ABSTRACT
Tiny nanoparticles of dexamethasone palmitate (DXP) were designed as transparent suspensions for intravitreal administration to treat age-related macular degeneration (AMD). The influence of three surfactants (PEG-40-stearate and Pluronic block copolymers F68 and F127) on nanoparticles size and stability was investigated and led to an optimal formulation based on Pluronic F127 stabilizing DXP nanoparticles. Size measurements and TEM revealed tiny nanoparticles (around 35 nm) with a low opacity, compatible with further intravitreal injection. X-Ray powder diffraction (XRPD) and transmission electronic microscopy (TEM) performed on freeze-dried samples showed that DXP nanoparticles were rather monodisperse and amorphous. The efficacy of DXP nanoparticles was assessed in vivo on pigmented rabbits with unilateral intravitreal injections. After breakdown of the blood-retinal barrier (BRB) induced by injection of rhVEGF165 with carrier protein, DXP nanoparticles induced a restoration of the BRB 1 month after their intravitreal injection. However, their efficacy was limited in time most probably by clearance of DXP nanoparticles after 2 months due to their small size.
Subject(s)
Dexamethasone , Nanoparticles , Animals , Glucocorticoids , Intravitreal Injections , Palmitates , RabbitsABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/pharmacokinetics , Dexamethasone/pharmacokinetics , Drug Compounding/methods , Drug Delivery Systems/methods , Nanoparticles/chemistry , Prodrugs/pharmacokinetics , Animals , Anti-Inflammatory Agents/chemistry , Cell Survival/drug effects , Crystallization , Dexamethasone/administration & dosage , Dexamethasone/chemistry , Drug Liberation , Drug Stability , Injections, Intravenous , Male , Mice , Mice, Inbred DBA , Nanoparticles/administration & dosage , Particle Size , Phosphatidylethanolamines/administration & dosage , Phosphatidylethanolamines/chemistry , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/chemistry , Prodrugs/administration & dosage , Prodrugs/chemistry , RAW 264.7 Cells , Tissue DistributionABSTRACT
{Mo(132)} Keplerate anion reacts with tellurites to give a soluble precursor to produce in hydrothermal conditions single-phase M1 MoVTeO light-alkanes oxidation catalyst. Characterization of this Te-containing intermediate by single-crystal X-ray diffraction, (125)Te NMR, UV-visible and redox titration reveals a molybdotellurite anion as a crown-capped Keggin derivative.
