title: Bioequivalence Methodologies for Topical Drug Products: In Vitro and Ex Vivo Studies with a Corticosteroid and an Anti-Fungal Drug.
abstract: To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application.
  
  
  
  In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed.
  
  
  
  For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment.
  
  
  
  In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A "one-size-fits-all" approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy.
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.|Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco, CEP: 50740-520, Recife-PE, Brazil.
authors.forename: Leila Bastos
authors.initials: LB
authors.lastname: Leal
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Cordery
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: M Begoña
authors.initials: MB
authors.lastname: Delgado-Charro
authors.affiliation: Chemical and Biological Engineering Department, Colorado School of Mines, Golden, Colorado, 80401, USA.
authors.forename: Annette L
authors.initials: AL
authors.lastname: Bunge
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK. r.h.guy@bath.ac.uk.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Guy
mesh_terms: D000287:Administration, Topical; D000305:Adrenal Cortex Hormones / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D001624:Betamethasone Valerate / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D065546:Drug Liberation; D004464:Econazole / Q000493:pharmacokinetics*; D006801:Humans; D008567:Membranes, Artificial; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000502:physiology*; D063465:Skin Cream; D013552:Swine; D013810:Therapeutic Equivalency
chemical_list: D000305:Adrenal Cortex Hormones; D000935:Antifungal Agents; D008567:Membranes, Artificial; D004464:Econazole; D001624:Betamethasone Valerate
keywords: IVIVC; dermatopharmacokinetics; in vitro release test; in vitro skin penetration; topical bioequivalence