Development of an effective two-equation turbulence modeling approach for simulating aerosol deposition across a range of turbulence levels.

Pharmaceutical aerosol systems present a significant challenge to computational fluid dynamics (CFD) modeling based on the need to capture multiple levels of turbulence, frequent transition between laminar and turbulent flows, anisotropic turbulent particle dispersion, and near-wall particle transport phenomena often within geometrically complex systems over multiple time scales. Two-equation turbulence models, such as the k-ω family of approximations, offer a computationally efficient solution approach, but are known to require the use of near-wall (NW) corrections and eddy interaction model (EIM) modifications for accurate predictions of aerosol deposition. The objective of this study was to develop an efficient and effective two-equation turbulence modeling approach that enables accurate predictions of pharmaceutical aerosol deposition across a range of turbulence levels. Key systems considered were the traditional aerosol deposition benchmark cases of a 90-degree bend (Re=6,000) and a vertical straight section of pipe (Re=10,000), as well as a highly complex case of direct-to-infant (D2I) nose-to-lung pharmaceutical aerosol delivery from an air-jet dry powder inhaler (DPI) including a patient interface and infant nasal geometry through mid-trachea (500

Development of uniform fenofibrate-loaded biodegradable microparticle by membrane emulsification.

Fenofibrate has shown therapeutic effects on diabetic retinopathy. However, fenofibrate can be rapidly cleared from the eye after a single intravitreal injection. Here, we aim to develop fenofibrate loaded PLGA microparticles (Feno-MP) with high drug loading and sustained in vitro release up to 6 months suitable for intravitreal injection. First, orthogonal array experimental design was applied for formulation optimization. The selected formulation parameters were used to formulate Feno-MP using homogenization method and direct membrane emulsification method. Both methods generated Feno-MP with high drug loading and sustained in vitro drug release more than 140 days. Unlike the polydisperse Feno-MP prepared using homogenization method, membrane emulsification method generated Feno-MP with uniform size distribution. By controlling the membrane pore size, 1.5 µm, 8 µm and 16 µm Feno-MP were formulated and we found that larger Feno-MP demonstrated higher drug loading, more sustained drug release in vitro with less burst drug release than the smaller Feno-MP. In conclusion, we developed Feno-MP with high drug loading and sustained release profile, and elucidated that changing the particle size could have notable impacts on drug loading and release kinetics. Formulating Feno-MP with uniform size distribution by membrane emulsification method would benefit the batch-to-batch repeatability.

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.

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.

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.

Characterizing the Effects of Nasal Prong Interfaces on Aerosol Deposition in a Preterm Infant Nasal Model.

The objective of this study was to characterize the effects of multiple nasal prong interface configurations on nasal depositional loss of pharmaceutical aerosols in a preterm infant nose-throat (NT) airway model. Benchmark in vitro experiments were performed in which a spray-dried powder formulation was delivered to a new preterm NT model with a positive-pressure infant air-jet dry powder inhaler using single- and dual-prong interfaces. These results were used to develop and validate a computational fluid dynamics (CFD) model of aerosol transport and deposition in the NT geometry. The validated CFD model was then used to explore the NT depositional characteristic of multiple prong types and configurations. The CFD model highlighted a turbulent jet effect emanating from the prong(s). Analysis of NT aerosol deposition efficiency curves for a characteristic particle size and delivery flowrate (3 µm and 1.4 L/min (LPM)) revealed little difference in NT aerosol deposition fraction (DF) across the prong insertion depths of 2-5 mm (DF = 16-24%) with the exception of a single prong with 5-mm insertion (DF = 36%). Dual prongs provided a modest reduction in deposition vs. a single aerosol delivery prong at the same flow for insertion depths < 5 mm. The presence of the prongs increased nasal depositional loss by absolute differences in the range of 20-70% compared with existing correlations for ambient aerosols. In conclusion, the use of nasal prongs was shown to have a significant impact on infant NT aerosol depositional loss prompting the need for prong design alterations to improve lung delivery efficiency.

In Vitro Analysis of Nasal Interface Options for High-Efficiency Aerosol Administration to Preterm Infants.

Background: An infant air-jet dry powder inhaler (DPI) platform has recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high-efficiency aerosolization with low actuation air volumes. The objective of this study was to investigate modifications to the nasal interface section of this platform to improve the aerosol delivery performance through preterm nose-throat (NT) models. Methods: Aerosol delivery performance of multiple nasal interface flow pathways and prong configurations was assessed with two in vitro preterm infant NT models. Two excipient-enhanced growth (EEG) dry powder formulations were explored containing either l-leucine or trileucine as the dispersion enhancer. Performance metrics included aerosol depositional loss in the nasal interface, deposition in the NT models, and tracheal filter deposition, which was used to estimate lung delivery efficiency. Results: The best performing nasal interface replaced the straight flexible prong of the original gradual expansion design with a rigid curved prong (∼20° curvature). The prong modification increased the lung delivery efficiency by 5%-10% (absolute difference) depending on the powder formulation. Adding a metal mesh to the flow pathway, to dissipate the turbulent jet, also improved lung delivery efficiency by ∼5%, while reducing the NT depositional loss by a factor of over twofold compared with the original nasal interface. The platform was also found to perform similarly in two different preterm NT models, with no statistically significant difference between any of the performance metrics. Conclusions: Modifications to the nasal interface of an infant air-jet DPI improved the aerosol delivery through multiple infant NT models, providing up to an additional 10% lung delivery efficiency (absolute difference) with the lead design delivering ∼57% of the loaded dose to the tracheal filter, while performance in two unique preterm airway geometries remained similar.

The Challenges and Opportunities in the Development of MicroRNA Therapeutics: A Multidisciplinary Viewpoint.

microRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the moderate efficacy of miR inhibitors, cell type-specific delivery, and adverse outcomes have impeded the development of miR therapeutics. These hurdles are rooted in the functional complexity of miR's role in disease and sequence complementarity-dependent/-independent effects in nontarget tissues. The advances in understanding miR's role in disease, the development of efficient miR inhibitors, and innovative delivery approaches have helped resolve some of these hurdles. In this review, we provide a multidisciplinary viewpoint on the challenges and opportunities in the development of miR therapeutics.

Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization.

Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C/15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance.

Advancement of the Infant Air-Jet Dry Powder Inhaler (DPI): Evaluation of Different Positive-Pressure Air Sources and Flow Rates.

PURPOSE: In order to improve the delivery of dry powder aerosol formulations to the lungs of infants, this study implemented an infant air-jet platform and explored the effects of different air sources, flow rates, and pulmonary mechanics on aerosolization performance and aerosol delivery through a preterm nose-throat (NT) in vitro model. METHODS: The infant air-jet platform was actuated with a positive-pressure air source that delivered the aerosol and provided a full inhalation breath. Three different air sources were developed to provide highly controllable positive-pressure air actuations (using actuation volumes of ~10 mL for the preterm model). While providing different flow waveform shapes, the three air sources were calibrated to produce the same flow rate magnitude (Q90: 90th percentile of flow rate). Multiple air-jet DPI designs were coupled with the air sources and evaluated with a model spray-dried excipient enhanced growth formulation. RESULTS: Compared to other designs, the D1-Single air-jet DPI provided improved performance with low variability across all three air sources. With the tested D1-Single air-jet and Timer air source, reducing the flow rate from 4 to 1.7 L/min marginally decreased the aerosol size and significantly increased the lung delivery efficiency above 50% of the loaded dose. These results were not impacted by the presence of downstream pulmonary mechanics (resistance and compliance model). CONCLUSIONS: The selected design was capable of providing an estimated >50% lung delivery efficiency of a model spray-dried formulation and was not influenced by the air source, thereby enabling greater flexibility for platform deployment in different environments.

Performance of Low Air Volume Dry Powder Inhalers (LV-DPI) when Aerosolizing Excipient Enhanced Growth (EEG) Surfactant Powder Formulations.

Efficient delivery of dry powder aerosols dispersed with low volumes of air is challenging. This study aims to develop an efficient dry powder inhaler (DPI) capable of delivering spray-dried Survanta-EEG powders (3-10 mg) with a low volume (3 mL) of dispersion air. A series of iterative design modifications were made to a base low air volume actuated DPI. The modifications included the replacement of the original capsule chamber with an integral dose containment chamber, alteration of the entrainment air flow path through the device (from single-sided (SS) to straight through (ST)), change in the number of air inlet holes (from one to three), varying the outlet delivery tube length (45, 55, and 90 mm) and internal diameter (0.60, 0.89, and 1.17 mm). The modified devices were evaluated by determining the influence of the modifications and powder fill mass on aerosol performance of spray-dried Survanta-EEG powders. The optimal DPI was also evaluated for its ability to aerosolize a micronized powder. The optimized dose containment unit DPI had a 0.21 mL powder chamber, ST airflow path, three-0.60 mm air inlet holes, and 90 mm outlet delivery tube with 0.89 mm internal diameter. The powder dispersion characteristics of the optimal device were independent of fill mass with good powder emptying in one 3 mL actuation. At 10 mg fill mass, this device had an emitted mass of 5.3 mg with an aerosol Dv50 of 2.7 µm. After three 3 mL actuations, >85% of the spray-dried powder was emitted from the device. The emitted mass of the optimal device with micronized albuterol sulfate was >72% of the nominal fill mass of 10 mg in one 3 mL actuation. Design optimization produced a DPI capable of efficient performance with a dispersion air volume of 3 mL to aerosolize Survanta-EEG powders.

Development and Characterization of Excipient Enhanced Growth (EEG) Surfactant Powder Formulations for Treating Neonatal Respiratory Distress Syndrome.

This study aimed to develop and characterize a spray-dried powder aerosol formulation of a commercially available surfactant formulation, Survanta® intratracheal suspension, using the excipient enhanced growth (EEG) approach. Survanta EEG powders were prepared by spray drying of the feed dispersions containing Survanta® (beractant) intratracheal suspension, hygroscopic excipients (mannitol and sodium chloride), and a dispersion enhancer (l-leucine or trileucine) in 5 or 20% v/v ethanol in water using the Buchi Nano Spray Dryer B-90 HP. Powders were characterized for primary particle size, morphology, phospholipid content, moisture content, thermal properties, moisture sorption, and surface activity. The aerosol performance of the powders was assessed using a novel low-volume dry powder inhaler (LV-DPI) device operated with 3-mL volume of dispersion air. At both ethanol concentrations, in comparison to trileucine, l-leucine significantly reduced the primary particle size and span and increased the fraction of submicrometer particles of the Survanta EEG powders. The l-leucine-containing Survanta EEG powders exhibited good aerosolization performance with ≥ 88% of the mass emitted (% nominal) after 3 actuations from the modified LV-DPI device. In addition, l-leucine-containing powders had a low moisture content (< 3% w/w) with transition temperatures close to the commercial surfactant formulation and retained their surface tension reducing activity after formulation processing. A Survanta EEG powder containing l-leucine was developed which showed efficient aerosol delivery from the modified LV-DPI device using a low dispersion air volume.

Excipient Enhanced Growth Aerosol Surfactant Replacement Therapy in an In Vivo Rat Lung Injury Model.

Background: In neonatal respiratory distress syndrome, breathing support and surfactant therapy are commonly used to enable the alveoli to expand. Surfactants are typically delivered through liquid instillation. However, liquid instillation does not specifically target the small airways. We have developed an excipient enhanced growth (EEG) powder aerosol formulation using Survanta®. Methods: EEG Survanta powder aerosol was delivered using a novel dry powder inhaler via tracheal insufflation to surfactant depleted rats at nominal doses of 3, 5, 10, and 20 mg of powder containing 0.61, 0.97, 1.73, and 3.46 mg of phospholipids (PL), whereas liquid Survanta was delivered via syringe instillation at doses of 2 and 4 mL/kg containing 18.6 and 34 mg of PL. Ventilation mechanics were measured before and after depletion, and after treatment. We hypothesized that EEG Survanta powder aerosol would improve lung mechanics compared with instilled liquid Survanta in surfactant depleted rats. Results and Conclusion: EEG Survanta powder aerosol at a dose of 0.61 mg PL significantly improved lung compliance and elastance compared with the liquid Survanta at a dose of 18.6 mg, which represents improved primary efficacy of the aerosol at a 30-fold lower dose of PL. There was no significant difference in white blood cell count of the lavage from the EEG Survanta group compared with liquid Survanta. These results provide an in vivo proof-of-concept for EEG Survanta powder aerosol as a promising method of surfactant replacement therapy.

Inhalable Dry Powder of Bedaquiline for Pulmonary Tuberculosis: In Vitro Physicochemical Characterization, Antimicrobial Activity and Safety Studies.

Bedaquiline is a newly developed anti-tuberculosis drug, conditionally approved by the United States Food and Drug Administration (USFDA) for treating drug-resistant tuberculosis in adults. Oral delivery of bedaquiline causes severe side effects such as increased hepatic aminotransferase levels and cardiac arrhythmias (prolongation of QT-interval). This study aimed to develop inhalable dry powder particles of bedaquiline with high aerosolization efficiency to reduce the side-effects of oral bedaquiline. Bedaquiline (with or without l-leucine) powders were prepared using a Buchi Mini Spray-dryer. The powders were characterized for physicochemical properties and for their in vitro aerosolization efficiency using a next-generation impactor (NGI). The formulation with maximum aerosolization efficiency was investigated for physicochemical and aerosolization stability after one-month storage at 20 ± 2 °C/30 ± 2% relative humidity (RH) and 25 ± 2 °C/75% RH in an open Petri dish. The cytotoxicity of the powders on A549 and Calu-3 cell-lines was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The powders were also evaluated for antimicrobial activity against Mycobacterium tuberculosis. The aerodynamic diameter of the l-leucine-containing powder was 2.4 µm, and the powder was amorphous in nature. The aerosolization efficiency (fine-particle fraction) of l-leucine-containing powder (fine-particle fraction (FPF): 74.4%) was higher than the bedaquiline-only powder (FPF: 31.3%). l-leucine containing powder particles were plate-shaped with rough surfaces, but the bedaquiline-only powder was spherical and smooth. The optimized powder was stable at both storage conditions during one-month storage and non-toxic (up to 50 µg/mL) to the respiratory cell-lines. Bedaquiline powders were effective against Mycobacterium tuberculosis and had a minimal inhibitory concentration (MIC) value of 0.1 µg/mL. Improved aerosolization may help to combat pulmonary tuberculosis by potentially reducing the side-effects of oral bedaquiline. Further research is required to understand the safety of the optimized inhalable powder in animal models.

Bedaquiline containing triple combination powder for inhalation to treat drug-resistant tuberculosis.

Drug-resistant tuberculosis (DR-TB) is an emerging health problem, challenging the effective control of global TB. Current treatment of DR-TB includes administration of multiple anti-TB drugs via oral and parenteral routes for a duration of 20-28 months. High systemic exposure, side effects and lengthy treatment time are problems affecting current treatment. The success rate of current lengthy treatment regimens is generally <50%. Bedaquiline, a new anti-TB drug is synergistic with pyrazinamide and in combination with moxifloxacin accelerates sputum-culture conversion. Therefore, a triple combination of these drugs may have the potential to shorten the treatment time and improve treatment success. Additionally, inhalation of these drugs in combination may be advantageous due to the direct delivery to the lungs, possibly reducing systemic exposure. This study aimed to develop an inhalable triple combination powder of bedaquiline, moxifloxacin and pyrazinamide and study their physicochemical properties and safety. An inhalable (aerodynamic diameter: ≤2.4 µm) triple combination powder of bedaquiline, moxifloxacin and pyrazinamide with 20% w/w of L-leucine was prepared using a Buchi Mini Spray-Dryer. Combination powder consisted of spherical and porous particles. In vitro aerosolization (fine particle fraction, FPF) determined using a next generation impactor (NGI) showed improved FPF as a combination powder (>75.0%) when compared to single drug-only formulations (<45.0%). The powder was non-toxic to A549 and Calu-3 cells up to 100 µg/mL and stable at 30 ±â€¯2% RH and ambient room temperature during one-month storage. This is the first study reporting the development of inhalable triple combination powder of bedaquiline, moxifloxacin and pyrazinamide with high aerosolization efficiency. The improved aerosolization may help to deliver a high dose of these drugs to treat drug-resistant tuberculosis.

The influence of storage relative humidity on aerosolization of co-spray dried powders of hygroscopic kanamycin with the hydrophobic drug rifampicin.

The purpose of this study was to investigate the influence of storage humidity on in vitro aerosolization and physicochemical properties of co-spray dried powders of kanamycin with rifampicin. The powders were stored for one-month in an open Petri dish at different relative humidities (RHs) (15%, 43%, and 75%) and 25 ± 2 °C. The in vitro aerosolization (fine particle fraction, FPF) of the powders was determined by a next generation impactor (NGI). The moisture content, particle morphology and crystallinity of the powders were determined by Karl Fischer titration, scanning electron microscopy, and X-ray powder diffractometry, respectively. At all RH, the FPF of hydrophobic rifampicin-only powder was unaffected but the FPF of hygroscopic kanamycin-only powder significantly decreased even at 43% RH. The kanamycin-only particles fused together, crystallized and formed hard cakes at 75% RH. The aerosolization of kanamycin and rifampicin in the combination powders remained unaffected at 15% and 43% RH, but aerosolization significantly decreased at 75% RH. Enrichment of the surface of the particles with hydrophobic rifampicin did not protect the combination powders from moisture uptake but it prevented particle agglomeration up to 43% RH. At 75% RH, the moisture uptake led to agglomeration of the particles of the combination powder particles and consequently an increase in aerodynamic diameter. Further studies are required to investigate how rifampicin enrichment prevents particle agglomeration, the possible mechanisms (e.g. particle interactions due to capillary forces or electrostatic forces) for the changes in the aerosolization and changes in surface composition during storage.

Carrier-free combination dry powder inhaler formulation of ethionamide and moxifloxacin for treating drug-resistant tuberculosis.

This study aimed to develop a combination dry powder formulation of ethionamide and moxifloxacin HCl as this combination is synergistic against drug-resistant Mycobacterium tuberculosis (Mtb). L-leucine (20% w/w) was added in the formulations to maximize the process yield. Moxifloxacin HCl and/or ethionamide powders with/without L-leucine were produced using a Buchi Mini Spray-dryer. A next generation impactor was used to determine the in vitro aerosolization efficiency. The powders were also characterized for other physicochemical properties and cytotoxicity. All the spray-dried powders were within the aerodynamic size range of <5.0 µm except ethionamide-only powder (6.0 µm). The combination powders with L-leucine aerosolized better (% fine particle fraction (FPF): 61.3 and 61.1 for ethionamide and moxifloxacin, respectively) than ethionamide-only (%FPF: 9.0) and moxifloxacin-only (%FPF: 30.8) powders. The combination powder particles were collapsed with wrinkled surfaces whereas moxifloxacin-only powders were spherical and smooth and ethionamide-only powders were angular-shaped flakes. The combination powders had low water content (<2.0%). All the powders were physically stable at 15% RH and 25 ± 2 °C during 1-month storage and tolerated by bronchial epithelial cell-lines up to 100 µg/ml. The improved aerosolization of the combination formulation may be helpful for the effective treatment of drug-resistant tuberculosis. Further studies are required to understand the mechanisms for improved aerosolization and test the synergistic activity of the combination powder.

Mussel-inspired immobilization of Au on bare and graphene-wrapped Ni nanoparticles toward highly efficient and easily recyclable catalysts.

Bimetallic nanocatalysts have been gaining huge research attention in the heterogeneous catalysis community recently owing to their tunable properties and multifunctional characteristics. In this work, we fabricated a bimetallic core-shell nanocomposite catalyst by employing a mussel-inspired strategy for immobilizing gold nanoparticles (AuNP) on the surface of nickel nanoparticles (NiNP). NiNPs obtained from the reduction of Ni(ii) were first coated with polydopamine to provide the anchoring sites towards the robust immobilization of AuNPs. The as-synthesized nanocomposite (Ni-PD-Au) exhibited outstanding catalytic activity while reducing methylene blue (MB) and 4-nitrophenol (4-NP) yielding rate constants 13.11 min-1 and 4.21 min-1, respectively, outperforming the catalytic efficiency of its monometallic counterparts and other similar reported catalysts by large margins. The superior catalytic efficiency of the Ni-PD-Au was attributed to the well-known synergistic effect, which was experimentally investigated and compared with prior reports. Similar bio-inspired immobilization of AuNPs was also applied on graphene-wrapped NiNPs (Ni-G) instead of bare NiNPs to synthesize another composite catalyst (Ni-G-PD-Au), which yet again exhibited synergistic catalytic activity. A comparative study between the two nanocomposites suggested that Ni-PD-Au excelled in catalytic activity but Ni-G-PD-Au provided noteworthy stability showing ∼100% efficiency over 17 repeated cycles. However, along with excellent synergistic performance, both nanocomposites demonstrated high magnetization and thermal stability up to 350 °C ascertaining their easy separation and sustainability for high-temperature applications, respectively.

High dose dry powder inhalers to overcome the challenges of tuberculosis treatment.

Tuberculosis (TB) is a major global health burden. The emergence of the human immunodeficiency virus (HIV) epidemic and drug resistance has complicated global TB control. Pulmonary delivery of drugs using dry powder inhalers (DPI) is an emerging approach to treat TB. In comparison with the conventional pulmonary delivery for asthma and chronic obstructive pulmonary disease (COPD), TB requires high dose delivery to the lung. However, high dose delivery depends on the successful design of the inhaler device and the formulation of highly aerosolizable powders. Particle engineering techniques play an important role in the development of high dose dry powder formulations. This review focuses on the development of high dose dry powder formulations for TB treatment with background information on the challenges of the current treatment of TB and the potential for pulmonary delivery. Particle engineering techniques with a particular focus on the spray drying and a summary of the developed dry powder formulations using different techniques are also discussed.