In Vitro Comparison of Local Nasal Vaccine Delivery and Correlation with Device Spray Performance.

PURPOSE: This study is the first vaccine candidate in vitro investigation with a focus on finding a correlation between the spray characteristics and the delivery efficiency of the local deposition in the nasal airways of infants under 24 months using various intranasal devices. METHODS: In vitro tests were developed to measure the spray characteristics of four intranasal delivery devices and how they regionally deliver a candidate vaccine formulation matrix in five nasal airway replicas (3 to 24 months). The correlation between the spray performance, geometric parameters, and delivery efficiency were assessed. RESULTS: All four devices performed consistently in terms of spray characteristics and were capable of delivering a high percentage of the candidate vaccine to the target areas, with a minimum delivery efficiency of 80%. Moreover, the delivery efficiency was affected by either the spray droplet size distribution or the distance between the nozzle tip and the internal nasal valve. Correlations between the spray performance and the in vitro local dose deposition were established. CONCLUSION: The infant nasal model tests can be complementary to device spray performance evaluation. In the absence of in vivo correlations, they can also facilitate the process of new product development by estimating delivery a priori.

Evaluation of Intranasal Vaccine Delivery Using Anatomical Replicas of Infant Nasal Airways.

PURPOSE: Nasal delivery is a favorable route for vaccination against most respiratory infections, as antigen deposited in the nasal turbinate and Waldeyer's ring areas induce mucosal and systemic immune responses. However, little is known about the nasal distribution of the vaccines, specifically for infants. METHODS: Anatomical nasal replicas of five subjects, 3-24 months, were developed to assess local intranasal vaccine delivery using MAD Nasal™ device, and understand impact of breathing conditions and administration parameters. High performance liquid chromatography was used to quantify the deposition pattern and determine the delivery efficiency. RESULTS: The delivery efficiency on average for all models was found to be 86.57±14.23%. There were no significant differences in the total delivery efficiency between the models in all cases. However, the regional deposition pattern was altered based on the model and subsequent administration. Furthermore, removing the foam tip from the MAD Nasal™ device, to study the impact of insertion length, did not significantly increase the efficiency within the two models tested, 5- and 16-month. CONCLUSION: Incorporating nasal replicas in testing provided a benchmark to determine the efficiency of a common intranasal vaccine delivery combination product. This proposed platform would allow comparing other potential nasal vaccine delivery devices.

Use of anatomically-accurate 3-dimensional nasal airway models of adult human subjects in a novel methodology to identify and evaluate the internal nasal valve.

The optimal method for radiographic evaluation of the internal nasal valve (INV) has not been established. The objective of this study was to develop a method to assess the cross-sectional area and the angle of the INV using anatomically-accurate 3D digital nasal airway models. Axial CT images of the paranasal sinuses of twenty adult subjects with healthy nasal airways (50% female and 50% age ≥ 50) were used to create the models. Patients with significant radiographic evidence of sinonasal disease were excluded. A primary cutting plane that passed through the edge of the nasal bone, upper lateral cartilage, and the head of the inferior turbinate was defined in coronal view. This primary coronal cutting plane was then rotated in 5° increments anteriorly while ensuring the anatomic criteria for the INV were still met. The cutting plane resulting in the minimum INV area was identified as the optimal cutting plane and the total cross-sectional area of INV in this plane,198.79 ± 54.57 mm2, was significantly less than the areas obtained using the existing methods for radiographic evaluation of the INV. The angle between the optimal cutting plane and nasal dorsum was 75.00 ± 10.26°, and the corresponding INV angle was 10.77 ± 6.02°.

Mechanistic Understanding of High Flow Nasal Cannula Therapy and Pressure Support with an In Vitro Infant Model.

Despite the increased use of high flow nasal cannula therapy, little has been done to predict airway pressures for a full breath cycle. A 3-month-old infant in vitro model was developed, which included the entire upper airway and the first three bifurcations of the lungs. A breathing simulator was used to create a realistic breath pattern, and high flow was provided using a Vapotherm unit. Four cannulas of varying sizes were used to assess the effects of the inner diameter and nasal occlusion of the cannulas on airway pressures. At 8 L min-1, end expiratory pressures of 0.821-1.306 cm H2O and 0.828-1.133 cm H2O were produced in the nasopharynx and trachea, respectively. Correlations were developed to predict full breath cycle airway pressures, based on the gas flow rate delivered, cannula dimensions, as well as the breathing flow rate, for the nasopharynx and trachea. Pearson correlation coefficients for the nasopharynx and trachea correlations were 0.991 and 0.992, respectively. The developed correlations could be used to determine the flow rate necessary for a cannula to produce pressures similar to CPAP settings. The proposed correlations accurately predict the regional airway pressure up to and including 7 cm H2O of support for the entire breath cycle.

In Vitro Measurement of Regional Nasal Drug Delivery with Flonase,® Flonase® Sensimist,™ and MAD Nasal™ in Anatomically Correct Nasal Airway Replicas of Pediatric and Adult Human Subjects.

Background: The majority of current nasal delivery devices, commercialized for children, are developed for adults. Differences in the dose reaching the target are expected due to significant differences between the pediatric and adult nasal airway geometries and their inhalation patterns. This study aims to compare the efficacy of most common nasal drug delivery devices in terms of regional delivery of suspension and solution formulations in pediatric and adult subjects. Methods: Anatomically correct nasal models of 2-, 5-, and 50-year old subjects were developed to evaluate regional nasal delivery of suspensions of fluticasone propionate and fluticasone furoate delivered with Flonase® and Flonase® Sensimist™, respectively, and the delivery of an aqueous solution of a model drug, administered with MAD Nasal™. Relevant inhalation patterns were considered for each nasal airway geometry. Controlled administration methods were used, and all contributing parameters, including particle size, velocity, and plume geometry, are reported. Results: Regional deposition patterns resulting from Flonase® Sensimist™ and Flonase® were not significantly different in each replica (p > 0.05), despite their different plume geometry and droplet size distributions. However, there was a significant difference in deposition of nasal sprays between the pediatric (2- and 5-year old) and adult models (p < 0.05), while no statistical differences were found between the two pediatric models (p > 0.05). The MAD atomizer resulted in different deposition patterns in all three subjects (p < 0.05). Conclusion: Nasal sprays are not adequate delivery devices for pediatric population, due to the narrower nasal passage and greater anterior deposition (∼60%). MAD atomizer resulted in significantly less anterior deposition (∼10%-15%) compared to the nasal pumps, but there was ∼30% run off to the throat. An in vitro platform incorporating anatomically correct nasal geometries and inhalation patterns can guide the development of age-appropriate nasal drug delivery devices.