PhD / Electrostatics of aerosols for inhalation is a relatively new research area. Charge properties of these particles are largely unknown but electrostatic forces have been proposed to potentially influence lung deposition. Investigation on the relationship between formulation and aerosol charging is required to understand the fundamental mechanisms. A modified electrical low pressure impactor was employed to measure the particles generated from metered dose inhalers and dry powder inhalers. This equipment provides detailed size and charge information of the aerosols. The particles were sized by impaction onto thirteen stages. The net charges in twelve of the size fractions were detected and recorded by sensitive electrometers. The drug deposits were quantified by chemical assay. The aerosol charge profiles of commercial metered dose inhalers were product-dependent, which was due to differences in the drug, formulation, and valve stem material. The calculated number of elementary charges per drug particle of size ≤ 6.06 μm ranged from zero to several ten thousands. The high charge levels on particles may have a potential effect on the deposition of the aerosol particles in the lung when inhaled. New plastic spacers marketed for use with metered dose inhalers were found to possess high surface charges on the internal walls, which was successfully removed by detergent-coating. Detergent-coated spacer had higher drug output than the new ones due to the reduced electrostatic particle deposition inside the spacer. Particles delivered from spacers carried lower inherent charges than those directly from metered dose inhalers. Those with higher charges might be susceptible to electrostatic forces inside the spacers and were thus retained. The electrostatic low pressure impactor was further modified to disperse two commercial Tubuhaler® products at 60 L/min. The DPIs showed drug-specific responses to particle charging at different RHs. The difference in hygroscopicity of the drugs may play a major role. A dual mechanistic charging model was proposed to explain the charging behaviours. The charge levels on drug particles delivered from these inhalers were sufficiently high to potentially affect deposition in the airways when inhaled. Drug-free metered dose inhalers containing HFA-134a and 227 produced highly variable charge profiles but on average the puffs were negatively charged, which was thought to be due to the electronegative fluorine atoms in the HFA molecules. The charges of both HFAs shifted towards neutrality or positive polarity with increasing water content. The spiked water might have increased the electrical conductivity and/or decreased the electronegativity of the bulk propellant solution. The number of elementary charges per droplet decreased with decreasing droplet size. This trend was probably due to the redistribution of charges amongst small droplets following electrostatic fission of a bigger droplet when the Raleigh limit was reached.

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.

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.

PhD / Electrostatics of aerosols for inhalation is a relatively new research area. Charge properties of these particles are largely unknown but electrostatic forces have been proposed to potentially influence lung deposition. Investigation on the relationship between formulation and aerosol charging is required to understand the fundamental mechanisms. A modified electrical low pressure impactor was employed to measure the particles generated from metered dose inhalers and dry powder inhalers. This equipment provides detailed size and charge information of the aerosols. The particles were sized by impaction onto thirteen stages. The net charges in twelve of the size fractions were detected and recorded by sensitive electrometers. The drug deposits were quantified by chemical assay. The aerosol charge profiles of commercial metered dose inhalers were product-dependent, which was due to differences in the drug, formulation, and valve stem material. The calculated number of elementary charges per drug particle of size ≤ 6.06 μm ranged from zero to several ten thousands. The high charge levels on particles may have a potential effect on the deposition of the aerosol particles in the lung when inhaled. New plastic spacers marketed for use with metered dose inhalers were found to possess high surface charges on the internal walls, which was successfully removed by detergent-coating. Detergent-coated spacer had higher drug output than the new ones due to the reduced electrostatic particle deposition inside the spacer. Particles delivered from spacers carried lower inherent charges than those directly from metered dose inhalers. Those with higher charges might be susceptible to electrostatic forces inside the spacers and were thus retained. The electrostatic low pressure impactor was further modified to disperse two commercial Tubuhaler® products at 60 L/min. The DPIs showed drug-specific responses to particle charging at different RHs. The difference in hygroscopicity of the drugs may play a major role. A dual mechanistic charging model was proposed to explain the charging behaviours. The charge levels on drug particles delivered from these inhalers were sufficiently high to potentially affect deposition in the airways when inhaled. Drug-free metered dose inhalers containing HFA-134a and 227 produced highly variable charge profiles but on average the puffs were negatively charged, which was thought to be due to the electronegative fluorine atoms in the HFA molecules. The charges of both HFAs shifted towards neutrality or positive polarity with increasing water content. The spiked water might have increased the electrical conductivity and/or decreased the electronegativity of the bulk propellant solution. The number of elementary charges per droplet decreased with decreasing droplet size. This trend was probably due to the redistribution of charges amongst small droplets following electrostatic fission of a bigger droplet when the Raleigh limit was reached.

Class of 2015 Abstract / Objectives: To evaluate the in vitro performance of various pressurized metered dose inhaler (pMDI) formulations by cascade impaction primarily focusing on throat deposition, fine particle fraction (FPF), and mass-median aerodynamic diameter (MMADR) measurements Methods: Ten solution pMDIs were prepared with varying cosolvent species in either low (8% w/w) or high (20% w/w) concentration. The chosen cosolvents were either alcohol (ethanol, n-propanol) or acetate (methyl-, ethyl-, and butyl acetate) in chemical nature. All formulations used HFA-134a propellant and 0.3% drug. The pMDIs were tested by cascade impaction with three different inlets to determine the aerodynamic particle size distribution (APSD), throat deposition, and FPF of each formulation. Theoretical droplet evaporation time (DET), a measure of volatility, for each formulation was calculated using the MMADR. Results: Highly volatile formulations with short DET showed consistently lower throat deposition and higher FPF than their lower volatility counterparts when using volume-constrained inlets. However, FPF values were not significantly different for pMDI testing with a non-constrained inlet. The MMADR values generated with volume-constrained inlets did not show any discernible trends, but MMADR values from the non-constrained inlet correlated with DET. Conclusions: Formulations with shorter DET exhibit lower throat deposition and higher FPF, indicating potentially better inhalational performance over formulations with longer DET. There appear to be predictable trends relating both throat deposition and FPF to DET. The shift in MMADR values for volume-constrained inlets suggests that large diameter drug particles are preferentially collected in these inlets.

No / Purpose The relative lung bioavailability of salbutamol sulfate particles produced using supercritical fluids (SEDS¿) and delivered by dry powder inhaler (DPI) was compared with the performance of a conventional micronized drug DPI using the same device design (Clickhaler¿, Innovata Biomed). Materials and Methods Twelve healthy volunteers and 11 mild asthmatic patients completed separate four-way randomised cross-over studies, assessing the relative bioavailability of salbutamol sulfate (urinary excretion method), formulated as SEDS¿ particles (three batches) and micronized particles (Asmasal¿ inhaler, UCB Pharma Ltd). Post-treatment improvements in patient lung function were assessed by measuring FEV1. Physicochemical evaluation of the three SEDS¿ batches revealed inter-batch differences in particle size and shape. Results There was no significant difference in the relative lung bioavailability of salbutamol and its bronchodilator response between the best performing SEDS¿ formulation and the Asmasal¿ inhaler in volunteers and patients, respectively. SEDS¿ salbutamol sulfate showing wafer like morphology gave greater fine particle dose, relative lung bioavailability and enhanced bronchodilation compared to other SEDS¿ batches containing elongated particles. Conclusions Active Pharmaceutical Ingredient (API) manufactured using supercritical fluids and delivered by DPI can provide similar lung bioavailability and clinical effect to the conventional micronized commercial product. Product performance is however notably influenced by inter-batch differences in particle characteristics.

No / Previously, dose emission below 30 L min(-1) through DPI has not been routinely determined. However, during routine use some patients do not achieve 30 L min(-1) inhalation flows. Hence, the aim of the present study was to determine dose emission characteristics for low inhalation flows from terbutaline sulphate Turbuhaler. Total emitted dose (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) of terbutaline sulphate Turbuhaler were determined using inhalation flows of 10-60 L min(-1) and inhaled volume of 4 L. TED and FPD increase significantly with the increase of inhalation flows (p <0.05). Flows had more pronounced effect on FPD than TED, thus, faster inhalation increases respirable amount more than it increases emitted dose. MMAD increases with decrease of inhalation flow until flow of 20L min(-1) then it decreases. In vitro flow dependent dose emission has been demonstrated previously for Turbuhaler for flow rates above 30 L min(-1) but is more pronounced below this flow. Minimal FPD below 30 L min(-1) suggests that during routine use at this flow rate most of emitted dose will impact in mouth. Flow dependent dose emission results suggest that Pharmacopoeias should consider the use variety of inhalation flows rather than one that is equivalent to pressure drop of 4 KPa.

No / Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution− absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence. / This work was in part funded by a grant from the Safety and Environmental Assurance Centre, Unilever Colworth, U.K. Particle sizing was performed by Steve Ingham, Institute of Pharmaceutical Science, King’s College London.

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.

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.