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30 February 2023 Inhalation Conclusions e excipient enhanced growth (EEG) formulation strategy is a breakthrough technology that has the potential to meet the long-elusive need for delivering medications directly into lung tissue without com- plications from first-pass metabolism, blood-volume dilution or systemic effects. ere are currently two programs seeking to advance this technology through toxicology studies sponsored by Quench Medical: budesonide for the treatment of asthma and gem- citabine for local treatment of non-small-cell lung cancer. In conjunction with Lonza, there has been a robust study of formulation and particle design, cul- minating in short-term stability and scale-up to clin- ically relevant scales. Although the two programs utilize a similar formu- lation design and manufacturing process, each faced unique challenges. In the case of budesonide, man- ufacturability was the challenge. ere was more emphasis in the gemcitabine program on stability results. In both cases, mannitol and sodium chloride were studied for their performance as a hygroscopic agent and different leucine levels were compared. In the comparison of hygroscopic excipients, sodium chloride had more favorable performance with both budesonide and gemcitabine. e decision in the budesonide case was based around the water sorption benefit of high amounts of sodium chloride while the decision for gemcitabine was focused on stability results. is may be due to the higher drug load of the formulation. Both programs resulted in a similar leucine loading of 30 wt%, which allowed for good dispersion and sta- bility performance. is is in the center of the range studied, suggesting a local optimum. Future work for It is hypothesized that, in this system, perhaps there is poorer leucine surface enrichment for the manni- tol formulation as a result of mannitol competition for the surface. With less leucine on the surface, this could lead to a difference in surface energy with the potential for particle growth or agglomeration over time on stability. Furthermore, this was illustrated visually by scanning electron microscope at the one- month timepoint, demonstrating crystalline growth occurred. (Figures 5 and 6.) Along with repeating the same testing panel as the initial timepoint, aerosol properties were determined using a Fast Screening Impactor (FSI) (MSP, a Divi- sion of TSI, Shorewood, MN, US) with a 5-micron cutoff plate. Introducing the FSI screening was a useful tool in deciphering among the formulations after one month to quantify aerosol behavior after stability and rank order formulations. Only the accelerated condition (40 °C/75% RH)was tested, to better gauge impacts of stability. is screening test, shown in Figure 7, highlighted the preference for 40/40/20%, 50/20/30% and 55/20/25% gem- citanibe/sodium chloride/leucine, based on aerosol performance after one month at 40 °C/75% RH. Considering the impact of stability on geometric particle size, not surprisingly, the mannitol formu- lation was outperformed by the sodium chloride aerosol properties. e aerodynamic properties of the 50/20/30% gemcitabine/sodium chloride/leu- cine (Gem/NaCl/Leu) formulation were among the best of all five formulations. is formulation also was among the highest in terms of yield and physi- cal stability characteristics. is formulation became the leading candidate, and was progressed through the remaining stability study, along with a backup sodium chloride formulation. Figure 5 Representative particle morphology captured by SEM for the sodium chloride formulation 40/40/20% Gem/NaCl/Leu. Figure 6 Representative particle morphology captured by SEM for the mannitol formulation 40/40/20% Gem/Mann/Leu.