title: Combined strategies for enhancing the transdermal absorption of midazolam through human skin.
abstract: OBJECTIVE
  Midazolam administration by intravenous or intramuscular injection produces pain and stress. For this reason, alternative methods of administration have been proposed. The transdermal administration of midazolam could improve patient comfort, which is especially important for children in the pre-operative period. We aimed to assess the effect of iontophoresis and chemical percutaneous enhancers applied individually and together, to determine if a synergistic effect is achieved when both enhancement techniques are simultaneously employed.
  
  
  METHODS
  This work reports the characterization of the passive diffusion of midazolam hydrochloride through human skin in vitro and evaluates the effect of iontophoresis application and chemical percutaneous enhancers on said diffusion when employed both individually and in combination.
  
  
  RESULTS
  Percutaneous absorption assays demonstrated that the physical technique of iontophoresis, when applied alone, moderately increased midazolam hydrochloride permeation flux through human skin, producing a similar effect to that obtained with R-(+)-limonene chemical enhancer. Among the strategies assayed, it was observed that Azone produced the most pronounced enhancement effect when applied separately. The combination of pre-treatment with Azone and iontophoresis exhibited a higher capacity for enhancing the transdermal flux of midazolam through human skin than Azone alone.
  
  
  CONCLUSIONS
  In conclusion, when applied individually, Azone exhibited the greatest enhancement effect on the transdermal diffusion of midazolam of the various strategies assayed. The combination of Azone and iontophoresis produce the highest transdermal steady-state flux of midazolam but no synergic effect was achieved when the two enhancement strategies were applied in combination, showing that although selecting the best conditions for iontophoresis application, it is less effective for augmenting the transdermal delivery of midazolam than the chemical enhancer Azone.
authors.affiliation: Departamento de Fisiología, Farmacología y Toxicología, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera, Moncada, Spain. cbalaguer@uch.ceu.es
authors.forename: Cristina
authors.initials: C
authors.lastname: Balaguer-Fernández
authors.forename: Andrés
authors.initials: A
authors.lastname: Femenía-Font
authors.forename: Vicente
authors.initials: V
authors.lastname: Muedra
authors.forename: Virginia
authors.initials: V
authors.lastname: Merino
authors.forename: Alicia
authors.initials: A
authors.lastname: López-Castellano
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D001381:Azepines / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002648:Child; D004058:Diffusion / Q000187:drug effects; D005260:Female; D006801:Humans; D007478:Iontophoresis / Q000379:methods*; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D012869:Skin Absorption / Q000187:drug effects*
chemical_list: D001381:Azepines; C035229:laurocapram; D008874:Midazolam