A preclinical pharmacokinetic modeling approach to the biopharmaceutical characterization of immediate and microsphere-based sustained release pulmonary formulations of rifampicin.

A rifampicin-hydroxypropyl-beta-cyclodextrin (RIF-HPCD) complex solution and two RIF-loaded PLGA microspheres with slow or fast release rates were nebulized into the rat lungs for a comparative biopharmaceutical evaluation. A pharmacokinetic model was applied to model systemic RIF concentrations and to predict the RIF concentrations in the lung epithelial lining fluid (ELF). With intravenous RIF and nebulized RIF-HPCD, plasma profiles and predicted RIF ELF profiles were superimposed indicating that RIF diffused almost instantaneously through the broncho-alveolar barrier. 5h post administration RIF ELF predicted concentrations were in agreement with experimental concentrations determined using the broncho-alveolar lavage (BAL) sampling method. Microsphere formulations resulted in different plasma concentration profiles, demonstrating RIF sustained release. The PK model predicted the ELF concentrations to be much higher with microspheres than with nebulized and IV RIF, over a prolonged time period, which was confirmed by BAL sampling. In conclusion this work demonstrated the benefit of using sustained-release microspheres administered as aerosols to maintain, over a prolonged time period, high levels of pulmonary concentrations of drugs characterized by a rapid absorption through the broncho-alveolar barrier. Moreover, PK modeling was a useful tool to build concentration-versus-time profiles in non-readily accessible ELF compartment and to assess the biopharmaceutical properties of aerosol formulations for lung delivery.

Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery.

The solvent evaporation method with premix membrane homogenization was applied, with class-3 ethyl acetate as organic solvent, to produce narrowly size-distributed rifampicin (RIF)-loaded poly(lactide-co-glycolide) (PLGA) microspheres for sustained lung delivery as aerosol. Microsphere formulations (simple or multiple emulsions, different PLGA and RIF concentrations) and process parameters (transmembrane pressure, SPG membrane pore diameter) were investigated as their effects on RIF content, microsphere size, aerodynamic properties of the freeze-dried powder and in vitro release profiles. Narrowly size distributed microspheres with diameters from 2 to 8 µm, satisfactory RIF contents (from 4.9 to 16.5%), 80% RIF release from 12h to 4 days, and adequate aerodynamic properties were prepared from a multiple emulsion and using SPG membrane pore diameter of 19.9 µm. The premix membrane homogenization appeared to be a rapid and efficient method to prepare monodisperse drug-loaded microspheres suitable for lung delivery as sustained-release microsphere aerosol.

Preparation of rifampicin-loaded PLGA microspheres for lung delivery as aerosol by premix membrane homogenization.

The water-in-oil solvent evaporation method with premix membrane homogenization was investigated to improve productivity of the preparation of narrowly size-distributed poly(lactide-co-glycolide) (PLGA) microspheres for rifampicin lung delivery as dry aerosols. Using ethyl acetate as organic solvent, a coarse oil-in-water emulsion (or premix) was prepared under magnetic stirring and homogenized by extrusion through a Shirasu porous glass (SPG) membrane (5.9 microm porosity). Microspheres were obtained after dilution and solvent evaporation. Formulation parameters investigated were: PLGA concentration, transmembrane pressure and oil:water volume ratio. The optimal formulation parameters were then applied to prepare rifampicin-loaded microspheres. Loaded microspheres were 1.72+/-0.16 microm in diameter with a span of 0.86+/-0.04 and a rifampicin content of 52+/-6 microg/mg microspheres. Release studies in phosphate-buffered saline showed a linear release profile with 40% rifampicin release over 4.5 days. The MMAD of 2.63 microm of freeze-dried microspheres should be suitable for aerosol administration and delivery into the rat lungs by intratracheal insufflation.