Laboratory Performance Testing of Aqueous Nasal Inhalation Products for Droplet/Particle Size Distribution: an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Although nasal inhalation products are becoming more and more important for the delivery of medicines, characterization of these products for quality control and assessment of bioequivalence is complicated. Most of the problems encountered are associated with the assessment of aerodynamic droplet/particle size distribution (APSD). The droplets produced by the various nasal devices are large, and for suspension products, individual droplets may contain multiple drug particles or none at all. Assessment of suspension products is further complicated by the presence of solid excipient particles. These complications make it imperative that the limitations of the instruments used for characterization as well as the underlying assumptions that govern the interpretation of data produced by these instruments are understood. In this paper, we describe various methodologies used to assess APSD for nasal inhalation products and discuss proper use, limitations, and new methodologies on the horizon.

Effects of Device Settings and E-Liquid Characteristics on Mouth-Throat Losses of Nicotine Delivered with Electronic Nicotine Delivery Systems (ENDS).

Currently it is not fully understood how the device settings and electronic liquid (e-liquid) composition, including their form of nicotine content, impact mouth and throat losses, and potentially lead to the variations in total nicotine delivery to the human lungs. An in situ size assessment method was developed for real-time measurements at the mouthpiece and outlet of a biorelevant mouth-throat to account for the dynamic nature of the aerosol. The aerosol size, temperature, and delivery through the mouth-throat replica and the exhaled aerosol between the puff intervals were measured at different wattages using various e-liquid compositions. The effects of body temperature and humidity on aerosol size and nicotine delivery were also explored to evaluate the importance of considering realistic in vivo conditions in in vitro measurements. Notably, in vitro tests with body temperature and humidity in mouth-throat model vs room conditions, resulted in larger aerosol size at the end of the throat (Dv50=5.83±0.33 µm vs 3.05±0.15 µm), significantly higher thoracic nicotine delivery (>90% vs 50-85%) potentially due to the lower exhaled amount (<10% vs 15-50%). Besides, higher VG/PG ratios resulted in significantly lower exhaled amount and higher mouth-throat nicotine deposition. One of the main outcomes of the study was finding significantly lower exhaled amount and higher thoracic nicotine delivery with nicotine salt form vs free-base. Considering body temperature and humidity also showed significant enhancement in nicotine delivery, so it is essential to account for biorelevant experimental conditions in benchtop testing.

Anatomically realistic nasal replicas capturing the range of nasal spray drug delivery in adults.

To improve the relationships between commonly conducted in vitro studies for locally-acting nasal spray drug products with in vivo regional deposition, this study developed a set of in vitro adult nasal geometries that captured the range of nasal drug delivery to the region posterior to internal nasal valve (INV), also known as posterior delivery (PD), and evaluated their performance with existing in vivo data. The PD of fluticasone propionate (FP) and fluticasone furoate (FF) in 40 nasal cavities was statistically analyzed to identify three airway models representing the low, mean, and high PD in adults. The models were also externally validated by comparing the in vitro nasal deposition from a different drug product (mometasone furoate (MF)) with the relevant in vivo data. The three selected geometries represented the low, mean, and high PD with multiple nasal sprays. They were verified in terms of reproducibility of in vitro data and validated by showing a reasonable agreement with preexisting in vivo MF PD despite differences in administration and defining the regions. The three models are envisioned to potentially facilitate the development of locally-acting nasal sprays and provide a better understanding of how in vitro metrics relate to in vivo regional nasal deposition.

Correlations to Estimate the Key Anatomical Dimensions of Pediatric Nasal Airways using Minimally Invasive Measurements of Intranasal Pressure Gradient.

Background: Understanding the morphology of nasal airways is important in determining the nasal airway deposition of inhaled aerosol. Moreover, objective assessment of the anatomy of human nasal airways is useful to develop a database of reference or normal values as a resource to investigate anatomical abnormalities of airways. Current methods for the objective assessment of the nasal airways are either limited to very few dimensions or can only be performed by specialized researchers. Thus, the main objective of this study was to determine the correlations between the intranasal pressure gradient (Δp) and the key anatomical dimensions of the pediatric nasal airways, which could in turn allow the extrapolation of nasal airway morphology based on simple minimally invasive measurements of pressure. Methods: The anatomical data and Δp were obtained from in vitro studies with nasal airway models of 11 infants ages 3-18 months and 13 children ages 4-14 years old. Key anatomical dimensions were identified based on both rhinology and aerosol dosimetry literature. These anatomic data, including the volume, V, surface area, As, length, L, and the minimum cross-sectional area of the replicas, Amin, were then analyzed for correlation with Δp and flow parameters, using Bernoulli's principle and dimensional analysis. Results: Strong correlations were found between Δp and As/L for children, and between Δp and V/As for infants. Additional pressure gradient correlations were developed with Amin, V/As, V∕L, and L. Conclusions: The correlations identified between anatomic data and Δp have clinical implications in pediatric rhinology, suggesting that certain aspects of airway anatomy in infants and children can be predicted through the measurement of Δp. The airway dimensions, predicted using Δp measurement, may be used in tandem with aerosol nasal deposition correlations that account for nasal airway dimensions.

In vitro evaluation of regional nasal drug delivery using multiple anatomical nasal replicas of adult human subjects and two nasal sprays.

Quantifying drug delivery to the site of action using locally-acting nasal suspension sprays is a challenging but important step toward understanding bioequivalence (BE) between test and reference products. The main objective of this study was to investigate the in vitro deposition pattern of two common but different locally-acting nasal suspension sprays using multiple nasal cavities. Twenty anatomically accurate nasal replicas were developed from high-resolution sinonasal computed tomography scans of adults with healthy nasal airways. The airways were segmented into two regions of anterior and posterior to the internal nasal valve. Both sides of the septum were considered separately; hence, 40 nasal cavities were studied. The positioning of the spray nozzle in all 40 cavities was characterized by the head angle, coronal angle, and the insertion depth. Despite using a controlled protocol to minimize the anterior losses, a wide range of variability in posterior drug delivery was observed. The observed intersubject variability using this in vitro method may have important implications for understanding BE of locally-acting nasal suspension sprays.

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.

An in vitro evaluation of importance of airway anatomy in sub-regional nasal and paranasal drug delivery with nebulizers using three different anatomical nasal airway replicas of 2-, 5- and 50-Year old human subjects.

Intranasal delivery of nebulized drugs with the consideration of the nasal anatomy is not adequately studied. The objective of this study was to evaluate nasal and paranasal drug delivery with nebulizers, with and without pulsating airflow, in three anatomically-different nasal models in different age groups, considering normal and bidirectional breathing techniques. Anatomically-accurate nasal models of 2-, 5-, and 50-year old subjects were developed and tested to quantify sub-regional deposition of an aqueous solution of a model drug, nebulized with PARI SinuStar™ and Sinus™ nebulizers. Paranasal delivery was significantly enhanced using pulsating nebulization under bidirectional breathing administration technique for all subjects (p < 0.05). Airway morphology resulted in significantly different drug delivery efficiency (p < 0.05). Use of a modified nasal adaptor enhanced the inhaled dose and resulted in significantly higher percent recovery, 68.41±13.56%, compared to the standard design,10.35±1.75%. In the adult subject, paranasal delivery was equal to 19.34±1.21%, and 5.99±0.95% using PARI Sinus™ nebulizer, with and without pulsating airflow, respectively. In the pediatric subjects, pulsating paranasal delivery was 12.80±0.28%, but without pulsating airflow no drug reached the target. This study confirmed that bidirectional breathing and pulsating airflow are beneficial for improved paranasal aerosol delivery in children similar to previous findings for adults.

Intranasal Filtration of Inhaled Aerosol in Human Subjects as a Function of Nasal Pressure Drop.

BACKGROUND: Intersubject variability in nasal deposition of inhaled aerosol is significant because of the differences in nasal anatomy and breathing rate. The notable limitation of the majority of previously developed predictive correlations is including a limited number of subjects. A few recent studies have considered a wide age range of subjects, but the resulting correlations require the knowledge of the dimensions of the nasal airways and the properties of inhaled gas. In this study empirical correlations are proposed to predict aerosol deposition in nasal airways of subjects of different age as a function of intranasal pressure drop and the particle aerodynamic diameter. METHODS: The experimental nasal deposition and pressure drop data in anatomically correct nasal replicas of 5 adults, 13 children aged 4-14 years, and 11 infants aged 3-18 months were reanalyzed. The range of aerodynamic diameter was 0.5-5.3 µm and physiological breathing at different activity levels was considered. Correlations between nasal deposition and a deposition parameter including the aerodynamic size of inhaled aerosol and nasal pressure drop were developed with nonlinear least-square algorithms. The general coefficient of determination r2 was used to evaluate the fitting accuracy for each correlation. RESULTS: New correlations were developed to predict the intranasal deposition of particles as a function of intranasal pressure drop and particle size for pediatric and adult subjects. The intranasal deposition fraction in adults and children can be calculated using the same correlation, whereas the intranasal deposition in infants followed a different trend line because of higher intranasal pressure drop in infants. CONCLUSION: This study was the first offering correlations to predict intranasal deposition in multiple age groups using only the aerodynamic size of inhaled aerosol and nasal pressure drop. These correlations include the effects of intersubject variability in nasal deposition within each age group and among different age groups.