Figure 1 - uploaded by William Doub
Content may be subject to copyright.
Source publication
The impaction force from an inhalation product is an important characteristics by which to characterize the spray plume. It is one of the plume characteristics that can be perceived by a patient, and is expected to be good measures of local delivery equivalence for inhalation drugs. A Stable Micro Systems TA-XT.plus Texture Analyser equipped with 7...
Context in source publication
Context 1
... profiles for all the tested products were symmetric with actuation velocity of 50 mm/s, actuation acceleration of 4000 mm/s 2 , and hold time of 100 ms. Figure 1 shows the instrument setup for impaction force measurement of nasal sprays and MDIs. For nasal spray impaction force measurements, the nasal spray pump was actuated upward using a SprayVIEW NSx automated actuator; For MDI impaction force measurements, the Texture Analyser was placed on its side with the MDI being discharged horizontally using a SprayVIEW MDx automated actuator. ...
Citations
... Due to inertia, large droplets sustain their speeds longer and travel faster than small droplets, thus reaching the back throat earlier. This is consistent with the cold sensation in the oropharynx during MDI actuation [1,48]. During this short period (0-3 ms), the spray plume still looks focused, reflecting the dominant convective mechanism during MDI actuation. ...
Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation–inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI–mouth–lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth–throat, and lung. Concerning the device–patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth–throat loss and increased lung doses in both the central and peripheral regions.
... In addition to the abovementioned parameters, which describe the dosage amount, spray plume shape and droplet size, the impaction force, and droplet velocity, which describe how strong or soft a spray plume is and are directly felt by patients, are also useful information for characterizing nasal spray products. Both impaction force and velocity could be used as a discriminative parameter for in vitro testing of nasal spray products (4)(5)(6). ...
... The drug delivery performance of a nasal spray product is greatly influenced by both the formulation properties and the device capabilities (8)(9)(10). In previous studies, design of experiments (DOE) methodology was used to elucidate interactions between four factors (actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant) with respect to their influences on nasal spray shot weight, DSD, spray pattern, plume geometry, and impaction force (5,11). The measured responses were fit to a polynomial model, and an analysis of the polynomial coefficients and their standard errors were used to identify the statistically significant factors and interaction terms for each model. ...
Droplet velocity is an important parameter that can be used to characterize nasal spray products. In this study, a phase-Doppler anemometry (PDA) system was used to measure the droplet velocities of nasal sprays. A survey of seven commercial nasal spray products showed a range of droplet velocities from 6.7 to 19.2 m/s, all significantly different from each other. A three-level, four-factor Box-Behnken design of experiments (DOE) methodology were applied to investigate the influences of actuation parameters and formulation properties on nasal spray droplet velocity using a set of placebo formulations. The DOE study shows that all four input factors (stroke length, actuation velocity, concentration of the gelling agent, and concentration of the surfactant) have significant influence on droplet velocity. An optimized quadratic model generated from the DOE results describes the inherent relationships between the input factors and droplet velocity thus providing a better understanding of the input factor influences. Overall, PDA provides a new in vitro characterization method for the evaluation of inhalation drugs through assessment of spray velocity and may assist in product development to meet drug delivery equivalency requirements.
... For pump C, the actuation profile was also symmetric with stroke length of 8.4 mm, velocity of 50 mm/s, acceleration of 4000 mm/s 2 , and hold time of 100 ms. Stroke lengths used were the maximum stroke lengths as determined using the Proveris Viota software; other parameters were as used in previous work (Guo et al., 2008(Guo et al., , 2009) and were adopted for the two types of nasal spray pumps, respectively. ...
To determine aerosol deposition during the inhalation drug delivery, it is important to understand the combination of velocity and droplet size together. In this study, phase Doppler anemometry (PDA) was used to simultaneously characterize the aerosol velocity and droplet size distribution (DSD) of three nasal spray pumps filled with water. Thirteen sampling positions were located in the horizontal cross-sectional area of the nasal spray plumes at a distance of 3cm from the pump orifice. The results showed droplet velocities near the center of the spray plume were higher and more consistent than those near the edge. The pumps examined showed significant differences in their aerosol velocity at the center of the spray plume, which suggest that this metric might be used as a discriminating parameter for in vitro testing of nasal sprays. Droplet size measurements performed using PDA were compared with results from laser light scattering measurements. The ability of PDA to provide simultaneous measurements of aerosol velocity and size makes it a powerful tool for the detailed investigation of nasal spray plume characteristics.
... It was noted that the study of particular instrumentation in FDA research does not imply agency endorsement of that technology. (64) Biomarker Strategies Facilitators: Richard C. Ahrens, M.D., University of Iowa, Dale P. Conner, Pharm.D., U.S. Food and Drug Administration and Partha Roy, Ph.D., U.S. Food and Drug Administration Scribe: Kevin C. Fitzgerald, R.Ph. ...
For the last several decades, the predominant method for delivering medicine to the surface of the eye has been the standard multiuse eye dropper. While being the most popular, this method has significant limitations. Recently, an effort has been made to explore the use of a directed toroidal vortex or "smoke ring" aerosol delivery system that may help overcome these limitations and enable delivery of precise amounts of formulation and drug to the ocular surface. Promising preliminary in vitro studies indicated dosing control, but the physical characteristics of the toriodal aerosol device performance and impaction forces related to patient comfort have yet to be established. Here, we experimentally investigate the mechanics and dynamics of these ocular aerosol vortices, including translational and rotational velocities, spatial droplet size distributions, and relative impaction forces in order to optimize the device performance and evaluate potential for clinical use. Maximal droplet velocity at various actuation forces was determined, and they were found to be all less than 6 m/s even at the highest actuation forces. Moreover, plume impaction forces were determined across a range of conditions and were all less than about 4.5 μN. Collectively, these studies showed that the physical and mechanical properties of the emitted drug-loaded vortices would be suitable for ocular administration.
As a result of the Montreal Protocol on Substances that Deplete the Ozone Layer, manufacturers of metered dose inhalers began reformulating their products to use hydrofluoroalkanes (HFAs) as propellants in place of chlorofluorocarbons (CFCs). Although the new products are considered safe and efficacious by the US Food and Drug Administration (FDA), a large number of complaints have been registered via the FDA's Adverse Events Reporting System (FAERS)—more than 7000 as of May 2013. To develop a better understanding of the measurable parameters that may, in part, determine in vitro performance and thus patient compliance, we compared several CFC- and HFA-based products with respect to their aerodynamic performance in response to changes in actuator cleaning interval and interactuation delay interval. Comparison metrics examined in this study were: total drug delivered ex-actuator, fine particle dose (<5 μm), mass median aerodynamic diameter, plume width, plume temperature, plume impaction force, and actuator orifice diameter. Overall, no single metric or test condition distinguishes HFA products from CFC products, but, for individual products tested, there were a combination of metrics that differentiated one from another. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
Monte Carlo simulations were applied to investigate the propagation of uncertainty in both input variables and response measurements on model prediction for nasal spray product performance design of experiment (DOE) models in the first part of this study, with an initial assumption that the models perfectly represent the relationship between input variables and the measured responses. In this article, we discard the initial assumption, and extended the Monte Carlo simulation study to examine the influence of both input variable variation and product performance measurement variation on the uncertainty in DOE model coefficients. The Monte Carlo simulations presented in this article illustrate the importance of careful error propagation during product performance modeling. Our results show that the error estimates based on Monte Carlo simulation result in smaller model coefficient standard deviations than those from regression methods. This suggests that the estimated standard deviations from regression may overestimate the uncertainties in the model coefficients. Monte Carlo simulations provide a simple software solution to understand the propagation of uncertainty in complex DOE models so that design space can be specified with statistically meaningful confidence levels.
This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating "local pulmonary delivery" equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented.
Design of experiment (DOE) methodology can provide a complete evaluation of the influences of nasal spray activation and formulation properties on delivery performance which makes it a powerful tool for product design purposes. Product performance models are computed from complex expressions containing multiple factor terms and response terms. Uncertainty in the regression model can be propagated using Monte Carlo simulation. In this study, four input factors, actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant were investigated for their influences on measured responses of spray pattern, plume width, droplet size distribution (DSD), and impaction force. Quadratic models were calculated and optimized using a Box-Behnken experimental design to describe the relationship between factors and responses. Assuming that the models perfectly represent the relationship between input variables and the measured responses, the propagation of uncertainty in both input variables and response measurements on model prediction was performed using Monte Carlo simulations. The Monte Carlo simulations presented in this article illustrate the propagation of uncertainty in model predictions. The most influential input variable variances on the product performance variance were identified, which could help prioritize input variables in terms of importance during continuous improvement of nasal spray product design. This work extends recent Monte Carlo simulations of process models to the realm of product development models.
