Mass Median Aerodynamic Diameter Research Articles

Mechanistic Modelling of Targeted Pulmonary Delivery of Dactinomycin Iron Oxide Loaded Nanoparticles for Lung Cancer Therapy

With the increase in respiratory conditions including lung cancer post covid-19 pandemic, drug-loaded nanoparticulate dry powder inhalers (DPIs) can facilitate targeted lung delivery as a patient-friendly, non-invasive method. The aim of this work was to synthesise and optimise iron oxide nanoparticles (IONPs) containing dactinomycin as a model drug, using Quality by Design (QbD) principles. Chitosan and sodium alginate were investigated as polymeric coatings. The mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), burst-effect (BE), entrapment-efficiency (EE) and the emitted-dose (ED) were investigated in initial screening studies and outcomes used to set up a Design of Experiments (DoE). Results revealed that chitosan IONPs were superior to that of sodium alginate in delivering DPI with optimal properties [ED (89.9%), FPF (59.7%), MMAD (1.59 µm) and BE (12.7%)]. Design space for targeted IONPs included formulations containing 2.1-2.5% dactinomycin and 0.5–0.9% chitosan. Differential scanning calorimetry and X-ray diffraction and SEM-EDS analysis revealed effective formation of IONPs, and TEM images revealed the production of spherical IONPs with particle size of 4.4 ± 0.77 nm. This work overcame the light sensitivity of dactinomycin to potentially target the high molecular weight drugs to the lungs, with controlled delivery based on a reduced burst effect.

Technical features of vaping drug delivery system for bronchodilator delivery

PurposeSeveral technical features influencing bronchodilator delivery were evaluated using different vaping drug delivery systems (VDDS). MethodsTerbutaline in powder form, combined with 1, 3- propanediol used as e-liquid was tested at different concentrations (1 and 2.5 mg/mL), power levels (15 W and 30 W), and set applied resistances (0.15 to 1.5 O) to compare the efficiency of three VDDS (GS AIR2, GS TANK, CUBIS). Samples were collected with a Glass Twin Impinger (GTI). A High Performance Liquid Chromatography (HPLC) was used for drug quantification. The Next Generation Impactor (NGI) measured particle size distribution. Results were also considered with a clinical jet nebulizer (Cirrus TM 2, 2 mL of terbutaline at 2.5 mg/mL). ResultsGS AIR2 with resistance = 1.5 O; power = 15 W, and [Terbutaline] = 2.5 mg/mL represents the optimal VDDS conditions to deliver a respirable dose of 20.05 ± 4.2 µg/puff with a mass median aerodynamic diameter (MMAD) of 1.41 ± 0.03 µm. Thus, 52 puffs were required (lasting approximately 15 min of vaping) to reach similar respirable dose and MMAD compared to nebulization. ConclusionWe proved that several crucial VDDS technical parameters govern the performance of respiratory bronchodilator delivery including the resistance, power level and atomizer design.

“Novel mucoadhesive PLGA-PVM/MA micro-nanocomposites loaded with felodipine intended for pulmonary administration by nebulization”

Poly(latic-co-glycolic) acid (PLGA) nanoparticles loaded with felodipine (FEL) were embedded in a mucoadhesive matrix of poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) to prepare micro-nanoparticulate composites by particle engineering. Composites were characterized for physical and rheological properties and formulated with inhalable grade lactose. In-vitro characterization studies such as drug release kinetics, and mucoadhesive, and aerodynamic properties were performed. The in-vivo efficacy was evaluated by administering the optimized composites by nebulization in hypertensive rats. The obtained FEL-PLGA-PVM/MA composites of 1,069 ± 82 nm showed sustained drug release and mucoadhesive properties. Bulk and tapped densities of composites mixed with lactose were 0.08–0.13 g/mL and 0.18–0.30 g/mL, respectively, with mass median aerodynamic diameters (MMAD) in a range of 1.29–12.0 µm. After pulmonary administration of the composites, a decrease in systolic and diastolic blood pressure was observed within the first 3 h, of −9.0 ± 1.3 % and −13.9 ± 3.3 %, respectively, with a maximal effect at 12 h (sustained during 144 h), in contrast to pure FEL, which showed no significant decrease in blood pressure (1.6 ± 2.7 % and 4.1 ± 4.1 %). Findings suggest that novel mucoadhesive FEL-PLGA-PVM/MA composites are a promising strategy formulation to treat systemic diseases by pulmonary route.

Study on mass concentration and morphology of SMAW fume particles with a new covered electrode using nano-CaTiO3 as an arc stabilizer

Advances in manufacturing emphasize on the development of sustainable and green manufacturing processes. Welding is a popular manufacturing process practiced worldwide. The paper presented here describes a new covered electrode for a shielded metal arc welding (SMAW) process wherein nano-sized calcium titanate (CaTiO3) powder was used as an arc stabilizer, replacing the conventional micro sized CaTiO3 in the flux. The effect of this flux modification on the mass concentration and morphology of welding fume particulates was systematically investigated. The mass concentration of coarse, fine and sub-micron sized fume particulates was measured by segregating the fumes in a four-stage personal cascade impactor. The particle mass distribution was estimated from the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the fume particulates. The morphology of fumes at each impactor stage was analysed using scanning electron microscopy and its count median diameter (CMD) was determined. The results indicated as much as 48 % reduction in total fumes and 54 % reduction in the breathing zone concentration of fumes when the entire CaTiO3 in the electrode flux was substituted with nano-CaTiO3. Morphological analysis indicated that a large fraction of the fumes from the conventional electrode were polydispersed particles, while the new electrodes predominantly contained monodispersed particles which have a relatively faster rate of removal from the lungs. Overall, the present work indicated that introducing nano sized CaTiO3 as an arc stabilizer to the flux covering of SMAW electrode could not only reduce the hazardous fume emissions but also reduce its biological activity and toxicity, thus making the process more sustainable and environment friendly.

A facile one-step jet-milling approach for the preparation of proliposomal dry powder for inhalation as effective delivery system for anti-TB therapeutics

Objective Physicochemical characterization and assessment of aerosol dispersion performance of anti-TB proliposome dry powders for inhalation (DPIs) prepared using a single-step jet-milling (JM) approach. Significance Conventional tuberculosis (TB) treatment involves isoniazid and rifampicin as first-line agents in extended oral multi-drug regimes. Liposomal DPIs are emerging as promising alternatives for targeted delivery of anti-TB agents to alveolar macrophages harboring Mycobacterium tuberculosis. However, traditional approaches for liposomal DPI preparation are tedious, time consuming and require sophisticated/expensive equipment. The proposed JM technique for preparation of proliposome DPIs could obviate these limitations and facilitate use of these drugs for more effective and safer treatment. Methods Proliposome DPIs containing isoniazid and/or rifampicin, cholesterol and cholesterol sulfate were successfully prepared via JM (injection pressure, 7.4 bar; milling pressure, 3.68 bar). Their physicochemical, content uniformity, and in vitro aerosol dispersion performance were assessed using scanning electron microscopy/energy-dispersive X-ray spectroscopy, transmission electron microscopy, dynamic light scattering/Zeta potential, X-ray diffraction spectroscopy, thermogravimetric analysis, high-performance liquid chromatography, and the Next-Generation Impactor. Results The DPIs exhibited consistent, spherically shaped, smooth particles. Drug particles were evenly distributed with acceptable content uniformity. Drug crystallinity was not significantly affected by milling and the formulations had minimal (<2.0%) water content. After reconstitution of the DPIs, the hydrodynamic size was about 370.9–556.2 nm and charge was –12.3 to –47.3 mV. Furthermore, the proliposome DPIs presented emitted dose (69.04–89.03%), fine particle fraction, <4.4 µm (13.7 − 57.8%), and mass median aerodynamic diameter (<3.0 µm), which satisfied the requirements for deep lung delivery. Conclusion The proposed approach was suitable for preparation of proliposome DPIs that could be deployed for local targeting of the lower respiratory tract for the treatment of TB.

Oral inhalation of cannabidiol delivered from a metered dose inhaler to alleviate cytokine production induced by SARS-CoV-2 and pollutants

Cannabidiol (CBD) was formulated as a metered dose inhaler (CBD-MDI) and evaluated in vitro for its efficacy as an inhaled dosage form against inflammation caused by the SARS-CoV-2 virus, lipopolysaccharide (LPS) from Escherichia coli, silica particles, nicotine, and coal tar. A CBD-MDI formulation was prepared with 50 mg of CBD in 10 mL for a CBD dose of 250 μg/puff. The formulation ingredients included CBD, absolute ethanol as a cosolvent, and HFA-134a as the propellant. High aerosol performance of CBD-MDI was obtained with mass median aerodynamic diameter of 1.25 ± 0.01 μm, geometric standard deviation of 1.75 ± 0.00, emitted dose of 244.7 ± 2.1 μg, and fine particle dose of 122.0 ± 1.6 μg. The cytotoxicity and anti-inflammatory effectiveness of CBD-MDI were performed in alveolar macrophage (NR8383) and co-culture of alveolar macrophage (NR8383) and human lung adenocarcinoma (A549) cell line. CBD delivered from an MDI was safe on respiratory cells and did not trigger an immune response in alveolar macrophages. CBD-MDI effectively reduced the generation of cytokines in immune cells treated with viral antigen S-RBD, bacterial antigen LPS, silica particles, and coal tar. The efficacy of CBD-MDI was comparable to budesonide. Furthermore, the findings demonstrated that the use of CBD-MDI was more effective in treatment rather than prevention when inflammation was induced by either a viral or bacterial stimulant.

Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.

PurposeTuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation.MethodsExcipient-free CPZEN-45 HCl has been spray dried into a powder with physicochemical characteristics, aerodynamic particle size distribution, and delivered dose suitable for consideration as an inhaled product.ResultsThe mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the powder delivered using a RS01 inhaler were 2.62 ± 0.04 μm and 1.76 ± 0.09, respectively. Additionally, the powder was physically and chemically stable after storage at ambient conditions for >1.5 years with particle size similar to freshly manufactured product. Overages in spray dried powder were recycled the powder and resprayed into drug product likewise resulting in negligible change in quality thus allowing for further preclinical characterization as necessary. CPZEN-45 was scaled up using pilot-scale manufacturing equipment where the density of the powder was increased to facilitate larger delivered doses without affecting the aerodynamic performance properties.ConclusionThe spray dried powders were suitable for pharmacokinetics, efficacy and preclinical toxicology studies. The final method of manufacture may be used directly for CGMP particle manufacture to support IND and Phase I clinical trials and beyond.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11095-022-03393-w.

Phenotypic characteristics and protective efficacy of an attenuated Mycoplasma hyopneumoniae vaccine by aerosol administration

With the improvement of large-scale breeding in pig farms, conventional head-by-head immunization has disadvantages with low efficiency and high cost. Considering that most pathogens leading to pulmonary diseases circulate from the respiratory mucosa, immunization through the respiratory tract route has been a highly attractive vaccine delivery strategy. In this study, to develop an effective Mycoplasma hyopneumoniae (Mhp) aerosol vaccine, a customized ultrasonic atomizer was developed. The aerodynamic diameter, activity, and content of the Mhp aerosol vaccine were measured. In addition, piglets were immunized with the Mhp aerosol vaccine, and the immunity of the animal challenge protection test was evaluated. At the end of nebulization, the mass median aerodynamic diameters (MMAD) and geometric standard deviation (GSD) of the aerosol were 2.98 ± 0.02 μm and 1.51 ± 0.02, respectively. Moreover, 10 min after nebulization, the MMAD and GSD of the aerosol were 2.76 ± 0.02 μm and 1.51 ± 0.01, respectively, which were hardly changed. Compared with theoretical value, the actual titer of aerosol vaccines presented in 50% color changing unit (CCU50) after nebulization decreased 0.6. The shape, size, and uniformity of collected aerosols are relatively stable. The proportion of Mhp in aerosol produced by vaccine stock solution and 10 times diluted vaccine solution was 76.52% and 58.82%, respectively, and the average number of Mhp in a single aerosol was 3.06 and 1.51, respectively. In addition, the aerosol vaccine antigen particles could be transported to the lower respiratory tract, a local mucosal immune response was induced in piglets. The vaccine colonized the respiratory tract and significantly decline the lung lesion index after aerosol vaccination. In conclusion, an effective aerosol vaccine against Mhp infection was developed. And this is the first effective assessment for Mhp live vaccine with aerosolization against infection in piglets.

The applications of Machine learning (ML) in designing dry powder for inhalation by using thin-film-freezing technology

Dry powder inhalers (DPIs) are one of the most widely used devices for treating respiratory diseases. Thin--film--freezing (TFF) is a particle engineering technology that has been demonstrated to prepare dry powder for inhalation with enhanced physicochemical properties. Aerosol performance, which is indicated by fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD), is an important consideration during the product development process. However, the conventional approach for formulation development requires many trial-and-error experiments, which is both laborious and time consuming. As a state-of-the art technique, machine learning has gained more attention in pharmaceutical science and has been widely applied in different settings. In this study, we have successfully built a prediction model for aerosol performance by using both tabular data and scanning electron microscopy (SEM) images. TFF technology was used to prepare 134 dry powder formulations which were collected as a tabular dataset. After testing many machine learning models, we determined that the Random Forest (RF) model was best for FPF prediction with a mean absolute error of ± 7.251%, and artificial neural networks (ANNs) performed the best in estimating MMAD with a mean absolute error of ± 0.393 μm. In addition, a convolutional neural network was employed for SEM image classification and has demonstrated high accuracy (>83.86%) and adaptability in predicting 316 SEM images of three different drug formulations. In conclusion, the machine learning models using both tabular data and image classification were successfully established to evaluate the aerosol performance of dry powder for inhalation. These machine learning models facilitate the product development process of dry powder for inhalation manufactured by TFF technology and have the potential to significantly reduce the product development workload. The machine learning methodology can also be applied to other formulation design and development processes in the future.

Preparation and characterization of slow dissolving linezolid salts for direct pulmonary delivery

Linezolid is a second line antituberculosis which is currently available in the form of oral and parenteral dosage form. Compared to oral and parenteral dosage forms, the direct delivery of antituberculosis drugs to the lungs has proven to be better in maintaining the desire drug concentration. The present investigation was aimed to prepare the slow dissolving salts of linezolid using with long chained fatty acids – lauric acid(LA), palmitic acid (PA) and stearic acid (SA) as counterions for direct pulmonary delivery. The rotary vacuum evaporator and lyophilizer were used sequentially to evaporate the solvent in which the drug and counterions were dissolved. The results of DSC (differential scanning calorimetry) study, microscopic analysis and PXRD (powder X-ray diffraction) study proved the formation of novel crystalline material due to reaction between drug and counterions. The results of FTIR (Fourier transform infrared spectroscopy) and 1H NMR (Nuclear magnetic resonance) confirmed the transfer of hydrogen ion from the carboxylic acid group (–COOH–) of the counterions to the amide (–CONH–) group of the drug and thus the salt formation. The in-vitro dissolution study performed in the simulated lung fluid (SLG), the prepared salts exhibited significantly slower dissolution compared to pure drug and physical mixture. MMAD (Median mass aerodynamic diameter) for all the prepared salt was found to be less than 5 μm which proved ability of the prepared salt particles to reach deep affected area. MIC (Minimum inhibitory concetration) study indicated no significant difference in the MIC value of the pure drug and the prepared salts.

Synthesis, Characterization and In Vitro Evaluation of Chitosan Nanoparticles Physically Admixed with Lactose Microspheres for Pulmonary Delivery of Montelukast.

This study aimed to synthesise montelukast-loaded polymeric nanoparticles via the ionic gelation method using chitosan as a natural polymer and tripolyphosphate as a crosslinking agent. Tween 80, hyaluronic acid and leucine were added to modify the physicochemical properties of nanoparticles, reduce the nanoparticles’ uptake by alveolar macrophages and improve powder aerosolisation, respectively. The nanoparticles ranged from 220 nm to 383 nm with a polydispersity index of ≤0.50. The zeta potential of nanoparticles ranged from 11 mV to 22 mV, with a drug association efficiency of 46–86%. The simple chitosan nanoparticles (F2) were more spherical in comparison to other formulations (F4–F6), while the roughness of hyaluronic acid (F5) and leucine (F6) added formulations was significantly high er than F2 and Tween 80 added formulation (F4). The DSC and FTIR analysis depict that the physical and chemical properties of the drug were preserved. The release of the drugs from nanoparticles was more sustained in the case of F5 and F6 when compared to F2 and F4 due to the additional coating of hyaluronic acid and leucine. The nanoparticles were amorphous and cohesive and prone to exhalation due to their small size. Therefore, nanoparticles were admixed with lactose microspheres to reduce particle agglomeration and improve powder dispersion from a dry powder inhaler (DPI). The DPI formulations achieved a dispersed fraction of 75 to 90%, a mass median aerodynamic diameter (MMAD) of 1–2 µm and a fine particle fraction (FPF) of 28–83% when evaluated using the Anderson cascade impactor from Handihaler®. Overall, the montelukast-loaded nanoparticles physically admixed with lactose microspheres achieved optimum deposition in the deep lung for potential application in asthmatic patients.

Development and characterization of nanodispersion-based sildenafil pressurized metered-dose inhaler using combined small-angle X-ray scattering, dynamic light scattering, and impactors

The objectives of this study were to develop and measure the hydrodynamic particle size of sildenafil citrate nanoparticles dispersed in a pressurized metered-dose inhaler (pMDI) using dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). Aerodynamic properties and charges of aerosolized particles after emission from the pMDI were monitored by next generation impactor (NGI) and electrical low pressure impactor (ELPI). Nanodispersion-based sildenafil citrate pMDI formulated with 0, 1, 5 and 10% poloxamer 188 (P188) as a surfactant namely formulations F1, F2, F3 and F4, respectively. The results showed no precipitated or crystal growth during 6 months. The particle size and polydispersity index of the F3 obtained from the DLS analysis were 9.0 ± 1.6 d nm and 0.421 ± 0.038, respectively. The respective characteristics obtained from the SAXS data were 5.2 ± 1.2 d nm. The results from SAXS were smaller than those obtained from DLS. Larger hydrodynamic shell contributed to the larger size of nanoparticles. The sildenafil citrate content of pMDI was 107–109.5% LA. The mass median aerodynamic diameter (MMAD) from NGI was 1.2–2 μm and the fine particle fraction was 60%. The formulation without P188 (F1) showed particles of 10–100 nm and 0.1–1 μm and exhibited a unipolar charge profile. The formulations with P188 exhibited a bipolar charge profile with the nano-size of 200 (F3) and 300–800 nm (F4). The formulations of pMDI exhibited either a unipolar charge or bipolar charge profile depending on the composition of the formulation. The sildenafil citrate pMDI with 5% P188 generated sub-micronized and nano-sized aerosols with bipolar charged particles. The DLS and SAXS techniques were alternative ways to determine the particle size and size distribution of the pMDI products. The EPLI is also suitable to assess the stability of the MDI products from charge measurement.

Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis.

Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 μm as measured by cascade impaction, and a volumetric median diameter of 4.09 μm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB.

Dry Powder Inhalers for Proteins Using Cryo-Milled Electrospun Polyvinyl Alcohol Nanofiber Mats.

To enable the efficient delivery of drugs to the lungs, the drug particle design for most dry powder inhalers (DPIs) involves reducing the aerodynamic particle size to a few microns using methods such as spray-drying or jet-milling. Stresses, including heat and the shear forces generated by the preparation processes, may result in the degradation and denaturation of drugs such as those based on peptides and proteins. Here, we showed that cryo-milled polyvinyl alcohol nanofiber mats loaded with α-chymotrypsin by electrospinning exhibited suitable inhalation properties for use in DPIs, while maintaining enzymatic activity. The cryo-milled nanofiber mats were porous to fine particles, and the particle size and drug stability depended on the freezing and milling times. The median diameter of the milled fiber mats was 12.6 μm, whereas the mass median aerodynamic diameter was 5.9 μm. The milled nanofiber mats were successfully prepared, while retaining the enzymatic activity of α-chymotrypsin; furthermore, the activity of milled fiber mats that had been stored for 6 months was comparable to the activity of those that were freshly prepared. This novel method may be suitable for the DPI preparation of various drugs because it avoids the heating step during the DPI preparation process.

Respiratory Tract Deposition of E-Cigarette Particles.

Total and regional deposition of inhaled electronic cigarette (E-cig) particles in the respiratory tract (RT) depends on both physical properties of the inhaled particles and biological factors of users, for example, breathing pattern or puff profile, airway anatomy, and regional ventilation. Accurate particle sizing of E-cig aerosols is essential for predicting particle deposition in the RT. Studies using a variety of sizing methods have shown mass median aerodynamic diameters ranging from 0.2 to 1.2 um and secondary count diameters in the ultrafine range (<0.1 μm). Incorporating these particle sizes into a multiple-path particle dosimetry (MPPD) model shows 10% to 45% total lung deposition by mass and 30% to 80% for ultrafine particles depending on the breathing patterns. These predictions are consistent with experimental measures of deposition fraction of submicron and ultrafine particles. While box-mod-type E-cig devices allow for full "direct-lung" inhalations of aerosol, the more recent pod-based, and disposable E-cigs (e.g., JUUL, Puff Bar, Stig) deliver the aerosol as a "mouth-to-lung" puff, or bolus, that is inhaled early in the breath followed to various degrees by further inhalation of ambient air. Measurement of realistic ventilation patterns associated with these various devices may further improve deposition predictions. Finally, while in vivo measures of RT deposition present a challenge, a recent methodology to radiolabel E-cig particles may allow for such measurements by gamma scintigraphy. Supported by NIH/NHLBI R01HL139369. © 2022 American Physiological Society. Compr Physiol 12: 1-10, year.

Inhaled aprotinin reduces viral load in mild‐to‐moderate inpatients with SARS‐CoV‐2 infection

Inhaled aprotinin reduces viral load in mild‐to‐moderate inpatients with SARS‐CoV‐2 infection

Anti-inflammatory, antipyretic efficacy and safety of inhaled Houttuynia cordata thunb. essential oil formulation

Ethnopharmacological relevanceHouttuynia cordata Thunb. (H. cordata) is a well-known folk traditional Chinese medicine that is renowned for its use in the management of inflammatory respiratory diseases and pneumonia. Its essential oils have demonstrated their anti-inflammatory efficacy in vitro, however, their in vivo biological effects via inhalation have not been elucidated. Aim of the studyThis study aims to evaluate the anti-inflammation and toxicology of H. cordata essential oil-containing formulation, H16 aerosol in vivo. Materials and methodsA laser diffraction particle size analyser and a Next Generation Impactor were used to measure the mass median aerodynamic diameter (MMAD) of the H16 aerosol. The anti-inflammatory and antipyretic effects of the H16 aerosol were evaluated in the xylene-evoked ear oedema and Brewer’s yeast-induced fever models, respectively. The biological safety of the H16 aerosol was evaluated by acute toxicity and local toxicity tests in animal models. ResultsOur data showed that the MMAD of the bioactive aerosol was 3–5 μm, which implied tracheal and pharyngeal deposits. Significant anti-inflammatory and antipyretic effects were also observed in the animal models treated with H16 aerosol. The maximum tolerable dose of H16 in rats was >2.5 mL/kg. Irritation was not found on respiratory tract mucosa in the local toxicity test. ConclusionsTaken together, the present study suggested that H16 could be delivered in the form of aerosol and possessed its antipyretic and anti-inflammatory effects. This study provides a new perspective for the development of a new herbal aerosol therapy and herbal modernization.

Dextran Mass Ratio Controls Particle Drying Dynamics in a Thermally Stable Dry Powder Vaccine for Pulmonary Delivery

PurposeThermally stable, spray dried vaccines targeting respiratory diseases are promising candidates for pulmonary delivery, requiring careful excipient formulation to effectively encapsulate and protect labile biologics. This study investigates the impact of dextran mass ratio and molecular weight on activity retention, thermal stability and aerosol behaviour of a labile adenoviral vector (AdHu5) encapsulated within a spray dried mannitol-dextran blend.MethodsComparing formulations using 40 kDa or 500 kDa dextran at mass ratios of 1:3 and 3:1 mannitol to dextran, in vitro quantification of activity losses and powder flowability was used to assess suitability for inhalation.ResultsIncorporating mannitol in a 1:3 ratio with 500 kDa dextran reduced viral titre processing losses below 0.5 log and displayed strong thermal stability under accelerated aging conditions. Moisture absorption and agglomeration was higher in dextran-rich formulations, but under low humidity the 1:3 ratio with 500 kDa dextran powder had the lowest mass median aerodynamic diameter (4.4 µm) and 84% emitted dose from an intratracheal dosator, indicating strong aerosol performance.ConclusionsOverall, dextran-rich formulations increased viscosity during drying which slowed self-diffusion and favorably hindered viral partitioning at the particle surface. Reducing mannitol content also minimized AdHu5 exclusion from crystalline regions that can force the vector to air–solid interfaces where deactivation occurs. Although increased dextran molecular weight improved activity retention at the 1:3 ratio, it was less influential than the ratio parameter. Improving encapsulation ultimately allows inhalable vaccines to be prepared at higher potency, requiring less powder mass per inhaled dose and higher delivery efficiency.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11095-022-03341-8.

Development of extra-fine particles containing nanosized meloxicam for deep pulmonary delivery: In vitro aerodynamic and cell line measurements

Pulmonary drug administration provides a platform for the effective local treatment of various respiratory diseases. Application of nano-sized active ingredients results in higher bioavailability because of their large specific surface area. Extra-fine dry powder inhalers reach the smaller airways, further improving therapeutic efficiency. Poorly water-soluble meloxicam was the selected active ingredient. We aimed to decrease the particle size into the nano range by wet milling and producing extra-fine inhalable particles via nano spray-drying. The diameter of the drug was reduced to 138 nm. The particle size of the dry products was between 1.1 and 1.5 µm, and the dispersed diameter was between 500 and 800 nm. Owing to the excipients (poly-vinyl-alcohol, leucine), the spray-dried particles presented nearly spherical morphology. The drug became partially amorphous. Thanks to the improved surface area, the solubility and the released and the diffused amount of the meloxicam increased in artificial lung media. The in vitro aerodynamic measurements showed that the leucine-containing formulations had outstanding fine particle fraction (FPF) deposition with 1.3 µm mass median aerodynamic diameter (MMAD). The aerodynamic particle counter test also proved the extra-fine aerodynamic particle size. The in vitro cell line experiments revealed the non-cytotoxicity of the products and the suppression of the interleukin concentration. Overall, the powders are suitable for deep pulmonary delivery and the local treatment of lung inflammations.

Lung toxicity profile of inhaled copper-nickel welding fume in A/J mice

Objective: Stainless steel welding creates fumes rich in carcinogenic metals such as chromium (Cr). Welding consumables devoid of Cr are being produced in an attempt to limit worker exposures to toxic and carcinogenic metals. The study objective was to characterize a copper-nickel (Cu-Ni) fume generated using gas metal arc welding (GMAW) and determine the pulmonary deposition and toxicity of the fume in mice exposed by inhalation. Materials and Methods: Male A/J mice (6–8 weeks of age) were exposed to air or Cu-Ni welding fumes for 2 (low deposition) or 4 (high deposition) hours/day for 10 days. Mice were sacrificed, and bronchoalveolar lavage (BAL), macrophage function, and histopathological analyses were performed at different timepoints post-exposure to evaluate resolution. Results and Discussion: Characterization of the fume indicated that most of the particles were between 0.1 and 1 µm in diameter, with a mass median aerodynamic diameter of 0.43 µm. Metal content of the fume was Cu (∼76%) and Ni (∼12%). Post-exposure, BAL macrophages had a reduced ability to phagocytose E. coli, and lung cytotoxicity was evident and significant (>12%–19% fold change). Loss of body weight was also significant at the early timepoints. Lung inflammation, the predominant finding identified by histopathology, was observed as a subacute response early that progressively resolved by 28 days with only macrophage aggregates remaining late (84 days). Conclusions: Overall, there was high acute lung toxicity with a resolution of the response in mice which suggests that the Cu-Ni fume may not be ideal for reducing toxic and inflammatory lung effects.