title: Fast-dissolving sublingual solid dispersion and cyclodextrin complex increase the absorption of perphenazine in rabbits.
abstract: OBJECTIVE
  The sublingual administration route as well as solid dispersion formation with macrogol 8000 and complexation with β-cyclodextrin (β-CyD) were investigated as ways for improving the absorption of perphenazine, a poorly water-soluble drug subjected to substantial first-pass metabolism.
  
  
  METHODS
  The absorption of perphenazine was studied in rabbits after sublingual administration of perphenazine/macrogol solid dispersion, solid perphenazine/β-CyD complex and plain micronized perphenazine, as well as after peroral administration of an aqueous perphenazine solution. Solid formulations were prepared by freeze-drying (perphenazine/macrogol solid dispersion) or spray-drying (perphenazine/β-CyD complex).
  
  
  RESULTS
  The value for area under the curve from 0 to 360 min (AUC(0-360 min) ) of perphenazine after peroral administration was only 8% of the AUC(0-360 min) value obtained after intravenous administration, while the corresponding values for the sublingually administered formulations were 53% (perphenazine/macrogol solid dispersion), 41% (perphenazine/β-CyD complex) and 64% (micronized perphenazine). There are three possible mechanisms to explain these results: avoidance of the first-pass metabolism; good sublingual absorption of perphenazine; and rapid dissolution rate of perphenazine from the studied formulations.
  
  
  CONCLUSIONS
  With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, the solid dispersion preparation and cyclodextrin complexation were postulated to be useful ways to attain successful sublingual administration of perphenazine. Good sublingual absorption was also achieved by micronization of perphenazine. As far as we are aware, this paper is one of the first to evaluate the sublingual administration of a solid dispersion in vivo.
authors.affiliation: School of Pharmacy/Pharmaceutical Chemistry, University of Eastern Finland, Kuopio, Finland. elina.turunen@uef.fi
authors.forename: Elina
authors.initials: E
authors.lastname: Turunen
authors.forename: Janne
authors.initials: J
authors.lastname: Mannila
authors.forename: Riikka
authors.initials: R
authors.lastname: Laitinen
authors.forename: Joakim
authors.initials: J
authors.lastname: Riikonen
authors.forename: Vesa-Pekka
authors.initials: VP
authors.lastname: Lehto
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Ketolainen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Järvinen
authors.forename: Pekka
authors.initials: P
authors.lastname: Jarho
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D008297:Male; D010316:Particle Size; D010546:Perphenazine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011817:Rabbits; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D014150:Antipsychotic Agents; D005079:Excipients; D047392:beta-Cyclodextrins; D011092:Polyethylene Glycols; D010546:Perphenazine; C031215:betadex