Purpose
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.
Methods
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.
Results
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%).
Conclusions
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.
To evaluate the regional delivery of conventional aerosol medications, a new whole-lung computational fluid dynamics modeling approach was applied for metered dose inhaler (MDI) and dry powder ...inhaler (DPI) aerosols delivered to healthy and constricted airways. The computational fluid dynamics approach included complete airways through the third respiratory bifurcation (B3) and applied the new stochastic individual pathway modeling technique beyond B3 through the remainder of the conducting airways together with a new model of deposition in the alveolar region. Bronchiolar (B8-B15) deposition fraction values were low (∼1%) for both MDI and DPI aerosols with the healthy geometry, whereas delivery to the constricted model was even lower, with deposition fraction values of 0.89% and 0.81% for the MDI and DPI, respectively. Calculating dose per unit surface area for the commercial MDI and DPI products resulted in approximately 10(-3) μg/cm(2) in the lower tracheobronchial region of B8-B15 and 10(-4) μg/cm(2) in the alveolar region. Across the lung, dose per unit surface area varied by 2 orders of magnitude, which increased to 4 orders of magnitude when the mouth-throat region was included. The MDI and DPI both provided very low drug dose per unit surface area to the small tracheobronchial and alveolar airways.
Several physicochemical parameters are thought to affect in vivo performance of cyclosporine ophthalmic emulsion, including globule size distribution, viscosity profile as a function of applied ...shear, pH, zeta potential, osmolality, and surface tension. Using a modeling approach, this study predicts cyclosporine ophthalmic emulsion drug bioavailability to the cornea and conjunctiva and tear film breakup time for human subjects as a function of the vehicle physicochemical properties viscosity, surface tension, and osmolality for products that are qualitatively (Q1) and quantitatively (Q2) the same. The change in tear film breakup time from baseline, a potential indirect measure of therapeutic benefit, was predicted to characterize the direct effect of the vehicle on efficacy. Bioavailability predictions showed that while individual predictions were sensitive to variations in corneal and conjunctival permeabilities, geometric mean ratios of the test-to-reference comparisons for formulations that are Q1 and Q2 the same showed little sensitivity. Parameter sensitivity analysis showed that bioavailability and change in tear film breakup time from baseline values were both very sensitive to viscosity, slightly sensitive to surface tension, and insensitive to osmolality. With further improvements, the modeling framework developed for this study may be useful for informing future recommendations of cyclosporine ophthalmic emulsion bioequivalence for potential generic drug products.
While a number of studies have considered the dynamics of ambient or environmental particles in the respiratory tract, far fewer have evaluated the transport and deposition of pharmaceutical aerosols ...from inhalers in the mouth-throat (MT) and tracheobronchial (TB) airways. The objective of this study was to develop a new stochastic individual path (SIP) modeling approach for simulating the MT and TB deposition of a pharmaceutical aerosol from a dry powder inhaler and to evaluate the effects of transient vs. steady state conditions and sampling of the airways. In the SIP approach, representative models of the MT and upper TB geometries are considered through the third respiratory bifurcation (B3; approximately lobar bronchi). Stochastic individual paths are then evaluated extending from B4 to the terminal bronchioles (B15) in which one branch of each bifurcation is continued and one is not. Three SIP geometries were considered extending into the lower right lung lobe through the end of the conducting airways. A commonly prescribed dry powder inhaler (DPI) was connected to the MT geometry and the deposition of drug mass from a realistic polydisperse pharmaceutical aerosol was evaluated. Predictions of deposited drug mass in the MT and upper TB geometries were found to be in good agreement with concurrent experimental results. Transient inhalation was shown to influence the deposition of particles in the MT and upper TB airways through B3, where the Womersley number is greater than 1. In contrast, transient conditions were found to have little influence on deposition in the TB region starting with B4, where steady state simulations provided a good representation of total, regional, bifurcation-averaged, and localized deposition. Furthermore, a single SIP model was shown to characterize both regional and highly localized deposition within a lung lobe assuming mean airway dimensions. The resulting SIP model provides a highly efficient method to simulate the regional and local deposition of pharmaceutical aerosols throughout the conducting airways. In comparison with performing fully transient simulations of all branches in the regions considered, the SIP modeling approach reduces computational effort by a factor of approximately 3×10
5 while predicting regional and local deposition values to within approximately 5%.
Display omitted
► Simulation of a DPI aerosol from the mouth through the terminal bronchioles. ► Develops concept of stochastic individual path (SIP) modeling. ► Transient inhalation affects deposition through the third bifurcation (B3). ► Steady state approximation is appropriate in B4–B15. ► A single SIP geometry can characterize deposition in each lung lobe.
Characteristic models of the upper conducting airways are needed to evaluate the performance of existing pharmaceutical inhalers and to develop new respiratory drug delivery strategies. Previous ...studies have focused on the development of characteristic mouth-throat (MT) geometries for orally inhaled products; however, characteristic upper tracheobronchial (TB) geometries are currently not available. In this study, a new characteristic model of the upper TB airways for an average adult male was developed based on an analysis of new and existing anatomical data. Validated computational fluid dynamics (CFD) simulations were used to evaluate the deposition of monodisperse and realistic polydisperse aerosols from multiple inhalers. Comparisons of deposition results between the new model and a simpler geometry were used to identify the effects of different anatomical features on aerosol deposition. The CFD simulations demonstrated a good match to regional pharmaceutical aerosol deposition from in vitro experiments in the same geometry. The deposition of both monodisperse and pharmaceutical aerosols was increased in the new TB geometry as a result of additional anatomical detail on a regional and highly localized basis. Tracheal features including an accurate coronal angle, asymmetry, and curvature produced a skewed laryngeal jet and significantly increased regional deposition. Branch curvature and realistic cross-sections increased deposition in the remainder of the TB model. A hexahedral mesh style was utilized to provide the best solution. In conclusion, a number of physiological features in the upper TB region were shown to influence deposition and should be included in a characteristic model of respiratory drug delivery.
Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of ...mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.
Graphical Abstract
Regulatory science for generic dry powder inhalers (DPIs) in the United States (U.S.) has evolved over the last decade. In 2013, the U.S. Food and Drug Administration (FDA) published the draft ...product-specific guidance (PSG) for fluticasone propionate and salmeterol xinafoate inhalation powder. This was the first PSG for a DPI available in the U.S., which provided details on a weight-of-evidence approach for establishing bioequivalence (BE). A variety of research activities including in vivo and in vitro studies were used to support these recommendations, which have led to the first approval of a generic DPI in the U.S. for fluticasone propionate and salmeterol xinafoate inhalation powder in January of 2019. This review describes the scientific and regulatory activities that have been initiated by FDA to support the current BE recommendations for DPIs that led to the first generic DPI approvals, as well as research with novel in vitro and in silico methods that may potentially facilitate generic DPI development and approval.
The development of generic, single‐entity, drug–device combination products for orally inhaled drug products is challenging in part because of the complex nature of device design characteristics and ...the difficulties associated with establishing bioequivalence for a locally acting drug product delivered to the site of action in the lung. This review examines in silico models that may be used to support the development of generic orally inhaled drug products and how model credibility may be assessed.
Regulatory science for generic dry powder inhalation products worldwide has evolved over the last decade. The revised draft guidance Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - ...Quality Considerations 1 (Revision 1, April 2018) that FDA issued summarizes product considerations and potential critical quality attributes (CQAs). This guidance emphasizes the need to apply the principles of quality by design (QbD) and elements of pharmaceutical development discussed in the International Conference for Harmonisation of (ICH) guidelines. Research studies related to quality were used to support guidance recommendations, which preceded the first approval of a generic DPI product in the U.S. This review outlines scientific and regulatory hurdles that need to be surmounted to successfully bring a generic DPI to the market. The goal of this review focuses on relevant issues and various challenges pertaining to CMC topics of the generic DPI quality attributes. Furthermore, this review provides recommendations to abbreviated new drug application (ANDA) applicants to expedite generic approvals.
Highlights • Elimination of the MouthPiece device and use a conical spray framework for the modelling. • CFD predicted a higher deposition on the rings (Zygote model) due to higher vorticity ...generation. • CFD predicted a higher deposition on the Zygote model, due to the slanting geometry. • Enhanced deposition in the 1st generation region due to the presence of the rings. • CFD predicted recirculation of lighter particles below the construction region (Zygote model).
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