Topical corticosteroids are widely used to treat inflammatory skin diseases. For instance, they are the recommended first-line therapy in Atopic Dermatitis (AD) according to the European Task Force on AD [1]. Inappropriate use may be related to adverse effects such as skin atrophy or suppression of the Hypothalamic Pituitary Axis (HPA) [2]. Corticosteroid derivatives and formulations have been developed in the last decades with the aim of increasing efficacy and decreasing the incidence of adverse effects. More recently, however, the interest is more focused on improving the vehicles to fulfil patients’ preference in order to improve adherence. Adherence to topical therapy is an important issue, particularly in chronic skin diseases, where it is reported to be low (30-50%) [3].

According to the ATC/DDD Index (Anatomical Therapeutic Chemical classification system and Defined Daily Dose), Mometasone Furoate (MF) 0.1% is a high potency corticosteroid. Authorized and marketed in Europe since the early 90´s, it has been widely used by dermatologists due to its potent efficacy and favourable safety profile for the treatment of inflammatory skin disorders [4]. MF is also licensed for the treatment of other clinical conditions such as rhinitis, rhino-sinusitis or nasal polyps.

Beyond designing new active corticosteroid congeners and focusing on the improvement of the benefit/risk ratio, the development of new formulations is also an important challenge. The use of vehicles more adapted to the patients’ needs (i.e. less messy and easy to apply) is considered one of the main strategies to tackle the general lack of adherence to topical corticosteroids. Therefore, corticosteroid formulations need to have appropriate cosmetic properties, which not only adequately fit the current state of the patients’ skin, but also fulfil their expectations and ameliorate their quality of life. Since traditional vehicles of MF might not have fully matched patients’ preferences, new topical formulations have recently been developed to optimize treatment modalities for every patient, skin and clinical situation in order to ensure adherence and improve ‘real life’ efficacy.

With the present article we want to give an overview of the current state of MF as a valuable and established topical medication, as well as review the data from its new formulations.

Topical corticosteroids are a great family of hydrocortisonederivative compounds with variable anti-inflammatory potency and side-effects profile. Their relative potency should be carefully considered when choosing the formulation for treating individual patients. While the least potent corticosteroids may be sufficient in certain conditions, clinical settings, and for long-term maintenance therapy, the same medication may be ineffective in other conditions (e.g. where hyperkeratosis is present such as in psoriasis, or when treating palms or soles). Due to the vasoconstrictive properties of topical corticosteroids, their relative potencies are measured with the vasoconstrictor assay (VCA) [5]. Based on pharmacodynamic measures, this assay provides objective and quantifiable data reflecting the delivery of the active agent through the skin barrier, its intrinsic activity at the receptor, and the rate of clearance from the site of application [6]. While the VCA is useful in clinical trials, its predictive value on outcomes is reduced in daily clinical practice, where patient adherence also plays a very important role.

Corticosteroid potency is not only influencing therapeutic effectiveness, but also the likelihood of adverse events. All topical corticosteroids theoretically possess the ability of systemic absorption and production of adrenal suppression [7]. The degree of suppression is directly related to potency and penetration, which increases with several factors: application to large surface areas, occlusion, inflamed skin, and higher concentrations.

In the early years following their introduction, topical corticosteroids were widely misused, often prescribed for the wrong conditions or in the wrong potencies fostering the so-called corticophobia (fear of corticosteroids) among patients and dermatologists. Nevertheless, specific guidelines can help to implement the safe and effective use of these topical medications [8]. Under appropriate medical supervision, unwanted side effects of topical corticosteroids should not be an issue.

The relative potency of a corticosteroid molecule can be greatly modified by different factors such as chemical modifications, vehicles, use of bandages, etc. When analyzing relative vasoconstriction, it is relevant to verify whether the experiment refers to the use of occlusion, to a simple solvent vehicle rather than the definitive formulation, or to an open testing procedure.

One way of optimizing penetration is by altering the formulation vehicle. Vehicles designed specifically for certain corticosteroids (taking into consideration their solubility and the rate of release from the vehicle) are more likely to be successful in clinical application [7]. Some vehicles also enhance the penetration and biological activity of the active compound [7]. Important factors are:

• Solubility and rate of release of the therapeutic agent in/from the vehicle

• Ability of the vehicle to hydrate the stratum corneum

• Stability of the active agent in the vehicle

• Chemical and physical interactions of the vehicle and the outermost layer of the epidermis

• The mode of action of the substance itself

Corticosteroids are formulated in different vehicles such an ointments, creams, emulsions, gels, lotions and solutions. In general, the more occlusive and hydrating the vehicle (i.e. ointment), the more penetrating and potent the corticosteroid, but also a larger likelihood of local and systemic side-effects.

In addition to the drug’s intrinsic potency and its optimal penetration, treatment adherence is a critical factor influencing the therapeutic effectiveness of topical corticosteroids. Treatment adherence has multiple dimensions, including patients’ acceptance, continuation and discontinuation of treatment [9]. The cosmetic properties of the vehicle influence convenience and patient acceptance, therefore determining treatment adherence. If the correct agent but the wrong vehicle is used, the response to therapy may be delayed, inadequate, or in some cases absent [10]. This might be the case in alcoholic solutions, which should be avoided in clinical conditions where drying effects are unwanted. Hence, it is important to consider the clinical condition and the patient’s preferences in order to find the most appropriate vehicle for any individual patient [11].

Chemical structure

Mometasone furoate is the 17-ester of the 16α-methyl of beclometasone with chlorine substituents in the 9α- and 21- position (Figure 1). The development of MF has been the result of scientific efforts aimed to separate the wanted from the unwanted effects of topical corticosteroids [12]. Halogenation of the 9α-position, substitution of the 21-OH by Cl (chlorine) and esterification of the 17-OH with furoate, considerably increase the binding affinities of mometasone to the corticosteroid receptor. The ester hydrolysis biotransformation reduces the receptor binding during the passage through the skin, therefore mometasone has a lower affinity to dermal than to epidermal cells [13]. All these chemical characteristics lead to improved efficacy but lower incidence of undesirable effects.

Figure 1: Chemical structure of mometasone furoate.

Ideally, a topical corticoid should permeate the stratum corneum and reach a therapeutic concentration in the skin, but without passing on to the systemic circulation in order to avoid further toxicity [7]. Topical steroids’ lipophilicity is closely related to this ability, and can be increased by several ways, including the esterification at the 17 or chlorination at the 21 positions, as it was done in MF [7].

MF has antipruritic, anti-inflammatory and vasoconstrictive properties [14]. Alike the other corticosteroids, the anti-inflammatory efficacy of the complex MF-corticosteroid receptor is mediated by the repression of inflammatory gene transcription either directly (via transrepression) or by activating transcription of anti-inflammatory/ repressive factors (transactivation) [15]. According to the ATC/ DDD Index, MF 0.1% belongs to the potent (group III) of topical corticosteroids (high potency) [4]. Nevertheless, it is characterized by low atrophogenicity as well as low systemic availability and, consequently, less risk of local adverse events and HPA suppression. The molecule MF is currently well established for the treatment of a variety of inflammatory corticosteroid-responsive dermatoses, such as chronic hand eczema, atopic dermatitis (AD), seborrhoeic dermatitis, and psoriasis [16-19].

Pharmacokinetics and safety profile

The specifically low and well-known rate of systemic side effects of MF is explained by the minimal degree of systemic absorption as was measured in pharmacokinetic studies with different formulations:

Cream [20]: The percutaneous absorption of MF cream 0.1% was evaluated in subjects receiving a single dose of radio-labelled ³H-cream which remained on intact skin for eight hours. Based on the amount of radioactivity excreted in the urine and faeces during the five-day study period, it was demonstrated that only approximately 0.4% of the applied dose was absorbed systemically. The radioactive amount found in plasma and red blood cells remained a few counts above background levels throughout the study.

Ointment [21]: A similar study with radio-labelled ³H-ointment was conducted in volunteers with intact skin. Based on the amounts of radioactivity excreted after an eight-hour application, approximately 0.7% of the applied dose was absorbed systemically without occlusion.

Solution [22]: The occlusive nature of the ointment base leads to a greater percutaneous absorption of a corticosteroid ointment compared to topical corticosteroids in a cream or solution formulation. Thus, the absorption following application of MF solution 0.1% is expected to be no greater than that of the ointment formulation.

Due to the low percutaneous absorption and rapid hepatic biotransformation, topically applied MF does not show a significant effect on the HPA [23]. The atrophogenic potential and risk of sensitisation of MF are considered to be low [19,24,25]. Not all the available corticosteroids have the same potential to induce skin atrophy. Wach F et al. [26] showed that MF has a lower effect on human keratinocytes and fibloblasts than other corticosteroids in vitro. It has been shown that MF, like tacrolimus, does not affect the expression of collagen mRNAs in human fibroblasts [27].

Clinical studies on mometasone furoate (atopic dermatitis, psoriasis)

MF has been extensively evaluated in several clinical trials (Table 1). They include studies evaluating MF 0.1% (cream, ointment and solution) to assess its efficacy and safety in the treatment of corticosteroid responsive dermatoses (mainly AD and psoriasis) in comparison to vehicle (non-active control) and other corticosteroids (active comparators) in a number of skin conditions. Globally, MF 0.1% was significantly more effective than the vehicle in all the indications studied and, when compared to active drugs, it showed comparable or even significantly better efficacy in the different settings. One proven advantage of MF over other corticoids is that only once daily application is needed to achieve the clinical effect.

Table 1: Study profile of the current mometasone furoate formulations in different skin diseases.

Atopic dermatitis: AD (or atopic eczema) is an extremely common disease that has a strong negative impact on the quality of life in affected patients [28]. Topical corticosteroids remain the mainstay of AD treatment [29]. Several clinical trials have been conducted to evaluate MF, both as cream and ointment formulation, in comparison to vehicle and other standard treatments. MF cream and ointment showed significantly superior efficacy than their vehicles, both administered once daily [30,31]. MF cream once daily, compared to other cream corticosteroids administered twice daily, was either significantly more effective in adults and children or comparable in efficacy [32-35]. MF ointment once daily showed comparable efficacy as other ointment comparators administered twice daily [36-38].

Psoriasis: Psoriasis is a chronic inflammatory skin disease with a relapsing and remitting course [39]. The occurrence of psoriasis varies according to age (lower prevalence in children) and geographic region (more frequent in countries more distant from the Equator) [40]. Since their introduction, topical corticosteroids have become a standard treatment of psoriasis [41]. Several clinical trials have evaluated MF in this indication comparing cream and ointment formulations with vehicle and active drugs. MF cream and ointment showed significantly superior efficacy than their vehicles, both administered once daily [42,43]. The efficacy of ointment and cream MF formulations administered once daily, as compared to cream and ointment comparators administered once, twice or three times per day showed comparable or significantly superior results [44-50].

Scalp Psoriasis: About 25% of patients suffering from psoriasis have scalp involvement [51]. Topical treatment options for this skin condition need a vehicle easy to administer and to remove from the hairy region. In fact, scalp psoriasis is a critical area for understanding patients’ vehicle preference [52]. MF was evaluated in a solution vehicle for the treatment of patients with scalp psoriasis in several clinical studies, showing the superiority of the MF 0.1% solution once daily as compared with its vehicle and active drugs administered once or twice per day [53-56].

Apart from these main indications, MF has also been evaluated for use in other skin diseases:

Genital lichen sclerosus

Lichen sclerosus (LS) is an inflammatory skin disease characterized by a lymphocytic response that predominantly affects the genital region and can be associated with several other autoimmune diseases [57]. Its pathogenesis is not yet fully understood, but there is increasing evidence suggesting underlying autoimmune mechanisms [57]. Topical steroids have become the mainstay of treatment for this condition where MF has shown effectiveness [57]. Cattaneo et al. [58] evaluated the efficacy and safety of MF in the treatment of vulvar LS. All 31 female patients showed a significant improvement and a decrease in symptoms, with nearly all subjects reaching complete symptomatic remission. Adherence was excellent, and no side effects were present. Clinical evidence in males is limited. A systematic review by Chi et al. [59] showed a significant improvement in the investigator-rated change in clinical grade of phimosis with MF 0.05% compared to placebo.

Vitiligo

Vitiligo is a skin disease characterized by depigmentation of the skin corresponding to a substantial loss of functioning epidermal and hair follicle melanocytes [60]. This skin condition often leads to substantial cosmetic disfigurement, particularly in patients with dark skin-types. According to the European guidelines for the management of this skin condition, topical corticosteroids lead to the best results on sun-exposed areas, dark skin and in new lesions [60]. MF is considered effective and largely devoid of the well-known local side-effects of potent and very potent corticosteroids. Recent studies have also shown that MF is effective and safe in the treatment of childhood vitiligo [61,62].

Contact dermatitis

Contact dermatitis or contact eczema describes a reaction pattern of the skin in response to external stimuli (i.e. irritant substances or allergens) [63]. Its clinical presentation very often includes a location of the skin lesions on the hands, especially in certain occupational groups [64]. Irritant contact dermatitis is a non-specific inflammatory disease, which involves in its pathogenesis the activation of innate immunity, whereas allergic contact dermatitis predominantly is a T-cell-mediated disease [65,66]. Topical corticosteroids are widely used for the treatment of contact dermatitis, as mentioned in the guidelines for the management of the disease entity from the British Association of Dermatologists [17]. The effectiveness of long-term intermittent use of MF in chronic hand eczema was demonstrated in an open prospective randomized trial [16].

MF currently is formulated in vehicles such as ointments, cream and solutions. Cosmetic properties of the vehicles and their ease of use are also important issues in the use of topical medications. The available mometasone cream (original product and generics) is a fatty cream with less than 5% of water, whereas the available solutions are alcoholic formulations with the risk of drying and stinging as potential side effects when applied to the scalp. In the current context of generally low adherence to topical corticosteroids, vehicles of topical drugs should be convenient in order to fulfil the patients’ expectations of coMFort in order to improve their treatment adherence. A regularity of application is crucial for patients suffering from chronic skin conditions. The patients’ adherence to treatment is improved if convenient and userfriendly topical formulations are provided. A medicinal product that is not accepted for cosmetic properties significantly impairs the success of treatment.

Despite the proven efficacy and safety of the available MF, there still seem to be some unmet needs regarding to its formulations. For this reason new, more patient preference-oriented vehicles have recently been developed.

Considering all the aforementioned, new pharmaceutical formulations have been developed and studied in order to broaden the clinical spectrum of MF use and ensure adherence. This new range of MF formulations includes a 33% water content o/w (oil in water) cream and a 36% water content emulsion. Both formulations will be shortly available commercially.

In the clinical trials, VCA was used for assessing in vivo bioavailability, and the psoriasis plaque test (PPT) was used for the assessment of the antipsoriatic action of the new MF formulations.

Cream (33% Water Content)

The new cream formulation is a white, semi-solid topical product on the base of an oil in water emulsion (33% water) which has shown a similar efficacy and tolerability compared to the previous mometasone cream formulation, but with the cosmetic properties of a lighter cream [12]. it has been evaluated in clinical phase I and II studies conducted to assess bioavailability, efficacy, tolerability as well as quality of life (Qol) and patient satisfaction in intact skin, psoriasis and AD [12,67] (Table 2).

Table 2: Summary of clinical trials evaluating the new mometasone formulations O/W cream (33 % water content) and emulsion (36 % water content).

The bioavailability, as measured by VCA, was studied in a singlecenter, randomized, observer-blind phase I study comparing the new formulation with its vehicle alone, the previous mometasone formulation (mometasone comparator, less than 5% water content) and class II & IV corticosteroid comparators with lower or higher potency [12]. Each preparation was used in a single application for 6 hours. The chromametric measurements demonstrated similar mean area under curve (AUC) values for the new MF cream, the mometasone comparator and clobetasol cream (higher-strength comparator), whereas a lower mean AUC value was noted for triamcinolone cream (lower-strength comparator). The clinical assessment reproduced the chromametric results: the vasoconstriction achieved with mometasone cream with 33% water content was comparable to the effect seen for the mometasone comparator and clobetasol cream and superior to the effect seen for triamcinolone cream. In the test fields treated with the vehicle cream, the majority of the subjects showed no vasoconstriction.

The tolerability of the new MF cream was evaluated in one singlecentre, randomized, double-blind phase I study in healthy skin, compared to its vehicle alone and two controls: negative (purified water) and positive (sodium dodecyl sulfate in water, SDS) [12]. The results showed a mild to moderate irritative potential. A higher irritation score was measured comparing the active compound and the vehicle with the negative control but a lower irritation score was seen compared to the positive control (SDS).

A phase II study (single-centre, randomized and observer-blind) evaluated the efficacy of the new MF formulation (in terms of noninferiority) compared to its vehicle and reference mometasone cream in psoriatic patients [12]. The PPT showed a strong positive effect of the new mometasone cream. The antipsoriatic effect was comparable to the effect seen with the reference MF cream and, as expected, no relevant effect was noted for the vehicle.

Another single-centre, randomized, double-blind phase II study evaluated the efficacy, cosmetic properties and patients’ acceptance of the new mometasone cream compared with the traditional more fatty cream in patients with mild to moderate AD [67]. Patients’ satisfaction was assessed by a questionnaire on cosmetic properties and contentment, and health-related Qol was recorded using the dermatology life quality index (DLQI). The overall assessment of the preparations was based on the clinical tool scoring atopic dermatitis (Scorad), the stratum corneum hydration, the patients’ statements on skin penetration, and the answers in the questionnaires on cosmetic properties and on quality of life. The results confirmed the bioequivalence and the comparable clinical efficacy of both preparations. However, the patient-reported preference showed a better acceptance of the new MF cream since 75% of patients stated that they preferred the new developed cream over the classical mometasone. In addition, the new formulation was found to be more convenient for daily application by patients (70% vs 40%) and to permeate more quickly than the reference mometasone (50% vs 10%). These characteristics may lead to an improved treatment adherence and better clinical results in real life clinical scenario[6].

Emulsion (36% Water Content)

This new MF formulation is a unique, fluid, 36% water content emulsion with no similar vehicle currently available in the market. Generally speaking the main differences between an emulsion and a solution is that the emulsion is more emollient in nature (in fact it is an o/w vehicle) and does not have alcohol in its formulation. Due to its very fluid properties, this product can e.g. be easily applied in hairy sites like the scalp. It does not have alcoholic content like the available mometasone solution, which implies the capability of being used where alcohol-based formulations are stinging or irritant. Two phase II studies have been carried out to evaluate its efficacy and tolerability in plaque and scalp psoriasis (Table 2).

In plaque psoriasis, the new formulation was compared with its vehicle and the reference product cream (water content <5%) in a single-centre, randomized, double-blind phase II study to assess efficacy and tolerability [68]. The effect of the treatments on the PPT was evaluated both clinically (visually and by palpating the respective test area) by the investigator and by 22 mhz ultrasound on days 1 (baseline), 5 and 12. Assessed clinically, the emulsion was superior to placebo on study days 5 and 12. Both the emulsion and the reference cream produced similar reductions in plaque thickness by study day 5, which was even more pronounced on day 12. This new, very fluid emulsion was therefore found to be as effective as a fatty cream in the treatment of body psoriasis.

A multi-centre, randomized, observer-blind phase IIb study assessed the efficacy of the new formulation compared to the reference mometasone solution in scalp psoriasis [69]. The non-inferiority of the new formulation was proved compared to the reference product based on clinical total sign score (TSS) assessments. The new mometasone emulsion was effective, well-tolerated and accepted by patients in the treatment of scalp psoriasis. It was shown to be non-inferior to the alcoholic reference MF solution in the primary outcomes of the study. These results make the new formulation a promising option for the treatment of scalp psoriasis.

The results of the clinical trials demonstrate the efficacy and safety of the new MF formulations compared to those currently available. Appropriate efficacy plus adequate safety and tolerability profile plus improved cosmetic properties and patients’ acceptance will foster treatment success [6].

A careful choice of the proper formulation is crucial for the success of the treatment in topical corticosteroids. MF is a well-studied corticosteroid with high potency but low rate of adverse effects. Traditionally available formulations for MF might not be suitable for all clinical skin conditions and patients’ needs. Therefore, new formulations have been developed:

New cream with improved cosmetic properties

Due to its increased patients’ preference, this cream seems ideal for the treatment of any inflammatory skin condition that requires the potency of MF. Due to the evanescent and fluid nature of this cream, patients with large areas affected by inflammation and dry skin are good candidates for this product.

Emulsion

Due to its efficacy in body and scalp psoriasis, together with its good cosmetic acceptance and tolerability, this product can be used, among other indications, as a solely once daily application for psoriasis affecting both the body and scalp. Treating all sites with just one daily application may be extremely useful for adherence purposes.

It has been shown that the new range of MF products is equivalent to the original products, as no clinical differences were found in the complete set of clinical trials designed for the new improved formulations. Nevertheless, the daily clinical practice is not a controlled environment. The better cosmetic acceptability and patients’ preference of the new range compared to the original formulations might lead to greater treatment adherence rates and treatment success in chronic inflammatory conditions (AD and psoriasis) in a daily clinical setting. It is important to highlight that available classical generics of mometasone do not produce cosmetic improvement as they are copies and based in the original range of products. Conversely, improved formulations, like new range of mometasone, offer added value to patients.

To sum up, MF fulfils all demands to be classified as a topical corticosteroid with a high benefit/risk ratio. The newly expanded range of 0.1% MF formulations enables to choose the optimal vehicle for a successful treatment of the individual patient, leading to increased treatment adherence and good clinical results.

SM has received honoraria as speaker and consultant and received a travel grant from almirall.

DA received consulting fees and / or honoraria from almirall, German Academy for Development Promotion and Health of the Child and Adolescent ev, GlaxoSmithKline GmbH, Govi publisher, Infectopharm Gmbh, l’Oreal Germany GmbH, MSDS sharp & dohme, nestlé germany, pierre fabre Germany, Taurus pharma Gmbh

AG received honoraria for medical advisory tasks from Almirall

MB received honoraria for medical advisory tasks from Almirall