published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Thesis (Ph. D.)--University of Sydney, 2007. / Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Pharmacy, Faculty of Pharmacy. Includes bibliographical references. Also issued in print.

Thesis: M.S., Massachusetts Institute of Technology, Department of Chemical Engineering, 1975 / Includes bibliographical references. / M.S. / M.S. Massachusetts Institute of Technology, Department of Chemical Engineering

Thesis (Ph. D.)--University of Alberta, 2010. / Title from pdf file main screen (viewed on July 17, 2010). A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, [Department of] Mechanical Engineering, University of Alberta. Includes bibliographical references.

Within the last two decades the consumer market has been deluged with a diversity of aerosol products. The acceptability and utility of these products is reflected by the number found in the household and industry. An antibiotic foam would obviate the necessity of manual application as is the case with the ointment or cream type products. Therefore, there would be less irritation to the already traumatized or infected sites by mechanical, chemical, or bacterial vectors. Thus, the objective of this research will be to systematically develop suitable aerosol foam systems which contain therapeutically effective topical antibiotics with a subsequent evaluation of their properties.

Chan, Ka Man Carmen. / "October 2009." / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 160-165). / Abstracts in English and Chinese. / Table of Contents --- p.I / Acknowledgements --- p.IV / Abstract --- p.V / Abstract (Chinese version) --- p.VIII / List of Figures --- p.X / List of Tables --- p.XVIII / Chapter Chapter One. --- Introduction / Chapter 1.1 --- Pulmonary drug delivery --- p.1 / Chapter 1.2 --- Inhalation drug delivery systems --- p.4 / Chapter 1.3 --- Dry powder inhalation aerosols --- p.5 / Chapter 1.3.1 --- Principle of operation of DPIs --- p.5 / Chapter 1.3.2 --- Aerodynamic diameter --- p.6 / Chapter 1.3.2.1 --- Fine particle fraction --- p.8 / Chapter 1.3.3 --- Dispersibility --- p.8 / Chapter 1.3.4 --- Factors that affect dispersibility --- p.9 / Chapter 1.3.4.1 --- Particle Size --- p.9 / Chapter 1.3.4.2 --- Particle Density and Morphology --- p.10 / Chapter 1.3.4.3 --- Interparticulate interactions一Cohesion and adhesion --- p.11 / Chapter 1.3.4.3.1 --- Surface energetics --- p.11 / Chapter 1.3.4.3.2 --- Effect of hygroscopicity and electrostatic charges --- p.12 / Chapter 1.4 --- Particle formation techniques for DPI formulation --- p.14 / Chapter 1.4.1 --- Spray-drying --- p.14 / Chapter 1.4.2 --- Surface modification --- p.16 / Chapter 1.5 --- Physical characterization --- p.17 / Chapter 1.5.1 --- Laser diffraction --- p.17 / Chapter 1.5.2 --- X-ray powder diffraction --- p.18 / Chapter 1.5.3 --- Thermal analysis --- p.19 / Chapter 1.5.4 --- Particle morphology and surface area --- p.20 / Chapter 1.5.5 --- In vitro aerosol performance --- p.21 / Chapter 1.6 --- Surface characterization --- p.21 / Chapter 1.6.1 --- X-ray photoelectric spectroscopy (XPS) --- p.21 / Chapter 1.6.2 --- Inverse gas chromatography --- p.22 / Chapter 1.7 --- Atomic force microscopy in pharmaceutical science --- p.23 / Chapter 1.7.1 --- Principle of operation --- p.24 / Chapter 1.7.1.1 --- Tapping mode --- p.27 / Chapter 1.7.1.2 --- Contact mode --- p.27 / Chapter 1.8 --- Scope of thesis --- p.29 / Chapter Chapter Two. --- Materials and Methods / Chapter 2.1 --- Materials --- p.32 / Chapter 2.2 --- Methods --- p.32 / Chapter 2.2.1 --- Optimization of spray-drying parameters --- p.32 / Chapter 2.2.2 --- Preparation of spray-dried salbutamol sulphate powders containing different concentrations of amino acid additive --- p.33 / Chapter 2.2.3 --- Physical characterization of spray-dried powders --- p.34 / Chapter 2.2.3.1 --- Particle size and size distribution --- p.34 / Chapter 2.2.3.2 --- Specific surface area --- p.35 / Chapter 2.2.3.3 --- X-ray powder diffraction --- p.35 / Chapter 2.2.3.4. --- Scanning electron microscopy --- p.36 / Chapter 2.2.3.5. --- Thermal analysis --- p.36 / Chapter 2.2.3.5.1 --- Thermogravimetric analysis (TGA) --- p.36 / Chapter 2.2.3.5.2 --- Differential scanning calorimetry (DSC) --- p.36 / Chapter 2.2.3.6 --- Water vapour sorption isotherm --- p.37 / Chapter 2.2.3.7 --- Density measurements --- p.37 / Chapter 2.2.3.8 --- In vitro particle deposition (MSLI) --- p.38 / Chapter 2.2.4 --- Surface characterization of the spray-dried powders --- p.39 / Chapter 2.2.4.1 --- X-ray photoelectric spectroscopy (XPS) --- p.39 / Chapter 2.2.4.2 --- Surface energy measurement by inverse gas chromatography (IGC) --- p.40 / Chapter 2.2.4.2.1 --- Calculation of standard free energy of adsorption --- p.41 / Chapter 2.2.4.2.2 --- Dispersive component of surface free energy and related thermodynamic parameters --- p.42 / Chapter 2.2.4.2.3 --- Specific interactions and associated acid-base properties --- p.43 / Chapter 2.2.5. --- Atomic Force Microscopy (AFM) --- p.43 / Chapter 2.2.5.1. --- Imaging --- p.43 / Chapter 2.2.5.2. --- Force measurements --- p.44 / Chapter 2.2.5.2.1 --- Adhesion force measurements --- p.44 / Chapter 2.2.5.2.2 --- Force curve data conversions --- p.44 / Chapter Chapter Three. --- "Optimal Spray-drying Conditions, Physical Characterization and Aerosol Performance of Additive-modified Spray-dried Salbutamol Sulphate particles" / Chapter 3.1 --- Optimization of spray-drying conditions --- p.46 / Chapter 3.2 --- Effect of phenylalanine on the spray-dried SS particles --- p.52 / Chapter 3.2.1. --- Phenylalanine as the additive --- p.52 / Chapter 3.2.1.1 --- In vitro aerosol performance --- p.53 / Chapter 3.2.1.2 --- Particle morphology --- p.55 / Chapter 3.2.1.3 --- Crystallinity --- p.62 / Chapter 3.2.1.4 --- Particle size distribution and specific surface area --- p.63 / Chapter 3.2.1.5 --- Density --- p.65 / Chapter 3.2.1.6 --- Thermal analysis --- p.66 / Chapter 3.2.1.7 --- Water vapour isotherm --- p.70 / Chapter 3.3 --- Effect of leucine on the spray-dried SS particles --- p.77 / Chapter 3.3.1. --- L-Leucine as the additive --- p.77 / Chapter 3.3.1.1 --- In vitro aerosol performance --- p.78 / Chapter 3.3.1.2 --- Particle morphology --- p.80 / Chapter 3.3.1.3 --- Crystallinity --- p.86 / Chapter 3.3.1.4 --- Particle size distribution and specific surface area --- p.87 / Chapter 3.3.1.5 --- Density --- p.90 / Chapter 3.3.1.6 --- Thermal analysis --- p.92 / Chapter 3.3.1.7 --- Water vapour isotherm --- p.95 / Chapter Chapter Four. --- Surface Characterization of Additive-modified Spray-dried Salbutamol Sulphate Particles / Chapter 4.1 --- X-ray photoelectric spectroscopy --- p.103 / Chapter 4.1.1 --- Phenylalanine --- p.103 / Chapter 4.1.2 --- Leucine --- p.104 / Chapter 4.2 --- Inverse gas chromatography --- p.105 / Chapter 4.2.1 --- Phenylalanine --- p.105 / Chapter 4.2.2 --- Leucine --- p.107 / Chapter 4.3 --- Atomic force microscopy --- p.109 / Chapter 4.3.1 --- Surface topography --- p.109 / Chapter 4.3.2 --- Adhesive force measurements --- p.118 / Chapter Chapter Five. --- Conclusions and Suggestions for Future Works / Chapter 5.1 --- Conclusions --- p.139 / Chapter 5.1.1 --- Physical properties --- p.139 / Chapter 5.1.2 --- Surface characteristics and aerosol performance --- p.140 / Chapter 5.2 --- Future studies --- p.142 / Appendix --- p.143 / References --- p.160

Chan, Pui. / "November, 2009." / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 108-114). / Abstracts in English and Chinese. / Table of Contents --- p.i / Acknowledgement --- p.vi / Abstract --- p.vii / Abstract (Chinese) --- p.ix / Chapter Chapter One --- Introduction / Chapter 1.1. --- Pulmonary Route for Drug Delivery --- p.2 / Chapter 1.2. --- Factors Affecting the Performance of Inhaled Formulations --- p.3 / Chapter 1.2.1. --- Particle Aerodynamic Diameter --- p.4 / Chapter 1.2.2. --- Dispersibility of Particles --- p.5 / Chapter 1.2.3. --- Clearance Mechanism in Lung and Dissolution of Particles --- p.6 / Chapter 1.3. --- Production of Dry Powder Inhalation by Spray Drying --- p.7 / Chapter 1.4. --- Approaches to Enhance Aerosol Performance of Spray Dried Particles --- p.8 / Chapter 1.4.1 --- Porous/Hollow Particles --- p.9 / Chapter 1.4.2 --- Non-Porous Corrugated Particles --- p.10 / Chapter 1.4.3 --- Blends and Ternary Systems --- p.10 / Chapter 1.4.4 --- Surface Energy and Crystallinity Modification --- p.11 / Chapter 1.4.5 --- Other Approaches to Enhancing Aerosol Performance --- p.12 / Chapter 1.5 --- Objectives and Rationale of the Present Study --- p.13 / Chapter 1.6 --- Scope of Present Study and Particle Characterization Techniques Employed --- p.14 / Chapter 1.6.1 --- Microscopy and Particle Density Measurements --- p.14 / Chapter 1.6.2 --- Particle Size Analysis and Particle Dispersibility --- p.15 / Chapter 1.6.3 --- Thermal Analysis and Particle Crystallinity --- p.15 / Chapter 1.6.4 --- Particle Surface Characterization --- p.16 / Chapter 1.6.5 --- Inverse Gas Chromatography --- p.18 / Chapter 1.6.6 --- Fractal Analysis --- p.19 / Chapter 1.6.6.1 --- Background and Origin of Fractal Analysis --- p.19 / Chapter 1.6.6.2 --- Use of Fractal Analysis in Pharmaceutical Research --- p.20 / Chapter 1.6.6.3 --- Methods for fractal analysis --- p.21 / Chapter 1.6.7 --- Atomic Force Microscopy --- p.23 / Chapter 1.6.7.1 --- Background of Atomic Force Microscopy --- p.23 / Chapter 1.6.7.2 --- Characterization of Surface Topography by Atomic Force Microscopy --- p.23 / Chapter 1.6.7.3 --- Measurement of Interaction Forces by Colloid Probe 226}0Ø Microscopy --- p.25 / Chapter 1.6.7.4 --- Use of Atomic Force Microscopy in Pharmaceutical Research --- p.27 / Chapter Chapter Two --- Materials and Methods / Chapter 2.1. --- Materials --- p.30 / Chapter 2.2. --- Equipment --- p.31 / Chapter 2.3. --- Methods --- p.33 / Chapter 2.3.1. --- Powder Preparation --- p.33 / Chapter 2.3.1.1 --- Preparation of Salbutamol Sulphate Samples --- p.33 / Chapter 2.3.1.2 --- Preparation of Disodium Cromoglycate Samples --- p.33 / Chapter 2.3.1.3 --- Preparation of ß-Galactosidase (BG) Samples --- p.34 / Chapter 2.3.2. --- Determination of Aerosol Performance --- p.35 / Chapter 2.3.3. --- Determination of Protein Activity for BG Samples --- p.36 / Chapter 2.3.3.1. --- Enzyme Assay Procedure --- p.37 / Chapter 2.3.3.2. --- Calculation of Enzyme Activity --- p.38 / Chapter 2.3.3.3. --- Determination of Enzyme Activity Retained in Spray-dried Samples --- p.38 / Chapter 2.3.4. --- Physicochemical Characterization of Particles --- p.39 / Chapter 2.3.4.1. --- Scanning Electron Microscopy --- p.39 / Chapter 2.3.4.2. --- Particle Density Determination --- p.39 / Chapter 2.3.4.3. --- Particle Size Analysis --- p.40 / Chapter 2.3.4.4. --- Thermal analysis --- p.41 / Chapter 2.3.4.5. --- Powder X-ray Diffraction --- p.42 / Chapter 2.3.4.6. --- Surface Area Determination --- p.42 / Chapter 2.3.4.7. --- Surface Composition Characterization --- p.43 / Chapter 2.3.4.8. --- Surface Tension Measurement --- p.44 / Chapter 2.3.4.9. --- Inverse Gas Chromatography --- p.45 / Chapter 2.3.4.9.1. --- Calculation of Standard Free Energy of Adsorption --- p.46 / Chapter 2.3.4.9.2. --- Calculation of Dispersive Component of Surface Free Energy --- p.47 / Chapter 2.3.4.9.3. --- Determination of Specific Interactions and Associated Acid-Base Properties --- p.48 / Chapter 2.3.4.10. --- Fractal Analysis --- p.49 / Chapter 2.3.4.11. --- Atomic Force Microscopy --- p.49 / Chapter Chapter Three --- Results / Chapter 3.1. --- In vitro Aerosol Performance --- p.52 / Chapter 3.2. --- Enzyme Activity Retained in BG Samples --- p.55 / Chapter 3.3. --- Scanning Electron Microscopy (SEM) --- p.56 / Chapter 3.3.1. --- SEM of Salbutamol Sulphate Formulations --- p.56 / Chapter 3.3.2. --- SEM of DSCG Formulations --- p.59 / Chapter 3.3.3. --- SEM of BG Formulations --- p.61 / Chapter 3.4. --- Density Measurements --- p.65 / Chapter 3.4.1. --- Densities of Salbutamol Sulphate Formulations --- p.65 / Chapter 3.4.2. --- Densities of DSCG Formulations --- p.66 / Chapter 3.4.3. --- Densities of BG Formulations --- p.67 / Chapter 3.5. --- Particle Size Analysis by Laser Diffraction --- p.68 / Chapter 3.5.1. --- Volume Mean Diameter Measurements --- p.68 / Chapter 3.5.2. --- Particle Size Distributions and Dispersion Patterns of Formulations --- p.70 / Chapter 3.6. --- Thermal Analysis --- p.75 / Chapter 3.7. --- Powder X-ray Diffraction --- p.80 / Chapter 3.8. --- Surface Area Measurements --- p.84 / Chapter 3.9. --- Surface Composition Characterization --- p.85 / Chapter 3.9.1. --- Surface Composition of Salbutamol Sulphate Formulations --- p.85 / Chapter 3.9.2. --- Surface Composition of DSCG Formulations --- p.88 / Chapter 3.9.3. --- Surface Composition of BG/BSA Formulations --- p.89 / Chapter 3.10. --- Surface Tension Measurements --- p.91 / Chapter 3.11. --- Inverse Gas Chromatography --- p.92 / Chapter 3.12. --- Fractal Analysis --- p.93 / Chapter 3.13. --- Atomic Force Microscopy --- p.94 / Chapter Chapter Four --- Discussion / Chapter 4.1. --- Influence of BSA on Aerosol Performance and Protein Integrity --- p.98 / Chapter 4.2. --- Influence of BSA on Physicochemical Properties of Particles --- p.98 / Chapter 4.2.1. --- Influence of BSA on surface corrugation --- p.98 / Chapter 4.2.2. --- Influence of BSA on particle size and dispersion behavior --- p.99 / Chapter 4.2.3. --- Influence of BSA on crystallinity and thermal properties of particles --- p.100 / Chapter 4.2.4. --- Influence of BSA on surface energetics of particles --- p.100 / Chapter 4.3. --- Relationship between Surface Corrugation and Aerosol Performance --- p.101 / Chapter 4.4. --- Mechanism of Surface Modification for BSA on Spray-dried Particles --- p.103 / Chapter Chapter Five --- Conclusions and Future Work / Chapter 5.1. --- Conclusions --- p.106 / Chapter 5.1.1. --- General Aerosolization-Enhancing Effect of BSA --- p.106 / Chapter 5.1.2. --- Surface Modifying Effect of BSA --- p.106 / Chapter 5.1.3. --- Relationship between Surface Corrugation and Aerosol Performance --- p.106 / Chapter 5.2. --- Future Work --- p.107 / References --- p.108

L’aérosolthérapie a pour objectif de délivrer un médicament dans les voies respiratoires. Le nébuliseur pneumatique est un dispositif permettant de générer des gouttelettes de liquide de diamètre micrométrique. Son processus d’atomisation a cependant été peu analysé. Ainsi, les performances du nébuliseur, caractérisées par le diamètre des gouttes et la masse de médicament inhalable par le patient, et atteignent un palier. Notre travail consiste à utiliser un modèle numérique diphasique en 3D basé sur une géométrie donnée et paramétré sous ANSYS Fluent. Plusieurs méthodes sont utilisées pour caractériser expérimentalement la génération de l’aérosol : l’ombroscopie, la diffractométrie laser et l’anémométrie phase Doppler. Notre modèle est validé par rapport aux données expérimentales et peut donc être exploité pour analyser les processus de génération. L’influence de plusieurs paramètres physiques sur les caractéristiques de l’aérosol produit est étudiée. Ainsi, l’étape de génération de gouttelettes est optimisée pour le développement d’un nouveau nébuliseur. Le transport des gouttes aux poumons du patient est optimisé empiriquement. / The purpose of aerosol therapy is to deliver drugs into respiratory airways. The jet nebulizer is a device used to generate liquid droplets with a diameter lower than 5 μm. However its atomization process was not much analyzed. Nebulizer performances, which are characterized with droplet size and drug mass inhaled by the patient, are empirically optimized and have reached a plateau. Our work consists in setting a 3D diphasic numerical model on ANSYS Fluent, based on a given geometry. Several methods are used to experimentally characterize aerosol generation: shadowgraphy, laser diffractometry and phase Doppler anemometry. Our model is validated by experimental data and helps predicting generation processes. The influence of several geometric and physical parameters on the output is studied. From these data, droplet generation is optimized for the development of a new nebulizer. Droplet transport to the patient lungs is empirically optimized.

La teicoplanine est utilisée par voie intraveineuse (IV) dans le traitement de la pneumonie acquise sous ventilation mécanique (PAVM) à Staphylocoque aureus méticilline résistant. Nous avons évalué la faisabilité et les bénéfices de la nébulisation de teicoplanine en ventilation mécanique (VM) par rapport à la voie IV. L’administration d’un aérosol de teicoplanine chez le rat a permis d’obtenir des concentrations pulmonaires 48 fois supérieures à celles après IV et des concentrations plasmatiques inférieures à celles après IV. Après avoir mesuré l’influence des nébuliseurs sur les paramètres ventilatoires du respirateur, nous avons sélectionné le nébuliseur Aeroneb Pro®. Les propriétés bactériologiques de l’antibiotique ne sont pas altérées par le nébuliseur et l’exposition d’un modèle d’épithélium pulmonaire in vitro à des doses 100 fois supérieures à celles utilisées en IV n’a pas montré de cytotoxicité. L’étude réalisée sur la nébulisation de teicoplanine chez le porc en VM a montré un dépôt pulmonaire moyen de 18,1%. En conclusion, la nébulisation de teicoplanine pourrait etre envisagée comme une nouvelle arme thérapeutique dans la PAVM. / Nebulization of teicoplanin should be an alternative way of administration in Ventilator-associated pneumonia (VAP) caused by Methicillin-resistant staphylococcus aureus. We assessed the faisibility and advantages of nebulization of teicoplanin in mechanical ventilation. After a nebulization of teicoplanin in a rat model, the lung concentrations were more than 48 times higher than the lung concentrations following intravenous administration. In the next study, we used an Aeroneb Pro® nebulizer selected according to its safe properties with ventilator which was evaluated in a bench study. Any cytotoxicity was observed with high doses of teicoplanin and nebulization did not affect its pharmacological properties. In mechanically ventilated piglets, teicoplanin was administered efficiently by nebulization wih an aerosol delivery of 18.1% [16.3-27.0]. Pharmacokinetic parameters are particularly consistent with this time-dependent antibiotic and emphasize the potential of airways delivery of teicoplanin. In conclusion, nebulization of teicoplanin adds a further challenge to the development of aerosol therapy of antibiotics in VAP.