Development of inhalable macromolecule delivery for local treatment of pulmonary diseases
Abstract
Inhalation is a promising route of drug administration for local treatment of pulmonary diseases. Among various inhalational drug delivery systems, inhalable dry powder is particularly attractive for delivery of macromolecules such as proteins or gene therapeutics because it avoids the use of propellants or dispersants that may negatively influence their stability. My thesis research concerns the development of dry powder inhalable (DPI) formulations of such macromolecule using spray drying technique. First of all, I aimed to develop a DPI formulation of non-viral gene delivery nanoparticles (NPs) for treatment of cystic fibrosis (CF). The presence of tenacious sputum covering CF epithelial cells represents both physical and chemical barriers for drug delivery. To overcome the sputum barrier, non-viral vector NPs were embedded in mannitol microparticles. Mannitol helped the passage of included NPs by rapidly dissolving in sputum and causing local influx of water around NPs. However, this passage improvement did not translate to improvement of gene delivery across the sputum layer, due to the aggregation of NPs in anionic environment of CF sputum. The chemical stability of the non viral vector has to be improved significantly in order to overcome sputum barrier and eventually find proper gene therapeutics for CF patient. Additionally, another DPI formulation of basic fibroblast growth factor (bFGF), a promising agent for therapy of asthma and chronic obstructive pulmonary disease, was developed. The formulation of bFGF DPI is challenging due to the poor stability of this protein. A DPI formulation of stable bFGF was produced by spray drying an aqueous solution of lactose and leucine as excipients. Finally, I investigated the mechanism by which leucine enhances dispersion of spray-dried particles to establish selection criteria for dispersion enhancers
Degree
Ph.D.
Advisors
Yeo, Purdue University.
Subject Area
Pharmaceutical sciences
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