[0080] In one aspect, the composition according to the invention may further comprise an oil selected from a group consisting of vegetable oils and fats, animal oils and fats, mineral oils, ester oils, silicon oils or waxes. Notably, the oil / fat is a vegetable oil / fat such as coconut oil, olive oil, sunflower oil and canola oil etc. Fats can be defined as bulk storage material produced by plants, animals and microorganisms that contain aliphatic moieties, such as fatty acid derivatives. These are mainly, but not entirely, mixtures of triglycerols (triglycerides) and are known as oils or fats depending on whether they are liquid or solid at room temperature. In the present context, the term "oil" also includes "fat" and oil / fat may also be produced synthetically or semi- synthetically. The concentration of the oil / fat in the emulsion is from about 3 to about 30% w / w, notably from about 5 to about 25% w / w.

[0081] The composition according to the invention may further comprise stabilising agent to provide for stabilization of an oil-in-water emulsion or cream composition according to the invention may suitably be carried out by adding one or more emulsifying agents. An emulsion of the present invention may therefore comprise one or more emulsifying agents. As seen from the examples herein use of three emulsifying agents having a HLB (hydrophilic- lipophilic balance) in the range 3-20, one with a high HLB, i.e. , a HLB of, from about 11 - 20 and two with a low HLB, i.e., a HLB of, from about 3 - 11 , gives the desired result with respect to stability without compromising the therapeutic effect.

[0082] Suitable emulsifying agents for use in a composition of the invention may be selected from the group consisting of glycerol alkyl esters, macrogol alkyl esters, polyoxyethyleneglycol alkyl esters, fatty acids, polyoxyethylene sorbitan esters, polyoxyethylene alkyl ethers, galactolipids.

[0083] Specific emulsifying agents for use in a composition of the invention are glycerol monostearate 40-55, macrogol stearate, and stearic acid.

[0084] The concentration of each emulsifier when present in an emulsion according to the present invention ranges from about 1 to about 5% w / w.

[0085] Furthermore, the composition according to the invention may comprise a viscosity-increasing agent. Viscosity-increasing agents suitable for use in an emulsion may be selected from the group consisting of fatty alcohols (concentration range: about 5 to about 15% of total emulsion) However, the concentration normally dependents on the specific type of fatty alcohol used and a person skilled in the art will know how to adjust the concentration of such specific concentrations to obtain the desired viscosity.

[0086] For example, a suitable viscosity-increasing agent is cetostearyl alcohol.

[0087] In general, the concentration of the viscosity-increasing agent in the form of a fatty alcohol ranges from 5% to 15 % w / w.

[0088] A composition according to present invention is intended for topical use, e.g., as a cream to apply on the skin. Accordingly, pH may be adjusted to a skinfriendly value taking into consideration stability issues relating to mometasone. A suitable pH is below 6 such as from about 3 to about 6 or from about 4.0 to about 5.0. pH may be adjusted by use of one or more pH adjusting agent, which is selected from the group consisting of hydrochloric acid, phosphoric acid, sodium hydroxide, citrate buffer, phosphate buffer, phthalate buffers, acetate buffers, succinate buffers. In order to arrive at a pH below 6 or about 4.0-5.0, a citrate buffer has proved to be suitable.

[0089] Moreover, an emulsion of the present invention may contain one or more fragrances. Addition of a preservative agent is normally not required as propylene glycol and C4 alkane-diols itself has antimicrobial effect when it is added in a sufficient concentration. Nevertheless, any suitable preservative agent may be added if needed.

[0090] In e.g., WO 2010 / 130428, a procedure is described which relates to the preparation of a composition and which is incorporated herein by reference in its entirety.

[0091] In one aspect, the composition for use according to the invention may e.g. comprise the following constituents; Mometasone furoate; 1 mg / g of total composition in a micronized state, such that 100% < 20pm, 99% < 15 pm, 80< 5 pm in particle size.

[0092] Coconut oil; 80mg / g of total composition

[0093] Stearic acid; 20 mg / g of total composition

[0094] Macrogol stearate; 30 mg / g of total composition

[0095] Glycerol monosterate 40-55; 30 mg / g of total composition

[0096] Cetostearyl alcohol; 70 mg / g of total composition

[0097] Propylene glycol; 250 mg / g of total composition

[0098] Sodium citrate; 2,7 mg / g of total composition

[0099] Citric acid (monohydrate); 2.5 mg / g of total composition

[0100] Water (purified), Ad 1g.

[0101] In a further aspect, the invention relates to use of a composition according to the invention in medicine.

[0102] Specifically, the invention relates to use of a composition according to the invention for treatment of e.g., any skin related disease or condition or any inflammatory condition.

[0103] In one aspect, the invention relates to treatment of conditions or diseases related to corticosteroid responsive dermatoses by administering the compositions of the invention. Such clinical conditions may be related to eczemas and dermatitis such as atopic eczema, chronic hand eczema, contact dermatitis, psoriasis, and localized bullous pemphigoid. The obvious aim being treating or ameliorating or preventing said conditions.

[0104] As is apparent from the disclosure, present invention finds application in inflammatory skin diseases and autoimmune skin diseases that responds to glucocorticoids.

[0105] Non-limiting examples of disease or conditions of corticosteroid responsive dermatoses are e.g., hyperkeratotic dermatosis, eczema, alopecia areata, asteatotic eczema, atopic dermatitis, contact dermatitis, discoid lupus, hand eczema, hyperkeratotic eczema, intertrigo, lichen planus, lichen sclerosus, lichen simplex chronicus, nummular eczema, poison ivy, psoriasis, scabies, seborrheic dermatitis and stasis dermatitis.

[0106] In one aspect, present invention relates to a composition for use in the treatment of a corticosteroid responsive dermatoses.

[0107] In another aspect, present invention relates to a composition for use in the treatment of psoriasis.

[0108] In yet a further aspect, present invention relates to a composition for use in the treatment of atopic dermatitis.

[0109] In yet a further aspect, present invention relates to a composition for use in the treatment of eczema.

[0110] The invention also relates to topical use or administration of the composition according to the invention. Specifically, the invention relates to topical administration onto areas where the skin is thin or otherwise considered too sensitive for any corticosteroid treatment. Non-limiting examples are topical applications onto skin in the arm pit area, facial area (and notably the eye area such as e.g., eye lids), groin area, or skin on the genital area or the rectal area. Another area which the composition according to the invention may be applied on, is the scalp.

[0111] A further application of the composition according to the invention is the topical application onto the skin of an infantile subject. For example, the composition according to the invention may be applied to the skin of a child in the age of 0-6 years of age, such as e.g., 6 months or older, such as e.g., 1 year or older, such as e.g., 18 months or older, such as e.g., 2 years or older, such as e.g., 3 years or older, such as e.g. 4 years or older, such as e.g. 5 years or older. In one aspect, the composition according to the invention allows for treatment of paediatric patients under 2 years of age, such as e.g., paediatric patients under 2 years of age, under 18 months of age, under 1 year of age, or under 6 months of age.

[0112] The composition according to the invention may be administered twice daily, or such as e.g., once daily, i.e. , one time every 24h. The composition according to the invention may also be administered once every 48h.

[0113] In one aspect, the composition according to the invention is for administration once daily.

[0114] In one preferred aspect, the composition according to the invention may be administered once and only once daily, i.e., one time only every 24h.

[0115] In one aspect, present invention relates to a composition for use according to any of the preceding claims, wherein the composition comprises; mometasone furoate, propylene glycol and / or butylene glycol, one or more suitable excipients, and water.

[0116] I another aspect, present invention relates to a composition for use according to any of the preceding claims, wherein the composition comprises; mometasone furoate, propylene glycol and / or butylene glycol, one or more excipients comprising one or more of refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid, and water.

[0117] In yet a further aspect, present invention relate to a composition for use according to any of the preceding claims, wherein the composition comprises; mometasone furoate in an amount of 0.1 % (w / w), propylene glycol and / or butylene glycol, in total 25% (w / w), one or more excipients selected from one or more of refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid and water, wherein the total amount of excipients correspond to 74.9 % (w / w).

[0118] In one aspect, the invention relates a composition for use in treatment of corticosteroid responsive dermatoses e.g. hyperkeratotic dermatosis, eczema, atopic dermatitis, psoriasis, seborrheic dermatitis, contact dermatitis, allergic dermatitis, wherein the composition is administered one daily, and wherein the composition is administered topically onto an area where skin is thin or otherwise considered too sensitive for corticoid steroid treatment, such as applications onto skin in the arm pit area, facial area (and notably the eye area such as e.g. eye lids), groin area, or skin on the genital area or onto the scalp, and wherein the composition is administered topically once daily. Thus, in a specific aspect, the invention relates a composition wherein said composition may be applied onto skin in the armpit area, facial area (and notably the eye area such as e.g., eye lids), groin area, or skin on the genital area, or onto the scalp, or the rectal area.

[0119] In another aspect, the composition according to the invention may be administered topically and once daily.

[0120] In another aspect, the invention relates to a method of treatment, the method comprising topically administering to a subject in need thereof, for treatment of corticosteroid responsive dermatoses e.g. hyperkeratotic dermatosis, eczema, atopic dermatitis, psoriasis, seborrheic dermatitis, contact dermatitis, allergic dermatitis, wherein the composition is administered one daily, and wherein the composition is administered topically onto skin and onto an area where skin is thin or otherwise normally considered too sensitive for corticoid steroid treatment, such as applications onto skin in the arm pit area, facial area (and notably the eye area such as e.g. eye lids), groin area, or skin on the genital area or onto the scalp, and wherein the composition is administered topically once daily.

[0121] As is evidenced by the examples, the composition according to present invention provides for a release profile of one or more glucocorticoids such that deep penetration into the deeper skin layers is prevented or greatly reduced in respect to other commercial products with the same GC and concentration, and thus circumventing entry into the systemic circulation, while at the same time providing for clinically relevant / effective doses of the one or more glucocorticoids.

[0122] The invention will be further illustrated in the below seen non-limiting examples. The below examples are merely for illustrative purpose and shall not be construed as limiting on the metes and bounds of the scope of the invention.

[0123] Examples

[0124] In Figure 1 the topical skin blanching of a mometasone furoate cream composition according to the invention was investigated against three relevant commercial comparator GC cream products, one with lower potency, one with identical GC (mometasone furoate) and strength together with one with higher potency according to the below.

[0125] Cream composition 0.1 % (w / w) Mometasone furoate according to the invention (class III, mometasone furoate, 0.1 %), and consequently comprising mometasone furoate in an amount of 0.1 % (w / w), propylene glycol and / or butylene glycol, in total 25% (w / w), refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid and water.

[0126] Kenacort-T® 0.1 % cream (class II, Triamcinolone acetonide, lower potency cream), batch no. 8A36196

[0127] Elocon 0.1 % creme (class III, mometasone furoate, same potency and concentration), batch no. 8NGFA11001

[0128] Dermovat® 0.05 % cream (class IV, Clobetasol propionate, higher potency), batch no. C346209.

[0129] Kenacort-T, Elocon, and Dermoval are used as comparative compositions.

[0130] This single-centre study was observer-blind for the creams with random assignment of the treatments to test fields on the right and left forearm in 30 healthy subjects. The test fields were compared intra-ind ividual ly .

[0131] Approximately 50 pl of each study preparation was applied to the respective test fields of approximately 2 cm2using teflon rings, self-adhesive ECG (electrocardiogram) rings and gauze. The test fields were covered with a single layer of gauze and fixed on the edges with an adhesive bandage to prevent contamination.

[0132] The composition according to the invention (Mometasone furoate 0.1 % cream) and three comparators, (Kenacort-T 0.1 % cream, Elocon 0.1% creme and Dermovat 0.05 % cream) were investigated. Two untreated test fields, one on each arm, served as controls. A single non-occlusive application of each composition was performed for 6 hours ± 10 minutes.

[0133] Skin colour measurements were made with a "Chroma-Meter CR 300" (Minolta, Ahrensburg, Germany). Values were measured in accordance with the L*a*b* system. The a*-value (redness value) is well accepted in the use of vasoconstrictor assays. Measurements were performed by lightly placing the measurement head on the test fields. Three measurements were taken from each field at each measurement series.

[0134] Chromametric measurements were performed at baseline (prior to treatment) and 1 , 2, 4, 6, 18 and 24 hours after the end of the treatment period.

[0135] The vasoconstriction can be correlated to the corticosteroid concentration at the site of the small blood vessels in dermis. Hence a low vasoconstriction reading is related to low corticosteroid concentration, when considering the same corticosteroid. A high vasoconstriction reading means high corticosteroid concentration at the site of the small blood vessels, when considering the same corticosteroid, and thereby a higher risk of both systemic and local side effects.

[0136] According to this study the onset of action from the cream composition according to the invention containing 0.1 % mometasone furoate shows a slower onset of action as compared to Elocon 0.1 % mometasone furoate cream. However, the duration is longer as compared to Elocon producing a similar area under the curve showing it to be equipotent to Elocon as presented in Figure 1 .

[0137] Table 1. Steady state fluxes, Jss (pg / cm2 / h) of mometasone furoate over porcine skin membranes after application of two creams for 6 h.

[0138] Table 1 present data on permeability of mometasone furoate over porcine skin as the steady state flux in pg / cm2 / h from a mometasone furoate composition according to the invention against a commercial mometasone furoate cream product i.e. , Elocon.

[0139] The porcine skin penetration study was conducted in flow through cells with sampling every second hour. Porcine ears were rinsed with cold water. Hair was carefully removed from the inner side of the ear with a trimmer and skin membranes were produced with a dermatome (TCM 3000 BL; Nouvag, Goldach, Switzerland) to a thickness of approximately 500 pm.

[0140] Before initiating the experiment, the skin was allowed to hydrate for one hour at 32°C in the diffusion cells with the dermal side exposed to the receptor media (a mixture of isotonic 20 mM citrate buffer (pH 4.5) and ethanol (70:30 v / v)) and with the stratum corneum side exposed to the ambient air.

[0141] The flow-through diffusion cells were mounted in a heat block according to the system designed by Clowes et al. (Clowes HM, Scott RC, Heylings JR (1994) Skin Absorption - Flow through or Static Diffusion Cells. Toxicology in Vitro 8(4): 8).

[0142] A water bath with circulation (Techne TE-10A thermoregulator; Bibby Scientific, Staffordshire, UK) was used to keep the temperature at 32±0.3°C. The creams were applied as infinite dose (260 mg / cm2) and the cells were occluded with Parafilm to maintain fixed boundary conditions. The receptor solution was continuously pumped through the cells with a flow rate of 1 .5 mL / h and collected as 3-mL aliquots. The collected aliquots were placed in sealed glass vials and stored at -20°C until mometasone furoate analysis. The creams were allowed contact with the skin membranes for 6 hours,

[0143] The mometasone furoate concentration in the samples were assayed using a HPLC-UV set-up (Waters Alliance 2695 separation module). A Kromasil C18 (250x4.6mm, 5pm) was used as separation column and a Phenomex C18 (4x3. Omm) was used as pre-column. The temperature of the columns was 30±2°C. The mobile phase, consisting of 75:25 vol% acetonitrile: water, was pumped through the system with a flow rate of 1 .5 mL / min. Detection of mometasone furoate was performed at A=249 nm using a Waters 2487 Dual A Absorbance Detector. 100pL of each sample was injected and mometasone furoate concentrations were calculated against a calibration curve comprising 0.012-1 ,2pg MF / mL.

[0144] Table 2. Accumulated amounts of mometasone furoate in porcine skin membranes after application of two creams for 6h, analysed after 6h and 12h Table 2 present data on the concentration of mometasone furoate in porcine skin after 6 h and 12 h i.e. , the retention of mometasone furoate at the site of action. The porcine skin penetration study was conducted in flow through cells. Porcine ears were rinsed with cold water. Hair was carefully removed from the inner side of the ear with a trimmer and skin membranes were produced with a dermatome (TCM 3000 BL; Nouvag, Goldach, Switzerland) to a thickness of approximately 500 pm, including epidermis and part of dermis.

[0145] Before initiating the experiment, the skin was allowed to hydrate for one hour at 32°C in the diffusion cells with the dermal side exposed to the receptor media (a mixture of isotonic 20 mM citrate buffer (pH 4.5) and ethanol (70:30 v / v)) and with the stratum corneum side exposed to the ambient air.

[0146] The flow-through diffusion cells were mounted in a heat block according to the system designed by Clowes et al. (Clowes HM, Scott RC, Heylings JR (1994) Skin Absorption - Flow through or Static Diffusion Cells. Toxicology in Vitro 8(4): 8). A water bath with circulation (Techne TE-10A thermoregulator; Bibby Scientific, Staffordshire, UK) was used to keep the temperature at 32±0.3°C.

[0147] The creams were applied as infinite dose (260 mg / cm2) and the cells were occluded with Parafilm to maintain fixed boundary conditions. The receptor solution was continuously pumped through the cells with a flow rate of 1 .5 mL / h. The creams were allowed contact with the skin membranes for 6 hours, thereafter the excess cream was removed. Half of the skin membranes were removed from the flow through cells and half were allowed to continue the experiment with the excess cream removed. After additionally 6 h (in total 12 h) the remaining skin membranes were removed. The removed skin membranes were gently dried with tissue wipes and the area which had been exposed in the diffusion cells (0.64 cm2) were isolated. Mometasone furoate was extracted from the skin membranes into 1 mL aceton itrile-water mixture (60:40) by sonication for 15 min (Ultrasonic cleaner; VWR, IL, USA). The extraction solution was then placed in a new vial and stored at -20°C until mometasone furoate analysis.

[0148] The mometasone furoate concentration in the samples were assayed using a HPLC-UV set-up (Waters Alliance 2695 separation module). A Kromasil C18 (250x4.6mm, 5pm) was used as separation column and a Phenomex C18 (4x3.0mm) was used as pre-column. The temperature of the columns was 30±2°C. The mobile phase, consisting of 75:25 vol% acetonitrile: water, was pumped through the system with a flow rate of 1 .5 mL / min. Detection of mometasone furoate was performed at A=249 nm using a Waters 2487 Dual A Absorbance Detector. 100pL of each sample was injected and mometasone furoate concentrations were calculated against a calibration curve comprising 0.012-1 ,2pg MF / mL.

Claims

Claims1 . A composition for use in the treatment of corticosteroid responsive dermatoses , wherein the composition is administered topically at least once every 48 h onto a skin area of a subject in need thereof, wherein the skin is thin or considered too sensitive for general topical corticosteroid treatment and / or where the subject is an infant, and wherein the composition is an oil- in-water emulsion or cream composition comprising one or more corticosteroids, water, and one or more glycols, and wherein the one or more corticosteroids is partially dissolved to an extent of about 40% to about 70% (w / w) and in micronized form, and wherein the one or more glycols are present in a concentration of about 25% (w / w).

2. The composition for use according to claim 1 , wherein the skin area is sensitive (thin) and selected from skin in the arm pit area, facial area (and notably the eye area such as e.g., eye lids), groin area, or skin in the genital area, or onto the scalp, or the rectal area etc.

3. The composition for use according to claim 1 or 2, wherein the corticosteroid responsive dermatoses are selected from, hyperkeratotic dermatosis, eczema, alopecia areata, asteatotic eczema, atopic dermatitis, contact dermatitis, discoid lupus, hand eczema, hyperkeratotic eczema, intertrigo, lichen planus, lichen sclerosis, lichen simplex chronicus, nummular eczema, poison ivy, psoriasis, scabies, seborrheic dermatitis and stasis dermatitis.

4. The composition for use according to claim 1 , wherein the condition is psoriasis.

5. The composition for use according to claim 1 , wherein the condition is atopic dermatitis.6 The composition for use according to claim 1 , wherein the condition is eczema.

7. The composition for use according to any of the preceding claims, wherein the subject is an infant under the age of 6 years or of 2 years of age or younger, such as e.g., under 18 months of age, e.g., under 1 year of age, or e.g., under 6 months of age.

8. The composition for use according to any of the preceding claims, wherein the corticosteroid is mometasone furoate.

9. The composition for use according to any of the preceding claims, wherein the one or more glycols are selected from propylene glycol and / or butylene glycol.

10. The composition for use according to any of the preceding claims, wherein the composition is administered once daily, or such as e.g., twice daily, or such as e.g., three times daily.11 . The composition for use according to any of the preceding claims, wherein the composition is administered topically on the skin for a period longer than e.g., 5 days, when the composition according to the invention is administered at least once daily, or the treatment may be for e.g. 6 days or longer, such as e.g. about 7 days or longer, such as e.g. about 8 days or longer, such as e.g. about 9 days or longer, such as e.g. about 10 days or longer, such as e.g. about 11 days or longer, such as e.g. about 12 days or longer, such as e.g. about 13 days or longer, such as e.g. about 14 days or longer, such as e.g. about 3 weeks or longer, such as e.g. about 4 weeks or longer, such as e.g. about 5 weeks or longer, such as e.g. about 6 weeks or longer, such as e.g. about 7 weeks or longer, such as e.g. about 8 weeks or longer etc.

12. The composition for use according to any of the preceding claims, wherein the period of treatment is longer than e.g. about 3 weeks, such as e.g. about 4 weeks or longer, such as e.g. about 5 weeks or longer, such as e.g. about 6 weeks or longer, such as e.g. about 7 weeks or longer, such as e.g. about 8 weeks or longer, such as e.g. about 9 weeks or longer, such as e.g. about 10 weeks or longer, such as e.g. about 15 weeks or longer, such as e.g. about 20 weeks or longer, such as e.g. about 25 weeks or longer, such as e.g. about up to 30 weeks.

13. The composition for use according to any of the preceding claims, wherein composition is administered to an area of skin larger than about 10% of the total area of skin of a body, such as e.g. about 20% or larger, such as e.g. about 25% or larger, such as e.g. about 30% or larger, such as e.g. about 35% or larger, such as e.g. about 40% or larger, such as e.g. about 45% or larger.

14. The composition for use according to any of the preceding claims, wherein composition is administered to an area of skin larger than about 20% of the total skin area of an individual but less than or equal to 60% of total skin area for adults, and more than 10% of the total skin area of an individual but less than or equal to 40% of total skin area for children.

15. The composition for use according to any of the preceding claims, wherein the composition comprises; mometasone furoate in an amount of 0.1 % (w / w), propylene glycol and / or butylene glycol, in total 25% (w / w), refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid and water.

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