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Polymeric film-forming systems (FFSs) are potential drug delivery systems for topical application to the skin. The FFSs form thin and transparent polymeric films in situ upon solvent evaporation. Their application convenience and cosmetic attributes, superior to conventional semi-solids, may offer improved patient compliance. This study represents the first phase of an investigation into the use of FFSs for prolonged dermal drug delivery. FFS formulations were distinguished based on their ability to sustain the release of betamethasone 17-valerate (BMV) in vitro over 72 h. The effect of film-forming polymer (hydrophilic: hydroxypropyl cellulose (Klucel™ LF); hydrophobic: polymethacrylate copolymers (Eudragit® NE and Eudragit® RS), and polyacrylate copolymer (Dermacryl® 79) was first determined, and then the impact of incorporation of plasticisers (triethyl citrate, tributyl citrate, and dibutyl sebacate) was examined. The Klucel film released a significantly higher amount of BMV than the hydrophobic FFS, 42 versus 4 μg/cm(2), respectively. The release was increased when a plasticiser was incorporated, and with higher enhancement ratios achieved with the more lipophilic plasticisers. In conclusion, the results show that FFSs can sustain drug release (hence representing useful systems for prolonged dermal therapy) and emphasise the importance of the formulation on drug delivery, with the type of polymer being of greatest significance.

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.

Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.

The promise of polymeric FFS as convenient and aesthetic platforms for sustained topical drug delivery is clear. Manipulation of the formulation allows the delivery profile to be customized and optimized to take advantage of both a rapid, initial input of drug into the skin (likely due to a transient period of supersaturation) and a slower, controlled release over an extended time from the residual film created thereafter.