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This research explored in-vitro and in-vivo performance of three salbutamol metered dose inhalers (MDIs): Ventolin Evohaler (Evo), Airomir (Airo) and Salamol. In the in-vitro studies, critical quality attributes of the MDI using an Andersen cascade impactor (ACI) were examined and included measurement of fine particle dose (FPD) and total delivered dose (TDD). Bioequivalence studies were conducted in humans using the urinary pharmacokinetic method. Post-inhalation urinary excretion of salbutamol in the first 0.5 hour (lung deposition, USAL0.5) and over 24 hours (total systemic bioavailability, USAL24) were compared to determine the bioequivalence of the MDIs. The spacers recommended for use with these inhalers were also studied, and charcoal block studies were performed to assess the extent of USAL0.5. The three MDIs had FPD (μg) of 78, 91 and 89, respectively; the latter pair was equivalent. Their USAL0.5 (6, 7 & 7 μg) was however not bioequivalent. These MDIs delivered equivalent dose (177, 174 & 180 μg) which reflected on their USAL24 (101, 84 & 97 μg). Nevertheless, USAL24 was inequivalent between Evo and Airo. The FPD of Evo with Volumatic (VOL), AeroChamber Plus (AERO) and Able spacer was 78, 68 and 74 μg, respectively. The AERO treatment method was not equivalent to the MDI while VOL and Able were equivalent between them. Spacer USAL0.5 (16, 15 & 14 μg) was not bioequivalent to the MDI but to each other. The spacer in-vitro TDD (95, 85 & 92 μg) was inequivalent to the MDI treatment method. In contrast, their USAL24 was bioequivalent (97, 85 & 90 μg). The FPD of Airomir with AERO (95 μg) was in-vitro equivalent while USAL0.5 (15 μg) of this treatment method was bio-inequivalent to the MDI alone. On the contrary, the TDD (110 μg) and USAL24 (84 μg) of AERO were respectively in-vitro inequivalent and bioequivalent to the MDI alone. The FPD (μg) of Salamol MDI alone and with VOL (84) and AERO (86) as well as between the spacers was equivalent. However, the USAL0.5 of the MDI was not bioequivalent to spacers (20 and 18 μg) despite being equivalent between the spacers. In contrast, the respective TDD (103 and 95 μg) of spacer treatment methods were in-vitro inequivalent to the MDI alone albeit having bioequivalent USAL24 (86 and 87 μg). The variations in the in-vitro performance of the three MDIs are most likely due to differences in their formulations and designs. As the performance metrics of the MDI influence lung deposition, substituting one MDI with another can have clinical implications. Although the spacers reduced in-vitro TDD of the MDI to about half, their use increased lung deposition by over two folds, the magnitude of which varied with the MDI and spacer type. Despite significant decrease in dose delivery, the total systemic bioavailability with the spacers was similar to that with the MDI alone. This systemic bioequivalence is more likely due to greater USAL0.5 with the spacers. The results of the charcoal block studies reinforced this outcome. The present study is unique as it used a clinically relevant salbutamol MDI dose (two puffs), assessed results for equivalence and analysed ACI deposition data further as stage groups. The deposition on adjacent ACI stages were grouped together as coarse, fine and extra-fine particle masses to identify their more likely deposition sites in the human respiratory tract. Moreover, this thesis describes highly sensitive and novel HPLC and SPE methods, developed and validated to quantify salbutamol in urinary and aqueous matrices. As the clinical effects of MDIs are related to their lung deposition, the current work emphasizes the importance of spacer use. Nevertheless, differences in dose delivery between spacers may have clinical consequences. Hence, only the specific spacer recommended for use with the MDI should be used. / World Federation, Stanmore, London and Sadaat Welfare Foundation, Bradford, West Yorkshire

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.