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In this paper we demonstrate that the use of multiple orifices can improve the fine particle fraction (FPF) of pressurised metered-dose inhaler solution formulations by up to 75% when compared to a single orifice with an equivalent cross sectional area (p<0.05). While prior work has relied on metal actuator components, improvements in micro injection moulding and micro drilling now make it possible to mass produce novel orifice shapes to achieve similar FPF gains in plastic parts, with orifice diameters less than 0.2 mm. The ability to create internal features inside the actuator is also demonstrated. We show through in vitro high speed imaging that twin orifice sprays merge quickly and act as a single, modified plume. We also show for the first time that FPF and fine particle dose (FPD) are strongly correlated with the distance at which the plume velocity decays to half its initial value (R 2 =0.997 and 0.95 respectively). When plume velocity & FPF are increased, mouthpiece deposition decreases. This suggests that while smaller orifices produce more fine particles, higher sustained plume velocities also entrain more of the fine particles produced at the periphery of the spray due to increased shear. The effect occurs within the mouthpiece and is thus unlikely to alter the flow field in the upper airway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This note investigates how small changes in the protrusion depth of a pressure transducer affect the pressure measurement of a moving shock wave. Measurements are undertaken with Kistler, Kulite, and PCB sensors in flush, recessed, and protruded sensor positions. Measurements of both absolute pressure and Mach number are shown to be insensitive to sensor protrusion depth. An assessment of sensor response time indicates a significantly shorter reaction time for the Kulite and PCB sensors compared with the Kistler sensor.

Acoustic measurements of unheated supersonic underexpanded jets with ideally expanded Mach numbers of 1.14, 1.38, and 1.50 are presented. Of the three components of supersonic jet noise, the focus is on the broadband shock-associated noise (BBSAN) component. Motivated by the modelling of BBSAN using the wavepacket framework, a traversable microphone ring is used to decompose the acoustic pressure into azimuthal Fourier modes. Unlike noise radiated downstream, BBSAN is dominated by azimuthal modes 1-3, which are approximately 3-4 dB/St stronger than the axisymmetric component. Crucially, the relative contribution of successive modes to BBSAN is sensitive to the observer angle and jet operating condition. Four azimuthal modes are necessary to reconstruct the total BBSAN signal to within 1 dB/St accuracy for the conditions presented here. The analysis suggests, however, that the number of modes required to maintain this accuracy increases as the peak frequency shifts upward. The results demonstrate the need to carefully consider the azimuthal content of BBSAN when comparing acoustic measurements to predictions made by jet noise models built on instability theory.

Purpose: Sprays from pressurised metered-dose inhalers are produced by a transient discharge of a multiphase mixture. Small length and short time scales have made the investigation of the governing processes difficult. Consequently, a deep understanding of the physical processes that govern atomisation and drug particle formation has been elusive., Methods: X-ray phase contrast imaging and quantitative radiography were used to reveal the internal flow structure and measure the time-variant nozzle exit mass density of 50 µL metered sprays of HFA134a, with and without ethanol cosolvent. Internal flow patterns were imaged at a magnification of 194 pixels/mm and 7759 frames per second with 150 ps temporal resolution. Spray projected mass was measured with temporal resolution of 1 ms and spatial resolution 6 µm × 5 µm., Results: The flow upstream of the nozzle comprised large volumes of vapour at all times throughout the injection. The inclusion of ethanol prevented bubble coalescence, altering the internal flow structure and discharge. Radiography measurements confirmed that the nozzle exit area is dominantly occupied by vapour, with a peak liquid volume fraction of 13%., Conclusion: Vapour generation in pMDIs occurs upstream of the sump, and the dominant volume component in the nozzle exit orifice is vapour at all times in the injection. The flow in ethanol-containing pMDIs has a bubbly structure resulting in a comparatively stable discharge, whereas the binary structure of propellant-only flows results in unsteady discharge and the production of unrespirable liquid masses.

Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice. We detected activated legumain by ex vivo imaging, confocal microscopy, and gel electrophoresis. Compared with healthy controls, legumain activity in the pancreas of caerulein-treated mice was increased in a time-dependent manner. Legumain was localized to CD68(+) macrophages and was not active in pancreatic acinar cells. Using a small-molecule inhibitor of legumain, we found that this protease is not essential for the initiation of pancreatitis. However, it may serve as a biomarker of disease, since patients with chronic pancreatitis show strongly increased legumain expression in macrophages. Moreover, the occurrence of legumain-expressing macrophages in regions of acinar-to-ductal metaplasia suggests that this protease may influence reprogramming events that lead to inflammation-induced pancreatic cancer., (Copyright © 2016 the American Physiological Society.)

Purpose: Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques., Methods: We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays., Results: Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 μm. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow., Conclusions: Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.

Purpose: Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution., Methods: In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 [Formula: see text] / [Formula: see text] IPBr., Results: Instantaneous concentration measurements were obtained with 1 ms temporal resolution and 5 [Formula: see text] spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo., Conclusions: Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.