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1
Azouz, Wahida Ahmed Abugrara. "Novel methodology to characterise how asthma and chronic obstructive pulmonary disease patients use their inhalers and methods to improve their inhaler technique : objective assessment of how patients use inhalers." Thesis, University of Huddersfield, 2012. http://eprints.hud.ac.uk/id/eprint/17484/.
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Inhaled administration is the mainstay of asthma and chronic obstructive pulmonary disease (COPD) management using either a pressurised metered dose inhaler (pMDI) or a dry powder inhaler (DPI). Poor disease control and increased hospitalisations is linked to poor inhaler technique. Previous studies to assess inhaler technique have used subjective measures and there is very limited data about the inhalation characteristics used by patients when they use their inhalers. Inhalation flow profiles when patients use their pMDI and inhalation pressure profiles when they use DPIs have been measured using 659 subjects (106 children with asthma [CHILD], 361 adults with asthma [ADULT], 142 COPD [COPD] and 50 healthy volunteers [HEALTHY]) in 5 separate studies. All patient studies used their real life inhaler technique. One of the studies also evaluated the value of using a pMDI co-ordination aid and training these patients to prolong their inhalation whilst a different one investigated the impact of using enhanced training when using a DPI. The first study, 20 CHILD, 57 ADULT and 32 COPD subjects, revealed that the mean (SD) inhalation flows through a pMDI were 108.9 (40.4), 146.0 (58.8) and 107 (50.6) L/min, respectively and only 7, 10 and 10 used a slow flow. In the second pMDI study involving, 20 CHILD, 130 ADULTS, 31 COPD patients, their flows were 70.5 (36.4), 131.4 (60.8) and 70.9 (28.1) L/min and 5, 53 and 10 used their pMDI with good co-ordination. However only 3, 6 and 9 patients had good co-ordination and slow flow. In the third study, 71 ADULT patients, the mean (SD) pMDI inhalation flow was 155.6 (61.5) L/min which decreased (p<0.001) to 112.3 (48.4) when the pMDI was fitted with a co-ordination aid. This was due to the increased resistance to airflow from the aid. Inhalation flow further reduced (p<0.001) to 73.9 (34.9) L/min when patients were trained to prolong their inhalations. Their inhaled volumes did not change whereas mean (SD) inhalation times were 1.60 (0.21), 1.92 (0.80) and 2.66 (1.03) seconds (p< 0.001) respectively. There was a good correlation between their inhaled volume and forced vital capacity with a ratio of 0.7 suggesting that the patient used a full inhalation. A DPI study, involving 16 CHILD, 53 ADULT and 29 COPD patients, measured inhalation characteristics through different DPIs (low to high resistance) when patients used their real life DPI inhalation manoeuvres. The inhalation characteristics were lower in CHILD and highest in ADULT. Overall flows were higher when using low resistance DPIs but the pressure changes and the acceleration of the inhalation flow were significantly higher with high resistance DPIs which suggest more efficient de-aggregation of the formulation. There was a tendency for more problems with low resistance DPIs than high resistance DPIs. The last study involved CHILD, ADULT, COPD and HEALTHY subjects (50 of each) when they inhaled through a Spiromax and a Turbuhaler (similar resistance) after standard verbal inhalation technique training and when using enhanced training with an IN-Check Dial. The order of inhalation characteristics was HEALTHY > ADULT > COPD > CHILD. Significant (p<0.001) improvements in the inhalation flows, pressure changes and acceleration of the flow were achieved in all groups after the enhanced training. The studies provide an insight into the inhalation characteristics of patients when they use different inhalers. The main problem with pMDI use was short inhalation times and when patients were trained to prolong their inhalation then flows reduced. Enhanced training when using a DPI significantly improved the technique of all patients.
2
Lord, John David. "Particle interactions in dry powder inhalations." Thesis, University of Bath, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336708.
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Kjellberg, Karolina Charlotte. "Microparticle adhesion in model metered dose inhalers." Thesis, University College London (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515063.
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Jones, Stuart Allen. "The formation of novel hydrofluoroalkane metered dose inhalers." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417774.
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Kopsch, Thomas. "Computational modelling and optimization of dry powder inhalers." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275902.
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Dry powder inhalers (DPIs) are a common therapeutic modality for lung diseases such as asthma, but they are also used to treat systemic diseases such as diabetes. Advantages of DPIs include their portable design and low manufacturing costs. Another advantage of DPIs is their breath activation, which makes them popular among patients. In a passive DPI drug is only released when the patient inhales. When the patient inhales, air flows through the device. The flow of air entrains a dry powder formulation inside the device and carries it to the lung. Currently, no DPI exists which can deliver drug independent of the patient to the desired target site in the lung. This is because drug release depends on the patient’s inhalation manoeuvre. To maximize the effect of the treatment it is necessary to optimize DPIs to achieve drug delivery that (A) is independent of the inhalation manoeuvre and (B) is targeted to the correct site in the lung. Therefore, this thesis aims to apply numerical and experimental methods to optimize DPIs systematically. First, two clinically justifiable cost functions have been developed corresponding to the DPI design objectives (A) and (B). An Eulerian-Eulerian (EE) computational fluid dynamics (CFD) approach has then been used to optimize a DPI entrainment geometry. Three different optimized entrainment geometries have been found corresponding to three different therapeutic applications. Second, the CFD approach has been validated experimentally. This is the first experimental study to validate an EE CFD approach for DPI modelling. Third, a personalized medicine approach to DPI design has been proposed. The development of this approach makes it possible to achieve the design objectives for patients with highly different lung functions. Finally, an adaptive DPI with a variable bypass element has been developed. This DPI achieves design objectives (A) and (B) for patients with highly different lung functions with a single device. In contrast to the personalized medicine approach, there is no need to select the optimal amount of bypass, since the device adapts automatically.
6
Parisini, Irene. "Improved aerosol deposition profiles from dry powder inhalers." Thesis, University of Hertfordshire, 2015. http://hdl.handle.net/2299/15931.
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Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major health burdens on the global population. To treat diseases of the lung, topical therapies using dry powder inhalers (DPIs) have been employed. However, a relatively small amount of dose (5.5 - 28 %) reaches the lung during DPI therapy leading to high inter-patient variability in therapy response and oropharyngeal deposition. Strategies were assessed to take patient variability in inhalation performance into account when developing devices to reduce throat deposition and to mitigate flow rate dependency of the emitted aerosol. A cyclone-spacer was manufactured and evaluated with marketed and in-house manufactured formulations. An in vivo study showed that a high resistance inhaler would produce longer inhalation times in lung disease patients and that a spacer with high resistance may prove a suitable approach to address inter-patient variability. Two spacer prototypes were evaluated with cohesively- and adhesively-balanced particle blends. The data suggested that the throat deposition dramatically decreased for the emitted particles when the spacers were used with the inhalers (e.g. 18.44 ± 2.79% for salbutamol sulphate, SS 4 kPa) due to high retention of the formulation within the spacer (87.61 ± 2.96%). Moreover, variation in fine particle fraction and dose was mitigated when increasing the flow rate (82.75 ± 7.34 %, 92.2 ± 7.7 % % and 77.0 ± 10.1 % at 30, 45 and 60 Lmin-1, respectively). The latter was an improvement over previous proposed DPI spacers, where variability in emitted dose due to airflow rate was a major issue. Due to the different physicochemical properties of the active pharmaceutical ingredients used in the formulation, throat deposition and respirable fraction for adhesively-balanced particles (e.g. SS) were double that of the cohesively- balanced particles (salmeterol xinafoate, SX) (e.g. 65.83 ± 8.99 % vs. 45.83 ± 5.04 % for SS:Coarse Lactose (CL) and SX:CL, respectively). Scanning electron microscopy revealed that surface-bound agglomerates were more freely removed from the carrier, but subject to decreased impaction-type deagglomeration forces in the spacer than for carrier-bound drug. An ex vivo study using breath profiles from healthy volunteers identified the minimization of differences between adhesively- and cohesively-balanced blends when full breath profiles were studied compared to square-wave airflow. Therefore the use of constant flow for in vitro testing should not be the sole flow regime to study aerosolization when developing new inhalation devices and formulations.
7
Grimes, Matthew, Paul Myrdal, and Poonam Sheth. "Cosolvent Effect on Droplet Evaporation Time, Aerodynamic Particle Size Distribution, and Differential Throat Deposition for Pressurized Metered Dose Inhalers." The University of Arizona, 2015. http://hdl.handle.net/10150/614123.
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Class of 2015 AbstractObjectives: 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.
8
Yang, Jiecheng. "DEM-CFD analysis of micromechanics for dry powder inhalers." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6019/.
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Dry powder inhalers (DPIs) are widely used for the therapy of respiratory and pulmonary diseases. In this study, a coupled discrete element method and computational fluid dynamics (DEM-CFD) is employed to investigate the micromechanics of carrier-based DPIs. The effects of van der Waals forces and electrostatic forces on the mixing process, and the influences of air flow and particle-wall impact on the dispersion process are examined. For the mixing of carrier and active pharmaceutical ingredient (API) particles in a vibrating container, it is found that vibration conditions affect the mixing performance. While there is an optimal mixing condition to maximise the number of API particles attaching to the carrier (i.e. contact number) for van der Waals cases, the contact number decreases with increasing vibration velocity amplitude and frequency for electrostatic force cases. It is also revealed that van der Waals forces (short range) and electrostatic forces (long range) result in different mixing behaviours. For the air flow induced and impact induced dispersion, it is found that the dispersion performance improves with increasing air velocity, impact velocity and impact angle, and reduces with increasing work of adhesion. The dispersion performance can be approximated using the cumulative Weibull distribution function governed by the ratio of air drag force to adhesive force or the ratio of impact energy to adhesion energy.
9
Harang, Marie. "Characterisation of aerosols generated by pressurised metered dose inhalers." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/characterisation-of-aerosols-generated-by-pressurised-metered-dose-inhalers(57ce7267-ffbe-4aad-8654-c7822e89b7a0).html.
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For over half a century, pressurised metered dose inhalers (pMDIs) have been the most sold inhaler devices for the treatment of lung diseases. However, they suffer from significant drug deposition in the mouth and throat, mainly due to the aerosolisation of large and fast-moving droplets. This causes a high occurrence of side effects and is wasteful of drug. They are also affected by a low consistency of dosing and as a result users might not benefit from maximal device efficiencies. The hypothesis of this work was that the performance of pMDIs is dependent on numerous factors which might alter the characteristics of their particles and their deposition location within the respiratory tract. For example, it was thought that the variations in actuation forces of pMDIs and temperatures at which they are used might contribute to their low consistency. A one-dimensional Matlab computational model was developed in order to calculate spray properties at the exit of the device where experimental measurements are difficult to conduct. The model simulated the discharge of pure HFA134a formulations and HFA134a-based suspension formulations containing uticasone propionate, the latter representing a commercially available formulation. The results showed that the actuation force of a 'healthy' adult led to a higher valve opening rate and to the aerosolisation of smaller droplets than the actuation force provided by a 'weak' adult. The model also showed that an increase of temperature led to the aerosolisation of smaller droplets. The model was validated using impaction measurements and laser techniques. The next generation impactor (NGI) experiments revealed the importance of actuation forces on the throat deposition. Automated actuation forces with high valve opening rates led to a lower throat deposition than a manual actuation force with low valve opening rate.
10
Traini, Daniela. "Physical properties and interactions in pressurised metered dose inhalers." Thesis, University of Bath, 2005. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415764.
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Hu, Chengjiu. "Investigation of factors influencing the development of pressurized metered dose inhalers /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Ammari, Wasem G. S. "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." Thesis, University of Bradford, 2010. http://hdl.handle.net/10454/4422.
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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.
13
Bennett, Fiona. "Electrostatic charge phenomena in powder processes for dry powder inhalers." Thesis, University of Sunderland, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365417.
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Pitcairn, Gary Roy. "The scintigraphic assessment of drug delivery from dry powder inhalers." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363603.
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Amass, Judith Mary. "A study of drug carrier interactions in dry powder inhalers." Thesis, University of Essex, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336939.
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Zheng, Chen. "The use of excipients to stabilise pressurised metered dose inhalers." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/113171/.
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This thesis concerns investigations of novel pressurised metered dose inhaler (pMDI) formulations containing tiotropium (Tio) in association with a secondary particulate (SP). A number of formulation and hardware variables were studied using in vitro methods to determine their influence on the performance of these novel formulations. Initial studies indicated that Tio was practically insoluble in HFA propellants and its solubility was not increased under raised moisture levels during long-term stability tests. Formulations with L-leucine (Leu) or lactose (Lac) as SP’s were investigated in Tio:SP ratios ranging from 1:2.5 to 1:25 and with different SP sieve fractions from < 20 μm to < 63 μm. Many formulations demonstrated improved aerosol characteristics compared with Tio alone, particularly in through life performance (TLP). The inclusion of fine SP’s (< 20 μm) was found to significantly improve dose uniformity, fine particle fraction (FPF) and fine particle dose (FPD). Tio:Lac formulated in HFA 227 resulted in slightly greater FPF and FPD but also a higher mass median aerodynamic diameter (MMAD) than when formulated in HFA 134a. With respect to the hardware parameters investigated, smaller actuator orifices (in the range 0.25-0.46 mm) and lower valve volume (25 μl instead of 50 μl) were generally associated with significantly increased FPF and reduced MMAD, whereas a smaller canister volume and fluorocarbon polymerization canisters tended to improve TLP. In comparison with marketed Tio products, comparable FPF’s to Spiriva Handihaler® (41%) and Spiriva Respimat® (53%) were demonstrated with bespoke Tio:Lac and Tio:Leu formulations respectively. The Tio:Leu formulation also had a much lower submicron fraction of Tio than Spiriva Respimat®. This research concerning Tio:SP pMDI formulations has demonstrated the advantages of including a SP to promote drug-SP association in the HFA suspension and promoting particle de-aggregation during propellant atomisation. Further research regarding direct measurement of particle interactions and aerodynamic behavior is warranted.
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Sheth, Poonam. "Theoretical and Experimental Behavior of Suspension Pressurized Metered Dose Inhalers." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/325231.
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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.
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Ammari, Wasem Ghazi Saleem. "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." Thesis, University of Bradford, 2010. http://hdl.handle.net/10454/4422.
Full textAbstract:
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.
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Dawson, Michelle Louise. "The stabilisation of micronised drug dispersion in a hydrofluoroalkane propellant system." Thesis, Cardiff University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266856.
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Fazel, Mohammad, Paul Myrdal, and Poonham Sheth. "The Effect of Drug Formulation on in vitro Performance Indices for Metered-Dose Inhalers with Regards to Varying Mouth-Throat Models." The University of Arizona, 2013. http://hdl.handle.net/10150/614257.
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Class of 2013 AbstractSpecific Aims: To elucidate the effect of the use of three different inlet configurations, percent ethanol in formulation, and propellant used on the percent respirable drug and MMAD of aerosolized particles from MDIs that contained beclomethasone dipropionate (BDP). Methods: The inlet configurations assessed in this study were the United States Pharmacopeia (USP) throat, the Alberta idealized mouth-throat replica (biological throat), and a large volume spacer (globe). ACI analyses were conducted on four different MDI formulations with regards to each of the three inlet configurations in quadruplicate. The two hydrofluoroalkane propellants assessed were HFA-134 and HFA-227. All four solution formulations contained 0.3% (w/w) beclomethasone dipropionate (BDP), two of which contained 8% (w/w) ethanol (one each with HFA-134a and HFA-227) and two contained 20% (w/w) ethanol (one each with HFA-134a and HFA-227). All experiments were conducted at a flow rate of 28.3L/min using an actuator with an orifice diameter of 0.29mm and a 50μL metered-valve. After each ACI test, the drug collected on each stage of the impactor was rinsed with known volumes of diluent and quantified by high performance liquid chromatography (HPLC). The MMAD was determined by using DistFit to lognormally fit the ACI data. The resiprable fraction was calculated as the mass of the drug collected on stages 3 through filter of the ACI divided by the total mass of the drug aerosolized. The two-sided student's t-test was the statistical test utilized, with an a priori alpha-value of 0.05. Main Results: The USP and biological throats had significantly lower percent respirable drug compared to the globe regardless of concentration of ethanol or propellant (p<0.05). The MMADs were significantly lower for configurations with the USP and biological throats as compared to the globe (p<0.05). The only formulation with a significant percent respirable drug difference between the USP and biological throats regarding was the 20% ethanol/HFA-227 formulation (20.9+/-0.15 and 16.8+/-1.3 respectively, p=0.005), with the USP throat having the significantly greater percent respirable drug. The USP throat had significantly larger MMADs compared to the biological throat regardless of formulation (p<0.05). For both propellants, the 8% ethanol formulation had significantly greater percent respirable drug compared to the 20% formulation for all three inlets (p<0.05). The 20% ethanol formulations had significantly higher MMADs compared to the 8% ethanol formulations in both the USP throat and globe and with both propellants (p<0.05). Only the 20% ethanol formulations demonstrated a significant difference when varying propellant while keeping all else constant, with the HFA-134a formulations having higher percent respirable drug with all inlets as compared to HFA-227 (p<0.05). When propellant used was varied with all else kept constant, the HFA-227 formulations had significantly higher MMADs compared to the HFA-134a formulations (p<0.05). Conclusion: It was found that significant differences in percent respirable drug and particle size (MMAD) resulting from varying inlet configurations was a function of formulation parameters, most notably, ethanol concentration. The differences may be attributed to factors that increased the time necessary for the evaporation of atomized particles prior to deposition in the impactor, the initial atomized droplet diameter, and/or the likelihood of particle impaction with regards to the mouth-throat inlet utilized. Further assessment is needed to evaluate the correlation of this data with in vivo analyses.
21
Gehmlich, Michael Grant. "Flow pattern effects on aerosol size distributions of dry powder inhalers." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0013/MQ60122.pdf.
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Tootla, Ruwaida G. H. "Evaluation of the effects of paediatric asthma inhalers on oral diseases." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406882.
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Fouda, Yahia M. "Experimental and computational study of multiphase flow in dry powder inhalers." Thesis, Loughborough University, 2014. https://dspace.lboro.ac.uk/2134/16557.
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Dry Powder Inhalers (DPIs) have great potential in pulmonary drug delivery; the granular powder, used as active ingredient in DPIs, is ozone friendly and the operation of DPIs ensures coordination between dose release and patient inhalation. However, the powder fluidisation mechanisms are poorly understood which leads to low efficiency of DPIs with 10-35 % of the dose reaching the site of action. The main aim of this thesis is to study the hydrodynamics of powder fluidisation in DPIs, using experimental and computational approaches. An experimental test rig was developed to replicate the process of transient powder fluidisation in an impinging air jet configuration. The powder fluidisation chamber was scaled up resulting in a two dimensional particle flow prototype, which encloses 3.85 mm glass beads. Using optical image processing techniques, individual particles were detected and tracked throughout the experimental time and domain. By varying the air flow rate to the test section, two particle fluidisation regimes were studied. In the first fluidisation regime, the particle bed was fully fluidised in less than 0.25 s due to the strong air jet. Particle velocity vectors showed strong convective flow with no evidence of diffusive motion triggered by inter-particle collisions. In the second fluidisation regime, the particle flow experienced two stages. The first stage showed strong convective flow similar to the first fluidisation regime, while the second stage showed more complex particle flow with collisional and convective flow taking place on the same time and length scales. The continuum Two Fluid Model (TFM) was used to solve the governing equations of the coupled granular and gas phases for the same experimental conditions. Sub-models for particle-gas and particle-particle interactions were used to complete the model description. Inter-particle interactions were resolved using models based on the kinetic theory of granular flow for the rapid flow regime and models based on soil mechanics for the frictional regime. Numerical predictions of the first fluidisation regime showed that the model should incorporate particle-wall friction and minimise diffusion, simultaneously. Ignoring friction resulted in fluidisation timing mismatch, while increasing the diffusion resulted in homogenous particle fluidisation in contrast to the aggregative convective fluidisation noticed in the experiments. Numerical predictions of the second fluidisation regime agreed well with the experiments for the convection dominated first stage of flow up to 0.3 s. However, later stages of complex particle flow showed qualitative discrepancies between the experimental and the computational approaches suggesting that current continuum granular models need further development. The findings of the present thesis have contributed towards better understanding of the mechanics of particle fluidisation and dense multiphase flow in DPI in particular, and particle bed fluidisation using impinging air jet in general. The use of TFM for predicting high speed convective granular flows, such as those in DPIs, is promising. Further studies are needed to investigate the form of particle-particle interactions within continuum granular flow models.
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Wei, Xiangyin. "Development of clinically relevant in vitro performance tests for powder inhalers." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4014.
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While realistic in vitro testing of dry powder inhalers (DPIs) can be used to establish in vitro–in vivo correlations (IVIVCs) and predict in vivo lung doses, the aerodynamic particle size distributions (APSDs) of those doses and their regional lung deposition remains unclear. Four studies were designed to improve testing centered on the behavior of Novolizer®. Different oropharyngeal geometries were assessed by testing different mouth-throat (MT) models across a realistic range of inhalation profiles (IPs) with Salbulin® Novolizer®. Small and large Virginia Commonwealth University (VCU) and Oropharyngeal Consortium (OPC) models produced similar ranges for total lung dose in vitro (TLDin vitro), while results for medium models differed significantly. While either group may be selected to represent variations in oropharyngeal geometry, OPC models were more difficult to use, indicating that VCU models were preferable. To facilitate simulation of human IPs through DPIs, inhalation profile data from a VCU clinical trial were analyzed. Equations were developed to represent the range of flow rate vs. time curves for use with DPIs of known airflow resistance. A new method was developed to couple testing using VCU MT models and simulated IPs with cascade impaction to assess the APSDs of TLDin vitro for Budelin® Novolizer®. This method produced IVIVCs for Budelin’s total lung dose, TLD, and was sufficiently precise to distinguish between values of TLDin vitro and their APSDs, resulting from tests using appropriately selected MT models and IPs. For example, for slow inhalation, TLD values were comparable in vivo and in vitro; TLDin vitro ranged from 12.2±2.9 to 66.8±1.7 mcg aerosolized budesonide while APSDs in vitro had mass median aerodynamic diameters of 3.26±0.27 and 2.17±0.03 µm, respectively. To explore the clinical importance of these variations, a published computational fluid dynamic (CFD) model was modified and coupled to accept the output of realistic in vitro tests as initial conditions at the tracheal inlet. While simplified aerosol size metrics and flow conditions used to shorten CFD simulations produced small differences in theoretical predictions of regional lung deposition, the results broadly agreed with the literature and were generally consistent with the median values reported clinically for Budelin.
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Gupta, Abhishek. "Optimizing the development and analysis of solution based metered dose inhalers." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280513.
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The current work focuses on the development and evaluation of techniques and models that can facilitate the development of solution based metered dose inhalers. These include an online reverse phase hplc method for analyte quantitation from propellant based pressurized metered dose inhalers. The technique ( direct injection method) finds applications in determining solubility of compounds in aerosol propellants and can possibly be used for stability analysis. With the development of this technique it would be feasible to generate a solubility database in order to understand the physico-chemical factors affecting the solubility and also possibly predict the solubility of compounds in HFA 134a propellant. The regular solution theory based on solubility parameter approach was evaluated for this purpose by utilizing a set of 35 diverse compounds in HFA 134a. A new product performance evaluation tool; the Model 3320 series Aerodynamic Particle Sizer (APS) used in conjunction with Model 3320 Impactor Inlet was evaluated for analysis of solution metered dose inhalers. The Model 3320 APS series provides rapid aerodynamic size distribution data and coupled with Model 3306 Impactor Inlet allows for the chemical analysis of the Inlet port, 'respirable' mass and 'non-respirable' mass. It was shown that in order to obtain comparable results between the Model 3306 Impactor Inlet and the Andersen Cascade Impactor (ACI), an extension to the USP throat may be necessary. The solubility data generated by the direct injection method coupled with the 'respirable deposition' data generated using the APS 3320 series can be used to optimize the product performance of cosolvent based solution metered dose inhalers.
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Huang, Wenhua. "Investigation of semipermeable coated tablet and liposomal dry powder inhaler formulation of salbutamol sulfate." HKBU Institutional Repository, 2010. http://repository.hkbu.edu.hk/etd_ra/1159.
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Nocella, Meira, Emily Kilber, Brittney Witmer, Paul Myrdal, and Kelly Karlage. "Comparison of Pharmaceutical Quality and Product Performance of Albuterol Inhalers Available in the US and Those Obtained in Mexico for a Fraction of US Cost." The University of Arizona, 2015. http://hdl.handle.net/10150/614025.
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Class of 2015 AbstractObjectives: American residents travel to Mexico to purchase medications, like albuterol inhalers, for 1/3 to 1/5 of the US price without prescription requirements. A previous bioequivalence study found clinical differences (P less than 0.05) between Ventolin and Assal, two Mexican manufactured albuterol inhaler brands. What other differences are there among such inhalers when we test more brands and analyze pharmaceutical qualities like respirable mass? This study seeks to provide some reasonable expectations for a medical tourist of Mexico who purchases albuterol metered dose inhalers (MDIs) by comparing the product performance of some of the brands available to the consumers in Mexico. Methods: This study examined the performance of albuterol MDIs obtained from pharmacies in Nogales, Mexico. At least two units were purchased for each of the following brands: Xeneric-S, Victory, Ventolin (GlaxoSmithKline), Assal, and Sacrusyt. At least two lot numbers of each brand were included, with the exception of Sacrusyt, for which a second lot was unavailable at the purchase times. Sample MDIs were compared to US-purchased albuterol inhalers, Proventil and Ventolin. Total dose and respirable mass were determined for each MDI. These parameters were measured by actuating each inhaler into a USP throat, coupled to a cascade impactor, which separates drug particles based on aerodynamic particle size. Particles with an aerodynamic diameter larger than 4.7 micrometers are considered non-respirable, while particles less than 4.7 micrometers are considered respirable and the total of respirable and non-respirable particles is the respirable mass. The total dose delivered is determined by calculating the amount of drug that deposits onto the throat and the impactor. Quantification of albuterol was determined by high performance liquid chromatography (HPLC). In brief, the HPLC assay utilized an Apollo C18 column with a mobile phase of 1 percent phosphoric acid:methanol (77:23) at a flow rate of 0.75mL/min; UV detection was at 225 nm. Results: Every inhaler was sold in a Spanish-labeled box containing a single page instruction insert and every inhaler label had a visible lot number, expiration date, and noted a 100 microgram dose. Listed manufacturing locations included China, Mexico, India, and Spain. All of the MDIs were purchased for about $3 to $5 each except for non-US Ventolin ($10-$20 each). The measurements of total dose and respirable mass among the five Mexican purchased brands of inhalers varied widely. The MDIs’ average total doses ranged from 57 to 75 micrograms per actuation, while the average total dose of the US purchased MDIs was 79 to 82 micrograms. The respirable mass of the non-US MDIs was more similar. Among the study MDIs, respirable mass ranged from 28 to 41 micrograms, which compares to 38 to 42 micrograms for the two US branded albuterol inhalers. To further investigate the variability among the study MDIs, student t-tests were performed to compare the mean respirable mass for each brand to that of the other four brands. All comparisons were significantly different (p less than 0.05) except for two (Sacrusyt vs Assal, p equals 0.89; Xeneric vs Ventolin, p equals 0.98). Conclusions: Since significant pharmaceutical variability was found among the albuterol MDIs evaluated in this study, clinicians and patients should be conscious of possible differences in quality, therapeutic efficacy, and safety for albuterol MDIs obtained in Mexico. Sample MDIs compared to each other were statistically different in total dose and respirable mass. Thus a patient who has used US MDIs before can’t necessarily expect to get the same dose from non-US brands.
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Grimble, David. "Ultra-thin film tribology of elastomeric seals in pressurised metered dose inhalers." Thesis, Loughborough University, 2009. https://dspace.lboro.ac.uk/2134/6376.
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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.
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Farkas, Dale. "Development of High Efficiency Dry Powder Inhalers for Use with Spray Dried Formulations." VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5158.
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Dry powder inhalers (DPIs) are advantageous for delivering medication to the lungs for the treatment of respiratory diseases because of the stability of the powders, relative low cost, synchronization of inhalation and dose delivery, and many design options that can be used for optimization. However, currently marketed DPIs are very inefficient in delivering medications to the lungs. This study has developed multiple new high efficiency DPIs for use with spray dried excipient enhanced growth (EEG) powder formulations based on the following platforms: capsule-based for oral inhalation, high-dose for oral inhalation, inline with 3D rod array dispersion, and inline with capillary jet dispersion. The capsule-based DPIs for oral inhalation implemented a 3D rod array for aerosol dispersion with optimal designs producing mass median aerodynamic diameters (MMADs) in the range of 1.3-1.5 µm and emitted doses in the range of 79-81%. Keys to inhaler success were the orientation of the capsule and inclusion of the 3D rod array. For the high-dose oral inhaler, performance was similar to the optimized capsule-based devices, while aerosolizing a much larger mass of powder. Surprisingly, removal of the fluidized bed of spheres improved performance producing a simple high dose device containing only a single dose sphere. The inline device using the 3D rod array was effective in producing particles of approximately 1.5 µm, at flow rates consistent with high flow therapy using a 1 L ventilation bag as the delivery mechanism. Using a capillary jet as the dispersion mechanism, further advances were made to allow for both delivery using a low volume (LV) of air and delivery in low flow therapy. This easily adaptable platform was able to produce a high quality aerosol out of a nasal cannula with an ED greater than 60% and a size (~2 µm) that should produce minimal extrathoracic losses. In conclusion, this study demonstrates (i) the design and optimization of DPIs capable of delivering EEG aerosols to the lungs using oral inhalation, (ii) the ability to deliver EEG aerosols using N2L aerosol administration, and (iii) the design of a new flexible LV-DPI device that is easily adaptable to multiple patients and delivery platforms, which are greatly needed in clinical environments.
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Clark, Andrew Reginald. "Metered atomisation for respiratory drug delivery." Thesis, Loughborough University, 1991. https://dspace.lboro.ac.uk/2134/7313.
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An investigation into the factors affecting the metered atomisation of superheated liquids has been carried out. The investigation was aimed primarily at developing an understanding of the factors which affect the performance of. respiratory drug delivery systems (Suspension Pressurised Metered Dose Inhalers). Initial investigations used a semi-empirical sizing technique, representing the human airways, to identify the major variables (formulation and geometric) which affect the performance of the MDI system. Computer models were developed to describe both continuous and metered discharge from a superheated-liquid aerosol generator. These models were based on the concept of thermal and dynamic equilibrium, but they were improved and extended, to describe metered discharge, by including empirical corrections obtained from continuous discharge experiments. Experimental investigations using 'instrumented inhalers' were used to confirm the validity of the computer model. The experimental investigations encompassed the use of conventional CFC's and the new non-chlorinated propellants 134A and 227. The computer models and droplet correlation function developed during these investigations represent powerful tools for use in the design of both current and future HFC/HFA powered metered dose inhaler delivery systems.
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Cheng, Sean Jikang. "Numerical and experimental study of cyclone separators for aerosol drug delivery." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608073.
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Telko, Martin Jan Hickey Anthony J. "Investigation of electrostatic charging phenomena in dry powder inhalers and the effect on deposition." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2474.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmaceutical Sciences." Discipline: Pharmaceutical Sciences; Department/School: Pharmacy.
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Alhamad, Bshayer R. "The Effect of Aerosol Devices and Administration Techniques on Drug Delivery in a Simulated Spontaneously Breathing Pediatric Model with a Tracheostomy." Digital Archive @ GSU, 2013. http://digitalarchive.gsu.edu/rt_theses/17.
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Background: Evidence on aerosol delivery via tracheostomy is lacking. The purpose of this study was to evaluate the effect of aerosol device and administration technique on drug delivery in a simulated spontaneously breathing pediatric model with tracheostomy.
Methods: Delivery efficiencies during spontaneous breathing with assisted and unassisted administration techniques were compared using the jet nebulizer (JN- MicroMist), vibrating mesh nebulizer (VMN- Aeroneb Solo) and pressurized metered-dose inhaler (pMDI- ProAirHFA). The direct administration of aerosols in spontaneously breathing patients (unassisted technique) was compared to administration of aerosol therapy via a manual resuscitation bag (assisted technique) attached to the aerosol delivery device and synchronized with inspiration. An in-vitro lung model consisted of an uncuffed tracheostomy tube (4.5 mmID) was attached to a collecting filter (Respirgard) which was connected to a dual-chamber test lung (TTL) and a ventilator (Hamilton). The breathing parameters of a 2 years-old child were set at an RR of 25 breaths/min, a Vt of 150 mL, a Ti of 0.8 sec and PIF of 20 L/min. Albuterol sulfate was administered with each nebulizer (2.5 mg/3 ml) and pMDI with spacer (4 puffs, 108 µg/puff). Each aerosol device was tested five times with both administration techniques (n=5). Drug collected on the filter was eluted with 0.1 N HCl and analyzed via spectrophotometry.
Results: The amount of aerosol deposited in the filter was quantified and expressed as inhaled mass and inhaled mass percent. The pMDI with spacer had the highest inhaled mass percent, while the VMN had the highest inhaled mass. The results of this study also found that JN had the least efficient aerosol device used in this study. The trend of higher deposition with unassisted versus assisted administration of aerosol was not significant (p>0.05).
Conclusions: Drug deposited distal to the tracheostomy tube with JN was lesser than either VMN or pMDI. Delivery efficiency was similar with unassisted and assisted aerosol administration technique in this in vitro pediatric model.
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Sharma, Ketan. "Chitosan nanoparticles for siRNA delivery to the lungs using pressurised metered dose inhalers and nebulisers." Thesis, University College London (University of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569066.
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Chen, Yang. "The influence of device and formulation parameters on aerosol electrostatics for pressurised metered dose inhalers." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13568.
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The aim of this thesis was to investigate the fundamental elements that influence aerosol electrostatic charge and performance of pressurised metered dose inhalers (pMDI). This was achieved by focusing on both physical and chemical parameters of the pMDI system, including orifice materials, geometries and formulation parameters. The electrostatic charges generated from pMDIs were successfully quantified using a modified Electrical Low Pressure Impactor (ELPI) and the magnitude and polarity of aerosol charges were found to be dependent on the actuator materials, nozzle geometries and the formulation used. Triboelectric charging trend was observed with different actuator materials selected from the triboelectric series, when using cone nozzle geometry actuators with drug free and low co-solvent pMDI formulations, respectively. Reversed charge polarities with higher throat deposition were observed with thermoplastic actuators, when curved nozzle geometries were used. The active pharmaceutical ingredients (API) dominated the charge profiles of pMDI formulations over actuator materials and nozzle designs. The studies presented in this thesis have provided valuable information with regards to the relationships between device/formulation parameters (actuator material, nozzle geometries and API) and aerosol electrostatic charge profiles generated from pMDI systems, hence provided fundamental knowledge for the future development of pMDIs and novel electrostatic spray systems.
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Zhu, Bing. "THE INFLUENCE OF FORMULATION VARIABLES ON PARTICLES GENERATED FROM SOLUTION BASED PRESSURIZED METERED DOSE INHALERS." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/9758.
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The main aims of this work were to investigate the aerosol performance, particle formation process and physico-chemical properties of particles produced from solution-based pressurized metered dose inhalers (pMDIs) formulated with different co-solvent concentrations. In addition, the influences of different active pharmaceutical compounds and glycerol as the non-volatile components were also evaluated. This thesis demonstrated the complex nature of particle formation in solution based pMDIs and investigated the influence of co-solvent (e.g. ethanol) and non-volatile additives (e.g. glycerol and drug type) on aerosol performance, particle maturation, morphology and the physico-chemical properties of the final ‘deposited’ drug system. Significant differences in all the above factors were observed when these variables were altered and the properties could be related to the mechanisms of aerosol generation and the nature of the additives. Ultimately, this enhanced the knowledge in the field that may be used when developing new solution based pMDI systems.
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Kinnunen, Hanne. "Active sites, agglomerates or increased cohesion? : investigations into the mechanism of how lactose fines improve dry powder inhaler performance." Thesis, University of Bath, 2012. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.564006.
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Dry powder inhalers (DPIs) are used for delivering drugs to the airways. In addition to the drug, the formulations often contain a coarse carrier, most commonly alpha lactose monohydrate. The presence of fine lactose particles in the formulation is known to improve the formulation performance. The active site, drug-fines agglomeration and increased cohesion theories have been suggested to explain improved DPI performance upon addition of fine excipient particles. This project aimed to investigate the validity of those theories. The viability of the active sites theory in explaining the improved DPI performance was investigated by studying the impact of loaded drug dose on the in vitro performance for formulation series prepared with coarse carriers with different surface characteristics. The formulations prepared with the rougher lactose carrier were seen to outperform the formulations prepared with the smoother carrier at all drug concentrations. These findings were concluded to be non-compatible with the active sites theory. The impact of addition of lactose fines with different size distributions on powder flow and fluidisation properties and in vitro performance was studied. Powder cohesion increased independent of size distribution of the fines, but did not necessarily correspond to improved performance. Therefore, the increased cohesion theory was concluded not to be the sole explanation for the improvement in DPI performance in the presence of lactose fines. Instead, the increase in performance could be preliminarily attributed to the formation of agglomerated systems. The formation and co-deposition of drug-fines agglomerates, and consequential improvement in the DPI performance was proved using morphologically directed Raman spectroscopy. The project also aimed to develop a universal model for predicting DPI performance based on the lactose properties for a wide range of carriers with different properties. No simple linear correlations between any the lactose properties and the final DPI performance were found. Therefore no single parameter can be used as a universal predictor for DPI performance. To establish more complex relationships, artificial neural networks were used for modelling the importance of different lactose properties in determining DPI performance. The proportion of fine lactose particles (<4.5 μm) was identified as the most important parameter. However, this parameter was capable of explaining only approximately half of the variation seen in the formulation performance. The current study showed that to obtain more accurate predictions for the purposes of quality-by-design approach, also other lactose properties need to be characterised.
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Kotian, Reshma. "Electrical Behavior of Non-Aqueous Formulations: Role of Electrostatic Interactions in Pressurized Metered Dose Inhalers (pMDIs)." Unavailable until 8/19/2013, 2008. http://hdl.handle.net/10156/2280.
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Muralidharan, Priyadarshini, and Priyadarshini Muralidharan. "Advanced Design and Development of Novel Microparticulate/Nanoparticulate Dry Powder Inhalers Targeting Underlying Mechanisms in Respiratory Diseases." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/626331.
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Chronic respiratory diseases such as asthma, COPD, pulmonary fibrosis are more prevalent throughout the world. For some of these diseases there is no cure, the current treatment options manages the symptoms and acute exacerbation. The new approach to find a curative therapy for respiratory diseases is by targeting the cellular / molecular pathways that either cause the disease or has the potential cure the disease. It becomes important to target the respiratory system in treating these diseases to increase the delivered dose and reduce the unwarranted adverse effects. Dry powder inhaler (DPI) is a targeted drug delivery dosage form commonly used to target the airways to treat respiratory diseases. There are two components to dry powder inhaler product – powdered drug formulation and inhaler device; a unified performance of the two is essential for a successful product. In this study, dry powder aerosol of novel drug compounds that targets the underlying cellular and molecular mechanism are developed for the first time. Advanced organic closed mode spray drying technique was used to the produce microparticulate/ nanoparticulate formulations. The formulation of the novel compounds involved utilizing sugar based excipients. Each formulation that was produced was comprehensively characterized in the solid state. The safety of these formulations were tested in in vitro human pulmonary cell lines. The in vitro aerosol dispersion of the spray dried drugs were tested using three FDA approved human inhaler devices. The influence of the inhaler device resistance and spray drying process conditions on the aerosol dispersion was evaluated. Preliminary testing of the formulations in in vivo animal models shows promising results in treating chronic respiratory diseases with these superior aerosol formulations.
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Althanyan, Mohammed S. "Use of nanoemulsion liquid chromatography (NELC) for the analysis of inhaled drugs. Investigation into the application of oil-in-water nanoemulsion as mobile phase for determination of inhaled drugs in dosage forms and in clinical samples." Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5184.
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There has been very little research into the bioanalytical application of Microemulsion High Performance Liquid Chromatography (MELC), a recently established technique for separating an active pharmaceutical ingredient from its related substances and for determining the quantity of active drug in a dose. Also, the technique is not good at separating hydrophilic drugs of very similar chemical structures.
Different phase diagrams of oil (octane or ethyl acetate), co-surfactant (butanol), surfactant (sodium dodecyl sulphate (SDS) or Brij-35) and buffer (Phosphate pH 3) were developed and several nanoemulsion mobile phases identified. Nanoemulsion mobile phase that is, prepared with SDS, octane, butanol and a phosphate buffer, failed to separate hydrophilic compounds with a very close chemical structure, such as terbutaline and salbutamol. A nanoemulsion mobile phase containing a non-ionic surfactant (Brij-35) with ethyl acetate, butanol and a phosphate buffer, was, however, successful in achieving a base line separation, and the method was validated for simultaneous determination of terbutaline and salbutamol in aqueous and urine samples.
An oil-in-water (O/W) NELC method was developed and validated for the determination of formoterol in an Oxis® Turbuhaler® using pre-column fluorescence derivatisation. Although the same mobile phase was extended for separation of formoterol in urine, the formoterol peak¿s overlap with endogenous peaks meant that fluorescence detection could not determine formoterol in urine samples. Solid phase extraction, concentrating the final analyte 40 times, enabled determination of a low concentration of formoterol in urine samples by UV detection. The method was validated and an acceptable assay precision %CV <4.89 inter-day and %CV <2.33 intra-day was achieved. Then after the application of O/W nanoemulsion mobile phase for HPLC was extended for the separation of lipophilic drugs. The nanoemulsion liquid chromatography (NELC) method was optimised for the determination of salmeterol and fluticasone propionate in good validation data was achieved.
This thesis shows that, in general, the performance of O/W NELC is superior to that of conventional High Performance Liquid Chromatography (HPLC) for the analysis of both hydrophilic and lipophilic drugs in inhaled dosage formulations and urine samples. It has been shown that NELC uses cheaper solvents and that analysis time is faster for aqueous and urine samples. This considerable saving in both cost and time will potentially improve efficiency within quality control.
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Almeziny, Mohammed Abdullah N. "Performance of two different types of inhalers : influence of flow and spacer on emitted dose and aerodynamic characterisation." Thesis, University of Bradford, 2009. http://hdl.handle.net/10454/4299.
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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.
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Shaik, Abdul Qaiyum. "Numerical modeling of two-phase flashing propellant flow inside the twin-orifice system of pressurized metered dose inhalers." Thesis, Loughborough University, 2010. https://dspace.lboro.ac.uk/2134/6161.
Full textAbstract:
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.
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Almeziny, Mohammed A. N. "Performance of two different types of inhalers. Influence of flow and spacer on emitted dose and aerodynamic characterisation." Thesis, University of Bradford, 2009. http://hdl.handle.net/10454/4299.
Full textAbstract:
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.
44
Althanyan, Mohammed Saad. "Use of nanoemulsion liquid chromatography (NELC) for the analysis of inhaled drugs : investigation into the application of oil-in-water nanoemulsion as mobile phase for determination of inhaled drugs in dosage forms and in clinical samples." Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5184.
Full textAbstract:
There has been very little research into the bioanalytical application of Microemulsion High Performance Liquid Chromatography (MELC), a recently established technique for separating an active pharmaceutical ingredient from its related substances and for determining the quantity of active drug in a dose. Also, the technique is not good at separating hydrophilic drugs of very similar chemical structures. Different phase diagrams of oil (octane or ethyl acetate), co-surfactant (butanol), surfactant (sodium dodecyl sulphate (SDS) or Brij-35) and buffer (Phosphate pH 3) were developed and several nanoemulsion mobile phases identified. Nanoemulsion mobile phase that is, prepared with SDS, octane, butanol and a phosphate buffer, failed to separate hydrophilic compounds with a very close chemical structure, such as terbutaline and salbutamol. A nanoemulsion mobile phase containing a non-ionic surfactant (Brij-35) with ethyl acetate, butanol and a phosphate buffer, was, however, successful in achieving a base line separation, and the method was validated for simultaneous determination of terbutaline and salbutamol in aqueous and urine samples. An oil-in-water (O/W) NELC method was developed and validated for the determination of formoterol in an Oxis® Turbuhaler® using pre-column fluorescence derivatisation. Although the same mobile phase was extended for separation of formoterol in urine, the formoterol peak's overlap with endogenous peaks meant that fluorescence detection could not determine formoterol in urine samples. Solid phase extraction, concentrating the final analyte 40 times, enabled determination of a low concentration of formoterol in urine samples by UV detection. The method was validated and an acceptable assay precision %CV <4.89 inter-day and %CV <2.33 intra-day was achieved. Then after the application of O/W nanoemulsion mobile phase for HPLC was extended for the separation of lipophilic drugs. The nanoemulsion liquid chromatography (NELC) method was optimised for the determination of salmeterol and fluticasone propionate in good validation data was achieved. This thesis shows that, in general, the performance of O/W NELC is superior to that of conventional High Performance Liquid Chromatography (HPLC) for the analysis of both hydrophilic and lipophilic drugs in inhaled dosage formulations and urine samples. It has been shown that NELC uses cheaper solvents and that analysis time is faster for aqueous and urine samples. This considerable saving in both cost and time will potentially improve efficiency within quality control.
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Manniello, Michele Dario. "Drug delivery to the lung in Cystic Fibrosis: deposition, dissolution, mucus interaction and microbiological evaluation of dry powder inhalers." Doctoral thesis, Universita degli studi di Salerno, 2018. http://hdl.handle.net/10556/3007.
Full textAbstract:
2016 - 2017The inhalation therapy consists of a direct administration of drugs for the treatment of lung diseases. A formulation for inhalation is a valid option in the symptomatic management of pulmonary diseases typical of cystic fibrosis (CF). This is a rare hereditary disease that affects the normal function of the exocrine glands of the mucosa, with the production of a dry and poorly flowing mucus even in the respiratory tract. The first objective of my PhD project was to evaluate the rheological behaviour of the CF sputum samples, kindly donated by the “G. Gaslini” Hospital of Genoa. Following the in vitro addition of HCO3 - to the sputum samples, a decrease in the viscosity of this material was therefore evaluated, compared to samples pre-treated with water alone. To verify if this evidence was accompanied by an increase in permeation of a drug through this sample, the second purpose was to evaluate the permeation of a drug through CF sputum. The Ketoprofen lysinate, a formulation in dry powder, called Dry Powder Inhaler (DPI), already developed in previous research work was selected. As the results show, the viscosity decrease was therefore accompanied by an increase in the permeation of the drug only after the addition of HCO3 - to the sputum samples... [edited by Author]
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Jones, Matthew D. "An investigation into the dispersion mechanisms of ternary dry powder inhaler formulations by the quantification of interparticulate forces." Thesis, University of Bath, 2006. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432383.
Full text
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Alaboud, S. "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." Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5686.
Full textAbstract:
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.
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Dalby, Richard Norman. "Reducing the particle size and decreasing the release rate of drugs delivered by metered dose inhalers to the respiratory tract /." Ann Arbor : UMI, 1988. http://www.gbv.de/dms/bs/toc/016101340.pdf.
Full text
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Liu, Jie. "Development, characterization and optimization of pressurized metered-dose inhalers formulated to deliver small organic drugs or proteins with hydrofluoroalkane propellants /." Digital version accessible at:, 1998. http://wwwlib.umi.com/cr/utexas/main.
Full text
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Ibn, Yakubu Sani. "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." Thesis, University of Bradford, 2009. http://hdl.handle.net/10454/4861.
Full textAbstract:
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.