To evaluate and develop a novel dissolution test method using tracheobronchial (TB) mimic filters for assessing the dissolution behavior of inhaled drugs targeting the tracheobronchial lung region. Fluticasone propionate (FP), a poorly soluble corticosteroid, was selected as the test drug. A novel filter-based apparatus (FBA) fractionated the inhaled dose into extrathoracic, tracheobronchial, and alveolar fractions. FP was delivered via dry powder inhaler (DPI) (Flovent Diskus, 250 µg) and pressurized metered-dose inhaler (pMDI) (Flovent HFA, 250 µg). Regional deposition estimates were compared between inhalers. Dissolution tests were performed on the captured TB dose using phosphate-buffered saline + 0.5 k_1 ), difference ( f_1 ), and similarity ( f_2 ) factors were calculated. Particle distribution and loading effects on the TB filter were assessed using scanning electron microscopy (SEM). The TB filter demonstrated consistent performance, with no drug loading effects observed for up to the highest drug loading tested, which was 7 actuations of the DPI ( 110 µg FP collected on the TB filter), or 5 actuations of the pMDI ( 170 µg). Dissolution profiles revealed no significant differences across DPI doses, and slower dissolution rates for the pMDI compared to the DPI, with k_1 values indicating significant differences (p < 0.05). SEM showed no particle aggregation or filter clogging. Similarity and difference factors supported these findings. The dissolution method discriminated between the two inhalers and is a promising new tool for use in the dissolution testing of orally inhaled drug products.

Background: Extrathoracic deposition is a large source of in vivo variability in dosing for pressurized metered dose inhaler (pMDI) aerosols. A majority of previous studies have focused on only total extrathoracic deposition for pMDIs. The present work evaluates regional deposition within the extrathoracic region to better understand the impact of actuator orifice diameter and inhalation flow rate on extrathoracic deposition of a suspension pMDI formulation of epinephrine. Methods: Regional deposition of a commercially available HFA (hydrofluoroalkane) suspension pMDI formulation of epinephrine was evaluated using plastic and metal versions of the newly developed sectioned Alberta Idealized Throat (s-AIT), divided into analogs of the oral cavity, the pharynx/larynx, and the upper trachea. Influences of actuator orifice diameter and inhaler insertion angle on regional extrathoracic deposition were evaluated in the plastic s-AIT at a 30 L/min flow rate, followed by additional testing in the metal s-AIT to evaluate effects across a range of flow rates (from 10 to 100 L/min). Results: Actuator orifice was found to strongly influence regional extrathoracic deposition of a commercially available epinephrine HFA suspension pMDI aerosol, with smaller actuator orifices yielding reduced oral cavity deposition and increased distal-filter (in vitro lung) deposition in both the plastic and metal s-AIT. Inhalation flow rate was found to strongly influence deposition in the metal s-AIT, with higher flow rates associated with reduced oral cavity deposition, increased pharynx/larynx deposition, and increased upper trachea deposition. Smaller orifices showed less variability in results as a function of inhaler insertion angle. Conclusions: Actuator orifice diameter (spanning 0.22-0.42 mm) can strongly influence regional deposition of an HFA epinephrine suspension pMDI aerosol within the extrathoracic region. Smaller actuator orifices may provide reduced oral cavity deposition and increased delivery to the lungs. Smaller actuator orifices may also reduce variability in extrathoracic deposition that is associated with patient use aspects such as inhaler insertion angle.

Background: Dry powders offer the potential to increase stability and reduce cold-chain requirements associated with the distribution of vaccines and other thermally sensitive products. The Alberta Idealized Nasal Inlet (AINI) is a representative geometry for in vitro characterization of nasal products that may prove useful in examining intranasal delivery of powders. Methods: Spray-dried trehalose powders were loaded at 10, 20, and 40 mg doses into active single-dose devices. Primary particle sizes (∼Dv50 = 10 µm for powder A and 25 µm for powder B), and sizes dispersed by devices, were evaluated using laser diffraction. The interior of the AINI was coated with a glycerol-surfactant mixture to mitigate particle bounce, and flow rates of 7.5 or 15 L/min were drawn through the AINI. Deposition of trehalose powder was determined in the four regions of the AINI (vestibule, turbinates, olfactory, and nasopharynx), a downstream preseparator, and an absolute filter (representing in vitro lung deposition) using liquid chromatography coupled with mass spectrometry. Results: Coating the AINI was effective in mitigating particle bounce for both trehalose powders. No difference in regional nasal deposition was observed when testing at a flow rate of 7.5 versus 15 L/min. A high fraction of both powders penetrated past the vestibule and deposited in the turbinates and nasopharynx for all loaded doses. For powder A, a non-negligible fraction of the recovered dose (up to 7%) is deposited on the filter, representing potential lung exposure. Conversely, a negligible fraction of the total recovered dose was deposited on the filter for powder B. Conclusion: Powders with a larger primary particle size showed reduced penetration through the nasal airways while maintaining high turbinate deposition. Optimized spray-dried powders offer the potential to target delivery to the peripheral nasal airways based on powder particle size while reducing lung exposure.

IntroductionThe 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 coveredThis 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 opinionAs 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.

While there has been considerable investigation into the deposition of inhaled aerosols in the airways of adults, less is known about where aerosols deposit in the lungs of children. Clinical investigation into aerosol deposition in children is complicated by ethical concerns surrounding ionizing radiation studies in children. To meet the need for non-clinical methods of estimating regional deposition in pediatric airways, multiple in silico models were developed to represent the lungs of girls and boys aged 6, 8, 10 and 12 years. The models were symmetric and used a singlepath deterministic approach to calculate aerosol deposition in the airways. Regional deposition estimates were provided for children using a fixed set of controlled breathing patterns before characterizing regional deposition during typical tidal breathing in each age group. Deposition patterns were found to be strongly influenced by inhalation flow rate and aerodynamic particle size. Differences between boys and girls in the fraction of inhaled aerosol depositing were minimal during fixed breathing patterns, with higher deposition in all regions of the younger age groups. However, when breathing patterns were adjusted to represent typical tidal breathing in each age group, age differences in the regional fraction of particles depositing became negligible. Moreover, peak deposition fractions in both the conducting and peripheral airways occurred within a narrow range of aerodynamic particle diameters between 2.4 and 2.6 mu m, a smaller size range than for adults. During exposure over a fixed period of time, age-related differences in minute ventilation resulted in a larger aerosol dose depositing in the intrathoracic airways of older children. Such differences suggest that to achieve comparative dosing in this age range, older children should inhale aerosols for a shorter time. These findings provide an improved understanding of regional deposition in pediatric airways and will assist in optimizing regional drug delivery to children.

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 (FiO(2)) through nasal cannulas during low-flow oxygen delivery. Parameters influencing variability in FiO(2) were evaluated, as was the hypothesis that measured FiO(2) 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 (t(i)/t(e)), breath waveform, and cannula prong insertion position were varied to determine their effect on measured FiO(2). In total, FiO(2) 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 FiO(2). Results: Measured FiO(2) 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 FiO(2) for measured values above 60%, but an empirical correction to the calculation provided good agreement with measured FiO(2) across the full range of experimental data.

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.

Inhaled aerosols have wide-ranging applications in the treatment and diagnosis of respiratory diseases. Methacholine challenge testing (MCT) is a diagnostic test frequently used to evaluate airway hyper-reactivity. We hypothesize that a significant fraction of the inhaled dose of meth-acholine is exhaled during treatment, given the small droplet sizes produced by nebulizers traditionally used for MCT. Here, an in vitro - in silico approach was developed to predict respi-ratory tract deposition achieved with various nebulizers proposed for use with MCT.Emitted doses, particle sizes, and the temperature and humidity of the nebulized airstream were experimentally measured for three nebulizers (RX160, Roxon Meditech; Hudson RCI Micro Mist [HRCI], Teleflex; AirLife Misty Max 10 [MM10], CareFusion) at methacholine chloride concentrations of 0.0625, 1, and 16 mg/mL in 0.9% saline solutions. Emitted doses at a con-centration of 1 mg/mL were measured to be 42.0 (SD 5.1) mu g from the RX160 over 120 s, 96.3 (SD 33.7) mu g from the HRCI over 60 s, and 162.3 (SD 38.4) mu g from the MM10 over 60 s. For a typical adult tidal inhalation, the inhaled dose was found to be half of the emitted dose. Our hygroscopic lung deposition model predicted considerable condensational growth within the respiratory tract for aerosols used with MCT. For the 1 mg/mL methacholine chloride solution, the fraction of the inhaled dose predicted to deposit in the lungs was 0.40 (8.3 mu g) for the RX160, 0.62 (29.6 mu g) for the HRCI, and 0.60 (48.7 mu g) for the MM10. Predicted exhaled dose fractions were greatest with the RX160 (0.60) and similar for the HCRI (0.34) and MM10 (0.36). Hygroscopic modeling thus suggests that the exhaled dose obtained during methacholine challenge testing is considerable, with the characteristics of the nebulizer influencing the relative proportion of the dose that is exhaled.

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.

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. 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. No filter (lung) deposition was detected for NasalCrom or Nasonex. Filter deposition ranged from 6 to 11

To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol with in silico deposition models. Such a two step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extrathoracic, tracheobronchial and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.

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).

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.

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.

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.

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.

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.