Mechanistic modeling of generic orally inhaled drug products: A workshop summary report.

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

Development of a High-Dose Infant Air-Jet Dry Powder Inhaler (DPI) with Passive Cyclic Loading of the Formulation.

Purpose: The objective of this study was to incorporate a passive cyclic loading strategy into the infant air-jet dry powder inhaler (DPI) in a manner that provides high efficiency aerosol lung delivery and is insensitive to powder mass loadings and the presence of downstream pulmonary mechanics.

Methods: Four unique air-jet DPIs were initially compared and the best performing passive design (PD) was selected for sensitivity analyses. A single preterm in vitro nose-throat (NT) model, air source, and nasal interface were utilized throughout.

Analysis of Nasal Interface Options for High-Efficiency Aerosol Administration to Preterm Infants.

An infant air-jet dry powder inhaler (DPI) platform has recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high-efficiency aerosolization with low actuation air volumes. The objective of this study was to investigate modifications to the nasal interface section of this platform to improve the aerosol delivery performance through preterm nose-throat (NT) models. Aerosol delivery performance of multiple nasal interface flow pathways and prong configurations was assessed with two preterm infant NT models.

Evaluation of the Polyhedral Mesh Style for Predicting Aerosol Deposition in Representative Models of the Conducting Airways.

A critical factor affecting the accuracy of Computational Fluid Dynamic (CFD) simulations and the time required to conduct them is construction of the computational mesh. This study aimed to evaluate the relatively new polyhedral mesh style for simulating aerosol deposition in the upper conducting airways compared with established meshing techniques and experimental data. Hexahedral and polyhedral mesh solutions were compared in two benchmark geometries: 1) a 90°-bend with flow characteristics similar to the extrathoracic airways of an adolescent child, and 2) a double bifurcation representing bifurcations B3-B5 in an adult.

Advancement of the Infant Air-Jet Dry Powder Inhaler (DPI): Evaluation of Different Positive-Pressure Air Sources and Flow Rates.

Purpose: In order to improve the delivery of dry powder aerosol formulations to the lungs of infants, this study implemented an infant air-jet platform and explored the effects of different air sources, flow rates, and pulmonary mechanics on aerosolization performance and aerosol delivery through a preterm nose-throat (NT) in vitro model.

Methods: The infant air-jet platform was actuated with a positive-pressure air source that delivered the aerosol and provided a full inhalation breath. Three different air sources were developed to provide highly controllable positive-pressure air actuations (using actuation volumes of ~10 mL for the preterm model).

High-Efficiency Dry Powder Aerosol Delivery to Children: Review and Application of New Technologies.

While dry powder aerosol formulations offer a number of advantages, their use in children is often limited due to poor lung delivery efficiency and difficulties with consistent dry powder inhaler (DPI) usage. Both of these challenges can be attributed to the typical use of adult devices in pediatric subjects and a lack of pediatric-specific DPI development. In contrast, a number of technologies have recently been developed or progressed that can substantially improve the efficiency and reproducibility of DPI use in children including: (i) nose-to-lung administration with small particles, (ii) active positive-pressure devices, (iii) structures to reduce turbulence and jet momentum, and (iv) highly dispersible excipient enhanced growth particle formulations.

CFD Guided Optimization of Nose-to-Lung Aerosol Delivery in Adults: Effects of Inhalation Waveforms and Synchronized Aerosol Delivery.

Purpose: The objective of this study was to optimize nose-to-lung aerosol delivery in an adult upper airway model using computational fluid dynamics (CFD) simulations in order to guide subsequent human subject aerosol delivery experiments.

Methods: A CFD model was developed that included a new high-flow nasal cannula (HFNC) and pharmaceutical aerosol delivery unit, nasal cannula interface, and adult upper airway geometry. Aerosol deposition predictions in the system were validated with existing and new experimental results.

Advancement of a Positive-Pressure Dry Powder Inhaler for Children: Use of a Vertical Aerosolization Chamber and Three-Dimensional Rod Array Interface.

Purpose: Available dry powder inhalers (DPIs) have very poor lung delivery efficiencies in children. The objective of this study was to advance and experimentally test a positive-pressure air-jet DPI for children based on the use of a vertical aerosolization chamber and new patient interfaces that contain a three-dimensional (3D) rod array structure.

Methods: Aerosolization performance of different air-jet DPI designs was first evaluated based on a 10 mg powder fill mass of a spray-dried excipient enhanced growth (EEG) formulation.

Initial Development of an Air-Jet Dry Powder Inhaler for Rapid Delivery of Pharmaceutical Aerosols to Infants.

Positive-pressure dry powder inhalers (DPIs) have recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high efficiency aerosolization with low actuation air-volumes (AAVs). The objective of this study was to initially develop the positive-pressure air-jet DPI platform for high efficiency aerosol delivery to newborn infants by using the nose-to-lung route. Aerosolization performance metrics of six air-jet DPIs were first assessed at AAVs that were consistent with full-term (30 mL) and preterm (10 mL) neonates.

Dry powder aerosol containing muco-inert particles for excipient enhanced growth pulmonary drug delivery.

Tenacious sputum poses a critical diffusion barrier for aerosol antibiotics used to treat cystic fibrosis (CF) lung infection. We conducted a proof-of-concept study using dense poly(ethylene glycol) coated polystyrene nanoparticles (PS-PEG NPs) as model muco-inert particles (MIPs) formulated as a powder using an excipient enhanced growth (EEG) strategy, aiming to minimize extrathoracic airway loss, maximize deposition in the airway and further overcome the sputum barrier in the CF lungs. The EEG aerosol formulation containing PS-PEG MIPs was prepared by spray drying and produced discrete spherical particles with geometric diameter of approximately 2 μm; and >80% of the powder dose was delivered from a new small-animal dry powder inhaler (DPI).

Excipient Enhanced Growth Aerosol Surfactant Replacement Therapy in an Rat Lung Injury Model.

In neonatal respiratory distress syndrome, breathing support and surfactant therapy are commonly used to enable the alveoli to expand. Surfactants are typically delivered through liquid instillation. However, liquid instillation does not specifically target the small airways.

Computational Fluid Dynamics (CFD) Simulations of Spray Drying: Linking Drying Parameters with Experimental Aerosolization Performance.

Purpose: The purpose of this study was to develop a new computational fluid dynamics (CFD)-based model of the complex transport and droplet drying kinetics within a laboratory-scale spray dryer, and relate CFD-predicted drying parameters to powder aerosolization metrics from a reference dry powder inhaler (DPI).

Methods: A CFD model of the Buchi Nano Spray Dryer B-90 was developed that captured spray dryer conditions from a previous experimental study producing excipient enhanced growth powders with L-leucine as a dispersion enhancer. The CFD model accounted for two-way heat and mass transfer coupling between the phases and turbulent flow created by acoustic streaming from the mesh nebulizer.

Mechanistic Understanding of High Flow Nasal Cannula Therapy and Pressure Support with an In Vitro Infant Model.

Despite the increased use of high flow nasal cannula therapy, little has been done to predict airway pressures for a full breath cycle. A 3-month-old infant in vitro model was developed, which included the entire upper airway and the first three bifurcations of the lungs. A breathing simulator was used to create a realistic breath pattern, and high flow was provided using a Vapotherm unit.

Use of computational fluid dynamics deposition modeling in respiratory drug delivery.

Introduction: Respiratory drug delivery is a surprisingly complex process with a number of physical and biological challenges. Computational fluid dynamics (CFD) is a scientific simulation technique that is capable of providing spatially and temporally resolved predictions of many aspects related to respiratory drug delivery from initial aerosol formation through respiratory cellular drug absorption.

Areas Covered: This review article focuses on CFD-based deposition modeling applied to pharmaceutical aerosols.

Recommendations for Simulating Microparticle Deposition at Conditions Similar to the Upper Airways with Two-Equation Turbulence Models.

The development of a CFD model, from initial geometry to experimentally validated result with engineering insight, can be a time-consuming process that often requires several iterations of meshing and solver set-up. Applying a set of guidelines in the early stages can help to streamline the process and improve consistency between different models. The objective of this study was to determine both mesh and CFD solution parameters that enable the accurate simulation of microparticle deposition under flow conditions consistent with the upper respiratory airways including turbulent flow.

Efficient Nose-to-Lung Aerosol Delivery with an Inline DPI Requiring Low Actuation Air Volume.

Purpose: To demonstrate efficient aerosol delivery through an in vitro nasal model using a dry powder inhaler (DPI) requiring low actuation air volumes (LV) applied during low-flow nasal cannula (LFNC) therapy.

Methods: A previously developed LV-DPI was connected to a LFNC system with 4 mm diameter tubing. System connections and the nasal cannula interface were replaced with streamlined components.

Development of an infant complete-airway in vitro model for evaluating aerosol deposition.

A complete-airway in vitro model would be very useful for toxicological dosimetry testing and for developing targeted inhaled medications in cases where conducting in vivo experiments are exceedingly difficult, as with infants. The objective of this study was to determine whether packed bed in vitro models, which contain spheres as the primary repeating unit, provide a realistic representation of aerosol deposition in the tracheobronchial region of infant lungs based on computational fluid dynamics (CFD) predictions. The packed bed (PB) CFD model contained an inlet consistent with airway bifurcation B3 (∼lobar bronchi) leading to a spherical array with voids between the spheres forming a divided flow pathway.

Application of an inline dry powder inhaler to deliver high dose pharmaceutical aerosols during low flow nasal cannula therapy.

Inline dry powder inhalers (DPIs) offer a potentially effective option to deliver high dose inhaled medications simultaneously with mechanical ventilation. The objective of this study was to develop an inline DPI that is actuated using a low volume of air (LV-DPI) to efficiently deliver pharmaceutical aerosols during low flow nasal cannula (LFNC) therapy. A characteristic feature of the new inline LV-DPIs was the use of hollow capillary tubes that both pierced the capsule and provided a pathway for inlet air and exiting aerosol.

In Vitro Assessment of Small Charged Pharmaceutical Aerosols in a Model of a Ventilated Neonate.

Aerosolized medications may benefit infants receiving mechanical ventilation; however, the lung delivery efficiency of these aerosols is unacceptably low. experiments were conducted to evaluate aerosol delivery through conventional and modified ventilation systems to the end of a 3mm endotracheal tube (ETT) under steady state and realistic cyclic flow conditions. System modifications were employed to investigate the use of small charged particles and included streamlined components, a reduction in nebulizer liquid flow rate, synchronization with inspiration, and implementation of a previously designed low-flow induction charger (LF-IC), which was further modified in this study.

Development of an Inline Dry Powder Inhaler That Requires Low Air Volume.

Background: Inline dry powder inhalers (DPIs) are actuated by an external air source and have distinct advantages for delivering aerosols to infants and children, and to individuals with compromised lung function or who require ventilator support. However, current inline DPIs either perform poorly, are difficult to operate, and/or require large volumes (∼1 L) of air. The objective of this study was to develop and characterize a new inline DPI for aerosolizing spray-dried formulations with powder masses of 10 mg and higher using a dispersion air volume of 10 mL per actuation that is easy to load (capsule-based) and operate.

The Development and Validation of an In Vitro Airway Model to Assess Realistic Airway Deposition and Drug Permeation Behavior of Orally Inhaled Products Across Synthetic Membranes.

Background: Current in vitro approaches to assess lung deposition, dissolution, and cellular transport behavior of orally inhaled products (OIPs) have relied on compendial impactors to collect drug particles that are likely to deposit in the airway; however, the main drawback with this approach is that these impactors do not reflect the airway and may not necessarily represent drug deposition behavior in vivo. The aim of this article is to describe the development and method validation of a novel hybrid in vitro approach to assess drug deposition and permeation behavior in a more representative airway model.

Methods: The medium-sized Virginia Commonwealth University (VCU) mouth-throat (MT) and tracheal-bronchial (TB) realistic upper airway models were used in this study as representative models of the upper airway.

Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition.

Purpose: To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms.

Methods: A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP).

Aerosol Drug Delivery During Noninvasive Positive Pressure Ventilation: Effects of Intersubject Variability and Excipient Enhanced Growth.

Background: Nebulized aerosol drug delivery during the administration of noninvasive positive pressure ventilation (NPPV) is commonly implemented. While studies have shown improved patient outcomes for this therapeutic approach, aerosol delivery efficiency is reported to be low with high variability in lung-deposited dose. Excipient enhanced growth (EEG) aerosol delivery is a newly proposed technique that may improve drug delivery efficiency and reduce intersubject aerosol delivery variability when coupled with NPPV.

Hemodynamic Parameters and Early Intimal Thickening in Branching Blood Vessels.

Intimal thickening due to atherosclerotic lesions or intimal hyperplasia in medium to large blood vessels is a major contributor to heart disease, the leading cause of death in the Western World. Balloon angioplasty with stenting, bypass surgery, and endarterectomy (with or without patch reconstruction) are some of the techniques currently applied to occluded blood vessels. On the basis of the preponderance of clinical evidence that disturbed flow patterns play a key role in the onset and progression of atherosclerosis and intimal hyperplasia, it is of interest to analyze suitable hemodynamic wall parameters that indicate susceptible sites of intimal thickening and/or favorable conditions for thrombi formation.