title: How do in-vitro release profiles of nanosuspensions from Alzet® pumps correspond to the in-vivo situation? A case study on radiolabeled fenofibrate.
abstract: In research and development sufficiently high and constant plasma levels of drug candidates are often requested, but simple solutions of hydrophobic drugs delivered from the commonly used micro-osmotic pumps cannot meet these demands. Nanosuspensions released from implanted osmotic devices can be a strategy to overcome this challenge but little is known about their pharmacokinetic behavior after subcutaneous application. In the current study, four different nanosuspension formulations containing iodinated fenofibrate were prepared, physicochemically characterized and investigated concerning their in-vitro release kinetics from osmotic pumps. One nanosuspension of lower viscosity exhibited thereby an unexpectedly first order release kinetics, whereas the higher viscous counterpart was released in the expected zero-order manner. To assess the relation of the in-vitro release kinetics to the in-vivo fate of nanosuspensions, various [(131)I] iodinated fenofibrate formulations were subcutaneously applied to mice. The biodistribution was followed by means of γ-scintigraphy and γ-scintillation. Two different nanosuspensions released from osmotic pumps were compared to bolus injections of a nanosuspension and an organic drug solution. The distribution and elimination of the bolus injected drug solution were almost completed within 48h. In contrast, a long lasting (>1week) depot at the injection site was formed by the bolus injected nanosuspension. Ex vivo examination of the organs showed a sustained, but exponential decrease of the radiolabel concentration. More constant drug levels in the organs were achieved within the nanosuspensions released from osmotic pumps. The organ levels of [(131)I] labeled fenofibrate were found to be more constant in case of the pump with the higher viscous nanosuspension in contrast to the lower viscous counterpart. However, the very different release profiles of the lower and higher viscous nanosuspension observed in-vitro were not observed in-vivo, as both pumps showed zero order release. In conclusion, nanosuspensions of poorly soluble compounds released from subcutaneously implanted osmotic pumps can be a suitable approach in pharmacokinetic studies. Although the in-vivo release of nanosuspensions differed in the expected release profile from the in-vitro test results, these in-vitro release tests present a valuable tool for the pre-selection of suitable nanosuspension candidates.
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Technology and Biopharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle/Saale, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hill
authors.forename: S
authors.initials: S
authors.lastname: Breyer
authors.forename: S
authors.initials: S
authors.lastname: Geissler
authors.forename: W
authors.initials: W
authors.lastname: Mier
authors.forename: U
authors.initials: U
authors.lastname: Haberkorn
authors.forename: M
authors.initials: M
authors.lastname: Weigandt
authors.forename: K
authors.initials: K
authors.lastname: Mäder
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D015918:Infusion Pumps, Implantable; D007456:Iodine Isotopes / Q000737:chemistry; D051379:Mice; D049329:Nanostructures; D013535:Suspensions; D014018:Tissue Distribution
chemical_list: D007456:Iodine Isotopes; D013535:Suspensions; D011345:Fenofibrate