Inhalable solid lipid nanoparticles of cyclosporine A for prolonged pulmonary exposure: nano-in-micro particles...

This study aimed to achieve prolonged pulmonary exposure of cyclosporine A (CsA) by developing an inhalable powder of solid lipid nanoparticles (SLN). The fine droplet drying (FDD) process, a powderization technique employing printing technologies, was used to fabricate uniform spherical particles with a narrow size distribution. The FDD process could prepare mannitol-based nano-in-microparticles of CsA-loaded SLN (SLN/CsA-FDD) with good redispersibility of embedded SLN/CsA. Compared to conventional spray-dried powders, SLN/CsA-FDD exhibited better aerosolization properties, with a fine particle fraction of 45.7 ±2.65%, possibly due to the improved morphological uniformity of the microparticles. The results highlight that the FDD process might contribute to the precise control of particle properties and aerodynamic behavior of respirable powders. In simulated lung fluid, SLN/CsA-FDD exhibited sustained release of CsA with a minimal initial burst, whereas nanosized CsA without a lipid carrier (nCsA) rapidly dissolved. After the intratracheal administration of SLN/CsA-FDD (100 µg-CsA/rat), the amount of CsA in the lung tissue at 3 h after the administration was 19-fold higher than that of nCsA, whereas systemic exposure was approximately 100 times lower than that of the orally administered CsA formulation at the nephrotoxic dose (10 mg-CsA/kg). These findings suggest that a dry powder inhaler based on SLN-embedded microparticles might be an effective approach for the non-systemic pulmonary delivery of CsA with prolonged pharmacological action.