Characterizing regional drug delivery within the nasal airways.

INTRODUCTION: The nose has been receiving increased attention as a route for drug delivery. As the site of deposition constitutes the first point of contact of the body with the drug, characterization of the regional deposition of intranasally delivered droplets or particles is paramount to formulation and device design of new products. AREAS COVERED: This review article summarizes the recent literature on intranasal regional drug deposition evaluated in vivo, in vitro and in silico, with the aim of correlating parameters measured in vitro with formulation and device performance. We also highlight the relevance of regional deposition to two emerging applications: nose-to-brain drug delivery and intranasal vaccines. EXPERT OPINION: As in vivo studies of deposition can be costly and time-consuming, researchers have often turned to predictive in vitro and in silico models. Variability in deposition is high due in part to individual differences in nasal geometry, and a complete predictive model of deposition based on spray characteristics remains elusive. Carefully selected or idealized geometries capturing population average deposition can be useful surrogates to in vivo measurements. Continued development of in vitro and in silico models may pave the way for development of less variable and more effective intranasal drug products.

High-Flow and Low-Flow Oxygen Delivery by Nasal Cannula Evaluated in Infant and Adult Airway Replicas.

BACKGROUND: The nasal cannula is widely regarded as a safe and effective means of administering low- and high-flow oxygen to patients irrespective of their age. However, variability in delivered oxygen concentration (FDO2 FDO2 ) via nasal cannula has the potential to pose health risks. The present study aimed to evaluate predictive equations for FDO2 over a large parameter space, including variation in breathing, oxygen flow, and upper-airway geometry representative of both young children and adults. METHODS: Realistic nasal airway geometries were previously collected from medical scans of adults, infants, and neonates. Nasal airway replicas based on these geometries were used to measure the FDO2 for low-flow oxygen delivery during simulated spontaneous breathing. The present study extends previously published data sets to include higher oxygen flows. The extended data sets included nasal cannula oxygen flows that ranged from 6 to 65 L/min for the adult replicas, and from 0.5 to 6 L/min for the infant replicas. For both age groups, FDO2 was measured over a range of breathing frequencies, inspiratory to expiratory time ratios, and tidal volumes. Measured FDO2 values were compared with values predicted by using a previously derived flow-weighted equation. RESULTS: For both age groups, FDO2 was observed to increase nonlinearly with the ratio between oxygen flow supplied to the nasal cannula and the average inhalation flow. The previously derived flow-weighted equation over-predicted FDO2 at higher oxygen flows. A new empirical equation, therefore, was proposed to predict FDO2 for either age group as a function of nasal cannula flow, tidal volume, and inspiratory time. Predicted FDO2 values matched measured values, with average relative errors of 2.4% for infants and 4.3% for adults. CONCLUSIONS: A new predictive equation for FDO2 was obtained that accurately matched measured data in both adult and infant airway replicas for low- and high-flow regimens.

Size-specific filtration efficiency and pressure drop of school-aged children's woven and nonwoven masks at varying face velocities.

BACKGROUND: Differences in physiology and breathing patterns between children and adults lead to disparate responses to aerosols of varying sizes. No standardized method exists for measuring the filtration efficiency (FE) of children's masks to reflect such differences. METHODS: Using an adult N95 mask as a control and two different face velocities (vf) (9.3 cm/s representing adults and 4.0 cm/s representing school-aged children), we tested the pressure drop (ΔP) through children's nonwoven masks (surgical and KN95) and children's woven masks (100% cotton and partially-cotton-based masks), as well as their size-specific FE between aerodynamic particle diameters of 0.02 and 2.01 µm. RESULTS: All three types of mask showed a 1 to 9% absolute increase in minimum FE at the lower vf and a significant decrease in ΔP. For children's surgical masks the increase in FE was significant for most of the examined particle sizes, but for children's woven masks the increase was limited to particles smaller than 0.04 µm. CONCLUSIONS: Lower vf for children is likely to lead to a higher FE, lower ΔP, and consequently higher filter qualities in children's masks. For woven masks, the FE for particles larger than 0.04 µm was low (typically <50%) for both vf's studied.

Variability in low-flow oxygen delivery by nasal cannula evaluated in neonatal and infant airway replicas.

BACKGROUND: The nasal cannula is considered a trusted and effective means of administering low-flow oxygen and is widely used for neonates and infants requiring oxygen therapy, despite an understanding that oxygen concentrations delivered to patients are variable. METHODS: In the present study, realistic nasal airway replicas derived from medical scans of children less than 3 months old were used to measure the fraction of oxygen inhaled (FiO2) through nasal cannulas during low-flow oxygen delivery. Parameters influencing variability in FiO2 were evaluated, as was the hypothesis that measured FiO2 values could be predicted using a simple, flow-weighted calculation that assumes ideal mixing of oxygen with entrained room air. Tidal breathing through neonatal and infant nasal airway replicas was controlled using a lung simulator. Parameters for nasal cannula oxygen flow rate, nasal airway geometry, tidal volume, respiratory rate, inhalation/exhalation, or I:E ratio (ti/te), breath waveform, and cannula prong insertion position were varied to determine their effect on measured FiO2. In total, FiO2 was measured for 384 different parameter combinations, with each combination repeated in triplicate. Analysis of variance (ANOVA) was used to assess the influence of parameters on measured FiO2. RESULTS: Measured FiO2 was not appreciably affected by the breath waveform shape, the replica geometry, or the cannula position but was significantly influenced by the tidal volume, the inhalation time, and the nasal cannula flow rate. CONCLUSIONS: The flow-weighted calculation overpredicted FiO2 for measured values above 60%, but an empirical correction to the calculation provided good agreement with measured FiO2 across the full range of experimental data.

Using Filters to Estimate Regional Lung Deposition with Pressurized Metered Dose Inhalers.

PURPOSE: To evaluate the suitability of a recently proposed apparatus that uses filters to directly fractionate the in vitro lung dose into regional deposition estimates for use with pressurized metered dose inhaler (pMDI) devices as a less resource intensive alternative to cascade impaction. METHODS: Using three commercially available pMDI devices (Asmanex HFA, Ventolin HFA, QVAR), regional deposition estimates were measured directly using the filter-based apparatus (FBA). Regional deposition estimates were also generated for the same inhalers by performing cascade impaction measurements and inputting the results to an in silico regional deposition model. Regional deposition for each inhaler was evaluated at an inhalation flow rate of 30 and 60 L/min. RESULTS: Total recovery of active pharmaceutical ingredient and extrathoracic deposition was independent of method used. The regional deposition estimates provided by each method were similar and captured the same trends. CONCLUSIONS: The direct measurement of estimated regional deposition is possible when using the FBA. This method is far less resource intensive than existing methods and so may be useful both for comparison of generic alternatives and the development of innovative products.

In Vitro Regional Deposition of Nasal Sprays in an Idealized Nasal Inlet: Comparison with In Vivo Gamma Scintigraphy.

PURPOSE: To compare in vitro regional nasal deposition measurements using an idealized nasal airway geometry, the Alberta Idealized Nasal Inlet (AINI), with in vivo regional deposition for nasal drug products. MATERIALS AND METHODS: One aqueous solution formulation (NasalCrom), one aqueous suspension formulation (Nasonex) and one nasal pressurized metered dose spray device (QNASL) were selected. Two spray orientation angles, 60° and 45° from the horizontal, were selected. A steady inhalation flow rate of 7.5 L/min was selected to simulate slow inhalation through a single nostril. After actuation, the AINI was disassembled. The mass of drug deposited in each region and a downstream filter, representing penetration of drug to the lungs, was determined using ultraviolet-visible (UV-Vis) spectrophotometry. RESULTS: No filter (lung) deposition was detected for NasalCrom or Nasonex. Filter deposition ranged from 6 to 11% for QNASL. For NasalCrom, 45% to 69% of the dose deposited in the AINI was deposited in the vestibule and 31% to 55% was deposited in the turbinates; for Nasonex, 66% to 74% (vestibule) and 26% to 34% (turbinates); for QNASL, 90% to 100% (vestibule) and 0% to 10% (turbinates). No statistically significant difference was observed between regional deposition in vivo and in vitro for any of the formulations, except that nasopharyngeal deposition with Nasonex differed by less than 1.56% from in vivo, which while statistically significant, is unlikely to be clinically significant. CONCLUSIONS: The AINI was able to mimic regional in vivo deposition for nasal drug products, permitting differentiation between devices based on regional deposition.

Characterization of dry powder inhaler performance through experimental methods.

Experimental methods provide means for the quality control of existing DPIs and for exploring the influence of formulation and device parameters well in advance of clinical trials for novel devices and formulations. In this review, we examine the state of the art of in vitro testing of DPIs, with a focus primarily on the development of accurate in vitro-in vivo correlations. Aspects of compendial testing are discussed, followed by the influence of flow profiles on DPI performance, the characterization of extrathoracic deposition using mouth-throat geometries, and the characterization of regional thoracic deposition. Additional experimental methods that can inform the timing of bolus delivery, the influence of environmental conditions, and the development of electrostatic charge on aerosolized DPI powders are reviewed. We conclude with perspectives on current in vitro methods and identify potential areas for future investigation, including the estimation of variability in deposition, better characterization of existing compendial methods, optimization of formulation and device design to bypass extrathoracic deposition, and the use of novel tracheobronchial filters that aim to provide more clinically relevant measures of performance directly from in vitro testing.

Intranasal delivery of a synthetic Entamoeba histolytica vaccine containing adjuvant (LecA + GLA-3 M-052 liposomes): In vitro characterization.

Amebiasis, a disease caused by the parasite Entamoeba histolytica, is estimated to cause millions of infections and at least 55,000 deaths globally each year. With no vaccine currently available, there is an urgent need for an accessible means of stimulating protective mucosal immunity. The objective of this study was to characterize the nasal spray of a novel amebiasis vaccine candidate from a syringe-based liquid atomization device, the Teleflex MAD Nasal™, in both adult and infant nasal airways. Human ergonomic testing was completed to determine realistic actuation parameters. Spray pattern, plume geometry, and droplet size distribution were measured to evaluate reproducibility of free plume characteristics. The Alberta Idealized Nasal Inlet (AINI) and three realistic infant nasal airways were used to determine the in vitro deposition profile in adult and infant airways, respectively. Collectively, in vitro results demonstrated the feasibility of delivering the vaccine candidate to target sites within the nasal airways. Penetration through the nasal airways that could lead to deposition in the lungs was below the limit of quantification for both adult and infant geometries, indicating a low likelihood of adverse events due to lung exposure. These results support continued investigation of intranasal delivery of the synthetic Entamoeba histolytica vaccine.

Empirical Deposition Correlations.

Traditionally, empirical correlations for predicting respiratory tract deposition of inhaled aerosols have been developed using limited available in vivo data. More recently, advances in medical image segmentation and additive manufacturing processes have allowed researchers to conduct extensive in vitro deposition experiments in realistic replicas of the upper and central branching airways. This work has led to a collection of empirical equations for predicting regional aerosol deposition, especially in the upper, nasal and oral airways. The present section reviews empirical correlations based on both in vivo and in vitro data, which may be used to predict total and regional deposition. Equations are presented for predicting total respiratory deposition fraction, mouth-throat fraction, nasal, and nose-throat fractions for a large variety of aerosol sizes, subject age groups, and breathing maneuvers. Use of these correlations to estimate total lung deposition is also described.

Spray Dried Rugose Lipid Particle Platform for Respiratory Drug Delivery.

PURPOSE: To develop a new lipid-based particle formulation platform for respiratory drug delivery applications. To find processing conditions for high surface rugosity and manufacturability. To assess the applicability of the new formulation method to different lipids. METHODS: A new spray drying method with a simplified aqueous suspension feedstock preparation process was developed for the manufacture of rugose lipid particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). A study covering a wide range of feedstock temperatures and outlet temperatures was conducted to optimize the processing conditions. Aerosol performance was characterized in vitro and in silico to assess the feasibility of their use in respiratory drug delivery applications. The applicability of the new spray drying method to longer-chain phospholipids with adjusted spray drying temperatures was also evaluated. RESULTS: Highly rugose DSPC lipid particles were produced via spray drying with good manufacturability. A feedstock temperature close to, and an outlet temperature lower than, the main phase transition were identified as critical in producing particles with highly rugose surface features. High emitted dose and total lung dose showed promising aerosol performance of the produced particles for use as a drug loading platform for respiratory drug delivery. Two types of longer-chain lipid particles with higher main phase transition temperatures, 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (22:0 PC), yielded similar rugose morphologies when spray dried at correspondingly higher processing temperatures. CONCLUSIONS: Rugose lipid particles produced via spray drying from an aqueous suspension feedstock are promising as a formulation platform for respiratory drug delivery applications. The new technique can potentially produce rugose particles using various other lipids.

Use of Airway Replicas in Lung Delivery Applications.

The use of extrathoracic airway replicas in optimization of drug delivery to the lungs with nebulizers, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs) is discussed. Such airway replicas have been useful in evaluating new pulmonary drug delivery platforms mainly based on the comparison of the total lung dose (TLD) and the aerodynamic particle size distribution (APSD) of the aerosol distal to the physical models. The ability of these in vitro methods to replicate in vivo results has allowed advancements in respiratory drug delivery and in the accuracy and utility of in vitro-in vivo correlations (IVIVCs).

Size-Specific Filtration Performance of N95 Respirators After Decontamination by Moist Heat Incubation.

Background: Decontamination and reuse of respirators have been proposed to mitigate the shortage of respirators during pandemics. The U.S. National Institute for Occupational Safety and Health (NIOSH)'s respirator filtration efficiency (FE) test has been used to confirm that decontamination procedures maintain minimum FE above 95% for N95s and similar respirators. However, it was hypothesized that the limited range of test particle sizes may not include the most penetrating particle size (MPPS) for all respirators, especially after decontamination by moist heat incubation (MHI). Materials and Methods: A custom-designed apparatus was used to measure size-specific FE for respirators across particle size bins between aerodynamic diameter of 0.07 and 1.97 µm using an electrical low-pressure impactor. FEs were measured for two N95 respirator models before and after 10 cycles of MHI. In addition, pressure drop through the respirator materials and scanning electron microscope (SEM) images of respirator layers were obtained before and after MHI. Results: For Kimtech™ brand N95 respirators, FE was not reduced at any size after MHI. For Safe Life brand N95s, FE was below 95% before MHI and decreased significantly after MHI. The MPPS for this respirator was outside the range defined in NIOSH test protocol, and increased after MHI. There was no appreciable change to the pressure drop through the two respirator models after MHI, nor was any deterioration in fiber integrity visible in SEM images. Conclusions: Based on the results of the present study and other studies in the literature, MHI can be used to decontaminate respirators without significant decrease in FE. However, potential effects of MHI on FE need to be assessed for each respirator model. The ability to evaluate size-specific FE across a wide range of particle sizes is important in identifying the MPPS and associated FE of respirators before and after MHI.

Comparison of airway pressures and expired gas washout for nasal high flow versus CPAP in child airway replicas.

BACKGROUND: For children and adults, the standard treatment for obstructive sleep apnea is the delivery of continuous positive airway pressure (CPAP). Though effective, CPAP masks can be uncomfortable to patients, contributing to adherence concerns. Recently, nasal high flow (NHF) therapy has been investigated as an alternative, especially in CPAP-intolerant children. The present study aimed to compare and contrast the positive airway pressures and expired gas washout generated by NHF versus CPAP in child nasal airway replicas. METHODS: NHF therapy was investigated at a flow rate of 20 L/min and compared to CPAP at 5 cmH2O and 10 cmH2O for 10 nasal airway replicas, built from computed tomography scans of children aged 4-8 years. NHF was delivered with three different high flow nasal cannula models provided by the same manufacturer, and CPAP was delivered with a sealed nasal mask. Tidal breathing through each replica was imposed using a lung simulator, and airway pressure at the trachea was recorded over time. For expired gas washout measurements, carbon dioxide was injected at the lung simulator, and end-tidal carbon dioxide (EtCO2) was measured at the trachea. Changes in EtCO2 compared to baseline values (no intervention) were assessed. RESULTS: NHF therapy generated an average positive end-expiratory pressure (PEEP) of 5.17 ± 2.09 cmH2O (mean ± SD, n = 10), similar to PEEP of 4.95 ± 0.03 cmH2O generated by nominally 5 cmH2O CPAP. Variation in tracheal pressure was higher between airway replicas for NHF compared to CPAP. EtCO2 decreased from baseline during administration of NHF, whereas it increased during CPAP. No statistical difference in tracheal pressure nor EtCO2 was found between the three high flow nasal cannulas. CONCLUSION: In child airway replicas, NHF at 20 L/min generated average PEEP similar to CPAP at 5 cm H2O. Variation in tracheal pressure was higher between airway replicas for NHF than for CPAP. The delivery of NHF yielded expired gas washout, whereas CPAP impeded expired gas washout due to the increased dead space of the sealed mask.

Using Filters to Estimate Regional Lung Deposition with Dry Powder Inhalers.

PURPOSE: To develop an in vitro method to rapidly evaluate regional lung doses delivered by pharmaceutical inhalers. Currently, cascade impactor measurements are used, but these are resource intensive and require significant post processing of in vitro data to arrive at regional deposition estimates. METHODS: We present a specialized filter apparatus that mimics tracheobronchial (TB) deposition of pharmaceutical aerosols emitted by commercially available dry powder inhalers (DPIs). The filter housing includes an electrostatic neutralizer to eliminate artificial electrostatic filtration effects. Regional deposition (tracheobronchial and alveolar) for four DPIs (Onbrez Breezhaler, Flovent Diskus, Pulmicort Turbuhaler, and Asmanex Twisthaler) was estimated using cascade impactor measurements and an in silico regional deposition model. These estimates were compared to direct measurements of regional deposition as provided by the TB filter mimic and an absolute filter placed downstream of the TB filter housing, representing the alveolar dose. RESULTS: The two methods were shown to provide similar estimates of extrathoracic, tracheobronchial, and alveolar deposition, as well as total recovery of active pharmaceutical ingredients. CONCLUSIONS: Because of its design, the TB filter apparatus makes it possible to estimate regional deposition with inhalers directly using variable inhalation profiles without any additional equipment or changes to the experimental configuration. This method may be useful to expedite development of both innovative and generic drug products as it provides regional respiratory tract deposition estimates using fewer resources than exisiting methods.

Deposition of Aerosols in the Lungs: Particle Characteristics.

Of the various particle properties that affect deposition in the respiratory tract, particle diameter and particle density are the most commonly considered, since their effect on deposition is well known and important, as has been discussed earlier in this chapter. However, there are several other particle properties that can affect particle deposition in the lungs. These include: 1) electrostatic charge on the particle, which can cause electrostatic forces to enhance deposition; 2) the shape of the particle, which can cause its trajectory to differ from that of a spherical particle and thereby alter its deposition; and 3) volatility of the particle i.e., its ability to condense or evaporate at its surface, which can change its diameter and in turn affect its deposition. In this section, we examine each of these three factors individually.

Trileucine as a dispersibility enhancer of spray-dried inhalable microparticles.

The formation of trileucine-containing spray-dried microparticles intended for pulmonary delivery was studied in depth. A single-particle method was employed to study the shell formation characteristics of trileucine in the presence of trehalose as a glass former, and an empirical correlation was proposed to predict the instance of shell formation. A droplet chain instrument was used to produce and collect monodisperse particles to examine morphology and calculate particle density for different levels of trileucine. It was observed that the addition of only 0.5 mg/mL (10% w/w) trileucine to a trehalose system could lower dried particle densities by approximately 1 g/cm3. In addition, a laboratory-scale spray dryer was used to produce batches of trileucine/trehalose powders in the respirable range. Raman spectroscopy demonstrated that both components were completely amorphous. Scanning electron microscopy and time-of-flight secondary ion mass spectrometry were used to study the particle morphologies and surface compositions. For all cases with trileucine, highly rugose particles with trileucine coverages of more than 60% by mass were observed with trileucine feed fractions of as little as 2% w/w. Moreover, it was seen that at lower trileucine content, smaller and larger particles of a polydisperse powder had slightly different surface compositions. The surface activity of trileucine was also modeled via a modified form of the diffusion equation inside an evaporating droplet that took into account initial surface adsorption and eventual surface desorption due to droplet shrinkage. Finally, using the Flory-Huggins theory, it was estimated that at room temperature, liquid-liquid phase separation would start when the trileucine reached an aqueous concentration of about 18 mg/mL. Besides the surface activity of trileucine, this low concentration was assumed to explain the substantial effect of trileucine on the morphology of spray-dried particles due to early phase separation. The methodology proposed in this study can be used in the rational design of trileucine-containing microparticles.

A simple HEPA filtering facepiece.

Shortages of efficient filtering facepiece respirators leave the public vulnerable to transmission of infectious diseases in small particle aerosols. This study demonstrates that a high-filtration-efficiency facepiece capable of filtering out >95% of 0.05µm particles while being worn can be simply produced with available materials.

On the particle formation of leucine in spray drying of inhalable microparticles.

The particle formation of L-leucine, a dispersibility-enhancing amino acid used in the spray drying of inhalable pharmaceutical aerosols, was extensively studied using three experimental methods, and the results were interpreted with the aid of theory. A comparative-kinetics electrodynamic balance was used to study the shell formation behavior in single evaporating microdroplets containing leucine and trehalose. Different concentration thresholds of solidification and shell formation were determined for trehalose and leucine, which were then used in the particle formation model to predict the properties of spray-dried particles. Furthermore, a droplet chain instrument was used to study the particle morphologies and particle densities that were not accessible in the single particle experiments. Lab-scale spray drying was also used to produce powders typical for actual pharmaceutical applications. Raman spectroscopy confirmed that a glass former, such as trehalose, can inhibit the crystallization of leucine. The surface compositions of these spray-dried powders were analyzed via time-of-flight secondary ion mass spectrometry. The leucine surface coverage in a polydisperse powder was determined to be a function of the particle size or the initial droplet diameter of each respective particle. This observation confirms the important role of leucine crystallization kinetics in its shell-forming capabilities. A critical supersaturation ratio of 3.5 was also calculated for leucine, at which it is assumed to instantaneously nucleate out of solution. This ratio was used as the threshold for the initiation of crystallization. Crystallinity predictions for the leucine-trehalose particles based on this supersaturation ratio were in good agreement with the solid-state characterizations obtained by Raman spectroscopy. This study improves the fundamental understanding of the particle formation process of leucine-containing formulations, which can apply to other crystallizing systems and potentially facilitate the rational design of such formulations with reduced experimental effort.