Biopharmaceutical Development of a Bifonazole Multiple Emulsion for Enhanced Epidermal Delivery Suñer-Carbó, Joaquim Calpena-Campmany, Ana Halbaut-Bellowa, Lyda Clares Naveros, Beatriz Rodriguez-Lagunas, María José Barbolini, Elena Zamarbide-Losada, Joanna Boix-Montañés, Antonio Multiple emulsion Bifonazole Pseudoplastic Drug release Skin penetration Skin permeation Skin integrity TEWL Epidermal histology Efficient topical delivery of imidazolic antifungals faces the challenge of overcoming its limited water solubility and its required long-lasting duration of treatments. In this paper, a hydrophilic multiple emulsion (ME) of Bifonazole (BFZ) is shown to maximize its skin retention, minimize its skin permeation, and maintain an acceptable level of being harmless in vivo. The formulations were pharmaceutically characterized and application properties were assessed based on viscosity measurements. Non-Newtonian pseudoplastic shear thinning with apparent thixotropy was observed, facilitating the formulation retention over the skin. The in vitro release profile with vertical diffusion cells showed a predominant square-root release kinetic suggesting an infinite dose depletion from the formulation. Ex vivo human skin permeation and penetration was additionally evaluated. Respective skin permeation was lower than values obtained with a commercial O/W formulation. The combination of amphoteric and non-ionic surfactants increased the bifonazole epidermal accumulation by a factor of twenty. This fact makes the possibility of increasing its current 24 h administration frequency more likely. Eventual alterations of skin integrity caused by the formulations were examined with epidermal histological analysis and in vivo preclinical measurements of skin elasticity and water retrograde permeation. Histological analysis demonstrated that the multiple emulsions were harmless. Additionally, modifications of in vivo skin integrity descriptors were considered as negligible. 2019-03-04T13:32:16Z 2019-03-04T13:32:16Z 2019-02-02 info:eu-repo/semantics/article Suñer-Carbó, Joaquim; Calpena-Campmany, Ana; Halbaut-Bellowa, Lyda; Clares Naveros, Beatriz; Rodriguez-Lagunas, María José; Barbolini, Elena; Zamarbide-Losada, Joanna; Boix-Montañés, Antonio. Biopharmaceutical Development of a Bifonazole Multiple Emulsion for Enhanced Epidermal Delivery. Pharmaceutics 2019, 11, 66. [ doi:10.3390/pharmaceutics11020066] 1424-8247 http://hdl.handle.net/10481/54886 10.3390/pharmaceutics11020066 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI