(M1330-01-07) Understanding the Relationship Between In Vitro Nasal Spray Characteristics and Intranasal Deposition in the Adult and Pediatric Populations

Purpose: For suspension formulations of locally acting nasal drug products, in vitro studies are included as part of the recommendations for establishing bioequivalence (BE) between a potential generic nasal product and its reference listed drug (RLD) [1]. While these in vitro BE studies can be more sensitive for detecting performance differences compared to in vivo studies, their clinical relevance may be limited as compared to other potential performance metrics (e.g., regional nasal deposition). Additionally, differences in nasal anatomy, both between and among adult and pediatric patients, can further complicate evaluating regional nasal deposition using standard in vitro methods. This study aims to develop in vitro anatomical nasal models of pediatric patients and evaluate the sensitivity of these models in detecting performance differences with nasal suspension products, as compared to previously developed in vitro adult nasal models.

Methods: Six realistic rapid prototyped computed tomography (CT)-based nasal airway models of three healthy adult and three healthy child subjects were used to assess the local drug deposition of three nasal sprays. The models were selected out of 40 adult and 40 child nasal cavities and represent three main levels: Low posterior deposition (PD) (L models), medium PD (M models), and high PD (H models). Child models were selected using a similar approach as performed for the adult models [2]. Subsequently, the selected cavities were cut into six regions, including the anterior region and five regions comprising the posterior region: front, inferior, middle, superior meatuses, and nasopharynx, to quantify the regional drug deposition (Figure 1). Three triamcinolone acetonide (TA) spray products, including one RLD product and two approved generics, T1 and T2, were used for in vitro characterization studies (i.e., droplet size distribution (DSD), plume geometry, and spray pattern), as well as in vitro deposition studies using the adult and pediatric nasal models via a controlled administration method [2,3]. Following actuation, the models were dismantled, and each region was separately rinsed with the solvent to collect and measure the amount of drug deposited in the region. A high-performance liquid chromatography (HPLC) method was developed and used to analyze the deposited drug. The procedure was repeated for all 3 products using 3 different batches and 3 units per batch. After obtaining the deposition percentage in each region, the total PD was calculated and used to perform the population bioequivalence (PBE) analyses for both generic products in all six nasal models [1].

Results: The results of spray characterization (Table 1) confirm a relatively small difference between the RLD, T1 and T2 products, as could be expected based on the established BE from approval with the U.S. Food and Drug Administration. Despite this similarity, anterior and posterior deposition are quite different for both the adult and pediatric nasal models. Only 7 of the conducted 24 analyses were determined to meet the PBE criteria (Table 2). In terms of posterior deposition, PBE could only be concluded for the T1 product in the adult H model, but in pediatric nasal models this product met PBE in the M and H models. PBE could not be concluded for the T2 product in any adult models, but the pediatric H model passed PBE for this product. Interestingly, both the adult and pediatric L models showed the same PBE conclusions for anterior and posterior deposition comparisons between the three products. However, the adult and pediatric M models showed the same PBE conclusions only for the T2 product. Similarly, the adult and pediatric H models showed the same PBE conclusions just for the T1 product. Also, PBE was established in both anterior and posterior regions in just one model (Child M model) for the T1 product. For the T2 product, PBE was not established in both the anterior and posterior regions for any singular model.

Conclusion: This study showed that for sprays with similar in vitro characteristics, in vitro regional deposition may vary within and between adult and pediatric patients. Differences in the PBE determination between products using the adult models as compared to the pediatric models suggest that anatomical differences between the adult and pediatric population could impact regional deposition performance between nasal suspension products. Further studies are needed to evaluate whether such differences with in vitro nasal deposition are indicative of similar performance differences in vivo.

References: [1] Product-specific Guidance for Fluticasone Propionate Metered Nasal Spray. June 2020. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_020121.pdf.
[2] Alfaifi, Ali, et al. "Anatomically realistic nasal replicas capturing the range of nasal spray drug delivery in adults." International Journal of Pharmaceutics 622 (2022): 121858.
[3] Golshahi, Laleh, et al. “Leveraging in vitro bioequivalence tests for locally-acting suspension nasal sprays with three anatomically-correct replicas of human nasal airways representing intersubject variability.” Respiratory Drug Delivery (RDD). 2022;1: 37-46.

Acknowledgements: Funding was provided by Contract 75F40120C00172 from the Department of Health and Human Services, US Food and Drug Administration. Views expressed in this manuscript do not necessarily reflect the official policies of the US Food and Drug Administration, nor does any mention of trade names, commercial practices or organizations imply endorsement by the United States Government.

Figure 1 - A) segmented child L model, B) segmented child M model, and C) segmented child H model.