iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

In vitro-in silico correlation of three-dimensional turbulent flows in an idealized mouth-throat model.

There exists an ongoing need to improve the validity and accuracy of computational fluid dynamics (CFD) simulations of turbulent airflows in the extra-thoracic and upper airways. Yet, a knowledge gap remains in providing experimentally-resolved 3D flow benchmarks with sufficient data density and completeness for useful comparison with widely-employed numerical schemes. Motivated by such shortcomings, the present work details to the best of our knowledge the first attempt to deliver in vitro-in silico correlations of 3D respiratory airflows in a generalized mouth-throat model and thereby assess the performance of Large Eddy Simulations (LES) and Reynolds-Averaged Numerical Simulations (RANS). Numerical predictions are compared against 3D volumetric flow measurements using Tomographic Particle Image Velocimetry (TPIV) at three steady inhalation flowrates varying from shallow to deep inhalation conditions. We find that a RANS k-ω SST model adequately predicts velocity flow patterns for Reynolds numbers spanning 1'500 to 7'000, supporting results in close proximity to a more computationally-expensive LES model. Yet, RANS significantly underestimates turbulent kinetic energy (TKE), thus underlining the advantages of LES as a higher-order turbulence modeling scheme. In an effort to bridge future endevours across respiratory research disciplines, we provide end users with the present in vitro-in silico correlation data for improved predictive CFD models towards inhalation therapy and therapeutic or toxic dosimetry endpoints.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10-6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

Fate of inhaled aerosols under the influence of glottal motion in a realistic in silico human tracheobronchial tree model.

Despite the prevalence of inhalation therapy in the treatment of various respiratory diseases, predicting and optimizing lung deposition fractions of inhaled drugs for maximal efficacy remains challenging due to the complex anatomical structures of the extra-thoracic airways, notably the glottal region. One of the widespread speculations in current insilico simulations lies in assuming a static glottis during inhalation, while in reality inhalation leads to significant glottis cross-sectional area expansion. The present work attempts to explore, insilico, the influence of transient movement of the glottal structures on inhalation therapy outcomes. To this end, we adopted a CT-based realistic human tracheobronchial tree (TB) model and explored transient airflows and deposition outcomes for a broad range of inhaled aerosols (i.e., dp=1-12 µm) under a dry powder inhaler (DPI) maneuver. Three different glottal expansion ratios, spanning static to 40 percent cross-sectional area expansion have been considered for the analysis. Our findings point to the tangible impact of glottal motion on airflow and particle deposition along the respiratory tract for a DPI maneuver, where a static glottis underpredicts the total particle deposition in the TB model for lower sized particles (dp≤ 3 µm) compared to predictions for all dynamic glottal motions. In contrast, for larger size particles (i.e., 5 ≤dp≤ 10 µm), a static glottis yields lower total deposition in the TB model compared with dynamic glottal motions. Our study also underlines that regional deposition of smaller micron-sized particles is most affected by glottal deformation in the conducting airways.

On the Validation of Generational Lung Deposition Computer Models Using Planar Scintigraphic Images: The Case of Mimetikos Preludium.

Background: Mechanistic computer models for calculation of total and regional deposition of aerosols in the lungs are important tools for predicting or understanding clinical studies and for facilitating development of pharmaceutical inhalation products. Validation of such models must be indirect since generational in vivo data are lacking. Planar scintigraphy is probably the most common method addressing regional lung deposition in humans. Scintigraphic regions of interest (ROI) contain mixtures of airway generations and can therefore not be directly compared to model results. We propose a method to translate computed deposition per generation to deposition in scintigraphic ROI to be able to compare computed results with corresponding results obtained in humans. Methods: The total and regional lung deposition computed by the one-dimensional algebraic typical-path software Mimetikos Preludium was compared for 18 study legs in 14 published deposition studies involving 9 dry powder inhaler brands to the activity in planar scintigraphic ROIs (oropharyngeal, central [C], intermediate, and peripheral [P]) using for the computed regional lung distribution a generic mapping of the contribution of each airway generation to the ROIs. Results: The computed oropharyngeal and total lung deposition correlated with high significance (p < 0.0001) to the scintigraphic results with a near one-to-one relationship. For the regional lung distribution, computed C, P, and P/C results correlated with high significance (p < 0.01) to the corresponding scintigraphic measures. The computed C (P) deposition was on average about 28% lower (8% higher) than the mean scintigraphic results. The computed P/C ratio was on average 29% higher than the mean scintigraphic ratio. Conclusions: The results indicate that both the computational deposition model and the mapping algorithm are valid. The small underprediction of the C region merits further investigations. We believe that this method may prove useful also for the validation of computational fluid particle dynamic lung deposition models.

Anatomical variability in the upper tracheobronchial tree: sex-based differences and implications for personalized inhalation therapies.

The morphometry of the large conducting airways is presumed to have a strong effect on the regional deposition of inhaled aerosol particles. Nevertheless, sex-based differences have not been fully quantified and are still largely ignored in designing inhalation therapies. To this end, we retrospectively analyzed high-resolution computed tomography scans for 185 individuals (90 women, 95 men) in the age range of 12-89 yr to determine airway luminal areas, airway lengths, and bifurcation angles. Only subjects free of chronic airway disease were considered. In men, luminal areas of the upper conducting airways were, on average, ∼30%-50% larger when compared with those in women, with the largest differences found in the trachea (289.72 ± 54.25 vs. 193.50 ± 42.37 mm2 for men and women, respectively). The ratio of the largest luminal area in men to the smallest luminal area in women (in any given segment) ranged between 4.5 and 8.6, the largest differences being found in the lobar bronchi. Sex-based differences were minor in the case of bifurcation angles (e.g., average main bifurcation angle: 93.04 ± 9.58° vs. 91.03 ± 9.81° for men and women, respectively), but large intersubject variability was found irrespective of sex (e.g., range of main bifurcation angle: 65.04°-122.01° vs. 69.46°-113.94° for men and women, respectively). Bronchial segments were shorter by ∼5%-20% in women relative to men, the largest differences being located in the upper lobes. False discovery rate analysis revealed statistically significant associations among morphometric measures of the right lung in women (but not in men), suggesting two phenotypes among women that we attribute to the smaller female thoracic volume.NEW & NOTEWORTHY We found significant sex-based morphometric differences in the central airways of healthy men and women that were only mildly attenuated in subsets matched for lung volume. Lumen areas were significantly larger in men (∼30%-50%). Large variability (∼75%-87%) in airway bifurcation angles (60°-122°) was found irrespective of sex. The branching pattern of the right main and right upper bronchi in women (but not in men) follows two phenotypes modulated by lung volume.

In silico optimization of targeted aerosol delivery in upper airways via Inhaled Volume Tracking.

BACKGROUND: Despite the widespread use of aerosol inhalation as a drug delivery method, targeted delivery to the upper airways remains an ongoing challenge in the quest for improved clinical response in respiratory disease. METHODS: Here, we examine in silico flow and particle dynamics when using an oral Inhaled Volume Tracking manoeuvre. A short pulsed aerosol bolus is injected during slow inhalation flow rates followed by clean air, and a breath-hold is initiated once it reaches the desired depth. We explore the fate of a broad particle size range (1-40 µm) for both upright and supine positions. FINDINGS: Our findings illustrate that despite attempts to mitigate dispersion using slower flow rates, the laryngeal jet disperses the aerosol bolus and thus remains a hurdle for efficient targeted delivery. Nevertheless, we show a decrease in extra-thoracic deposition; large aerosols in the range of 10-30 µm potentially outperform existing inhalation methods, showing deposition fractions of up to 80% in an upright orientation. INTERPRETATION: The improved deposition during Inhaled Volume Tracking shows promise for clinical applications and could be leveraged to deliver larger payloads to the upper airways.

In Silico Optimization of Fiber-Shaped Aerosols in Inhalation Therapy for Augmented Targeting and Deposition across the Respiratory Tract.

Motivated by a desire to uncover new opportunities for designing the size and shape of fiber-shaped aerosols towards improved pulmonary drug delivery deposition outcomes, we explore the transport and deposition characteristics of fibers under physiologically inspired inhalation conditions in silico, mimicking a dry powder inhaler (DPI) maneuver in adult lung models. Here, using computational fluid dynamics (CFD) simulations, we resolve the transient translational and rotational motion of inhaled micron-sized ellipsoid particles under the influence of aerodynamic (i.e., drag, lift) and gravitational forces in a respiratory tract model spanning the first seven bifurcating generations (i.e., from the mouth to upper airways), coupled to a more distal airway model representing nine generations of the mid-bronchial tree. Aerosol deposition efficiencies are quantified as a function of the equivalent diameter (dp) and geometrical aspect ratio (AR), and these are compared to outcomes with traditional spherical particles of equivalent mass. Our results help elucidate how deposition patterns are intimately coupled to dp and AR, whereby high AR fibers in the narrow range of dp = 6-7 µm yield the highest deposition efficiency for targeting the upper- and mid-bronchi, whereas fibers in the range of dp= 4-6 µm are anticipated to cross through the conducting regions and reach the deeper lung regions. Our efforts underscore previously uncovered opportunities to design the shape and size of fiber-like aerosols towards targeted pulmonary drug delivery with increased deposition efficiencies, in particular by leveraging their large payloads for deep lung deposition.

Targeting inhaled fibers to the pulmonary acinus: Opportunities for augmented delivery from in silico simulations.

Non-spherical particles, and fibers in particular, are potentially attractive airborne carriers for pulmonary drug delivery. Not only do they exhibit a high surface-to-volume ratio relative to spherical aerosols, but their aerodynamic properties also enable them to reach deep into the lungs. Until present, however, our understanding of the deposition characteristics of inhaled aerosols in the distal acinar lung regions has been mostly limited to spheres. To shed light on the fate of elongated aerosols in the pulmonary depths, we explore through in silico numerical simulations the deposition and dispersion characteristics of ellipsoid-shaped fibers in a physiologically-realistic acinar geometry under oscillatory breathing flow conditions mimicking various inhalation maneuvers. The transient translation and rotational movement of micron-sized elongated particles under drag, lift, and gravitational forces are simulated as a function of size (dp) and aspect ratio (AR). Our findings underscore how acinar deposition characteristics are intimately linked to the geometrical combination of dp and AR under oscillatory flow conditions. Surprisingly, the elongation of the traditionally recommended size range of spherical particles (i.e., 2-3 µm) for acinar deposition may lead to a decrease in deposition efficiency and dispersion. Instead, our findings advocate how elongating particles (i.e., high AR) in the larger size range of 4-6 µm might be leveraged for improved targeted deposition to the acinar regions. Together, these results point to new windows of opportunities in selecting the shape and size of micron-sized fibers for targeted pulmonary deposition. Such in silico efforts represent an essential stepping stone in further exploring aerosol drug carrier designs for inhalation therapy to the deep lungs.

Targeted Drug Delivery to Upper Airways Using a Pulsed Aerosol Bolus and Inhaled Volume Tracking Method.

The pulmonary route presents an attractive delivery pathway for topical treatment of lung diseases. While significant progress has been achieved in understanding the physical underpinnings of aerosol deposition in the lungs, our ability to target or confine the deposition of inhalation aerosols to specific lung regions remains meagre. Here, we present a novel inhalation proof-of-concept in silico for regional targeting in the upper airways, quantitatively supported by computational fluid dynamics (CFD) simulations of inhaled micron-sized particles (i.e. 1-10 µm) using an intubated, anatomically-realistic, multi-generation airway tree model. Our targeting strategy relies on selecting the particle release time, whereby a short-pulsed bolus of aerosols is injected into the airways and the inhaled volume of clean air behind the bolus is tracked to reach a desired inhalation depth (i.e. airway generations). A breath hold maneuver then follows to facilitate deposition, via sedimentation, before exhalation resumes and remaining airborne particles are expelled. Our numerical findings showcase how particles in the range 5-10 µm combined with such inhalation methodology are best suited to deposit in the upper airways, with deposition fractions between 0.68 and unity. In contrast, smaller (< 2 µm) particles are less than optimal due to their slow sedimentation rates. We illustrate further how modulating the volume inhaled behind the pulsed bolus, prior to breath hold, may be leveraged to vary the targeted airway sites. We discuss the feasibility of the proposed inhalation framework and how it may help pave the way for specialized topical lung treatments.

Multiscale in silico lung modeling strategies for aerosol inhalation therapy and drug delivery.

Inhalation therapy is a hallmark of modern respiratory medicine. Over recent years, computational fluid-particle dynamics (CFPD) simulations of respiratory airflows and aerosol deposition in the lungs have rapidly developed into an increasingly mature research field in the biomedical engineering realm, owing, among others, to tremendous advances in computational capabilities and available resources. Despite such progress, the intrinsic anatomical and physiological complexity of the lungs prevents the straightforward implementation of 'brute force' simulation strategies applied across the entire pulmonary tract. Here, we discuss how knowledge gathered from recent in silico studies can be purposefully leveraged to design efficient hybrid multiscale lung models and explore quantitatively via computational fluid-particle dynamics inhalation therapy outcomes. In contrast to the efforts geared toward patient-specific applications, we argue instead that such in silico strategies hold tremendous promise for broad inter-subject variability studies that can help foster the development of clinically efficient inhalation therapies across large human patient populations.

Targeting inhaled aerosol delivery to upper airways in children: Insight from computational fluid dynamics (CFD).

Despite the prevalence of inhalation therapy in the treatment of pediatric respiratory disorders, most prominently asthma, the fraction of inhaled drugs reaching the lungs for maximal efficacy remains adversely low. By and large drug delivery devices and their inhalation guidelines are typically derived from adult studies with child dosages adapted according to body weight. While it has long been recognized that physiological (e.g. airway sizes, breathing maneuvers) and physical transport (e.g. aerosol dynamics) characteristics are critical in governing deposition outcomes, such knowledge has yet to be extensively adapted to younger populations. Motivated by such shortcomings, the present work leverages in a first step in silico computational fluid dynamics (CFD) to explore opportunities for augmenting aerosol deposition in children based on respiratory physiological and physical transport determinants. Using an idealized, anatomically-faithful upper airway geometry, airflow and aerosol motion are simulated as a function of age, spanning a five year old to an adult. Breathing conditions mimic realistic age-specific inhalation maneuvers representative of Dry Powder Inhalers (DPI) and nebulizer inhalation. Our findings point to the existence of a single dimensionless curve governing deposition in the conductive airways via the dimensionless Stokes number (Stk). Most significantly, we uncover the existence of a distinct deposition peak irrespective of age. For the DPI simulations, this peak (∼ 80%) occurs at Stk ≈ 0.06 whereas for nebulizer simulations, the corresponding peak (∼ 45%) occurs in the range of Stk between 0.03-0.04. Such dimensionless findings hence translate to an optimal window of micron-sized aerosols that evolves with age and varies with inhalation device. The existence of such deposition optima advocates revisiting design guidelines for optimizing deposition outcomes in pediatric inhalation therapy.

Discrete multi-physics simulations of diffusive and convective mass transfer in boundary layers containing motile cilia in lungs.

In this paper, the mass transfer coefficient (permeability) of boundary layers containing motile cilia is investigated by means of discrete multi-physics. The idea is to understand the main mechanisms of mass transport occurring in a ciliated-layer; one specific application being inhaled drugs in the respiratory epithelium. The effect of drug diffusivity, cilia beat frequency and cilia flexibility is studied. Our results show the existence of three mass transfer regimes. A low frequency regime, which we called shielding regime, where the presence of the cilia hinders mass transport; an intermediate frequency regime, which we have called diffusive regime, where diffusion is the controlling mechanism; and a high frequency regime, which we have called convective regime, where the degree of bending of the cilia seems to be the most important factor controlling mass transfer in the ciliated-layer. Since the flexibility of the cilia and the frequency of the beat changes with age and health conditions, the knowledge of these three regimes allows prediction of how mass transfer varies with these factors.

Transport of ellipsoid fibers in oscillatory shear flows: Implications for aerosol deposition in deep airways.

It is widely acknowledged that inhaled fibers, e.g. air pollutants and anthropogenic particulate matter, hold the ability to deposit deep into the lungs reaching the distal pulmonary acinar airways as a result of their aerodynamic properties; these particles tend to align with the flow and thus stay longer airborne relative to their spherical counterpart, due to higher drag forces that resist sedimentation. Together with a high surface-to-volume ratio, such characteristics may render non-spherical particles, and fibers in particular, potentially attractive airborne carriers for drug delivery. Until present, however, our understanding of the dynamics of inhaled aerosols in the distal regions of the lungs has been mostly limited to spherical particles. In an effort to unravel the fate of non-spherical aerosols in the pulmonary depths, we explore through numerical simulations the kinematics of ellipsoid-shaped fibers in a toy model of a straight pipe as a first step towards understanding particle dynamics in more intricate acinar geometries. Transient translational and rotational motions of micron-sized ellipsoid particles are simulated as a function of aspect ratio (AR) for laminar oscillatory shear flows mimicking various inhalation maneuvers under the influence of aerodynamic (i.e. drag and lift) and gravitational forces. We quantify transport and deposition metrics for such fibers, including residence time and penetration depth, compared with spherical particles of equivalent mass. Our findings underscore how deposition depth is largely independent of AR under oscillatory conditions, in contrast with previous works where AR was found to influence deposition depth under steady inspiratory flow. Overall, our efforts underline the importance of modeling oscillatory breathing when predicting fiber deposition in the distal lungs, as they are inhaled and exhaled during a full inspiratory cycle. Such physical insight helps further explore the potential of fiber particles as attractive carriers for deep airway targeting.

Experimental methods for flow and aerosol measurements in human airways and their replicas.

Recent developments in the prediction of local aerosol deposition in human lungs are driven by the fast development of computational simulations. Although such simulations provide results in unbeatable resolution, significant differences among distinct methods of calculation emphasize the need for highly precise experimental data in order to specify boundary conditions and for validation purposes. This paper reviews and critically evaluates available methods for the measurement of single and disperse two-phase flows for the study of respiratory airflow and deposition of inhaled particles, performed both in vivo and in replicas of airways. Limitations and possibilities associated with the experimental methods are discussed and aspects of the computational calculations that can be validated are indicated. The review classifies the methods into following categories: 1) point-wise and planar methods for velocimetry in the airways, 2) classic methods for the measurement of the regional distribution of inhaled particles, 3) standard medical imaging methods applicable to the measurement of the regional aerosol distribution and 4) emerging and nonconventional methods. All methods are described, applications in human airways studies are illustrated, and recommendations for the most useful applications of each method are given.