Highly Drug-Loaded Nanoaggregate Microparticles for Pulmonary Delivery of Cyclosporin A

Nanoparticles have the advantages of improving the solubility of poorly water-soluble drugs, facilitating the drug across biological barriers, and reducing macrophage phagocytosis in pulmonary drug delivery. However, nanoparticles have a small aerodynamic particle size, which makes it difficult to achieve optimal deposition when delivered directly to the lungs. Therefore, delivering nanoparticles to the lungs effectively has become a popular research topic.

Nanoaggregate microparticles were used as a pulmonary drug delivery strategy for the improvement of the bioavailability of cyclosporine A (CsA). The nanoaggregate microparticles were prepared with polyvinyl pyrrolidone (PVP) as the excipient by combining the anti-solvent method and spray drying process. The physicochemical properties, aerodynamic properties, in vivo pharmacokinetics and inhalation toxicity of nanoaggregate microparticles were systematically evaluated.

The optimal nanoparticles exhibited mainly spherical shapes with the particle size and zeta potential of 180.52 nm and -19.8 mV. The nanoaggregate microparticles exhibited irregular shapes with the particle sizes of less than 1.6 µm and drug loading (DL) values higher than 70%. Formulation NM-2 as the optimal nanoaggregate microparticles was suitable for pulmonary drug delivery and probably deposited in the bronchiole and alveolar region, with FPF and MMAD values of 89.62% and 1.74 μm. In addition, inhaled NM-2 had C _max and AUC_0-∞ values approximately 1.7-fold and 1.8-fold higher than oral cyclosporine soft capsules (Neoral^®). The inhalation toxicity study suggested that pulmonary delivery of NM-2 did not result in lung function damage, inflammatory responses, or tissue lesions.

The novel nanoaggregate microparticles for pulmonary drug delivery could effectively enhance the relative bioavailability of CsA and had great potential for clinical application.