In vitro evaluation of intersubject variability in pediatric intranasal drug delivery using nasal spray suspension products

Abstract

Evaluation of the regional intranasal delivery of locally acting drugs in children is challenging. Anatomical nasal airway replicas potentially can provide a robust pre-clinical tool to test the performance of devices and formulations. However, there is often a challenge in identifying the nasal geometries that can reasonably be indicative of in vivo regional mass distribution of administered drug. This in vitro study was designed to investigate the regional intranasal drug delivery in 20 children, 2–11 years old (50% 2–6 years old and 50% female), using two commercially available suspension nasal spray products with different nozzle designs, plume characteristics, and active pharmaceutical ingredients. High-resolution computed tomography scans of the sinonasal region of pediatric human subjects with healthy nasal airways, reviewed and scored by a head and neck surgeon, were used to develop 20 three-dimensional (3D) replicas of the nasal airways. The 3D replicas were segmented into the two regions: anterior and posterior to the internal nasal valve (INV). They were then rapid prototyped in high clarity rigid plastic (Accura ClearVue). Each side of the septum of the 20 subjects was examined separately, resulting in 40 singular nasal cavities. A nozzle-specific spray tip holder was designed for each case to ensure consistent administration (insertion length, sagittal angle, and coronal angle) in all replicates. The wide range of posterior drug delivery observed in the forty geometries indicated significant intersubject variability in pediatric intranasal drug delivery. Three nasal geometries representing low, medium, and high levels of drug delivery to the target region, posterior to the INV, were chosen from the 40 nasal cavities. Our vision is that these three nasal geometries can potentially be beneficial in determining whether performance differences between test and reference nasal spray products are present that may affect their bioequivalence in children. They also may be useful when applied in parallel with similar adult nasal geometries, previously developed following a similar procedure, to provide additional insights into pediatric nasal drug delivery with innovator products in children in lieu of extending clinical studies to include pediatric subjects.