Fine Particle Fraction Research Articles

Exploration of Nanomedicine-Based Dry Powder Inhalation Formulation Co-Loaded with Erlotinib and Curcumin for Treatment of Non-Small Cell Lung Cancer

Erlotinib is used as first-line chemotherapy for the treatment of non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancers. Curcumin has potential antitumor effects in different types of cancer including NSCLS with additional chemopreventive and radioprotective effects. The aim of the study was to develop erlotinib and curcumin co-loaded dry powder inhalation (EC-DPI) formulation using nanoprecipitation technique with a goal of achieving a stronger cytotoxic effect against A549 cancer cells. The optimized DPI formulation resulted in suitable particle size (313.28 ± 26.19 nm), polydispersity index (0.156 ± 0.016) and zeta potential (29.4 ± 1.22 mV). Carr’s index (6.62 ± 1.43) and Hausner ratio (1.058 ± 0.03) demonstrated excellent flowability of the powder. The fine particle fraction (64.7 ± 7.8%) and mass median aerodynamic diameter (2.98 ± 0.04 [Formula: see text]m) of the optimized formulation revealed good aerosol performance and its suitability for direct delivery to the lungs. In-vitro cytotoxic potential of EC-DPI was determined against A549 cancer cells and compared with curcumin-loaded DPI formulation (C-DPI) and erlotinib-loaded DPI formulation (E-DPI). The IC[Formula: see text] values for E-DPI and C-DPI were found to be 36.6 ± 2.4 [Formula: see text]M and 24.4 ± 2.7 [Formula: see text]M, respectively. The IC[Formula: see text] value for EC-DPI was 20.5 ± 2.1 [Formula: see text]M confirming the synergistic effect of both drugs against A549 cancer cells. The internalization of the drug inside A549 cells was detected by a cellular uptake study. The EC-DPI demonstrated the highest cellular uptake (0.07 ± 0.006 ng/[Formula: see text]g) followed by the formulation containing curcumin (0.05 ± 0.003 ng/[Formula: see text]g) and erlotinib (0.03 ± 0.004 ng/[Formula: see text]g) alone at the end of 6 h. Hence, the developed DPI formulation can be considered as a potential therapeutic approach for the direct delivery of erlotinib and curcumin to treat NSCLC.

Dandelion inspired microparticles with highly efficient drug delivery to deep lung

Active pharmaceutical ingredient (API) embedded dry powder for inhalation (AeDPI) shows higher drug loading and delivery dose for directly treating various lung infections. Inspired by the dandelion, we propose a novel kind of AeDPI microparticle structure fabricated by spray freeze drying technology, which would potentially enhance the alveoli deposition efficiency. When inhaling, such microparticles are expected to be easily broken-up into fragments containing API that acts as ‘seed’ and could be delivered to alveoli aided by the low density ‘pappus’ composed of excipient. Herein, itraconazole (ITZ), a first-line drug for treating pulmonary aspergillosis, was selected as model API. TPGS, an amphiphilic surfactant, was used to achieve stable primary ITZ nanocrystal (INc) suspensions for spray freeze drying. A series of microparticles were prepared, and the dandelion-like structure was successfully achieved. The effects of feed liquid compositions and freezing parameters on the microparticle size, morphology, surface energy, crystal properties and in vitro aerosol performance were systematically investigated. The optimal sample (SF(-50)D-INc7Leu3-2) in one-way experiment showed the highest fine particle fraction of ∼ 68.96 % and extra fine particle fraction of ∼ 36.87 %, equivalently ∼ 4.60 mg and ∼ 2.46 mg could reach the lung and alveoli, respectively, when inhaling 10 mg dry powders. The response surface methodology (RSM) analysis provided the optimized design space for fabricating microparticles with higher deep lung deposition performance. This study demonstrates the advantages of AeDPI microparticle with dandelion-like structure on promoting the delivery efficiency of high-dose drug to the deep lung.

Pulmonary delivery of magnolol-loaded nanostructured lipid carriers for COPD treatment

Chronic obstructive pulmonary disease (COPD) is a prevalent lung condition characterized by airflow obstruction, disability, and high mortality rates. Magnolol (MA), known for its anti-inflammatory and antioxidant properties, holds the potential for alleviating COPD symptoms. However, MA faces challenges like poor aqueous solubility and low bioavailability. Herein MA-loaded nanostructured lipid carriers (MA-NLC) were prepared using emulsification and solvent evaporation. These carriers exhibited a particle size of (19.67 ± 0.36) nm, a polydispersity index of (0.21 ± 0.01), and a zeta potential of (−5.18 ± 0.69) mV. The fine particle fraction of MA-NLC was (68.90 ± 0.07)%, indicating minimal lung irritation and enhanced safety. Pulmonary delivery of MA-NLC via nebulizer actively targeted the diseased lung tissues, facilitated slow release, and overcame the challenges of low oral absorption and bioavailability associated with MA. This formulation prolonged the residence time of MA and optimized its therapeutic effect in pulmonary tissues. Upon pulmonary administration, MA-NLC effectively regulated inflammatory and oxidative stress markers in COPD models, demonstrating its potential as a promising therapeutic platform for COPD management.

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.

Effect of Magnesium Stearate and Fines on Delivery of Dry Powder for Inhalation using Sucrose as a Carrier

Typically, lactose is utilised as carrier in Dry Powder Inhaler commercially. However, with the widening scope of DPI in therapeutic categories other than COPD and asthma, a need for the alternate carrier is arising. In this study, we used sucrose, a non-reducing sugar, as an alternate carrier. Effect of addition of fines and magnesium stearate was studied on powder flow properties and aerosolization performance. The air jet milling technique was used to generate sucrose fines. DSC and XRD studies showed no change in sucrose polymorph upon micronization. Levosalbutamol sulphate was used as a model drug, powder blends were prepared by low shear tumbling type blender. Powder formulations were studied for PSD, blend homogeneity, and flow properties. The percentage of particles smaller than 5 microns rose when fines were added as indicated by PSD data. SEM study revealed that the added fines get adsorbs on the coarse carrier, thus minimizing the adhesive interactions between drug and coarse carrier. In-vitro deposition was studied using low and high resistance devices on glass Twin Stage Impinger (TSI). Addition of fines and the magnesium stearate improves aerosolization performance showing higher Fine Particle Fraction (FPF) by almost 2 folds than the formulation containing coarse carrier alone.

Influence of particle diameter on aerosolization performance and release of budesonide loaded mesoporous silica particles

The potential of micron-sized amorphous mesoporous silica particles as a novel controlled release drug delivery system for pulmonary administration has been investigated. Mesoporous silica formulations were demonstrated to provide a narrower particle size distribution and (spherical) shape uniformity compared to commercial micronized formulations, which is critical for repeatable and targeted aerosol delivery to the lungs. The release profiles of a well-known pulmonary drug loaded into mesoporous particles of different mean particle diameters (2.4, 3.9 and 6.3 µm) were analysed after aerosolization in a modified Andersen Cascade Impactor. Systematic control of the release rate of drug loaded into the particles was demonstrated in simulated lung fluid by variation of the mean particle diameter, as well as an enhanced release compared to a commercial micronized formulation. The mesoporous silica formulations all demonstrated an increased release rate of the loaded drug and moreover, under aerosolization from a commercial, low-cost dry powder inhaler (DPI) device, the formulations showed excellent performance, with low retainment and commercially viable fine particle fractions (FPFs). In addition, the measured median mass aerodynamic diameter (MMAD) of the different formulations (2.8, 4.1 and 6.2 µm) was shown to be tuneable with particle size, which can be helpful for targeting different regions in the lung. Together these results demonstrate that mesoporous silica formulations offer a promising novel alternative to current dry powder formulations for pulmonary drug delivery.

Preparation and Evaluation of Inhalable Microparticles with Improved Aerodynamic Performance and Dispersibility Using L-Leucine and Hot-Melt Extrusion.

Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility while simultaneously maintaining the high aerodynamic performance of inhalable microparticles. This study explored using LEU in HME to improve dispersibility and maintain the high aerodynamic performance of inhalable microparticles. Formulations with crystalline itraconazole (ITZ) and LEU were made via co-jet milling and HME followed by jet milling. The LEU ratio varied, comparing solubility, homogenization, and aerodynamic performance enhancements. In HME, ITZ solubility increased, and crystallinity decreased. Higher LEU ratios in HME formulations reduced the contact angle, enhancing mass median aerodynamic diameter (MMAD) size and aerodynamic performance synergistically. Achieving a maximum extra fine particle fraction of 33.68 ± 1.31% enabled stable deep lung delivery. This study shows that HME combined with LEU effectively produces inhalable particles, which is promising for improved drug dispersion and delivery.

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.

Improved creep strength of 10% Cr steels with low N and high B content via increasing quenching temperature

An increase in quenching temperature from 1050 °C to 1100 °C is found to be an effective approach to improving the creep strength at 650 °C in two Re-containing 10% Cr martensitic steels with low N and high B contents. Creep time at creep tests of 650 °C/120 MPa increases at the expense of the appearance of the steady-state creep stage in both steels. Moreover, the room yield strength and ultimate tensile strength are also increased by 10% with increasing quenching temperature in the steel with 0.8% Cu, whereas tensile tests at 650 °C do not reveal the increment in strength in both steels. Improvement in creep and tensile properties is caused by an increase in particle strengthening due to M23C6 carbides, mainly in both steels. The NbX, VX, and “Cu”-clusters/precipitates make minor contributions to the change in particle strengthening. Refinement of M23C6 carbides in both steels is accompanied by an increase in particle number density along the martensitic laths and an increase in the fraction of fine particles with sizes below 50 nm. Such changes in M23C6 carbide dispersions are caused by an increase in the lath area per unit volume and the enrichment of the solid solution with boron because of the dissolution of W2B particles with increasing quenching temperatures.

Effect of fluticasone propionate/formoterol and fluticasone furoate/vilanterol on adolescents with chronic bronchial obstruction

BackgroundThe combination of inhaled corticosteroid and long-acting beta-agonist (ICS/LABA) has shown superiority in improving lung function (FEV1) compared with ICS. The clinical effect of ICS/LABA depends on the fine-particle fraction (FPF) and the pulmonary deposition. ObjectiveWe sought to compare the efficacy of two combinations of an inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA), fluticasone propionate/formoterol and fluticasone furoate/vilanterol, in asthmatic adolescents with chronic bronchial obstruction. MethodsFluticasone propionate/formoterol (FP/FORM) (125/5 μg 2 doses twice daily via the k-haler®) and fluticasone furoate/vilanterol (FF/VI) (92/22 μg once daily via the Ellipta®) were administered to adolescents aged 12 to 17 years who required regular anti-asthmatic medication and had a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio below -1.65 SD in a 2-sequence, 16-week crossover trial. The primary efficacy end point was change in FEV1 compared to baseline. Secondary end points were FEV1/FVC, maximal expiratory flow at 50% of the forced vital capacity (MEF50), impulse oscillometry indices respiratory resistance at 5 Hz (R5), difference of R5 and R20 (R5−20), area of reactance (AX), and Asthma Control Test. ResultsBoth ICS/LABA combinations resulted in a significant improvement in FEV1 and MEF50 Z-scores without any significant difference between FP/FORM and FF/VI. Forty percent of patients achieved a normal prebronchodilator FEV1/FVC Z-score with either treatment. AX or R5−20 did not improve significantly with either treatment. ConclusionBoth ICS/LABA combinations demonstrated significant improvements in FEV1 Z-score. Over one-third of the asthmatic adolescents with prolonged bronchial obstruction achieved a normal prebronchodilator FEV1/FVC level.

Multi-year analysis of physical interactions between solar PV arrays and underlying soil-plant complex in vegetated utility-scale systems

Concerns over the land use changes impacts of solar photovoltaic (PV) development are increasing as PV energy development expands. Co-locating utility-scale solar energy with vegetation may maintain or rehabilitate the land's ability to provide ecosystem services. Previous studies have shown that vegetation under and around the panels may improve the performance of the co-located PV and that PV may create a favorable environment for the growth of vegetation. While there have been some pilot-scale experiments, the existence and magnitude of these benefits of vegetation has not been confirmed in a utility-scale PV facility over multiple years. In this study we use power output data coupled with microclimatic measurements in temperate climates to assess these potential benefits. This study combines multi-year microclimatic measurements to analyze the physical interactions between PV arrays and the underlying soil-vegetation system in three utility-scale PV facilities in Minnesota, USA. No significant cooling of PV panels or increased power production was observed in PV arrays with underlying vegetation. Fine soil particle fraction was the highest in soils within PV arrays with the vegetation which was attributable to the lowest wind speeds from the compounding suppression of wind by vegetation and PV arrays. Soil moisture and soil nutrient response to re-vegetation varied between PV facilities, which could be attributed to differing soil texture. No statistically significant vegetation-driven panel cooling was observed in this climate. This finding prompts a need for site-specific studies to identify contributing factors for environmental co-benefits in co-located systems.

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.

Enrichment and fractionation of rare earth elements (REEs) in ion-adsorption-type REE deposits: Constraints of an iron (hydr)oxide–clay mineral composite

Abstract Ion-adsorption-type rare earth element (REE) deposits are the source of more than 90% of global heavy REEs (HREEs). Thus, understanding the ore genesis of REEs, particularly the distribution characteristics and enrichment mechanisms of HREEs, is vital for efficient exploration and mining of ion-adsorption-type REE deposits worldwide. The characteristics and petrogenesis of bedrock, and the aqueous mobility of REEs, are known to be important factors controlling REE accumulation and fractionation in the weathering crust of REE deposits. However, the effect of REE adsorption on secondary minerals, which is a crucial step in deposit formation, remains poorly understood. This problem was addressed by the study described herein, which involved a systematic analysis of the complete weathering profile (78 m) of the Renju ion-adsorption-type REE deposit in South China and a simulated adsorption experiment. Clay minerals and iron (Fe) (hydr)oxides are the dominant REE adsorbents in the weathering crust and most are micro-to-nanosized particles. Thus, the fine particle fraction (&amp;lt; 2 μm) was separated from field samples, to better disclose their effects on the concentration and redistribution of REEs. Phase compositions and morphologies were characterized by X-ray diffraction, Mössbauer spectrometry, and scanning/transmission electron microscopy (SEM/TEM), which revealed that various clay minerals and Fe (hydr)oxides form composites along the profile of the deposit. Composites of ferrihydrite–kaolinite, goethite–kaolinite/halloysite, and hematite–kaolinite/halloysite were found to be distributed in the semi-weathered, completely weathered, and topsoil layers, respectively, with different sizes and shapes. The concentrations and partition patterns of REEs in different occurrence states were distinguished after sequential extraction. Ion-exchangeable-REEs were the major state and enriched in the upper completely weathered layer. These species were found to be adsorbed onto kaolinite and halloysite via electrostatic attraction, without obvious fractionation. Fe (hydr)oxides were determined to comprise ca. 20% of REEs at most depths and over 50% of REEs in the topsoil and semi-weathered layer. It was found that Fe (hydr)oxides scavenge REEs through complexation and oxidation, resulting in HREE enrichment and a positive cerium (Ce) anomaly, respectively. In addition, compared with crystalline Fe (hydr)oxides, amorphous Fe (hydr)oxides immobilize more REEs but exhibit weaker preferential adsorption of HREEs. The above-described findings are consistent with the results of simulated experiments for REE adsorption onto a clay mineral–Fe (hydr)oxide composite (Bt-60), which was obtained from hydrothermal processing of biotite. Furthermore, the distributions and stabilities of LREEs and HREEs were distinguished by TEM–energy–dispersive spectroscopy (EDS) of Bt-60 before and after REE extraction by ammonium sulfate. The phase transformation pathways of clay minerals and Fe (hydr)oxides, and their different enrichment and fractionation characteristics in REEs, were also discussed in terms of the structure and surface properties of minerals, adsorption mechanisms, and variations in chemical properties across the REE group. The results shed new light on how clay minerals and Fe (hydr)oxides affect the enrichment and fractionation of REEs in ion-adsorption-type deposits.

Inflammatory-Targeted Lipid Carrier as a New Nanomaterial to Formulate an Inhaled Drug Delivery System.

There is a pressing need for efficacious therapies in the field of respiratory diseases and infections. Lipid nanocarriers, administered through aerosols, represent a promising tool for maximizing therapeutic concentration in targeted cells and minimizing systemic exposure. However, this approach requires the application of efficient and safe nanomaterials. Palmitoylethanolamide (PEA), an endocannabinoid-like endogenous lipid, plays a crucial role in providing protective mechanisms during inflammation, making it an interesting material for preparing inhalable lipid nanoparticles (LNPs). This report aims to preliminarily explore the in vitro behavior of LNPs prepared with PEA (PEA-LNPs), a new inhalable inflammatory-targeted nanoparticulate drug carrier. PEA-LNPs exhibited a size of about 250 nm, a rounded shape, and an marked improvement in PEA solubility in comparison to naked PEA, indicative of easily disassembled nanoparticles. A twin glass impinger instrument was used to screen the aerosol performance of PEA-LNP powders, obtained via freeze-drying in the presence of two quantities of mannose as a cryoprotectant. Results indicated that a higher amount of mannose improved the emitted dose (ED), and in particular, the fine particle fraction (FPF). A cytotoxicity assay was performed and indicated that PEA-LNPs are not toxic towards the MH-S alveolar macrophage cell line up to concentrations of 0.64 mg/mL, and using coumarin-6 labelled particles, a rapid internalization into the macrophage was confirmed. This study demonstrates that PEA could represent a suitable material for preparing inhalable lipid nanocarrier-based dry powders, which signify a promising tool for the transport of drugs employed to treat respiratory diseases and infections.

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.

Triple combination dry powder formulation of pretomanid, moxifloxacin, and pyrazinamide for treatment of multidrug-resistant tuberculosis

Both latent and multidrug-resistant tuberculosis (TB) have been causing significant concern worldwide. A novel drug, pretomanid (PA-824), has shown a potent bactericidal effect against both active and latent forms of Mycobacterium tuberculosis (MTb) and a synergistic effect when combined with pyrazinamide and moxifloxacin. This study aimed to develop triple combination spray dried inhalable formulations composed of antitubercular drugs, pretomanid, moxifloxacin, and pyrazinamide (1:2:8 w/w/w), alone (PaMP) and in combination with an aerosolization enhancer, L-leucine (20 % w/w, PaMPL). The formulation PaMPL consisted of hollow, spherical, dimpled particles (<5 μm) and showed good aerosolization behaviour with a fine particle fraction of 70 %. Solid-state characterization of formulations with and without L-leucine confirmed the amorphous nature of moxifloxacin and pretomanid and the crystalline nature of pyrazinamide with polymorphic transformation after the spray drying process. Further, the X-ray photoelectron spectroscopic analysis revealed the predominant surface composition of L-leucine on PaMPL dry powder particles. The dose–response cytotoxicity results showed pyrazinamide and moxifloxacin were non-toxic in both A549 and Calu-3 cell lines up to 150 µg/mL. However, the cell viability gradually decreased to 50 % when the pretomanid concentration increased to 150 µg/mL. The in vitro efficacy studies demonstrated that the triple combination formulation had more prominent antibacterial activity with a minimum inhibitory concentration (MIC) of 1 µg/mL against the MTb H37Rv strain as compared to individual drugs. In conclusion, the triple combination of pretomanid, moxifloxacin, and pyrazinamide as an inhalable dry powder formulation will potentially improve treatment efficacy with fewer systemic side effects in patients suffering from latent and multidrug-resistant TB.

Development of Paclitaxel Proliposomal Dry Powder Inhaler (PTX-PLM-DPI) by Freeze-Drying Method for Lung Cancer

Despite various efforts, a successful selective delivery system for chemotherapeutic agents for lung cancer is still lacking. Dry powder inhaler (DPI) systems based on proliposomes (PLMs) could be a potential system for the efficient delivery of paclitaxel to lungs. PLM-based DPI prepared with a freeze-drying method can therefore be an alternative. Paclitaxel-loaded PLM-based DPI (PTX-PLM-DPI) powders were prepared using the method of thin film deposition on a carrier followed by freeze drying. These were prepared using soya phosphatidylcholine (SPC) and cholesterol as the lipids and mannitol as the carrier. The reconstituted liposomes were evaluated in terms of size, morphology, drug entrapment, release and cytotoxicity. The DPI powders were evaluated for their flow property, surface topography, dose uniformity and in vitro lung deposition. Stable and free-flowing PTX-PLM-DPI powder was obtained that could be reconstituted into homogenous liposomal vesicles &lt; 200 nm as confirmed by TEM and SEM studies. The liposomes showed drug entrapment of 92.64 ± 1.4% and diffusion-controlled release of up to 28% in 24 h. These liposomes showed better dose-dependent cytotoxicity in A549 cells in comparison to paclitaxel suspension with IC50 values of 46 ± 0.87 ng/mL and 154.9 ± 3.64 ng/mL, respectively. In vitro lung deposition studies of the PTX-PLM-DPI showed sufficient deposition with the fine particle fraction (FPF) of 50.86 ± 2.8% of particles with an aerodynamic diameter less than 5 µ. Hence, it canbe concluded that PLM-based DPI prepared by freeze drying can be a promising, stable, safe and free-flowing system for the enhanced lung delivery of paclitaxel.

Preparation, Optimization and In Vitro Characterization of Fluticasoneloaded Mixed Micelles Based on Stearic Acid-g-chitosan as a Pulmonary Delivery System.

The primary objective of this study was to optimize formulation variables and investigate the in vitro characteristics of fluticasone propionate (FP)-loaded mixed polymeric micelles, which were composed of depolymerized chitosan-stearic acid copolymer (DC-SA) in combination with either tocopheryl polyethylene glycol succinate or dipalmitoylphosphatidylcholine for pulmonary drug delivery. A D-optimal design was employed for the optimization procedure, considering lipid/ polymer ratio, polymer concentration, drug/ polymer ratio, and lipid type as independent variables. Dependent variables included particle size, polydispersion index, zeta potential, drug encapsulation efficiency, and loading efficiency of the polymeric micelles. Additionally, the nebulization efficacy and cell viability of the optimal FP-loaded DC-SA micellar formulations were evaluated. The mixed polymeric micelles were successfully prepared with properties falling within the desired ranges, resulting in four optimized formulations. The release of FP from the optimal systems exhibited a sustained release profile over 72 hours, with 70% of the drug still retained within the core of the micelles. The nebulization efficiency of these optimal formulations reached up to 63%, and the fine particle fraction (FPF) ranged from 41% to 48%. Cellular viability assays demonstrated that FP-loaded DC-SA polymeric micelles exhibited lower cytotoxicity than the free drug but were slightly more cytotoxic than empty mixed micelles. In conclusion, this study suggests that DC-SA/ lipid mixed micelles have the potential to serve as effective carriers for nebulizing poorly soluble FP.

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.