Aerosols in Medicine (AIM) Lab
Mission
The Aerosols in Medicine (AIM) Lab in the VCU College of Engineering seeks to improve the treatment of respiratory and other diseases through the development of highly effective pharmaceutical aerosol products.
Lab Director
Worth Longest, Ph.D.
Harris Exceptional Scholar Professor
Department of Mechanical and Nuclear Engineering
Department of Pharmaceutics
Prevalence and Impact of Respiratory Diseases
Respiratory diseases as a group are the third leading cause of death in the United States (1) and worldwide (2), and for a period during the COVID-19 pandemic became the leading cause of death in the US (3). Asthma affects approximately 10% of children under 18 years of age in the US (4), with 90% of all cases sub-optimally controlled (5). One reason for poor asthma control may be that the small respiratory airways (deep within the lungs) receive insufficient drug concentration due to poor drug delivery efficiency in this region combined with the large surface area of the small airways (6). Approximately 10% of the population above 40-years-old in the US and in most of the world have COPD (7). While bronchodilators may relieve COPD symptoms on a short-term basis, there are currently no available therapies that can effectively address the small airway inflammation that is the hallmark of this disease and causes progression leading to reduced lung function and emphysema (8). Considering the pediatric population, the World Health Organization estimates that 2 million children under the age of 5 die of pneumonia each year (9). Approximately 1.2% of US births are preterm and require surfactant replacement therapy to improve lung function and reduce the risk of respiratory distress syndrome (10).
Current Challenges in Medical Aerosol Delivery
As a targeted drug delivery modality, medical aerosols offer a number of advantages including increased concentrations of therapeutics in the lungs (likely leading to increased efficacy) and decreased concentrations in other areas of the body (likely leading to reduced side effects), as well as the elimination of first pass hepatic metabolism that can degrade the medication and stress or damage the liver (11-13). Successful examples of inhaled pharmaceutical products include the use of inhaled steroids and bronchodilators to control asthma symptoms in a majority of asthmatics without the side effects of oral steroids (14) and the use of inhaled antibiotics, which have significantly extended the life-expectancy of cystic fibrosis patients over the last 20 years (15, 16). While these and other applications have been successful, a number of significant current challenges have limited the effective use of medical aerosols, especially when the underlying drug or biological has a narrow therapeutic window, significant side effects, is difficult to aerosolize or requires high dose delivery to the lungs. These significant challenges are described further below:
Significant Challenges in Medical Aerosol Delivery
Significant challenges that currently persist in the field of medical aerosol delivery include achieving high efficiency aerosol administration to the lungs with low mouth-throat (MT) depositional loss (17, 18) (which leads to ingestion of the medication and off-target effects), overcoming high intersubject variability in lung dose (19), targeting inhaled therapies to specific lung regions (20), achieving sufficient concentrations of inhaled therapeutics on the large surface-area of the small airways (21, 22), delivering high dose medications without the requirement of continuous nebulization (23), and overcoming the natural barriers and clearance mechanisms of the lungs (24). Delivering inhaled medications to children and infants is especially challenging due to narrow airway diameters (compared with adults), low inhaled air volumes, and often the inability to follow inhalation instructions required for adult aerosol delivery products (17).
Significant Challenges in Medical Aerosol Development
In the area of medical aerosol development, well controlled aerosol administration to test animals is a significant current challenge, which if not properly addressed can lead to the failure of otherwise promising new therapeutics (25). Accurate determination of pharmaceutical aerosol deposition within the lungs has historically required human subject testing, which is expensive and time consuming to perform (26). Performing these predictions with a combination of complete-airway CFD simulations and realistic in vitro experiments is another current challenge that is rapidly progressing and has the potential to reduce the cost of developing new medical aerosol therapies (27, 28).
The Aim Lab seeks to address these and other related significant challenges in the field of aerosolized medicine through a combined application of engineering and pharmaceutical science tools, methods and skill sets.
Research Impact
Solving the significant challenges currently facing the delivery of medical aerosols is expected to have a number of positive impacts primarily centered on improving the treatment of respiratory diseases with new and existing therapeutics (11, 12, 29, 30) as well as reducing the cost of inhaled medications (31, 32). Research in the AIM Lab is currently focused on the following impact areas:
Improving Treatment of Respiratory Diseases with New Inhaled Medications
Considering improved disease treatment with new therapeutics, significant resources are often dedicated to developing molecular and biological therapies that are highly effective at the preclinical molecular/structural biology level and in cellular or tissue culture systems (33, 34). However, these otherwise promising therapeutics often fail at the preclinical animal or clinical human testing stage because insufficient attention is paid to lung delivery of the aerosol resulting in insufficient lung dose or uncontrolled and unknown lung doses of the medication (25, 35). By solving many of the challenges related to the lung delivery of inhaled medicines in both animals and humans, adequate and well controlled delivery profiles can be achieved enabling a focus on the biological activity of new therapeutics. As a result, more new inhaled therapeutics will likely advance through the clinical testing phase and result in effective tools for the mitigation, reversal or prevention of respiratory diseases.
Improving the Efficacy of Existing Inhaled Medications
As with new inhaled medications, it is expected that a number of existing inhaled therapies, some with excellent safety profiles like disodium cromoglycate, have poor targeting to or distribution within the lungs leading to marginal efficacy (6, 35-37). The pharmaceutical industry and research community continually search for new therapies to supplant these existing and established therapies as the best route to improve disease treatment. However, improved formulation and targeting of existing inhaled therapies is a viable alternative approach to the improved treatment of respiratory diseases that offers reduced cost and often a higher probability for success in human subjects.
Reducing the Cost of Inhaled Medications through Development of Generic Inhaled Products
As a more direct cost saving strategy for the consumer, generic inhaled medications are available for some products after initial patent expiration. A current limitation to the availability of more generic inhaled products entering the market is the time and expense associated with conducting large in vivo efficacy trials (31, 32). The development and use of effective complete-airway CFD simulations and realistic in vitro testing models are currently being explored by the AIM Lab in collaboration with the Hindle Lab and US FDA Office of Generic Drugs to reduce in vivo drug trails and accelerate the approval of more generic inhaled medications (38-40).
Outcomes of Active Projects
Example 1: Particles that Change Size to Target Deposition Within the Lungs
Examples of active project outcomes from our lab include the development of aerosol delivery technologies that modify particle size within the lungs to better target the region of drug delivery (41, 42). These controlled condensational growth techniques have demonstrated the ability to reduce mouth-throat or general extrathoracic depositional loss from the typical range of 30-90% of the inhaled dose by one or more orders of magnitude (43-46) and to increase drug delivery to the small tracheobronchial airways by a factor of 30- to 40-fold (41, 47).
Example 2: Small Particle Dry Powder Inhaler (DPI) and Nebulizer Systems
We have also recently developed nebulizer (48, 49) and dry powder platforms (44, 50-55) for generating and administering condensational growth aerosol delivery techniques. Our air-jet delivery platform combined with highly dispersible powder formulations reduces the air volume required to effectively form a high quality aerosol from ~1 Liter to approximately 5-10 mL (54), which enables high efficiency dry powder aerosol administration to infants (56) and children (17, 57-59). Our heated-dryer system (HDS) nebulized-based platform can administer high dose medications to adults and children with approximately 1% mouth-throat depositional loss and the ability to target the difficult to reach small tracheobronchial airways.
Example 3: Inhaled Antibiotic and Surfactant Products for Infants and Children
We are actively developing high dose dry powder inhaler (DPI) platforms for children with cystic fibrosis that can achieve ~80% lung delivery efficiency and administer a high dose of antibiotic aerosol within seconds (17, 57-60), compared with initial nebulizer technology that required hours per day to complete the administration process and have lung delivery efficiencies in the range of 10% (11, 61). We are developing aerosolized surfactant delivery platforms that can administer dry powder surfactant replacement therapies to infants or adults in respiratory distress without the side effects and risks of endotracheal tube intubation, mechanical ventilation, and high volume liquid instillation through the endotracheal tube (56, 62). A version of the infant rapid aerosol delivery system is currently being developed with manual actuation components for use in low resource settings.
Example 4: Dry Powder Aerosol Administration to Test Animals
We are currently applying our air-jet based dry powder platform to develop efficient and well controlled aerosol delivery platforms for test animals including rats (62), ferrets and rabbits.
Lab Skills and Methods
To address challenges in the field of aerosolized medicine, the AIM lab specializes in a thorough understanding of transport phenomena including fluid mechanics, heat and mass transfer, turbulence, thermodynamics, pharmacokinetics and multiphase flows, together with aerosol science, lung biology and lung physiology. Specific skills developed by lab members often fall into the areas of:
Computational fluid dynamics (CFD)
Inhaler and aerosol generation/delivery device development
Development and use of characteristic and complete airway models
Particle engineering
These skills are applied to various aspects of the medical aerosol delivery process from particle formation during spray drying and aerosol generation within an inhaler through particle deposition in the distal airways and post-deposition transport including drug dissolution, absorption and clearance. Each skill area is described further below.
Computational Fluid Dynamics
Computational Fluid Dynamics: CFD analysis is an emphasis of the AIM Lab (27, 28) and has been applied to all levels of medical aerosol delivery including developing predictive correlations for spray-dried particle performance (57, 63, 64), dry powder aerosol formation (65), inhaler performance (DPI, MDI, softmist and nebulizer devices) (20, 49, 66-69), extrathoracic particle deposition including inhaler turbulent jet and spray momentum effects (20, 66, 67, 70), complete-airway particle transport (39, 40), and post-deposition particle transport (22, 38, 71, 72).
Device Development
Device Development: Inhalers and medical aerosol delivery devices are conceptualized with initial CFD findings, fabricated with 3D printing and other microfabrication processes, and tested in collaboration with the VCU Hindle Lab (17, 69). Currently one delivery platform has progressed through the initial stage of human subject testing while multiple other platforms are in various stages of preclinical evaluation including animal testing.
Characteristic Airway Models
Characteristic Airway Models: Our lab has developed a series of realistic upper airway models for both adults and children, which can be used with in vitro experiments to predict lung aerosol delivery efficiency results, and these predictions have been shown to agree with in vivo studies for pharmaceutical aerosols (73-75) resulting in successful in vitro-in vivo correlations (IVIVCs). The adult mouth-throat (MT) line of these airway models has been validated with a broad set of in vivo data (75, 76) and is currently available for sale through a commercial partner (RDD Online).
Particle Engineering
Particle Engineering: As a forth skill area, the AIM lab has recently begun work in the field of particle engineering with an emphasis on CFD prediction of dry powder aerosol behavior (65), and in-house spray dryer development to implement design ideas that are conceptualized in CFD. These AIM Lab efforts are complementary to our work with the VCU Hindle Research Group, which has extensive experience with spray drying, particle engineering, and pharmaceutical powder analysis and characterization (44, 77, 78).
Computational Fluid Dynamics
Device Development
Characteristic Airway Models
Particle Engineering
Collaborations and Pharmaceutical Aerosol Product Development Pipeline (PDP)
The AIM Lab works closely with the Hindle Research Group, directed by Dr. Michael Hindle, which is part of the VCU School of Pharmacy Aerosol Research Group. The Hindle Lab specializes in pharmaceutical aerosol formulation and device development, aerosol and particle characterization, and realistic in vitro drug delivery assessment. Our collaborative work is based on the premise that aerosol drug delivery strategy, formulation and device are all critical and mutually dependent elements for successful development of a pharmaceutical inhalation product. Therefore, the most effective pharmaceutical aerosol solutions can be achieved when the elements of delivery strategy, formulation and device are each considered important and developed simultaneously.
For a specific pharmaceutical aerosol delivery challenge, our collaborative process can be viewed as a Product Development Pipeline (PDP), which is illustrated in Figure 1 below. Individual components that are typically led by each group are indicated as Eng (AIM Lab) and Pharm (Hindle Lab), with areas that heavily overlap indicated as Both. Additional collaborators with the AIM Lab at VCU include Dr. Laleh Golshahi (nasal drug delivery and in vitro aerosol testing), Dr. Rebecca Heise (animal testing and lung mechanics), Dr. Bruce Rubin (pediatric and infant drug delivery), and Dr. Qingguo Xu (animal testing, particle engineering and targeted drug delivery).
Figure 1. Medical aerosol Product Development Pipeline (PDP) employed by the AIM Lab (Eng) and Hindle Research Group (Pharm) in collaboration with other pharmaceutical, medical and biomedical researchers at VCU.
Concurrent CFD and Realistic In Vitro Assessment of Medical Aerosol Systems
For individual elements of the Product Development Pipeline (PDP), such as dry powder inhaler development, the AIM and Hindle Labs implement a concurrent CFD and realistic in vitro analysis, as illustrated in Figure 2 (17, 27). In this approach, both CFD and realistic in vitro analysis techniques are applied simultaneously in order to take advantage of each method’s strengths and to minimize each method’s weaknesses.
Description of Concurrent CFD and Realistic In Vitro Analysis
In concurrent analysis, realistic in vitro experiments are used to assess initial and key prototype performance of both aerosol formation and lung delivery efficiency as a benchmark. CFD models are developed of key system aspects, such as mouthpiece aerosol transport and extrathoracic depositional loss. The CFD models are first validated with the initial in vitro data. Once validated, the CFD models are then used to generate valuable insights into system transport characteristics and explore design alternatives. Best performing model designs or strategies are then produced and tested experimentally to verify system performance improvements. In some instances, quantitative relations are formed between CFD-predicted parameters and experimental critical quality attributes (or performance metrics), such as device emitted dose and mass median aerodynamic diameter (MMAD) (53, 60, 63, 64, 79-81). For example, in the quantitative concurrent analysis of Longest et al. (63), aerosol dispersion parameters were used to capture both emitted dose and aerosol size for a series of air-jet dry powder inhalers (DPIs). These or similar dispersion parameters were then used to optimize DPI performance for low (64) and high (81) air-actuation-volume devices based on CFD analysis. Optimized devices were then prototyped and tested experimentally in respective studies. This concurrent analysis approach has been applied to the development of dry powder formulations for high dispersion (65), powder aerosolization within DPIs (63, 64, 81), aerosol transmission through inhalers (79, 80), and aerosol delivery strategies (41, 47, 82-84).
Figure 2. Schematic of concurrent CFD and realistic in vitro analysis that has been implemented to increase the lung delivery efficiency of pharmaceutical aerosols based on improvements in the areas of powder dispersion, device performance, and delivery strategy development.
Product Development Pipeline Components
Research projects in the AIM Lab can be categorized based on where they fall within the different components (or steps) of the PDP process, which are Strategy Development, Implementation (i.e., Pharmaceutical Science Engineering), Assessment, and Optimization. These components are evaluated for multiple applications considered by the lab including the development of an antibiotic DPI product for children with cystic fibrosis and the development of dry powder surfactant products for infants and adults. Each of the PDP steps is briefly described below followed by links to relevant articles and summaries.
Strategy Development
Description of Strategy Development
Strategy development refers to the overall transport approaches that are implemented to achieve the specified drug delivery goals of a given application. While selection of the base inhaler class (MDI, DPI, softmist, or nebulizer) and formulation type (dry powder or nebulized droplet) are included, strategy development goes much further and focuses on selection of transport approaches and enabling technologies that go beyond current inhaler capabilities and can be used to meet the significant challenges of many new aerosolized medication applications or to substantially improve the delivery of existing medications. For example, controlled condensational growth approaches may be selected to minimize extrathoracic depositional loss and better control the region of aerosol deposition within the lungs (47, 85). Inhalation control or an exhalation maneuver may also be used to enhance drug targeting to and within the lungs (20, 69). Previous studies have illustrated that charged small particles may evade upper airway deposition and increase alveolar delivery (86). Nose-to-lung aerosol administration with sufficiently small particles may be an effective delivery approach for adults receiving simultaneous noninvasive ventilation (NIV) (46, 87-90), infants and children that are too young to use a mouthpiece (17, 56-59, 91), or to treat the nasal and lung airways simultaneously. After particle deposition, adjuvants may be used to increase drug effectiveness, shield mucus interactions, and enhance spreading or uptake. Nanoparticle aggregates can be implemented to significantly improve the dissolution and uptake of highly insoluble medications, and to increase the percentages of respiratory epithelial cells receiving the drug (22).
Consider, for example, the medical aerosol delivery challenge of administering a high dose surfactant aerosol to the lungs of an infant in respiratory distress. With current nebulizer devices, lung delivery efficiency is typically below 1% of the nebulizer loaded dose and delivery times may require multiple hours for high dose delivery (35, 56, 92). For this application, a more efficient strategy would be nose-to-lung administration of a sufficiently small aerosol particle size using a low-air-volume positive-pressure DPI (56). The excipient enhanced growth approach could also be included to enhance lung delivery of the aerosol and minimize exhalation of the dose (93, 94).
Upon initial strategy selection, the Strategy Development phase evaluates the feasibility of the approach using CFD simulations and in vitro screening experiments. CFD simulations are highly beneficial at this stage to test transport ideas and understand the transport physics without the requirement to develop the delivery device (which is performed in Implementation). In vitro screening is conducted to evaluate strategy feasibility and to generate data needed to validate the CFD model predictions, often with preliminary or test formulations and devices.
Implementation
Description of Implementation
Implementation refers to the development of formulations and devices required to realize the proposed drug delivery strategy. Another term for this phase is Pharmaceutical Engineering, which is the application of engineering principles and tools to address drug development and delivery challenges. It is within the Implementation phase that both the drug formulation and inhalation device are developed. As described in the section on Concurrent CFD and Realistic In Vitro Assessments, implementation often involves a concurrent CFD and in vitro development process. As an example of the Implementation phase, a submicrometer aerosol strategy can be used to minimize mouth-throat depositional loss. However, creating a submicrometer aerosol with a dry powder inhaler (DPI) is a considerable challenge. In collaboration with the Hindle Lab, we have developed formulation and DPI device combinations capable of producing a submicrometer aerosol (43, 44, 53, 95). The DPI devices are based on CFD simulations, which indicated that a new 3D rod array structure could most effectively deaggregate different powder formulation (52, 53). The resulting DPI products were then optimized through a combination of CFD simulations, rapid prototyping, and in vitro testing. This new line of inhalers is capable of producing submicrometer aerosols with negligible mouth-throat depositional loss and little sensitivity to inhalation flow rate (52). Furthermore, inline versions of the DPI were developed for application to ventilation tubing and aerosol delivery during noninvasive ventilation (51).
Assessment
Description of Assessment
Assessment involves the prediction of aerosol lung delivery, deposition and uptake using computational simulations, realistic in vitro experiments and in vivo animal models leading to human subject testing. Computational fluid dynamics (CFD) provides a powerful tool for predicting the transport and deposition of gases and particles in the respiratory tract (27, 28). However, due to the complexity of the respiratory airways, CFD models are typically limited to relatively small regions (28). The AIM Lab has developed the stochastic individual pathway (SIP) modeling approach to simulate whole-lung aerosol transport and deposition with CFD (20, 66, 67). The approach simulates the upper airways through approximately the lobar bronchi using characteristic models derived from medical CT scans. These models are also 3D printed for generating corresponding in vitro deposition data. Transport and deposition in the remainder of the tracheobronchial airways are then evaluated using the SIP approach in which ensembles of individual pathways are created and simulated. Finally, alveolar deposition is simulated using a new space-filling alveolar geometry that approximates a complete acinus with airflow driven by wall motion (96). We have extensively validated CFD predictions of upper airway deposition with concurrent in vitro data (from the Hindle Lab) for MDIs, DPIs, nebulizers, and softmist inhalers (17, 20, 27, 45, 60, 66-68, 87, 91, 97, 98). The SIP approach was demonstrated as an effective method to simulate lung deposition of pharmaceutical aerosols with computational savings of multiple orders of magnitude compared with simulating all of the tracheobronchial airways (67). Implementation of the space-filling alveolar model provides an efficient mechanism to simulate complete airway deposition of pharmaceutical aerosols using CFD (96). Comparisons between CFD predictions and in vivo data of pharmaceutical aerosol regional lung deposition are in very close agreement (39, 99). Research is ongoing to further improve the physical realism of the complete-airway models, match 3D in vivo SPECT data of pharmaceutical aerosol deposition, and evaluate diseased airway states.
In vivo animal testing provides a means to determine biological safety and efficacy of inhaled medications. Due to differences in airway anatomy, scale and ventilation parameters, drug delivery efficiency and lung distribution for human platforms cannot be directly assessed in animal models. As a result, our lab is working on dedicated animal aerosol delivery platforms to better assess drug formulation behavior and biological efficacy with controlled high efficiency lung deposition (62).
Complete-airway CFD simulations coupled with realistic in vitro experiments are intended to reduce the need for human subject testing. Nevertheless, human subject benchmark data is required in order to test new medical aerosol delivery strategies for which previous data may not exist. Furthermore, human subject trials are ultimately required to determine the safety and efficacy of new inhaled therapies. We have recently completed human subject safety testing (100, 101) of a heated-dryer system (HDS) and plan to use this system for initial lung delivery efficiency testing of the excipient enhanced growth (EEG) aerosol delivery strategy.
Optimization
Description of Optimization
As with all engineering design approaches, feedback and iteration through the process development loop is a critical process. An advantage of CFD implementation is that transport behavior can be well characterized and quantified at the mechanistic level. Resulting correlations of system behavior can be used to implement a quantitative analysis and design (QAD) approach that guides the optimization process (79, 80). As a result, limitations identified in the assessment phase can quickly be addressed with modifications to the strategy and implementation for reevaluation. Furthermore, use of CFD and realistic in vitro experiments also allows assessment of lung delivery and deposition with multiple optimization cycles before conducting expensive and time consuming human subject experiments (102). As a result of this optimization process, human subject trials have a high probability for success in terms of high lung delivery efficiency of the aerosol, regional targeting of aerosol deposition and accurate assessment of biological efficacy.
Enabling Technologies
In the areas of Strategy Development, Implementation, Assessment and Optimization our group has developed a number of Enabling Technologies for the administration of medical aerosols. A summary of these enabling technologies is provided below with links to relevant granted patents, published patent applications and published studies. Patents developed by our group and in collaboration with the Hindle Lab are also summarized on the Patents Page.
Condensational Aerosols: Dry Powder Nose-to-Lung Aerosol Administration
Aerosol Administration with High Flow Nasal Cannula (HFNC): Small Volume System
Small-Particle Aerosol Generation with Non-Invasive Ventilation (NIV)
Streamlined Ventilation Components: Nasal Cannula, Ventilator Y-Connectors and T-Connectors, Nebulizer Connectors
In Vitro Characteristic Airway Models for Testing Pharmaceutical Products
Animal Dry-Powder Aerosol Delivery Device (operated with low air volumes)
Applications and Active Projects
Current application themes that are being addressed by the AIM lab include:
Platform development and testing of condensational growth technology in human subjects
High efficiency and high dose dry powder antibiotic aerosol administration to children with cystic fibrosis (CF)
High efficiency and high dose dry powder surfactant aerosol administration to infants in respiratory distress
Use of surfactant aerosols to treat acute respiratory distress syndrome (ARDS) and to prevent the need for mechanical ventilation with viral-induced lung inflammation
Development of combination anti-inflammatory medications capable of effectively targeting the large and small tracheobronchial (TB) airways in uncontrolled asthma
Application of realistic in vitro and computational assessment methods to facilitate the review and approval of generic inhaled medications (nasal sprays and orally inhaled drug products)
Development of very-low-dose dry powder devices for efficient and well-controlled aerosol administration to test animals
Current Funding
NIH/NICHD R01 HD087339
Title: High Efficiency Inhalation Delivery of Tobramycin for Children with Cystic Fibrosis
Objective: The objective of this project is to develop inhaled antibiotic formulations and inhalation devices specifically for the pediatric cystic fibrosis patient population.
NIH/NHLBI R01 HL107333
Title: High Efficiency Aerosol Delivery using the Excipient Enhanced Growth Concept: A Human Proof of Concept Study
Objective: The objective of this translational project is to determine the in vivo lung delivery efficiency of excipient enhanced growth submicrometer aerosols administered during high flow nasal cannula (HFNC) therapy using a new HFNC aerosol delivery unit.
NIH/NHLBI R01 HL139673
Title: High Efficiency Delivery of Surfactant Aerosols to Infants during Noninvasive Ventilation
Objective: The objective of this project is to develop inhaled surfactant formulations for delivery during non-invasive ventilation.
US Food and Drug Administration HHSF223201810144C
Title: Evaluating relationships between in vitro nasal spray characterization test metrics for bioequivalence and nasal deposition in silico and in vitro.
Objective: The objective of this study is to develop in vitro and CFD methods to characterize nasal spray suspension products in terms of deposition and clearance from the nose.
US Food and Drug Administration 75F40120C00172
Title: Evaluation of current approaches used to establish bioequivalence of nasal sprays for local action in children.
Objective: The objective of this study is to develop in vitro and CFD methods to characterize nasal spray suspension products in terms of deposition and clearance from the nose for children and relate these predictions to pharmacokinetic blood levels of drug concentration.
Bill and Melinda Gates Foundation INV-018833
Title: Modeling of Aerosolized Surfactant Care – 2 – VCU
Objective: The objective of this study is to implement CFD and realistic in vitro modeling to assess and improve existing Bill and Melinda Gates Foundation technology for delivering aerosolized surfactants to infants experiencing respiratory distress.
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42. Hindle M, and Longest PW. Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: Evaluation of formulation and delivery device. J. Pharm. Pharmacol. 2012;64:1254-1263.
43. Son Y-J, Longest PW, and Hindle M. Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: Effect of spray drying process conditions on aerosol performance. International Journal of Pharmaceutics. 2013;443:137-145.
44. Son Y-J, Longest PW, Tian G, and Hindle M. Evaluation and modification of commercial dry powder inhalers for the aerosolization of submicrometer excipient enhanced growth (EEG) formulation. Eur. J. Pharm. Sci. 2013;49:390-399.
45. Longest PW, Tian G, Li X, Son Y-J, and Hindle M. Performance of combination drug and hygroscopic excipient submicrometer particles from a softmist inhaler in a characteristic model of the airways. Annals of Biomedical Engineering. 2012;40:2596-2610.
46. Golshahi L, Longest PW, Azimi M, Syed A, and Hindle M. Intermittent aerosol delivery to the lungs during high flow nasal cannula therapy. Respiratory Care. 2014;59:1476-1486.
47. Tian G, Longest PW, Li X, and Hindle M. Targeting aerosol deposition to and within the lung airways using excipient enhanced growth. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2013;26:248-265.
48. Longest PW, Walenga RL, Son Y-J, and Hindle M. High efficiency generation and delivery of aerosols through nasal cannula during noninvasive ventilation. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2013;26:266-279.
49. Spence BM, Longest PW, Wei X, Dhapare S, and Hindle M. Development of a high flow nasal cannula (HFNC) and pharmaceutical aerosol combination device. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2019;32:224-241.
50. Behara SRB, Farkas DR, Hindle M, and Longest PW. Development of a high efficiency dry powder inhaler: effects of capsule chamber design and inhaler surface modifications. Pharmaceutical Research. 2014;31:360-372.
51. Behara SRB, Longest PW, Farkas DR, and Hindle M. Development of high efficiency ventilation bag actuated dry powder inhalers. International Journal of Pharmaceutics. 2014;465:52-62.
52. Behara SRB, Longest PW, Farkas DR, and Hindle M. Development and comparison of new high-efficiency dry powder inhalers for carrier-free formulations. Journal of Pharmaceutical Sciences. 2014;103:465-477.
53. Longest PW, Son Y-J, Holbrook LT, and Hindle M. Aerodynamic factors responsible for the deaggregation of carrier-free drug powders to form micrometer and submicrometer aerosols. Pharmaceutical Research. 2013;30:1608-1627.
54. Farkas D, Hindle M, and Longest PW. Development of an inline dry powder inhaler that requires low air volume. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2018;31:255-265.
55. Farkas D, Hindle M, and Longest PW. Application of an inline dry powder inhaler to deliver high dose pharmaceutical aerosols during low flow nasal cannula therapy. International Journal of Pharmaceutics. 2018;546:1-9.
56. Howe C, Hindle M, Bonasera S, Rani V, and Longest PW. Initial development of an air-jet dry powder inhaler for rapid delivery of pharmaceutical aerosols to infants. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2020;DOI: 10.1089/jamp.2020.1604
57. Bass K, Farkas D, and Longest W. Optimizing Aerosolization Using Computational Fluid Dynamics in a Pediatric Air-Jet Dry Powder Inhaler. AAPS PharmSciTech. 2019;20:329.
58. Farkas D, Bonasera S, Bass K, Hindle M, and Longest PW. Advancement of a Positive-Pressure Dry Powder Inhaler for Children: Use of a Vertical Aerosolization Chamber and Three-Dimensional Rod Array Interface. Pharmaceutical Research. 2020;37
59. Farkas D, Hindle M, Bonasera S, Bass K, and Longest W. Development of an inline dry powder inhaler for oral or trans-nasal aerosol administration to children. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2020;33:83-98.
60. Bass K, and Longest PW. Development of DPI patient interfaces for improved aerosol delivery to children. AAPS PharmSciTech. 2020;21:157.
61. Geller DE. Aerosol antibiotics in cystic fibrosis. Respiratory Care. 2009;54:658-670.
62. Kamga Gninzeko FJ, Valentine MS, Tho CK, Chindal SR, Boc S, Dhapare S, Momin MAM, Hassan A, Hindle M, and Farkas DR. Excipient Enhanced Growth Aerosol Surfactant Replacement Therapy in an In Vivo Rat Lung Injury Model. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2020;33:314-322.
63. Longest W, and Farkas D. Development of a New Inhaler for High-Efficiency Dispersion of Spray-Dried Powders Using Computational Fluid Dynamics (CFD) Modeling. The AAPS Journal. 2019;21:25.
64. Longest W, Farkas D, Bass K, and Hindle M. Use of Computational Fluid Dynamics (CFD) Dispersion Parameters in the Development of a New DPI Actuated with Low Air Volumes. Pharmaceutical Research. 2019;36:110.
65. Longest P, Farkas D, Hassan A, and Hindle M. Computational Fluid Dynamics (CFD) Simulations of Spray Drying: Linking Drying Parameters with Experimental Aerosolization Performance. Pharmaceutical Research. 2020;37:101-101.
66. Longest PW, Tian G, Delvadia R, and Hindle M. Development of a stochastic individual path (SIP) model for predicting the deposition of pharmaceutical aerosols: Effects of turbulence, polydisperse aerosol size, and evaluation of multiple lung lobes. Aerosol Science and Technology. 2012;46:1271-1285.
67. Tian G, Longest PW, Su G, Walenga RL, and Hindle M. Development of a stochastic individual path (SIP) model for predicting the tracheobronchial deposition of pharmaceutical aerosols: Effects of transient inhalation and sampling the airways. Journal of Aerosol Science. 2011;42:781-799.
68. Longest PW, and Hindle M. Evaluation of the Respimat Soft Mist inhaler using a concurrent CFD and in vitro approach. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2009;22:99-112.
69. Longest W, Spence B, and Hindle M. Devices for Improved Delivery of Nebulized Pharmaceutical Aerosols to the Lungs. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2019;32:317-339.
70. Longest PW, Hindle M, Das Choudhuri S, and Xi J. Comparison of ambient and spray aerosol deposition in a standard induction port and more realistic mouth-throat geometry. Journal of Aerosol Science. 2008;39:572-591.
71. Rygg A, Hindle M, and Longest PW. Absorption and clearance of pharmaceutical aerosols in the human nose: Effects of nasal spray suspension particle size and properties. Pharmaceutical Research. 2016;33:909-921.
72. Rygg A, and Longest PW. Absorption and clearance of pharmaceutical aerosols in the human nose: Development of a CFD model. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2016;29:416-431.
73. Delvadia R, Hindle M, Longest PW, and Byron PR. In vitro tests for aerosol deposition II: IVIVCs for different dry powder inhalers in normal adults. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2013;26:138-144.
74. Delvadia R, Longest PW, and Byron PR. In vitro tests for aerosol deposition. I. Scaling a physical model of the upper airways to predict drug deposition variation in normal humans. Journal of Aerosol Medicine. 2012;25:32-40.
75. Wei X, Hindle M, Kaviratna A, Huynh BK, Delvadia RR, Sandell D, and Byron PR. In Vitro Tests for Aerosol Deposition. VI: Realistic Testing with Different Mouth–Throat Models and In Vitro—In Vivo Correlations for a Dry Powder Inhaler, Metered Dose Inhaler, and Soft Mist Inhaler. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2018;31:358-371.
76. Kaviratna A, Tian G, Liu X, Delvadia R, Lee S, and Guo C. Evaluation of Bio-relevant Mouth-Throat Models for Characterization of Metered Dose Inhalers. AAPS PharmSciTech. 2019;20:130.
77. Son Y-J, Longest PW, and Hindle M. Aerosolization characteristics of dry powder inhaler formulations for the enhanced excipient growth application: Effect of spray drying conditions. Respiratory Drug Delivery 2012. 2012;3:899-902.
78. Hassan A, Farkas D, Longest W, and Hindle M. Characterization of excipient enhanced growth (EEG) tobramycin dry powder aerosol formulations. International Journal of Pharmaceutics. 2020;591:120027.
79. Hindle M, and Longest PW. Quantitative analysis and design of a spray aerosol inhaler. Part 2: Improvements in mouthpiece performance. Journal of Aerosol Medicine and Pulmonary Drug Delivery 2013;26:237-247.
80. Longest PW, and Hindle M. Quantitative analysis and design of a spray aerosol inhaler. Part 1: Effects of dilution air inlets and flow paths. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2009;22:271-283.
81. Bass K, Farkas D, and Longest PW. Optimizing Aerosolization Using Computational Fluid Dynamics in a Pediatric Air-Jet Dry Powder Inhaler. AAPS PharmSciTech. 2019;20
82. Longest PW, Tian G, Li X, Son YJ, and Hindle M. Performance of Combination Drug and Hygroscopic Excipient Submicrometer Particles from a Softmist Inhaler in a Characteristic Model of the Airways. Annals of Biomedical Engineering. 2012;40:2596-2610.
83. Tian G, Longest PW, Su G, and Hindle M. Characterization of respiratory drug delivery with enhanced condensational growth (ECG) using an individual path model of the entire tracheobronchial airways. Annals of Biomedical Engineering. 2011;39:1136-1153.
84. Longest PW, and Hindle M. Condensational growth of combination drug-excipient submicrometer particles: Comparison of CFD predictions with experimental results. Pharmaceutical Research. 2012;29:707-721.
85. Hindle M, and Longest PW. Evaluation of enhanced condensational growth (ECG) for controlled respiratory drug delivery in a mouth-throat and upper tracheobronchial model. Pharmaceutical Research. 2010;27:1800-1811.
86. Holbrook LT, Hindle M, and Longest PW. Generating charged pharmaceutical aerosols intended to improve targeted drug delivery in ventilated infants. Journal of Aerosol Science. 2015;88:35-47.
87. Golshahi L, Tian G, Azimi M, Son Y-J, Walenga RL, Longest PW, and Hindle M. The use of condensational growth methods for efficient drug delivery to the lungs during noninvasive ventilation high flow therapy. Pharmaceutical Research. 2013;30:2917-2930.
88. Golshahi L, Walenga RL, Longest PW, and Hindle M. Development of a transient flow aersol mixer-heater system for lung delivery of nasally administered aerosols using a nasal cannula. Aerosol Science and Technology. 2014;48:1009-1021.
89. Walenga RL, Longest PW, Kaviratna A, and Hindle M. Aerosol drug delivery during noninvasive positive pressure ventilation: Effects of intersubject variability and excipient enhanced growth. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2017;30:190-205.
90. Walenga RL, Tian G, Hindle M, Yelverton J, Dodson K, and Longest PW. Variability in nose-to-lung aerosol delivery. Journal of Aerosol Science. 2014;78:11-29.
91. Bass K, Boc S, Hindle M, Dodson K, and Longest W. High-Efficiency Nose-to-Lung Aerosol Delivery in an Infant: Development of a Validated Computational Fluid Dynamics Method. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2019;32:132-148.
92. El Taoum KK, Xi J, Kim J, and Berlinski A. In vitro evaluation of aerosols delivered via the nasal route. Respiratory Care. 2015;60:1015-1025.
93. Longest PW, Azimi M, and Hindle M. Optimal delivery of aerosols to infants during mechanical ventilation. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2014;27:371-385.
94. Longest PW, and Tian G. Development of a new technique for the efficient delivery of aerosolized medications to infants on mechanical ventilation. Pharmaceutical Research. 2015;32:321-336.
95. Behara SRB, Farkas D, Hindle M, and Longest PW. Development of a high efficiency dry powder inhaler: Effects of a new capsule orientation and surface coatings. Pharmaceutical Research. 2013;Incorrect -do not use:1608-1627.
96. Khajeh-Hosseini-Dalasm N, and Longest PW. Deposition of particles in the alveolar airways: Inhalation and breath-hold with pharmaceutical aerosols. Journal of Aerosol Science. 2015;79:15-30.
97. Longest PW, Golshahi L, Behara SRB, Tian G, Farkas DR, and Hindle M. Efficient nose-to-lung (N2L) aerosol delivery with a dry powder inhaler. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2015;28:189-201.
98. Bass K, and Longest W. A new approach to reduce interface and extrathoracic depositional losses with pediatric dry powder inhalers. RDD 2020, Palm Desert CA. 2020;
99. Longest PW, Tian G, Khajeh-Hosseini-Dalasm N, and Hindle M. Validating whole-lung CFD predictions of DPI aerosol deposition at multiple flow rates. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2016;(in review)
100. Spence B, DeWilde C, Priday A, Syed A, Dhapare S, Wei X, Longest PW, and Hindle M. Implementation of a combination device for high efficiency aerosol delivery and high-flow nasal cannula therapy in adult human subjects. Respiratory Drug Delivery 2020. 2020;3:723-728.
101. Spence B, Momin M, Dhapare S, Wei X, Longest PW, and Hindle M. Synchronizing high efficiency aerosol delivery with inhalation during high flow nasal cannula therapy. Respiratory Drug Delivery 2020. 2020;3:712-722.
102. Dutta R, Spence B, Wei X, Dhapare S, Hindle M, and Longest PW. CFD Guided Optimization of Nose-to-Lung Aerosol Delivery in Adults: Effects of Inhalation Waveforms and Synchronized Aerosol Delivery. Pharmaceutical Research. 2020;37:1-18.