In Vitro Analysis of Nasal Interface Options for High-Efficiency Aerosol Administration to Preterm Infants

Abstract

Background: An infant air-jet dry powder inhaler (DPI) platform has recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high-efficiency aerosolization with low actuation air volumes. The objective of this study was to investigate modifications to the nasal interface section of this platform to improve the aerosol delivery performance through preterm nose-throat (NT) models. Methods: Aerosol delivery performance of multiple nasal interface flow pathways and prong configurations was assessed with two in vitro preterm infant NT models. Two excipient-enhanced growth (EEG) dry powder formulations were explored containing either l-leucine or trileucine as the dispersion enhancer. Performance metrics included aerosol depositional loss in the nasal interface, deposition in the NT models, and tracheal filter deposition, which was used to estimate lung delivery efficiency. Results: The best performing nasal interface replaced the straight flexible prong of the original gradual expansion design with a rigid curved prong (∼20° curvature). The prong modification increased the lung delivery efficiency by 5%-10% (absolute difference) depending on the powder formulation. Adding a metal mesh to the flow pathway, to dissipate the turbulent jet, also improved lung delivery efficiency by ∼5%, while reducing the NT depositional loss by a factor of over twofold compared with the original nasal interface. The platform was also found to perform similarly in two different preterm NT models, with no statistically significant difference between any of the performance metrics. Conclusions: Modifications to the nasal interface of an infant air-jet DPI improved the aerosol delivery through multiple infant NT models, providing up to an additional 10% lung delivery efficiency (absolute difference) with the lead design delivering ∼57% of the loaded dose to the tracheal filter, while performance in two unique preterm airway geometries remained similar.

Keywords: air-jet DPI; high-dose DPI; infant DPI; nasal prong; nose-to-lung aerosol delivery; rapid aerosol administration; trans-nasal aerosol delivery.

FIG. 1.

Overview of air-jet DPI and nasal interface connection with expanded internal view, illustrating attachment to the outlet of the air-jet DPI. Expanded view depicts interface flow pathway and prong regions as a midplane sectioned view and as a flow passage outline. DPI, dry powder inhaler.

FIG. 2.

Overview of the infant air-jet DPI aerosol delivery system connected to a preterm infant NT airway model. Expanded view of the air-jet DPI illustrates internal components, including the aerosolization chamber. NT, nose–throat.

FIG. 3.

Internal airflow geometries of each air-jet DPI from device inlet (left side of each image) to the device outlet(s) (right side of each image) and central aerosolization chamber. (a) D1-Single and (b) D1-Dual. The outlet capillaries lead to the inlet of the nasal interfaces.

FIG. 4.

Overview of the infant NT airway model and regional sections. Top panels provide isometric views of regional sections, and lower panels provide top and side views of the same nasal models with 1 cm scale bars. (a) Scaled-6mo model and (b) Preterm NT model.

FIG. 5.

Interface Set 1: Nasal interface designs (internal surfaces) beginning with the air-jet DPI outlet capillary (left side), followed by different flow pathways and ending with the same flexible straight prong. (a) Original GE-S, (b) MM design 1 (MM-1), (c) MM design 2 (MM-2), (d) MM design 3 (MM-3), and (e) DC design. All designs shown have a 3 mm internal prong diameter. Gray shaded area indicates location of mesh for MM designs (b–d). DC, direct capillary; GE-S, single gradual expansion; MM, metal mesh.

FIG. 6.

Interface Set 2: Axial sectioned view of dual prong nasal interface designs from air-jet outlet capillary (left side of each image) to the straight flexible prongs (right side of each image). (a) Initial (GE-Dual) design and (b) Extended prong (GE-Dual-Flex) design.

FIG. 7.

Interface Sets 3 and 4: Internal airflow geometry of curved prong designs from air-jet outlet capillary (left side of each image) to the curved prong (right side of each image). Pictured are the (a) 3 mm inner diameter versions for the short curve prongs used in Interface Set 3 (Rigid-3) and (b) large curve prong used in Interface Set 4 (Large Curve).

FIG. 8.

Interface Set 5: Internal airflow geometry of combined flow pathway and curved prong designs from air-jet outlet capillary (left side of each image) to the curved prong (right side of each image). (a) MM-1-C design and (b) MM-3-C design. Gray shaded area indicates location of MM.

FIG. 9.

Pictures of infant NT models during in vitro experimental setup for the (a) Scaled-6m model and (b) Preterm NT model.

FIG. 10.

Experimentally determined mean drug deposition fractions (based on loaded dose) of the l-leucine formulation (Batch 3) using the D1-Single air-jet DPI and Rigid-3 nasal interface across different Q90 flow rates. Anterior nose, MP, and throat deposition fractions were combined as Total NT deposition. Tracheal filter deposition is an estimate of lung delivery efficiency. Error bars denote ±1 standard deviation. MP, middle passage; NT, nose-throat.

FIG. 11.

Experimentally determined mean drug deposition fraction (based on loaded dose) using the D1-Single air-jet DPI and Rigid-3 nasal interface. Total NT deposition represents sum of infant NT regional depositions fractions for each respective model. Tracheal filter deposition is an estimate of lung delivery efficiency. Comparison of aerosol delivery performance presented side by side for each formulation (trileucine on the left and Batch 4 l-leucine on the right) in two different infant NT models. Error bars denote ±1 standard deviation.