Correlation of drug release with pulmonary drug absorption profiles for nebulizable liposomal formulations

Abstract Liposomes have attracted extensive attention as inhalative drug delivery vehicles. The preparation of tailored liposomal formulations (i.e. nebulization stability and controlled drug release profiles) would facilitate new perspectives for the treatment of pulmonary diseases. 5(6)-Carboxyfluorescein (CF)-loaded submicron liposomal formulations with varying phase transition temperatures were prepared from lipid blends in different molar ratios. Their physicochemical properties, in vitro dye release, stability to nebulization (Aeroneb® Pro) and ex vivo pulmonary dye absorption and distribution characteristics were investigated. Phase transitions of liposomes were adjusted below and above body temperature (32.9–55.2 °C). The amount of CF released from liposomes in vitro correlated well with their membrane fluidity. An increase in phase transition temperature resulted in an extended dye release profile. All formulations revealed aerodynamic particle sizes of ∼4 μm with remarkable stability when nebulized by vibrating-mesh technology (percentage of encapsulated model drug ∼80%). Analogous to the release results observed in vitro , liposomal formulations revealing phase transitions above body temperature displayed an increased pulmonary CF retention in an ex vivo lung model. Consequently, an in vitro – ex vivo correlation was established, which demonstrated an excellent agreement of the dye release results with the absorption profiles observed in the biological system ( R 2  ⩾ 0.91). Overall, the concept of liposomal “phase transition release” is promising for controlled pulmonary drug delivery applications. The ex vivo technique enables a reliable determination of lung-specific pharmacokinetics of drug delivery vehicles, which enhances tailored carrier preparation and testing during early formulation development.