Dr. Sara E. Maloney Norcross

Effect of oropharyngeal geometry on the aerodynamic performance of antimycobacterial dry powder formulations

Mycobacterial pulmonary infections, including those caused by Mycobacterium tuberculosis and Mycobacterium abscessus, are notoriously challenging to treat and require prolonged and complex regimens for successful eradication. Treatment is further complicated in resource-limited settings, where access to effective antibiotics and reliable cold-chain systems is limited and patients may not live near healthcare facilities. To address these challenges, our work has focused on developing inhalable dry powders of antimycobacterial agents, such as tigecycline and spectinamide derivatives. These formulations are designed for patient self-administration and ambient storage conditions, improving global accessibility and adherence.

A critical step in developing effective inhaled therapies is robust benchtop characterization. Current standardized methods, such as those described in USP General Chapter <601>, recommend assessment of delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD). These standardized methods enable meaningful comparisons between formulations and across different laboratories. However, it is unsurprising that these methods do not accurately predict in vivo performance. While there are multiple reasons for this discrepancy, one easily addressable aspect is the use of the USP induction port at the entrance to a cascade impactor. This 90° bent metal tube does not reflect the oropharyngeal geometry of humans.

Virginia Commonwealth University (VCU) has piloted the development of polymer human oropharyngeal models. The oropharyngeal volumes and dimensions of a subset of the normal adult population were averaged, and the result was turned into a “medium” oropharyngeal model. From there, scaled up and scaled down versions of the model were created to represent “large” and “small” oropharyngeal models, respectively. While not representative of individual patient-to-patient differences, these models are a significant improvement in physiological relevance over the USP induction port. This career development grant would allow for the procurement of the three VCU polymer oropharyngeal models, allowing our research group to move our APSD measurements of antimycobacterial therapies toward improved physiological relevance. By integrating these models in our workflow, we aim to generate more predictive in vitro data for current and future inhaled antimycobacterial formulations. The incorporation of these models in our benchtop APSD analyses is the first step of many we will take to improve in vitro in vivo correlations of inhaled antimycobacterial agents, ultimately accelerating the development and global deployment of effective inhaled therapies for pulmonary mycobacterial infections.

Career Development Proposal
As an early-career researcher specializing in inhaled therapies for pulmonary mycobacterial infections, I am committed to bridging the translational gap between benchtop research and clinical application. I am currently a Research Chemist 3 at RTI International, an independent, nonprofit research institute dedicated to improving the human condition through science-based solutions. Prior to joining RTI, I completed my Ph.D. in Chemistry (analytical focus) in 2021 under the direction of Dr. Mark H. Schoenfisch at the University of North Carolina at Chapel Hill. During this time, I focused on the development of novel therapies for chronic wound infections and catheter-related bloodstream infections. In January 2022, I transitioned to a position as a post-doctoral researcher in aerosol drug delivery at RTI working under Dr. Anthony J. Hickey. It was at this time that I found my niche. I quickly recognized the urgent need for better interventions for pulmonary mycobacterial infections, including those caused by Mycobacterium tuberculosis and Mycobacterium abscessus, which are challenging to treat due to inherent drug resistance and limited access to effective therapies. I have made it my mission to spend my research career focusing on the mitigation of these challenges.

In October of 2022, I was promoted to a Research Chemist at RTI, starting my career path as an independent researcher. Through 2023, I worked closely with Dr. Hickey to learn all that he could teach me in the field of pulmonary drug delivery and made many close connections with collaborators spanning a range of complementary fields. Following Dr. Hickey’s retirement from RTI in January 2024, I have stepped into the role of principal investigator, leading RTI’s programs on inhaled and intranasal drug delivery. I now lead a small team of Ph.D. and M.S. level biomedical engineers and chemists, where my group primarily focuses on prevention and treatment strategies for pulmonary mycobacterial infections. I serve as the program director/principal investigator or co-investigator on five grants funded by NIAID, all of which focus on the development of vaccine and inhaled therapy development. While we have made significant strides in these areas, I am currently working to improve our benchtop physiological relevance. In vitro characterization of inhaled drug products often fails to predict in vivo performance, hindering clinical translation and consuming resources for preclinical studies for formulations that are unlikely to succeed. My interdisciplinary training in both analytical chemistry and aerosol drug delivery uniquely positions me to address the translational challenges of inhaled antimycobacterial therapies by enabling me to design and evaluate inhaled therapies with both rigorous analytical technique and a deep understanding of respiratory drug delivery.

The long-term goals for my research career are to (1) develop, optimize, and characterize inhaled antimycobacterial therapies, (2) perform formulation development of novel prevention methods (e.g., vaccines) for pulmonary mycobacterial infections, and (3) improve benchtop testing methods for inhalation and intranasal products to improve in vitro in vivo correlations. This career development grant will allow me to make progress toward achieving these goals by initiating the incorporation of physiological relevance in aerodynamic characterization of nebulized and dry powder inhalation aerosols. Although I am experienced in formulation and standardized aerodynamic characterization, I am seeking to further develop my expertise in physiologically relevant aerosol testing. This grant will address this gap by supporting new equipment acquisition, expert collaboration, and conference participation. My research group currently has a breathing simulator capable of breathing profiles relevant for nebulized products, allowing for immediate integration between the oropharyngeal models and breathing profiles. We also plan to purchase a breathing simulator capable of profiles relevant for DPI testing when funding allows to expand our potential for physiologically relevant testing conditions.

If funded through this Career Development Grant, I will first work to validate our methodology using antimycobacterial formulations we have previously prepared and published, focusing on tigecycline and a spectinamide analogue. It will be important for us to note whether there are differences for each powder between the USP induction port and the three oropharyngeal models. Furthermore, by evaluating multiple dry powder identities, we can see if the differences we observe for one antimycobacterial powder translate to other powders or if each formulation responds to changes in oropharyngeal size and geometry distinctively. Nebulizer formulations of an antimycobacterial drug will also be evaluated using the oropharyngeal throats connected to the cascade impactor, with and without the incorporation of a breathing simulator. These validation steps will allow us to implement the use of oropharyngeal models in the development and characterization of future inhaled dry powder and nebulizer formulations. By working to improve in vitro in vivo correlations, my work aims to bridge the translational gap in inhaled therapies, ultimately accelerating the development of effective treatments for patients with pulmonary mycobacterial infections.

RTI provides ongoing support to ensure my facilities and resource needs are met, fostering both my career and research growth. Additional support from DDL through this Career Development Grant will enable the purchase of physiologically relevant oropharyngeal models and support my participation at DDL, where I will present my research group’s ongoing work and expand my professional network. I will continue to seek guidance from senior colleagues and collaborators, and I will leverage the DDL conference to build new mentorships and collaborations with leaders in the field. The support will be pivotal in my transition from early independence to becoming a recognized expert in the field of inhaled drug delivery formulation and characterization. The purchase of equipment and conference participation will directly enable me to generate new data and collaborations to support future grant applications, supporting my growth as an independent, externally funded investigator. I am dedicated to advancing inhaled therapies for pulmonary mycobacterial infections, and this grant represents a critical step in my journey toward becoming a leader in the field. I share the DDL committee’s commitment to advancing respiratory science and am grateful for your consideration.