UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Engineering Nanoparticle Agglomerates as Dry Powders for Pulmonary Drug Delivery

......................................................................................... 4 ACKNOWLEDGEMENTS ....................................................................... 6 LIST OF TABLES ............................................................................... 11 LIST OF FIGURES ............................................................................. 13 LIST OF ABBREVIATIONS ................................................................ 17 1. GENERAL INTRODUCTION ............................................................ 20 1.1. The human respiratory tract .................................................. 20 1.2. Inhalation aerosols and particle aerodynamic diameter ........ 23 1.3. Particle deposition in the respiratory tract ............................ 24 1.3.1. Inertial impaction ............................................................... 24 1.3.2. Gravitational sedimentation ................................................. 25 1.3.3. Brownian diffusion .............................................................. 25 1.3.4. Interception ....................................................................... 26 1.3.5. Electrostatic precipitation ..................................................... 26 1.4. Delivery devices .................................................................... 27 1.4.1. Nebulisers .......................................................................... 27 1.4.2. Pressurised metered-dose inhalers (pMDIs) ........................... 28 1.4.3. Dry powder inhalers (DPIs) .................................................. 30 1.5. Particle engineering for pulmonary drug delivery.................. 39 1.5.1. Spray drying ...................................................................... 39 1.6. Nanoparticles in drug delivery ............................................... 46 1.6.1. Nanocrystals ...................................................................... 49 1.7. Nanoparticles and pulmonary drug delivery .......................... 60 1.7.1. Applications and advantages of nanosuspensions in pulmonary drug delivery ............................................................................... 60 1.7.2. Delivery of nanocrystals as dry powders for inhalation: challenges and opportunities ......................................................................... 61 1.7.3. Formation of nanoparticle agglomerates as dry powders for inhalation .................................................................................... 62 1.8. RESEARCH HYPOTHESIS ........................................................ 68 1.9. THESIS AIMS AND OBJECTIVES ............................................. 68 2. NANOPARTICLE AGGLOMERATES OF INDOMETACIN .................... 71 2.