Betamethasone Valerate Foam: a Look at the Clinical Data
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Review: Clinical Trial Outcomes Betamethasone valerate foam: a look at the clinical data Clin. Invest. (2014) 4(3), 259–267 Topical corticosteroids and especially betamethasone valerate (BMV) have Avner Shemer1, Nicole Sakka1 & been used topically to relieve many inflammatory skin conditions such as Dov Tamarkin*2 psoriasis and atopic dermatitis. The vehicle used to deliver topical drugs 1Department of Dermatology, the Chaim Sheba Medical Center, Affiliated with the can influence the performance of these topical applications. BMV has Tel-Aviv University, Sackler School of Medicine, traditionally been available in creams, ointments, lotions and sprays. In Tel Hashomer, Israel the early 2000s, a topical hydroethanolic BMV foam became commercially 2Foamix Ltd., 2 Holzman Street, Weizmann available. Subsequently, alcohol-free emulsion- and petrolatum-based Science Park, Rehovot 76704, Israel foam formulations were also developed. This manuscript reviews the *Author for correspondence: Tel.: +972 52 457 5677 properties of BMV foams and clinical studies that have been conducted Fax: +972 8 853 1102 to assess their efficacy and safety as treatments for scalp and non-scalp [email protected] psoriasis, as well as other dermatological inflammatory conditions. Keywords: betamethasone valerate • foam • psoriasis • topical corticosteroids Topical corticosteroids have been ranked in four groups consisting of seven classes ranging from ultra-high potency preparations (class 1) to low-potency prepara- tions (class 7). Betamethasone valerate (BMV) is a mid-potency corticosteroid (class 3–5, depending on the dosage form), used topically to relieve inflammatory skin conditions. It is used as a treatment for psoriasis, atopic dermatitis and other corticosteroid-responsive dermatoses. The vehicle used to deliver topical drugs can influence the performance of these drugs. The vehicle can have a direct effect on the condition of the skin as a barrier, as it can enhance or retard delivery of the active agent to the target site of action. In addition, it can affect the skin’s physical appearance and sensory properties, attributes that can influence patient compliance. Adherence to medication is a major concern in the treatment of dermatological conditions, as it impacts the success of therapy [1] . For example, studies consistently suggest that in psoriasis, up to 40% of patients do not use their medication as directed [2]. Thus, considerable efforts have been applied to the development of optimized topical formulations. BMV has traditionally been available in creams, ointments, lotions and sprays. In the early 2000s, Luxiq®, a topical hydroethanolic BMV foam, became available. More recently, additional types of foam comprising BMV, including emulsion- and petrolatum-based foams, are currently under development. This manuscript reviews the properties of BMV foams and the clinical studies that have been conducted to assess their efficacy and safety as treatments for scalp and non-scalp psoriasis, as well as other dermatological inflammations. The information herein was captured from an extensive search of the published academic literature, via PubMed and additional means literature searchs, patent databases and regulatory documents from the US FDA Freedom of Information database. BMV foam: formulation properties The use of foam in dermatology was first reported in 1977 by Woodward and Berry, who studied the therapeutic benefit of Betamethasone benzoate, in a hydroethanolic ‘quick-break’ foam, in comparison with a corresponding semisolid form [3]. The first 10.4155/CLI.14.13 © 2014 Future Science Ltd ISSN 2041-6792 259 Review: Clinical Trial Outcomes Shemer, Sakka & Tamarkin commercial topical dermatological foams were intro- The petrolatum-based BMV foam comprises 85% duced in 2002. These were hydroethanolic foam for- petrolatum, 3% oil components, and about 3% foam mulations of clobetasol propionate 0.05% foam (Olux®) stabilizing agents. It has the functionality of an oint- and BMV 0.12% foam (Luxiq), which were developed ment, which can form an occlusive layer, build up the by Connetics Corp. (CA, USA) [3–5]. The vehicle of skin barrier, and retain skin hydration. This foam is these foams consists of ethanol (~60%), purified water, water-free and it does not require preservatives [8,9,15]. propylene glycol, cetyl alcohol, stearyl alcohol, polysorb- The Foamix foams are not thermolabile. Unlike ate 60, citric acid and potassium citrate. The foam is Luxiq, they do not readily collapse upon exposure dispensed from an aluminum can that is pressurized to skin temperature. Instead, they spread easily and by a hydrocarbon propellant (propane and butane) absorb rapidly into the skin upon application of mild and it is thermolabile; that is, it melts upon exposure shear-force, allowing comfortable application and well- to elevated temperature, such as the temperature of the directed administration to the target area. The differ- skin [6]. The high concentration of ethanol in the for- ence between quick breaking thermolabile foam and mulation – compared with other vehicles – induces the breakable foam is illustrated in Figure 1. In the figure, delivery of corticosteroids through the stratum corneum the breakable foam is stable, resulting in facile appli- as demonstrated by in vitro studies [6]. cation and spreading, while the hydroethanolic foam Ethanol also promotes fast drying and thereby instantly melts on the fingers (within a few seconds), attempts to address the sticky feeling left by many which makes application to the target site challenging topical formulations after application. However, alco- and the foam difficult to spread over large skin areas. hol is a defatting agent and may cause skin to become dry and cracked. Due to this undesirable property, BMV foam for psoriasis hydro alcoholic foams have not been proposed for the Psoriasis is an inflammatory skin condition. Plaque pso- treatment of atopic dermatitis, an inflammatory skin riasis is the most frequent type and clinically presents disorder most frequently affecting children, which can as thick plaques covered by silvery scales at the sides of manifest with pruritic, dry skin usually symmetrically preferential sites such as the elbows, knees, lower back, distributed on skin folds and less often other locations. and scalp. Treating scalp psoriasis with traditional The stinging associated with use of ethanol on atopic creams and ointments is somewhat challenging, as they skin is another primary reason alcohol-based foams are are difficult to apply under the hair and leave greasy not recommended for atopic dermatitis. residues, while foam is easier to apply and it does not In addition, because the hydroethanolic foams are cause any greasiness. The BMV hydroethanolic foam, thermolabile, their usage is hindered by the recommen- Luxiq, was tested in Phase II and III clinical studies in dation not to dispense them directly onto the hands or scalp psoriasis and in additional studies that were con- to the target skin area, as the foam melts on contact with ducted in patients with non-scalp psoriasis [16–18]. These warm skin, as illustrated in the prescribing information studies were extensively reviewed by Stein in 2005 [19] . leaflet of Luxiq [7]. The alcohol content of these foams has been associated with transient stinging or burning Clinical studies for scalp psoriasis upon application, which may limit their usefulness for Among the adverse events associated with topical some patients. corticosteroid use, the most serious is hypothalamic– Three new versions of BMV foam, an emulsion- pituitary–adrenal (HPA) axis suppression, which can based BMV foam and a petrolatum-based BMV foam result in skin atrophy and in extreme cases, may be life have been developed by Foamix Ltd (Rehovot, Israel) threatening. The safety of Luxiq was initially tested by [8,9]. These compositions include low concentrations Franz et al. in 18 patients with specific emphasis on its of nonionic surfactants to minimize skin irritation. potential to cause HPA axis suppression. This study Additionally, Foamix developed a new version of revealed no evidence of increased toxicity or HPA-axis hydroethanolic foam that is not thermolabile, and so suppression for the BMV foam [16] . Franz et al. subse- its usability is preferred to the original Luxiq. [10,11] quently conducted a pivotal Phase III clinical trial in The new emulsion-based formulation of BMV foam, scalp psoriasis in 1999 [16] . This study, which was sub- which has the functional properties of a cream, was mitted to the FDA for drug approval, was a multicenter, developed with the aim of treating patients with psoria- randomized, double-blind, double-dummy, placebo, and sis and atopic dermatitis. It contains 30% capric/caprylic active-controlled, parallel-group comparison study of the trigyceride (MCT oil), which is a skin-conditioning efficacy and safety of Luxiq in treating scalp psoriasis. emollient [8,9,12]. The oil provides symptomatic relief In total, 190 male and female patients with moderate of skin dryness, which is often associated with skin to severe scalp psoriasis were enrolled and randomly diseases such as psoriasis and atopic dermatitis [13,14] . assigned to four treatment groups in a ratio of 2:1:2:1: 260 www.future-science.com future science group Betamethasone valerate foam: a look at the clinical data Review: Clinical Trial Outcomes Luxiq, the respective foam vehicle, BMV lotion, and Foamix emollient Hydroethanolic placebo lotion. Applications of the