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Drug Delivery

Drug Delivery - Poster Session E

Poster X3 - Growing particles: A necessary step towards non-invasive aerosolized surfactant treatments for newborns with respiratory distress syndrome

Saturday, October 26, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Annually, ~1.3 million infants worldwide develop respiratory distress syndrome (RDS), a life-threatening disease resulting from insufficient lung surfactant at birth1,2. Current treatments are invasive, involving intubation and liquid bolus instillation of surfactant, often followed by mechanical ventilation. Infant intubation is a difficult high-risk procedure, and invasive mechanical ventilation is associated with significantly increased risks of bronchopulmonary dysplasia, neurological disorders, and mortality3,4. A non-invasive aerosol therapy for administering inhaled surfactant to the alveolar region has been envisioned as a logical, highly advantageous replacement to instillation. However, current aerosol systems result in poor lung delivery efficiency and require very high doses5,6, often higher than that with instillation. To improve aerosol delivery efficiency, the excipient enhanced growth (EEG) concept is proposed for a dry powder synthetic lung surfactant (SLS) formulation. EEG involves adding to the formulation a hygroscopic excipient that absorbs water in the humid airway environment and increases the initial particle size. Computational and realistic in vitro testing in adult and pediatric subjects shows deposition in the upper airways can be avoided by initially aerosolizing small particles that then grow to enhance deposition in the deeper lung regions, thereby enabling regional targeting and avoiding exhalation of the dose7,8. This study seeks to quantify the hygroscopic growth of a novel SLS-EEG formulation by comparing particle size increases out of a specially-designed infant interface through a 3D-printed anatomically-correct preterm nose-throat (NT) and upper tracheobronchial airway (TB) model (including the third (lobar) respiratory bifurcation (B3)) under dry (no growth) and humid (i.e., physiologically realistic) conditions.

Materials and

Methods:  SLS-EEG formulations were prepared using a Büchi S-300 Mini Spray Dryer (Büchi Labortechnik AG, Flawil, Switzerland) and composed of 55:7.5:2.5:9:6:20% w/w of DPPC, POPG, B-YL, mannitol, sodium chloride, and l-leucine, respectively. The experimental setup (Figure 1) consisted of the aerosol delivery system (ADS), which included the auto-actuator for controllably aerosolizing the powder, low-volume infant air-jet DPI, and patient interface; a 1.5 kg preterm airway model; a cylindrical (lung) growth chamber to mimic a 2-s particle residence time (based on a ~1 s breathing cycle and ~1 s breath-hold to enhance deposition) for condensational growth to occur; and a Next Generation Impactor (NGI) for particle sizing. The NT model through NGI were placed in an environmental cabinet operated at 15±2%, 22°C and 99±1%, 37°C for dry and humid experiments, respectively. For humid experiments, the NT through growth chamber were pre-wetted at 40 – 42°C using the Vapotherm® 2000i for 5 – 10 min to create a thin moisture layer, consistent with airway surface liquid. 30 mg of powder was loaded into the DPI and aerosolized using 10 mL of air at a Q90 (the flow rate at which 90% of the values fall below) of 3 LPM. The device was actuated four times. All experimental components were washed with metered amounts of methanol, and the samples were analyzed with a validated HPLC method. Three replicates were performed for each experimental set. The mass median aerodynamic diameter (MMAD), fine particle fractions (FPF), and geometric standard deviation (GSD) were quantified for each condition.

Results, Conclusions, and Discussions: Particle size distribution (PSD) characterizations for dry and humid experiments, measured at the lung chamber outlet, are provided in Table 1. The MMAD exiting the lung chamber was significantly larger at 3.11 μm under realistic humid conditions as compared to the MMAD of 1.82 μm under dry conditions, producing a high growth ratio (humid-to-dry MMAD ratio) of 1.72. All metrics in Table 1 indicate a significant shift to larger aerosol sizes under humidified conditions as a result of condensational growth as also illustrated in Fig. 2. The FPF < 5 μm was ~5% less for the particles in humid conditions, perhaps due to the significant growth of the relatively large particles that were then filtered by the upper TB region. Importantly, there was ~10x reduction in the FPF < 1 μm in humid conditions, demonstrating nearly complete growth of all particles at residence times consistent with transport within the deep lung. Due to decreases in these FPFs, the GSD was significantly less for humid conditions. This narrower particle size distribution exiting B3 could lead to more consistent results in alveolar deposition between patients and facilitate tuning of the optimal particle size needed for alveolar deposition since polydispersity is a source of variability and complexity. For FPF < 2.5 μm, there was about half as much dose for humid experiments, indicating appreciable growth above the 2.5 µm size range. Particles greater than 2 μm are expected to greatly reduce exhalation loss and increase deposition in the alveolar region; thus, this powder formulation can likely achieve high deposition at the site of action.

Particle size measurements following a 2-s residence time and filtration through the outlet of B3 of the TB region were performed in dry and humid conditions. Realistic humid conditions produced a high growth ratio of 1.72, outlet MMAD of 3.11 µm, and favorable PSD for deep lung deposition. This PSD revealed a narrower distribution with ~2/3 of the dose greater than 2.5 μm, which should significantly enhance alveolar deposition and avoid dose exhalation. The SLS-EEG powder is thus a core component of an effective non-invasive aerosol surfactant therapy strategy.

Acknowledgements (Optional):  Sarah Strickler would like to acknowledge receipt of funding through the Peter Byron Research Assistantship. This work was also funded by the National Heart, Lung and Blood Institute of the National Institutes of Health under Award Number R01HL139673. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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