Design of liposomal aerosols for improved delivery of rifampicin to alveolar macrophages

The present study was aimed at preparation, characterization, and performance evaluation of rifampicin-loaded aerosolized liposomes for their selective presentation to alveolar macrophages, that being the most dense site of tuberculosis infection. Egg phosphatidylcholine (PC)- and cholesterol (Chol)-based liposomes were modified by imparting negative charge (using dicetylphosphate, DCP) or by coating them with alveolar macrophage-specific ligands (maleylated bovine serum albumin, MBSA; and O-steroyl amylopectin, O-SAP). The prepared formulations were characterized in vitro for vesicle morphology, mean vesicle size, and percent drug entrapment. Pressurized packed systems based on preformed liposomal formulations in chlorofluorocarbon aerosol propellants were prepared. In vitro airway penetration efficiency of the liposomal aerosols was determined by percent dose reaching the base of the lung, it was recorded 1.5-1.8 times higher as compared to plain drug solution-based aerosol. Percent viability of Mycobacterium smegmatis inside macrophages (in vitro) after administration of drug (in vivo) was in the range of 7-11% in the case of ligand-anchored liposomal aerosols, while it was recorded to be 45.7 and 31.6% in case of plain drug and plain neutral liposomal aerosol (based on PC:Chol)-treated macrophages. Results suggest the preferential accumulation of MBSA- and O-SAP-coated formulations in the lung macrophages, which was further reflected in the periodically monitored in vivo tissue distribution studies. Higher lung drug concentration was recorded in case of ligand-anchored liposomal aerosols and negatively charged liposomal aerosols (based on PC:Chol:DCP) as compared to plain drug and plain liposome-based aerosols. The drug was estimated in the lung in high concentration even after 24 h. The drug localization index calculated after 6 h was nearly 1.4- and 3.5-fold, respectively, for both ligand-appended liposome-based systems as compared to negatively charged and plain neutral liposome-based aerosolized systems. These results suggest that the ligand-anchored liposomal aerosols are not only effective in rapid attainment of high-drug concentration in lung with high population of alveolar macrophages but also maintain the same over prolonged period of time. The significance of targeting potential of the developed systems was established. (C) 2003 Elsevier B.V. All rights reserved.