Optimization of PEGylated nanoemulsions for improved pharmacokinetics of BCS class II compounds

Abstract The objective of the study was the optimization of nanoemulsion formulations to prevent their rapid systemic clearance after intravenous administration. An amphiphilic PEG derivative DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(polyethylene glycol) with different chain lengths and concentration was used as a nanoemulsion droplet surface modifier. The danazol loading in all nanoemulsions was kept on the same level of ∼2 mg/mL. In the present investigation, PEGylated and non-PEGylated nanoemulsions were compared in vitro phagocytosis by incubating with lung macrophages and in vivo after intravenous administration in rats. Danazol-containing nanoemulsions (NE) modified with various PEG chain lengths (2000-10 000) and concentrations (3-12 mg/mL) were prepared and characterized. Nanoemulsion droplets were reproducibly obtained in the size range of 213-340 nm. The non-PEGylated NE had the surface charge of −25.4 mV. This absolute charge value decreased with increasing chain length and concentration. With increase in chain length and density the macrophage uptake decreased which could be due to decrease in surface charge and hydrophilicity of droplets. The greatest shielding of the NE droplets was reached with DSPE-PEG5000 at the concentration of 6 mg/mL where the surface charge changed to −1.27 mV. Following intravenous administration a maximum danazol exposure (401 ± 68.2 h ng/mL) was observed with the lowest clearance rate (5.06 ± 0.95 L/h/kg) from 6 mg/mL DSPE-PEG5000 nanoemulsion. PEG5000 and PEG10000 altered the pharmacokinetic of danazol by decreasing clearance and volume of distribution which is likely explained by the presence of hydrophilic shields around the droplets that prevent their rapid systemic clearance and tissue partitioning.