Category: Formulation and Quality
Purpose: Nasal sprays are commonly used to deliver locally-acting drugs (e.g. corticosteroids) to treat allergic rhinitis. Quantifying drug delivery to the site of action within the nasal cavity is challenging from a regulatory perspective and is known to be highly variable and dependent upon patient mode of use, patient anatomical variability, and formulation properties. Currently in vitro spray plume geometry data are used to compare different products as part of the assessment of bioequivalence. However, these current in vitro nasal spray testing methods do not consider the complexity of the nasal airway anatomy and intersubject variability. Therefore, this study aimed to develop the next generation of in vitro test methods and investigate the in vitro deposition patterns of drug from two nasal sprays, administered using controlled methods, in a series of twenty anatomical nasal airway replicas.
Methods: Physical nasal airway replicas were developed from anonymized computed tomography (CT) images of twenty adult subjects with healthy nasal airways (half male and half ≥50 years old) by including the entire nasal cavity and nasopharynx down to the end of C1 vertebra. The models were segmented into two regions of anterior and posterior nasal deposition relative to the internal nasal valve. The anterior section of each replica was rapid prototyped using a flexible rubbery material (TANGO PLUS 27A) in order to easily insert and maneuver the tip of nasal sprays into the nostrils. The posterior section of each replica was rapid prototyped using high clarity rigid plastic (Accura ClearVue). Nasal spray deposition studies were performed using two test products, Flonase® (fluticasone propionate 50 µg per 100 µl spray), and Flonase® Sensimist™ (fluticasone furoate 27.5 µg per 50 µl spray), with 2 sprays actuated into the right nostril of each replica. Twenty units of each nasal spray with identical lot number and expiration date were purchased and each replica was tested with a unique spray unit. The positioning of the spray nozzle in the nostril was recorded and characterized across all 20 subjects by the head angle (Flonase®: 57.9±5.1°, Flonase® Sensimist™: 48.3±6.3°), coronal angle (Flonase®: 39.5±10.0°, Flonase® Sensimist™: 36.7±7.3°), and the insertion depth (Flonase®: 15.1±2.6 mm, Flonase® Sensimist™:12.5±0.0 mm). The values are presented as mean ± standard deviation. A realistic in vivo breathing pattern representing gentle sniffing  was simulated using a breathing simulator (ASL5000, Ingmar Medical). The Mighty Runt Actuation Station (InnovaSystems, Inc.) was synchronized with the breathing simulator and two actuation force (AF) levels, 5.8 and 7.2kg, were applied to actuate the Flonase® at the start of nasal inhalation. The Flonase® Sensimist™ spray was hand actuated at the beginning of inhalation using the same breathing pattern. Analytical quantification of fluticasone propionate (Flonase®) and fluticasone furoate (Flonase® Sensimist™) recovered from the nasal models was performed using a validated high-performance liquid chromatography (HPLC) method. The drug recovery was calculated as the mass of drug in the entire nasal model as a percentage of the labeled dose. The mass of drug reaching the posterior region (posterior dose; PD) is expressed as the percentage of the recovered dose.
Results: The spray weight values for 2 sprays were 190.8±4.4 mg, and 193.8±2.6 mg for the Flonase® using 5.8 and 7.2 kg actuation force, respectively, and 108.9±3.0 mg for the Flonase® Sensimist™. Across the 20 replica models, the recovered doses were 76.1±9.0% and 78.6±7.2%, respectively, using 5.8kg and 7.2kg actuation forces for the Flonase®, and 89.1±5.9% for the Flonase® Sensimist™. The PD values across the 20 models were 58.1±22.7% and 57.5±19.8 % for the Flonase® using 5.8 kg and 7.2 kg actuation forces, respectively, and 56.5±15.7% for the Flonase® Sensimist™. The range of PD with Flonase® was 21-89% at 5.8 kg and 24-85% at 7.2 kg. With Flonase® Sensimist™ this range was 29-92%.
Conclusion: Despite using a controlled administration protocol to minimize the anterior losses a wide range of posterior delivery was observed for Flonase® and Flonase® Sensimist™. The results show the importance of the nasal airway anatomy in determining the fraction of delivered dose reaching the posterior region. Thus, to improve the current in vitro test methods, anatomical airway geometries and intersubject variability must be considered.
Reference:  D. V. Doughty et al., (2011). Drug Development and Industrial Pharmacy, 37(3), 359–366.
Michele Manniello– Richmond, Virginia
Michele Manniello– Richmond, Virginia
Sana Hosseini– Richmond, Virginia
Michael Hindle– Professor, Virginia Commonwealth University, Richmond, Virginia
Theodore Schuman– Richmond, Virginia
Worth Longest– Professor, Virginia Commonwealth University, Richmond, Virginia
Dennis Sandell– Blentarp, Skane Lan, Sweden
Laleh Golshahi– Richmond, Virginia