BACKGROUND Inhalation therapy has proven to be the best way to control the asthma and chronic obstructive pulmonary disease symptoms. The most commonly used delivery system to control these symptoms is the metered-dose inhaler. The primary goal of this study is to demonstrate an association between incorrect inhaler use and patient age. METHODS This is a cross-sectional study, performed at Centro Médico Naval “Cirujano Mayor Santiago Távara”, in Callao, Peru, in 2014. Patients older than 18 years that used metered-dose inhalers were included. We used film recordings of patients using a metered-dose inhaler and compared their technique with the recommendations on the guidelines on the correct use of inhalers of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). The main variables measured were age and incorrect inhaler use. The results were analyzed with the Chi squared test for bivariate analysis, and for multivariate analysis we used the Poisson regression model with robust variance. RESULTS We included 378 patients in the analysis; 167 were older than 60 years. An association was found between incorrect inhalator technique and age (p=0.014) (PR 1.19 95% CI 1.03 to 1.37). The highest prevalence of incorrect technique was found in the young adult population (88%). There was no association between the incorrect technique and the person who taught it (p=0.114). Finally, this study showed that 81.2% of the study population presented an incorrect inhalation technique. CONCLUSIONS The percentage of incorrect inhaler use, in the general population is high. Even if we found no association between an incorrect technique and the person who taught it; still, there is a high percentage of errors and it was even demonstrated that being instructed by a pulmonologist does not guarantee a correct performance of metered-dose inhaler inhalations. / INTRODUCCIÓN La terapia inhalatoria ha demostrado ser la más rápida y eficaz para el control del asma y la enfermedad pulmonar obstructiva crónica. El inhalador de dosis medida es el más usado por la población. El objetivo de este estudio es evidenciar la asociación entre la técnica inhalatoria incorrecta y la edad. MÉTODOS Estudio observacional, analítico, de corte transversal realizado en Perú durante 2014. Se incluyeron pacientes desde los 18 años que utilizaran inhalador de dosis medida. Se utilizó una lista de verificación de pasos establecidos por la Sociedad Española de Neumología y Cirugía Torácica y filmaciones para evaluar la técnica inhalatoria de los pacientes. Las variables principales fueron la edad y la mala técnica inhalatoria práctica. Para el análisis bivariado se utilizó la prueba Chi cuadrado y para el análisis multivariado regresión de Poisson con varianza robusta. RESULTADOS Se incluyeron 378 pacientes; 167 fueron mayores de 60 años. El estudio reveló que el 81,2% de la población presentó una incorrecta técnica inhalatoria. Se encontró asociación entre la edad y la técnica inhalatoria incorrecta (p=0,014) (PR 1,19 con IC 95% 1,03-1,37). El grupo etario con mayor frecuencia de técnica incorrecta fue el de adultos jóvenes (88%). CONCLUSIONES La frecuencia de uso incorrecto del inhalador en la población es alta y esta característica predomina en el grupo de adultos jóvenes. A pesar de no haber asociación entre la persona que enseña la técnica inhalatoria y el desempeño de la misma, se demostró que existe alta frecuencia de errores, incluso en aquellos pacientes instruidos por un médico especialista.

Class of 2012 Abstract / 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: Aerosol therapy using albuterol is one of the most prescribed asthma treatments. The most frequently used methods of aerosol delivery are pneumatic jet nebulizer (JN), pressurized metered-dose inhaler (pMDI), and breath-actuated nebulizer (BAN). Choosing among these devices is usually not based on thorough comparison of efficiency or cost. We compare the efficiency of these three devices using a spontaneously breathing adult model. METHODS: We connected each aerosol generator—JN, BAN, or pMDI with a valved holding chamber (VHC)—to the face of an adult teaching manikin. Below the bifurcation, an elbow adaptor was connected to a corrugated tube and was angled to be at a lower level than the collecting filter to prevent droplets from dripping directly into the collecting filter. From the collecting filter, another corrugated tube was connected to a prevention filter, which was then connected to an adult breathing simulator. Spontaneous breathing parameters were VT 450 mL, RR 20/min, and I: E ratio 1:2. First, we compared JN, BAN (2.5 mg/3 mL), and pMDI (4 puffs); second, we compared JN and BAN 2.5 mg/0.5 mL plus 0.5 mL normal saline. Data were analyzed using spectrophotometry (276 nm). One-way ANOVA and independent sample t-tests were used (p<0.05). RESULTS: There were no differences in inhaled mass percentage (p=0.172) JN, BAN, and pMDI in the first experiment. Treatment time with BAN was significantly longer (p=0.0001) than with JN or pMDI. In the second experiment, BAN delivered more medication (p=0.004) than jet nebulizer. Treatment time was significantly less with JN (p=0.010). There was no difference in residual volume among JN and BAN in both experiment (p=0.765, p=0.115). CONCLUSIONS: All the devices that were compared using a 3 ml or 4 pMDI puffs delivered comparable amount of medication with no significant difference. However, BAN using 1ml fill volume delivers more drug compared to JN. Additionally, treatment time was longest with BAN. Even with reduction of its filling volume, BAN delivers a higher amount of medication to that of pMDI but was not statistically significant.

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 2012 Abstract / 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.

Class of 2015 Abstract / 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.

Embargoed until July 2016. / 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.

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.

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.