Inhalable microparticulate carriers for the treatment of pulmonary tuberculosis

Purpose. To produce liposomes and poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) containing second-line antitubercular drugs, namely capreomycin sulfate (C), ofloxacin (Ofx) and cycloserine (Cs) for pulmonary delivery. Methods. PLGA MS containing C and Cs and Ofx were prepared by spray-drying of S/O dispersion and drug-polymer solutions. C and Ofx were dissolved in water and dispersed in the organic phase, while Cs and Ofx were spray-dried as dissolved in different water-organic mixtures. Liposomes were produced by a freeze-thawing method by using a mixture of phosphatidylcholines. A method concerning spray-drying of a nanodispersion of the drugs in a lipid solution was also attempted. Liposomes and MS preparations were characterized for particle size by SPOS and dynamic light scattering, morphology by SEM and drug content by HPLC methods. The respirable fraction was evaluated by a twin stage impinger. Macrophage uptake was investigated over time by microscopy observation, co-incubating NR8383 murine alveolar macrophages with blank and loaded liposomes and MS. Results. C loaded PLGA MS had better features when the S/O method was employed, while Cs and Ofx loaded MS were obtained by direct spray-drying of polymer-drug organic solutions. Such particles possessed a volume mean diameter of about 5 μm and irregular shape and surface. Drug content were similar for the two methods (5-10%, w/w), but efficiencies reached about 60- 70%. Liposomes were regular in shape and reached about 50% encapsulation efficiency. The respirable fraction resulted around 70%. The uptake study revealed that a complete uptake occurred over about 3 hours and initial activation of macrophages was fast with no significant differences among preparations. Conclusion. These results suggest that the developed loaded liposomes and PLGA MS, although requiring some improvements, possess potential as pulmonary delivery systems of second-line antitubercular drugs.