Characterization of sustained-release formulations of inhaled rifampin for tuberculosis therapy

Tuberculosis (TB) is an infectious pulmonary disease and is considered to be the primary cause of death due to a single microorganism. Although current therapeutic interventions for the treatment of TB are effective, they are associated with a variety of medical complications such as rash, fever, gastrointestinal disturbances, and nervous system related symptoms. These complications can be explained, in part, on the basis of higher systemic exposure of the drugs used to treat TB. One of the ways to increase the efficacy and duration of local effect is by administering the sustained release form of the drug. This would lead to eradication of the active bacteria in the lung macrophages and simultaneously reduce the drugs' systemic side effects.; This study proposed a strategy to improve the effectiveness in TB therapy by providing sustained inhalation drug delivery systems. Rifampin, one of the most widely used drugs for TB therapy, was chosen as a model drug. Two polymer based systems, nanothin coatings of polymer onto drug powder by Pulsed Laser Deposition (PLD) and conventional polymer based microspheres prepared by a standard spray-drying method were developed. The formulations were prepared using poly lactic acid (PLA) and its copolymer, poly lactic co-glycolic acid (PLGA). The PLD-coated formulations were prepared under 30 min-coating time while the spray-drying formulations were prepared using various amounts of polymers (10–95%). The chemical changes of the polymer after pulsed-laser ablation and spray-drying was investigated. Ablation of polymer by the PLD technique indicated a reduction in molecular weight (M_w) and the appearance of minor degradation products under high-energy density. On the other hand, neither changes in M_w nor the appearance of degradation products was observed after using the spray-drying process, although there was some modification in polymer tacticity. The release characteristics of the formulations, the particle-size distribution and the cytotoxicity in a murine alveolar macrophage cell line were also evaluated. Both preparations showed a reduction in the in vitro drug release although the microspheres were more versatile in controlling the release rate. Both techniques were comparable in the respirable fractions, mass median aerodynamic diameter (MMAD), and the lack of cytotoxicity in the cell culture model. The efficacy of the treatment in the TB-infected macrophages and the pharmacokinetic study of the formulations in rats were also performed. The treatment efficacy was significantly higher for the sustained-release formulation as compared to the free drug. The pharmacokinetic (PK) study showed that although polymer coated drug particles obtained after both coating procedures exhibited sustained drug release, the spray-drying technique was a superior method for prolonging the mean residence time of the drug in the lung.