Development of a Bedaquiline–Rifampicin Co-Amorphous Drug-Drug Delivery System for Tuberculosis Treatment

Tuberculosis remains a major cause of mortality globally. Treatment of tuberculosis requires a long duration with multiple drug regimen. Unfortunately, tuberculosis drug resistance is emerging, resulting in a treatment failure rate of 14% in new cases. Bedaquiline, a poorly soluble second-line drug is used to treat multidrug-resistant tuberculosis in combination with first-line anti-tuberculosis drugs. Bedaquiline is often ad-ministered with rifampicin, as this combination has demonstrated additive intracellular bactericidal and faster onset of action compared to bedaquiline monotherapy. However, co-administration with rifampicin has been reported to increase bedaquiline clearance, reducing concentration of bedaquiline in the blood by up to 25%. There is a need for alternative pharmaceutical formulations to enhance bedaquiline bioavailability and treatment success of tuberculosis. Co-amorphous drug delivery systems have the potential to improve the water solubility and bioavailability of poorly soluble drugs. In an aim to enhance the solubility of bedaquiline when co-administered with rifampicin, we have prepared co-amorphous systems of rifampicin and bedaquiline fumarate. First, miscibility of the components was assessed using Hansen solubility parameters. Then, the solid co-amorphous drug was prepared by fast solvent evaporation, and characterized using PXRD, TGA-DSC, FTIR, dissolution rate, and accelerated stability study. Results show that the co-amorphous form exhibited better dissolution for bedaquiline without compromising rifampicin dissolution. Furthermore, the co-amorphous product remained stable under stress conditions for 30 days. These findings suggest that co-amorphous systems of rifampicin and bedaquiline fumarate may represent a viable strategy to improve treatment outcomes for patients with multidrug-resistant tuberculosis treated with these drugs and decrease pill burden.