(W1130-02-10) Excipient Enhanced Growth (EEG) Synthetic Lung Surfactant Powder Formulation for Treating Neonatal Respiratory Distress Syndrome (NRDS)

Purpose: Neonatal respiratory distress syndrome (NRDS) is the most common lung disease in preterm neonates and remains a major cause of infant death. Instilled surfactant replacement therapy (SRT) is the recommended therapy for the treatment of NRDS [1,2]. However, liquid bolus instillation of SRT has some challenges including non-uniform distribution of the surfactant in the lung airways, respiratory related side effects arising from pouring a high liquid volume through the endotracheal tube and the requirement of a relatively high dosage of surfactant [3]. These problems could be eliminated by aerosol delivery of a surfactant formulation. This study aims to prepare and characterize a synthetic lung surfactant excipient enhanced growth (EEG) powder formulation.

Methods: Three batches of synthetic lung surfactant powder formulation were prepared by spray drying of feed dispersions containing phospholipid, surfactant protein mimic, hygroscopic excipients and dispersion enhancer following a previously reported spray drying procedure [4]. Powders were collected and, following 30 minutes equilibration at 20±5%RH / 24±2ºC, stored at 0%RH / −20ºC. The phospholipid content of the synthetic lung surfactant EEG powders was determined by LC-MS, and the primary particle size of the powders was determined using the Sympatec HELOS with RODOS/M disperser. Solid-state properties were evaluated by X-ray powder diffraction (XRPD) conducted using the Rigaku Miniflex 6G. In preparation for in vivo testing, aerosol performance in two in vitro models was evaluated. Firstly, simulated lung delivery was performed by endotracheal insufflation into a 3D-printed rabbit upper tracheobronchial (TB) airway model. Secondly, nose to lung delivery was tested in a preterm infant nose-throat (NT) airway model. In each case, the air-jet DPI was connected to the airway model and actuated with a positive-pressure air source at 3 L/min (rabbit TB model) and 4 L/min (preterm infant NT model), respectively. In both experiments an actuation air volume of ~10 mL was used to deliver 10 mg of powder aerosol. In the in vitro rabbit study, the DPI was connected to the airway model by an endotracheal tube (ETT), and aerosol was delivered through the ETT and tracheobronchial region (TB) to a lung chamber and outlet filter. For the in vitro preterm infant study, aerosol was delivered through one nostril of the preterm infant NT model and collected on the outlet tracheal filter (Figure 1) [5]. The aerosolization performance was determined based on the phospholipid emitted dose and in vitro lung delivery efficiency as measured from the phospholipid deposited on the tracheal filter (for preterm infant NT study) and chamber plus outlet filter (for in vitro rabbit study).

Results: Spray drying of the feed dispersions to produce three batches of powder formulation resulted in a mean spray rate of ~0.40mL/min and recovered powder yields of 70-77%. The primary particle size (Dv50) of the powders was 0.81±0.02µm with 100% particles < 5µm. The phospholipid content was between 98.2 and 101.4% of the theoretical content with no significant differences among the three batches. X-ray powder diffraction (Figure 2) showed evidence of crystalline structure in the synthetic lung surfactant powder formulations. The in vitro rabbit study showed 80.4±0.1% dose emitted from the rabbit device with 57.3±2.7% lung delivery efficiency (Figure 3a). For the preterm infant NT study, the mean (SD) emitted dose from the infant air-jet DPI was 90.8±3.4% of the nominal loaded dose with a lung delivery efficiency of 42.4±1.4% (Figure 3b).

Conclusion: We have successfully produced a synthetic lung surfactant EEG powder with high lung delivery efficiency when aerosolized using a low actuation air volume that would be suitable for treatment of premature neonates and would overcome the challenges of currently used liquid bolus instillation during surfactant replacement therapy. Future studies will examine in vivo efficacy in a rabbit animal model.

References: 1. Sardesai S et al., Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future. Pediatr Res 2017, 81: 240-8.
2. Dyer J: Neonatal respiratory distress syndrome: tackling a worldwide problem. Pharm Ther 2019, 44: 12.
3. El-Gendy N et al., Delivery and performance of surfactant replacement therapies to treat pulmonary disorders. Ther Deliv 2013, 4: 951-980.
4. Boc S et al., Development and Characterization of Excipient Enhanced Growth (EEG) Surfactant Powder Formulations for Treating Neonatal Respiratory Distress Syndrome. AAPS PharmSciTech 2021, 22: 1-12.
5. Momin MAM et al., Surfactant Powder Delivery from Infant Air-Jet Dry Powder Inhaler (DPI): Effect of Flow Rate and DPI Design. In “Respiratory Drug Delivery (RDD) 2022 Conference” at Omni Orlando, ChampionsGate, Florida, USA held on May 1-5, 2022.
6. Howe C,M., Advancement of the Infant Air-Jet Dry Powder Inhaler (DPI): Evaluation of Different Positive-Pressure Air Sources and Flow Rates. Pharm Res 2021, 38: 1615-32.

Acknowledgements:This study was funded by the Bill and Melinda Gates Foundation. The funding body was not involved in the collection, analysis, and interpretation of data and in writing the abstract.

Infant air-jet DPI platform attached to preterm infant nose-throat (NT) model for regional deposition and lung delivery efficiency study (modified and reproduced from [6]).

X-ray Powder diffractograms of the synthetic lung surfactant powders.

Aerosol performance of spray-dried synthetic lung surfactant powder using (a) in vitro rabbit TB model and (b) preterm infant nose-throat (NT) model (bars represent the mean values; error bars represent standard deviations, n=3).