Comparative performance study of paperboard disposable spacers versus commercial valved holding chambers for aerosol delivery.

PURPOSE: The aim of this study is to evaluate and compare the performance, for the administration of fluticasone propionate with a pressurized metered-dose inhaler (pMDI), of two low-tech paperboard spacers versus two commercially available valved holding chambers (VHC). METHODS: According to the Canadian standard CAN/CSA-Z264.1-02, total emitted dose (TED) and aerodynamic size distribution were measured for the pMDI in combination with 4 different spacers: a homemade paper cup spacer, the DispozABLE® paperboard spacer, the AeroChamber Plus® plastic VHC, and the Vortex® aluminium VHC. RESULTS: The two disposable paperboard spacers had a lower TED compared to the aluminium VHC, but delivered more than 2.5 times the dose of fluticasone than the commercial plastic VHC. The 3 antistatic devices (i.e. the aluminium VHC, the paperboard DispozABLE® spacer and the paper cup spacer) delivered a significantly higher dose of fine particles than the less antistatic plastic VHC. Their fine particle fraction was statistically similar to that obtained with pMDI without spacer. This respirable fraction ensures an optimal therapeutic effect. All spacers limited the flow of coarse particles, thus avoiding adverse effects on the trachea and oropharynx. CONCLUSION: We have shown that inexpensive and low-tech paperboard spacers are interesting alternatives for the administration of aerosols.

Aerosol Delivery Efficiency With High-Flow Nasal Cannula Therapy in Neonatal, Pediatric, and Adult Nasal Upper-Airway and Lung Models.

BACKGROUND: High-flow nasal cannula (HFNC) systems employ different methods to provide aerosol to patients. This study compared delivery efficiency, particle size, and regional deposition of aerosolized bronchodilators during HFNC in neonatal, pediatric, and adult upper-airway and lung models between a proximal aerosol adapter and distal aerosol circuit chamber. METHODS: A filter was connected to the upper airway to a spontaneously breathing lung model. Albuterol was nebulized using the aerosol adapter and circuit at different clinical flow settings. The aerosol mass deposited in the upper airway and lung was quantified. Particle size was measured with a laser diffractometer. Regional deposition was assessed with a gamma camera at each nebulizer location and patient model with minimum flow settings. RESULTS: Inhaled lung doses ranged from 0.2-0.8% for neonates, 0.2-2.2% for the small child, and 0.5-5.2% for the adult models. Neonatal inhaled lung doses were not different between the aerosol circuit and adapter, but the aerosol circuit showed marginally greater lung doses in the pediatric and adult patient models. Impacted aerosols and condensation in the non-heated HFNC and aerosol delivery components contributed to the dispersion of coarse liquid droplets, high deposition (11-44%), and occlusion of the supine neonatal upper airway. In contrast, the upright pediatric and adult upper-airway models had minimal deposition (0.3-7.0%) and high fugitive losses (∼24%) from liquid droplets leaking out of the nose. The high impactive losses in the aerosol adapter (56%) were better contained than in the aerosol circuit, resulting in less cannula sputter (5% vs 22%), fewer fugitive losses (18% vs 24%), and smaller inhaled aerosols (5 µm vs 13 µm). CONCLUSIONS: The inhaled lung dose was low (1-5%) during HFNC. Approaches that streamline aerosol delivery are needed to provide safe and effective therapy to patients receiving aerosolized medications with this HFNC system.

In Vitro Comparison of Aerosol Delivery in High-Frequency Assisted Airway Clearance Devices With Integrated Nebulizers.

BACKGROUND: High-frequency assisted airway clearance systems combine positive expiratory pressure or oscillatory positive airway pressure with integrated nebulizers to improve the delivery of aerosols and assist with airway clearance. This aerosol study evaluated lung delivery efficiency during positive expiratory pressure and oscillatory positive airway pressure therapy of 2 high-frequency assisted airway clearance/nebulizer systems. METHODS: Aerosol delivery was evaluated during positive expiratory pressure therapy of 10 cm H2O and oscillatory positive airway pressure therapy of 20 cm H2O with the BiWaze Clear and the Volara high-frequency assisted airway clearance/nebulizer systems. The handset and nebulizer were attached to an anatomic upper-airway model via a mouthpiece and placed into a plethysmograph. A tracheal filter was placed to capture the inhaled aerosol. A vacuum filter entrained fugitive aerosols from the plethysmograph. After nebulization of technetium in 3.0 mL normal saline solution, the components were scanned by using scintigraphy and the decay-corrected radiation counts were referenced to the initial nebulizer technetium charges. RESULTS: Aerosol delivery during positive expiratory pressure therapy of 10 cm H2O resulted in higher lung deposition with the BiWaze Clear versus the Volara (28 vs 6.2%; P < .001; 95% CI 16.5-27.7), and higher fugitive losses (23.7 vs 2.8%; P = .004) and nebulizer losses (55 vs 3.3%; P < .001) with the Volara than with the BiWaze Clear. Aerosol delivery during oscillatory positive airway pressure of 20 cm H2O resulted in a higher lung deposition with the BiWaze Clear versus the Volara (16.3 vs 7.3%; P = .005; 95% CI 3.3-15) and higher fugitive (22.3 vs 3.8%; P = .02) and nebulizer (58.8 vs 7.2%; P = .004) losses with the Volara. There were no differences at the other locations during testing. CONCLUSIONS: The BiWaze Clear system showed greater delivery efficiency than did the Volara during positive expiratory pressure and oscillatory positive airway pressure. The high residual nebulizer dose and fugitive aerosol losses through the handset leak valve contributed to the lower delivery efficiency observed with the Volara. The nebulizer type, circuit design, and handset are important factors when targeting effective aerosol delivery to the lungs with high-frequency assisted airway clearance therapy.

Numerical and experimental evaluation of nasopharyngeal aerosol administration methods in children with adenoid hypertrophy.

Administering aerosol drugs through the nasal pathway is a common early treatment for children with adenoid hypertrophy (AH). To enhance therapeutic efficacy, a deeper understanding of nasal drug delivery in the nasopharynx is essential. This study uses an integrated experimental, numerical modelling approach to investigate the delivery process of both the aerosol mask delivery system (MDS) and the bi-directional delivery system (BDS) in the pediatric nasal airway with AH. The combined effect of respiratory flow rates and particle size on delivery efficiency was systematically analyzed. The results showed that the nasopharyngeal peak deposition efficiency (DE) for BDS was approximately 2.25-3.73 times higher than that for MDS under low-flow, resting and high-flow respiratory conditions. Overall nasopharyngeal DEs for MDS were at a low level of below 16 %. For each respiratory flow rate, the BDS tended to achieve higher peak DEs (36.36 % vs 9.74 %, 37.80 % vs 14.01 %, 34.58 % vs 15.35 %) at smaller particle sizes (15 µm vs 17 µm, 10 µm vs 14 µm, 6 µm vs 9 µm). An optimal particle size exists for each respiratory flow rate, maximizing the drug delivery efficiency to the nasopharynx. The BDS is more effective in delivering drug aerosols to the nasal cavity and nasopharynx, which is crucial for early intervention in children with AH.

Practical Considerations in Dose Extrapolation from Animals to Humans.

Animal studies are an important component of drug product development and the regulatory review process since modern practices have been in place, for almost a century. A variety of experimental systems are available to generate aerosols for delivery to animals in both liquid and solid forms. The extrapolation of deposited dose in the lungs from laboratory animals to humans is challenging because of genetic, anatomical, physiological, pharmacological, and other biological differences between species. Inhaled drug delivery extrapolation requires scrutiny as the aerodynamic behavior, and its role in lung deposition is influenced not only by the properties of the drug aerosol but also by the anatomy and pulmonary function of the species in which it is being evaluated. Sources of variability between species include the formulation, delivery system, and species-specific biological factors. It is important to acknowledge the underlying variables that contribute to estimates of dose scaling between species.

Tracheomalacia Reduces Aerosolized Drug Delivery to the Lung.

Rationale: Neonates with respiratory issues are frequently treated with aerosolized medications to manage lung disease or facilitate airway clearance. Dynamic tracheal collapse (tracheomalacia [TM]) is a common comorbidity in these patients, but it is unknown whether the presence of TM alters the delivery of aerosolized drugs. Objectives: To quantify the effect of neonatal TM on the delivery of aerosolized drugs. Methods: Fourteen infant subjects with respiratory abnormalities were recruited; seven with TM and seven without TM. Respiratory-gated 3D ultrashort echo time magnetic resonance imaging (MRI) was acquired covering the central airway and lungs. For each subject, a computational fluid dynamics simulation modeled the airflow and particle transport in the central airway based on patient-specific airway anatomy, motion, and airflow rates derived from MRI. Results: Less aerosolized drug reached the distal airways in subjects with TM than in subjects without TM: of the total drug delivered, less particle mass passed through the main bronchi in subjects with TM compared with subjects without TM (33% vs. 47%, p = 0.013). In subjects with TM, more inhaled particles were deposited on the surface of the airway (48% vs. 25%, p = 0.003). This effect becomes greater with larger particle sizes and is significant for particles with a diameter >2 µm (2-5 µm, p ≤ 0.025 and 5-15 µm, p = 0.004). Conclusions: Neonatal patients with TM receive less aerosolized drug delivered to the lungs than subjects without TM. Currently, infants with lung disease and TM may not be receiving adequate and/or expected medication. Particles >2 µm in diameter are likely to deposit on the surface of the airway due to anatomical constrictions such as reduced tracheal and glottal cross-sectional area in neonates with TM. This problem could be alleviated by delivering smaller aerosolized particles.

Inhaled drug delivery: a randomized study in intubated patients with healthy lungs.

BACKGROUND: The administration technique for inhaled drug delivery during invasive ventilation remains debated. This study aimed to compare in vivo and in vitro the deposition of a radiolabeled aerosol generated through four configurations during invasive ventilation, including setups optimizing drug delivery. METHODS: Thirty-one intubated postoperative neurosurgery patients with healthy lungs were randomly assigned to four configurations of aerosol delivery using a vibrating-mesh nebulizer and specific ventilator settings: (1) a specific circuit for aerosol therapy (SCAT) with the nebulizer placed at 30 cm of the wye, (2) a heated-humidified circuit switched off 30 min before the nebulization or (3) left on with the nebulizer at the inlet of the heated-humidifier, (4) a conventional circuit with the nebulizer placed between the heat and moisture exchanger filter and the endotracheal tube. Aerosol deposition was analyzed using planar scintigraphy. RESULTS: A two to three times greater lung delivery was measured in the SCAT group, reaching 19.7% (14.0-24.5) of the nominal dose in comparison to the three other groups (p < 0.01). Around 50 to 60% of lung doses reached the outer region of both lungs in all groups. Drug doses in inner and outer lung regions were significantly increased in the SCAT group (p < 0.01), except for the outer right lung region in the fourth group due to preferential drug trickling from the endotracheal tube and the trachea to the right bronchi. Similar lung delivery was observed whether the heated humidifier was switched off or left on. Inhaled doses measured in vitro correlated with lung doses (R = 0.768, p < 0.001). CONCLUSION: Optimizing the administration technique enables a significant increase in inhaled drug delivery to the lungs, including peripheral airways. Before adapting mechanical ventilation, studies are required to continue this optimization and to assess its impact on drug delivery and patient outcome in comparison to more usual settings.

A direct contact pig influenza challenge model for assessing protective efficacy of monoclonal antibodies.

Monoclonal antibodies (mAbs) can be used to complement immunization for the therapy of influenza virus infection. We have established the pig, a natural large animal host for influenza A, with many physiological, immunological, and anatomical similarities to humans, as an appropriate model for testing mAbs. We have evaluated the protective efficacy of the strongly neutralizing human anti-hemagglutinin mAb, 2-12C in the pig influenza model. Intravenous administration of recombinant 2-12C reduced virus load and lung pathology, however, it did not prevent virus nasal shedding and, consequently, transmission. This may be because the pigs were directly infected intranasally with a high dose of the H1N1pdm09 virus. To address this, we developed a contact challenge model in which the animals were given 2-12C and one day later co-housed with donor pigs previously infected intra-nasally with H1N1pdm09. 2-12C pre-treatment completely prevented infection. We also administered a lower dose of 2-12C by aerosol to the respiratory tract, but this did not prevent shedding in the direct challenge model, although it abolished lung infection. We propose that the direct contact challenge model of pig influenza may be useful for evaluating candidate mAbs and emerging delivery platforms prior to clinical trials.

Evaluation of a Novel Dry Powder Surfactant Aerosol Delivery System for Use in Premature Infants Supported with Bubble CPAP.

Aerosolized lung surfactant therapy during nasal continuous positive airway pressure (CPAP) support avoids intubation but is highly complex, with reported poor nebulizer efficiency and low pulmonary deposition. The study objective was to evaluate particle size, operational compatibility, and drug delivery efficiency with various nasal CPAP interfaces and gas humidity levels of a synthetic dry powder (DP) surfactant aerosol delivered by a low-flow aerosol chamber (LFAC) inhaler combined with bubble nasal CPAP (bCPAP). A particle impactor characterized DP surfactant aerosol particle size. Lung pressures and volumes were measured in a preterm infant nasal airway and lung model using LFAC flow injection into the bCPAP system with different nasal prongs. The LFAC was combined with bCPAP and a non-heated passover humidifier. DP surfactant mass deposition within the nasal airway and lung was quantified for different interfaces. Finally, surfactant aerosol therapy was investigated using select interfaces and bCPAP gas humidification by active heating. Surfactant aerosol particle size was 3.68 µm. Lung pressures and volumes were within an acceptable range for lung protection with LFAC actuation and bCPAP. Aerosol delivery of DP surfactant resulted in variable nasal airway (0-20%) and lung (0-40%) deposition. DP lung surfactant aerosols agglomerated in the prongs and nasal airways with significant reductions in lung delivery during active humidification of bCPAP gas. Our findings show high-efficiency delivery of small, synthetic DP surfactant particles without increasing the potential risk for lung injury during concurrent aerosol delivery and bCPAP with passive humidification. Specialized prongs adapted to minimize extrapulmonary aerosol losses and nasal deposition showed the greatest lung deposition. The use of heated, humidified bCPAP gases compromised drug delivery and safety. Safety and efficacy of DP aerosol delivery in preterm infants supported with bCPAP requires more research.

Nebulization of Model Hydrogel Nanoparticles to Macrophages at the Air-Liquid Interface.

Nanoparticle evaluation within the pulmonary airspace has increasingly important implications for human health, with growing interest from drug delivery, environmental, and toxicology fields. While there have been widespread investigations of nanoparticle physiochemical properties following many routes of administration, nanoparticle behavior at the air-liquid interface (ALI) is less well-characterized. In this work, we fabricate two formulations of poly(ethylene)-glycol diacrylate (PEGDA)-based model nanoparticles to establish an in vitro workflow allowing evaluation of nanoparticle charge effects at the ALI. Both cationic and anionic PEGDA formulations were synthesized with similar hydrodynamic diameters around ~225 nm and low polydispersity, with expected surface charges corresponding with the respective functional co-monomer. We find that both formulations are readily nebulized from an aqueous suspension in a commercial Aeroneb® Lab Nebulizer, but the aqueous delivery solution served to slightly increase the overall hydrodynamic and geometric size of the cationic particle formulation. However, nanoparticle loading at 50 µg/ml of either formulation did not influence the resultant aerosol diameter from the nebulizer. To assess aerosol delivery in vitro, we designed a 3D printed adapter capable of ensuring aerosol delivery to transwell 24-well culture plates. Nanoparticle uptake by macrophages was compared between traditional cell culture techniques and that of ALI-cultured macrophages following aerosol delivery. Cell viability was unaffected by nanoparticle delivery using either method. However, only traditional cell culture methods demonstrated significant uptake that was dependent on the nanoparticle surface charge. Concurrently, ALI culture resulted in lower metabolic activity of macrophages than those in traditional cell culture, leading to lower overall nanoparticle uptake at ALI. Overall, this work demonstrates that base-material similarities between both particle formulations provide an expected consistency in aerosol delivery regardless of the nanoparticle surface charge and provides an important workflow that enables a holistic evaluation of aerosolizable nanoparticles.

Assessment of Scanning Mobility Particle Sizer (SMPS) for online monitoring of delivered dose in an in vitro aerosol exposure system.

Real-time monitoring of dosimetry is critical to mitigating the constraints of offline measurements. To address this need, the use of the Scanning Mobility Particle Sizer (SMPS) to estimate the dose delivered through the Dosimetric Aerosol in Vitro Inhalation Device (DAVID) was assessed. CuO nanoparticles suspended in ethanol at different concentrations (0.01-10 mg/mL) were aerosolized using a Collison nebulizer and diluted with air at a ratio of either 1:3 (setup 1) or 1:18 (setup 2). From the aerosol volume concentrations measured by the SMPS, density of CuO (6.4 g/cm3), collection time (5-30 min), flow rate (0.5 LPM) and deposition area (0.28 cm2), the mass doses (DoseSMPS) were observed to increase exponentially over time and ranged from 0.02 ± 0.001 to 84.75 ± 3.49 µg/cm2. The doses calculated from the Cu concentrations determined by Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES) (DoseICP) also increased exponentially over time (0.01 ± 0.01-97.25 ± 1.30 µg/cm2). Regression analysis between DoseICP and DoseSMPS showed R2 ≥ 0.90 for 0.1-10 mg/mL. As demonstrated, the SMPS can be used to monitor the delivered dose in real-time, and controlled delivery of mass doses with a 226-fold range can be attained in ≤30 min in DAVID by adjusting the nebulizer concentration, dilution air and time.

Advancement of a high-dose infant air-jet dry powder inhaler (DPI) with passive cyclic loading: Performance tuning for different formulations.

There is a current medical need for a dry powder aerosol delivery device that can be used to efficiently and consistently administer high dose therapeutics, such as inhaled antibiotics, surfactants and antivirals, to the lungs of infants. This study considered an infant air-jet dry powder inhaler (DPI) that could be actuated multiple times with minimal user interaction (i.e., a passive cyclic loading strategy) and focused on the development of a metering system that could be tuned for individual powder formulations to maintain high efficiency lung delivery. The metering system consisted of a powder delivery tube (PDT) connecting a powder reservoir with an aerosolization chamber and a powder supporting shelf that held a defined formulation volume. Results indicated that the metering system could administer a consistent dose per actuation after reaching a steady state condition. Modifications of the PDT diameter and shelf volume provided a controllable approach that could be tuned to maximize lung delivery efficiency for three different formulations. Using optimized metering system conditions for each formulation, the infant air-jet DPI was found to provide efficient and consistent lung delivery of aerosols (∼45% of loaded dose) based on in vitro testing with a preterm nose-throat model and limited dose/actuation to <5 mg.

Aerosolized miR-138-5p and miR-200c targets PD-L1 for lung cancer prevention.

The development of chemopreventive strategies with the ability to prevent the progression of lung lesions to malignant cancers would reduce the mortality and morbidity resulting from this deadly disease. Delivery of microRNA (miRNA) by inhalation is a novel method for lung cancer prevention. In this study, we investigated the combined efficacy of aerosolized miR-138-5p and miR-200c miRNA mimics in lung cancer prevention. Combination of the two miRNAs inhibited Benzo(a)pyrene (B((a))P)-induced lung adenomas and N-nitroso-tris-chloroethylurea (NTCU)-induced lung squamous cell carcinomas with no detectable side effects. Using single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC), we found that both miRNAs inhibited programmed cell death ligand 1 (PD-L1) expression. Our flow cytometry results showed that aerosolized delivery of combined miRNAs increased CD4+ and CD8+ T cells and reduced the expression of programmed cell death protein 1 (PD-1) and T-regulatory cells. Our results demonstrated that the delivery of aerosolized microRNAs targeting PD-L1 can be highly effective in preventing lung cancer development and progression in mice.

Effects of different mesh nebulizer sources on the dispersion of powder formulations produced with a new small-particle spray dryer.

The objective of this study was to explore the aerosolization performance of powders produced with different mesh nebulizer sources in the initial design of a new small-particle spray dryer system. An aqueous excipient enhanced growth (EEG) model formulation was spray dried using different mesh sources and the resulting powders were characterized based on (i) laser diffraction, (ii) aerosolization with a new infant air-jet dry powder inhaler, and (iii) aerosol transport through an infant nose-throat (NT) model ending with a tracheal filter. While few differences were observed among the powders, the medical-grade Aerogen Solo (with custom holder) and Aerogen Pro mesh sources were selected as lead candidates that produced mean fine particle fractions <5 µm and <1 µm in ranges of 80.6-77.4% and 13.1-16.0%, respectively. Improved aerosolization performance was achieved at a lower spray drying temperature. Lung delivery efficiencies through the NT model were in the range of 42.5-45.8% for powders from the Aerogen mesh sources, which were very similar to previous results with a commercial spray dryer. Ultimately, a custom spray dryer that can accept meshes with different characteristics (e.g., pore sizes and liquid flow rates) will provide particle engineers greater flexibility in producing highly dispersible powders with unique characteristics.

Aerosolized sulfated hyaluronan derivatives prolong the survival of K18 ACE2 mice infected with a lethal dose of SARS-CoV-2.

Despite several vaccines that are currently approved for human use to control the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent medical need for therapeutic and prophylactic options. SARS-CoV-2 binding and entry in human cells involves interactions of its spike (S) protein with several host cell surface factors, including heparan sulfate proteoglycans (HSPGs), transmembrane protease serine 2 (TMPRSS2), and angiotensin-converting enzyme 2 (ACE2). In this paper we investigated the potential of sulphated Hyaluronic Acid (sHA), a HSPG mimicking polymer, to inhibit the binding of SARS-CoV-2 S protein to human ACE2 receptor. After the assessment of different sulfation degree of sHA backbone, a series of sHA functionalized with different hydrophobic side chains were synthesized and screened. The compound showing the highest binding affinity to the viral S protein was further characterized by surface plasmon resonance (SPR) towards ACE2 and viral S protein binding domain. Selected compounds were formulated as solutions for nebulization and, after being characterized in terms of aerosolization performance and droplet size distribution, their efficacy was assessed in vivo using the K18 human (h)ACE2 transgenic mouse model of SARS-CoV-2 infection.

Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder.

Treprostinil palmitil (TP), a prodrug of treprostinil, is being developed as an inhalation powder (TPIP) for the treatment of patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to interstitial lung disease (PH-ILD). In ongoing human clinical trials, TPIP is administered via a commercially available high resistance (HR) RS01 capsule-based dry powder inhaler (DPI) device manufactured by Berry Global (formerly Plastiape), which utilizes the patient's inspiratory flow to provide the required energy to deagglomerate and disperse the powder for delivery to their lungs. In this study, we characterized the aerosol performance of TPIP in response to changes in inhalation profiles to model more realistic use scenarios, i.e., for reduced inspiratory volumes and with inhalation acceleration rates that differ from those described in the compendia. The emitted dose of TP for all combinations of inhalation profiles and volumes ranged narrowly between 79 and 89% for the 16 and 32 mg TPIP capsules at the 60 LPM inspiratory flow rate but was reduced to 72-76% for the 16 mg TPIP capsule under the scenarios at the 30 LPM peak inspiratory flow rate. There were no meaningful differences in the fine particle dose (FPD) at all conditions at 60 LPM with the 4 L inhalation volume. The FPD values for the 16 mg TPIP capsule ranged narrowly between 60 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L, while the FPD values for the 32 mg TPIP capsule ranged between 53 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L for the 60 LPM flow rate. At the 30 LPM peak flow rate, the FPD values for the 16 mg TPIP capsule ranged narrowly between 54 and 58% of the loaded dose at both extremes of the ramp rates for inhalation volumes down to 1 L. Based on these in vitro findings, the TPIP delivery system appears not to be affected by the changes in inspiratory flow profiles or inspiratory volumes that might be expected to occur in patients with PAH or PH associated with underlying lung conditions such as ILD.

Assessing of low-tech solutions for aerosol delivery: Comparative performance study of manufactured versus homemade spacers.

PURPOSE: This study aims to evaluate the performance of low-cost homemade spacers compared with manufactured valved holding chambers (VHCs) for fluticasone propionate delivery via a pMDI (pressurized Metered Dose Inhaler). METHODS: The Total Emitted Dose (TED) and particle size distribution were measured for pMDI alone or connected to the different spacers, according to CAN/CSA-Z264.1-02 standard. Two types of low-cost alternative and manufactured spacers were investigated: 500 mL plastic bottle and 553 mL aluminium can; non-antistatic plastic VHCs and aluminium antistatic VHCs. RESULTS: The TED of homemade plastic bottle vs plastic VHC were similar in the 20-23% range. In contrast, the TED of homemade aluminium can was higher compared to aluminium VHC (83% vs 68%). The Fine Particle Fraction (FPF) was similar for the two plastic-based spacers (in the 12.68-17.60% range), although it was greater for the aluminium can compared to aluminium VHC (51% vs 42%). However, all spacers have limited large particles fraction, mainly deposited in the oropharyngeal tract, potentially decreasing side effects. CONCLUSION: We demonstrated that low-tech solutions as homemade spacers have at least similar performances to VHC medical devices composed of same material (aluminium or plastic). Thus, low-cost homemade spacers represent alternatives in case of emergency and without VHCs nearby.

In Vitro Evaluation of Nebulized Pharmaceutical Aerosol Delivery to the Lungs Using a New Heated Dryer System (HDS).

The objective of this study was to develop a new heated dryer system (HDS) for high efficiency lung delivery of nebulized aerosol and demonstrate performance with realistic in vitro testing for trans-nasal aerosol administration simultaneously with high-flow nasal cannula (HFNC) therapy and separately for direct oral inhalation (OI) of the aerosol. With the HDS-HFNC and HDS-OI platforms, new active synchronization control routines were developed to sense subject inhalation and coordinate drug aerosol delivery. In vitro experiments were conducted to predict regional drug loss and lung delivery efficiency in systems that included the HDS with various patient interfaces, realistic airway models, and simulated breathing waveforms. For the HDS-HFNC platform and a repeating breathing waveform, total system loss was < 10%, extrathoracic deposition was approximately 6%, and best-case lung delivery efficiency was 75-78% of nebulized dose. Inclusion of randomized breathing with the HFNC system decreased lung delivery efficiency by ~ 10% and had no impact on nasal depositional loss. For the HDS-OI platform and best-case mouthpiece, total system loss was < 8%, extrathoracic deposition was < 1%, and lung delivery efficiency was > 90% of nebulized dose. Normal vs. deep randomized oral inhalation had little impact on performance of the HDS-OI platform and environmental aerosol loss was negligible. In conclusion, both platforms demonstrated the potential for high efficiency lung delivery of the aerosol with the HDS-OI platform having the added advantages of nearly eliminating extrathoracic deposition, being insensitive to breathing waveform, and preventing environmental aerosol loss.

Development of a High-Dose Infant Air-Jet Dry Powder Inhaler (DPI) with Passive Cyclic Loading of the Formulation.

PURPOSE: The objective of this study was to incorporate a passive cyclic loading strategy into the infant air-jet dry powder inhaler (DPI) in a manner that provides high efficiency aerosol lung delivery and is insensitive to powder mass loadings and the presence of downstream pulmonary mechanics. METHODS: Four unique air-jet DPIs were initially compared and the best performing passive design (PD) was selected for sensitivity analyses. A single preterm in vitro nose-throat (NT) model, air source, and nasal interface were utilized throughout. While the majority of analyses were evaluated with a model spray-dried excipient enhanced growth (EEG) formulation, performance of a Surfactant-EEG formulation was also explored for the lead DPI design. RESULTS: Two devices, PD-2 and PD-3, evaluated in the preterm model achieved an estimated lung delivery efficiency of 60% with the model EEG formulation, and were not sensitive to the loaded dose (10-30 mg of powder). The PD-3 device was also unaffected by the presence of downstream pulmonary mechanics (infant lung model) and had only a minor sensitivity to tripling the volume of the powder reservoir. When using the Surfactant-EEG formulation, increasing the actuation flow rate from 1.7 to 4.0 L/min improved lung delivery by nearly 10%. CONCLUSIONS: The infant air-jet DPI platform was successfully modified with a passive cyclic loading strategy and capable of providing an estimated > 60% lung delivery efficiency of a model spray-dried formulation with negligible sensitivity to powder mass loading in the range of 10-30 mg and could be scaled to deliver much higher doses.