Dissertations / Theses on the topic 'Pressurised metered dose inhaler (pMDI)'

The assessment of drug formulations delivered by the pressurised metered dose inhaler and used in the treatment of Asthma are assessed commercially using cascade impactors which are the preferred instruments for the assessment of particle size and respirable mass or fraction delivered by inhalation devices. The fundamental principle underpinning the design of cascade impactors is particle motion defined by Stokes theory. The analysis of impactor data raises a number of functional issues as calibration curves have long tails, which are not easily explained by a simplistic application of Stokes law. The atomisation process, propellant flashing, evaporation and aerodynamic properties of the residual drug particle detennine the distribution of the drug particles within the lung and resultant therapeutic effect. The research uses mathematical modelling and computational fluid dynamics (CFD) to evaluate the flow and inertial deposition in the USP throat and the plates of the ACI which is the most widely used cascade impactor. The CFD analysis shows the flow in the outlet section of the USP throat to be unstable for the basic design, when coupled to an outlet extension and when coupled to the ACI via the standard coupler and first jet stage. The modelling also provides insight as to why the calibration curves of the ACI have long tails and reveals a number of issues with the design of the ACI coupler and the fundamental design of impactor jet arrays as well as the position and functional response of upper impactor plates. Additional particle sizing methodologies were used to assess the lognonnal characteristics of the atomised droplets and residual drug particles. The experimental data was compared to current atomisation model and modification recommended and a proposed alternative model with improved fit to the data.

Within pressurised Metered Dose Inhalers (pMDIs) the contact between the valve components and elastomeric seals is of major significance, representing the main contributory factor to the overall system frictional characteristics. Therefore, the seal performance is extremely important and must be optimised to meet the contradictory requirements of preventing leakage and allowing smooth actuation. The environmentally driven trend to HFA formulations as opposed to CFC based ones has deteriorated this problem due to poor lubrication conditions and it has, consequently, increased the frictional losses during the pMDI actuation (hysteresis cycle). Research has been conducted into the key areas of the inhaler mechanism. As such, the contact pressure distribution and resulting reactions have been investigated, with emphasis on the correct treatment of the elastomer (seal) characteristics. The modelling of the device has been conducted within the environment of the multibody dynamics commercial software ADAMS, where a virtual prototype has been built using solid CAD geometries of the valve components. An equation was extrapolated to describe the relation between the characteristics of the ultra thin film contact conditions (sliding velocity, surface geometry, film thickness and reaction force) encountered within the inhaler valve and integrated into the virtual prototype allowing the calculation of friction within the conjuncture (due to viscous shear and adhesion). The latter allowed the analysis and optimisation of key device parameters, such as seal geometry, lubricant properties etc. It has been concluded that the dominant mechanism of friction is adhesion, while boundary lubrication is the prevailing lubrication regime due to the poor surface roughness to film thickness ratio. The multibody dynamics model represents a novel multi physics approach to study the behaviour of pMDIs, including rigid body inertial dynamics, general elasticity, surface interactions (such as adhesion), hydrodynamics and intermolecular surface interactions (such as Van der Waals forces). Good agreement has been obtained against experimental results at component and device level.

Active Pharmaceutical Ingredients (APIs) are frequently prepared for delivery to the lung for local topical treatment of diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, or for systemic delivery. One of the most commonly used devices for this purpose is the pressurised metered dose inhaler (pMDI) whereby drugs are formulated in a volatile propellant held under pressure. The compound is aerosolised to a respirably sized dose on actuation, subsequently breathed in by the user. The use of hydrofluoroalkanes (HFAs) in pMDIs since the Montreal Protocol initiated a move away from chlorofluorocarbon (CFC) based devices has resulted in better performing products, with increased lung deposition and a concomitant reduction in oropharyngeal deposition. The physical properties of HFA propellants are however poorly understood and their capacity for solubilising inhaled pharmaceutical products (IPPs) and excipients used historically in CFCs differ significantly. There is therefore a drive to establish methodologies to study these systems in-situ and post actuation to adequately direct formulation strategies for the production of stable and efficacious suspension and solution based products. Characterisation methods have been applied to pMDI dosage systems to gain insight into solubility in HFAs and to determine forms of solid deposits after actuation. A novel quantitative nuclear magnetic resonance method to investigate the physical chemistry of IPPs in these preparations has formed the centrepiece to these studies, accessing solubility data in-situ and at pressure for the first time in HFA propellants. Variable temperature NMR has provided thermodynamic data through van’t Hoff approaches. The methods have been developed and validated using budesonide to provide limits of determination as low as 1 μg/mL and extended to 11 IPPs chosen to represent currently prescribed inhaled corticosteroids (ICS), β2-adrenoagonists and antimuscarinic bronchodilators, and have highlighted solubility variations between the classes of compounds with lipophilic ICSs showing the highest, and hydrophilic β2- agonist/antimuscarinics showing the lowest solubilities from the compounds under study. To determine solid forms on deposition, a series of methods are also described using modified impaction methods in combination with analytical approaches including spectroscopy (μ-Raman), X-ray diffraction, SEM, chromatography and thermal analysis. Their application has ascertained (i) physical form/morphology data on commercial pMDI formulations of the ICS beclomethasone dipropionate (QVAR®/Sanasthmax®, Chiesi) and (ii) distribution assessment in-vitro of ICS/β2-agonist compounds from combination pMDIs confirming co-deposition (Seretide®/Symbicort®, GlaxoSmithKline/AstraZeneca). In combination, these methods provide a platform for development of new formulations based on HFA propellants. The methods have been applied to a number of ‘real’ systems incorporating derivatised cyclodextrins and the co-solvent ethanol, and provide a basis for a comprehensive study of solubilisation of the ICS budesonide in HFA134a using two approaches: mixed solvents and complexation. These new systems provide a novel approach to deliver to the lung, with reduced aerodynamic particle size distribution (APSD) potentially accessing areas suitable for delivery to peripheral areas of the lung (ICS) or to promote systemic delivery.

Class of 2015 Abstract<br>Objectives: To evaluate the in vitro performance of various pressurized metered dose inhaler (pMDI) formulations by cascade impaction primarily focusing on throat deposition, fine particle fraction (FPF), and mass-median aerodynamic diameter (MMADR) measurements Methods: Ten solution pMDIs were prepared with varying cosolvent species in either low (8% w/w) or high (20% w/w) concentration. The chosen cosolvents were either alcohol (ethanol, n-propanol) or acetate (methyl-, ethyl-, and butyl acetate) in chemical nature. All formulations used HFA-134a propellant and 0.3% drug. The pMDIs were tested by cascade impaction with three different inlets to determine the aerodynamic particle size distribution (APSD), throat deposition, and FPF of each formulation. Theoretical droplet evaporation time (DET), a measure of volatility, for each formulation was calculated using the MMADR. Results: Highly volatile formulations with short DET showed consistently lower throat deposition and higher FPF than their lower volatility counterparts when using volume-constrained inlets. However, FPF values were not significantly different for pMDI testing with a non-constrained inlet. The MMADR values generated with volume-constrained inlets did not show any discernible trends, but MMADR values from the non-constrained inlet correlated with DET. Conclusions: Formulations with shorter DET exhibit lower throat deposition and higher FPF, indicating potentially better inhalational performance over formulations with longer DET. There appear to be predictable trends relating both throat deposition and FPF to DET. The shift in MMADR values for volume-constrained inlets suggests that large diameter drug particles are preferentially collected in these inlets.

Background: Aerosol therapy has been established as an efficient form of drug delivery to pediatric and adult patients with respiratory diseases; however, aerosol delivery to the pediatric population is quite challenging. While some studies compare jet nebulizer (JN), vibrating mesh nebulizer (VMN), or JN and pMDI, there is no study comparing these three devices in pediatric and young children. The aim of this study quantifies aerosol deposition using JN, VMN, and pMDI/VHC in a simulated pediatric with active and passive breathing patterns. Methods: Each aerosol generator was placed between manual resuscitator bag (Ambu SPUR II Disposable Resuscitator, Ambu Inc, Glen Burnie, MD) and infant facemask (Mercury Medical, Cleanwater, FL), which was held tightly against the SAINT model. Breathing parameters used in this study were Vt of 100 mL, RR of 30 breaths/min, and I:E ratio of 1: 1.4. Active and passive breathing patterns were used in this study with aerosol device; active breathing pattern was created using a ventilator (Esprit Ventilator, Respironics/Philips Healthcare, Murrysville, PA) connected to a dual chamber test lung (Michigan Instruments, Grand Rapids, MI), which was attached to an absolute filter (Respirgard II, Vital Signs Colorado Inc, Englewood, CO), to collect aerosolized drug, connected to the SAINT model. Pediatric resuscitator bag was run at 10 L/min of oxygen and attached to aerosol generator with facemask. In passive breathing pattern, SAINT model was attached to test lung and ventilated using the resuscitator bag with the same breathing parameters. Each aerosol device was tested three times (n=3) with each breathing patterns. Drug was eluted from the filter and analyzed using spectrophotometry. The amount of drug deposited on the filter was quantified and expressed as a percentage of the total drug dose. To measure the differences in the inhaled drug mass between JN, VMN, and pMDI/VHC in active or passive breathing, one-way analysis of variance (one-way ANOVA) was performed. To quantify the difference in aerosol depositions between the two breathing patterns, independent t-test was performed. A p < 0.05 was considered to be statistically significant. Results: Although the amount of aerosol deposition with the JN was the same in passive and active breathing without any significant difference, the VMN was more efficient in active breathing than the JN (p = 0.157 and p = 0.729, respectively). pMDI/VHC had the greatest deposition in the simulated spontaneous breathing (p=0.013) Conclusion: Aerosol treatment may be administered to young children using JN, VMN, or pMDI/VHC combined with resuscitator bag. Using pMDI/VHC with resuscitator bag is the best choice to deliver albuterol in spontaneously breathing children. Further studies are needed to determine the effectiveness of these aerosol generators with different type of resuscitator bag and different breathing parameters.

Class of 2012 Abstract<br>Specific Aims: To evaluate the in vitro throat deposition and respirable mass of the QVAR® pressurized metered-dose inhaler (pMDI) alone or coupled to an accessory device, such as the AeroChamber Valved Holding ChamberTM or various nonconventional accessory devices. Methods: The performance of the AeroChamber and nonconventional accessory devices, including a toilet paper roll, paper towel roll, rolled paper, plastic bottle spacer, plastic bottle reverse-flow holding chamber, and nebulizer reservoir tubing, were compared to no accessory device. Throat deposition and respirable mass were evaluated using a United States Pharmacopeia (USP) inlet ("throat") coupled to instrumentation for particle size analysis. Each configuration was tested with three actuations and repeated in quadruplicate. The amount of drug deposition was quantified using high-performance liquid chromatography. The data were analyzed using multiple independent t-tests assuming unequal variances. An a priori α-threshold of 0.05 was used with a Bonferroni corrected α of 0.007. Main Results: Compared to the pMDI alone, all of the accessory devices had significantly lower throat deposition (p < 0.001) and significantly higher respirable fraction (p < 0.001). Differences in respirable mass were not significant for any accessory device (p ≥ 0.049), except the paper towel roll and the nebulizer reservoir tubing (p < 0.001). Conclusions: Under these testing circumstances, nonconventional accessory devices, such as the toilet paper roll, rolled paper, plastic bottle spacer, and plastic bottle reverse-flow holding chamber, effectively reduce throat deposition and maintain respirable mass compared to a QVAR pMDI alone. Therefore, they may be suitable alternatives to commercial spacers.

Background: HFNC system is a novel device used with aerosol therapy and seems to be rapidly accepted. Although there are some studies conducted on HFNC and vibrating mesh nebulizer, the effect of HFNC on aerosol delivery using jet nebulizer or pressurized metered-dose inhaler (pMDI) has not been reported. In an effort to examine the effect of HFNC on aerosol deposition, this study was conducted to quantify aerosol drug delivery with or without a HFNC using either pMDI or jet nebulizer. Methodology: The SAINT model, attached to an absolute filter (Respirgard II, Vital Signs Colorado Inc., Englewood, CO, USA) for aerosol collection, was connected to a pediatric breathing simulator (Harvard Apparatus, Model 613, South Natick, MA, USA). To keep the filter and the SAINT model in upright position to collect aerosolized drug, an elbow adapter was connected between the absolute filter and the breathing simulator. An infant HFNC (Optiflow, Fisher & Paykel Healthcare LTD., Auckland, New Zealand) ran at 3 l/min O2 was attached to the nares of the SAINT model. Breathing parameters used in this study were Vt of 100 mL, RR of 30 breaths/min, and I:E ratio of 1: 1.4. Aerosol drug was administered using: 1) Misty-neb jet nebulizer (Allegiance Healthcare, McGaw Park, Illinois, USA) powered by air at 8 l/min using pediatric aerosol facemask (B&F Medical, Allied Healthcare Products, Saint Louis, MO, USA) to deliver albuterol sulfate (2.5 mg/3 mL NS), and 2) Four actuations of Ventolin HFA pMDI (90 μg/puff) (GlaxoSmithKline, Research Triangle Park, NC, USA) combined with VHC (AeroChamber plus with Flow-Vu, Monaghan Medical, Plattsburgh, NY, USA). Aerosol was administered to the model with and without the HFNC and another without (n=3). Drug was collected on an absolute filter, eluted and measured using spectrophotometry. Independent t tests were performed for data analysis. Statistical significance was determined with a p value of <0.05. Results: The mean inhaled mass percent was greatest for pMDI with (p = 0.0001) or without HFNC (p = 0.003). Removing HFNC from the nares before aerosol treatment trended to increase drug delivery with the jet nebulizer (p = 0.024), and increased drug delivery by 6 fold with pMDI (p = 0.003). Conclusions: Aerosol drug may be administered in pediatrics receiving HFNC therapy using either jet nebulizer or pMDI. However, using pMDI, either with or without HFNC, is the best option. When delivering medical aerosol by mask, whether by jet nebulizer or pMDI, removing HFNC led to an increase in inhaled mass percent. However, the benefit of increased aerosol delivery must be weighed against the risk of lung derecruitment when nasal prongs are removed.

Class of 2012 Abstract<br>Specific Aims: To evaluate the in vitro throat deposition and respirable mass of the QVAR® pressurized metered-dose inhaler (pMDI) alone or coupled to an accessory device, such as the AeroChamber Valved Holding ChamberTM or various nonconventional accessory devices. Methods: The performance of the AeroChamber and nonconventional accessory devices, including a toilet paper roll, paper towel roll, rolled paper, plastic bottle spacer, plastic bottle reverse-flow holding chamber, and nebulizer reservoir tubing, were compared to no accessory device. Throat deposition and respirable mass were evaluated using a United States Pharmacopeia (USP) inlet ("throat") coupled to instrumentation for particle size analysis. Each configuration was tested with three actuations and repeated in quadruplicate. The amount of drug deposition was quantified using high-performance liquid chromatography. The data were analyzed using multiple independent t-tests assuming unequal variances. An a priori α-threshold of 0.05 was used with a Bonferroni corrected α of 0.007. Main Results: Compared to the pMDI alone, all of the accessory devices had significantly lower throat deposition (p < 0.001) and significantly higher respirable fraction (p < 0.001). Differences in respirable mass were not significant for any accessory device (p ≥ 0.049), except the paper towel roll and the nebulizer reservoir tubing (p < 0.001). Conclusions: Under these testing circumstances, nonconventional accessory devices, such as the toilet paper roll, rolled paper, plastic bottle spacer, and plastic bottle reverse-flow holding chamber, effectively reduce throat deposition and maintain respirable mass compared to a QVAR pMDI alone. Therefore, they may be suitable alternatives to commercial spacers.

Pressurized metered dose inhalers (pMDIs) are widely utilized to manage diseases of the lungs, such as asthma and chronic obstructive pulmonary disease. They can be formulated such that the drug and/or nonvolatile excipients are dissolved or dispersed in the formulation, rendering a solution or suspension formulation, respectively. While the formulation process for solution pMDIs is well defined, the formulation process of pMDIs with any type of suspended entity can be lengthy and empirical. The use of suspended drug or the addition of a second drug or excipient in a suspension pMDI formulation may non-linearly impact the product performance of the drug of interest in the formulation; this requires iterative testing of a series of pMDIs in order to identify a formulation with the most potential for success. One of the primary attributes used to characterize the product performance and quality control of inhaled medications is the residual aerodynamic particle size distribution (APSD) of the aerosolized drug. Along with clinical factors, formulation and device parameters have a significant impact on APSD. In this study, a computational model was developed using the principles of statistics and physical chemistry to predict the residual APSD generated by suspension pMDIs based on formulation, device, and raw drug or excipient substance considerations. The formulations modeled and experimentally evaluated consist of a suspended drug or excipient with/without a dissolved drug or excipient in a cosolvent-propellant system. The in silico model enables modeling a process that is difficult to delineate experimentally and contributes to understanding the link between pMDI formulation and device to product performance. The ability to identify and understand the variables that affect atomization and/or aerosol disposition , such as initial droplet size, suspended micronized drug or excipient size, and drug or excipient concentration, facilitates defining the design space for suspension pMDIs during development and improves recognizing the sensitive of the APSD is on each hardware and formulation variable. This model can later be applied to limit batch-to-batch variation in the manufacturing process and selecting plausible suspension pMDI formulations with quality design as the end goal.

This research was concerned with the experimental and theoretical investigation of the spray issued from a pressurised metered-dose inhaler (pMDI) and has been motivated by the urgent need to find suitable replacements to the environmentally destructive Cf'Csbased propellants currently used and to extend the working knowledge of the device. The majority of the experimental work was conducted using phase-Doppler anemometry (PDA), a single particle light scattering technique which provides the simultaneous measurement of drop size, velocity and concentration, yielding the most detailed temporal and spatial analysis of the pMDI spray to date. The PDA analysis was complemented by a visual investigation of the near-orifice flow field in an attempt to obtain information on the primary atomization process. The theoretical investigation of the pMDI spray consisted of constructing a model of the fluid flow through the pMDI during a single actuation that was based on a quasi-steadystate separated flow analysis and included a qualitative and quantitative description of the primary atomization process. The construction of a model of the resultant spray was based on the solution of the multiphase transport equations using computational fluid dynamics (eFD) techniques, with the theoretical results being validated against the experimental data. The spray issued from a pMDI was found to be an unsteady, transient, threedimensional, multiphase fluid flow, generally characterised by high initial drop velocities with steep axial velocity radial gradients, small drop sizes, high levels of turbulence and a mean spray cone angle of approximately eleven degrees. The visualisation of the near-orifice flow field suggested that flash evaporation was the primary atomization mechanism, producing a finely pre-atomized spray. The pMDI spray was affected by attitude, it having been observed that the patternation of the spray was biased in the downward direction and this was a consequence of the asymmetric geometry of the actuator nozzle. The results predicted at the near-orifice measurement locations by the theoretical spray model suggested that the theoretical actuator flow model successfully simulated the fluid flow through the pMDI and the primary atomization process during a single actuation for a placebo hydrofluoroalkane formulation. However, the resultsproduced by the theoretical spray model could only be considered as preliminary until further numerical analysis is conducted.

Pressurized metered-dose inhalers (pMDIs) are the most widely-prescribed inhaler devices for therapeutic aerosol delivery in the treatment of lung diseases. In spite of its undoubted therapeutic and commercial success, the propellant flow mechanics and aerosol formation by the pMDIs is poorly understood. The process involves a complex transient cavitating turbulent fluid that flashes into rapidly evaporating droplets, but details remain elusive, partly due to the difficulty of performing experiments at the small length scales and short time scales. The objective of the current work is the development of a numerical model to predict the internal flow conditions (pressure, temperature, velocity, void fraction, quality, etc.) and provide deeper insight into the atomization process and fluid mechanics involved in the twin-orifice of pMDIs. The main focus is propellant metastability, which has been identified by several past authors as a key element that is missing in accounts of pMDI performance. First the flashing propellant flow through single orifice systems (both long and short capillary tubes) was investigated using three different models : homogeneous equilibrium model (HEM), delayed equilibrium model (DEM) and improved delayed equilibrium model (IDEM). Both, the pure propellants and the propellant mixtures were used as working fluid. The numerical results were compared with the experimental data. For long capillary tubes the three models gave reasonable predictions, but the present results showed that DEM predicts the mass flow rate well for pure propellants and IDEM predicts the mass flow rate well for propellant mixtures. For short capillary tubes, the present results showed that DEM predicts the mass flow rate and pressure distribution along the short tube better compared to HEM and IDEM. The geometry of the twin-orifice system of a pMDI is complex and involves several singularities (sudden enlargements and sudden contractions). Various assumptions were made to evaluate their effect on the vaporisation process and to evaluate the flow variables after the shock at the exit of the spray orifice when the flow is choked. Also, three different propellant flow regimes were explored at the inlet of the valve orifice. A specific combination of assumptions, which offers good agreement with the experimental data was selected for further computations. Numerical investigations were carried out using delayed equilibrium model (DEM) with these new assumptions to validate the two-phase metastable flow through twin-orifice systems with continuous flows of various propellants studied previously by Fletcher (1975) and Clark (1991). A new correlation was developed for the coefficient in the relaxation equation. Along with this correlation a constant coefficient was used in the relaxation equation to model the metastability. Both the coefficients showed good agreement against the Fletcher's experimental data. The comparison with the Clark s experimental data showed that the new correlation coefficient predicted the mass flow rate well in compare to that of the constant coefficient, but over predicted the expansion chamber pressure. The DEM with both the coefficients for continuous discharge flows were applied to investigate the quasi-steady flashing flow inside the metered discharge flows at various time instants. The DEM results were compared with the Clark s metered discharge experimental data and the well established homogeneous equilibrium model (HEM). The comparison between the HEM and DEM with Clark s (1991) experimental data showed that the DEM predicted the mass flow well in compare to that of HEM. Moreover, both the models underpredicted the expansion chamber pressure and temperature. The findings of the present thesis have given a better understanding of the role played by the propellant metastability inside the twin-orifice system of pMDIs. Also, these have provided detailed knowledge of thermodynamic state, void fraction and critical velocity of the propellant at the spray orifice exit, which are essential step towards the development of improved atomisation models. Improved understanding of the fluid mechanics of pMDIs will contribute to the development of next-generation pMDI devices with higher treatment efficacy, capable of delivering a wider range of therapeutic agents including novel therapies based around.

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.

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.

Tese de Doutoramento em Engenharia Mecânica<br>Asthma is a respiratory disease that causes chronic airway inflammation. Affecting more than 300 million individuals worldwide, it is a growing public health hazard. Inhalation therapy is the preferred strategy for medication delivery. This therapy is executed through specific delivery devices, whereas the pressurized Metered-Dose Inhaler (pMDI) is one of the most preferred. However, the pMDI efficiency is highly dependent on a correctly executed inhalation procedure. For children under 5 years old (or elderly individuals), it is advisable to use the pMDI coupled with an add-on device (i.e. spacer). Within the spacers, the Valved Holding Chamber (VHC) is the mostly used, due to its good capacity to reduce the pMDI spray coarse fraction and the oral-pharyngeal deposition ( 80%). Additionally, the VHC’s one-way valve allows the patient to maintain his tidal breathing during treatment. The VHC typically delivers a Fine Particle Mass (FPM) that is 20% of the labelled dose. Several design characteristics dictate the VHC performance, such as, the dimensions and the materials. The study herein focus on the assessment of eight commercial VHCs, through experimental and numerical methods. An experimental setup was developed, allowing the evaluation of the devices at constant flow rate (30 L/min and 60 L/min) and at variable flow (sine breath pattern). The waveform was obtained through a breathing simulator specially developed for this purpose, based in a cam-follower mechanism. The salbutamol sulphate (i.e. Ventolin) was collected using a cascade impactor (i.e. MSLI), and assessed by UV-Vis spectrophotometry analysis. Several metrics, regarding VHC performance, were calculated. Results have shown that the VHC capacity reduce the oral-pharyngeal deposition (64% - 94%), which is deeply related with the VHC valve design. It was observed that the VHC reduces the plume coarse fraction ( 70%), keeping the FPM bioequivalent to the pMDI solo. A correlation between the fine particle fraction and the volume of air passing through the VHC was proposed. Patient relevant metrics were suggested to classify the VHC devices upon quantitative and qualitative characteristics. A Computational Fluid Dynamics (CFD) model was developed where the air flow (i.e. 60 L/min)) was calculated along with the pMDI spray modelling as a discrete phase. The spray particle-wall interaction was modelled using different approaches and compared against literature and experimental data. This study, shed some light upon the spray evaporation process inside the VHC, showing that the efficiency of evaporation process is related with the VHC volume. A new VHC design, based in CFD dimensional optimisation of the VHC body is proposed, which shows an improvement of the FPM delivered.<br>A asma é uma doença respiratória que causa a inflamação crónica das vias aéreas. Mundialmente, afeta mais de 300 milhões de indivíduos e é um problema crescente de saúde publica. A terapia de inalação é a estratégia preferida para administrar a medicação de controlo ou de alívio. Esta terapia é executada através de dispositivos específicos, entre os quais o Inalador Pressurizado com Válvula Doseadora (IPVD) é o mais usual. Contudo, a eficiência do IPVD é dependente de uma técnica de inalação correta. Para crianças com menos de 5 anos (ou idosos), é recomendável o uso do IPVD acoplado a um espaçador. Entre os espaçadores, a Câmara Expansora (CE) é a mais utilizada, devido à sua boa capacidade de redução das partículas grandes do aerossol do IPVD, e da redução da deposição orofaringeal ( 80%). Adicionalmente, a válvula de sentido único da CE, permite que o paciente mantenha a sua respiração normal durante o tratamento. A CE emite, tipicamente, uma massa de partículas finas (MPF) que é 20% da dose calibrada do IPVD. Este estudo foca-se na avaliação de oito CEs, através de uma metodologia experimental e numérica. Uma instalação experimental foi projetada para a avaliação dos dispositivos a fluxo constante (30 L/min e 60 L/min) e variável (um padrão respiratório sinusoidal). A onda foi obtida através de um simulador respiratório especialmente desenvolvido para este propósito, o qual foi baseado num mecanismo cam-seguidor. O sulfato de salbutamol (Ventilan HFA) foi recolhido utilizando um impactor em cascata em vários estágios (Aparelho C da Farmacopeia Portuguesa), e quantificado por espetrofotometria UV-Visivel. Foram calculadas várias métricas sobre o desempenho das CEs. Os resultados demonstram a capacidade da CE para reduzir a deposição orofaringeal (64% - 94%), a qual está intrinsecamente relacionada com o design da válvula do dispositivo. Foi observado que a CE reduz a fração de partículas grandes na pluma ( 70%), mantendo a MPF bioequivalente à emitida pelo IPVD. Foi proposta uma correlação entre a fração de partículas finas e o volume de ar que atravessa a CE. Foram também sugeridas métricas com relevância para o paciente, que classificam as CEs de forma quantitativa e qualitativa. Foi desenvolvido um modelo de Dinâmica Computacional de Fluidos (DCF), onde o fluxo de ar (a 60 L/min) foi calculado juntamente com o aerossol do IPVD, tendo sido este modelado como uma fase discreta. A interação entre partícula e parede foi modelada utilizando diferentes aproximações matemáticas, sendo posteriormente comparadas com a literatura e dados experimentais. Este estudo contribui com um melhor conhecimento do processo de evaporação das gotas do aerossol dentro da CE, onde se verificou que este processo está relacionado com o volume da CE. Foi proposto em novo design para CE, baseado numa otimização das dimensões do corpo da CE, que demonstra melhoria da MPF emitida.