No / The dose emitted from dry powder inhalers may be inhalation flow-dependent. Using an ex vivo method, the Electronic Lung¿, we have measured the aerodynamic characteristics of the emitted dose for both active constituents from Seretide® Diskus® (salmeterol xinafoate 50 mcg; fluticasone propionate 500 mcg) and Symbicort® Turbuhaler® (formoterol 6 mcg; budesonide 200 mcg).1 Electronic inhalation profiles were collected from 20 severe asthmatics (mean PEFR 53% predicted) when they inhaled using a placebo Seretide® Diskus® and a placebo Symbicort® Turbuhaler®. These were replayed in the Electronic Lung¿ with the respective active inhaler in situ. Mean(S.D.) peak inhalation flow rates (PIFR) through the Diskus® and Turbuhaler® were 94.7(32.9) and 76.8(26.2) l min¿1, respectively. From the Electronic Lung¿ the Diskus® inhalation profiles provided a mean(S.D.) fine particle dose (FPD) for fluticasone propionate and salmeterol of 20.4(4.8) and 18.4(4.4)% labelled dose. For Turbuhaler® inhalation profiles the FPD was 23.1(12.9) and 20.7(11.1)% labelled dose for budesonide and formoterol, respectively. The linear (p < 0.001) relationships between FPD against PIFR for budesonide and formoterol were 3 (p = 0.002) and 2.8 (p = 0.007) times steeper than fluticasone propionate and salmeterol, respectively. The results highlight a more significant effect of inspiratory flow on variable dosage emission when using the Symbicort® Turbuhaler® compared with the Seretide® Diskus®.

The primary aim was to validate and implement a urinary pharmacokinetic method for terbutaline to determine the relative lung and systemic bioavailability following inhalation and to measure the in-vitro characteristics of the emitted dose by these inhalation methods. Two new robust, accurate and sensitive high performance liquid chromatography methods for the determination of terbutaline in aqueous and urine samples were validated in accordance with the FDA and ICH guidelines. Terbutaline was extracted using solid phase extraction with salbutamol and bamethane as internal standards. The accuracy, precision, lower limit of detection and recovery for both methods were within recognized limits. The in-vitro characteristics of terbutaline sulphate inhalers were measured according to standard compendial methodology as well as adaptation of this methodology to simulate routine patient use. The dose emission of terbutaline sulphate from a Bricanyl Turbuhaler was determined using an inhalation volume of 4 L at inhalation flows of 10-60 L min-1. The particle size distribution was measured using an Anderson Cascade Impactor (ACI) with a mixing inlet valve to allow measurement at different flows. A steady increase in total emitted dose (TED) and the fine particle dose (FPD) was observed as the inhalation flow increased thereby highlighting the flow dependent dose emission characteristics of the Turbuhaler. The in-vitro dose emission characteristics of terbutaline sulphate from Bricanyl MDIs were measured according to the standard compendial methodology at a flow of 28.3 L min-1 using a 4 L inhalation volume. The TED and particle size distribution of terbutaline sulphate from the Bricanyl MDI were determined alone and with different spacers [AeroChamber Max (AMAX), AeroChamber Plus (APLUS), Fisonair and Nebuhaler]. The TED from the MDI alone was significantly higher than all MDI+spacers (p<0.001). The MDI with APLUS resulted in the smallest mass median aerodynamic diameter (MMAD) and the highest fine particle fraction (FPF). The MDI with AMAX resulted in the highest FPD. The in-vitro characteristics of terbutaline sulphate from Bricanyl respules using the Aeroneb Pro (vibrating mesh) and Sidestream jet nebulisers were determined by the CEN methodology and the Next Generation Impactor (NGI) methodology. The Aeroneb Pro was found to have significantly better aerodynamic properties than the Sidestream. The results from the NGI method were significantly different from the CEN method suggesting further evaluation of both methods. Cooling the NGI decreased the evaporation effect. Twelve healthy volunteers (6 females) completed in-vivo urinary terbutaline pharmacokinetic studies to determine the relative bioavailability following inhalation. The differences between the amounts excreted 0.5, 1, 2, 4, 6 and 24 hour post inhalation from a Bricanyl MDI (I) and oral (O) dosing of 500 µg terbutaline sulphate and with the co-administration of oral charcoal (IC and OC, respectively) were studied. No terbutaline was found in OC samples. The amount of terbutaline excreted 30 minutes post I and IC were significantly (p<0.001) higher than post O suggesting that the amount of terbutaline excreted 30 minutes post dosing can be used as an index of the lung deposition. The amount of terbutaline excreted 24 hour post I was significantly (p<0.01) higher than post O suggesting that the amount of terbutaline excreted 24 hour post dosing can be used as an index of the relative systemic bioavailability. The dose response relationships and the low inter and intra-subject variability studies confirm the feasibility of this method. To demonstrate the application of the method the effect of inhalation technique on the lung and systemic bioavailability following inhalation from a dry powder inhaler was evaluated. The effect of different spacers on the dose emitted from the Bricanyl MDI and the effect of different nebulisers on the dose emitted were also studied using twelve healthy volunteers (6 females) for each study. A fast inhalation flow using the Bricanyl Turbuhaler resulted in significantly higher amounts of terbutaline excreted 0.5 and 24 hour post dosing (2 doses of 500µg terbutaline sulphate from Bricanyl Turbuhaler) than slow inhalation flow (p<0.001). The Bricanyl MDI alone resulted in a significantly higher amount of terbutaline excreted 24 hour post dosing (2 doses of 250µg terbutaline sulphate from Bricanyl MDI) and significantly lower amounts excreted 30 minutes post dosing than the MDI+Spacers. The AMAX provided a greater amount of urinary terbutaline excreted 30 minutes post dosing than the APLUS and Nebuhaler. The Aeroneb Pro resulted in significantly higher amounts of terbutaline excreted 0.5 and 24 hour post dosing (1 dose of 5mg/2ml terbutaline sulphate from Bricanyl respule) than a Sidestream Jet nebuliser (p<0.001). Further application of the method was demonstrated by 12 (6 female) COPD non-invasive mechanically ventilated patients. One dose of 2mg in 0.8ml terbutaline sulphate respiratory solution from Aeroneb Pro and one dose of 5mg in 2ml terbutaline sulphate respiratory solution from Sidestream jet nebuliser resulted in a similar amounts of urinary terbutaline excreted 0.5 and 24 hour post dosing. The results were consistent with the results of the ex-vivo study performed on the same patients. The thesis highlights extension of the urinary pharmacokinetic method following inhalation to terbutaline and its application in volunteer and patient studies.

The primary aim was to validate and implement a urinary pharmacokinetic method for terbutaline to determine the relative lung and systemic bioavailability following inhalation and to measure the in-vitro characteristics of the emitted dose by these inhalation methods. Two new robust, accurate and sensitive high performance liquid chromatography methods for the determination of terbutaline in aqueous and urine samples were validated in accordance with the FDA and ICH guidelines. Terbutaline was extracted using solid phase extraction with salbutamol and bamethane as internal standards. The accuracy, precision, lower limit of detection and recovery for both methods were within recognized limits. The in-vitro characteristics of terbutaline sulphate inhalers were measured according to standard compendial methodology as well as adaptation of this methodology to simulate routine patient use. The dose emission of terbutaline sulphate from a Bricanyl Turbuhaler was determined using an inhalation volume of 4 L at inhalation flows of 10-60 L min-1. The particle size distribution was measured using an Anderson Cascade Impactor (ACI) with a mixing inlet valve to allow measurement at different flows. A steady increase in total emitted dose (TED) and the fine particle dose (FPD) was observed as the inhalation flow increased thereby highlighting the flow dependent dose emission characteristics of the Turbuhaler. The in-vitro dose emission characteristics of terbutaline sulphate from Bricanyl MDIs were measured according to the standard compendial methodology at a flow of 28.3 L min-1 using a 4 L inhalation volume. The TED and particle size distribution of terbutaline sulphate from the Bricanyl MDI were determined alone and with different spacers [AeroChamber Max (AMAX), AeroChamber Plus (APLUS), Fisonair and Nebuhaler]. The TED from the MDI alone was significantly higher than all MDI+spacers (p<0.001). The MDI with APLUS resulted in the smallest mass median aerodynamic diameter (MMAD) and the highest fine particle fraction (FPF). The MDI with AMAX resulted in the highest FPD. The in-vitro characteristics of terbutaline sulphate from Bricanyl respules using the Aeroneb Pro (vibrating mesh) and Sidestream jet nebulisers were determined by the CEN methodology and the Next Generation Impactor (NGI) methodology. The Aeroneb Pro was found to have significantly better aerodynamic properties than the Sidestream. The results from the NGI method were significantly different from the CEN method suggesting further evaluation of both methods. Cooling the NGI decreased the evaporation effect. Twelve healthy volunteers (6 females) completed in-vivo urinary terbutaline pharmacokinetic studies to determine the relative bioavailability following inhalation. The differences between the amounts excreted 0.5, 1, 2, 4, 6 and 24 hour post inhalation from a Bricanyl MDI (I) and oral (O) dosing of 500 µg terbutaline sulphate and with the co-administration of oral charcoal (IC and OC, respectively) were studied. No terbutaline was found in OC samples. The amount of terbutaline excreted 30 minutes post I and IC were significantly (p<0.001) higher than post O suggesting that the amount of terbutaline excreted 30 minutes post dosing can be used as an index of the lung deposition. The amount of terbutaline excreted 24 hour post I was significantly (p<0.01) higher than post O suggesting that the amount of terbutaline excreted 24 hour post dosing can be used as an index of the relative systemic bioavailability. The dose response relationships and the low inter and intra-subject variability studies confirm the feasibility of this method. To demonstrate the application of the method the effect of inhalation technique on the lung and systemic bioavailability following inhalation from a dry powder inhaler was evaluated. The effect of different spacers on the dose emitted from the Bricanyl MDI and the effect of different nebulisers on the dose emitted were also studied using twelve healthy volunteers (6 females) for each study. A fast inhalation flow using the Bricanyl Turbuhaler resulted in significantly higher amounts of terbutaline excreted 0.5 and 24 hour post dosing (2 doses of 500µg terbutaline sulphate from Bricanyl Turbuhaler) than slow inhalation flow (p<0.001). The Bricanyl MDI alone resulted in a significantly higher amount of terbutaline excreted 24 hour post dosing (2 doses of 250µg terbutaline sulphate from Bricanyl MDI) and significantly lower amounts excreted 30 minutes post dosing than the MDI+Spacers. The AMAX provided a greater amount of urinary terbutaline excreted 30 minutes post dosing than the APLUS and Nebuhaler. The Aeroneb Pro resulted in significantly higher amounts of terbutaline excreted 0.5 and 24 hour post dosing (1 dose of 5mg/2ml terbutaline sulphate from Bricanyl respule) than a Sidestream Jet nebuliser (p<0.001). Further application of the method was demonstrated by 12 (6 female) COPD non-invasive mechanically ventilated patients. One dose of 2mg in 0.8ml terbutaline sulphate respiratory solution from Aeroneb Pro and one dose of 5mg in 2ml terbutaline sulphate respiratory solution from Sidestream jet nebuliser resulted in a similar amounts of urinary terbutaline excreted 0.5 and 24 hour post dosing. The results were consistent with the results of the ex-vivo study performed on the same patients. The thesis highlights extension of the urinary pharmacokinetic method following inhalation to terbutaline and its application in volunteer and patient studies. / Egyptian Culture Office in UK, Missions Department in Egypt

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.

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.