Inhaled Drug Delivery Research Articles

Prediction of Transport and Deposition of Porous Particles in the Respiratory System Using Eulerian-Lagrangian Approach.

Deep lung delivery is crucial for respiratory disease treatment. Although nano and submicron particles exhibited a good deposition efficiency in deep regions of the lung, powder nonuniformity and particle agglomeration reduce their efficiency. Inhalation of porous particles (PPs) can overcome the mentioned challenges due to their larger size and low-density. The present study numerically investigates the deposition and penetration efficiency of orally inhaled PPs. A revised drag coefficient was implemented for PP transport. A realistic mouth-throat to the fifth generation of the lung was reconstructed from CT-scan images. A dilute suspension of uniformly distributed particles was considered at three inhalation flow rates (15, 30, and 45 L/min). Governing equations of the flow field and particle transport are solved using an Eulerian-Lagrangian approach. The results demonstrate that inhaling PPs significantly reduces the total and regional deposition of particles. There was also a critical porosity value under moderate and high inhalation flow rates for large PPs. Below this critical value, PP deposition efficiency substantially decreases. Additionally, it was also found that under low inhalation flow rates, the impact of porosity value is negligible. Almost 95% of the PPs penetrate the lower branches. These findings provide particle engineers and pharmaceutics with profound insight into developing novel inhalation techniques and drug delivery methods for deep lung delivery.

Multi-scale modeling of aerosol transport in a mouth-to-truncated bronchial tree system

Computational fluid particle dynamics (CFPD) is widely employed to predict aerosol transport in a truncated bronchial tree model on account of its capacity to reveal details of flow field and particle movement. However, setting a physiologically consistent boundary condition in the CFPD for the idealized or image-based truncated bronchial tree model is still a challenge. This paper proposes a multi-scale modeling method, which contains an Extend-Bronchial tree-Network (EBN) boundary condition for a mouth-to-truncated bronchi system. The comparison between EBN boundary condition and a commonly used uniform pressure (UP) boundary condition is conducted. Subsequently, EBN method is used to study the nano-micron (100nm-10μm) particles transport in the mouth-to-truncated bronchi model at different inhalation volume rates (15, 60, 90L/min). Results show that EBN method is more physiologically rational and two methods differ in flow distribution in lobes, vortex structure, and particle transport. The maximum difference in flow rate distribution in lobes between two methods is about 20%, while the maximum relative disparity of particle penetration fraction from lobes and deposition fraction in the TLB is about 93% and 30%, respectively. Meanwhile, this paper reveals the variation of deposition fraction and penetration fraction with the changes in particle diameter and inhalation volume. Deposition efficiency, deposition hotspots and deposition mechanism are also analyzed with inlet Stokes number (Stk) and Reynolds number (Re). This research establishes a foundation for the simulation of aerosol transport in a whole respiratory tract and provides references for inhalation drug delivery and air pollutant management.

Evaluation of the efficacy of inhalation application of bacteriophage preparations in bronchopneumonia associated with Klebsiella pneumoniae

Against the background of increasing antibiotic resistance among pathogens of bovine bronchopneumonia, interest in phagotherapy as a therapeutic tool is revived. Inhaled phagotherapy in turn has the potential to change the treatment regimen for bacterial respiratory infections, including those caused by antibiotic-resistant bacteria. Inhaled drug delivery tools allow the delivery of bacteriophages directly to the lesion. An important advantage, especially when it comes to bacteriophages, is the ability to use smaller doses of drugs than would be required if another route of administration were chosen. The article presents the results of evaluating the efficacy of the inhalation method of administration of commercial bacteriophage preparations in a mouse model. Mice were divided into five groups (1,2-animals exposed to <I>Klebsiella pneumonia</I> infection and undergoing bacteriophage inhalation (n=6), 3-animals exposed to infection and not undergoing therapy (n=3), 4- control group of animals not exposed to infection (n=3)). Inhalations were performed using a compressor four-mode Neb-Aid inhaler (Flaem Nuova, Italy). Rapidflyam 2 nebuliser was used in mode I (particle size 0.8-2.0 μm). The results demonstrate the effectiveness of the developed therapy scheme, which allows further use of bactriophage-containing preparations in infectious diseases of animals.

Tanshinone IIA Loaded Inhaled Polymer Nanoparticles Alleviate Established Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by chronic, progressive scarring of the lung parenchyma, leading to an irreversible decline in lung function. Apart from supportive care, there is currently no specific treatment available to reverse the disease. Based on the fact that tanshinone IIA (TAN) had an effect on protecting against TGF-β1-induced fibrosis through the inhibition of Smad and non-Smad signal pathways to avoid myofibroblasts activation, this study reported the development of the inhalable tanshinone IIA-loaded chitosan-oligosaccharides-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CPN@TAN) for enhancing the pulmonary delivery of tanshinone IIA to treat pulmonary fibrosis. The CPN@TAN with a size of 206.5 nm exhibited excellent in vitro aerosol delivery characteristics, featuring a mass median aerodynamic diameter (MMAD) of 3.967 ± 0.025 μm and a fine particle fraction (FPF) of 70.516 ± 0.929%. Moreover, the nanoparticles showed good stability during atomization and enhanced the mucosal penetration capabilities. The results of confocal spectroscopy confirmed the potential of the nanoparticles as carriers that facilitated the uptake of drugs by NIH3T3, A549, and MH-S cells. Additionally, the nanoparticles demonstrated good in vitro biocompatibility. In a mouse model of bleomycin-induced pulmonary fibrosis, noninvasive inhalation of aerosol CPN@TAN greatly suppressed collagen formation and facilitated re-epithelialization of the destroyed alveolar epithelium without causing systemic toxicity compared with intravenous administration. Consequently, our noninvasive inhalation drug delivery technology based on polymers may represent a promising paradigm and open the door to overcoming the difficulties associated with managing pulmonary fibrosis.

Evaluation of a novel pediatric asthma inhalation drug delivery device: a focus on patient accessibility, ease of use, dosage feedback, and future directions

Objective Pediatric asthma management faces challenges in medication delivery through oral inhalation devices. While dry powder inhalers (DPIs) are increasingly prescribed to children, many do not receive their prescribed dosage due to insufficient inspiratory flow. This study investigates the utilization of metered-dose inhalers (MDIs) and DPIs among pediatric patients with asthma, focusing on medication delivery challenges. Methods Two survey cohorts comprising a total of 42 caregivers of patients with asthma were conducted. Modifications in the second cohort addressed neutral Likert scale responses to obtain more nuanced feedback. Results Caregivers expressed concerns about uncertainties in their child’s ability to use both MDIs and DPIs and challenges in ensuring proper dosage. Notably, 42% of caregivers in the second cohort rated their child’s inhaler usage as unable, indicating a significant worry about the efficacy of current delivery methods. Additionally, 50% of caregivers across both cohorts expressed uncertainties about their child receiving the full medication dosage. In response to identified challenges with DPIs, an adaptor device emerged as a potential solution, with caregivers exhibiting positive perceptions post-exposure. Features prioritized for the device include ease of use and assurance of dose delivery. Conclusions The study highlights caregiver preferences and the need for innovations to ensure effective medication delivery for pediatric asthma patients. A DPI adaptor device shows promise in addressing technical issues and alleviating caregiver concerns, ultimately contributing to more effective asthma management. Future research should refine these devices based on caregiver feedback to meet the evolving needs of the pediatric asthma population.

Prevalence and Management of Chronic Obstructive Pulmonary Disease in the Gulf Countries with a Focus on Inhaled Pharmacotherapy.

Background: Chronic obstructive pulmonary disease (COPD) is a preventable, progressive disease and the third leading cause of death worldwide. The epidemiological data of COPD from Gulf countries are very limited, as it remains underdiagnosed and underestimated. Risk factors for COPD include tobacco cigarette smoking, water pipe smoking (Shisha), exposure to air pollutants, occupational dusts, fumes, and chemicals. Inadequate treatment of COPD leads to worsening of disease. The 2024 GOLD guidelines recommend use of inhaled bronchodilators, corticosteroids, and adjunct therapies for treatment and management of COPD patients based on an individual assessment of the severity of symptoms and risk of exacerbations. This article reviews COPD pharmacotherapy in the Gulf countries and explores the role of nebulization in the management of COPD in this region. Methods: To review the COPD pharmacotherapy in the Gulf Countries, literature search was conducted using PubMed, Medline, Cochrane Systematic Reviews, and Google Scholar databases (before December 2022), using search terms such as COPD, nebulization, inhalers/inhalation, aerosols, and Gulf countries. Relevant articles from the reference list of identified studies were reviewed. Consensus statements, expert opinion, and other published review articles were included. Results: In the Gulf countries, pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers, and nebulizers are used for drug delivery to COPD patients. pMDIs and DPIs are most prone to errors in technique and other common device handling errors. Nebulization is another mode of inhalation drug delivery, which is beneficial in certain patient populations such as the elderly and patients with cognitive impairment, motor or neuromuscular disorders, and other comorbidities. Conclusion: There is no major difference between Gulf countries and rest of the world in the approach to management of COPD. Nebulizers should be considered for patients who have difficulties in accessing or using MDIs and DPIs, irrespective of geographical location.

The Role of Inhaled Chitosan-Based Nanoparticles in Lung Cancer Therapy.

Lung cancer is the leading cause of cancer-related mortality worldwide, largely due to the limited efficacy of anticancer drugs, which is primarily attributed to insufficient doses reaching the lungs. Additionally, patients undergoing treatment experience severe systemic adverse effects due to the distribution of anticancer drugs to non-targeted sites. In light of these challenges, there has been a growing interest in pulmonary administration of drugs for the treatment of lung cancer. This route allows drugs to be delivered directly to the lungs, resulting in high local concentrations that can enhance antitumor efficacy while mitigating systemic toxic effects. However, pulmonary administration poses the challenge of overcoming the mechanical, chemical, and immunological defenses of the respiratory tract that prevent the inhaled drug from properly penetrating the lungs. To overcome these drawbacks, the use of nanoparticles in inhaler formulations may be a promising strategy. Nanoparticles can assist in minimizing drug clearance, increasing penetration into the lung epithelium, and enhancing cellular uptake. They can also facilitate increased drug stability, promote controlled drug release, and delivery to target sites, such as the tumor environment. Among them, chitosan-based nanoparticles demonstrate advantages over other polymeric nanocarriers due to their unique biological properties, including antitumor activity and mucoadhesive capacity. These properties have the potential to enhance the efficacy of the drug when administered via the pulmonary route. In view of the above, this paper provides an overview of the research conducted on the delivery of anticancer drug-loaded chitosan-based nanoparticles incorporated into inhaled drug delivery devices for the treatment of lung cancer. Furthermore, the article addresses the use of emerging technologies, such as siRNA (small interfering RNA), in the context of lung cancer therapy. Particularly, recent studies employing chitosan-based nanoparticles for siRNA delivery via the pulmonary route are described.

Rifabutin loaded inhalable β-glucan microparticle based drug delivery system for pulmonary TB

Inhalable microparticle-based anti TB drug delivery systems are being investigated extensively for Tuberculosis [TB] treatment as they offer efficient and deep lung deposition with several advantages over conventional routes. It can reduce the drug dose, treatment duration and toxic effects and optimize the drug bioavailability. Yeast derived β-glucan is a β-[1–3/1–6] linked biocompatible polymer and used as carrier for various biomolecules. Due to presence of glucan chains, particulate glucans act as PAMP and thereby gets internalized via receptor mediated phagocytosis by the macrophages. In this study, β-glucan microparticles were prepared by adding l-leucine as excipient, and exhibited 70% drug [Rifabutin] loading efficiency. Further, the sizing and SEM data of particles revealed a size of 2–4 µm with spherical dimensions. The FTIR and HPLC data confirmed the β-glucan composition and drug encapsulations efficiency of the particles. The mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD] data indicated that these particles are inhalable in nature and have better thermal stability as per DSC thermogram. These particles were found to be non-toxic upto a concentration of 80 µg/ml and were found to be readily phagocytosed by human macrophage cells in-vitro as well as in-vivo by lung alveolar macrophage. This study provides a framework for future design of inhalable β-glucan particle based host-directed drug delivery system against pulmonary TB.

An individualised 3D computational flow and particle model to predict the deposition of inhaled medicines — A case study using a nebuliser

Background and objective: Drug inhalation is generally accepted as the preferred administration method for treating respiratory diseases. To achieve effective inhaled drug delivery for an individual, it is necessary to use an interdisciplinary approach that can cope with inter-individual differences. The paper aims to present an individualised pulmonary drug deposition model based on Computational Fluid and Particle Dynamics simulations within a time frame acceptable for clinical use. Methods:We propose a model that can analyse the inhaled drug delivery efficiency based on the patient’s airway geometry as well as breathing pattern, which has the potential to also serve as a tool for a sub-regional diagnosis of respiratory diseases. The particle properties and size distribution are taken for the case of drug inhalation by using nebulisers, as they are independent of the patient’s breathing pattern. Finally, the inhaled drug doses that reach the deep airways of different lobe regions of the patient are studied. Results:The numerical accuracy of the proposed model is verified by comparison with experimental results. The difference in total drug deposition fractions between the simulation and experimental results is smaller than 4.44% and 1.43% for flow rates of 60 l/min and 15 l/min, respectively. A case study involving a COVID-19 patient is conducted to illustrate the potential clinical use of the model. The study analyses the drug deposition fractions in relation to the breathing pattern, aerosol size distribution, and different lobe regions. Conclusions:The entire process of the proposed model can be completed within 48 h, allowing an evaluation of the deposition of the inhaled drug in an individual patient’s lung within a time frame acceptable for clinical use. Achieving a 48-hour time window for a single evaluation of patient-specific drug delivery enables the physician to monitor the patient’s changing conditions and potentially adjust the drug administration accordingly. Furthermore, we show that the proposed methodology also offers a possibility to be extended to a detection approach for some respiratory diseases.

Novel inhaled andrographolide for treatment of lung cancer: In vitro assessment

Andrographolide is a plant-based compound that showed promising activity against lung cancer. However, the compound's poor water solubility and low bioavailability limit its oral administration. Inhaled drug delivery of andrographolide is highly favourable as it delivers active ingredients directly into the affected lungs. In the current study, we compared in vitro aerosol performance, anti-cancer activity and storages stability of two (2) inhalable andrographolide formulations. Formulation 1 was prepared using precipitation and spray drying techniques, while Formulation 2 was prepared via direct spray drying technique. Drug morphology and physicochemical properties were confirmed using scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis. In vitro aerosol dispersion profile was evaluated using the next-generation impactor (NGI). Formulation 1 consisted of elongated crystals while Formulation 2 was made up of amorphous spherical particles. Both formulations had an inhalable fraction (<5 μm) of more than 40 %, making them suitable for pulmonary drug delivery. The formulations also showed an IC25 of less than 100 μg/mL against the human lung carcinoma cells (A549). Formulation 1 and 2 was stable in a vacuum condition at 30 °C for up to 6 and 3 months, respectively. Novel inhalable andrographolide dry powders were successfully produced with a good aerosol profile, potent anti-cancer activity and adequate storage stability, which deserve further in vivo investigations.

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.

Abstract 491: Aerosol delivery of immunotherapy and hesperetin nanoparticles in murine lung cancer model

Abstract Purpose: Radiation is the most common modality for lung cancer treatment method. Radiationinduces apoptosis, causing cancer cells to be fragmented and expose the cancer-associatedantigens to the tumor microenvironment. These can be recognized by antigen-presenting cells(APC) to induce the antineoplastic effect by activating cytotoxic T cells. Our prior studies showadding immunoadjuvant like AntiCD40 with radiation can further activate the APCs in its anti-tumor (M1) format. Recent studies have shown that flavonoids like Hesperetin, an ACE2receptor agonist also can induce apoptosis in cancer cells whereas ACE2 receptors are abundant in lung cancer cells.This project aims to develop a novel treatment for non-small cell lung cancer (NSCLC) using nanotechnology for inhalation drug delivery Hesperetin, a flavonoid with antioxidant and pro-apoptotic activity; bound to PLGA-coated nanoparticles (Hesperetin Nanoparticles, HNPs) andAntiCD40 aiming for localized targeted dosing to reduce the treatment-related systemic toxicity.We plan to test the efficacy and safety of this aerosol spray. Methods: In-vitro studies were performed in human A549 (ATCC) and murine LLC1 (ATCC)lung cancer cell lines for growth (MTT) and clonogenic survival assays to demonstrate the anti-cancer cell activity of Hesperetin (Sigma). Next, HNP was prepared using NanoFabTx™ nano-formulation reagent kits (Millipore-Sigma). A syngeneic orthotopic murine model of Lungadenoma was generated in wild (+/+) C57/BL6 background mice with similar background LLC1cell lines. We developed syngeneic orthotopic murine lung tumors with luciferase genetransfected LL/2-Luc2 (ATCC) Lewis Lung Cancer cell line in wild-type C57BL/6 mice(Techonic). Lung tumor-bearing mice were treated with HNP, antiCD40, or both with aerosolspray with a control group treated with the solvent (dH2O) only. To assess the drug delivery withaerosol treatment ex-vivo lung tissue was analyzed for Fluorescence tagged antiCD40 andnanoparticle uptakes. A survival assay was performed to analyze the efficacy of aerosoltreatment of HNPs with or without AntiCD40. All cohorts were also analyzed for body score, body weight, and liver and kidney functions. Results: We were able to successfully develop an aerosol drug delivery model to administer bothAnti-CD40 and HNP in a murine lung cancer model. In our analysis of an orthotopic murinelung cancer model, we demonstrate a high intake of the HNP and AntiCD40 by the cancer cellssparing the normal lung tissue. Moreover, the highest percentage of survival rate was observed with the combination aerosol treatment with HNP+AntiCD40 (p&amp;lt;0.001), compared to CD40alone (p&amp;lt;0.01) or HNP (p&amp;lt;0.01) alone. Comments: This treatment model will allow us to make the lung cancer treatment method easilyavailable for the mass population without having hazardous radiation treatment in the lungcancer model. Citation Format: Sayeda Yasmin-Karim, Geraud Richard, Amanda Fam, Alina-Marissa Ogurek, G. Mike Makrigiorgos. Aerosol delivery of immunotherapy and hesperetin nanoparticles in murine lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 491.

Hydrogenated Soy Phosphatidylcholine Liposomes Stimulate Differential Expression of Chemokines And Cytokines by Rat Alveolar Macrophages In Vitro

Liposomes are being developed as inhalable drug delivery systems, but concerns remain about their impact on the lungs. To better understand the impact of liposomes and their physicochemical properties on alveolar macrophages, the cytokine and chemokine expression profile of rat alveolar Nr8383 macrophages exposed to 0.1 and 1 mg/ml hydrogenated soy phosphatidylcholine (HSPC) liposomes was examined. Expression patterns varied considerably between liposomes in a concentration-dependent manner, with both anti- and pro-inflammatory chemokines/cytokines produced. Uncharged liposomes induce the greatest production of cytokines and chemokines, followed by PEGylated liposomes. The most significant increase in cytokine/chemokine expression was seen for IL-2 (up to 24-fold), IL-4 (up to 5-fold), IL-18 and VEGF (up to 10-fold), while liposome exposure significantly reduced MIP1 expression (5-fold). In summary, we demonstrate that liposome surface properties promote variable patterns of cytokine and chemokine secretion by alveolar macrophages. This suggests that the type of liposome employed may influence the type of immune response generated in the lung and by extension, dictate how inhaled liposomal nanomedicines affect the lungs response to inhaled toxicants and local infections.

Recent Developments in Aerosol Pulmonary Drug Delivery: New Technologies, New Cargos, and New Targets.

There is nothing like a global pandemic to motivate the need for improved respiratory treatments and mucosal vaccines. Stimulated by the COVID-19 pandemic, pulmonary aerosol drug delivery has seen a flourish of activity, building on the prior decades of innovation in particle engineering, inhaler device technologies, and clinical understanding. As such, the field has expanded into new directions and is working toward the efficient delivery of increasingly complex cargos to address a wider range of respiratory diseases. This review seeks to highlight recent innovations in approaches to personalize inhalation drug delivery, deliver complex cargos, and diversify the targets treated and prevented through pulmonary drug delivery. We aim to inform readers of the emerging efforts within the field and predict where future breakthroughs are expected to impact the treatment of respiratory diseases.

In-flight electro-neutralisation electrospray for pulmonary drug delivery

Pulmonary drug delivery does not only provide non-invasive therapy for local lung diseases but also remarkably enhances systemic absorption of therapeutics owing to the tremendous surface area of the lung and fast transport of active molecules across the respiratory epithelia. In comparison to traditional delivery systems, electrohydrodynamic atomisation (EHDA) is superior in terms of size and production rate control but the high surface charges of resulting particles prohibit its use in drug delivery. To overcome this challenge, we developed an in-flight electro-neutralisation electrospray (IFENE) method which enables the generation of mists of particles in respirable size range with little to no charge. Our approach uses low-frequency alternating current (AC) to produce charge-neutralised sprays with initial velocity due to oppositely charged droplets combination. Experiments and simulations with pure liquid as the working solution were conducted to reveal the underlying mechanism. The applied frequency is found to be the main factor that influences spray stability and formation. Poly (vinylidene fluoride) (PVDF) and PVDF with curcumin solution were electrosprayed via IFENE, producing sprays of organic particles with controlled sizes and neutralised charges. The capability of coupling particle generation in the respirable size range (below 5 μm) and charge reduction (under 400 femtoamperes), along with its simple setup makes IFENE a promising platform technology in inhalation drug delivery.

Enhancing Inhalation Drug Delivery: A Comparative Study and Design Optimization of a Novel Valved Holding Chamber.

This paper presents an innovative approach to the design optimization of valved holding chambers (VHCs), crucial devices for aerosol drug delivery. We present the design of an optimal cylindrical VHC body and introduce a novel valve based on particle impaction theory. The research combines computational simulations and physical experiments to assess the performance of various VHCs, with a special focus on the deposition patterns of medication particles within these devices. The methodology incorporates both experimental and simulation approaches to validate the reliability of the simulation. Emphasis is placed on the deposition patterns observed on the VHC walls and the classification of fine and large particles for salbutamol sulfate particles. The study reveals the superior efficacy of our valve design in separating particles compared to commercially available VHCs. In standard conditions, our valve design allows over 95% of particles under 7 μm to pass through while effectively filtering those larger than 8 μm. The optimized body design accomplishes a 60% particle mass flow fraction at the outlet and an average particle size reduction of 58.5%. When compared numerically in terms of size reduction, the optimal design outperforms the two commercially available VHCs selected. This study provides valuable insights into the optimization of VHC design, offering significant potential for improved aerosol drug delivery. Our findings demonstrate a new path forward for future studies, aiming to further optimize the design and performance of VHCs for enhanced pulmonary drug delivery.

Practical Considerations in Dose Extrapolation from Animals to Humans.

Animal studies are an important component of drug product development and the regulatory review process since modern practices have been in place, for almost a century. A variety of experimental systems are available to generate aerosols for delivery to animals in both liquid and solid forms. The extrapolation of deposited dose in the lungs from laboratory animals to humans is challenging because of genetic, anatomical, physiological, pharmacological, and other biological differences between species. Inhaled drug delivery extrapolation requires scrutiny as the aerodynamic behavior, and its role in lung deposition is influenced not only by the properties of the drug aerosol but also by the anatomy and pulmonary function of the species in which it is being evaluated. Sources of variability between species include the formulation, delivery system, and species-specific biological factors. It is important to acknowledge the underlying variables that contribute to estimates of dose scaling between species.

The potential of leveraging electrostatics for improved inhaled drug delivery to the lungs

In this short perspective, we explore the potential of leveraging electrostatic forces in the lungs to enhance pulmonary drug delivery methods and optimize drug delivery efficiency and therapeutic outcomes. Alongside conventional mechanisms such as diffusion, gravitational sedimentation, and impaction, we delve into electrostatic mechanisms, utilizing a non-dimensional analysis approach for insights into aerosol drug delivery. While often overlooked in inhalation therapy, our considerations emphasize the significance of electrostatic interactions on drug deposition, particularly in the deep lung, where, in the future, tailored electrostatic charges can strategically offer new possibilities for localized therapeutic effects for respiratory diseases.

ACE2 Receptor-Targeted Inhaled Nanoemulsions Inhibit SARS-CoV-2 and Attenuate Inflammatory Responses.

Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin-converting enzyme 2 （ACE2）receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor-binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug-targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches are innovatively combined by designing a nanoemulsion (NE) drug delivery system (termed NE-AYQ) for inhalation that targets binding to ACE2 receptors. This inhalation-delivered remdesivir nanoemulsion (termed RDSV-NE-AYQ) effectively inhibits the infection of target cells by both wild-type and mutant viruses. The RDSV-NE-AYQ strongly inhibits Severe acute respiratory syndrome coronavirus 2 at two dimensions: they not only block the binding of the virus to host cells at the cell surface but also restrict virus replication intracellularly. Furthermore, in the mouse model of acute lung injury, the inhaled drug delivery system loaded with anti-inflammatory drugs (TPCA-1-NE-AYQ) can significantly alleviate the lung tissue injury of mice. This smart combination provides a new choice for dealing with possible emergencies in the future and for the rapid development of inhaled drugs for the treatment of respiratory diseases.

Lipidated brush-PEG polymers as low molecular weight pulmonary drug delivery platforms

ABSTRACT Objectives Nanomedicines are being actively developed as inhalable drug delivery systems. However, there is a distinct utility in developing smaller polymeric systems that can bind albumin in the lungs. We therefore examined the pulmonary pharmacokinetic behavior of a series of lipidated brush-PEG (5 kDa) polymers conjugated to 1C2, 1C12 lipid or 2C12 lipids. Methods The pulmonary pharmacokinetics, patterns of lung clearance and safety of polymers were examined in rats. Permeability through monolayers of primary human alveolar epithelia, small airway epithelia and lung microvascular endothelium were also investigated, along with lung mucus penetration and cell uptake. Results Polymers showed similar pulmonary pharmacokinetic behavior and patterns of lung clearance, irrespective of lipid molecular weight and albumin binding capacity, with up to 30% of the dose absorbed from the lungs over 24 h. 1C12-PEG showed the greatest safety in the lungs. Based on its larger size, 2C12-PEG also showed the lowest mucus and cell membrane permeability of the three polymers. While albumin had no significant effect on membrane transport, the cell uptake of C12-conjugated PEGs were increased in alveolar epithelial cells. Conclusion Lipidated brush-PEG polymers composed of 1C12 lipid may provide a useful and novel alternative to large nanomaterials as inhalable drug delivery systems.