Nanosuspension Formulations for Low-Soluble Drugs: Pharmacokinetic Evaluation Using Spironolactone as Model Compound

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Abstract
Various particle sizes of spironolactone as a model low solubility drug were formulated to yield micro-and nanosuspensions of the type solid lipid nanoparticles and DissoCubes®. Seven oral and one i.v. formulations were tested in an in vivo pharmacokinetic study in rats with the aim of characterizing the bioavailability of spironolactone on the basis of its metabolites canrenone and 7-α-thiomethylspirolactone. In addition, a dose escalation study was carried out using nonmicronized spironolactone suspension as well as a nanosuspension type DissoCubes®. On the basis of AUC as well as Cmax ratios, three groups of formulations were distinguished. The biggest improvement was seen with a solid lipid nanoparticle formulation yielding a 5.7-fold increase in AUC for canrenone and a similar improvement based on the Cmax metric, followed by a group of three formulations containing nanosized, micronized, and coarse drug material and surfactant. The DissoCubes® nanosuspension yielded highly significant improvements i...