Methods for the Assessment of Bioequivalence of Topical Dosage Forms: Correlations, Optimization Strategies, and Innovative Approaches

Abstract

The assessment of bioavailability/bioequivalence (BA/BE) of topical products not intended to be absorbed into the systemic circulation presents a formidable challenge, since the usual approach of measuring drug concentration in blood/plasma/serum is generally deemed inappropriate. Although various methods have been attempted as surrogate to establish BA/BE of topical products for local action, to date, only one such method, specifically for the assessment of the BE of topical corticosteroids, the vasoconstrictor assay (VCA) also known as the human skin blanching assay (HBSA) has been accepted by the Food and Drug Administration (FDA) and by most other regulatory agencies. This chapter describes the VCA and its features and requirements including data from visual assessment which are now currently considered obsolete and the more acceptable instrumental method using a chromameter. Correlations between visual assessment and chromameter data as well as between the VCA and dermatopharmacokinetic (tape stripping) data are also provided. The dermatopharmacokinetic approach using tape stripping is also described and novel approaches to optimize the method for BE assessment by determining appropriate dose durations using the E max model and standardization of skin thickness and the resulting implications are presented. The application of dermal microdialysis (DMD) is also described and data showing its application for the BE assessment of a nonsteroidal anti-inflammatory agent (NSAID) (ketoprofen gel) as well as its use to measure the diffusion and flux of a corticosteroid through the skin are discussed. The recent FDA guidance on the BE of acyclovir ointments where an in vitro approach has been described is also included and in vitro data comparing the release of acyclovir from cream dosage forms are provided. Finally, a novel method, open flow microperfusion (OFM) is described where its dermal application to study drug penetration into skin dermal open flow microdiffussion (dOFM) presents a new and exciting potential technique for the BA/BE assessment of topical dosage forms.