OBJECTIVES: 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). KEY FINDINGS: 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.
OBJECTIVES: 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). KEY FINDINGS: 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: Selma Bekri; Pierre Bourdely; Carmelo Luci; Nathalie Dereuddre-Bosquet; Bin Su; Frédéric Martinon; Véronique M Braud; Irene Luque; Pedro L Mateo; Sara Crespillo; Francisco Conejero-Lara; Christiane Moog; Roger Le Grand; Fabienne Anjuère Journal: Front Immunol Date: 2017-02-01 Impact factor: 7.561