title: Nanocrystal-based per-oral itraconazole delivery: superior in vitro dissolution enhancement versus Sporanox® is not realized in in vivo drug absorption.
abstract: Nanoscience holds true promise in enabling efficient formulation development and in vivo delivery of poorly water soluble drugs. The objective of this study was to formulate solid oral nanocrystal delivery systems of itraconazole, and thus enhance the oral bioavailability of the very poorly soluble drug. Nanocrystal suspensions were prepared by a rapid wet milling technique, after which the suspensions were transformed into solid dosage forms by both freeze drying and granulating. Finally, the obtained nanocrystalline powders were capsule-packed as well as compacted to tablets. After in vitro analysis, the formulations (nanocrystal suspension (NPs), freeze dried NPs, granulated NPs) were tested in vivo in a rat model, and compared with commercial itraconazole formulation (Sporanox). Importantly, the results indicated rapid dissolution of the nanocrystalline itraconazole with enhanced bioavailability compared to physical mixture. Drug dissolution in vitro was immediate from NPs and freeze dried powder, and differed significantly from the marketed product (P=0.004 and 0.002, correspondingly) until 30min. Freeze drying was detected to be especially advantageous for the solid dosage forms. It is possible to maintain the original character of the nanocrystals, e.g. rapid dissolution, even after tableting of the nanocrystalline powders. Interestingly, the marketed product out-performed the nanocrystalline formulations in vivo, even though the nanocrystals provided reasonable bioavailability of itraconazole absorption as well. The efficient in vitro dissolution enhancement of the nanocrystalline formulations compared to Sporanox® was not realized in in vivo drug absorption.
authors.affiliation: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Electronic address: annika.sarnes@helsinki.fi.
authors.forename: Annika
authors.initials: A
authors.lastname: Sarnes
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; Institute of Biomedicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
authors.forename: Miia
authors.initials: M
authors.lastname: Kovalainen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Merja R
authors.initials: MR
authors.lastname: Häkkinen
authors.affiliation: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Laaksonen
authors.affiliation: Orion Pharma R&D, Formulation Research, Espoo, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Laru
authors.affiliation: Orion Pharma R&D, Formulation Research, Espoo, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Kiesvaara
authors.affiliation: Oy Medfiles Ltd., Kuopio, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Ilkka
authors.affiliation: Santen Oy, Tampere, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Oksala
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Rönkkö
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Järvinen
authors.affiliation: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Hirvonen
authors.affiliation: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood; D004337:Drug Carriers / Q000737:chemistry*; D017964:Itraconazole / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D017964:Itraconazole
keywords: Bioavailability; Dissolution; In vivo studies; Poorly water soluble drugs; Solid oral nanocrystal formulation; Wet milling