Search Results (144)

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 clinical efficacy of inhalation therapy in chronic respiratory diseases is fundamentally constrained by particle deposition patterns. This study employs computational fluid dynamics (CFD) and response surface methodology (RSM) to elucidate the mechanistic interplay of deposition determinants through multifactorial sensitivity mapping. The study comprises two key components: (i) the development of an accurate three-dimensional respiratory airway model spanning from the oral cavity to the fifth-generation bronchi and (ii) the integration of a Box–Behnken Design (BBD) experimental framework with computational fluid dynamics simulations. Furthermore, we developed a multifactorial regression model to analyze the synergistic interactions among deposition determinants. The study demonstrated a positive correlation between breath-holding time and drug deposition efficiency, revealing a hierarchical order of critical parameters: peak flow rate > breath-holding time > particle diameter. These findings have important implications for optimizing respiratory drug delivery strategies in clinical settings. Full article

Background: Vibrating mesh nebulizers (VMNs) are not only used to deliver typical pulmonary drugs but are also a promising platform for novel formulations and therapeutic applications. Typically, these devices operate continuously or on demand and are directly connected to the outflow interface (mouthpiece or mask) without valving systems that could spare the drug during exhalation. This paper examines the possibility of increasing the delivery of inhaled budesonide aerosol by attaching a valved holding chamber (VHC) to selected VMNs. Methods: A laboratory in vitro study was conducted for seven budesonide (BUD) nebulization products (0.25 mg/mL). The rates of aerosol delivery from VMNs alone or VMN + VHC systems were determined gravimetrically for a simulated breathing cycle, while droplet size distributions in mists were measured by laser diffraction. Results: The VMN + VHC systems increased the amount of aerosol available for inhalation and the fraction of fine particles that could penetrate the pulmonary region. Depending on the VMN and BUD product, a relative increase of 30–300% in the total drug delivery (T) and 50–350% in the pulmonary drug availability (P) was obtained. The results are explained by the reduction in aerosol losses during exhalation (the fugitive emission) by the VHC and the simultaneous elimination of the largest droplets due to coalescence and deposition in the chamber. Both VMN and BUD affected the aerosol’s properties and discharge mass and thus the actual benefits of the VHC. Conclusions: While the results confirm the superiority of VMN + VHC over VMNs alone in nebulizing BUD suspensions, they also show that it is difficult to predict the effects quantitatively without testing the individual nebulizer–chamber–drug combination. 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: Celastrol (Cela), a phytochemical extracted from Tripterygium wilfordii, has been extensively investigated for its potential anti-inflammatory, anti-psoriatic, antioxidant, neuroprotective, and antineoplastic properties. However, its clinical translation is limited due to poor bioavailability, low solubility, and nonspecific toxicity. This study aimed to develop and evaluate an inhalable Cela-loaded nanoemulsion (NE) formulation to enhance targeted drug delivery and therapeutic efficacy in non-small cell lung cancer (NSCLC). Methods: The NE formulation was optimized using Capmul MCM (25%), Tween 80 (20%), Transcutol HP (5%), and water (50%) as the oil, surfactant, co-surfactant, and aqueous phase, respectively. Physicochemical characterization included globule size, zeta potential, and drug release in simulated lung fluid. In vitro aerosolization performance, cytotoxicity in NSCLC cell lines (A549), scratch and clonogenic assays, and 3D tumor spheroid models were employed to assess therapeutic potential. Results: The NE showed a globule size of 201.4 ± 3.7 nm and a zeta potential of −15.7 ± 0.2 mV. Drug release was sustained, with 20.4 ± 5.5%, 29.1 ± 10%, 64.6 ± 4.1%, and 88.1 ± 5.2% released at 24, 48, 72, and 120 h, respectively. In vitro aerosolization studies indicated a median aerodynamic particle size of 4.8 ± 0.2 μm, confirming its respirability in the lung. Cell culture studies indicated higher toxicity of NE-Cela in NSCLC cells. NE-Cela significantly reduced A549 cell viability, showing a ~6-fold decrease in IC₅₀ (0.2 ± 0.1 μM) compared to Cela alone (1.2 ± 0.2 μM). Migration and clonogenic assays demonstrated reduced cell proliferation, and 3D spheroid models supported its therapeutic activity in tumor-like environments. Conclusions: The inhalable NE-Cela formulation improved Cela’s physicochemical limitations and demonstrated enhanced anti-cancer efficacy in NSCLC models. These findings support its potential as a targeted, well-tolerated therapeutic option for lung cancer treatment. Full article

Flavonoids, like Hesperetin, have been shown to be an ACE2 receptor agonists with antioxidant and pro-apoptotic activity and can induce apoptosis in cancer cells. ACE2 receptors are abundant in lung cancer cells. Here, we explored the application of Hesperetin bound to PegPLGA-coated nanoparticles (Hesperetin nanoparticles, HNPs) and anti-CD40 antibody as an aerosol treatment for lung tumor-bearing mice. The Hesperetin nanoparticles (HNPs) were engineered using a nano-formulation microfluidic technique and polymeric nanoparticles. The in vitro studies were performed in human A549 (ATCC) and murine LL/2-Luc2 (ATCC) lung cancer cell lines. A syngeneic orthotopic murine model of lung cancer was generated in wild (+/+) C57/BL6 background mice with luciferase-positive cell line LL/2-Luc2 cells. Lung tumor-bearing mice were treated via aerosol inhalation with HNP, anti-CD40 antibody, or both. Survival was used to analyze the efficacy of the aerosol treatment. The cohorts were also analyzed for body condition score, weight, and liver and kidney function. Analysis of an orthotopic murine lung cancer model demonstrated a differential uptake of the HNPs and anti-CD40 by the cancer cells. A higher survival rate was observed when the combination of aerosol treatment with HNPs was added with the treatment with anti-CD40 (p < 0.001), as compared to anti-CD40 alone (p < 0.01). Moreover, two tumor-bearing mice survived long-term with the combination treatment, and their tumors were diminished. Subsequently, these two mice were shown to be refractory to the development of subcutaneous tumors, indicating systemic resilience to developing new tumors. Using an inhalation-based administration, we successfully established a treatment model of increased therapeutic efficacy with HNPs and anti-CD40 in an orthotopic murine lung cancer model. Our findings open the possibility of improved lung cancer treatment using nanoparticles like flavonoids and immunoadjuvants. 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

This study investigates the atomization process in Respimat^® Soft Mist^TM Inhalers (SMIs) using a validated Volume of Fluid (VOF)-to-Discrete Phase Model (DPM) to simulate the transition from colliding liquid jets to aerosolized droplets. Key parameters, including colliding jet inlet velocity, surface tension, and liquid viscosity, were systematically varied to analyze their impact on the atomization, i.e., aerosolized droplet size distributions. The VOF-to-DPM simulation results indicate that higher jet inlet velocities enhance ligament fragmentation, producing finer and more uniform droplets while reducing total atomized droplet mass. The relationship between surface tension and atomization performance in colliding jet atomization is not monotonic. Reducing surface tension plays a complex dual role in the atomization process. On the one hand, lower surface tension enhances the likelihood of liquid jet breakup into a liquid sheet, leading to the formation of smaller ligaments under the same airflow conditions and shear forces. This increases the probability of generating more secondary droplets. On the other hand, reduced surface tension also destabilizes the liquid surface shape, decreasing the formation of fine, high-sphericity droplets in regimes where surface tension is a dominant force. Viscosity also influences atomization through complex mechanisms, i.e., lower viscosity reduces resistance to ligament breakup but promotes droplet interactions and coalescence, while higher viscosity suppresses ligament fragmentation, generating larger droplets and reducing atomization efficiency. The validated VOF-to-DPM framework provides critical insights for enhancing the performance and efficiency of inhalation therapies. Future work will incorporate nozzle geometry, jet impingement angles, and surfactant effects to better understand and optimize the atomization process in SMIs, focusing on achieving preferred droplet size distributions and emitted doses for enhanced drug delivery efficiency in human respiratory systems. Full article

Transmucosal drug products, such as aerosols, films, semisolids, suppositories, and tablets, have been developed for the treatment of various human diseases and conditions. Transmucosal drug absorption is highly influenced by the biological structures of the mucosa and the physiological environment specific to the administration route (e.g., nasal, rectal, and vaginal). Over the last few decades, in vitro permeation testing (IVPT) using animal tissues or in vitro cell cultures have been utilized as a cost-effective and efficient tool for evaluating drug release and permeation behavior, assisting in formulation development and quality control of transmucosal drug delivery systems. This review summarizes the key mucosal permeation barriers associated with representative transmucosal administration routes, as well as considerations for IVPT method development. It highlights various IVPT methods, including vertical diffusion cell, flow-through diffusion cell, Ussing chamber, and transwell systems. Additionally, future perspectives are discussed, such as the use of optical methods to study in vitro drug permeation and the development of in vitro–in vivo correlation (IVIVC) for transmucosal drug development. The potential of IVPT as part of in vitro bioequivalence assessment strategies for locally acting transmucosal drug products is also highlighted. Full article

Background/Objectives: Aerosolized medications are common practice for mechanically ventilated pediatric patients. Infants often receive nebulized medications via hand ventilation using an anesthesia bag, but evidence on optimal aerosol delivery with this method is limited. For this study, various configurations of the Mapleson breathing circuit were tested to optimize albuterol delivery to a simulated pediatric model. Methods: Using a simulated pediatric lung model (ASL 5000) with the semi-open Mapleson anesthesia circuit, 2.5 mg/3 mL of albuterol sulfate solution was nebulized to a viral/bacterial filter (Respiguard 202). Four models were compared with varying fresh gas flows (FGFs), small-volume nebulizer (SVN) placements, and adjusting dead space. Five Registered Respiratory Therapists (RRTs) bagged the aerosol into a collection filter following defined ventilation parameters. Each model was tested in random order to avoid fatigue bias. Albuterol concentrations eluted from in-line filters were measured by spectrophotometry (absorbance at 276 nm). Results: No inter-user variability was observed among the RRTs. Significant differences in albuterol recovered were noted between models (One Way ANOVA, Tukey’s post hoc, n = 5). Model 4, with the nebulizer closest to the collecting filter, recovered 21.77 ± 1.89% of albuterol. The standard clinical model was the least effective, with only 0.10 ± 0.17% albuterol recovery. Conclusions: Modifying the anesthesia breathing circuit significantly improved aerosol drug delivery efficiency. Our findings suggest that current clinical practices for nebulized drug delivery are inefficient and can be markedly improved with simple adjustments in nebulizer positioning and gas flow within the circuit. 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

Background: Acute and chronic sinusitis significantly impact patients’ quality of life. Effective drug delivery to paranasal sinuses is crucial for treating these conditions. However, medications from conventional devices like nasal drops, sprays, and nebulized mists often fail to penetrate the small ostia and reach the sinuses. This study aims to assess the effectiveness of e-vape-generated aerosols entering and filling paranasal sinus cavities, particularly the maxillary sinus. Methods: The aerosol droplets were generated using an electronic vaporizer (e-vape) and were composed solely of vegetable glycerin (VG) and propylene glycol (PG). Patient-specific, transparent nose-sinus models, including one with post-uncinectomy surgery, were used to evaluate the effectiveness of these e-vape-generated VG-PG aerosols in entering the sinuses under unidirectional and bidirectional airflow conditions. Visualizations from various nasal model views and lighting conditions were recorded. Particle size distribution measurements of the e-vape aerosol were conducted using a laser diffraction particle size analyzer. Results: E-vape-generated VG-PG droplets effectively enter paranasal sinuses under specific administration conditions. E-vape aerosol droplet size measurements revealed a mean particle size ranging from 2.895 to 3.359 μm, with a median particle size (D50) averaging 2.963 μm. The speed of aerosol entering the paranasal sinuses is directly proportional to the ostia size; larger ostia result in faster sinus entry. A continuous moderate flow is necessary to gradually fill the paranasal sinus cavities. The aerosol entry into sinuses was observed at 2 L/min and decreased with increasing flow rate. The mechanisms of aerosol entry involve maintaining a positive pressure gradient across the ostial canal, a non-equilibrium transverse pressure distribution, and a two-way flow through the ostium. Gravitational forces and recirculation currents further enhance the deposition of e-vape aerosols. Comparative tests showed that traditional delivery devices exhibited limited penetration into paranasal sinuses. Conclusions: This study demonstrated that e-vape-generated aerosols could serve as a vehicle for delivering active pharmaceutical ingredients (APIs) directly to the paranasal sinuses, improving treatment outcomes. 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

Designing and standardizing drug formulations are crucial for ensuring the safety and efficacy of medications. Nanomedicine utilizes nano drug delivery systems and advanced nanodevices to address numerous critical medical challenges. Currently, oral and intranasal aerosol drug delivery (OIADD) is the primary method for treating respiratory diseases worldwide. With advancements in disease understanding and the development of aerosolized nano drug delivery systems, the application of OIADD has exceeded its traditional boundaries, demonstrating significant potential in the treatment of non-respiratory conditions as well. This study provides a comprehensive overview of the applications of oral and intranasal aerosol formulations in disease treatment. It examines the key challenges limiting the development of nanomedicines in drug delivery systems, formulation processes, and aerosol devices and explores the latest advancements in these areas. This review aims to offer valuable insights to researchers involved in the development of aerosol delivery platforms. Full article

Background/Objectives: This study aimed to fabricate, optimize, and characterize nanostructured lipid carriers (NLCs) loaded with trans-resveratrol (TRES) as an anti-cancer drug for pulmonary drug delivery using medical nebulizers. Methods: Novel TRES-NLC formulations (F1–F24) were prepared via hot, high-pressure homogenization. One solid lipid (Dynasan 116) was combined with four liquid lipids (Capryol 90, Lauroglycol 90, Miglyol 810, and Tributyrin) in three different ratios (10:90, 50:50, and 90:10 w/w), with a surfactant (Tween 80) in two different concentrations (0.5 and 1.5%), and a co-surfactant, soya phosphatidylcholine (SPC S-75; 50 mg). Results: Amongst the analyzed 24 TR-NLC formulations, F8, F14, and F22 were selected based on their physicochemical stability when freshly prepared and following storage (4 weeks 25 °C), as well as in terms of particle size (<145 nm), polydispersity index (PDI; <0.21) and entrapment efficiency (>96%). Furthermore, F14 showed greater stability at 4 and 25 °C for six months and exhibited enhanced aerosolization performance, demonstrating the greater deposition of TRES in the later stages of the next-generation impactor (NGI) when using an air-jet nebulizer than when using an ultrasonic nebulizer. The F14 formulation exhibited greater stability and release in acetate buffer (pH 5.4), with a cumulative release of 95%. Conclusions: Overall, formulation F14 in combination with an air-jet nebulizer was identified as a superior combination, demonstrating higher emitted dose (ED; 80%), fine particle dose (FPD; 1150 µg), fine particle fraction (FPF; 24%), and respirable fraction (RF; 94%). These findings are promising in the optimization and development of NLC formulations, highlighting their versatility and targeting the pulmonary system via nebulization. Full article