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.

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).

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 () and (ii) drug half-life in lumen () to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes.

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.

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.

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.

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.

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

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 data are lacking. Planar scintigraphy is probably the most common method addressing regional lung deposition in humans.

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.

Multiscale 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.

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.

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 for regional targeting in the upper airways, quantitatively supported by computational fluid dynamics (CFD) simulations of inhaled micron-sized particles (i.

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.

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.

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.

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.