This research was aimed at the development and validation of new in vitro methods capable of predicting in vivo drug deposition from dry powder inhalers, DPIs, in lung-normal human adults. Three physical models of the mouth, throat and upper airways, MT-TB, were designed and validated using the anatomical literature. Small, medium and large versions were constructed to cover approximately 95% of the variation seen in normal adult humans of both genders. The models were housed in an artificial thorax and used for in vitro testing of drug deposition from Budelin Novolizer DPIs using a breath simulator to mimic inhalation profiles reported in clinical trials of deposition from the same inhaler. Testing in the model triplet produced results for in vitro total lung deposition (TLD) consistent with the complete range of drug deposition results reported in vivo. The effect of variables such as in vitro flow rate were also predictive of in vivo deposition. To further assess the method’s robustness, in vitro drug deposition from 5 marketed DPIs was assessed in the “medium” MT-TB model. With the exception of Relenza Diskhaler, mean values for %TLD+SD differed by only < 2% from their literature in vivo. The relationship between inhaler orientation and in vitro regional airway deposition was determined. Aerosol drug deposition was found to depend on the angle at which an inhaler is inserted into the mouth although the results for MT deposition were dependent on both the product and the formulation being delivered. In the clinic, inhalation profiles were collected from 20 healthy inhaler naïve volunteers (10M, 10F) before and after they received formal inhalation training in the use of a DPI. Statistically significant improvements in Peak Inhalation Flow Rate (PIFR) and Inhalation Volume (V) were observed following formalized training. The shapes of the average inhalation profiles recorded in the clinic were found to be comparable to the simulated profiles used in the in vitro deposition studies described above. In conclusion, novel in vitro test methods are described that accurately predict both the average and range of aerosol airway drug deposition seen from DPIs in the clinic.

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

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution. The physicochemical properties of multi-component dry powder inhaler (DPI) formulation were characterized by a number of techniques. In addition, the in vitro aerosol dispersion performance, storage stability test, and in vitro drug release of selected spray-dried (SD) multi-component systems were conducted. The physicochemical study revealed that multi-component aerosol particles possessed essential particle properties suitable for deep lung delivery. In general, the multi-component particles (typically 0.5 to 2 µm) indicated that the designed SD aerosol particles could potentially penetrate deep lung regions (such as respiratory bronchiolar and alveolar regions) by sedimentation and diffusion, respectively. The essential particle properties including narrow size distribution, spherical particle and smooth surface morphologies, and low water content (or water vapor sorption) could potentially minimize interparticulate interactions. The study of in vitro aerosol dispersion performance showed that majority of SD multi-component aerosols exhibited low values (less than 5µm) of MMAD, high values (approximately above 30% up to 60.4%) of FPF, and high values (approximately above 90%) of ED, respectively. The storage stability study showed that azithromycin–incorporated multi-component aerosol particles stored at 11 and 40% RH with no partial crystallization were still suitable for deep lung delivery. Compared to SD pure azithromycin particles, the azithromycin-incorporated multi-component particles exhibited an enhanced initial release. The targeted microparticulate and nanoparticulate multi-component dry powder aerosol formulations with essential particle properties for deep lung pulmonary delivery were successfully produced by using spray drying from organic solution. The promising experimental data suggest the multi-component formulations could be further investigated in in vivo studies for the purpose of commercialization.

There has been very little research into the bioanalytical application of Microemulsion High Performance Liquid Chromatography (MELC), a recently established technique for separating an active pharmaceutical ingredient from its related substances and for determining the quantity of active drug in a dose. Also, the technique is not good at separating hydrophilic drugs of very similar chemical structures. Different phase diagrams of oil (octane or ethyl acetate), co-surfactant (butanol), surfactant (sodium dodecyl sulphate (SDS) or Brij-35) and buffer (Phosphate pH 3) were developed and several nanoemulsion mobile phases identified. Nanoemulsion mobile phase that is, prepared with SDS, octane, butanol and a phosphate buffer, failed to separate hydrophilic compounds with a very close chemical structure, such as terbutaline and salbutamol. A nanoemulsion mobile phase containing a non-ionic surfactant (Brij-35) with ethyl acetate, butanol and a phosphate buffer, was, however, successful in achieving a base line separation, and the method was validated for simultaneous determination of terbutaline and salbutamol in aqueous and urine samples. An oil-in-water (O/W) NELC method was developed and validated for the determination of formoterol in an Oxis® Turbuhaler® using pre-column fluorescence derivatisation. Although the same mobile phase was extended for separation of formoterol in urine, the formoterol peak¿s overlap with endogenous peaks meant that fluorescence detection could not determine formoterol in urine samples. Solid phase extraction, concentrating the final analyte 40 times, enabled determination of a low concentration of formoterol in urine samples by UV detection. The method was validated and an acceptable assay precision %CV <4.89 inter-day and %CV <2.33 intra-day was achieved. Then after the application of O/W nanoemulsion mobile phase for HPLC was extended for the separation of lipophilic drugs. The nanoemulsion liquid chromatography (NELC) method was optimised for the determination of salmeterol and fluticasone propionate in good validation data was achieved. This thesis shows that, in general, the performance of O/W NELC is superior to that of conventional High Performance Liquid Chromatography (HPLC) for the analysis of both hydrophilic and lipophilic drugs in inhaled dosage formulations and urine samples. It has been shown that NELC uses cheaper solvents and that analysis time is faster for aqueous and urine samples. This considerable saving in both cost and time will potentially improve efficiency within quality control.

Surface energetics play a key role in the delivery of a dry powder inhaler formulation into the lungs, as there must be a sufficient balance of adhesive and cohesive forces to allow optimal lung delivery. In this study, measuring the surface energies of a set of single drug and carrier (budesonide or theophylline with either mannitol or lactose) with different levels of surfactant using Inverse Gas Chromatography, and comparing them to their lung deposition performance using a Next Generation Impactor established a relationship between the two. A 1:10 mixing ratio of budesonide with either carrier was found to have the highest FPF. Coating the carriers with 0.05% sodium lauryl sulphate resulted in a further increase in the FPF when using either budesonide or theophylline as the API, and the same results were seen when a sonocrystallised version of the API was substituted for the micronised form. The calculated IGC values then showed that the highest performing formulations had the lowest dispersive energy and total free surface energy. Furthermore, a trend was observed in the work of adhesion (Wa) and work of cohesion (Wc) for each set of formulations depending on which API was chosen, where for the less polar drug (budesonide) a higher Wa/Wc ratio was associated with the highest formulation performance, and for the more polar drug (theophylline) a smaller Wa/Wc ratio was associated with the highest formulation performance, enabling the estimation of lung performance for a set of single drug and carrier using their surface energy data. / Kuwait’s government and the Ministry of Health of Kuwait

This thesis is based around examination of three mainstream inhaled drugs Formoterol, Budesonide and Beclomethasone for treatment of asthma and COPD. The areas investigated are these which have been raised in reports and studies, where there are concern, for drug use and assessment of their use. In reporting this work the literature study sets out a brief summary of the background and anatomy and physiology of the respiratory system and then discuses the mechanism of drug deposition in the lung, as well as the methods of studying deposition and pulmonary delivery devices. This section includes the basis of asthma and COPD and its treatment. In addition, a short section is presented on the role of the pharmacist in improving asthma and COPD patient's care. Therefore the thesis is divided into 3 parts based around formoterol, budesonide and beclomethasone. In the first case the research determines the in-vitro performance of formoterol and budesonide in combination therapy. In the initial stage a new rapid, robust and sensitive HPLC method was developed and validated for the simultaneous assay of formoterol and the two epimers of budesonide which are pharmacologically active. In the second section, the purpose was to evaluate the aerodynamic characteristics for a combination of formoterol and the two epimers of budesonide at inhalation flow rates of 28.3 and 60 L/min. The aerodynamic characteristics of the emitted dose were measured by an Anderson cascade impactor (ACI) and the next generation cascade impactor (NGI). In all aerodynamic characterisations, the differences between flow rates 28.3 and 60 were statistically significant in formoterol, budesonide R and budesonide S, while the differences between ACI and NGI at 60 were not statistically significant. Spacers are commonly used especially for paediatric and elderly patients. However, there is considerable discussion about their use and operation. In addition, the introduction of the HFAs propellants has led to many changes in the drug formulation characteristics. The purpose of the last section is to examine t h e performance of different types of spacers with different beclomethasone pMDIs. Also, it was to examine the hypothesis of whether the result of a specific spacer with a given drug/ brand name can be extrapolated to other pMDIs or brand names for the same drug. The results show that there are different effects on aerodynamic characterisation and there are significant differences in the amount of drug available for inhalation when different spacers are used as inhalation aids. Thus, the study shows that the result from experiments with a combination of a spacer and a device cannot be extrapolated to other combination.

<p>The main aim of the thesis was to explore the potential of supercritical fluid (SF) techniques in the field of drug delivery. In particular, the relatively recently developed solution-enhanced dispersion by supercritical fluids (SEDS) technology has been employed in the preparation of particles/powders. </p><p>The manufacturing, stability and bioavailability of a dosage form strongly depend on the physicochemical properties of the formulation particles. For example, dry powder inhalation (DPI) for administering drugs to the respiratory tract require particles in a narrow size range (1-5 μm) to be effective. The identification of polymorphs and control of purity are also important issues since the physicochemical properties and therapeutic effects of the alternative forms of a drug may differ substantially. Solvent-based traditional crystallisation processes provide the product that may require further down-stream processing to obtain particles for advanced drug delivery applications. This can result in unwanted changes in the physicochemical properties of the particles and thus affect the performance of the dosage form. SF processing has addressed many of the challenges in particle formation research. Among several SF technologies developed for particle processing over the last decade, the SEDS process with its specially designed co-axial nozzle with mixing chamber has resulted in improved control over the particle formation process. Carbon dioxide (CO₂) was used as the SF, because it has low critical points and is non-toxic, non-flammable and relatively inexpensive. </p><p>The initial part of the thesis concerns the formation of particles of model drugs such as hydrocortisone, budesonide and flunisolide using SEDS technology and the determination of the influence of processing conditions and solvents on particle characteristics such as size, shape and crystal structure. Particles of model drugs of differing shapes in a size range suitable for inhalation delivery were prepared. In the process, two new polymorphic forms of flunisolide were identified. This was the first report of SEDS technology being shown as a polymorph-screening tool. The remainder of the thesis deals with the development of SEDS technology for precipitating therapeutic proteins such as recombinant human growth hormone (hGH) from aqueous solutions. Powders of hGH were precipitated using SEDS without significant changes in the chemical or physical stability of the protein. The addition of sucrose to hGH in the feed solution promoted precipitation and minimised the detrimental effects of the solvent and/or the process on the physical aggregation of the protein. </p><p>In conclusion, this thesis highlights the applicability of the SEDS process in drug delivery research and advances general understanding of the particle formation phenomenon. The SEDS process may also prove to be a potential alternative technology for the precipitation of stable powders of therapeutic proteins.</p>

The main aim of the thesis was to explore the potential of supercritical fluid (SF) techniques in the field of drug delivery. In particular, the relatively recently developed solution-enhanced dispersion by supercritical fluids (SEDS) technology has been employed in the preparation of particles/powders. The manufacturing, stability and bioavailability of a dosage form strongly depend on the physicochemical properties of the formulation particles. For example, dry powder inhalation (DPI) for administering drugs to the respiratory tract require particles in a narrow size range (1-5 μm) to be effective. The identification of polymorphs and control of purity are also important issues since the physicochemical properties and therapeutic effects of the alternative forms of a drug may differ substantially. Solvent-based traditional crystallisation processes provide the product that may require further down-stream processing to obtain particles for advanced drug delivery applications. This can result in unwanted changes in the physicochemical properties of the particles and thus affect the performance of the dosage form. SF processing has addressed many of the challenges in particle formation research. Among several SF technologies developed for particle processing over the last decade, the SEDS process with its specially designed co-axial nozzle with mixing chamber has resulted in improved control over the particle formation process. Carbon dioxide (CO2) was used as the SF, because it has low critical points and is non-toxic, non-flammable and relatively inexpensive. The initial part of the thesis concerns the formation of particles of model drugs such as hydrocortisone, budesonide and flunisolide using SEDS technology and the determination of the influence of processing conditions and solvents on particle characteristics such as size, shape and crystal structure. Particles of model drugs of differing shapes in a size range suitable for inhalation delivery were prepared. In the process, two new polymorphic forms of flunisolide were identified. This was the first report of SEDS technology being shown as a polymorph-screening tool. The remainder of the thesis deals with the development of SEDS technology for precipitating therapeutic proteins such as recombinant human growth hormone (hGH) from aqueous solutions. Powders of hGH were precipitated using SEDS without significant changes in the chemical or physical stability of the protein. The addition of sucrose to hGH in the feed solution promoted precipitation and minimised the detrimental effects of the solvent and/or the process on the physical aggregation of the protein. In conclusion, this thesis highlights the applicability of the SEDS process in drug delivery research and advances general understanding of the particle formation phenomenon. The SEDS process may also prove to be a potential alternative technology for the precipitation of stable powders of therapeutic proteins.

An issue of inhalation therapy is a complex topic, actively discussed in last decades, and its progress in various scientific fields is more than required. First part of this thesis brings a theoretical introduction into principles of aerosol therapy and into the requirements resulting from them. Commonly available technologies of inhalers and nebulisers for medical usage, parameters that determinate their effectivity are briefly described. Usage mistakes influencing the effectivity of inhalation are discussed, as well. Second part deals with experimental measurements of aerosol that selected inhalers generate. It also describes difficulties connected with the methods of these measurements, with sampling and following analyses. Gained results are compared with an available literature.