Spray-dried polymeric nanoparticles for enhanced vodobatinib oral dissolution kinetics: formulation design and effects of hydrophobic co-core.

Vodobatinib, a third-generation tyrosine kinase inhibitor, exhibits limited oral bioavailability in its crystalline form, necessitating intensive dosing regimens. Here, we sought to improve the oral dissolution kinetics of vodobatinib through the development of an amorphous formulation. Flash NanoPrecipitation, a scalable antisolvent precipitation technique, has previously been employed to formulate nanocarriers with amorphous cores for strongly hydrophobic small molecules. Vodobatinib is insufficiently hydrophobic for encapsulation by this route, so co-encapsulation of vodobatinib with one of two hydrophobic co-cores, carnauba wax or vitamin E acetate, via Flash NanoPrecipitation is explored. The effects of drug loading, hydrophobic co-core physicochemistry, and weight fraction on formulation characteristics and performance are examined. Following Flash NanoPrecipitation, all nanocarrier suspensions were spray dried using a 1:1 nanocarrier:matrix former mass ratio to yield water-dispersible powders. The dried nanocarriers were evaluated for crystalline content, dissolution kinetics, and dispersibility in water. Vodobatinib-carnauba wax nanocarriers (40 wt% drug in the dried powder) exhibited the smallest size increase, 10%, upon resuspension of all formulations tested. Vodobatinib-vitamin E acetate nanocarriers exhibited more aggregation during drying but nevertheless exhibited a >50% larger area under the curve compared to vodobatinib-carnauba wax nanocarriers in vitro at equal drug loadings. This difference is attributed to crystallinity: vodobatinib-carnauba wax nanocarriers were found to contain crystalline vodobatinib and carnauba wax, while vodobatinib-vitamin E acetate nanocarriers exhibited predominately amorphous character. The use of a non-crystalline hydrophobic co-core was therefore the superior option for driving vodobatinib precipitation into nanocarriers with improved dissolution kinetics, despite a larger nanocarrier size increase during spray drying.