Efficacy of microencapsulated rifampin in Mycobacterium tuberculosis-infected mice

Rifampin is a first-line drug useful in the treatment of tuberculosis. By u sing biocompatible polymeric excipients of lactide and glycolide copolymers , two microsphere formulations were developed for targeted and sustained de livery of rifampin, with minimal dosing. A small-microsphere formulation, w ith demonstrated ability to inhibit intracellularly replicating Mycobacteri um tuberculosis H37Rv, was tested along with a large-microsphere formulatio n in an infected mouse model. Results revealed that by using a single treat ment of the large-microsphere formulation, it was possible to achieve a sig nificant reduction in M. tuberculosis H37Rv CFUs in the lungs of mice by 26 days postinfection. A combination of small (given as two injections on day 0 and day 7) and large (given as one injection at day 0) rifampin-loaded m icrosphere formulations resulted in significant reductions in CFUs in the l ungs by 26 days, achieving a 1.23 log(10) reduction in CFUs. By comparison, oral treatment with 5, 10, or 20 mg of rifampin/kg of body weight, adminis tered every day, resulted in a reduction of 0.42, 1.7, or 1.8 log(10) units , respectively. Thus the microsphere formulations, administered in one or t wo doses, were able to achieve results in mice similar to those obtained wi th a daily drug regimen within the range of the highest clinically tolerate d dosage in humans. These results demonstrate that microsphere formulations of antimycobacterial drugs such as rifampin can be used for therapy of tub erculosis with minimal dosing.