Supersaturation of Calcipotriene and Betamethasone Dipropionate in a Novel Aerosol Foam Formulation for Topical Treatment of Psoriasis Provides Enhanced Bioavailability of the Active Ingredients

Abstract

IntroductionPrevious studies have demonstrated the superior efficacy of a novel aerosol foam formulation of fixed combination calcipotriene 0.005% (Cal) and betamethasone dipropionate 0.064% (BD), compared with the ointment formulation. The aim of this study is to ascertain whether enhanced bioavailability of the active ingredients due to supersaturation and/or occlusive properties can explain the observed greater clinical efficacy.MethodsSolubility and evaporation experiments were conducted to examine the abilities of Cal/BD aerosol foam ingredients to create a supersaturated environment. Optical microscopy, Raman imaging and X-ray powder diffraction were used to examine the physical state of Cal and BD in the formulations after application, and determine whether a supersaturated state remained stable for clinically relevant time periods. In vitro skin penetration and ex vivo biomarker assays were conducted to compare the skin penetration and bioavailability of Cal and BD from the aerosol foam and ointment formulations, respectively. Occlusive properties were examined via transepidermal water loss.ResultsSolubility studies showed that Cal and BD solubility increased with increasing dimethyl ether (DME) content. Both active ingredients are completely dissolved in the final aerosol foam formulation. DME rapidly evaporates after spraying, and the amount was reduced to 0.5% of the initial amount after 2 min. This led to the formation of a supersaturated environment, where Cal and BD crystals were absent for at least 26 h after application. Cal/BD aerosol foam had significantly greater in vitro skin penetration and had increased bioavailability compared with Cal/BD ointment. Both formulations effectively occluded the skin.ConclusionA stable supersaturated solution of Cal/BD in the aerosol foam leads to increased bioavailability and explains the improved clinical effect when compared to the Cal/BD ointment.FundingThe studies included in the paper are all conducted by LEO Pharma A/S or CROs on behalf of LEO Pharma A/S.

New Calcipotriol/Betamethasone Dipropionate Foam Formulation for the Treatment of Psoriasis: An Overview

“…In most patients' samples, plasma concentrations of calcipotriol and betamethasone dipropionate and its metabolites were below the quantification's lower limit. 26,27 These results are consistent with those of tissue distribution's studies in rats administered with radiolabelled calcipotriol and betamethasone dipropionate, that showed that the kidney and liver had the highest radioactivity level. 27 In vitro skin penetration and ex vivo biomarker assays were conducted to compare the skin penetration and bioavailability of Cal and BD from the aerosol foam and ointment formulations, respectively.…”

“…22 Cal/BD aerosol foam should be applied topically to the affected areas once daily for a maximum of 4 weeks, not exceeding 15 g daily or 60g every 4 days. 26,27,23 Clinical and pharmacological effects of the two active agents are well known, and its action mechanism in plaque psoriasis has been approached by several authors. 2,3,26 Treatment goal is to clear the psoriatic plaques by inhibiting the underlying inflammation and normalizing skin homeostasis, keratinocyte proliferation and differentiation, and to provide immunomodulation.…”

“…26,27,23 Clinical and pharmacological effects of the two active agents are well known, and its action mechanism in plaque psoriasis has been approached by several authors. 2,3,26 Treatment goal is to clear the psoriatic plaques by inhibiting the underlying inflammation and normalizing skin homeostasis, keratinocyte proliferation and differentiation, and to provide immunomodulation. 13 In combination, calcipotriol and betamethasone promote greater anti-inflammatory and anti-proliferative effects than either component alone.…”

“…27 In vitro skin penetration and ex vivo biomarker assays were conducted to compare the skin penetration and bioavailability of Cal and BD from the aerosol foam and ointment formulations, respectively. Cal/BD foam applied to in vitro skin is maintained for at least 26 …”

Innovation in Topical Therapy for Psoriasis with Corticostereoid and Vitamin D Analogue Commbination

“…The rate-limiting step for most topical treatments is the concentration of active ingredients dissolved in the vehicle One potential method of enhancing the rate of skin penetration is to increase the concentration of active ingredients dissolved in the applied product beyond the normal solubility limit, ie create a supersaturated solution A recent study with Cal/BD aerosol foam demonstrated that a stable supersaturated environment was created and maintained for clinically relevant time periods (at least 26 hours in the laboratory setting) 21 -This state was created after rapid evaporation of the propellants during application and may explain the observed increase in bioavailability of Cal/BD aerosol foam versus Cal/BD ointment 21…”