Search Results (166)

Background/Objectives: The integration of machine learning (ML) and artificial intelligence (AI) has revolutionized the pharmaceutical industry by improving drug discovery, development and manufacturing processes. Based on literature data, an ML model was developed by our group to predict the formation of binary co-amorphous systems (COAMSs) for inhalation therapy. The model’s ability to develop a dry powder formulation with the necessary properties for a predicted co-amorphous combination was evaluated. Methods: An extended experimental validation of the ML model by co-milling and X-ray diffraction analysis for 18 API-API (active pharmaceutical ingredient) combinations is presented. Additionally, one COAMS of rifampicin (RIF) and ethambutol (ETH), two first-line tuberculosis (TB) drugs are developed further for inhalation therapy. Results: The ML model has shown an accuracy of 79% in predicting suitable combinations for 35 APIs used in inhalation therapy; experimental accuracy was demonstrated to be 72%. The study confirmed the successful development of stable COAMSs of RIF-ETH either via spray-drying or co-milling. In particular, the milled COAMSs showed better aerosolization properties (higher ED and FPF with lower standard deviation). Further, RIF-ETH COAMSs show much more reproducible results in terms of drug quantity dissolved over time. Conclusions: ML has been shown to be a suitable tool to predict COAMSs that can be developed for TB treatment by inhalation to save time and cost during the experimental screening phase. Full article

This review explores recent advancements in inhaled nanoparticle formulations and inhalation devices, with a focus on various types of nanoparticles used for inhalation to treat inflammatory lung diseases and the types of devices used in their delivery. Medical nebulizers have been found to be the most appropriate type of inhalation devices for the pulmonary delivery of nanoparticles, since formulations can be prepared using straightforward techniques, with no need for liquefied propellants as in the case of pressurized metered dose inhalers (pMDIs), or complicated preparation procedures as in the case of dry powder inhalers (DPIs). We demonstrated examples of how formulations should be designed considering the operation mechanism of nebulizers, and how an interplay of factors can affect the aerosol characteristics of nanoparticle formulations. Overall, nanoparticle-based formulations offer promising potential for the treatment of inflammatory lung diseases due to their unique physicochemical properties and ability to provide localized drug delivery in the lung following inhalation. Full article

The synthesis of oxide nanopowders through ultrasonic spray pyrolysis (USP) represents a sustainable method for producing high-purity, spherical particles tailored for advanced material applications. Recent developments in USP synthesis leverage the continuous transport of aerosols from an ultrasonic generator to a high-temperature furnace, with nanopowders collected efficiently using an electrostatic precipitator. This study explored the use of USP for titanium oxysulfate and aluminum nitrate solutions derived from the aluminum industry, focusing on resource recovery and waste reduction. Titanium oxysulfate was synthesized by leaching slag, generated during the reduction of red mud, with sulfuric acid under oxidizing, high-pressure conditions. After purification, the titanium oxysulfate solution was processed using USP in a hydrogen reduction atmosphere to yield spherical titanium dioxide (TiO₂) nanopowders. The hydrogen atmosphere enabled precise control over the nanoparticles’ morphology and crystallinity, enhancing their suitability for use in applications such as photocatalysis, pigments, and advanced coatings. In parallel, both synthetic and laboratory solutions of aluminum nitrate [Al(NO₃)₃] were prepared. The laboratory solution was prepared by leaching aluminum hydroxide oxide (AlOOH) with hydrochloric acid to form aluminum chloride (AlCl₃), followed by a conversion to aluminum nitrate through the addition of nitric acid. The resulting aluminum nitrate solution was subjected to USP, producing highly uniform, spherical alumina (Al₂O₃) nanopowders with a narrow size distribution. The resulting nanopowders, characterized by their controlled properties and potential applicability, represent an advancement in oxide powder synthesis and resource-efficient manufacturing techniques. Full article

The present investigation aimed to formulate and optimize sustained release proliposome dry powder for inhalation of Voriconazole (VZ) and its in vitro and in vivo evaluation. The proliposome-based dry powder for inhalation was formulated by spray drying technique using Phospholipon 90H and cholesterol in the lipid phase, mannitol as a carrier, and L-leucine as a dispersing agent. A face-centered central composite design was used to study the influence of factors on responses, vesicle size, VZ entrapment efficiency, and drug release. The optimized formulation was further characterized by FTIR, FESEM, DSC, XRD, and evaluated for in vitro drug release, in vitro aerosol deposition, and in vivo lung retention study in Wistar rats. For the optimized batch F-5 proliposome formulation, vesicle size was observed as 191.7 ± 0.049 nm with PDI 0.328 ± 0.009, entrapment efficiency as 72.94 ± 0.56%, and cumulative drug release after 8 h of dissolution was 82.0 ± 0.14%. The median mass aerodynamic diameter (MMAD) generated by optimized formulation F5 was significantly lower (3.85 ± 0.15 µm, p < 0.0001) as compared to spray-dried voriconazole (SD-VZ) (8.35 ± 0.23 µm). In vivo studies demonstrated a profound enhancement in lung retention (3.8-fold) compared to SD-VZ and oral VZ dispersion. Conclusively, proliposome formulation of voriconazole is a plausible and convincing approach for pulmonary fungal infections, considering its sustained release behaviour and prolonged lung retention. Full article

Cyclodextrins (CDs) enhance the solubility of poorly water-soluble drugs like ibuprofen (IBU), making them promising carriers for pulmonary drug delivery. This route lowers the required dose, minimizing side effects, which could be beneficial in treating cystic fibrosis. In this study, a nano-spray-drying technique was applied to prepare CD/IBU complexes using sulfobutylether-β-cyclodextrin (SBECD) or (2-Hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin chloride (QABCD) as carriers as well as mannitol (MAN) and leucine (LEU) as aerosolization excipients. Various investigation techniques were utilized to examine and characterize the samples, including a Master Sizer particle size analyzer, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). We applied in vitro Andersen Cascade Impactor measurements and in silico simulation analysis to determine the sample’s aerodynamic properties. We also performed in vitro dissolution and diffusion tests. Applying formulations with optimal aerodynamic properties, we achieved an improved ~50% fine particle fraction values based on the Andersen Cascade Impactor measurements. The in vitro dissolution and diffusion studies revealed rapid IBU release from the formulations; however, the QABCD-based sample exhibited reduced membrane diffusion compared to SBECD due to the formation of electrostatic interactions. Full article

Background/Objectives: Herein, we demonstrate the development and characterization of ceftriaxone (CTX)-loaded liposomal nanoparticles (NPs) intended to be applicable to the management of lower respiratory tract infections (LRTIs) associated with resistant bacteria. Methods: The CTX-loaded liposomal NPs were fabricated by a thin film hydration approach. Results: The particle size of the NPs, determined by a Zetasizer, was within the range of 90–536 nm. Microscopic examination by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) revealed that particles are spherical in shape and have retained their original morphology even after freeze-drying. Attenuated total reflection-Fourier transform infrared (ATR-FTIR), differential scanning calorimetry (DSC), thermogravimetric (TG), and powder X-ray diffraction (PXRD) spectra exhibited that CTX is incorporated into the liposomes with no possible interaction between drug and excipients. The formation of the CTX-loaded liposomal NPs was dependent on the concentrations of phospholipids, cholesterol and mannitol; however, no considerable differences were observed in entrapment efficiency and loading capacity of CTX formulations (F6–F10). Using a twin-stage impinger (TSI), the in vitro aerosolization of the formulations were carried out at a flow rate of 60 ± 5 L/min and CTX was determined by a validated HPLC method and the prepared liposomal formulations produced promising fine particle fraction (FPF) between 47 and 62%. The prepared formulation (F6) showed prolonged CTX release of 94.0% ± 5.7 and 95.9% ± 3.9 at 24 h and 48 h, respectively. The drug release followed the Hixon–Crowell model, with CTX being transported through Fickian diffusion. Conclusions: These results highlight the prepared CTX-loaded inhaled liposomal formulation would be suitable for pulmonary delivery and extend the successful antibiotic delivery strategies for the effective management of LRTIs. Full article

The aerosol deposition (AD) method utilizes high kinetic-energy submicron powders to impact and form a film on a substrate. It is a highly efficient deposition method, capable of producing films or coatings with a strong interfacial bonding and a dense nano-grain structure without thermal assistance. In this work, PbZr_0.53Ti_0.47O₃ (PZT53/47) films (~1.2 μm thick) were deposited on Pt/Ti/Si(100) substrates via the AD method. After a conventional annealing process (700 °C for 1 h), these PZT53/47 films displayed a dense, crack-free, nano-grained morphology, corresponding to an optimal electrical performance. A large maximum polarization (P_max = 70 μC/cm²) and a small coercive field (E_c = 104 kV/cm) were achieved under the maximum applicable electric field of 1.6 MV/cm. The PZT53/47 films also exhibited a large small-field dielectric constant of ~984, a high tunability of 72%, and a low leakage current of ~3.1 × 10⁻⁵ A/cm² @ 40 V. Moreover, the transverse piezoelectric coefficient (e_31.f) of these AD-processed films was as high as −4.6 C/m², comparable to those of sputter-deposited PZT53/47 films. These high-quality PZT53/47 thick films have broad applications in piezoelectric micro-electromechanical systems. Full article

Background/Objective: Surface enrichment of hydrophobic excipients via spray drying has been demonstrated as an efficient way to protect the dry powder inhaler formulations against moisture-induced deterioration in aerosol performance. However, the impact of such surface enrichment on dissolution and cellular uptake is less investigated, which can affect the safety and efficacy of dry powder inhalers (DPIs). Methods: In the present work, hygroscopic colistin was coated with leucine or trileucine, at different weight ratios during spray drying. All the powders were exposed to 75% relative humidity for one week. The aerosol performance was compared before and after the moisture exposure. Various solid-state characterizations, including particle size, particle morphology, crystallinity, water sorption/desorption, and surface composition, were conducted to evaluate the properties of spray-dried colistin with/without leucine or trileucine. Results: The results indicated that leucine or trileucine could protect the aerosol performance of spray-dried colistin against moisture deterioration. Leucine crystallized after spray drying with colistin, and such crystal leucine could further hinder water uptake when leucine was at a 20% or higher weight ratio. Trileucine did not crystallize after spray drying with colistin nor reduce the water uptake. Interestingly, trileucine showed a superior moisture protective effect to that of leucine, which could be attributed to its better surface enrichment efficiency than that of leucine due to its lower water solubility. Conclusions: Importantly, our results showed that the surface enrichment with leucine and trileucine did not significantly affect in vitro dissolution of colistin in the Franz cell test and cellular uptake of colistin in the H441 lung epithelium cell model, which could be attributed to small particle size and incomplete surface coverage by leucine or trileucine. Full article

This manuscript provides a comprehensive review of advancements in dry powder inhaler (DPI) technology for pulmonary and systemic drug delivery, focusing on proteins, peptides, nucleic acids, and small molecules. Innovations in spray-drying (SD), spray freeze-drying (SFD), and nanocarrier engineering have led to enhanced stability, bioactivity, and aerosol performance. Studies reveal the critical role of excipients, particle morphology, and device design in optimizing deposition and therapeutic efficacy. Applications include asthma, cystic fibrosis, tuberculosis (TB), and lung cancer, with emerging platforms such as ternary formulations and siRNA-loaded systems demonstrating significant clinical potential. Challenges such as stability, scalability, and patient adherence are addressed through novel strategies, including Quality by Design (QbD) approaches and advanced imaging tools. This work outlines pathways for future innovation in pulmonary drug delivery. Full article

Dry powder inhalers (DPI’s) are becoming increasingly popular due to growing interest in pulmonary drug delivery and their performance is the net result of a series of processes carried out during the formulation development and manufacturing process such as excipient selection, blending, milling, filling, and spray drying. To reach the small airways of the deep lung, the active pharmaceutical ingredients (API) particles need to have an aerodynamic diameter of 1–5 μm to avoid impaction and particle sedimentation in the upper respiratory tract, and due to this small particle size, the powder becomes highly cohesive resulting in poor flow. Therefore, API is usually blended with a coarse carrier to improve flowability, and due to its large size, it is more fluidizable than the micronized drug. Carrier-based DPI formulations usually consist of micronized drugs, a coarse carrier, and additional components, such as micronized lactose and force control agents, including magnesium stearate or leucine. Additionally, the manufacturing process of DPIs relies heavily on powder processing technologies, such as the micronization of API, blending, and powder filling. The aerosol performance of a DPI is significantly affected by the selection of formulation components and the processing of the formulation and, therefore, it is crucial to evaluate these parameters. This review will discuss different factors influencing the aerosol performance of carrier-based DPIs, including formulation components, device considerations, and manufacturing parameters. Additionally, novel technologies pertaining to the optimization of DPI performance are also discussed. Full article

Zinc sulphide is a widely used inorganic powder, and its production has reached quantities greater than 1000 t/year. Therefore, in accordance with OECD guideline 436, an acute inhalation test was implemented to provide more accurate data. This study is crucial for ensuring the safety of workers exposed to zinc sulphide dust and complying with regulatory requirements for REACH. Due to particle-specific properties, the maximum attainable concentration of zinc sulphide for an inhalation study was not certain. Two dry dispersion systems were used to aerosolize the zinc sulphide powder, and the generated aerosol was supplied to a nose-only inhalation exposure system. The results showed a maximum attainable concentration of 0.82 mg/L at an MMAD of 1.5 µm over a 4 h exposure. In the inhalation study, all six rats showed no specific symptoms and good health status and survived a post-exposure observation period of up to 14 days. From the results observed, the status of Not classified was derived according to CLP. Based on the experimental results, an LC50 was not determined but is considered to be higher than 0.82 mg/L (the maximum achievable aerosol concentration). These findings highlight the importance of documenting efforts to achieve aerosol conditions when concentrations required by OECD test guidelines cannot be reached. Full article

In this study, Fe₆₀Co_10−xNi₁₅Cr₁₅Si_x (x = 0, 4, and 8) powders were successfully prepared using the aerosol method and employed to produce high-entropy coatings on Q235 steel via laser cladding. The microstructure and phase composition of the coatings were analyzed using scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray diffraction. Corrosion resistance and potential were evaluated through electrochemical analysis and Kelvin probe force microscopy. The results show that the Fe₆₀Co_10−xNi₁₅Cr₁₅Si_x coatings exhibit excellent metallurgical bonding with no visible porosity or cracks. The coating primarily consists of an FCC structure; however, as the Si content increases, the structure transitions to a mixed FCC + BCC phase. The addition of Si also refines the grain size in the alloy system. Electrochemical analysis reveals that the Si0 and Si4 coatings exhibit similar corrosion behavior, while the Si8 coating shows a significant drop in corrosion potential, reducing its corrosion resistance. As the Si content increases, grain refinement leads to more grain boundaries, but the corrosion resistance decreases due to the lower corrosion performance of Si compared to Co. Considering both cost and corrosion resistance, the Si4 coating offers a balance of low cost and excellent corrosion resistance. Full article

Background/Objectives: Curcumin is well known for its great anti-inflammatory and antioxidant efficacy, representing a potential strategy for the treatment of respiratory disorders. However, several drawbacks, such as chemical instability, poor water solubility and rapid metabolism, result in low bioavailability, limiting its clinical applications. In this study, curcumin nanocrystals were incorporated into mannitol-based microparticles to obtain an inhalable dry powder. Methods: A curcumin nanosuspension was produced by wet-ball media milling and thoroughly characterized. Spray drying was then used to produce mannitol microparticles incorporating curcumin nanocrystals. In vitro release/dissolution tests were carried out in simulated lung fluids, and the aerosolization properties were evaluated using a Next-Generation Impactor (NGI, Apparatus E Ph. Eu.). Results: The incorporation of curcumin nanocrystals into mannitol-based microparticles influenced their morphological properties, such as geometric diameters, and flowability. Despite these changes, nebulization studies confirmed optimal MMAD values (<5 µm), while multi-step dissolution/release studies evidenced the influence of mannitol. Conclusions: The developed curcumin nanocrystals-loaded mannitol microparticles show promise as an inhalable treatment for respiratory diseases, combining effective aerodynamic properties with controlled drug release. Full article

Background: Spray drying, whilst a popularly employed technique for powder formulations, has limited applications for large-scale proliposome manufacture. Objectives: Thus, the aim of this study was to investigate spray drying parameters, such as inlet temperature (80, 120, 160, and 200 °C), airflow rate (357, 473, and 601 L/h) and pump feed rate (5, 15, and 25%), for individual carbohydrate carriers (trehalose, lactose monohydrate (LMH), and mannitol) for 24 spray-dried (SD) formulations (F1–F24). Methods: Following optimization, the SD parameters were trialed on proliposome formulations based on the same carriers and named as spray-dried proliposome (SDP) formulations. Drug delivery of the formulations was assessed using a dry powder inhaler (DPI) in combination with a next-generation impactor (NGI). Results: Upon analysis, formulations F6 (SD-mannitol), F15 (SD-trehalose), and F20 (SD-LMH) demonstrated high production yields (84.01 ± 3.25, 72.55 ± 5.42, and 70.03 ± 3.39%, respectively), small particle sizes (2.96 ± 1.42, 4.55 ± 0.46, and 5.16 ± 1.32 µm, respectively) and low moisture contents (0.25 ± 0.03, 3.76 ± 0.75, and 1.99 ± 0.77%). These SD optimized parameters were then employed for SDP formulations employing dimyristoly phosphatidylcholine (DMPC) as a phospholipid and beclomethasone dipropionate (BDP) as the model drug. Upon spray drying, SDP-mannitol provided the highest production yield (82.45%) and smallest particle size (2.64 µm), as well as high entrapment efficiency (98%) and a high fine particle dose, fine particle fraction, and respirable fraction (285.81 µg, 56.84%, 86.44%, respectively). Conclusions: The study results are a promising step in the optimization of the large-scale manufacture of proliposome formulations and highlight the versatility of the instrument and variability of formulation properties with respect to the carriers employed for targeting the pulmonary system using dry powder inhalers. Full article

Background: This study explores the development and characterization of spray-dried composite microparticles consisting of levofloxacin (LVX, a broad-spectrum antibiotic), and ambroxol (AMB, a mucolytic agent that has antibacterial and antibiofilm properties), for the intended application of the drug against lower respiratory tract infections (LRTIs). Methods: A range of LVX to AMB mass ratios (1:1, 1:0.5, and 1:0.25) were prepared, with and without the use of the dispersibility enhancer leucine (LEU), and spray-dried following pre-optimized parameters to achieve the required particle size (1–5 µm) and flow properties. The formulations were characterized by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and a thermogravimetric analysis (TGA). The in vitro aerosolization performance of the new formulation was evaluated with a twin-stage impinger (TSI) at a flow rate of 60 ± 5 L/min. Using a validated RP-HPLC method, LVX and AMB were quantitatively determined. Results: The combined spray-dried LVX, AMB, and LEU particles were spherically shaped with sizes ranging from 1.9 to 2.9 µm, thus complying with the size requirements for effective deep lung deposition. The dispersibility enhancer leucine produced a high yield and enhanced the flow properties and aerosolization characteristics of the spray-dried formulations. The LVX to AMB mass ratios showed a remarkable impact on the aerosolization properties, with the LVX to AMB 1:1 mass ratio demonstrating the best flow and FPFs for both drugs. There must be a balanced ratio of these components for spray drying the composite particles to obtain composite particles of the required size and with the appropriate flow property. The addition of 5% of LEU significantly (p < 0.005) improved the FPF of all the formulations, probably by enhancing the surface hydrophobicity of the composite particles. Conclusions: The spray-dried combined antibiotics formulation has a strong potential for efficient lung delivery intended for the management of LRTIs. Full article