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Yes / Two different types of dry powder inhalers (Easyhaler® and RS01®) were used in this work to evaluate the ex vivo and in vitro performance of a budesonide inhaled formulation with recrystallised mannitol, commercial DPI-grade mannitol, or lactose. The aerodynamic performance of the budesonide formulation with recrystallised mannitol was superior when RS01® was used (FPF = 45.8%) compared to Easyhaler® (FPF = 14%). However, the aerodynamic profile was very poor in both devices when commercial mannitol was used. Interestingly, the aerosol performance of the marketed budesonide formulation significantly improved when RS01® was used compared to Easyhaler® (the original device for the formulation). Due to the significant increases in the surface energy of the commercial mannitol formulation, the aerodynamic performance of the formulation was very poor. This work demonstrates the impact of inhaler devices on the performance of inhaled formulations and considers the particle surface energy during formulation development.

The dynamics of particle laden flows are integral to the analysis of toxic particle deposition and medical respiratory aerosol delivery. Computational fluid-particle dynamics (CFPD) can play a critical role in developing a better understanding of particle laden flows, especially in a number of under-explored areas. The applications considered in this study include both the numerical aspects and the physical phenomena of respiratory aerosol transport. Objective I: Considering the effects of mesh type and grid convergence, four commonly implemented mesh styles were applied to a double bifurcation respiratory geometry and tested for flow patterns and aerosol deposition. Results indicated that the mesh style employed had a significant effect on the transport and deposition of aerosols with hexahedral meshes being most accurate. Objective II: In order to evaluate the effects of bronchoconstriction under exhalation conditions, normal and constricted pediatric airway models were considered. Results include (i) a significant increase in deposition for constricted airways, and (ii) a novel correlation for deposition during exhalation based on the Dean and Stokes numbers. Objective IIIa: Considering evaluation of an aerosol size sampler, an eight-stage Andersen cascade impactor (ACI) was numerically analyzed. The numerical simulations indicated high non-uniformity and recirculation in the flow field. Numerical predictions of retention fraction matched well with existing experiments (0.5 – 11% error). Objective IIIb: As an extension to this study, numerical predictions of electrostatic charge effects on aerosol transport and deposition in the ACI were presented. Charges consistent with standard pharmaceutical pressurized metered dose inhalers and dry powder inhalers were considered. The numerical predictions indicated that charged aerosols deposit as if they were 5 – 85% larger due to electrostatic effects. Applications of the studies considered include (i) quantitative guidance in selecting numerical mesh styles and development of standard grid convergence criteria, (ii) the development of more accurate whole-lung deposition models that better evaluate exhalation conditions,(iii) improvements in the design of pharmaceutical assessment and delivery devices, and (vi) correction values to account for electrostatic charge on pharmaceutical aerosols.

In this work, airflow and particle transport are studied using mathematical and image-based models of pulmonary acinus. Numerical results predict that airflow in the presence of wall motion in a three-dimensional honey-comb like geometry is characterized by the presence of a recirculation region within the alveolar cavity and a weak entraining flow between alveolar duct and cavity. Alveolar flow in distal generations is characterized by higher alveolar flow rates, larger entrainment of ductal flow and absence of recirculatory flow inside alveoli. The study of transport constitutes assessment of mixing visualized by the tracking of massless particles and the study of transport and deposition of aerosols. The phenomenon of steady streaming is found to hold the key to the origin of kinematic mixing in the alveolus, the alveolar mouth and the alveolated duct. This mechanism provides the explanation for observed folding of material lines and increases in material surface area, and has no bearing on whether the geometry is expanding or if flow separates within the cavity or not. Streaming results in non-zero drift of particles between the beginning and end of a breathing cycle. Based on flow conditions and resultant convective mixing measures, we conclude that significant convective mixing in the duct and within an alveolus could originate only in the first few generations of the acinar tree as a result of non-zero inertia, flow asymmetry and large KC number. Evidence of streaming and related Lagrangian drift is also observed in image-based acinar models. Finally, particle deposition calculations are performed on the models of pulmonary acinus considered in this study.

While realistic in vitro testing of dry powder inhalers (DPIs) can be used to establish in vitro–in vivo correlations (IVIVCs) and predict in vivo lung doses, the aerodynamic particle size distributions (APSDs) of those doses and their regional lung deposition remains unclear. Four studies were designed to improve testing centered on the behavior of Novolizer®. Different oropharyngeal geometries were assessed by testing different mouth-throat (MT) models across a realistic range of inhalation profiles (IPs) with Salbulin® Novolizer®. Small and large Virginia Commonwealth University (VCU) and Oropharyngeal Consortium (OPC) models produced similar ranges for total lung dose in vitro (TLDin vitro), while results for medium models differed significantly. While either group may be selected to represent variations in oropharyngeal geometry, OPC models were more difficult to use, indicating that VCU models were preferable. To facilitate simulation of human IPs through DPIs, inhalation profile data from a VCU clinical trial were analyzed. Equations were developed to represent the range of flow rate vs. time curves for use with DPIs of known airflow resistance. A new method was developed to couple testing using VCU MT models and simulated IPs with cascade impaction to assess the APSDs of TLDin vitro for Budelin® Novolizer®. This method produced IVIVCs for Budelin’s total lung dose, TLD, and was sufficiently precise to distinguish between values of TLDin vitro and their APSDs, resulting from tests using appropriately selected MT models and IPs. For example, for slow inhalation, TLD values were comparable in vivo and in vitro; TLDin vitro ranged from 12.2±2.9 to 66.8±1.7 mcg aerosolized budesonide while APSDs in vitro had mass median aerodynamic diameters of 3.26±0.27 and 2.17±0.03 µm, respectively. To explore the clinical importance of these variations, a published computational fluid dynamic (CFD) model was modified and coupled to accept the output of realistic in vitro tests as initial conditions at the tracheal inlet. While simplified aerosol size metrics and flow conditions used to shorten CFD simulations produced small differences in theoretical predictions of regional lung deposition, the results broadly agreed with the literature and were generally consistent with the median values reported clinically for Budelin.

The present work aimed at assessing the dose emission and aerodynamic particle size characteristics of formoterol fumarate from Atimos Modullite, a metered dose inhaler (MDI) and Foradil Aeroliser, Easyhaler, and Oxis Turbuhaler dry powder inhalers (DPI) at different inhalation flow rates and volumes using in vitro methodology. Recognised methods have been adopted and validated to generate the results. The in vitro characteristics of formoterol were measured according to standard pharmacopeial methodology with adaptation to simulate routine patient use. The dose emission from the Atimos Modulite was determined using inhalation volumes of 4 and 2 L and inhalation flows of 10, 28.3, 60, and 90 L/min. The %nominal dose emitted was consistent between the various flow rates and inhalation volumes of 4 and 2L. The particle size distribution was measured using an Anderson Cascade Impactor (ACI) combined with a mixing inlet valve to measure particle size distribution at inhalation flow rates below 30 L/min. The particle size distribution of formoterol from Atimos Modulite was measured using inhalation flows of 15, 28.3, 50, and 60 L/min with and without different spacers, Aerochamber and Volumatic. The mean fine particle dose (%nominal dose) through an Atimos without spacer were 53.52% (2.51), 54.1% (0.79), 53.37% (0.81), 50.43% (1.92) compared to Aerochamber 63.62% (0.44), 63.86% (0.72), 64.72% (0.47), 59.96% (1.97) and Volumatic 62.40% (0.28),63.41% (0.52), 64.71% (0.61), 58.43% (0.73), respectively. A small decrease in the fine particle dose was observed as the inhalation flow increased, but this was not significant. The respective mean mass aerodynamic diameter (MMAD) increased as the flow rate was increased from 15 of 60 L/min. Results also suggests that the use of spacers provides better lung deposition for patients with problems using MDI. The dose emission from the Foradil Aeroliser was determined using inhalation volumes of 4 and 2 L, at inhalation flows of 10, 15, 20, 28.3, 60, and 90 L/min plus two inhalations per single dose. The %nominal dose emitted using 2 L inhalation volume was approximately half when compared to results obtained using inhalation volume of 4 L. A significantly (p<0.001) higher amount of drug was also emitted from Easyhaler® at inhalation volume of 4 L through flow rates of 10, 20, 28.3, 40, and 60 L/min compared 2 L. Similar results were observed through Oxis Turbuhaler at inhalation flow rates of 10, 20, 28.3, 40, and 60 L/min. Comparative studies were also carried out to evaluate the particle size distribution of formoterol through the DPIs. The nominal fine particle dose through Aeroliser using inhalation flows of 10, 20, 28.3, 60 and 90 L/min were 9.23%, 14.70 %, 21.37%, 28.93%, and 39.70% for the 4 L and 4.17%, 5.55%, 7.28%, 8.41%, and 11.08% for the 2 L, respectively. The respective MMAD significantly (p<0.001) decreased with increasing flow rates. Aeroliser performance showed significant (p<0.001) increase in the % nominal fine particle dose for two inhalations compared to one inhalation at both 4 and 2 L. The Easyhaler was measured using inhalation flows of 10, 20, 28.3, 40, 60 L/min. The nominal fine particle dose were 19.03%, 27.09%, 36.89%, 49.71% and 49.25% for the 4 L and 9.14%, 15.44%, 21.02%, 29.41%, 29.14% for the 2 L, respectively. The respective MMAD significantly (p<0.001) decreased with increasing flow rates. Easyhaler performance at both 4 and 2 L showed no significant differences between one and two inhalations at low flow rates (10, 20, 28.3), but this was significant (p<0.05) at higher flow rates (40 and 60 L/min). The Oxis Turbuhaler was also measured using inhalation flows of 10, 20, 28.3, 40, 60 L/min. The nominal fine particle dose were 12.87%, 24.51%, 28.25%, 34.61%, 40.53% for the 4 L and 8.55%, 15.31%, 21.36%, 19.53%, 22.31% for the 2 L, respectively. Turbuhaler performance showed significant (p<0.05) differences between one and two inhalations at varying flow rates 2 L inhalation volumes, but not at 4 L. The use of Foradil Aeroliser delivers small particles as the Oxis Turbuhaler using two inhalations hence delivering formoterol deep into the lungs. Also, this thesis shows that high flow resistance of Turbuhaler will indeed influence the ability of patients with severe asthma or children to use the system. Beside, Easyhaler produced the highest drug delivery to the lungs, thus, making it a more desirable system to use, especially for children and asthma sufferers.

The present work aimed at assessing the dose emission and aerodynamic particle size characteristics of formoterol fumarate from Atimos Modullite, a metered dose inhaler (MDI) and Foradil Aeroliser, Easyhaler, and Oxis Turbuhaler dry powder inhalers (DPI) at different inhalation flow rates and volumes using in vitro methodology. Recognised methods have been adopted and validated to generate the results. The in vitro characteristics of formoterol were measured according to standard pharmacopeial methodology with adaptation to simulate routine patient use. The dose emission from the Atimos Modulite was determined using inhalation volumes of 4 and 2 L and inhalation flows of 10, 28.3, 60, and 90 L/min. The %nominal dose emitted was consistent between the various flow rates and inhalation volumes of 4 and 2L. The particle size distribution was measured using an Anderson Cascade Impactor (ACI) combined with a mixing inlet valve to measure particle size distribution at inhalation flow rates below 30 L/min. The particle size distribution of formoterol from Atimos Modulite was measured using inhalation flows of 15, 28.3, 50, and 60 L/min with and without different spacers, Aerochamber and Volumatic. The mean fine particle dose (%nominal dose) through an Atimos without spacer were 53.52% (2.51), 54.1% (0.79), 53.37% (0.81), 50.43% (1.92) compared to Aerochamber 63.62% (0.44), 63.86% (0.72), 64.72% (0.47), 59.96% (1.97) and Volumatic 62.40% (0.28),63.41% (0.52), 64.71% (0.61), 58.43% (0.73), respectively. A small decrease in the fine particle dose was observed as the inhalation flow increased, but this was not significant. The respective mean mass aerodynamic diameter (MMAD) increased as the flow rate was increased from 15 of 60 L/min. Results also suggests that the use of spacers provides better lung deposition for patients with problems using MDI. The dose emission from the Foradil Aeroliser was determined using inhalation volumes of 4 and 2 L, at inhalation flows of 10, 15, 20, 28.3, 60, and 90 L/min plus two inhalations per single dose. The %nominal dose emitted using 2 L inhalation volume was approximately half when compared to results obtained using inhalation volume of 4 L. A significantly (p<0.001) higher amount of drug was also emitted from Easyhaler® at inhalation volume of 4 L through flow rates of 10, 20, 28.3, 40, and 60 L/min compared 2 L. Similar results were observed through Oxis Turbuhaler at inhalation flow rates of 10, 20, 28.3, 40, and 60 L/min. Comparative studies were also carried out to evaluate the particle size distribution of formoterol through the DPIs. The nominal fine particle dose through Aeroliser using inhalation flows of 10, 20, 28.3, 60 and 90 L/min were 9.23%, 14.70 %, 21.37%, 28.93%, and 39.70% for the 4 L and 4.17%, 5.55%, 7.28%, 8.41%, and 11.08% for the 2 L, respectively. The respective MMAD significantly (p<0.001) decreased with increasing flow rates. Aeroliser performance showed significant (p<0.001) increase in the % nominal fine particle dose for two inhalations compared to one inhalation at both 4 and 2 L. The Easyhaler was measured using inhalation flows of 10, 20, 28.3, 40, 60 L/min. The nominal fine particle dose were 19.03%, 27.09%, 36.89%, 49.71% and 49.25% for the 4 L and 9.14%, 15.44%, 21.02%, 29.41%, 29.14% for the 2 L, respectively. The respective MMAD significantly (p<0.001) decreased with increasing flow rates. Easyhaler performance at both 4 and 2 L showed no significant differences between one and two inhalations at low flow rates (10, 20, 28.3), but this was significant (p<0.05) at higher flow rates (40 and 60 L/min). The Oxis Turbuhaler was also measured using inhalation flows of 10, 20, 28.3, 40, 60 L/min. The nominal fine particle dose were 12.87%, 24.51%, 28.25%, 34.61%, 40.53% for the 4 L and 8.55%, 15.31%, 21.36%, 19.53%, 22.31% for the 2 L, respectively. Turbuhaler performance showed significant (p<0.05) differences between one and two inhalations at varying flow rates 2 L inhalation volumes, but not at 4 L. The use of Foradil Aeroliser delivers small particles as the Oxis Turbuhaler using two inhalations hence delivering formoterol deep into the lungs. Also, this thesis shows that high flow resistance of Turbuhaler will indeed influence the ability of patients with severe asthma or children to use the system. Beside, Easyhaler produced the highest drug delivery to the lungs, thus, making it a more desirable system to use, especially for children and asthma sufferers.

Abstract Combustion generated ultrafine particles have been found to be responsible for adverse effects on human health. New emission reduction technologies and fuels will change the composition of particle emissions. It is important to confirm that the new reduction technologies are designed to minimise the adverse health effects. In this doctoral thesis the potential health effects caused by traffic and industrially generated particles were studied using epidemiological, experimental and in silico studies. The effects of short-term changes in PM2.5 on the respiratory health of symptomatic children living near a steel works were studied to investigate whether specific sources of PM2.5 have the possible health effects. The PM2.5 emission sources were identified: long-range transport, a steel works, soil and street dust and a mechanical engineering works. Significant associations were not found between respiratory symptoms and PM2.5 or the sources markers. The deposition of traffic-related particles into the human respiratory system was computed using the lung deposition model. Particle size distribution was measured from diesel- and compressed natural gas (CNG)-fuelled busses and an off-road diesel engine under different combustion situations. The majority of the measured traffic-related particle numbers reach the alveolar region of the lungs. There were differences in the deposition of particles when different catalysts, engines or fuels were used. CNG or a diesel particulate filter (DPF) significantly reduced lung exposure to particles. Also physical activity, age and gender affected the deposition of particles. The diesel particles comprised compounds (carcinogenic PAHs, transition metals), which may have the ability to generate reactive oxygen. This study provides new knowledge how of the emission abatement technologies and fuels affects particle number and their composition, as well health hazards. Cleaner technology (CNG, DPF), emits significantly fewer particles in numbers, especially large particles, but they emit high amounts of small-size particles, which penetrate most easily to the deepest parts of the lungs. In addition, particles from engines with DPF include the largest variety of transition metals and other hazardous compounds compared to combustion systems having different emission after-treatment units. / Tiivistelmä Palamisprosesseista peräisin olevien ultrapienten hiukkasten on todettu olevan haitallisia ihmisen terveydelle. Uudet pako- ja savukaasujen puhdistusteknologiat ja polttoaineet vaikuttavat hiukkaspäästöihin ja niiden koostumukseen. Uusien menetelmien käytön tulee vähentää hiukkasten mahdollisia terveyshaittoja. Tässä väitöskirjassa tutkittiin liikenteestä ja teollisuudesta peräisin olevien hiukkasten mahdollisia terveyshaittoja käyttäen epidemiologista, kokeellista ja in silico- menetelmiä. Työssä tutkittiin PM2.5-hiukkasten lyhytaikaisvaihtelun yhteyttä terästehtaan läheisyydessä asuvien hengitystieoireisten lasten terveyteen ja päästölähteiden yhteyttä mahdollisiin terveysvaikutuksiin. Merkittäviä PM2.5-päästölähteitä olivat kaukokulkeuma, terästehdas, maaperä ja tiepöly sekä konepaja. Tutkimuksessa ei havaittu lasten hengitystieoireiden ja PM2.5:n tai päästölähteiden merkkiaineiden välillä merkittävää yhteyttä. Liikenneperäisten hiukkasten kulkeutumista ihmisen hengitysteihin tutkittiin keuhkodepositiomallilla. Diesel- ja maakaasukäyttöisten (CNG) bussien ja dieselkäyttöisen työkoneen hiukkaskokojakaumat mitattiin eri palamisolosuhteissa. Suurin osa mitatuista hiukkaslukumääristä kulkeutui keuhkojen alveolaaritasolle. Erilaisten katalysaattorien, moottoreiden tai polttoaineiden käytön seurauksena hiukkasten lukumääräpitoisuudet vaihtelivat ja siten hiukkasten kulkeutumisessa hengitysteihin oli eroja. CNG:n tai hiukkassuodattimen (DPF) käyttö vähensi merkittävästi hiukkaslukumääriä ja keuhkojen altistumista hiukkasille. Myös liikunta, ikä ja sukupuoli vaikuttivat hengitysteihin kulkeutuvien hiukkasten määriin. Dieselhiukkaset sisälsivät yhdisteitä (karsinogeeniset PAH:t, siirtymämetallit), jotka tuottavat hengitysteissä reaktiivisia happiradikaaleja. Tämä tutkimus antaa uutta tietoa päästövähennysmenetelmien ja polttoaineiden vaikutuksista hiukkasten lukumäärään ja koostumukseen sekä hiukkasten terveyshaitoihin. Puhtaamman teknologian käyttö (CNG, DPF) vähentää huomattavasti pakokaasun hiukkasten lukumäärää, etenkin suurten hiukkasten, mutta tuottaa silti suuria määriä pieniä hiukkasia, jotka kulkeutuvat helpommin keuhkojen syvimpiin osiin. Lisäksi moottoreiden hiukkaspäästöt käytettäessä hiukkassuodatinta, sisälsivät enemmän erilaisia siirtymämetalleja ja muita haitallisia aineita verrattuna polttoon, jossa käytettiin muita päästöjen jälkikäsittelymenetelmiä.