Nano-in-Micro POxylated Polyurea Dendrimers and Chitosan Dry Powder Formulations for Pulmonary Delivery

• Published in: Particle & particle systems characterization 2016-11, Vol.33 (11), p.851-858
• Main Authors: Restani, Rita B., Silva, A. Sofia, Pires, Rita F., Cabral, Renato, Correia, Ilídio J., Casimiro, Teresa, Bonifácio, Vasco D. B., Aguiar-Ricardo, Ana
• Format: Article
• Language: English
• Subjects: Aerodynamics; Biocompatibility; Chitosan; Drug delivery systems; dry powder formulations; Drying; Lungs; Mathematical models; Nanostructure; polyurea dendrimers; pulmonary delivery; spray drying; supercritical carbon dioxide
• ISSN: 0934-0866; 1521-4117
• DOI: 10.1002/ppsc.201600123

Pulmonary administration offers excellent advantages over conventional drug delivery routes, including increasing therapeutics bioavailability, and avoiding long‐term safety issues. Formulations of nano‐in‐micro dry powders for lung delivery are engineered using (S)‐ibuprofen as a model drug. These biodegradable formulations comprise nanoparticles of drug‐loaded POxylated polyurea dendrimers coated with chitosan using supercritical‐fluid‐assisted spray drying. The formulations are characterized in terms of morphology, particle‐size distribution, in vitro aerodynamic particle pulmonary distribution, and glutathione‐S‐transferase assay. It is demonstrated that ibuprofen‐loaded nanoparticles can be successfully incorporated into microspheres with adequate aerodynamic properties, mass median aerodynamic diameter (1.86–3.83 μm), and fine particle fraction (28%–45%), for deposition into the deep lung. The (S)‐ibuprofen dry powder formulations show enhanced solubility, high swelling behavior and a sustained drug release at physiologic pH. Also, POxylated polyureas decrease the (S)‐ibuprofen toxic effect on cancer cellular growth. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS) assays show no significant cytotoxicity on the metabolic activity of human lung adenocarcinoma ephithelial (A549) cell line for the lowest concentration (1 × 10−3 m), even for longer periods of contact with the cells (up to 120 h), and in the normal human dermal fibroblasts cell line the toxic effect is also reduced. Nano‐in‐micro dry powder formulations with high swelling rate enable efficient drug delivery to the deep lung. Nontoxic (S)‐ibuprofen‐loaded nanoparticles are incorporated in chitosan microparticles using supercritical‐fluid‐assisted spray drying. The biocompatible and biodegradable formulations show high cellular uptake and promising physical and chemical properties, suitable for smart delivery through the lungs for both systemic and local delivery.