Date of Award

2010

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Sally-Ann Cryan

Keywords

Lung Diseases

Abstract

Traditional formulations for pulmonary drug delivery mainly focused on two approaches: (i) Dissolving or suspending the drug in a solvent or propellant to produce liquid aerosols or (ii) Blending drug particulates with dry carrier particles typically composed of sugars. Although effective for localised delivery of small drug molecules, these methods did not meet the complex formulation and delivery challenges posed by the newer biotechnology-derived medicines. One of the many avenues being explored to overcome these issues is the use of novel controlled drug release technologies. While such systems are available in the market for the oral and the parenteral routes, lung equivalent models remain elusive. If developed and optimised, these carrier-based formulations have the potential to not only provide controlled drug release, but also offer other advantages such as increased drug penetration to the distal parts of the lung, prolonged residence time of the drug in situ, and improved in vivo drug stability. While a number of biodegradable polymers have been studied for drug delivery to the lungs, little comparative data on the aerodynamic properties or toxicity and immunogenic potential of these polymers is available to allow formulation scientists to assess their usefulness for particular applications, e.g. local versus systemic delivery. In the present study, a range of commonly available polymers was used to prepare inhalable aerosol particles. A comparative evaluation of these particles was performed to judge their suitability as carriers for local or systemic delivery of proteins in the lungs (Chapters 2 and 3). As drug transport across the respiratory epithelium can also be an issue, various permeation enhancers were also screened for their effectiveness in promoting the absorption of a model protein (Chapter 4). Certain polymers showed particular promise for specfi protein delivery needs in the lungs, such as HPC to improve flow properties and sodium hyaluronate, alginate and chitosan for controlled drug release. In general, the polysaccharides showed no in vitro toxicity and immunogenicity as compared to the proteins (gelatin and ovalbumin) or the synthetic polymer, Poly (lactide-co-glycolide). Using a cell-based screening method, the transport of the model protein, parathyroid hormone (PTH) in the presence of permeation enhancers was found to be formulation dependent. While solutions containing sodium taurocholate (STC) and poly-L-arginine showed increased PTH transport, no difference in transport levels were observed when the formulations were administered as a dry powder (Chapter 4). Spray drying, in general, compromised the stability and bioactivity of PTH. Due to their surfactant-like properties, the inclusion of STC and sodium dioctyl sulfosuccinate in the formulations improved the stability of PTH against spray drying induced stresses (Chapter 4).

Bioresponsive 'smart' polymers that respond to environmental stimuli such as the presence of enzymes were explored in the next two chapters. The aim was to develop microparticles degradable by the enzyme elastase as potential drug carriers to treat lung diseases such as emphysema and Chronic Obstructive Pulmonary Disease (COPD) associated with high levels of this enzyme. Two novel technologies were developed: 1) a system based on natural polymers consisting of an interpenetrating network of a protein (elastin) and a polysaccharide (alginate) (Chapter 5) and 2) a synthetic polymer-based system consisting of a crosslinked network of polyethylene glycol (PEG) with elastase sensitive peptide sequences inserted in the backbone (Chapter 6).

Although the elastin-alginate system showed favourable properties, including high drug encapsulation, good aerosolisation performance and no cytotoxicity, the use of animal-derived excipients, non-specific drug release and possible degradation by other enzymes are limitations to be overcome (Chapter 5). The PEG-based systems have a peptide sequence in the network that can be cleaved only by the target enzyme (in this case, elastase). These systems are therefore tailored to display high enzyme specificity (Chapter 6). Further work on improving the drug loading and aerosolisabilly of these systems is however, required. The use of relatively safe excipients and mild particle fabrication conditions coupled with high enzyme specificity makes the PEG-based systems better suited as enzyme targeted drug delivery systems.

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Comments

A thesis submitted to the National University of Ireland in 2010 for the degree of Doctor of Philosophy 2010.