Higher Fine Particle Fraction Research Articles

In Vitro Evaluation of Colistin Conjugated with Chitosan-Capped Gold Nanoparticles as a Possible Formulation Applied in a Metered-Dose Inhaler.

Inhaled colistin is used to treat pneumonia and respiratory infections through nebulization or dry powder inhalers. Nevertheless, the development of a metered-dose inhaler (MDI) for colistin, which could enhance patient convenience and treatment efficacy, has not yet been developed. Colistin is known for its ability to induce cellular toxicity. Gold nanoparticles (AuNPs) can potentially mitigate colistin toxicity. Therefore, this study aimed to evaluate the antimicrobial effectiveness of colistin conjugated with chitosan-capped gold nanoparticles (Col-CS-AuNPs) and their potential formulation for use with MDIs to deliver the aerosol directly to the deep lung. Fourier-transform infrared spectroscopy, nuclear magnetic resonance, and elemental analysis were used to characterize the synthesized Col-CS-AuNPs. Drug release profiles fitted with the most suitable release kinetic model were evaluated. An MDI formulation containing 100 µg of colistin per puff was prepared. The aerosol properties used to determine the MDI performance included the fine particle fraction, mass median aerodynamic diameter, and geometric standard deviation, which were evaluated using the Andersen Cascade Impactor. The delivered dose uniformity was also determined. The antimicrobial efficacy of the Col-CS-AuNP formulation in the MDI was assessed. The chitosan-capped gold nanoparticles (CS-AuNPs) and Col-CS-AuNPs had particle sizes of 44.34 ± 1.02 and 174.50 ± 4.46 nm, respectively. CS-AuNPs effectively entrapped 76.4% of colistin. Col-CS-AuNPs exhibited an initial burst release of up to 60% colistin within the first 6 h. The release mechanism was accurately described by the Korsmeyer-Peppas model, with an R2 > 0.95. The aerosol properties of the Col-CS-AuNP formulation in the MDI revealed a high fine particle fraction of 61.08%, mass median aerodynamic diameter of 2.34 µm, and geometric standard deviation of 0.21, with a delivered dose uniformity within 75-125% of the labeled claim. The Col-CS-AuNP MDI formulation completely killed Escherichia coli at 5× and 10× minimum inhibitory concentrations after 6 and 12 h of incubation, respectively. The toxicity of CS-AuNP and Col-CS-AuNP MDI formulations in upper and lower respiratory tract cell lines was lower than that of free colistin. The stability of the Col-CS-AuNP MDI formulation was maintained for at least 3 months. The Col-CS-AuNP MDI formulation effectively eradicated bacteria over a 12-h period, showing promise for advancing lung infection treatments.

Nanocrystal Agglomerates of Curcumin Prepared by Electrospray Drying as an Excipient-Free Dry Powder for Inhalation.

Curcumin has shown beneficial effects on pulmonary diseases with chronic inflammation or abnormal inflammatory responses, including chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis. Clinical applications of curcumin are limited due to its chemical instability in solution, low water solubility, poor oral bioavailability, and intestinal and liver first-pass metabolism. Pulmonary delivery of curcumin can address these challenges and provide a high concentration in lung tissues. The purpose of the current work was to prepare a novel inhalable dry powder of curcumin nanocrystals without added excipients using electrospray drying (ED) with improved dissolution and aerosolization properties. ED of curcumin was performed at 2 and 4% w/v concentrations in acetone. Physicochemical properties of the formulated powders were evaluated by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), density and powder flow measurements, and in vitro dissolution. The in vitro deposition studies were conducted using next-generation impactor (NGI) and aerosol performance and aerodynamic particle size parameters were calculated for prepared formulations. ED could produce agglomerates of nanocrystals with a size of about 500 nm at an acceptable yield of about 50%. PXRD and FTIR data revealed that prepared nanocrystals were in a stable crystalline state. The bulk and tapped density of prepared agglomerates were in the range appropriate for pulmonary delivery. Formed nanocrystals could significantly improve the dissolution rate of water-insoluble curcumin. The optimized formulation exhibited acceptable recovered dose percentage, high emitted dose percentage, optimum mean mass median aerodynamic diameter, small geometric standard deviation, and high fine-particle fraction that favors delivery of curcumin to the deep lung regions. The ED proved to be an efficient technique to prepare curcumin nanocrystals for pulmonary delivery in a single step, at a mild condition, and with no surfactant.

Tailoring Dry Microparticles for Pulmonary Drug Delivery: Ultrasonic Spray Freeze-Drying with Mannitol and Salbutamol Sulphate

Spray freeze-drying has emerged as a valid alternative to traditional spray drying to produce therapeutic dry microparticles. In particular, the spherical shape and high porosity of spray freeze-dried microparticles make them suitable for pulmonary drug delivery through dry powder inhalers. However, an appropriate particle size and fine particle fraction are required to guarantee lung deposition. This study used ultrasonic spray freeze-drying to generate dry microparticles composed of mannitol either alone or added with the bronchodilator salbutamol sulphate. The influence of the solid concentration and the feed flow rate on the particle size, morphology, surface area, porosity, and crystallinity was investigated. Growing particle size was observed, increasing the concentration and feed flow rate. Similarly, the addition of the drug led to a larger particle size and surface area. The in vitro simulation of drug deposition highlighted the dependence of the aerodynamic properties on the solid concentration and feed flow rate. Due to the lower density and particle geometric size, the highest fine particle fraction (26%) and smallest mass median aerodynamic diameter (4.4 μm) were reached at the lowest solid concentration and feed flow rate.

Effect of recycled powder on the yield stress of cement paste with varied superplasticizers

The influence of superplasticizer on the yield stress of cement pastes with recycled powder (RP) was examined in the study. Four superplasticizers were used to obtain the similar fluidity by adjusting the dosage. The results show that the 10% RP decreases the yield stress of paste compared to the reference paste at the same fluidity, but 20% and 30% RP increases the yield stress, ranging from 11 to 599%. The superplasticizer with adsorptive group of phosphate-type minimizes the yield stress of paste than that of polycarboxylate -type, but it made a significant increment in yield stress as the incorporating of RP increased. Besides, the polycarboxylate superplasticizer with the higher molecular weight of side chain and charge density led to lower yield stress. Based on the Yodel model, the yield stress of paste with RP was analyzed by the polymer adsorption and particle packing density of particles to reveal the influence of RP with different superplasticizers on the colloidal interaction and contact network among the particles. The packing density of particles with recycled powder was a little higher than the reference paste, but the higher fraction of fine particles made a stronger PSD effect, which improved the particle contact interaction. On the other hand, due to the higher polymer adsorption of recycled powder than cement, especially for superplasticizer with phosphate group, the average surface coverage was increased, which extended the separation distance, so that colloidal interaction among particles was weaken.

Cyclodextrin MOFs modified dry powder inhalers quadruple bioavailability of luteolin to ameliorate fibrosing interstitial lung disease

Fibrosing interstitial lung disease (ILD) is a pathological condition that is highly heterogeneous and lethal, and has few effective treatment choices. Other than pirfenidone and nintedanib for the therapy of idiopathic pulmonary fibrosis, no medications are currently licensed for the treatment of ILD. Luteolin is a common flavonoid with multiple biological effects such as anti-inflammation but with poor solubility and absorption. In this study, we loaded luteolin into γ-cyclodextrin metal–organic frameworks (CD-MOFs) to deliver the medicine to the lungs using dry powder inhalers; in vitro pulmonary deposition results showed LUT@CDMOF had a high fine particle fraction (FPF) (59.77 ± 3.48%). LUT@CDMOF effectively inhibited ILD progression in the BLM-induced fibrosing ILD model rats. When compared to oral administration, the inhalation of LUT@CDMOF dry powder in rats showed considerable improvements in absorption and bioavailability, with a tmax of 0.08 h and a high absolute bioavailability (82%) of LUT (The AUC(0-t) and Cmax of inhal. LUT@CDMOF respectively increased about 4.03 times and 9.11 times, when compared with the i.g. LUT group). These studies demonstrate the potent anti-inflammatory activities of LUT@CDMOF. The inhaled LUT@CDMOF might be considered as a promising new strategy in the treatment of fibrosing ILD.

Lipid-based particle engineering via spray-drying for targeted delivery of antibiotics to the lung

Pulmonary delivery of antibiotics for the treatment of tuberculosis provides several benefits compared to conventional oral and parenteral administration. API-loaded particles delivered directly to alveolar macrophages, where Mycobacterium tuberculosis resides, can reduce the required dose and decrease the severe side effects of conventional treatment. In this work, lipid-microparticles loaded with rifampicin were engineered via spray-drying to be administered as a carrier-free dry powder for inhalation. Although, it is well-known that spray-drying of lipid-based excipients is strongly limited, a completely lipid-based formulation using diglycerol full ester of behenic acid was produced. The solid state of the lipid, providing high melting temperature, absence of polymorphism and monophasic crystallization, led to high yield of spray-dried particles (83%). Inhalable particles of mass median aerodynamic diameter of 2.36 µm, median geometric size of 2.05 µm, and negative surface (-50.03 mV) were engineered. Such attributes were defined for deep lung deposition and targeted delivery of antibiotics to alveolar macrophages. Superior aerodynamic performance as carrier-free DPI was associated to a high fine particle fraction of 79.5 %. No in vitro cytotoxic effects were found after exposing epithelial cell lines and alveolar macrophages. In vitro uptake of particles into alveolar macrophages indicated the efficiency of their targeted delivery. The use of highly processable and safe lipid-based excipients for particle engineering via spray-drying can extend the availability of materials for functionalized applications for pulmonary delivery.

Sodium hyaluronate dry powder inhalation in combination with sodium cromoglycate prepared using optimized spray drying conditions

Sodium hyaluronate (SHA) is an anti-inflammatory and protective agent against bronchoconstriction, and sodium cromoglicate (SCG) prevents exercise-induced bronchoconstriction and inflammation. Based on the pharmacological properties of both substances, this study aimed to develop a dry powder inhaler (DPI) of SHA alone and in combination with SCG. The target of the study was to develop flowable formulations without any surfactants by using the spray drying method. To obtain respirable SHA and SCG:SHA particles, variables of the spray dryer, such as inlet temperature, atomized air flow, and feed solution, were changed. The particles 1–8 μm in size were produced with high yield by spray drying and increasing the ethanol percentage of the feed solution (60%), which is the most remarkable parameter. After that, physicochemical characterizations were performed. The aerosol performance of DPI formulations prepared using lactose was evaluated using Handihaler® DPI. The fine particle fraction (FPF) was 36% for the SHA formulation, whereas it was 52 and 53% for SCG and SHA, respectively, in the SCG:SHA formulation. Consequently, both particles were produced reproducibly by spray drying, and inhaled SHA and SCG:SHA dry powder formulations were developed due to their high FPF and flowability with lactose.

Pulmonary delivery of spray-dried Nisin ZP antimicrobial peptide for non-small cell lung cancer (NSCLC) treatment

Nisin ZP is an antimicrobial peptide (AMP) produced by the bacterium Lactococcus lactis, and we have previously demonstrated anticancer activity in NSCLC (A549) cells. In this study, we formulated a nisin ZP dry powder (NZSD) using a spray dryer to facilitate inhaled delivery for the treatment of NSCLC. Nisin ZP was spray-dried with mannitol, l-leucine, and trehalose in a ratio of 75:15:10 using Büchi mini spray-dryer B-290 in different drug loadings (10, 20, and 30% w/w). NZSD powder revealed a good powder yield of >55% w/w with ≤3 % w/w moisture content and high nisin ZP drug loading for all the peptide ratios. The NZSD powder particles were irregularly shaped with corrugated morphology. The presence of an endothermic peak in DSC thermograms and attenuated crystalline peaks in PXRD diffractograms confirmed the semi-crystalline powder nature of NZSD. The anticancer activity of nisin ZP was maintained after fabricating it into NZSD powder and showed a similar inhibitory concentration to free nisin ZP. Stability studies indicated that NZSD powders were stable for three months at 4 and 25 ℃ with more than 90% drug content and semi-crystalline nature, as confirmed by DSC and PXRD. Aerosolization studies performed using NGI indicated an aerodynamic diameter (MMAD) within the desired range (1–5 µm) and a high fine particle fraction (FPF > 75%) for all peptide ratios, suggesting powder deposition in the lung's respiratory airways. In conclusion, a dry powder of nisin ZP was formulated using a spray dryer with enhanced storage stability and suitable for inhaled delivery.

Surface Modification of lactose carrier particles using a fluid bed coater to improve fine particle fraction for dry powder inhalers

Surface roughness of carrier particles can impact dry powder inhaler (DPI) performance. There are opposing views on the effect of roughness on DPI performance. Hence, a systematic approach is needed to modify carrier surfaces and evaluate the impact on drug delivery. Carrier particle surfaces were modified by fluid bed coating with saturated lactose containing micronized lactose of different sizes (2, 5 and 8 μm) and coated to different levels (20, 40, 60 and 80%). Their drug delivery performance was assessed by the fine particle fraction (FPF). Roughness parameters, mean arithmetic roughness (Ra) and arithmetic mean height (Sa), of the carrier particles, were also evaluated using optical profilometry and scanning laser microscopy. Generally, particles of higher Ra had higher FPF. Higher Sa resulted in higher FPF only for particles with 60 and 80% coat levels. Reduced contact surface area between the drug particle and rougher carrier particle resulted in easier drug detachment during aerosolization. The 5 µm micronized lactose produced optimal carrier particles with respect to FPF and surface roughness. The study highlighted that with the ideal particles for surface roughening and coating level, surface roughening could be efficiently achieved by fluid bed coating for superior DPI performance.

"Cluster Bomb" Based Bismuth Nano-in-Micro Spheres Formed Dry Powder Inhalation for Thermo-Radio Sensitization Effects of Lung Metastatic Breast Cancer.

Lung metastatic breast cancer (LMBC) is mainly diagnosed through CT imaging and radiotherapy could be the most common method in the clinic to inhibit tumor proliferation. While the sensitivity of radiotherapy is always limited due to the hypoxic tumor microenvironment and high doses of irradiation easily induce systemic cytotoxicity. Metal-based materials applied as radiosensitizers have been widely investigated to improve efficiency and reduce the doses of irradiation. Herein, it is aimed to overcome these problems by designing biodegradable lipid-camouflaged bismuth-based nanoflowers (DP-BNFs) as both a photo-thermo-radiosensitizer to develop a novel photothermal therapy (PTT) and radiotherapy combination strategy for LMBC treatment. To achieve effective lung deposition, "Cluster Bomb" structure-based DP-BNFs nano-in-micro dry powder inhalation (DP-BNF@Lat-MPs) are formulated through spray-dried technology. The DP-BNFs "cluster" in the microsphere to improve their tumor-targeted lung deposition with a high fine particle fraction followed by burst releasing of DP-BNFs for targeting delivery and LMBC therapy. The DP-BNF@Lat-MPs exhibit excellent photothermal conversion efficiency, radiotherapy enhancement, and CT imaging ability in vitro, which synergistically inhibit cell proliferation and metastasis. In vitro and in vivo data prove that combining PTT and radiotherapy with DP-BNF@Lat-MPs as a thermo-radio dual-sensitizer significantly enhances LMBC tumor metastasis inhibition with good biocompatibility and low toxicity.

Inhalable aerosol microparticles with low carrier dosage and high fine particle fraction prepared by spray-freeze-drying

Co-suspension drug-loading technology, namely Aerosphere™, can improve fine particle fraction (FPF) and delivered dose content uniformity (DDCU). However, because of its poor drug-loading efficacy, the phospholipid carrier dosage in Aerosphere™ is usually dozens of times greater than that of the drug, resulting in a high material cost and blockage of the actuator. In this study, spray-freeze-drying (SFD) technology was used to prepare inhalable distearoylphosphatidylcholine (DSPC)-based microparticles for pressurized metered-dose inhalers (pMDI). Water-soluble, low-dose formoterol fumarate was used as an indicator to evaluate the aerodynamic performance of the inhalable microparticles. Water-insoluble, high-dose mometasone furoate was used to investigate the effects of drug morphology and drug-loading mode on the drug delivery efficiency of the microparticles. The results demonstrated that DSPC-based microparticles prepared using the co-SFD technology not only achieved higher FPF and more consistent delivered dose than those of drug crystal-only pMDI, but the amount of DSPC was also reduced to approximately 4% of that prepared using the co-suspension technology. This SFD technology may also be used to improve the drug delivery efficiency of other water-insoluble and high-dose drugs.

Development of excipients free inhalable co-spray-dried tobramycin and diclofenac formulations for cystic fibrosis using two and three fluid nozzles

This study aims to investigate the effect of physicochemical properties and aerosol performance of two (2FN) and three-fluid nozzles (3FN) on the inhalable co-formulation of tobramycin and diclofenac dry powders. Combination formulations of tobramycin and diclofenac at 2:1 and 4:1 w/w ratios were prepared at a laboratory scale using a spray dryer in conjunction with a 2FN or 3FN. Powder size, morphology, solid-state characteristics, and aerodynamic and dissolution properties were characterised. The nozzle types and the formulation composition influenced the yield, particle size, solid-state properties, aerosolization behaviour and dissolution of the co-spray dried formulations. In particular, using the 2FN the co-spray dried formulation of tobramycin and diclofenac at 2:1 w/w showed smaller particle size (D50, 3.01 ± 0.06 μm), high fine particle fractions (FPF) (61.1 ± 3.6% for tobramycin and 65.92 ± 3 for diclofenac) and faster dissolution with approx. 70% diclofenac released within 3 h and approx. 90% tobramycin was released within 45 min. However, the 3FN for the co-spray dried formulation of tobramycin and diclofenac at a 2:1 w/w ratio showed a larger particle size (D50, 3.42 ± 0.02 μm), lower FPF (40.6 ± 3.4% for tobramycin and 36.9 ± 0.84 for diclofenac) and comparative slower dissolution with approx. 60% diclofenac was released within 3 h and 80% tobramycin was released within 45 min. A similar trend was observed when the tobramycin to diclofenac ratio was increased to 4:1 w/w. Overall results suggest that spray drying with 2FN showed a superior and viable approach to producing excipients-free inhalable co-spray dried formulations of tobramycin and diclofenac. However, the formulation produced using the 3FN showed higher enrichment of hydrophobic diclofenac and an ability to control the tobramycin drug release in vitro.

Dry Powder Inhalers Based on Chitosan-Mannitol Binary Carriers: Effect of the Powder Properties on the Aerosolization Performance.

Carriers play an important role in improving the aerosolization performance of dry powder inhalers (DPIs). Despite that intensive attention had been paid to the establishment of the advanced carriers with controllable physicochemical properties in recent years, the design and optimization of carrier-based DPIs remain an empiricism-based process. DPIs are a powder system of complex multiphase, and thus their physicochemical properties cannot fully explain the powder behavior. A comprehensive exposition of powder properties is demanded to build a bridge between the physicochemical properties of carriers and the aerosolization performance of DPIs. In this study, an FT-4 powder rheometer was employed to explore the powder properties, including dynamic flow energy, aeration, and permeability of the chitosan-mannitol binary carriers (CMBCs). CMBCs were self-designed as an advanced carrier with controllable surface roughness to obtain enhanced aerosolization performance. The specific mechanism of CMBCs to enhance the aerosolization performance of DPIs was elaborated based on the theory of pulmonary delivery processes by introducing powder properties. The results exhibited that CMBCs with appropriate surface roughness had lower special energy, lower aeration energy, and higher permeability. It could be predicted that CMBC-based DPIs had greater tendency to fluidize and disperse in airflow, and the lower adhesion force between particles enabled drugs to be detached from the carrier to achieve higher fine particle fractions. The specific mechanism on how physicochemical properties influenced the aerosolization performance during the pulmonary delivery processes could be figured out with the introduction of powder properties.

State of the Art in Capsule-Based Dry Powder Inhalers: Deagglomeration Techniques and the Consequences for Formulation Aerosolization.

Commercially available dry powder inhalers (DPIs) are usually devices in a fixed combination with the intended formulation, and a change in medication by the physician often forces the patient to use a different device, requiring the patient to relearn how to use it, resulting in lower adherence and inadequate therapy. To investigate whether DPIs can achieve successful outcomes regardless of the formulation and flow rate used, a novel DPI and two commercially available devices were compared in vitro for their deagglomeration behavior for different binary blends and a spray-dried particle formulation. The results demonstrate that the novel device achieved the highest fine particle fraction (FPF) regardless of the formulations tested. In the binary mixtures tested, the highest emitted fraction was obtained by shaking out the powder due to the oscillating motion of the capsule in the novel device during actuation. For DPIs with high intrinsic resistance to airflow, similar FPFs were obtained with the respective DPI and formulation, regardless of the applied flow rate. Additionally, the development and use of binary blends of spray-dried APIs and carrier particles may result in high FPF and overcome disadvantages of spray-dried particles, such as high powder retention in the capsule.

Leucine improves the aerosol performance of dry powder inhaler formulations of siRNA-loaded nanoparticles

Thermostable dry powder inhaler (DPI) formulations with high aerosol performance are attractive inhalable solid dosage forms for local treatment of inflammatory lung diseases. We recently demonstrated that lipidoid-polymer hybrid nanoparticles (LPNs) loaded with small interfering RNA (siRNA) directed against tumor necrosis factor alpha (TNF-α) mediate efficient intracellular siRNA delivery and reduce inflammation in vivo. Here, we show that mixtures of the stabilizing excipients trehalose (Tre) and dextran (Dex), in combination with the shell-forming dispersion enhancer leucine (Leu), stabilize TNF-α siRNA-loaded LPNs during spray drying into nanocomposite microparticles, and result in DPI formulations with high aerosol performance. At low Leu content (0 to 10%, w/w), the DPI formulations were amorphous, and exhibited poor aerosol performance. When the Leu content was increased from 20 to 60% (w/w), the surface content of Leu increased from 39.2 to 68.1 mol%, and the flowability was significantly improved. Microscopy analysis suggest that the improved powder dispersibility is the result of a wrinkled surface morphology, which reduces the surface area available for interparticle interactions. Increasing the Leu content further (to above 10%, w/w) did not influence the aerosol performance, and the aerosol yield was maximal at 30–40% Leu (w/w). Formulations containing 40% Leu and a Tre:Dex ratio of 10:90 (w/w) displayed a high fine particle fraction and aerosol properties suitable for inhalation. The chemical integrity of TNF-α siRNA was preserved in the solid state, and biodistribution studies in mice showed that pulmonary administration of DPI formulations with high aerosol performance resulted in homogenous deep lung deposition. Our results demonstrate that at optimal ratios, ternary excipient mixtures of Leu, Tre and Dex protect TNF-α siRNA-loaded LPNs during spray drying. Hence, this study shows that microparticles with an amorphous Tre/Dex matrix and a crystalline Leu shell efficiently stabilize the nanocomposite LPNs in the solid state, and ensure aerosol properties suitable for inhalation.

Crystallization induced flower-like lactose as potential carriers for dry powder inhaler application

The study documents the flower-like lactose particles as potential carriers to improve Dry Powder Inhaler (DPI) efficiency. The lactose particles (LMx, LMf) are prepared by anti-solvent crystallization and compared with commercial lactose carriers (Inhalac 251; LMc). Formulations of 1.48% w/w drug loading are prepared using salbutamol sulfate (model drug) and different lactose carriers. The carrier properties are correlated with %FPF using principal component analysis. The analytical results confirm LMx is α-lactose monohydrate, LMf comprises α and β-lactose. Time-resolved crystal growth shows that the LMx particle is agglomerated structure while, LMf particle appear as flower-like structure of size (~45.37–63.92 μm) with high surface and aerodynamic properties compared to LMc. The in-vitro aerosolization studies resulted in higher fine particle fraction (%FPF) for formulations with LMx (~33.23%) and LMf (~44.85%) compared to LMc (~23.40%). The high %FPF is mainly attributed to the higher surface roughness, amorphicity, surface energy of engineered lactose carriers.

Pulmonary delivery of resveratrol-β-cyclodextrin inclusion complexes for the prevention of zinc chloride smoke-induced acute lung injury

Smoke bombs are often used in military/fire training, which can produce a large amount of zinc chloride (ZnCl2) smoke. Inhalation of ZnCl2 smoke usually causes acute lung injury (ALI) that would likely develop to acute respiratory distress syndrome (ARDS). However, there is no effective prevention or treatment strategy for the smoke-induced ALI. Resveratrol (RES) is a natural polyphenol with good anti-inflammatory and anti-apoptotic activities, but its low solubility, stability, and bioavailability restrict its clinical application. In this study, an inhalable RES formulation composed of RES-β-cyclodextrin inclusion complexes (RES-β-CD) was prepared for the prevention of ZnCl2 smoke-induced ALI. RES-β-CD powders had a small mass median aerodynamic diameter of 3.61 μm and a high fine particle fraction of 38.84%, suitable for pulmonary inhalation. RES-β-CD exhibited low BEAS-2B cytotoxicity. Pulmonary delivery of RES-β-CD to mice remarkably prevented the smoke-induced ALI with downregulation of TNF-α, IL-1β, STAT3, and GATA3, and upregulation of T-bet and Foxp3. RES-β-CD protected the respiratory function, percutaneous oxygen saturation, physical activity, lung capillary integrity, and lung liquid balance, alleviating inflammation and apoptosis. Pulmonary delivery of the positive drug, budesonide (BUD), also alleviated the smoke-induced ALI by reduction of inflammation and cell apoptosis. RES-β-CD exhibited the regulation of the Th1/Th2 and Treg/Th17 balances, while BUD did not show any effect on immune balances. In conclusion, pulmonary delivery of RES-β-CD is a promising anti-inflammatory and anti-apoptosis strategy for the prevention of ZnCl2 smoke-induced ALI by direct lung drug distribution and regulation of immune balance.

Nano-in-Microparticles for Aerosol Delivery of Antibiotic-Loaded, Fucose-Derivatized, and Macrophage-Targeted Liposomes to Combat Mycobacterial Infections: In Vitro Deposition, Pulmonary Barrier Interactions, and Targeted Delivery.

Nontuberculous mycobacterial infections rapidly emerge and demand potent medications to cope with resistance. In this context, targeted loco-regional delivery of aerosol medicines to the lungs is an advantage. However, sufficient antibiotic delivery requires engineered aerosols for optimized deposition. Here, the effect of bedaquiline-encapsulating fucosylated versus nonfucosylated liposomes on cellular uptake and delivery is investigated. Notably, this comparison includes critical parameters for pulmonary delivery, i.e., aerosol deposition and the noncellular barriers of pulmonary surfactant (PS) and mucus. Targeting increases liposomal uptake into THP-1 cells as well as peripheral blood monocyte- and lung-tissue derived macrophages. Aerosol deposition in the presence of PS, however, masks the effect of active targeting. PS alters antibiotic release that depends on the drug's hydrophobicity, while mucus reduces the mobility of nontargeted more than fucosylated liposomes. Dry-powder microparticles of spray-dried bedaquiline-loaded liposomes display a high fine particle fraction of >70%,as well as preserved liposomal integrity and targeting function. The antibiotic effect is maintained when deposited as powder aerosol on cultured Mycobacterium abscessus. When treating M. abscessus infected THP-1 cells, the fucosylated variant enabled enhanced bacterial killing, thus opening up a clear perspective for the improved treatment of nontuberculous mycobacterial infections.

From laminar to turbulent flow in a dry powder inhaler: The effect of simple design modifications

In order to better understand powder dispersion in dry powder inhaler (DPI) devices, a new powder disperser was designed, which uses flow modifiers to alter powder fluidization behavior so as to physically replicate various flow conditions observed in a range of commercial DPIs. The influence of these modifiers on the performance of the DPI was analyzed for flowrates progressing from laminar (15 L/min) to transitional (30 L/min), and finally turbulent flow regimes (60 L/min) in the device. The aerosol performance of the disperser was measured using a Next Generation Impactor. For flowrate in the laminar regime, powder evacuation from the disperser was generally insufficient (<30%), which was increased to >85% when the device was operated in the turbulent flow regime. In contrast, the highest fine particle fraction (FPF) and lowest throat deposition were achieved when operating in the transitional flow regime. The FPF could be increased further by applying flow modifications such as narrowing the air passage before the powder pocket, inducing localized turbulence (by a grid) near the powder pocket, and by changing the loading position of the powder. Flow modifiers had the most noticeable effect under a laminar flow regime, however, the device operated most efficiently under a transitional flow regime.

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline.

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir–theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature–composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.