Novel compositions for topical 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 hours onto an area of ​​the skin of a subject in need thereof whose skin is thin or considered too sensitive for common topical corticosteroid treatments, and / or the subject is an infant, wherein the composition is an oil-in-water emulsion or cream composition comprising one or more corticosteroids, water, and one or more glycols, wherein the one or more corticosteroids are partially dissolved to the extent of 40-70% by weight and in micronized form, and the one or more glycols are present in a concentration of 25% by weight.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention provides novel pharmaceutical compositions comprising a corticosteroid or a pharmaceutically acceptable derivative thereof in the form of an oil-in-water emulsion, particularly a cream composition. The compositions are suitable for topical use on sensitive skin areas, e.g., thin skin areas, larger treatment areas, longer treatment durations, and for use in children. In particular, the compositions according to the invention are suitable for dermal use, i.e., for administration of the composition to the skin. [Background technology]

[0002] Background of the Invention Glucocorticoid derivatives are some of the most effective and widely prescribed compounds for treating inflammatory and autoimmune diseases.

[0003] However, their therapeutic use is limited by an unfavorable side effect profile in the skin, including epidermal thinning (atrophy), striae, senile purpura, telangiectasia, perioral dermatitis, acne, rosacea, impaired wound healing, increased skin fragility, and risk of infection. Systemic side effects from topical skin treatments become a concern when higher-strength glucocorticoids, thinner skin areas, occlusion, larger treatment areas, and longer treatment periods are required. These are similar to side effects seen with systemic administration of glucocorticoids, including HPA axis suppression, Cushing's syndrome, corticosteroid-associated Addisonian crisis, and growth retardation. These adverse effects are similar to those seen in individuals with abnormally high endogenous production of glucocorticoids (Cushing's syndrome) and in elderly populations (Bigas, J. et al., Cell Death & Disease, 2018, 9(588)).

[0004] Glucocorticoids penetrate the stratum corneum and bind to glucocorticoid receptors in the 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)).

[0005] The British National Formulary states that children's skin is sensitive and therefore they are likely to be more susceptible to topical steroids, and therefore topical steroids should be avoided in children or, if necessary, used with caution and for shorter periods. Also, in adults, application of potent corticosteroids to large areas of affected psoriatic skin results in sufficient systemic absorption to produce not only adrenal suppression but also some degree of cortisone overload with greater frequency and rate than previously suggested (Garden JM, Freinkel RK, Arch Dermatol. 1986 Sep;122(9)).

[0006] Several examples of topical compositions are known in the art.

[0007] 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, the compositions being in the form of water-in-oil (w / o) emulsions.

[0008] WO 91 / 08733 (Schering Corp) relates to oil-in-water (o / w) emulsions containing a lipophilic active drug substance (e.g., mometasone). The examples demonstrate the need to use N-methyl-2-pyrrolidone to enhance the vasoconstrictor effect. In the examples, propylene glycol is used at a concentration of 10% w / w.

[0009] WO 2008 / 126076 (Perrigo Israel Pharmaceuticals Ltd.) relates to a low-dose mometasone formulation. An exemplary formulation is a cream containing 0.075% mometasone, a polyol, a gelling agent, an oily phase, and water. To reduce the toxicity of mometasone formulations, a low-dose mometasone formulation is desirable. The formulation of WO 2008 / 126076 is believed to have relatively low systemic steroid absorption. No in vivo studies have been reported. Summary of the Invention [Problem to be solved by the invention]

[0010] However, the compositions of the prior art do not appear to address the above-mentioned problems, and consequently, there remains a need for locally acting pharmaceutical skin formulations that can achieve adequate clinical efficacy and simultaneously overcome undesirable corticosteroid side effects, and that provide effective and safe treatment suitable for larger skin treatment areas, longer treatment durations, and areas with thin skin, or in the treatment of young children, i.e., on sensitive skin. [Means for solving the problem]

[0011] Description of the invention The present invention relates to a composition which may take any form, in particular in the form of an emulsion, or a cream or cream-like composition, for example an oil-in-water cream composition.

[0012] The composition according to the present invention is suitable for topical application on the skin of a subject. Specifically, the composition can be applied topically to the skin in areas where the skin is thin and therefore more sensitive to the above-mentioned corticosteroid side effects. A non-limiting example of a particularly sensitive skin area is the skin on the face, especially near the eye area, for example, the eyelids. Other examples are the armpits, groin area and genital area.

[0013] Compositions according to the invention having 0.1% (w / w) mometasone furoate are also suitable for use on larger skin areas, for example, for adults, more than 20% but not more than 60% of an individual's total skin area, and for children, more than 10% but not more than 40% of an individual's total skin area.

[0014] The compositions of the present invention are also suitable for use in young children, such as those up to about 6 months of age, or up to about 1 year of age, or up to about 18 months of age, or up to about 3 years of age. In infants, the stratum corneum, the skin barrier, is thinner and more permeable. The stratum corneum is more permeable in the younger infant age group (3-6 months of age) and continues to exhibit higher permeability than mature skin throughout the first year of life [Community Practitioner 2010]. As children age, there is a significant decrease in permeability and a concomitant decrease in moisture content (which plateaus at about age 5) [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].

[0015] Compositions according to the invention may be administered topically about once a day, such as once every two days (ie, once every 48 hours).

[0016] The composition may include a glucocorticosteroid or corticosteroid, such as mometasone or any acceptable pharmaceutical salt or ester thereof.

[0017] The composition according to the invention may further comprise one or more glycols, such as propylene glycol (propane-1,2-diol), or, for example, butylene glycol (e.g., 1,3-butanediol). In principle, however, any glycol having two hydroxyl groups on different carbon atoms (dihydroxy hydrocarbons) may be used in the composition according to the invention.

[0018] The concentration of the glycol or glycols may be, for example, about 25% (w / w).

[0019] The compositions according to the present invention allow for the solubility of the corticosteroid to be from about 40% to about 70% (w / w) of the total amount of corticosteroid in the composition.

[0020] Additionally, compositions according to the present invention may comprise, for example, about 30 to about 60% (w / w) total amount of corticosteroid in undissolved form in the composition. The undissolved corticosteroid may be in particulate form, e.g., micronized form.

[0021] As will be apparent to one skilled in the art, the amount of dissolved and undissolved corticosteroid taken together will equal 100% of the total amount of corticosteroid used in the compositions according to the present invention.

[0022] In one aspect, the present invention relates to the use of a composition according to the present invention for the treatment of a skin-related inflammatory condition or an autoimmune disease.

[0023] The present invention also relates to the use of a composition according to the invention for the treatment of a skin-related inflammatory condition or an autoimmune disease, wherein the composition is administered topically onto the skin.

[0024] In a further embodiment, the present invention relates to the use of a composition according to the present invention, wherein the composition is administered once daily. In another embodiment, the present invention relates to the use of a composition according to the present invention, wherein the composition is administered once every 48 hours.

[0025] In a still further aspect, the present invention relates to the use of a composition according to the present invention for the treatment of a skin-related inflammatory condition or an autoimmune disease, wherein the composition is administered topically onto an area of ​​thin skin over a large skin area for an extended treatment period, or wherein the composition is administered topically onto the skin to a child. [Brief explanation of the drawings]

[0026] drawing [Figure 1] The topical bioavailability of a mometasone furoate composition according to the present invention relative to three relevant commercially available comparator GC cream products is illustrated. The topical bioavailability of corticosteroids can be demonstrated by the vasoconstrictor assay, as first 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 for establishing bioequivalence for topical corticosteroid compositions. Specifically, the figures illustrate the whitening effect from a cream composition according to the invention containing 0.1% mometasone furoate compared to three commercially available corticosteroid creams: Kenacort-T 0.1% (triamcinolone acetonide, a corticosteroid of lower potency), Elocon 0.1% (mometasone furoate, a corticosteroid of the same potency and concentration), and Dermovat 0.05% (clobetasol propionate, a higher potency). DETAILED DESCRIPTION OF THE INVENTION

[0027] Detailed Description of the Invention In one aspect, the present invention provides an oil-in-water (o / w) emulsion comprising mometasone furoate as the active drug substance.

[0028] Furthermore, the emulsion may contain a C4 alkanediol, in which the two hydroxyl groups are linked to two different carbon atoms, and the alkane may be linear or branched. The C4 alkanediol may be butanediol (butylene glycol), such as 1,3-butanediol, or a C3 alkanediol, such as propylene glycol (propane-1,2-diol). A preferred material is butylene glycol.

[0029] However, the o / w composition may also contain propylene glycol.

[0030] The present invention provides effective treatment in sensitive skin areas, over larger treatment areas, for longer treatment periods, or for the treatment of children, and undesirable systemic corticosteroid side effects may be reduced or entirely eliminated.

[0031] It has been surprisingly discovered that a particular cream formulation according to the present invention exhibits particular properties that make it suitable for treating thin, sensitive skin, in that it does not alter the natural skin barrier function of the stratum corneum, as determined by skin resistance. When the cream was applied to the skin membrane for 12 hours, the pre / post resistance ratio was 0.16 for a commercially available glucocorticoid (GC) cream (Elocon), a more than six-fold reduction in skin barrier resistance, corresponding to a disruptive effect on the stratum corneum. This reduction in stratum corneum resistance facilitates penetration of the active ingredient, thereby increasing the risk of systemic effects. No reduction in skin resistance was detected for the GC cream composition of the present invention, i.e., the pre / post resistance ratio of 1.14 is comparable to that of an undisturbed stratum corneum.

[0032] The formulations according to the present invention have also been shown to produce significantly lower flux of GC (glucocorticoid) through the skin compared to commercially available GC creams. However, lower flux, while beneficial when considering possible systemic side effects, may be detrimental to clinical efficacy. Blanching studies according to Figure 1 have shown similarities in blanching, i.e., bioavailability, and consequently, the present inventors have surprisingly found that compositions according to the present invention have lower flux of GC while simultaneously achieving clinically relevant effects.

[0033] As is apparent from the above, the abbreviation "GC" is intended to mean glucocorticoids, or synonymously glucocorticosteroids. In another embodiment, this terminology is intended to mean corticosteroids.

[0034] The formulations according to the present invention surprisingly show comparable GC retention / accumulation effects in the epidermis and dermis (equivalent concentrations to commercially available GC creams). GC from the formulations according to the present invention penetrate the stratum corneum more slowly, penetrating the epidermis and dermis approximately 14 times less than commercially available GC creams. However, accumulation in the epidermis and dermis is comparable due to slower clearance from the epidermis and dermis, ensuring comparable clinical efficacy with slightly different time profiles.

[0035] This combination effect is very attractive for topical GC combinations in that clinical efficacy is maintained and systemic side effects are reduced.

[0036] It has been surprisingly discovered that the compositions and novel treatment regimens according to the present invention allow for a slower onset and longer duration of action when compared to the commercially available composition, Elocon, and produce similar AUCs (area under the curve) as measured from skin blanching according to Figure 1, thereby demonstrating bioequivalence.

[0037] The permeability (steady state flux) of mometasone furoate through porcine skin from a composition according to the invention to the receptor medium, presented in Table 1, shows an approximately 14-fold lower flux compared to Elocon, indicating a lower penetration of mometasone furoate through the stratum corneum through the epidermis and dermis to the larger blood vessels in the subcutaneous tissue.

[0038] At the same time, it is observed that the concentration of corticosteroid in the epidermis / dermis is maintained for a longer time according to Table 2. The ratio of mometasone furoate concentration (Elocon / composition according to the invention) in the skin samples decreases from 6 to 12 hours.

[0039] Thus, the present compositions and treatment regimens achieve a slower concentration increase in the epidermis and dermis while simultaneously reaching therapeutic levels similar to Elocon. The therapeutic concentrations in the epidermis and dermis remain for a longer period of time, i.e., permeation data show a lower tendency to migrate further down into the dermis and subcutaneous tissue, i.e., to reach deeper into the skin layers and come into contact with larger blood vessels, thereby showing a lower tendency to be readily available for systemic absorption.

[0040] This ensures comparable efficacy to that observed with prior art compositions and prior art treatments and dosage regimens, and consequently, the present invention provides comparable efficacy as indicated by comparable area under the curve (AUC) to that observed with prior art compositions and prior art treatments and dosage regimens.

[0041] Lower permeability through the stratum corneum and higher affinity for the epidermis and dermis ensures lower systemic uptake through larger blood vessels, thereby reducing systemic side effects such as hypothalamic pituitary adrenal (HPA) axis suppression, Cushing's syndrome, growth retardation in children, hyperglycemia and diabetes, cataracts, glaucoma, etc.

[0042] A further consequence of the surprising effects found by the inventors of the present invention is that the pharmacokinetic profile allows for a reduction in application frequency, e.g., to strictly once-daily administration, which further results in increased patient compliance.

[0043] Furthermore, as described herein, the observed pharmacodynamic profile allows the compositions according to the invention to be well tolerated in areas with thin skin or thin skin that is usually very sensitive to corticosteroid treatment. Such areas may be, for example, the face, especially the eyelids, scalp, or genital area, and young children, who generally have thinner skin than adult patients. Other areas of the body that may be relevant to the invention are those parts of the body where skin meets skin, i.e., the armpits, groin area, and rectal area or other skin creases.

[0044] In one embodiment, the term "thin skin" may be intended to mean an area of ​​the body where the skin thickness is about 1.0 mm or less, for example, about 0.5 mm or less.

[0045] In a further aspect, the invention may involve the use of the composition on skin that is considered to be sensitive. As described herein, sensitive skin is skin that is normally considered too sensitive for any topical steroid composition, and treatment with such a composition would be associated with unwanted side effects.

[0046] In another embodiment, the term "thin skin" may be intended to encompass any area of ​​the body where the skin is normally considered too sensitive to steroid treatment.

[0047] As described herein, skin is composed of three major layers (starting from the outside with the epidermis, followed by the dermis and subcutaneous tissue). The outermost layer, the epidermis, is divided into five layers (starting from the outside with the stratum corneum, followed by the stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale). The outermost layer, the stratum corneum, functions to form a barrier that protects us from infection, dehydration, chemicals, and mechanical stress. The stratum corneum is also the skin barrier through which topical pharmaceutical active ingredients enter body tissues.

[0048] Corticosteroids are better absorbed and more permeable in thin epidermal areas, such as the eyelids, compared to thicker epidermal areas, such as the soles. The difference in penetration between the two varies by 300-fold. Skin that is sensitive to steroids or skin that is more susceptible to local and systemic steroid side effects is defined in the literature as the thinner and more sensitive skin that is the subject of the present invention. Thus, the skin on the palms of the hands and the soles of the feet is generally not considered to be thin skin.

[0049] As described herein, the skin barrier of children, that is, the stratum corneum, is thinner and does not fully develop until 2 years old.This means that children up to 2 years old are more susceptible to topical steroid absorption, for example, and therefore more sensitive to steroid side effects compared with adults.Therefore, the topical steroids with higher potency are generally not recommended for use in children under 2 years old, and the use of strong topical steroids in this patient group is recommended only with great caution.However, the present invention can be applied to, for example, the patient group of children under about 2 years old.

[0050] In children over 2 years of age and adults, certain areas of the body have thinner skin and are more sensitive to systemic side effects, such as from topical steroids. The thickness of the stratum corneum varies from person to person and may vary more depending on the location on the body. However, the present invention is suitable for application in areas that are typically considered too thin or too sensitive for any steroid treatment (topical administration). The greatest absorption occurs through the thin skin of the eyelids, genitals, and skin creases. Thus, the use of potent topical steroids is usually best avoided in these areas. As described herein, the inventors of the present invention have surprisingly discovered that the formulations disclosed herein are suitable for use in the aforementioned areas.

[0051] Thus, in one embodiment, compositions according to the present invention may be administered to the skin in the facial area, for example, the eyelids.

[0052] It is also observed that skin becomes thinner as people age or as a result of sun damage, medications, or lifestyle factors. Epidermal thickness decreased somewhat faster in men (7.2% of initial value / 10 years) than in women (5.7%).

[0053] The table below lists the thickness of the stratum corneum at different body locations and is made from measurements from 301 normal individuals.

[0054] [Table 1]

[0055] As described herein, the present invention relates to topical treatment of skin that may be considered thin skin. Such areas are typically considered too sensitive for topical steroid treatment. In one embodiment, thin skin is defined as an area where the stratum corneum is in the range of about 4 μm to about 17 μm (estimated stratum corneum thickness), and may include, for example, the genital area, face, neck, scalp, and torso. In another embodiment, thin skin may include an area of ​​skin where the stratum corneum is in the range of about 4 μm to about 14 μm (estimated stratum corneum thickness), and may include, for example, the genital area, face, neck, and scalp.

[0056] The compositions according to the invention are also suitable for use on larger skin areas, such as those recommended for treatment of up to 60% of the total skin area (total body surface area) for adults and up to 40% of the total body surface for children, when potent corticosteroids (European Class III), such as 0.1% mometasone furoate, are used.

[0057] Thus, the present invention both provides a clinically effective treatment while simultaneously reducing the incidence of undesirable side effects such as epidermal thinning (atrophy), stretch marks, senile purpura, telangiectasia, perioral dermatitis, acne, rosacea, impaired wound healing, and increased skin fragility, risk of infection, HPA axis suppression, Cushing's syndrome, corticosteroid-associated Addison's crisis, and growth retardation. In one aspect, the present invention provides a clinically effective treatment while simultaneously reducing the incidence of HPA axis suppression.

[0058] Thus, in one embodiment, the present invention can provide topical treatment in the facial area for a period of, for example, more than 5 days when the composition according to the present invention is administered at least once a day. Thus, the treatment can be, for example, 6 days or more, for example, about 7 days or more, for example, about 8 days or more, for example, about 9 days or more, for example, about 10 days or more, for example, about 11 days or more, for example, about 12 days or more, for example, about 13 days or more, for example, about 14 days or more, for example, about 3 weeks or more, for example, about 4 weeks or more, for example, about 5 weeks or more, for example, about 6 weeks or more, for example, about 7 weeks or more, for example, about 8 weeks or more, etc.

[0059] In a further embodiment, the present invention may provide treatment for young children or for sensitive areas where the skin is thin and otherwise considered too sensitive for long-term treatment. Consequently, in this embodiment, the present invention may provide treatment for a period of, for example, more than about 3 weeks, such as about 4 weeks or more, for example about 5 weeks or more, for example about 6 weeks or more, such as about 7 weeks or more, for example about 8 weeks or more, for example about 9 weeks or more, for example about 10 weeks or more, such as about 15 weeks or more, for example about 20 weeks or more, for example about 25 weeks or more, for example up to about 30 weeks of treatment. During such extended treatment periods, it is expected that the compositions according to the present invention will be administered at least once a day.

[0060] In still further embodiments, the present invention also provides for the treatment of larger areas of skin. Thus, in one embodiment, the present invention provides for the treatment of more than about 20% of the total area of ​​skin on the body, such as about 25% or more, for example about 30% or more, such as about 35% or more, for example about 40% or more, for example about 45% or more.

[0061] As is evident from the examples herein, the oil-in-water emulsion of the present invention provides a therapeutic effect of mometasone furoate 0.1% comparable to that of the commercially available w / o emulsion (Elocon® 0.1% cream), while simultaneously reducing the undesirable side effects described above, allowing, for example, the treatment of young children and topical application in areas with thin and sensitive skin.

[0062] The abbreviation "% w / w" should be understood to refer to weight percent, measured as the weight of the active ingredient or additive relative to the weight of the completed composition as a whole, unless otherwise indicated. For example, when the concentration of one or more glycols is described as, for example, about 25% (w / w), this means that the 25% is calculated as the weight ratio between the weight of the glycol and the weight of the complete composition, particularly including the glycol. Another example is when, for example, 30 to about 60% (w / w) of the total amount of corticosteroid in a composition is described as being in undissolved form. This is intended to mean that 30 to 60% of the total amount of corticosteroid is in undissolved form, while the remaining portion, 40 to 70% of the corticosteroid, is dissolved in the composition, calculated as the weight ratio between undissolved / dissolved corticosteroid.

[0063] The inventors have found that the use of a corticosteroid, such as mometasone (e.g., mometasone furoate) at relatively high concentrations (15% to 45% w / w) and a C4 alkanediol (e.g., butylene glycol) or a C3 alkanediol (e.g., propylene glycol) allows for the formulation of an o / w emulsion in which mometasone is at least partially dissolved (as evidenced by the examples herein). Furthermore, it appears possible to obtain an o / w emulsion with therapeutic efficacy similar to that observed with Elocon cream, i.e., the o / w emulsion only needs to be applied strictly once daily. To this end, as shown by the results reported herein, an appropriate weight ratio between the alkanediol and water in the o / w emulsion appears to be important for once-daily administration and a reduced observed side effect profile. A ratio that is too high or too low does not appear to result in the desired effect and / or bioavailability. Another factor that appears to be important is the presence of mometasone in micronized form (e.g., mometasone furoate). Typically, mometasone is undissolved (or only partially dissolved) in the compositions of the present invention. The results reported herein demonstrate the importance of having undissolved mometasone in micronized form. Thus, generally, 100% of the mometasone particles have a particle size of at most 20 μm, 99% have a particle size of at most 15 μm, and 80% have a particle size of at most 5 μm, as measured using laser scattering methods. When particle size is determined using optical microscopy (the preferred method when particle size is measured in the final composition), the mometasone particles should not exceed 40 μm. The majority of particles (more than 80%, as assessed visually by microscope) have a size of 10-20 μm. Final particle growth in the composition over time, as measured by optical microscopy, should not result in particles exceeding 100 μm. Other factors may also affect the results, such as the nature of the other ingredients used. However, the two most important factors in the compositions of the present invention appear to be weight ratio and particle size as discussed above.

[0064] For propylene glycol, a suitable weight ratio between propylene glycol and water is about 1:1 to about 1:3. A similarly suitable weight ratio between butylene glycol and water is contemplated to be about 1:1 to about 1:3. Furthermore, it is possible to obtain emulsions having balanced contents of mometasone (e.g., mometasone furoate) and C4 alkanediol or C3 alkanediol and water that are bioequivalent, in the sense that the composition is equipotent to w / o Elocon Cream.

[0065] The compositions of the present invention contain two phases, a continuous aqueous phase and a dispersed oil phase that is uniformly distributed in the continuous phase (i.e., as commonly found in oil-in-water emulsions). Furthermore, the active drug substance, e.g., mometasone (e.g., mometasone furoate), is partially dissolved and partially present in the form of fine particles, in particular, micronized form.

[0066] In one aspect, the present invention relates to an oil-in-water emulsion composition comprising mometasone or a pharmaceutically acceptable derivative thereof and propylene glycol or a C4 alkanediol, which may be linear or branched, wherein the concentration of the C4 alkanediol or propylene glycol is 20 to 45% w / w.

[0067] More specifically, the present invention provides oil-in-water emulsions comprising mometasone or a pharmaceutically acceptable derivative thereof and, where relevant, a C4 alkanediol, which may be linear or branched, in a concentration of 15 to about 45% w / w, e.g., 20% to 45% w / w, 15% to 30% w / w, or 20% to 30% w / w. It is contemplated that other alkanediols may be used in combination with butylene glycol as well. Propylene glycol and butylene glycol are generally considered to be relatively non-toxic substances with minimal irritation effects. Pentylene glycol and hexylene glycol have even less irritation effects after topical administration; therefore, it is contemplated that such substances may be used in higher concentrations than propylene glycol and butylene glycol (i.e., about 20% to 50% w / w, particularly about 30% to 45% w / w). When pentylene glycol or hexylene glycol is used in combination with butylene glycol, the concentration of pentylene glycol or hexylene glycol is about 1% w / w to about 20% w / w (particularly, about 5% w / w to about 20% w / w).

[0068] The incorporation of the C4 alkanediol or C3 alkanediol is crucial to achieving the desired effect, not only in terms of the amount of C4 alkanediol or C3 alkanediol in the emulsion, but also in terms of the concentration of the C4 alkanediol or C3 alkanediol expressed as a concentration in the total emulsion, or more particularly, as the ratio between the C4 alkanediol or C3 alkanediol and water. When the oil-in-water emulsion of the present invention is applied to the skin, the water in the composition is prone to evaporation. Thus, not only can the weight ratio between the C4 alkanediol or C3 alkanediol and water in the composition be important, but the ratio between the C4 alkanediol and mometasone or a pharmaceutically acceptable derivative thereof can have an impact on the therapeutic outcome. It is intended that one or more of these factors is decisive for whether an emulsion with suitable properties in terms of therapeutic effect is obtained.

[0069] In accordance with the present invention, the active pharmaceutical ingredient may be one or more glucocorticosteroids (or used synonymously herein; glucocorticoids) or any ester or pharmaceutically acceptable salt thereof. Non-limiting examples include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide, beclomethasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone, dipropionate, and the like. These include 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.

[0070] In one aspect, the invention relates to the betamethasone type of corticosteroids, such as beclomethasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone.

[0071] In this context, the term "mometasone" includes mometasone or a pharmaceutically acceptable derivative thereof. Thus, the term includes mometasone itself and suitable ester derivatives, e.g., esters with organic acids commonly used in formulations, including furoate esters. Furthermore, mometasone or a pharmaceutically acceptable derivative thereof includes any form, e.g., anhydrous form, hydrated forms, including monohydrates, solvates other than hydrates, etc., as well as amorphous, polymorphic, and crystalline forms thereof. In this context, all calculations relating to mometasone or a pharmaceutically acceptable derivative thereof are based on mometasone furoate. Therefore, if another derivative is used, the equivalent amount of mometasone furoate must be calculated based on the molecular weight of the derivative and mometasone furoate.

[0072] The concentration of mometasone or any suitable corticosteroid (calculated as mometasone furoate) in the emulsion or cream composition of the invention may be about 0.01% to 2% w / w, usually 0.05% to 0.2% w / w, 0.075% to 0.2% w / w, for example about 0.1% w / w.

[0073] In emulsions according to the invention, mometasone (mometasone furoate) or any suitable corticosteroid is not completely dissolved and therefore some of the mometasone or pharmaceutically acceptable derivative thereof is present in undissolved form, typically at about 25 to about 35% w / w of the total amount of mometasone present in the emulsion.

[0074] In another embodiment, mometasone (mometasone furoate) or any suitable corticosteroid is present in the composition according to the invention in an amount of about 30% to about 60% (w / w) in undissolved form and is also present in the composition in micronized form. Conversely, the composition according to the invention allows for mometasone (mometasone furoate) or any suitable corticosteroid to be present in the composition in an amount of about 40% to about 70% (w / w) dissolved.

[0075] To improve the dispersibility and absorption rate of undissolved mometasone or any corticosteroid used in the composition, mometasone should be used in micronized form. As is evident from the examples herein, mometasone, e.g., mometasone furoate, should be used in micronized form, with 100% having a particle size of at most 20 μm, 99% having a particle size of at most 15 μm, and 80% having a particle size of at most 5 μm (as determined by laser scattering). During the manufacturing process, it is intended that mometasone furoate may be partially dissolved but not completely dissolved. This appears to be important for controlling the particle size in the final composition. If mometasone is completely dissolved during the manufacturing process, there is a risk that the mometasone precipitated in the composition will have a particle size that is too large, which will adversely affect the release of the active substance and not result in the desired release to the skin. Therefore, it is expected that the average particle size (and / or particle size distribution) of the mometasone furoate used will be important for obtaining reproducible therapeutic results.

[0076] In one embodiment, the C4 alkanediol is butylene glycol. A specific example is butane-1,3-diol. It is expected that other diols in combination with butylene glycol may also be suitable for use in this context, provided that they are suitable and safe for topical use.

[0077] As noted above, the concentration of C4 alkanediol (abbreviated herein as "alkanediol") or propylene glycol in the emulsions of the present invention is about 15% to about 45% w / w. As discussed above, the concentration will depend on the particular C4 alkanediol used. Generally, the concentration of C4 alkanediol, particularly butylene glycol, is about 20% to about 40% w / w, e.g., about 20% to about 30% w / w.

[0078] In one embodiment, the concentration of C4 alkanediol (abbreviated herein as "alkanediol") or propylene glycol in an emulsion of the present invention is about 25% (w / w).

[0079] As mentioned above, the weight ratio of alkanediol to water appears to be very important for achieving the desired therapeutic effect. Furthermore, the weight ratio between butylene glycol and mometasone (M) can also be a useful parameter for determining the amount of alkanediol in the emulsion of the present invention. For example, the lower limit is usually 7.5 or more, such as in the range of 7.5 to 100, and the upper limit is usually 4500 or less, such as in a ratio of 600 to 4500. Typically, the ratio is 75 or more, e.g., 75 to 900 or about 150 to about 450, where M is calculated as mometasone furoate. Specifically, the weight ratio between alkanediol and mometasone (M) is 200 to 300, e.g., 200, 225, 250, 275, or 300, where M is calculated as mometasone furoate.

[0080] Thus, in one aspect, the present invention relates to a composition, which may be an oil-in-water emulsion or cream composition, comprising one or more glucocorticoids, particularly mometasone furoate, and one or more glycols, particularly propylene glycol or a C4 alkanediol, wherein the corticosteroid is present in an amount of about 0.1% (w / w), while also present in undissolved micronized form in an amount of about 30% to about 60% (w / w) of the total amount of 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 components of the composition may be any other suitable additive or vehicle, e.g., water, suitable for any pharmaceutical application. As will be fully apparent to those skilled in the art, the sum of all components or constituents of the composition totals 100% (w / w).

[0081] The compositions according to the present invention may further comprise a range of suitable vehicles or additives.

[0082] In one embodiment, the composition according to the present invention may further comprise an oil selected from the group consisting of vegetable oils and fats, animal oils and fats, mineral oils, ester oils, silicon oils, or waxes. In particular, the oil / fats are vegetable oils and fats, such as palm oil, olive oil, sunflower oil, and canola oil. Fats can be defined as bulk storage materials containing aliphatic moieties, such as fatty acid derivatives, produced by plants, animals, and microorganisms. These are primarily, if 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 this context, the term "oil" also includes "fats," and oils / fats can also be synthetically or semi-synthetically produced.

[0083] The concentration of oil / fat in the emulsion is from about 3 to about 30% w / w, particularly from about 5 to about 25% w / w.

[0084] The composition according to the present invention may further comprise a stabilizer that provides stabilization of the oil-in-water emulsion, or the cream composition according to the present invention may be suitably implemented by adding one or more emulsifiers. Thus, the emulsion of the present invention may comprise one or more emulsifiers. As can be seen from the examples herein, the use of three emulsifiers with an HLB (hydrophilic-lipophilic balance) in the range of 3 to 20 (one with a high HLB, i.e., about 11 to 20, and two with a low HLB, i.e., about 3 to 11) produces desirable results in terms of stability without compromising the therapeutic effect.

[0085] Suitable emulsifiers for use in the compositions of the present invention may be selected from the group consisting of glycerol alkyl esters, macrogol alkyl esters, polyoxyethylene glycol alkyl esters, fatty acids, polyoxyethylene sorbitan esters, polyoxyethylene alkyl ethers, galactolipids.

[0086] Particular emulsifiers for use in the compositions of the present invention are glycerol monostearate 40-55, macrogol stearate, and stearic acid.

[0087] The concentration of each emulsifier, when present in an emulsion according to the present invention, ranges from about 1 to about 5% w / w.

[0088] Additionally, the composition according to the present invention may contain a viscosity-increasing agent. Viscosity-increasing agents suitable for use in the emulsion may be selected from the group consisting of fatty alcohols (concentration range: about 5 to about 15% of the total emulsion). However, the concentration will usually depend on the specific type of fatty alcohol used, and those skilled in the art will know how to adjust the concentration of such specific concentrations to obtain the desired viscosity.

[0089] For example, a suitable viscosity increasing agent is cetostearyl alcohol.

[0090] Generally, the concentration of the viscosity increasing agent in the form of a fatty alcohol ranges from 5% to 15% w / w.

[0091] The composition according to the present invention is intended for topical use, for example, as a cream to be applied to the skin. Therefore, taking into account the stability issues associated with mometasone, the pH may be adjusted to a skin-friendly value. A suitable pH is less than 6, for example, from about 3 to about 6 or from about 4.0 to about 5.0. The pH may be adjusted by using one or more pH adjusters selected from the group consisting of hydrochloric acid, phosphoric acid, sodium hydroxide, citrate buffer, phosphate buffer, phthalate buffer, acetate buffer, and succinate buffer. Citrate buffer has been shown to be suitable for achieving a pH of less than 6 or from about 4.0 to 5.0.

[0092] Furthermore, the emulsion of the present invention may contain one or more fragrances. Since propylene glycol and C4 alkanediol themselves have antibacterial effects when added in sufficient concentrations, the addition of a preservative is usually not required. Nevertheless, any suitable preservative may be added if necessary.

[0093] For example, procedures are described in WO 2010 / 130428, which is incorporated herein by reference in its entirety, for preparing the compositions.

[0094] In one embodiment, a composition for use according to the present invention may comprise, for example, the following components: Mometasone furoate; 1 mg / g total composition, micronized, particle size 100%≦20 μm, 99%≦15 μm, 80≦5 μm. Coconut oil; 80 mg / g total composition Stearic acid: 20 mg / g total composition Macrogol stearate: 30 mg / g total composition Glycerol monostearate 40-55; 30 mg / g total composition Cetostearyl alcohol: 70 mg / g total composition Propylene glycol: 250 mg / g total composition Sodium citrate: 2.7 mg / g total composition Citric acid (monohydrate); 2.5 mg / g total composition Water (purified), up to 1g.

[0095] In a further aspect, the present invention relates to the use of a composition according to the invention in medicine.

[0096] In particular, the present invention relates to the use of a composition according to the present invention for the treatment of, for example, any skin-related disease or condition or any inflammatory condition.

[0097] In one aspect, the present invention relates to the treatment of conditions or diseases associated with corticosteroid-responsive dermatoses by administering a composition of the present invention. Such clinical conditions may be related to eczema and dermatitis, such as atopic eczema, chronic hand eczema, contact dermatitis, psoriasis, and topical bullous pemphigoid. The express purpose is to treat, ameliorate, or prevent said conditions.

[0098] As is evident from this disclosure, the present invention has application to inflammatory and autoimmune skin diseases that respond to glucocorticoids.

[0099] Non-limiting examples of corticosteroid-responsive dermatologic diseases or conditions are, for example, 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.

[0100] In one aspect, the present invention relates to a composition for use in the treatment of a corticosteroid-responsive skin disease.

[0101] In another aspect, the present invention relates to a composition for use in the treatment of psoriasis.

[0102] In a still further aspect, the present invention relates to a composition for use in the treatment of atopic dermatitis.

[0103] In a still further aspect, the present invention relates to a composition for use in the treatment of eczema.

[0104] The present invention also relates to the topical use or administration of the compositions according to the invention. In particular, the present invention relates to topical administration on areas where the skin is thin or otherwise considered too sensitive for any corticosteroid treatment. Non-limiting examples are topical application to the skin in the axillary area, the facial area (especially the eye area, e.g., the eyelids), the groin area, or the skin over the genital or rectal area. Another area onto which the compositions according to the invention may be applied is the scalp.

[0105] Another application of the composition according to the present invention is topical application to the skin of infants.For example, the composition according to the present invention can be applied to the skin of children aged 0-6 years, for example, 6 months or older, for example, 1 year or older, for example, 18 months or older, for example, 2 years or older, for example, 3 years or older, for example, 4 years or older, for example, 5 years or older.In one embodiment, the composition according to the present invention can treat pediatric patients under 2 years old, for example, pediatric patients under 2 years old, under 18 months old, under 1 year old, or under 6 months old.

[0106] The compositions according to the invention may be administered twice a day, or for example once a day, i.e. once every 24 hours. The compositions according to the invention may also be administered once every 48 hours.

[0107] In one embodiment, the composition according to the invention is for once-daily administration.

[0108] In one preferred embodiment, the compositions according to the invention may be administered once and only once per day, ie, once every 24 hours.

[0109] In one aspect, the present invention relates to a composition for use according to any of the preceding claims, the composition comprising: Mometasone furoate, propylene glycol and / or butylene glycol, one or more suitable additives, and water Includes.

[0110] In another aspect, the present invention relates to a composition for use according to any of the preceding claims, the composition comprising: Mometasone furoate, propylene glycol and / or butylene glycol, one or more excipients including one or more of refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid; and water Includes.

[0111] In a still further aspect, the present invention relates to a composition for use according to any of the preceding claims, the composition comprising: Mometasone furoate in an amount of 0.1% (w / w), propylene glycol and / or butylene glycol, a total of 25% (w / w); One or more additives selected from one or more of refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid, and water (the total amount of additives corresponds to 74.9% (w / w)) Includes.

[0112] In one aspect, the invention relates to a composition for use in the treatment of corticosteroid-responsive skin diseases, such as hyperkeratotic skin diseases, eczema, atopic dermatitis, psoriasis, seborrheic dermatitis, contact dermatitis, allergic dermatitis, wherein the composition is administered once daily, and the composition is administered topically onto an area where the skin is thin or otherwise considered too sensitive for corticosteroid treatment (e.g., application onto the skin in the axillary area, the facial area (particularly the eye area, e.g., eyelids), the groin area, or the skin of the genital area or scalp), and the composition is administered topically once daily.

[0113] Thus, in a particular embodiment, the present invention relates to a composition that may be applied to the skin in the axillary region, the facial region (particularly the eye region, e.g., the eyelids), the groin region, or the skin of the genital region or scalp, or on the rectal region.

[0114] In another embodiment, the compositions according to the present invention may be administered topically once daily.

[0115] In another aspect, the invention relates to a method of treatment, the method comprising administering topically to a subject in need thereof, for the treatment of a corticosteroid-responsive skin condition, such as hyperkeratotic skin condition, eczema, atopic dermatitis, psoriasis, seborrheic dermatitis, contact dermatitis, allergic dermatitis, wherein the composition is administered once daily, the composition is administered topically onto the skin and onto areas where the skin is thin or otherwise normally considered too sensitive for corticoid steroid treatment (e.g., application onto the skin in the axillary area, the facial area (particularly the eye area, e.g., eyelids), the groin area, or the skin of the genital area or scalp), the composition is administered topically once daily.

[0116] As evidenced by the examples, the compositions according to the invention provide a release profile of one or more glucocorticoids such that deep penetration into deeper skin layers is prevented or greatly reduced with respect to other commercially available products with the same GC and concentration, thus avoiding entry into the systemic circulation, while simultaneously achieving a clinically relevant / effective dose of the one or more glucocorticoids.

[0117] The present invention is further illustrated in the non-limiting examples found below. The examples below are for illustrative purposes only and should not be construed as limitations on the boundaries of the scope of the present invention. [Example]

[0118] Example In Figure 1, the local skin whitening of a mometasone furoate cream composition according to the present invention was investigated against three relevant commercial comparator GC cream products (one with lower potency, one with the same GC (mometasone furoate) and strength, and one with higher potency, as follows:

[0119] The cream composition according to the invention contains 0.1% (w / w) mometasone furoate (Class III, mometasone furoate, 0.1%), resulting in an amount of mometasone furoate of 0.1% (w / w), propylene glycol and / or butylene glycol, a total of 25% (w / w); Refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid and water. Kenacort-T® 0.1% Cream (Class II, triamcinolone acetonide, lower potency cream), Batch No. 8A36196 Elocon 0.1% cream (Class III, mometasone furoate, same potency and concentration), batch number 8NGFA11001 Dermovat® 0.05% cream (Class IV, clobetasol propionate, higher potency), batch number C346209. Kenacort-T, Elocon, and Dermoval are used as comparative compositions.

[0120] This single-center study was observer-blind with random assignment of treatment to test areas on the right and left forearms of 30 healthy subjects. Test areas were compared within individuals. Approximately 50 μl of each study preparation was applied to approximately 2 cm 2 test areas using Teflon rings, adhesive ECG (electrocardiogram) rings, and gauze. 2 was applied to each test area. The test area was covered with a single layer of gauze and secured over the edges with adhesive bandages to prevent contamination.

[0121] A composition according to the invention (mometasone furoate 0.1% cream) and three comparative controls (Kenacort-T 0.1% cream, Elocon 0.1% cream, and Dermovat 0.05% cream) were investigated. Two untreated test areas (one on each arm) served as controls. A single non-occlusive application of each composition was performed for 6 hours ± 10 minutes.

[0122] Skin color measurements were performed with a "Chroma-Meter CR300" (Minolta, Ahrensburg, Germany). Values ​​were measured by the L*a*b* system. The a* value (redness value) is well accepted for use in vasoconstrictor assays. Measurements were performed by gently placing the measuring head on the test area. Three measurements were taken from each area in each measurement series.

[0123] Color measurements were taken at baseline (before treatment) and at 1, 2, 4, 6, 18 and 24 hours after the end of the treatment period.

[0124] Vasoconstriction can be related to corticosteroid concentrations at the site of microvasculature in the dermis. Thus, when considering the same corticosteroid, a low vasoconstriction reading is related to a low corticosteroid concentration. When considering the same corticosteroid, thereby a higher risk of both systemic and local side effects, a high vasoconstriction reading means a high corticosteroid concentration at the site of microvasculature.

[0125] According to this study, the onset of action from a cream composition according to the present invention containing 0.1% mometasone furoate shows a slower onset of action compared to Elocon 0.1% mometasone furoate cream, however, as shown in Figure 1, the duration is longer compared to Elocon producing a similar area under the curve, indicating that it is equipotent to Elocon.

[0126] [Table 2]

[0127] Table 1 shows the steady-state flux (μg / cm) from a mometasone furoate composition according to the present invention relative to a commercially available mometasone furoate cream product, i.e., Elocon. 2 Data are presented for the permeability of mometasone furoate across porcine skin as saturates / hour.

[0128] Pig skin permeation studies were performed in a flow-through cell with sampling every 2 hours. Pig ears were rinsed with cold water. Hair was carefully removed from the inside of the ear with a trimmer, and the skin membrane was trimmed to approximately 500 μm thickness with a dermatologist (TCM3000BL; Nouvag, Goldach, Switzerland).

[0129] Before starting the experiment, the skin was hydrated in the diffusion cell for 1 h at 32°C, with the skin side exposed to the receptor medium (a mixture of isotonic 20 mM citrate buffer (pH 4.5) and ethanol (70:30 v / v)) and the stratum corneum side exposed to ambient air.

[0130] 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).

[0131] The temperature was maintained at 32±0.3°C using a circulating water bath (Techne TE-10A thermostat; Bibby Scientific, Staffordshire, UK).

[0132] Cream was administered at an infinite dose (260 mg / cm 2 ) and the cell was sealed with parafilm to maintain fixed boundary conditions. The receptor solution was continuously pumped through the cell at a flow rate of 1.5 mL / h and collected in 3 mL aliquots. The collected aliquots were placed in sealed glass vials and stored at -20°C until mometasone furoate analysis. The cream was allowed to come into contact with the skin membrane for 6 hours.

[0133] The mometasone furoate concentration in the samples was assayed using an HPLC-UV system (Waters Alliance 2695 Separation Module). A Kromasil C18 (250 × 4.6 mm, 5 μm) was used as the separation column, and a Phenomex C18 (4 × 3.0 mm) was used as the precolumn. The column temperature was 30 ± 2 °C. A mobile phase consisting of 75:25% acetonitrile:water (v / v) was pumped through the system at a flow rate of 1.5 mL / min. Detection of mometasone furoate was performed at λ = 249 nm using a Waters 2487 Dual λ absorbance detector. 100 μL of each sample was injected, and the mometasone furoate concentration was calculated against a calibration curve containing 0.012–1.2 μg MF / mL.

[0134] [Table 3]

[0135] Table 2 presents data on the concentration of mometasone furoate in pig skin after 6 and 12 hours, i.e., the retention of mometasone furoate at the site of action. Pig skin permeation studies were performed in a flow-through cell. Pig ears were rinsed with cold water. Hair was carefully removed from the inside of the ear with a trimmer, and skin films were prepared with a dermatologist (TCM3000BL; Nouvag, Goldach, Switzerland) to a thickness of approximately 500 μm, including the epidermis and part of the dermis.

[0136] Before starting the experiment, the skin was hydrated in the diffusion cell for 1 hour at 32°C, with the skin side exposed to the receptor medium (a mixture of isotonic 20 mM citrate buffer (pH 4.5) and ethanol (70:30 v / v)) and the stratum corneum side exposed to ambient air.

[0137] 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). The temperature was maintained at 32 ± 0.3°C using a circulating water bath (Techne TE-10A thermostat; Bibby Scientific, Staffordshire, UK).

[0138] The cream was applied at an infinite dose (260 mg / cm²), and the cell was sealed with parafilm to maintain fixed boundary conditions. The receptor solution was continuously pumped through the cell at a flow rate of 1.5 mL / h. The cream was allowed to contact the skin membrane for 6 hours, after which excess cream was removed. Half of the skin membrane was removed from the flow-through cell, and the experiment continued on that half. After another 6 hours (12 hours in total), the remaining skin membrane was removed. The removed skin membrane was gently dried with tissue paper, and the exposed area was isolated in a diffusion cell (0.64 cm²). Mometasone furoate was extracted from the skin membrane into 1 mL of an acetonitrile-water mixture (60:40) by sonication for 15 minutes (Ultrasonic cleaner; VWR, IL, USA). The extracted solution was then placed in a new vial and stored at -20°C until mometasone furoate analysis.

[0139] The mometasone furoate concentration in the samples was assayed using an HPLC-UV system (Waters Alliance 2695 Separation Module). A Kromasil C18 (250 × 4.6 mm, 5 μm) was used as the separation column, and a Phenomex C18 (4 × 3.0 mm) was used as the precolumn. The column temperature was 30 ± 2 °C. A mobile phase consisting of 75:25% acetonitrile:water (v / v) was pumped through the system at a flow rate of 1.5 mL / min. Detection of mometasone furoate was performed at λ = 249 nm using a Waters 2487 Dual λ absorbance detector. 100 μL of each sample was injected, and the mometasone furoate concentration was calculated against a calibration curve containing 0.012–1.2 μg MF / mL.

Claims

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

2. 2. The composition for use according to claim 1, wherein the skin area is sensitive (thin) and is selected from the skin in the axillary area, the facial area (especially the eye area, e.g. the eyelids), the groin area, or the skin in the genital area or the scalp or the rectal area.

3. 3. The composition for use according to claim 1 or 2, wherein the corticosteroid-responsive dermatosis is selected from 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.

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

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

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

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

8. The composition for use according to any one of claims 1 to 7, wherein the corticosteroid is mometasone furoate.

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

10. The composition for use according to any of claims 1 to 9, which is administered once a day, or such as twice a day, or such as three times a day.

11. 11. The composition for use according to any of claims 1 to 10, wherein for example the composition according to the invention is administered topically onto the skin for a period of more than 5 days when administered at least once a day, or said treatment may be for, for example, 6 days or more, such as about 7 days or more, for example about 8 days or more, such as about 9 days or more, for example about 10 days or more, such as about 11 days or more, for example about 12 days or more, such as about 13 days or more, for example about 14 days or more, such as about 3 weeks or more, for example about 4 weeks or more, such as about 5 weeks or more, for example about 6 weeks or more, such as about 7 weeks or more, for example about 8 weeks or more.

12. 12. The composition for use according to any of claims 1 to 11, wherein the duration of treatment is, for example, more than about 3 weeks, such as about 4 weeks or more, for example about 5 weeks or more, such as about 6 weeks or more, for example about 7 weeks or more, such as about 8 weeks or more, for example about 9 weeks or more, such as about 10 weeks or more, for example about 15 weeks or more, such as about 20 weeks or more, for example about 25 weeks or more, such as up to about 30 weeks.

13. 13. The composition for use according to any of claims 1 to 12, wherein the composition is administered to an area of ​​skin of more than about 10%, such as about 20% or more, for example about 25% or more, such as about 30% or more, for example about 35% or more, such as about 40% or more, for example about 45% or more of the total area of ​​skin on the body.

14. 14. The composition for use according to any of claims 1 to 13, wherein the composition is administered to an area of ​​skin that is greater than about 20% but not greater than 60% of the individual's total skin area for adults, and greater than 10% but not greater than 40% of the individual's total skin area for children.

15. Mometasone furoate in an amount of 0.1% (w / w), Propylene glycol and / or butylene glycol, a total of 25% (w / w), Refined coconut oil, stearic acid, macrogol stearate, glycerol monostearate 40-55, sodium citrate, citric acid and water A composition for use according to any one of claims 1 to 14, comprising:

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