In vitro–in vivo evaluation of nanosuspension release from subcutaneously implantable osmotic pumps

Abstract

Utilizing poorly soluble drug candidates in pharmacokinetic studies remains challenging in preclinical drug development. We investigated a nanosuspension-based delivery system to achieve constant drug plasma levels by applying the nanoparticles via subcutaneously implanted micro-osmotic pumps. Various nanosuspension formulations were characterized in vitro prior to Alzet® pump release by means of dynamic light scattering (DLS), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and rheological measurements. In vitro formulation release was checked by HPLC/UV. The in vivo experiments compared plasma-concentration time profiles of subcutaneously injected nanosuspensions with those of formulations delivered by pumps. Two Poloxamer 338 containing nanosuspensions with different viscosities were found to be stable over observation time, physically resistant against biorelevant media and showed only a low amorphous part after preparation. The more viscous nanosuspension with 31.65 mPas revealed in vitro the expected zero-order release, while the low viscous formulation with 2.18 mPas showed first order release. In in vivo experiments, the higher viscous nanosuspension released from osmotic pumps exhibited elevated plasma levels compared to the lower viscous formulation. Compared to bolus injected nanosuspensions constant plasma levels could be maintained by adapting the viscosity of the nanosuspension. Subcutaneously implanted osmotic pumps prove to be a valuable delivery system for nanosuspensions in pharmacokinetic studies by consideration of the key parameter viscosity in release kinetics.