Dry-Powder Inhaler Formulation of Rifampicin: An Improved Targeted Delivery System for Alveolar Tuberculosis.

Abstract

The delivery of antitubercular drugs through direct lung targeting can lead to reduction in the dose as well as side effects of the drug. In the present investigation, carrier (lactose)-based dry-powder inhaler of rifampicin was prepared to achieve direct targeting of the drug into the lungs. The dry powder inhaler formulation was prepared by simply mixing micronized rifampicin with coarse and fine lactose preblend. Preliminary blends of the drug were prepared with various lactose grades (Inhalac®, Respitose,® and Lactohale®). Rotahaler® and Revolizer® were evaluated for the performance. The 32 factorial design was used to optimize the amount of drug (X1) and amount of fine lactose (X2). In vitro lung deposition was carried out using Andersen Cascade Impactor. The % cell viability studies of the formulation were carried out using murine macrophage J774 cell lines. The in vivo toxicity was determined using histopathology. Further in vivo pulmonary pharmacokinetics of the developed dry-powder inhaler (DPI) formulation was carried out in comparison to the marketed formulation in the rat lungs. Based on preliminary trials, Inhalac 230 and Inhalac 400 were selected as coarse and fine lactose grades, respectively. Rotahaler® exhibited better DPI performance with the evaluated drug blends. The mass median aerodynamic diameter (MMAD) was in the range of 4.3-5.8 μm with the maximum fine particle fraction of 28.9%. The formulation exhibited negligible cytotoxicity on macrophage J774 cell lines with about 75%-80% cell viability at 6- and 12-hour exposure. The histopathological examination revealed negligible toxicity of DPI in comparison to the marketed formulation. The in vivo pulmonary pharmacokinetic studies of the DPI formulation in rats showed higher drug concentration in lungs in comparison to the marketed formulation. The carrier-mediated dry-powder inhaler of rifampicin could serve as an improved and efficient system for local targeting of drugs into the lungs.