Nanoscale Lipophilic Prodrugs of Dexamethasone with Enhanced Pharmacokinetics

The encapsulation of glucocorticoids, such as dexamethasone, in nanoparticles (NPs) faces two main issues: a low drug loading and the destabilization of the nanoparticle suspension due to drug crystallization. Here, we successfully formulated a prodrug of dexamethasone, dexamethasone palmitate (DXP), into nanoparticles stabilized by the sole presence of distearoyl- sn-glycero-3-phosphoethanolamine- N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG₂₀₀₀). Two formulation processes, nanoprecipitation and emulsion-evaporation, allowed the formation of stable nanoparticles. By adjusting the drug/lipid ratio and the DXP concentration, nanoparticles of DXP (DXP-NPs) with a size between 130 and 300 nm can be obtained. Owing to the presence of DSPE-PEG₂₀₀₀, a high drug entrapment efficiency of 98% w/w was reached for both processes, corresponding to a very high equivalent dexamethasone drug loading of around 50% w/w in the absence of crystallization upon storage at 4 °C. The anti-inflammatory activity of DXP-NPs was preserved when incubated with macrophages activated with lipopolysaccharide. Pharmacokinetics parameters were evaluated after intravenous (IV) injection of DXP-NPs to healthy mice. The release of DXM from DXP-NPs in plasma was clearly controlled up to 18 h compared with the free drug, which was rapidly eliminated from plasma after administration. In conclusion, a novel type of nanoparticle combining the advantages of prodrugs and nanoparticles was designed, easy to produce with a high loading efficiency and leading to modified pharmacokinetics and tissue distribution after IV administration.