Mass Median Aerodynamic Diameter Research Articles

Inhalable spray-dried porous microparticles containing dehydroandrographolide succinate phospholipid complex capable of improving and prolonging pulmonary anti-inflammatory efficacy in mice.

Due to the unique physiological barriers within the lungs, there are considerable challenges in developing drug delivery systems enabling prolonged drug exposure to respiratory epithelial cells. Here, we report a PulmoSphere-based dry powder technology that incorporates a drug-phospholipid complex to promote intracellular retention of dehydroandrographolide succinate (DAS) in respiratory epithelial cells following pulmonary delivery. The DAS-phospholipid complex has the ability to self-assemble into nanoparticles. After spray-drying to produce PulmoSphere microparticles loaded with the drug-phospholipid complex, the rehydrated microparticles discharge the phospholipid complex without altering its physicochemical properties. The microparticles containing the DAS-phospholipid complex exhibit remarkable aerodynamic properties with a fine particle fraction of ∼ 60% and a mass median aerodynamic diameter of ∼ 2.3μm. These properties facilitate deposition in the alveolar region. In vitro cell culture and lung tissue explants experiments reveal that the drug-phospholipid complex prolongs intracellular residence time and lung tissue retention due to the slow intracellular disassociation of drug from the complex. Once deposited in the lungs, the DAS-phospholipid complex loaded microparticles increase and extend drug exposure to the lung tissues and the immune cells compared to the free DAS counterpart. The improved drug exposure to airway epithelial cells, but not immune cells, is related to a prolonged duration of pulmonary anti-inflammation at decreased doses in a mouse model of acute lung injury induced by lipopolysaccharide. Overall, the phospholipid complex loaded microparticles present a promising approach for improved treatment of respiratory diseases, e.g. pneumonia and acute respiratory distress syndrome.

Dry powder inhalation containing muco-inert ciprofloxacin and colistin co-loaded liposomes for pulmonary P. Aeruginosa biofilm eradication

Pseudomonas aeruginosa (PA), a predominant pathogen in lung infections, poses significant challenges due to its biofilm formation, which is the primary cause of chronic and recalcitrant pulmonary infections. Bacteria within these biofilms exhibit heightened resistance to antibiotics compared to their planktonic counterparts, and their secreted toxins exacerbate lung infections. Diverging from traditional antibacterial therapy for biofilm eradication, this study introduces a novel dry powder inhalation containing muco-inert ciprofloxacin and colistin co-encapsulated liposomes (Cipro-Col-Lips) prepared using ultrasonic spray freeze drying (USFD) technique. This USFD dry powder is designed to efficiently deliver muco-inert Cipro-Col-Lips to the lungs. Once deposited, the liposomes rapidly diffuse into the airway mucus, reaching the biofilm sites. The muco-inert Cipro-Col-Lips neutralize the biofilm-secreted toxins and simultaneously trigger the release of their therapeutic payload, exerting a synergistic antibiofilm effect. Our results demonstrated that the optimal USFD liposomal dry powder formulation exhibited satisfactory in vitro aerosol performance in terms of fine particle fraction (FPF) of 44.44 ± 0.78 %, mass median aerodynamic diameter (MMAD) of 4.27 ± 0.21 μm, and emitted dose (ED) of 99.31 ± 3.31 %. The muco-inert Cipro-Col-Lips effectively penetrate the airway mucus and accumulate at the biofilm site, neutralizing toxins and safeguarding lung cells. The triggered release of ciprofloxacin and colistin works synergistically to reduce the biofilm’s antibiotic resistance, impede the development of antibiotic resistance, and eliminate 99.99 % of biofilm-embedded bacteria, including persister bacteria. Using a PA-beads induced biofilm-associated lung infection mouse model, the in vivo efficacy of this liposomal dry powder aerosol was tested, and the results demonstrated that this liposomal dry powder aerosol achieved a 99.7 % reduction in bacterial colonization, and significantly mitigated inflammation and pulmonary fibrosis. The USFD dry powder inhalation containing muco-inert Cipro-Col-Lips emerges as a promising therapeutic strategy for treating PA biofilm-associated lung infections.

Preparation and evaluation of inhalable S-allylmercapto-N-acetylcysteine and nintedanib co-loaded liposomes for pulmonary fibrosis

Orally marketed products nintedanib (NDNB) and pirfenidone (PFD) for pulmonary fibrosis (PF) are administered in high doses and have been shown to have serious toxic and side effects. NDNB can cause the elevation of galectin-3, which activates the NF-κB signaling pathway and causes the inflammatory response. S-allylmercapto-N-acetylcysteine (ASSNAC) can alleviate the inflammation response by inhibiting the TLR-4/NF-κB signaling pathway. Therefore, we designed and prepared inhalable ASSNAC and NDNB co-loaded liposomes for the treatment of pulmonary fibrosis. The yellow, spheroidal co-loaded liposomes with a particle size of 98.32±1.98 nm and zeta potential of -22.5 ± 1.58 mV were produced. The aerodynamic fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of NDNB were >50 % (81.14 %±0.22 %) and <5 μm (1.79 μm±0.06 μm) in the nebulized liposome solution, respectively. The results showed that inhalation improved the lung deposition and retention times of both drugs. DSPE-PEG 2000 in the liposome formulation enhanced the mucus permeability and reduced phagocytic efflux mediated by macrophages. ASSNAC reduced the mRNA over-expressions of TLR-4, MyD88 and NF-κB caused by NDNB, which could reduce the NDNB's side effects. The Masson's trichrome staining of lung tissues and the levels of CAT, TGF-β1, HYP, collagen III and mRNA expressions of Collagen I, Collagen III and α-SMA in lung tissues revealed that NDNB/Lip inhalation was more beneficial to alleviate fibrosis than oral NDNB. Although the dose of NDNB/Lip was 30 times lower than that in the oral group, the inhaled NDNB/Lip group had better or comparable anti-fibrotic effects to those in the oral group. According to the expressions of Collagen I, Collagen III and α-SMA in vivo and in vitro, the combination of ASSNAC and NDNB was more effective than the single drugs for pulmonary fibrosis. Therefore, this study provided a new scheme for the treatment of pulmonary fibrosis.

Formulation and evaluation of inhaled Sildenafil-loaded PLGA microparticles for treatment of pulmonary arterial hypertension (PAH): A novel high drug loaded formulation and scalable process via hot melt extrusion technology (Part Ⅰ)

In recent years, several techniques were employed to develop a local sustained pulmonary delivery of sildenafil citrate (SC) as an alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). Most of these methods, however, need to be improved due to limitations of scalability, low yield production, low drug loading, and stability issues. In this study, we report the use of hot-melt extrusion (HME) as a scalable process for making Poly (lactic-co-glycolic acid) (PLGA) microparticles with high SC load. The prepared particles were tested in vitro for local drug delivery to the lungs by inhalation. Sodium bicarbonate was included as a porogen in the formulation to make the particles more brittle and to impart favorable aerodynamic properties. Six formulations were prepared with different formulation compositions. Laser diffraction analysis was used to estimate the geometric particle size distribution of the microparticles. In-vitro aerodynamic performance was evaluated by the next-generation cascade impactor (NGI). It was reported in terms of an emitted dose (ED), an emitted fraction (EF%), a respirable fraction (RF%), a fine particle fraction (FPF%), a mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). The formulations have also been characterized for surface morphology, entrapment efficiency, drug load, and in-vitro drug release. The results demonstrated that PLGA microparticles have a mean geometric particle size between 6 and 14 µm, entrapment efficiency of 77 to 89 %, and SC load between 17 and 33 % w/w. Fifteen percent of entrapped sildenafil was released over 24 h from the PLGA microparticles, and seventy percent over 7 days. The aerodynamic properties included fine particle fraction ranging between 19 and 33 % and an average mass median aerodynamic diameter of 6–13 µm.

Aerosol deposition and emission from a United States Pharmacopeia‐induction port when using a pressurized metered‐dose inhaler with and without a valved holding chamber

AbstractThe testing of pharmaceutical aerosols includes measuring the aerodynamic particle size distribution, which is usually performed on cascade impactors. In the next generation impactor (NGI), the aerosol dose is introduced through an induction port (IP), being separated into different aerodynamic diameter ranges by seven stages and a micro‐orifice collector. The IP plays an important role in estimating the oropharyngeal deposition fraction. While the IP retains mainly large particles, it also tends to retain particles in the respirable range. In this work, the deposition of particles in the IP of an NGI is studied, both experimentally and through computational fluid dynamic (CFD) simulations. Experimental tests are conducted both with the pressurized metered‐dose inhaler (pMDI) alone and in conjunction with a cylindrical valved holding chamber (VHC). For each case, the total mass deposition that occurs in the VHC, IP, and NGI stages is measured, as well as the mass median aerodynamic diameter of the aerosol leaving the IP. The CFD simulations show minimal variations in results regardless of the injection method due to the relatively low velocity and spray angle of the pMDI‐generated aerosol. If the flap‐valve is removed from the VHC, significant particle deposition occurs upstream or within the valve region, with downstream air recirculation contributing to small particle deposition. Based on the CFD results, a correlation is proposed to accurately predict the particle escape fraction of the IP and VHC, which allows estimation of the tannin distribution of particles collected in the NGI stages, especially those corresponding to the range of respirable particles.

Synergistic combination of antimicrobial peptide and isoniazid as inhalable dry powder formulation against multi-drug resistant tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) has posed a serious threat to global public health, and antimicrobial peptides (AMPs) have emerged to be promising candidates to tackle this deadly infectious disease. Previous study has suggested that two AMPs, namely D-LAK120-A and D-LAK120-HP13, can potentiate the effect of isoniazid (INH) against mycobacteria. In this study, the strategy of combining INH and D-LAK peptide as a dry powder formulation for inhalation was explored. The antibacterial effect of INH and D-LAK combination was first evaluated on three MDR clinical isolates of Mycobacteria tuberculosis (Mtb). The minimum inhibitory concentrations (MICs) and fractional inhibitory concentration indexes (FICIs) were determined. The combination was synergistic against Mtb with FICIs ranged from 0.25 to 0.38. The INH and D-LAK peptide at 2:1 mole ratio (equivalent to 1: 10 mass ratio) was identified to be optimal. This ratio was adopted for the preparation of dry powder formulation for pulmonary delivery, with mannitol used as bulking excipient. Spherical particles with mass median aerodynamic diameter (MMAD) of around 5 µm were produced by spray drying. The aerosol performance of the spray dried powder was moderate, as evaluated by the Next Generation Impactor (NGI), with emitted fraction and fine particle fraction of above 70 % and 45 %, respectively. The circular dichroism spectra revealed that both D-LAK peptides retained their secondary structure after spray drying, and the antibacterial effect of the combination against the MDR Mtb clinical isolates was successfully preserved. The combination was found to be effective against MDR Mtb isolates with KatG or InhA mutations. Overall, the synergistic combination of INH with D-LAK peptide formulated as inhaled dry powder offers a new therapeutic approach against MDR-TB.

Formulation of Folate Receptor-Targeted Silibinin-Loaded Inhalable Chitosan Nanoparticles by the QbD Approach for Lung Cancer Targeted Delivery.

Aim: Targeted delivery of chemotherapeutics by functionalized nanoparticles exhibits a wonderful prospect for cancer treatment. The main objective of this research was to develop folate receptor-targeted silibinin (SB)-loaded inhalable polymeric nanoparticles (FA-CS-SB-NPs) for the treatment of lung cancer. Method: The qbD approach was implemented to prepare SB-loaded nanoparticles. Folic acid was conjugated by electrostatic conjugation in an optimized batch. The therapeutic potentials of formulations were determined using a lung cancer cell-bearing rat model. Result: Optimized formulation exhibited a spherical surface with a mean particle size of 275 ± 1.20 nm, a PDI of 0.234 ± 0.07, a ζ-potential of 32.50 ± 0.21, an entrapment efficiency of 75.52 ± 0.87%, and a CDR of 63.25 ± 1.21% at 48 h. Aerodynamic behaviors such as the mass median aerodynamic diameter (MMAD) and geometric size distribution (GSD) were found to be 2.75 ± 1.02 and 3.15 ± 0.88 μm, respectively. After 24 h of incubation with FA-CS-SB-NPs, the IC50 value was found to be 24.5 g/mL. FA-SB-CS-NPs maintained a significantly higher deposition of SB in lung tissues. Conclusions: Thus, the noninvasive nature and target specificity of FA-CS-SB-NPs pave the way for pulmonary delivery for treating lung cancer.

Using Dry Dispersion Laser Diffraction to Assess Dispersibility in Spheronized Agglomerate Formulations.

In this study, dry dispersion laser diffraction was used to study the dispersibility of spheronized agglomerate formulations and identify geometric particle size metrics that correlated well with aerodynamic particle size distribution (APSD). Eleven unique batches of agglomerates were prepared for both laser diffraction and cascade impaction testing. Correlations between the particle size distribution (PSD) and aerodynamic particle size distribution (APSD) metrics for the eleven agglomerate batches were determined in a semi-empirical manner. The strongest correlation between APSD and PSD was observed between the impactor-sized mass (%ISM) and the cumulative PSD fraction <14.5 µm. The strongest correlation with fine particle fraction (FPF) was observed with the cumulative PSD fraction <0.99 micron (R-squared = 0.974). In contrast to the other APSD metrics, good correlations were not found between the mass median aerodynamic diameter (MMAD) and the cumulative PSD fractions. Overall, the implementation of laser diffraction as a surrogate for cascade impaction has the potential to streamline product development. Laser diffraction measurements offer savings in labor and turnaround time compared to cascade impaction.

Inhaled dry powder liposomal azithromycin for treatment of chronic lower respiratory tract infection

A dry powder inhaled liposomal azithromycin formulation was developed for the treatment of chronic respiratory diseases such as cystic fibrosis and bronchiectasis. Key properties including liposome size, charge and encapsulation efficiency powder size, shape, glass transition temperature (Tg), water content and in vitro respiratory deposition were determined. Antimicrobial activity against cystic fibrosis (CF) respiratory pathogens was determined by MIC, MBC and biofilm assays. Cytotoxicity and cellular uptake studies were performed using A549 cells. The average liposome size was 105 nm, charge was 55 mV and encapsulation efficiency was 75 %. The mean powder particle size d[v,50] of 4.54 µm and Mass Median Aerodynamic Diameter (MMAD) was 5.23 µm with a mean Tg of 76˚C and water content of 2.1 %. These excellent physicochemical characteristics were maintained over one year. Liposomal loaded azithromycin demonstrated enhanced activity against P. aeruginosa clinical isolates grown in biofilm. The formulation was rapidly delivered into bacterial cells with > 75 % uptake in 1 h. Rapid uptake into A549 cells via a cholesterol-dependent endocytosis pathway with no cytotoxic effects apparent. These data demonstrate that this formulation could offer benefits over current treatment regimens for people with chronic respiratory infection.

CFPD-PK simulation of inhaled Delta-9-tetrahydrocannabinol aerosol dynamics: Transport, deposition, and translocation in a mouth-to-G10 subject-specific human airway

Medical cannabis is increasingly used as an alternative therapy for various conditions, including chronic pain, multiple sclerosis, epilepsy, and cancer-related symptoms. However, it is crucial to ensure that patients receive the intended dose of tetrahydrocannabinol (THC) from inhaled cannabis for optimal therapeutic effect without overdose risk. This requires a comprehensive understanding of the factors that influence the pharmacokinetics (PKs) of THC in the respiratory system. However, accurate estimation of lung dosimetry and blood concentration of inhaled THC remains challenging partially because the influence of diversified patient-specific puff patterns on inhaled THC transport, deposition, and translocation is still not well quantified. To address the knowledge gap mentioned above, this study employed a hybrid computational fluid-particle dynamics (CFPD) and PK model to evaluate factors that influence delivered doses of THC to the human respiratory system and the resultant THC-plasma concentration-time profile. Specifically, this study compared multiple puff waveforms for inhalation-holding-exhalation (IHE) with total puff volumes from 55 to 82 ml for 2 or 3 s, hold durations from 0 to 5 s, and three puff waveforms (i.e., square, sinusoidal, and realistic). THC deposition in the airways was recorded during all phases for each case using either 452,849 particles per second for the 1.128-μm monodisperse cases or 399,866 particles per second for the polydisperse cases, with the mass median aerodynamic diameter (MMAD) of 1.128 μm. Pulmonary air-THC particle flow transport dynamics, THC particle deposition data, and THC vapor absorption were predicted using CFPD for four airway regions, then scaled by region-specific bioavailability factors. The deposited THC mass in airway regions represents the initial mass entering a 3-compartment PK model, to predict the THC-plasma concentration-time profiles. The CFPD-PK results revealed significant variability in THC transport, deposition, and plasma concentration based on IHE factors. Specifically, larger puff volumes and longer holding times enhanced THC deposition in deeper airways and increased THC-plasma concentrations. Realistic transient puff waveforms predicted higher particle deposition and THC-plasma concentrations than simplified square waveforms. Polydisperse particle distributions show more realistic deposition patterns than monodisperse particle simulations. This study provides insights into the complexity of THC inhalation therapy, emphasizing the importance of considering individualized puff patterns and realistic particle size distributions in accurately predicting therapeutic outcomes, which is highly related to THC deposition in the lung and THC plasma concentration. These findings and the CFPD-PK modeling framework offer guidance for clinicians in prescribing personalized THC dosages, support regulatory science in evaluating inhalation devices, and contribute to ongoing research aimed at optimizing THC delivery for maximum therapeutic effectiveness while minimizing potential overdose risks.

Aerosolizable Pyrazinamide-Loaded Biodegradable Nanoparticles for the Management of Pulmonary Tuberculosis.

Background: Pyrazinamide is a Biopharmaceutical Classification System class III antibiotic indicated for active tuberculosis. Methods: In the present work, pyrazinamide-loaded biodegradable polymeric nanoparticles (PNPs) based dry powder inhaler were developed using the double emulsion solvent evaporation technique and optimized using design of experiments to provide direct pulmonary administration with minimal side effects. Batches were characterized for various physicochemical and aerosol performance properties. Results: Optimized batch exhibited particle size of 284.5 nm, % entrapment efficiency of 71.82%, polydispersibility index of 0.487, zeta potential of -17.23 mV, and in vitro drug release at 4 hours of 79.01%. Spray-dried PNPs were evaluated for drug content, in vitro drug release, and kinetics. The particle mass median aerodynamic diameter was within the alveolar region's range (2.910 μm). In the trachea and lung, there was a 2.5- and 1.2-fold increase in in vivo deposition with respect to pure drug deposition, respectively. In vitro drug uptake findings showed that alveolar macrophages with pyrazinamide PNPs had a considerably higher drug concentration. Furthermore, accelerated stability studies were carried out for the optimized batch. Results indicated no significant change in the evaluation parameters, which showed stability of the formulation for at least a 6-month period. Conclusion: PNPs prepared using biodegradable polymers exhibited efficient pulmonary drug delivery with decent stability.

A Novel Combined Dry Powder Inhaler Comprising Nanosized Ketoprofen-Embedded Mannitol-Coated Microparticles for Pulmonary Inflammations: Development, In Vitro-In Silico Characterization, and Cell Line Evaluation.

Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4-4.5 µm), fine particle fraction (56-71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.

Nebulisation of Paclitaxel, Sotatercept and Iloprost for pulmonary hypertension for lung cancer. From In vitro to In vivo.

Background: Pulmonary hypertension is common symptom among several diseases. The consequences are severe for several organs. Pulmonary hypertension is usually under-diagnosed and the main symptom observed is dyspnea with or without exercise. Currently we have several treatment modalities administered orally, via inhalation, intravenously and subcutaneously. In advanced disease then heart or lung transplantation is considered. The objective of the study was to investigate the optimum method of aerosol production for the drugs: iloprost, paclitaxel and the novel sotatercept. Materials and Methods: In our experiment we used the drugs iloprost, paclitaxel and the novel sotatercept, in an experimental concept of nebulization. We performed nebulization experiments with 3 jet nebulizers and 3 ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5μm in mass median aerodynamic diameter. Results: We concluded that paclitaxel cannot produce small droplets and is also still very greasy and possible dangerous for alveoli. However; iloprost vs sotatercept had smaller droplet size formation at both inhaled technologies (1.37<2.23 and 1.92<3.11, jet and ultrasound respectively). Moreover; residual cup designs C and G create the smallest droplet size in both iloprost and sotatercept. There was no difference for the droplet formation between the facemask and cone mouthpieces. Discussion: Iloprost and sotatercept can be administered as aerosol in any type of nebulisation system and they are both efficient with the residual cups loaded with small doses of the drug (2.08 and 2.12 accordingly).

Inhalable dry powders of microRNA-laden extracellular vesicles prepared by thin-film freeze-drying

Extracellular vesicles (EVs) are endogenous vesicles that comprise a variety of submicron vesicular structures. Among these, exosomes have been widely investigated as delivery systems for small and large molecules. Herein, the thin-film freeze-drying technology was utilized to engineer aerosolizable dry powders of miR-335-laden induced EVs (iEV-335) generated in B cells for potential delivery into the lung to treat primary lung cancer and/or pulmonary metastases. The size distribution, structure, and morphology of iEV-335 were preserved after they were subjected to thin-film freeze-drying with the proper excipients. Importantly, iEV-335, in liquid or reconstituted from thin-film freeze-dried powders, were equally effective in downregulating SOX4 gene expression in LM2 human triple-negative mammary cancer cells. The iEV-335 dry powder compositions showed mass median aerodynamic diameters (MMAD) of around 1.2 µm with > 60 % of the emitted doses had an MMAD of ≤ 3 µm, indicating that the powders can potentially achieve efficient deposition within the alveolar region following oral inhalation, which is desirable for treatment of primary lung cancer and pulmonary metastases. Overall, it is concluded that it is feasible to apply thin-film freeze-drying to prepare aerosolizable dry powders of iEVs for pulmonary delivery.

Repurposing ebselen as an inhalable dry powder to treat respiratory tract infections

Respiratory tract infections (RTIs) are one of the leading causes of death globally, lately exacerbated by the increasing prevalence of antimicrobial resistance. While antimicrobial resistance could be overcome by developing new antimicrobial agents, the use of a safe repurposed agent having potent antimicrobial activity against various RTIs can be an efficient and cost-effective alternative to overcome the long and complex process of developing and testing new drugs. Ebselen, a synthetic organoselenium drug originally developed to treat noise-inducing hearing problems, has shown promising antimicrobial activity in vitro against several respiratory pathogens including viruses (e.g., SARS-CoV-2, influenza A virus) and bacteria (e.g., Mycobacterium tuberculosis, Streptococcus pneumoniae, and Staphylococcus aureus). Inhaled drug delivery is considered a promising approach for treating RTIs, as it can ensure effective drug concentrations at a lower dose, thereby minimizing the side effects that are often encountered by using oral or injectable drugs. In this study, we developed inhalable ebselen dry powder formulations using a spray-drying technique. The amino acids leucine, methionine, and tryptophan were incorporated with ebselen to enhance the yield and aerosolization of the dry powders. The amino acid-containing ebselen dry powders showed a better yield (37–56.4 %) than the amino acid-free formulation (30.9 %). All dry powders were crystalline in nature. The mass median aerodynamic diameter (MMAD) was less than 5 µm for amino acids containing dry powders (3–4 µm) and slightly higher (5.4 µm) for amino acid free dry powder indicating their suitability for inhalation. The aerosol performance was higher when amino acids were used, and the leucine-containing ebselen dry powder showed the highest emitted dose (84 %) and fine particle fraction (68 %). All amino acid formulations had similar cytotoxicity as raw ebselen, tested in respiratory cell line (A549 cells), with half-maximal inhibitory concentrations (IC50) between 100 and 250 μg/mL. Raw ebselen and amino acid-containing dry powders showed similar potent antibacterial activity against the Gram-positive bacteria S. aureus and S. pneumoniae with minimum inhibitory concentrations of 0.31 μg/mL and 0.16 μg/mL, respectively. On the other hand, raw ebselen and the formulations showed limited antimicrobial activity against the Gram-negative pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae. In summary, in this study we were able to develop amino-acid-containing inhalable dry powders of ebselen that could be used against different respiratory pathogens, especially Gram-positive bacteria, which could ensure more drug deposition in the respiratory tract, including the lungs. DPIs are generally used to treat lung (lower respiratory tract) diseases. However, DPIs can also be used to treat both upper and lower RTIs. The deposition of the dry powder in the respiratory tract is dependent on its physicochemical properties and this properties can be modulated to target the intended site of infection (upper and/or lower respiratory tract). Further studies will allow the development of similar formulations of individual and/or combination of antimicrobials that could be used to inhibit a number of respiratory pathogens.

A Technical Feasibility of Aqueous Aerosol Generation Based on the Flashing Jet: Impact of Surfactant, Electrolyte, and Drug Concentration

AbstractThis study aimed to investigate the atomization mechanism of a flashing jet (FJ), focusing on the potential factors that influence the atomization performance of the device. Those factors include surfactant, electrolyte, and drug concentration. In this work, Tween 80, sodium chloride (NaCl), and salbutamol sulfate (SBS) were used for the study. The aerosol's mass median aerodynamic diameter (MMAD) was investigated for analysis. The drug delivery ability of the FJ prototype was compared with the Pari nebulizer. Our data suggested that the MMAD of aerosol decreased as the concentration of Tween 80 increased, but the critical micelle concentration point was not influenced. Upon adding NaCl to pure water, with the increase of NaCl concentration, the MMAD of aerosol initially decreased significantly and then increased, reaching the lowest point when 0.05% NaCl was used. A higher concentration of SBS was beneficial for the atomization performance. When the SBS concentration was 5 mg/mL, the MMAD values of the FJ prototype and Pari nebulizer were 2.28 ± 0.15 and 1.03 ± 0.21 μm, respectively, and the fine particle dose (%TDD) of the FJ prototype and Pari nebulizer was 50.99 ± 5.88 and 53.51 ± 4.58%, respectively. Interestingly, the concentration of SBS has no effect on the residual dosage level of the FJ prototype, indicating that it can be applied in atomizing high-concentration solutions. In summary, surfactant, electrolyte, and drug concentration played an important role in the atomization performance of the FJ prototype and these ingredients are also crucial factors that should be considered in future formulation studies.

Predictability Augmentation by In-silico Study to In-vivo and In-vitro Results of Lung Doses of Airborne Fine and Ultrafine Particles Inhaled by Humans at Industrial Workplaces

This study correlates computational predictions with in vivo and in vitro experimental results of inhaled fine and ultrafine particulate matter (PM) transport, dissemination, and deposition in the human respiratory airways. Epidemiological studies suggest that workplace exposure to anthropogenic pollutant PMs is a risk factor for increased susceptibility to acute broncho-pulmonary illnesses. However, investigations on detailed human inhalation and PM transport processes are restrictive from time, cost, and ethical perspectives. Computational simulation based on the Multiple Path Particle Dosimetry (MPPD) model was employed to quantify the risks associated with workplace exposure of these PMs. Here, the physical, mechanical, and electrical properties of PMs of carbon black (CB) and ultrafine particles (UFPs) from wire-cut electrical discharge machining (WEDM), with mass median aerodynamic diameter (CMAD) in the range of 1 nm to 1000 nm, were used as input parameters of MPPD. Additionally, it mimicked occupational workers’ age, body mass index, and oronasal-combinational nose and mouth breathing exposure time. The deposition results were compared with several vivo and in vitro experimental data reported in the literature, and satisfactory agreements were found. For example, a total lung dose of CB-PMs of 100 nm is the highest (28%), while a 380 nm dose is the lowest (15%). Afterward, deposition increases with particle size, reaching 26% for 1000 nm. In the case of WEDM-UFPs, about 98% of all 1.0 nm inhaled particles remain in the lung. Subsequently, the deposition dose decreases with the particle size and reaches up to 28% for 100 nm particles. Approximately 51% of deposited WEDM-UFPs are of CMAD ≤ 5 nm. The images of lung geometry also observed the maximum deposited mass and mass flux rate in the head, tracheobronchial, and pulmonary airways.

Development of Novel Spray-dried Microparticles to Treat Cystic Fibrosis: A Tri-drug Approach.

Cystic fibrosis is the predominant autosomal recessive disorder known to reduce life expectancy. Research findings indicate that around 60 to 70% of adult individuals with this condition carry infections of Pseudomonas aeruginosa. The ongoing research investigates the potential synergy of merging ivacaftor and ciprofloxacin to address bacterial infections. The two drugs were spray-dried into microparticles, which were then coated with Lsalbutamol and were to be delivered by a dry powder inhaler. Microparticles were generated by applying the spray drying method, utilizing bovine serum albumin and L-leucine in their preparation. Additionally, L-salbutamol was mixed and adsorbed onto the surface of the spray-dried microparticles, and it acted as a bronchodilator. The microparticles produced via spray drying exhibited a particle size measuring 1.6 ± 0.04 μm, along with a polydispersity ratio of 0.33. Their zeta potential measured -27.3 ± 1.1 mV, while the mass median aerodynamic diameter of these microparticles was 3.74 ± 0.08 μm. SEM, XRD, and FTIR studies confirmed the entrapment of ivacaftor and ciprofloxacin. The morphology was observed by SEM and TEM scans. Antibacterial synergy was confirmed through the agar broth and dilution method, and the formulation's safety was established based on the outcomes of the MTT assay. Using spray-dried microparticles containing ciprofloxacin, ivacaftor, and L-salbutamol presents a novel approach to the treatment of cystic fibrosis.

Numerical study on the effect of the realistic mouth-inhaler positions on orally inhaled drug delivery in pediatric intersubject upper airways

The relative position between the pediatric upper airway and the inhalation device during real inhalation administration has significant effects on the delivery efficiency of orally inhaled drugs. Morphological variability plays an important role in this process. However, the mouth-throat differences between adults and children were usually neglected because most of the commercial inhalation devices currently are designed for adults or older adolescents. The main objective of this study is to investigate these effects by four realistic pediatric mouth-throat (RMT) geometries. In addition, an idealized mouth-throat (IMT) model was developed to validate the numerical model and to compare with the RMT models. Computational fluid dynamics (CFD) simulations were performed to investigate the flow pattern and deposition pattern in these models and the results were compared with the cascade impactor experiments, replica experiments and in vivo results. No significant correlation (p > 0.1) between the relative position parameters and inhaler insertion depth can be noticed among the RMT models. Notably, significant variability in the inhaler posture was observed in RMT models, especially for the S4 model. Airflow structure shows that the RMT model has a complex onset of turbulence, reverse flow and subsequently vortex formation when compared with the IMT model. The oral cavity is the region with the largest deposition fraction (DF) and deposition efficiency (DE). The DF and DE of the oral cavity are negatively correlated to the position parameter (Lm) when mass median aerodynamic diameter (MMAD) of indacaterol 150 μg was utilized as the input particle parameter. The relative position between the inhaler and oral cavity has significant effects on the particle transport and deposition. Furthermore, in silico results overestimated the lung deposition in comparison to the in vivo and experimental results when MMAD was used as input. To resolve the disparity between the in silico and in vivo results, a modified prediction method based on the cascade impactor and original in silico results was proposed and a good correlation of the relative contribution of pulmonary absorption to total systemic exposure (flung) was found between the predicted and observed results. The findings of present work will provide useful information in understanding the particle transport and deposition in the pediatric airways for the design of inhaler.

Using particle dimensionality-based modeling to estimate lung carcinogenicity of 3D printer emissions.

The use of 3D printing technologies by industry and consumers is expanding. However, the approaches to assess the risk of lung carcinogenesis from the emissions of 3D printers have not yet been developed. The objective of the study was to demonstrate a methodology for modeling lung cancer risk related to specific exposure levels as derived from an experimental study of 3D printer emissions for various types of filaments (ABS, PLA, and PETG). The emissions of 15 filaments were assessed at varying extrusion temperatures for a total of 23 conditions in a Class 1,000 cleanroom following procedures described by ANSI/CAN/UL 2904. Three approaches were utilized for cancer risk estimation: (a) calculation based on PM2.5 and PM10 concentrations, (b) a proximity assessment based on the pulmonary deposition fraction, and (c) modeling based on the mass-weighted aerodynamic diameter of particles. The combined distribution of emitted particles had the mass median aerodynamic diameter (MMAD) of 0.35 μm, GSD 2.25. The average concentration of PM2.5 was 25.21 μg/m3 . The spline-based function of aerodynamic diameter allowed us to reconstruct the carcinogenic potential of seven types of fine and ultrafine particles (crystalline silica, fine TiO2 , ultrafine TiO2 , ambient PM2.5 and PM10, diesel particulates, and carbon nanotubes) with a correlation of 0.999, P < 0.00001. The central tendency estimation of lung cancer risk for 3D printer emissions was found at the level of 14.74 cases per 10,000 workers in a typical exposure scenario (average cumulative exposure of 0.3 mg/m3 - years), with the lowest risks for PLA filaments, and the highest for PETG type.