Pulmonary Delivery Research Articles

Investigation of Factors Influencing the Effectiveness of Deformable Nanovesicles for Insulin Nebulization Inhalation.

Nebulized inhalation offers a noninvasive method for delivering drugs to treat both local respiratory and systemic diseases. In this study, insulin was used as a model drug to design a series of deformable nanovesicles (DNVs) with key quality attributes, including particle size, deformability, and drug load capacity. We investigated the effects of these properties on aerosol generation, macrophage phagocytosis, and bloodstream penetration. The results showed that deformability improved nebulization performance and reduced macrophage phagocytosis, benefiting local and systemic delivery. However, the advantage of DNVs for transmembrane penetration was not evident in the alveolar epithelium. Within the size range of 80-490 nm, the smaller the particle size of IPC-DNVs, the easier it is to evade clearance by macrophages and the more effective the in vivo hypoglycemic efficacy will be. In the drug load range of 3-5 mg/mL, a lower drug load resulted in better hypoglycemic efficacy. The area above the blood glucose decline curve with time (AAC) of nebulized DNVs was 2.32 times higher than that of the insulin solution, demonstrating the feasibility and advantages of DNVs in the pulmonary delivery of biomacromolecule drugs. This study provides insights into the construction and formulation optimization of pulmonary delivery carriers.

Nanostructure-Mediated Transport of Therapeutics through Epithelial Barriers.

The ability to precisely treat human disease is facilitated by the sophisticated design of pharmacologic agents. Nanotechnology has emerged as a valuable approach to creating vehicles that can specifically target organ systems, effectively traverse epithelial barriers, and protect agents from premature degradation. In this review, we discuss the molecular basis for epithelial barrier function, focusing on tight junctions, and describe different pathways that drugs can use to cross barrier-forming tissue, including the paracellular route and transcytosis. Unique features of drug delivery applied to different organ systems are addressed: transdermal, ocular, pulmonary, and oral delivery. We also discuss how design elements of different nanoscale systems, such as composition and nanostructured architecture, can be used to specifically enhance transepithelial delivery. The ability to tailor nanoscale drug delivery vehicles to leverage epithelial barrier biology is an emerging theme in the pursuit of facilitating the efficacious delivery of pharmacologic agents.

Bottlebrush Polyethylene Glycol Nanocarriers Translocate across Human Airway Epithelium via Molecular Architecture-Enhanced Endocytosis.

Pulmonary drug delivery is critical for the treatment of respiratory diseases. However, the human airway surface presents multiple barriers to efficient drug delivery. Here, we report a bottlebrush poly(ethylene glycol) (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by a molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (∼1000) low molecular weight (∼1000 g/mol) polyethylene glycol (PEG) chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of ∼250 nm, a cross-section of ∼20 nm, and a hydrodynamic diameter of ∼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture-enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a carrier for pulmonary and mucosal drug delivery.

Histological Assessment of Respiratory Tract and Liver of BALB/c Mice Nebulized with Tocilizumab.

Pulmonary drug delivery offers a minimally invasive and efficient method for treating lung conditions, leveraging the lungs' extensive surface area and blood flow for rapid drug absorption. Nebulized therapies aim to deliver drugs directly to the lung tissue. This study investigates the histological impact of nebulized tocilizumab-a monoclonal antibody targeting IL-6, traditionally administered intravenously for rheumatoid arthritis and severe COVID-19-on a murine model. Thirty BALB/c mice were nebulized with tocilizumab (10 mg, 5 mg, and 2.5 mg) and six controls were nebulized with saline solution. They were euthanized 48 h later, and their organs (lungs, nasal mucosa, and liver) were analyzed by a microscopic histological evaluation. The results indicate that all the mice survived the 48 h post-nebulization period without systemic compromise. The macroscopic examination showed no abnormalities, and the histopathological analysis revealed greater lung vascular changes in the control group than in the nebulized animals, which is attributable to the euthanasia with carbon dioxide. Additionally, increased alveolar macrophages were observed in the nebulized groups compared to controls. No significant histological changes were observed in the liver, indicating the safety of nebulized tocilizumab. In conclusion, these findings suggest the potential of nebulized tocilizumab for treating pulmonary inflammation, warranting further research to establish its efficacy and safety in clinical settings.

Enhancing pulmonary delivery and immunomodulation of respiratory diseases through virus-mimicking nanoparticles

This study introduces the nanobromhexine lipid particle (NBL) platform designed for effective pulmonary drug delivery. Inspired by respiratory virus transport mechanisms, NBL address challenges associated with mucus permeation and inflammation in pulmonary diseases. Composed of low molecular weight polyethylene glycol-coated lipid nanoparticles with bromhexine hydrochloride, NBL exhibit a size of 118 ± 24 nm, a neutral zeta potential, osmolarity of 358 ± 28 mOsmol/kg, and a pH of 6.5. Nebulizing without leakage and showing no toxicity to epithelial cells, NBL display mucoadhesive properties with a 60% mucin-binding efficiency. They effectively traverse the dense mucus layer of Calu-3 cultures in an air-liquid interface, as supported by a 55% decrease in MUC5AC density and a 29% increase in nanoparticles internalization compared to non-exposed cells. In assessing immunomodulatory effects, NBL treatment in SARS-CoV-2-infected lung cells leads to a 40-fold increase in anti-inflammatory MUC1 gene expression, a proportional reduction in pro-inflammatory IL-6 expression, and elevated anti-inflammatory IL-10 expression. These findings suggest a potential mechanism to regulate the excessive IL-6 expression triggered by virus infection. Therefore, the NBL platform demonstrates promising potential for efficient pulmonary drug delivery and immunomodulation, offering a novel approach to addressing mucus permeation and inflammation in pulmonary diseases.

Macrophage-targeted versus free calcitriol as host-directed adjunct therapy against Mycobacterium tuberculosis infection in mice is bacteriostatic and mitigates tissue pathology

Host-directed therapy (HDT) with vitamin D in tuberculosis (TB) is beneficial only if the subject is deficient in vitamin D. We investigated pulmonary delivery of 1,25-dihydroxy vitamin D3 (calcitriol) in mice infected with Mycobacterium tuberculosis (Mtb). We made two kinds of dry powder inhalations (DPI)— soluble particles or poly(lactide) (PLA) particles. We compared treatment outcomes when infected mice were dosed with a DPI alone or as an adjunct to standard oral anti-TB therapy (ATT). Mice infected on Day 0 were treated between Days 28–56 and followed up on Days 57, 71, and 85. Neither DPI significantly reduced Mtb colony forming units (CFU) in the lungs. Combining DPI with ATT did not significantly augment bactericidal activity in the lungs, but CFU were 2-log lower in the spleen. CFU showed a rising trend on stopping treatment, sharper in groups that did not receive calcitriol. Lung morphology and histology improved markedly in animals that received PLA DPI; with or without concomitant ATT. Groups receiving soluble DPI had high mortality. DPI elicited cathelicidin, interleukin (IL)-1 and induced autophagy on days 57, 71, and 85. Macrophage-targeted calcitriol is therefore bacteriostatic, evokes innate microbicidal mechanisms, and mitigates pathology arising from the host response to Mtb.

Polyvinyl alcohol-based capsule shells manufactured by injection molding as ready-to-use moisture barriers for the development of delivery systems

In this work, feasibility of injection molding was demonstrated for manufacturing capsule shells. 600 µm-thick prototypes were successfully molded with pharmaceutical-grade low-viscosity polyvinyl alcohols (PVAs), possibly added with a range of different fillers. They showed reproducible weight and thickness (CV < 2 and 5, respectively), compliant behavior upon piercing (holes diameter analogous to the reference), tunable release performance (immediate and pulsatile), and moisture protection capability. To assess the latter, an on-line method relying on near infrared spectroscopy measurements was set-up and validated. Based on the data collected and considering the versatility IM would provide for product shape/thickness/composition, PVA-based molded shells could help widening the portfolio of ready-to-use capsules, representing an interesting alternative to those commercially available. Indeed, these capsules could be filled with various formulations, even those with stability issues, and intended either for oral administration or for pulmonary delivery via single-dose dry powder inhalers.

Efficient Nebulization and Pulmonary Biodistribution of Polymeric Nanocarriers in an Acute Lung Injury Preclinical Model

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by acute hypoxemic respiratory failure. Pneumonia and sepsis are the most common causes, turning ARDS into a critical public health problem. Despite recent advances in pharmacological strategies, clinical trials have not demonstrated a reduction in ARDS‐associated mortality. This is in part connected to the singularity of the pulmonary physiological barrier, which hampers drug delivery, specifically at distal areas. To this aim, the use of polymeric nanocarriers as a platform for the efficient delivery of therapeutics to the lungs by nebulization is introduced. Herein, poly(lactic‐co‐glycolic acid) (PLGA) nanocapsules (NCs) loaded with human serum albumin, as an inhalable nanotherapeutic are prepared. The production of stable NCs aerosols in the inhalable range is achieved using a commercial device, while the nanocarrier's physicochemical parameters are only minimally altered after nebulization. Importantly, in vivo studies with healthy and acute lung injury animals show that after inhalation, the NCs are homogeneously distributed throughout the lungs, arriving at the distal areas. The NCs are internalized by alveolar type II cells, avoiding macrophage‐mediated lung clearance. These features make the PLGA NCs excellent vehicles for noninvasive pulmonary delivery, facilitating a ready‐to‐be‐used nanomedicine.

Aerosol dosimetry in the whole conducting zone of a murine left-lung using CF-PD and LSFM images

Aerosol dosimetry in respiratory airways is relevant for pulmonary drug delivery and inhalation toxicology. Consequently, computational fluid-particle dynamics (CF-PD) modelling of pulmonary aerosol delivery is an active research field. Additionally, mice are the most commonly used animals in medical research. Technological advances have provided information on whole mice lung morphologies with unprecedented high resolution. Therefore, in this study, we used high-resolution light sheet fluorescent microscopy (LSFM) images of a healthy C57BL/6 mouse lung with a constant air flow rate of 72 ml/min, to extract an anatomical 3-dimensional (3D) geometry of the entire airway tree of the left lung from the primary bronchi to the most distal bronchioles excluding the trachea. The airways were segmented based on an order- and generation-based method. Also, to compare the morphological data and regional deposition, a generation-based investigation including 25 generations was employed in the present model. One-way coupling of CF-PD modeling was applied to model an intubated and mechanically-ventilated mouse. Maximum values of the velocity and vorticity magnitude of 3.2 m/s and 200,000 1/s were reached in the second order, respectively, and maximum pressure and wall shear stress levels were 30 Pa and 3.5 Pa, respectively. Finally, order- and generation-based particle deposition efficiency and dose per lung area were obtained for the particle size range of 1 μm ≤ dp ≤ 10 μm yielding pronounced hotspot deposition patterns mainly near the proximal bifurcations. The results showed a positive correlation between deposition efficiency and particle size due to a size-dependent increase in inertial and gravitational effects. Maximum regional deposition and normalized dose was seen for 10 μm particles in the 1st order of the murine left lung. Smaller peak sizes of deposition efficiency were seen in the third and fourth orders of the mouse left lung due to almost complete loss of the largest particles in lower order airways. It also justifies the close to zero deposition efficiency in the highest orders (fifth to sixth). Both lung morphology as well as total and regional aerosol deposition showed reasonably good agreement with empirical data from the literature. The present CF-PD model with accurate realistic lung morphology, improves our knowledge of airway aerosol deposition hotspots. The obtained modeling method and the qualitative results can be implemented on human airways.

Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing.

We present an efficient approach for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to rapidly create a library of complex functional ionizable lipopolymers. We synthesized a diverse library of 155 polymers, formulated them into polyplexes to establish structure-activity relationships crucial for endosomal escape and efficient transfection. After discovering a lead structure, lipopolymer-lipid hybrid nanoparticles are introduced to preferentially deliver to and elicit effective mRNA transfection in lung endothelium and immune cells, including T cells with low in vivo toxicity. The lipopolymer-lipid hybrid nanoparticles showed 300-fold improvement in systemic mRNA delivery to the lung compared to in vivo -JetPEI ® . Lipopolymer-lipid hybrid nanoparticles demonstrated efficient delivery of mRNA-based therapeutics for treatment of two different disease models. Lewis Lung cancer progression was significantly delayed after treatment with loaded IL-12 mRNA in U155@lipids after repeated i.v. administration. Systemic delivery of human CFTR (hCFTR) mRNA resulted in production of functional form of CFTR protein in the lungs. The functionality of hCFTR protein was confirmed by restoration of CFTR- mediated chloride secretion in conductive airway epithelia in CFTR knockout mice after nasal instillation of hCFTR mRNA loaded U155@lipids. We further showed that, U155@lipids nanoparticles can deliver complex CRISPR-Cas9 based RNA cargo to the lung, achieving 5.6 ± 2.4 % gene editing in lung tissue. Moreover, we demonstrated successful PD-1 gene knockout of T cells in vivo . Our results highlight a versatile delivery platform for systemic delivering of mRNA of various sizes for gene therapy for a variety of therapeutics.

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.

Design of Experiment (DoE) Approach for Developing Inhalable PLGA Microparticles Loaded with Clofazimine for Tuberculosis Treatment.

Tuberculosis (TB) is an airborne bacterial infection caused by Mycobacterium tuberculosis (M. tb), resulting in approximately 1.3 million deaths in 2022 worldwide. Oral therapy with anti-TB drugs often fails to achieve therapeutic concentrations at the primary infection site (lungs). In this study, we developed a dry powder inhalable formulation (DPI) of clofazimine (CFZ) to provide localized drug delivery and minimize systemic adverse effects. Poly (lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) containing CFZ were developed through a single emulsion solvent evaporation technique. Clofazimine microparticles (CFZ MPs) displayed entrapment efficiency and drug loading of 66.40 ± 2.22 %w/w and 33.06 ± 1.45 µg/mg, respectively. To facilitate pulmonary administration, MPs suspension was spray-dried to yield a dry powder formulation (CFZ SD MPs). Spray drying had no influence on particle size (~1 µm), zeta potential (-31.42 mV), and entrapment efficiency. Solid state analysis (PXRD and DSC) of CFZ SD MPs studies demonstrated encapsulation of the drug in the polymer. The drug release studies showed a sustained drug release. The optimized formulation exhibited excellent aerosolization properties, suggesting effective deposition in the deeper lung region. The in vitro antibacterial studies against H37Ra revealed improved (eight-fold) efficacy of spray-dried formulation in comparison to free drug. Hence, clofazimine dry powder formulation presents immense potential for the treatment of tuberculosis with localized pulmonary delivery and improved patient compliance.

Practitioner experiences of pulmonary rehabilitation service delivery during COVID-19 and impact on future service delivery

Introduction During COVID-19, pulmonary rehabilitation as we know it ceased to exist. The service needed to adapt rapidly to the requirements of the patient group, while complying with government isolation guidelines. Most groups moved online, but with little time to evaluate the service. What can we learn from this roll out to ensure practitioners continue to deliver a safe and effective pulmonary rehabilitation service. Aim To explore the opinions of physiotherapist and respiratory nursing specialists’ on how pulmonary rehabilitation has changed due to COVID-19 and the impact on future service delivery. Methods A qualitative design was used to gain in-depth understanding of lived experiences. Forty nine participants completed the online survey of 14 open ended questions, and a four-stage thematic analysis used to identify emergent themes. Findings Three main themes were identified- a need for best practice, a need for patient centred care, and acknowledging the emotional stressors of COVID-19 on vulnerable patients. Conclusion Patients should be offered both online and face-to-face options for pulmonary rehabilitation, to promote patient centred care; providing options to participate in effective rehabilitation without physical or emotional restriction; and to increase staff training to enable practitioners to provide the increasingly complex and holistic service required.

Front Cover: Targeted Redox Balancing through Pulmonary Nanomedicine Delivery Reverses Oxidative Stress Induced Lung Inflammation (ChemMedChem 11/2024)

Front Cover: Targeted Redox Balancing through Pulmonary Nanomedicine Delivery Reverses Oxidative Stress Induced Lung Inflammation (ChemMedChem 11/2024)

Solid Lipid Nanoparticles for Pulmonary Delivery of Biopharmaceuticals: A Review of Opportunities, Challenges, and Delivery Applications.

Biopharmaceuticals such as nucleic acids, proteins, and peptides constitute a new array of treatment modalities for chronic ailments. Invasive routes remain the mainstay of administering biopharmaceuticals due to their labile nature in the biological environment. However, it is not preferred for long-term therapy due to the lack of patient adherence and clinical suitability. Therefore, alternative routes of administration are sought to utilize novel biopharmaceutical therapies to their utmost potential. Nanoparticle-mediated pulmonary delivery of biologics can facilitate both local and systemic disorders. Solid lipid nanoparticles (SLNs) afford many opportunities as pulmonary carriers due to their physicochemical stability and ability to incorporate both hydrophilic and hydrophobic moieties, thus allowing novel combinatorial drug/gene therapies. These applications include pulmonary infections, lung cancer, and cystic fibrosis, while systemic delivery of biomolecules, like insulin, is also attractive for the treatment of chronic ailments. This Review explores physiological and particle-associated factors affecting pulmonary delivery of biopharmaceuticals. It compares the advantages and limitations of SLNs as pulmonary nanocarriers along with design improvements underway to overcome these limitations. Current research illustrating various SLN designs to deliver proteins, peptides, plasmids, oligonucleotides, siRNA, and mRNA is also summarized.

Pulmonary fibroblast-specific delivery of siRNA exploiting exosomes-based nanoscaffolds for IPF treatment

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease that leads to interstitial inflammation, lung damage, and eventually life-threatening complications. Among various pathologic factors, Smad4 is a pivotal molecule involved in the progression and exacerbation of IPF. It mediates nuclear transfer of Smad2/Smad3 complexes and initiates the transcription of fibrosis-promoting genes. Thus, the inhibition of Smad4 expression in pulmonary fibroblasts by small interfering RNAs (siRNAs) might be a promising therapeutic strategy for IPF. Herein, we engineered exosome membranes (EM) by cationic lipid (i.e., DOTAP) to load siRNAs against Smad4 (DOTAP/siSmad4@EM), and investigated their specific delivery to pulmonary fibroblasts for treating IPF in a mouse model via pulmonary administration. As reference nanoscaffolds, undecorated DOTAP/siSmad4 complexes (lipoplexes, consisting of cationic lipid DOTAP and siRNAs) and siSmad4-loaded lipid nanoparticles (DOTAP/siSmad4@lipo, consisting of lipoplexes fused with DPPCChol liposomes) were also prepared. The results showed that DOTAP/siSmad4@EM exhibited a higher cellular uptake and gene silencing efficacies in mouse pulmonary fibroblasts (viz., MLg2908) as compared to the two reference nanoscaffolds. Furthermore, the outcomes of the in vivo experiments illustrated that DOTAP/siSmad4@EM could significantly down-regulate the Smad4 expression with augmented anti-fibrosis efficiency. Additionally, the DOTAP/siSmad4@EM conferred excellent biocompatibility with low cytokine levels in bronchoalveolar lavage fluid and proinflammatory responses in the pulmonary area. Taken together, the outcomes of our investigation imply that specific inhibition of Smad4 expression in pulmonary fibroblasts by pulmonary administrated DOTAP/siSmad4@EM is a promising therapeutic strategy for IPF, which could safely and effectively deliver siRNA drugs to the targeted site of action.

A Review on Investigating the Interactions between Nanoparticles and the Pulmonary Surfactant Monolayer with Coarse-Grained Molecular Dynamics Method.

Pulmonary drug delivery has garnered significant attention due to its targeted local lung action, minimal toxic side effects, and high drug utilization. However, the physicochemical properties of inhaled nanoparticles (NPs) used as drug carriers can influence their interactions with the pulmonary surfactant (PS) monolayer, potentially altering the fate of the NPs and impairing the biophysical function of the PS monolayer. Thus, the objective of this review is to summarize how the physicochemical properties of NPs affect their interactions with the PS monolayer. Initially, the definition and properties of NPs, as well as the composition and characteristics of the PS monolayer, are introduced. Subsequently, the coarse-grained molecular dynamics (CGMD) simulation method for studying the interactions between NPs and the PS monolayer is presented. Finally, the implications of the hydrophobicity, size, shape, surface charge, surface modification, and aggregation of NPs on their interactions with the PS monolayer and on the composition of biomolecular corona are discussed. In conclusion, gaining a deeper understanding of the effects of the physicochemical properties of NPs on their interactions with the PS monolayer will contribute to the development of safer and more effective nanomedicines for pulmonary drug delivery.

Simple, and highly efficient edge-effect surface acoustic wave atomizer

Conventional surface acoustic wave (SAW) atomizers require a direct water supply on the surface, which can be complex and cumbersome. This paper presents a novel SAW atomizer that uses lateral acoustic wetting to achieve atomization without a direct water supply. The device works by simply pressing a piece of wetted paper strip against the bottom of an excited piezoelectric transducer. The liquid then flows along the side to the unmodified surface edge, where it is atomized into a well-converging mist in a stable and sustainable manner. We identified this phenomenon as the edge effect, using numerical simulation results of surface displacement mode. The feasibility of the prototype design was demonstrated by observing and investigating the integrated process of liquid extraction, transport, and atomization. We further explored the hydrodynamic principles of the change and breakup in liquid film geometry under different input powers. Experiments demonstrate that our atomizer is capable of generating high-quality fine liquid particles stably and rapidly even at very high input power. Compared to conventional SAW atomizer, the dispersion of mist width can be scaled down by 70%, while the atomization rate can be increased by 37.5%. Combined with the advantages of easy installation and robustness, the edge effect-based atomizer offers an attractive alternative to current counterparts for applications requiring high efficiency and miniaturization, such as simultaneous synthesis and encapsulation of nanoparticles, pulmonary drug delivery and portable inhalation therapy.

Preclinical Pharmacokinetic Study and Lung Penetration of a Coumarin Extracted from Zanthoxylum tingoassuiba.

The compound 6-methoxyseselin, derived from Zanthoxylum tingoassuiba, demonstrates various therapeutic properties, including vasorelaxation, antinociceptive, anti-inflammatory, and immunomodulatory effects, along with recently discovered antiasthmatic properties. This study aimed to evaluate its preclinical pharmacokinetics and pulmonary delivery in Balb/c mice. The method involved administering the compound via inhalation and intravenous routes, followed by blood sample collection for analysis using high-performance liquid chromatography with diode array detection (HPLC-DAD). The results indicated good linearity, precision, accuracy, and stability of the compound in the biological samples. Pharmacokinetic parameters such as the rate of elimination, half-life, clearance, volume of distribution, area under the curve, and mean residence time were determined for both administration routes, showing similar profiles. The lung concentrations were notably higher than the plasma concentrations, indicating significant lung penetration. These findings suggest 6-methoxyseselin as a promising candidate for new anti-asthmatic drugs, supported by its favorable pharmacokinetic profiles and high lung penetration factors. This study represents the first exploration of the pharmacokinetics and pulmonary delivery of 6-methoxyseselin in mice, highlighting its potential for further drug development.

Pulmonary delivery of icariin-phospholipid complex prolongs lung retention and improves therapeutic efficacy in mice with acute lung injury/ARDS

Icariin has been shown the promising therapeutic potential to treat inflammatory airway diseases, yet its poor lung distribution and retention restrict the clinical applications. To this end, this work aimed to prepare an icariin-phospholipid complex (IPC) formulation for sustained nebulization delivery that enabled excellent inhalability, improved lung exposure and prolonged duration of action. Icariin was found to react with soybean phospholipid to form supramolecular IPC, which was able to self-assemble into nanoparticle suspension. The suspension was stable during steam sterilization and nebulization processes, and its aerosols generated by a commercial nebulizer exhibited excellent aerodynamic properties and delivery efficiency. In vitro studies showed that the formation of complex sustained drug release, enhanced lung affinity and slowed lung clearance. The drug distribution in lung epithelial lining fluid (ELF) also demonstrated in vivo sustained release after intratracheal administration to mice. In addition, compared to free icariin, IPC improved the drug exposure to lung tissues and immune cells in the ELF by 4.61-fold and 39.5-fold, respectively. This resulted in improved and prolonged local anti-inflammatory effects up to 24 h in mice with lipopolysaccharide (LPS)-induced acute lung injury. Moreover, IPC improved survival rate of mice with acute respiratory distress syndrome (ARDS). Overall, the present phospholipid complex represented a promising formulation of icariin for the treatment of acute lung injury/ARDS by nebulization delivery.