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ABSTRACT: The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The optimized device and formulation was then tested in a realistic in vitro mouth-throat - tracheobronchial (MT-TB) model. An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), L-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30:48:20:2 was prepared using a Büchi Nano spray dryer. The aerosolization performance of the EEG formulation was evaluated with 5 conventional DPIs: Aerolizer, Novolizer, HandiHaler, Exubera and Spiros. To improve powder dispersion, the HandiHaler was modified with novel mouth piece (MP) designs. The aerosol performance of each device was assessed using a next generation impactor (NGI) at airflow rates generating a pressure drop of 4 kPa across the DPI. In silico and in vitro deposition and hygroscopic growth of formulations was studied using a MT-TB airway geometry model. Both Handihaler and Aerolizer produced high emitted doses (ED) together with a significant submicrometer aerosol fraction. A modified HandiHaler with a MP including a three-dimensional (3D) array of rods (HH-3D) produced a submicrometer particle fraction of 38.8% with a conventional fine particle fraction (% <5μm) of 97.3%. The mass median diameter (MMD) of the aerosol was reduced below 1 μm using this HH-3D DPI. The aerosol generated from the modified HandiHaler increased to micrometer size (2.8 μm) suitable for pulmonary deposition, when exposed to simulated respiratory conditions, with negligible mouth-throat (MT) deposition (2.6%).
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 04/2013; · 2.61 Impact Factor
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ABSTRACT: Abstract Background: Previous studies have characterized the size increase of combination submicrometer particles composed of a drug and hygroscopic excipient when exposed to typical airway thermodynamic conditions. The objective of this study was to determine the deposition and size increase characteristics of excipient enhanced growth (EEG) aerosols throughout the tracheobronchial (TB) airways and to evaluate the potential for targeted delivery. Methods: Submicrometer particles composed of a poorly water-soluble drug (insulin) and hygroscopic excipient (sodium chloride) were considered at drug:excipient mass ratios of 50:50 and 25:75. A previously validated computational fluid dynamics model was used to predict aerosol size increase and deposition in characteristic geometries of the mouth-throat (MT), upper TB airways through the third bifurcation (B3), and remaining TB airways through B15. Additional validation experiments were also performed for albuterol sulfate:mannitol particles. Both growth of combination particles and deposition are reported throughout the conducting airways for characteristic slow and deep (SD) and quick and deep (QD) inhalations. Results: For all EEG cases considered, MT deposition was less than 1% of the drug dose, which is at least one order of magnitude lower than with state-of-the-art and conventional inhalers. Final aerosol sizes exiting the TB region and entering the alveolar airways were all greater than 3 μm. For SD inhalation, deposition fractions of 20% were achieved in the lower TB region of B8-B15, which is a factor of 20-30×higher than conventional delivery devices. With QD inhalation, maximum alveolar delivery of 90% was observed. Conclusions: Increasing the dose delivered to the lower TB region by a factor of 20-30×or achieving 90% delivery to the alveolar airways was considered effective aerosol targeting compared with conventional devices. The trend of higher flow rates resulting in better alveolar delivery of aerosols is unique to EEG and may be used to design highly efficient dry powder inhalers.
Journal of Aerosol Medicine and Pulmonary Drug Delivery 01/2013; · 2.20 Impact Factor
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ABSTRACT: Excipient enhanced growth (EEG) of inhaled submicrometer pharmaceutical aerosols is a recently proposed method intended to significantly reduce extrathoracic deposition and improve lung delivery. The objective of this study was to evaluate the size increase of combination drug and hygroscopic excipient particles in a characteristic model of the airways during inhalation using both in vitro experiments and computational fluid dynamic (CFD) simulations. The airway model included a characteristic mouth-throat (MT) and upper tracheobronchial (TB) region through the third bifurcation and was enclosed in a chamber geometry used to simulate the thermodynamic conditions of the lungs. Both in vitro results and CFD simulations were in close agreement and indicated that EEG delivery of combination submicrometer particles could nearly eliminate MT deposition for inhaled pharmaceutical aerosols. Compared with current inhalers, the proposed delivery approach represents a 1-2 order of magnitude reduction in MT deposition. Transient inhalation was found to influence the final size of the aerosol based on changes in residence times and relative humidity values. Aerosol sizes following EEG when exiting the chamber (2.75-4.61 μm) for all cases of initial submicrometer combination particles were equivalent to or larger than many conventional pharmaceutical aerosols that frequently have MMADs in the range of 2-3 μm.
Annals of biomedical engineering 07/2012; · 2.41 Impact Factor
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ABSTRACT: Deposition characteristics of MDI and DPI aerosols were compared throughout the conducting airways for the first time using a combination of in vitro experiments and a newly developed stochastic individual path (SIP) model for different inhalation profiles.
In vitro experiments were used to determine initial particle distribution profiles and to validate computational fluid dynamics (CFD) model results for a MDI and DPI delivering the same dose of drug in a geometry of the mouth-throat and tracheobronchial airways. The validated CFD model was then used to predict the transport and deposition of the drug using correct and incorrect inhalation profiles for each inhaler.
The MDI delivered approximately two times more drug to the tracheobronchial region compared with the DPI for both correct and incorrect inhalation profiles. Errors in inhalation reduced the deposited tracheobronchial dose by approximately 30% for both inhalers. The DPI delivered the largest dose to the mouth-throat (~70%) and the MDI delivered the largest dose to the alveolar airways (~50%).
The developed in silico model provides new insights into the lung delivery of pharmaceutical aerosols and can be applied in future studies in combination with pharmacokinetic analysis to establish bioequivalence between devices.
Pharmaceutical Research 01/2012; 29(6):1670-88. · 4.09 Impact Factor
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ABSTRACT: The objective of this study was to evaluate the delivery of inhaled pharmaceutical aerosols using an enhanced condensational growth (ECG) approach in an airway model extending from the oral cavity to the end of the tracheobronchial (TB) region. The geometry consisted of an elliptical mouth-throat (MT) model, the upper TB airways extending to bifurcation B3, and a subsequent individual path model entering the right lower lobe of the lung. Submicrometer monodisperse aerosols with diameters of 560 and 900 nm were delivered to the mouth inlet under control (25 °C with subsaturated air) or ECG (39 or 42 °C with saturated air) conditions. Flow fields and droplet characteristics were simulated using a computational fluid dynamics model that was previously demonstrated to accurately predict aerosol size growth and deposition. Results indicated that both the control and ECG delivery cases produced very little deposition in the MT and upper TB model (approximately 1%). Under ECG delivery conditions, large size increases of the aerosol droplets were observed resulting in mass median aerodynamic diameters of 2.4-3.3 μm exiting B5. This increase in aerosol size produced an order of magnitude increase in aerosol deposition within the TB airways compared with the controls, with TB deposition efficiencies of approximately 32-46% for ECG conditions. Estimates of downstream pulmonary deposition indicted near full lung retention of the aerosol during ECG delivery. Furthermore, targeting the region of TB deposition by controlling the inlet temperature conditions and initial aerosol size also appeared possible.
Annals of biomedical engineering 03/2011; 39(3):1136-53. · 2.41 Impact Factor
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ABSTRACT: Aerosol drug delivery during noninvasive ventilation (NIV) is known to be inefficient due to high depositional losses. To improve drug delivery efficiency, the concept of enhanced condensational growth (ECG) was recently proposed in which a submicrometer or nanoaerosol reduces extrathoracic deposition and subsequent droplet size increase promotes lung retention. The objective of this study was to provide proof-of-concept that the ECG approach could improve lung delivery of nasally administered aerosols under conditions consistent with NIV.
Aerosol deposition and size increase were evaluated in an adult nose-mouth-throat (NMT) replica geometry using both in vitro experiments and CFD simulations. For the ECG delivery approach, separate streams of a submicrometer aerosol and warm (39°C) saturated air were generated and delivered to the right and left nostril inlets, respectively. A control case was also considered in which an aerosol with a mass median aerodynamic diameter (MMAD) of 4.67 μm was delivered to the model.
In vitro experiments showed that the ECG approach significantly reduced the drug deposition fraction in the NMT geometry compared with the control case [14.8 (1.83)%-ECG vs. 72.6 (3.7)%-control]. Aerosol size increased from an initial MMAD of 900 nm to a size of approximately 2 μm at the exit of the NMT geometry. Results of the CFD model were generally in good agreement with the experimental findings. Based on CFD predictions, increasing the delivery temperature of the aerosol stream from 21 to 35°C under ECG conditions further reduced the total NMT drug deposition to 5% and maintained aerosol growth by ECG to approximately 2 μm.
Application of the ECG approach may significantly improve the delivery of pharmaceutical aerosols during NIV and may open the door for using the nasal route to routinely deliver pulmonary medications.
Journal of Aerosol Medicine and Pulmonary Drug Delivery 03/2011; 24(2):103-18. · 2.20 Impact Factor
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ABSTRACT: Most previous models of vapour absorption in the respiratory tract have assumed steady state flow fields and steady state diffusion into the airway walls. However, recent studies have shown that transient absorption flux into the walls of the upper airways can significantly influence predicted uptake or deposition values. The disadvantage of accounting for transient absorption into the airway walls is a more complex boundary condition and numerical model. The objective of this study was to evaluate the effects of both transient flow fields and transient mass absorption on the uptake of highly and moderately soluble compounds in an upper airway model. The geometry consisted of the mouth-throat region coupled with a multilayer wall model containing air, mucus, tissue, and blood phases. Based on previous studies, a boundary condition that represents transient absorption into the airway walls was applied. A new dosimetry program, named transient absorption of chemical species (TAOCS) 1.0, was developed and implemented to determine the coefficients needed for the transient boundary condition expression and to apply the boundary condition to the computational fluid dynamics (CFD) model. Both steady state and transient conditions were considered for the airflow field and wall absorption. The case of perfect wall absorption with a zero surface concentration was also considered. Results indicated that steady state airflow provided a reasonable approximation to transient airflow conditions in terms of total and local deposition (values within 10-30%). However, the simulation of transient wall absorption was critical unless the compound was highly soluble (with a mucus-air partition coefficient ≥320), in which case a perfect absorption boundary condition was accurate to within a relative difference of 50%. Still, the perfect absorption boundary condition did not accurately capture local deposition enhancement factor values. Based on these findings, implementation of the transient absorption boundary condition appears critical to predict local deposition characteristics for even highly soluble compounds. Use of the TAOCS program simplified the implementation of the complex transient absorption condition making the CFD simulation process more efficient and user-friendly.
Inhalation Toxicology 11/2010; 22(13):1047-63. · 1.92 Impact Factor
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ABSTRACT: The absorption of moderately and highly soluble vapors into the walls of the conducting airways was previously shown to be a transient process over the timescale of an inhalation cycle. However, a boundary condition to predict the transient wall absorption of vapors in CFD simulations does not exist. The objective of this study was to develop and test a boundary condition that can be used to predict the transient absorption of vapors in CFD simulations of transport in the respiratory airways. To develop the boundary condition, an analytical expression for the concentration of an absorbed vapor in an air-mucus-tissue-blood (AMTB) model of the respiratory wall was developed for transient and variable air-phase concentrations. Based on the analytical expression, a flux boundary condition was developed at the air-mucus interface as a function of the far-field air-phase concentration. The new transient boundary condition was then implemented to predict absorption in a realistic model of the extrathoracic nasal airways through the larynx (nasal-laryngeal geometry). The results of the AMTB wall model verified that absorption was highly time dependent over the timescale of an inhalation cycle (approximately 1-2 s). At 1 s, transient conditions resulted in approximately 2-3 times more uptake in tissue and 20-25 times less uptake in blood than steady state conditions for both acetaldehyde and benzene. Application of this boundary condition to computational fluid dynamics simulations of the nasal-laryngeal geometry showed, as expected, that transient absorption significantly affected total deposition fractions in the mucus, tissue, and blood. Moreover, transient absorption was also shown to significantly affect the local deposition patterns of acetaldehyde and benzene. In conclusion, it is recommended that future analyses of vapors in the conducting airways consider time-dependent wall absorption based on the transient flux boundary condition developed in this study. Alternatively, a steady state absorption condition may be applied in conjunction with correction factors determined from the AMTB wall model.
Journal of Biomechanical Engineering 05/2010; 132(5):051003. · 1.90 Impact Factor
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ABSTRACT: Previous studies have approximated the absorption of vapors into the walls of the respiratory tract as a steady state process. However, non-dimensional analysis indicates that the absorption of vapors in the conducting airways is time-dependent over the timescale of a breathing cycle. The objective of this study was to evaluate the mass transport of sample chemical species through a simple multilayer system composed of mucus, tissue, and blood components on a transient basis. Individual multilayer models were considered that represent the wall dimensions of the nasal extrathoracic (ET(2)), bronchial (BB), and bronchiolar (bb) airways. Sample vapors considered were acetaldehyde and benzene, which are highly soluble and moderately soluble in mucus, respectively. To determine absorption, mass transport was calculated based on an existing analytical steady state solution, a new analytical transient solution, and a numerical transient solution. Results indicated that concentrations within the mucus and tissue layers were highly time dependent in the ET(2) and BB regions and moderately time dependent in the bb airways over the timescale of an inhalation cycle, which is approximately 1-2 s. Fluxes of vapors into the tissue and blood varied with time for approximately 6-8 s in the BB region and 0.6-0.8 s in the bb model. The associated transient blood uptake of acetaldehyde and benzene in the upper ET(2) and BB regions varied from steady state values by a factor of approximately 30 after 1 s. Under similar conditions, transient uptake in the bb model varied from steady state conditions by a factor of approximately 1.3. Surprisingly, inclusion of chemical reactions in the mucus and tissue modified the transient uptake predictions only for very large values of reaction rate coefficients (K > 100 min(-1)). In summary, transient effects significantly impact the absorption of vapors into the walls of the upper respiratory tract (ET(2) and BB regions) and may largely diminish the effects of chemical reactions over the timescale of an inhalation cycle. Furthermore, the transient analytical solution that was developed provides the basis for an improved boundary condition in future CFD simulations of air-phase transport and wall absorption.
Annals of biomedical engineering 10/2009; 38(2):517-36. · 2.41 Impact Factor
