Development of high-concentration long-acting injectable formulations of TBAJ-587 and TBAJ-876 as an extended...

This study investigated the potential of developing long-acting injectable (LAI) formulations of the next-generation diarylquinoline antibacterial compounds TBAJ-587 and TBAJ-876, which have the potential to impact the tuberculosis (TB) treatment by providing an extended treatment option. The performance of these compounds, formulated as LAIs, were evaluated based on particle size stability, drug loading capacity, and in vivo pharmacokinetics in rats. The data showed that particularly high drug loadings could be obtained in aqueous suspensions using the salt forms of TBAJ-587 and TBAJ-876, with concentrations up to 750 mg/mL TBAJ-587 fumarate and 650 mg/mL TBAJ-876 tartrate, expressed as the equivalent concentration of free base. A long-term stability study of the TBAJ-876 tartrate formulation suggested that a relatively stable suspension was defined when stored at both ambient temperature and at 40 °C. In contrast, the TBAJ-587 fumarate suspension formulation showed significant particle size growth as a function of time, indicating physical instability in the colloidal system. Analysis of both compounds by X-ray powder diffraction (XRPD) revealed no major changes in the crystal structure following milling or after 24 weeks of storage at 40 °C. The in vivo pharmacokinetic study in rats showed that the suspensions containing either TBAJ-587 fumarate or TBAJ-876 tartrate offered a promising LAI option for the prolonged treatment of TB, as all formulations achieved prolonged drug plasma exposure for at least three months following administration.