Optimization of Extended-Release ZL-004 Nanosuspensions for In Vivo Pharmacokinetic Study to Enhance Low Solubility and Compliance

Abstract

ZL-004, a promising small molecule that increases white blood cell counts, was developed for extended-release nanosuspensions to improve low solubility and compliance of patients. In vivo pharmacokinetic studies of nanosuspensions with different particle sizes and administration volumes were conducted. Unexpectedly, Cmax of NS-PC-L (1156 nm) was 1.3 fold higher than NS-PB-L (836 nm), and area under plasma concentration-time curve (AUC) was similar. It suggested that in vivo behavior of nanosuspensions was influenced significantly by the original dissolved drug, which did not only rely on the particle size but also the amount of the free stabilizers. In addition, smaller administration volume (0.1 mL) achieved significantly lower Cmax and AUC than the higher volume (0.5 mL), due to the reduced amount of dissolved drug. DSC and XPRD demonstrated that the crystal forms of nanosuspensions prepared by the precipitation method and high-pressure homogenization were similar; therefore, in vivo behaviors did not show significant differences. An additional 0.15% PEG 4000 enhanced the redispersity and maintained the particle size for 3 months. Finally, a nanosuspensions with the desired initial release was achieved, which lasted approximately 32 days steadily after a single dose. AUC and t1/2 were 161.2 fold and 22.9 fold higher than oral administration.