Development of highly concentrated bedaquiline suspensions for usage as long-acting injectable formulations

Tuberculosis (TB) remains a global health problem with an enormous treatment burden and poor treatment adherence, contributing to the emergence of drug resistance. This study investigated the potential of formulating a highly concentrated long-acting injectable (LAI) formulation with bedaquiline fumarate, which could potentially be used as a novel long-term treatment strategy against TB and the prevention of drug resistance. Using wet media milling, micro- and nanosuspensions of bedaquiline fumarate were prepared and evaluated to determine a suitable stabilizer, drug loading capacity, short- and long-term particle size stability, and pharmacokinetic behavior in rats. The stability study revealed a relatively small, but continuous particle size growth over a six-month period when stabilized with 4 % (w/v) polysorbate 20, most pronounced at 40 °C storage. The bedaquiline fumarate salt exhibited superior drug loading capacity compared to the free base form of the compound. When the free base was used in the suspension a viscous paste was obtained at concentrations of 300 mg in 1 mL milling media, whereas the suspensions containing the fumarate salt remained an easy flowing liquid at concentrations as high as 969.5 mg in 1 mL milling media (equivalent to 800 mg free base). Female Spraque-Dawley rats were injected intramuscular with 0.1 mL of one of three formulations, which were identical in composition but differed in particle size distribution. The formulations had mean particle sizes (D 50 value) of 0.391 µm, 3.15 µm, 7.80 µm. Particle size displayed a central role in the initial drug release kinetics with smaller particle size profiles yielding higher plasma concentrations. Prolonged plasma concentrations were observed for all three formulations over the 3-months in vivo study. A relatively high sustained plasma concentration of bedaquiline was observed in the animals at the termination of the study suggesting that the prolonged effect continued beyond the investigated three-month period. These data supported the feasibility of LAI bedaquiline formulations as a treatment option for three months with the potential for an even longer duration. However, further studies are needed to optimize the formulations physical stability.