In-vitro inhalation performance for formoterol dry powder and metred dose inhalers. In-vitro characteristics of the emitted dose from the formoterol dry powder and metred dose inhalers to identify the influence of inhalation flow, inhalation volume and the number of inhalation per dose.
SupervisorAssi, Khaled H.
Metered dose inhaler (MDI)
The University of Bradford theses are licenced under a Creative Commons Licence.
InstitutionUniversity of Bradford
DepartmentSchool of Pharmacy
MetadataShow full item record
AbstractThe 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.
Showing items related by title, author, creator and subject.
Investigations to identify the influence of the inhalation manoeuvre on the ex-vivo dose emission and the in-vitro aerodynamic dose emission characteristics of dry powder inhalers: Studies to identify the influence of inhalation flow, inhalation volume and the number of inhalations per dose on the ex-vivo dose emission and the in-vitro aerodynamic dose emission characteristics of dry powder inhalers.Chrystyn, Henry; Assi, Khaled H.; Ibn Yakubu, Sani (University of BradfordInstitute of Pharmaceutical Innovation, 2011-04-04)Currently available dry powder inhalers (DPIs) for drug delivery to the lungs require turbulent energy to generate and disperse aerosol particles in the respirable range ¿5¿m during inhalation. The patient's inspiratory effort together with the resistance inside the device creates this energy. Different inhalers provide varying degrees of resistance to inhalation flow and require different inhalation techniques for the generation and delivery of drug fine particles in respirable size range to the lungs. The aim of this research programme was to identify the influence of inhalation flow, inhalation volume and the number of inhalations per dose on the ex-vivo dose emission and the in-vitro aerodynamic dose emission characteristics of the salbutamol Accuhaler®, Easyhaler®, and Clickhaler® and the terbutaline Turbuhaler® DPIs. A high-performance liquid chromatography method for the assay of salbutamol sulphate and terbutaline sulphate in aqueous samples was modified and accordingly validated. In-vitro dose emission of the four different DPIs was measured using the pharmacopoeia method with modifications to simulate varying inhalation flows within patient and between patients. The ranges of the total emitted dose (% nominal dose) at the inhalation flow range of 10 - 60 Lmin-1, following one and two inhalations per metered dose for 2L and 4L inhaled volumes were as follows: the Accuhaler (52.64- 85.11; 61.88-85.11 and 59.23-85.11; 62.81-85.11); the Easyhaler (68.35-91.99; 79.94-91.99 and 73.83-92.51; 80.40-92.51); the Clickhaler (46.55-96.49; 51.12-96.49 and 51.18-101.39; 59.71-101.39) as well as the Turbuhaler (46.08-88.13; 51.95-88.13 and 48.05-89.22; 48.64-89.22). The results highlight that the four inhalers have flow-dependent dose emission property to a varying degree using 2L and 4 L inhaled volumes. There was no significant difference in the total emitted dose between a 2L inhaled volume and a 4L inhaled volume at each inhalation flow. Furthermore, the total emitted dose from the Easyhaler®, Clickhaler®, and Turbuhaler® was significantly (p¿0.001) greater with two inhalations than one inhalation per metered dose across the range of inhalation flow (10 ¿ 60) Lmin-1. This effect was only observed at inhalation flow less than 30 Lmin-1 with the Accuhaler®. Overall there is a significant difference in the total emitted dose. The ex-vivo dose emission of the four different DPIs has been determined using the In- Check Dial device to train twelve non-smoking healthy adult volunteers to inhale at slow (30 Lmin-1) and fast (60 L min-1) inhalation flows through the device with its dial set corresponding to each inhaler. Subsequently each volunteer inhaled at the trained inhalation flows through each active inhaler. The local ethics committee approval was obtained prior to the study and all volunteers gave signed informed consent. The results obtained demonstrate that the studied inhalers have flow-dependent dose emission, thereby enhancing confidence in the use of the In-Check Dial® to identify a patient¿s inhalation flows through a variety of DPIs. Also the total emitted dose determined by ex-vivo methodology was significantly (p¿0.05) greater with two inhalations than one inhalation per metered dose. The results of the in-vitro aerodynamic dose emission characteristics highlight that the fine particle dose (FPD) from the four studied inhalers is flow dependent. Also the minimum inhalation flow to generate the (FPD) with the appropriate characteristics for lung deposition has been identified to be 20 L min-1 for the Accuhaler®, Easyhaler® and Clickhaler®, while that for the Turbuhaler® is about 30 L min-1. Also the inhalation volume above 2L and the number of inhalations for each dose have respectively no significant (p¿0.05) influence on the FPD emitted from the four studied inhalers. The results support the present instructions to patients using these inhalers to inhale once for each dose as fast as they can.
Evaluation of novel tool to ensure asthma and COPD patients use the approved inhalation technique when they use an inhaler. Clinical pharmacy studies investigating the impact of novel inhalation technique training devices and spacers on the inspiratory characteristics, disease control and quality of life of patients when using their inhalers.Chrystyn, Henry; Smythe, James W.; Ammari, Wasem G.S. (University of BradfordBradford School of Pharmacy, 2010-09-01)Many respiratory patients misuse their inhaler. Although training improves their inhaler technique, patients do forget the correct inhaler use with time. In the current work, three clinical studies investigated novel tools designed with feedback mechanisms to ensure patients use the correct inhalation method when using their inhaler. Research Ethics Committee approval was obtained and all the participants signed an informed consent form. In the first study, the recruited asthmatic children (n=17) and adults (n=39) had their metered dose inhaler (MDI) technique assessed. Those who attained the recommended inhalation flow rate (IFR) of < 90 l/min through their MDI formed the control group. Whilst those who had a poor MDI technique with an IFR ¿ 90 l/min were randomized into either the verbal counselling (VC) group; or the 2ToneTrainer (2TT) group that, in addition to the verbal training, received the 2ToneTrainer MDI technique training device equipped with an audible feedback mechanism of correct inhalation flow. All the participants were assessed on two occasions (6 weeks apart) for their inhalation flow rate, asthma control and quality of life. The study showed that the 2ToneTrainer tool was as efficient as verbal training in improving and maintaining the asthmatic patients¿ MDI technique, particularly using the recommended slow inhalation flow through the MDI. Although statistically insignificant, potential improvement in quality of life was demonstrated. The 2ToneTrainer tool has the advantage of being available to the patients all the time to use when they are in doubt of their MDI technique. In the second research study, the inhalation profiles of asthmatic children (n=58) and adults (n=63), and of COPD patients (n=63) were obtained when they inhaled through the novel Spiromax dry powder inhaler (DPI) which was connected to an electronic pressure change recorder. From these inspiratory profiles; the peak inhalation flow, inhalation volume and inhalation acceleration rate were determined. The variability (23% - 58%) found in these inhalation profile parameters among various patient groups would be expected in all DPIs. The effect of the inhalation acceleration rates and volumes on dose emission characteristics from DPIs should be investigated. Attention, though, should be paid to the patients¿ realistic inhalation profile parameters, rather than the recommended Pharmacopoeial optimal inhalation standard condition, when evaluating the in-vitro performance of DPIs. Finally, in preschool asthmatic children, the routine use of the current AeroChamber Plus spacer (n=9) was compared with that of a novel version; the AeroChamber Plus with Flow-Vu spacer (n=10) over a 12-week period. The Flow-Vu spacer has a visual feedback indicator confirming inhalation and tight mask-face seal. The study showed that the new AeroChamber Plus with Flow-Vu spacer provided the same asthma control as the AeroChamber Plus in preschool children and maintained the same asthma-related quality of life of their parents. However, the parents preferred the new Flow-Vu spacer because its visual feedback indicator of inhalation reassured them that their asthmatic children did take their inhaled medication sufficiently.
Determination of the Relative Bioavailability of salbutamol to the lungs following inhalation from dry powder inhaler formulations containing drug substance Manufactured by supercritical fluids and micronizationRichardson, Catherine H.; de Matas, Marcel; Hosker, K.; Mukherjee, R.; Wong, Ian; Chrystyn, Henry (2007)Purpose The relative lung bioavailability of salbutamol sulfate particles produced using supercritical fluids (SEDS¿) and delivered by dry powder inhaler (DPI) was compared with the performance of a conventional micronized drug DPI using the same device design (Clickhaler¿, Innovata Biomed). Materials and Methods Twelve healthy volunteers and 11 mild asthmatic patients completed separate four-way randomised cross-over studies, assessing the relative bioavailability of salbutamol sulfate (urinary excretion method), formulated as SEDS¿ particles (three batches) and micronized particles (Asmasal¿ inhaler, UCB Pharma Ltd). Post-treatment improvements in patient lung function were assessed by measuring FEV1. Physicochemical evaluation of the three SEDS¿ batches revealed inter-batch differences in particle size and shape. Results There was no significant difference in the relative lung bioavailability of salbutamol and its bronchodilator response between the best performing SEDS¿ formulation and the Asmasal¿ inhaler in volunteers and patients, respectively. SEDS¿ salbutamol sulfate showing wafer like morphology gave greater fine particle dose, relative lung bioavailability and enhanced bronchodilation compared to other SEDS¿ batches containing elongated particles. Conclusions Active Pharmaceutical Ingredient (API) manufactured using supercritical fluids and delivered by DPI can provide similar lung bioavailability and clinical effect to the conventional micronized commercial product. Product performance is however notably influenced by inter-batch differences in particle characteristics.