Rational Design and Relative Bioperformance of High Drug Load Grazoprevir Amorphous Nanoparticle Formulations

This work looked to determine if a rationally designed amorphous nanoparticle formulation of Grazoprevir (GZP) could provide a benefit over its amorphous dispersion formulation by either enabling superior bioperformance or accessing higher drug loadings. GZP-ethylcellulose nanoparticles were created at two different drug loadings (33 and 66%) by high pressure homogenization. The GZP-ethylcellulose nanoparticles could rapidly release the drug, but neither system could match the extent of release of the amorphous dispersion. This limited extent of release lead to the GZP-ethylcellulose nanoparticle formulations faileding to present equivalent performance as the amorphous solid dispersion formulation in dog PK studies. Two GZP- HPMCAS-L nanoparticle formulations (50/50 GZP/HPMCAS-L and 45/45/10 GZP/HPMCAS-L/SLS) were made by a coprecipiation process followed by spray drying. These materials were analyzed and found to be composed of nanoparticles of pure amorphous drug which is stabilized by the excipients.This was confirmed by characterization techniques such as ultracentrifugation and FIB-SEM. Bio-relevant dissolution experiments demonstrated that both formulations could match the extent of drug release of the GZP amorphous dispersion formulation, but only the 45/45/10 GZP/HPMCAS-L/SLS could match the rate of release of the amorphous dispersion. The 45/45/10 GZP/HPMCAS-L/SLS nanoparticle formulation and the amorphous dispersion formulation were evaluated in a dog PK study, with the 45/45/10 GZP/HPMCAS-L/SLS formulation provided equivalent PK. These results highlight the potential benefit of directly designed nanoparticle formulations to maximize formulation bioperformance at higher drug loadings or to enable smaller dosage forms.