Preparation and evaluation of biodegradable rifampicin microparticles using supercritical fluid technique for pulmonary delivery

Abstract

It is of interest to apply a supercritical fluid technology for production of inhalable biodegradable microparticles of rifampicin. The polyhydroxy acids[poly(DL-lactide-co-glvcolide) copolymer composition 50:50 (PLGA), poly(DL-lactide)(DL-PLA), and poly(L-lactide)(L-PLA)] were used for preparation of drug-loaded microparticles. The solutions of rifampicin and polymer in methylene chloride at various rations were sprayed into supercritical carbon dioxide. The effect of the type and content of polymer, operating pressure, temperature, solution concentration and feed rate of solution on the characteristics of products were investigated. With 50-100% polymer content of DL-PLA and PLGA, polymer or polymer-drug film occurred. The DL-PLA and PLGA microparticles of 20-40% polymer content had volumetric mean diameter larger than 18 um and exhibited irregular shape particles forming large and porous agglomerates. The spherical drug loaded microparticles of L-PLA polymer was formed at high polymer content (70-100%). The microparticles prepared using 60% L-PLA polymer content was in spherical and irregular shapes. The shape of L-PLA microparticles became content was in spherical and irregular shapes. The shape of L-PLA microparticles became more irregular with decreasing polymer content. The microparticles prepared from 60% L-PLA and 40% rifampicin had good drug loading (23.30%) and a mean size of 4.07 µm but their release of drug was rather rapid. The microparticles prepared from 70% L-PLA and 30% rifampicin was the preferred formula because it had good drug loading (16.33%) with mean of 3.40 µm and showed sustained release property throughout 24 hours. The microparticles prepared from 80% L-PLA and 20% rifampicin had low drug loading (8.13%) with mean size of 3.37 µm and their releases of drug was rather slow. The mass medium aerodynamic diameter of the microparticles prepared from 70% L-PLA and 30% rifampicin with lactose (< 45 µm) in 1:2 ratio and with lactose (45-90 µm) in 1:2 ratio were 4.86 µm and 4.29 µm, respectively. L-PLA rifampicin loaded microparticles prepared by supercritical anti-solvent (SAS) process was of a suitable size to be used in dry powder inhaler formulation for pulmonary delivery. SAS process showed that no decomposition of rifampicin occurred during the processing. The analysis from XRD, FTIR and DSC indicated that processed rifampicin produced by SAS technique was not corresponding to that of rifampicin in the previous reports. Not only the molecular weight of polymer but also the source of polymer influenced on the characteristics of microparticles. The bactericidal efficacy of L-PLA rifampicin loaded microparticles produced by SAS technique against Mycobacterium Tuberculosis was similar to that of unprocessed rifampicin.