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

Yongpeng Huang, Hui Tang, Xiangyan Meng, Dongxin Liu, Yanli Liu, Bo Chen, Zhiyun Zou State Key Laboratory of NBC Protection for Civilian, Beijing, People’s Republic of ChinaCorrespondence: Bo Chen; Zhiyun Zou, Email NBC_BoChen@163.com; zouzhiyun65@163.comIntroduction: 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.Methods: 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.Results: 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 Cmax and AUC0-∞ 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.Conclusion: The novel nanoaggregate microparticles for pulmonary drug delivery could effectively enhance the relative bioavailability of CsA and had great potential for clinical application. Keywords: pulmonary drug delivery, dry powder inhalers, nanoaggregate microparticles, aerosol performance, pharmacodynamic study, inhalation toxicity