Dry Powder Aerosol Nanocomposite Microparticles for the Treatment of Pulmonary Diseases

Abstract

Dry powder aerosols have attracted increasing attention for the treatment of pulmonary diseases due to their capability of providing direct and efficient drug delivery to the lungs. Unfortunately, barriers exist in the implementation of dry powder pulmonary delivery systems, including: (1) dry powder aerosols with aerodynamic diameters smaller than 1 μm will often be exhaled; (2) particles with aerodynamic diameters above 5 μm tend to deposit in the mouth, throat or upper lung mucosa and will then be eliminated due to mucosal clearance mechanisms; and (3) particles larger than 1 μm that deposit in the deep lung area may be cleared from the alveoli via macrophages. Spray-dried nanocomposite microparticles (nCmP), combining the advantages of nanoscale and microscale carriers, can be employed to overcome these issues. Microscale powders facilitate effective deep lung deposition while the embedded nanoscale carriers can provide multiple functions such as the protection of active ingredients from degradation, enhancement of the solubility of drugs, controlled drug release, and reduction of systemic side effects. Several nCmP systems have been developed for various applications, but few comprehensive studies have been completed to illustrate how to effectively engineer optimal nCmP systems with desired properties including: targeted deposition in airways, controlled release of payloads, ability of overcoming physiological barriers, and favorable formulation stability. This dissertation focuses on the development, characterization, and optimization of various dry powder aerosol nanocomposite microparticle systems for the treatment of pulmonary diseases. In the production of nCmP, acetalated dextran (Ac-Dex) nanoparticles loaded with therapeutics are synthesized, suspended in an excipient solution or DI water, and transformed into microscale dry powder microparticles via spray drying. Upon pulmonary administration, the nCmP will deposit on the surface of the mucosal layer of the lungs and decompose into free NP, allowing the nanoparticles to reach the mucus and/or cell epithelium and then release drug(s) at sustained rate. Nanoparticles were prepared using Ac-Dex with different degradation rates to control the drug release profiles. In this work, various therapeutics were encapsulated in nanoparticles, and subsequently nCmP, for applications in the treatment of cystic fibrosis-related lung infections or pulmonary arterial hypertension. The physical properties of the nanoscale carriers in terms of size, size distribution, and surface properties were modified by manipulating the parameters of the nanoparticle preparation process. Dry powder aerosols embedded with nanoparticles were formulated using spray drying. The aerosol performance was optimized by manipulating the composition of feed solution and spray drying parameters.