Effective control of tuberculosis (TB) currently requires the use of long and cumbersome chemotherapeutic regimens. In order to design effective regimens that can be administered intermittently (i.e. once-weekly or less often) by inhalation or intravenous injection, novel methods of sustained drug delivery need to be rigorously explored. Recent advances in polymeric matrix-like particulate systems can provide the foundation needed to significantly improve the delivery of antituberculosis drugs. This application proposes to first develop, micropartices encapsulating various combinations of first-line anti-TB drugs using the newly developed poly(ether-anhydride) polymer and to analyze their physicochemical properties. Following that, extensive pharmacokinetic (PK) studies will be conducted in mice to determine the optimal dosage and frequency of administration of the prepared drug-loaded microparticles. Microparticle design parameters will be optimized as indicated by PK analysis. In the final phase, the applicant will rigorously determine the efficacy of intermittent poly(ether-anhydride) microparticle-based combinations in a well-defined, highly prognostic murine model of active tuberculosis designed to mimic the treatment of human disease.
| Rosenthal, Ian M; Zhang, Ming; Williams, Kathy N et al. (2007) Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med 4:e344 |
| Rosenthal, Ian M; Williams, Kathy; Tyagi, Sandeep et al. (2006) Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. Am J Respir Crit Care Med 174:94-101 |
