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The route of administration of a therapeutic agent has a substantial impact on its success. Therapeutic antibodies are usually administered systemically, either directly by intravenous route, or indirectly by intramuscular or subcutaneous injection. However, treatment of diseases contained within a specific tissue necessitates a better alternate route of administration for targeting localised infections. Inhalation is a promising non-invasive strategy for antibody delivery to treat respiratory maladies because it provides higher concentrations of antibody in the respiratory airways overcoming the constraints of entry through systemic circulation and uncertainity in the amount reaching the target tissue. The nasal drug delivery route is one of the extensively researched modes of administration, and nasal sprays for molecular drugs are deemed successful and are presently commercially marketed. This review highlights the current state and future prospects of inhaled therapies, with an emphasis on the use of monoclonal antibodies for the treatment of respiratory infections, as well as an overview of their importance, practical challenges, and clinical trial outcomes.Key points• Immunologic strategies for preventing mucosal transmission of respiratory pathogens.• Mucosal-mediated immunoprophylaxis could play a major role in COVID-19 prevention.• Applications of monoclonal antibodies in passive immunisation.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with pathophysiological characteristics of transforming growth factor-β (TGF-β), and reactive oxygen species (ROS)-induced excessive fibroblast-to-myofibroblast transition and extracellular matrix deposition. Macrophages are closely involved in the development of fibrosis. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key molecule regulating ROS and TGF-β expression. Therefore, Nrf2 signaling modulation might be a promising therapy for fibrosis. The inhalation-based drug delivery can reduce systemic side effects and improve therapeutic effects, and is currently receiving increasing attention, but direct inhaled drugs are easily cleared and difficult to exert their efficacy. Therefore, we aimed to design a ROS-responsive liposome for the Nrf2 agonist dimethyl fumarate (DMF) delivery in the fibrotic lung. Moreover, we explored its therapeutic effect on pulmonary fibrosis and macrophage activation. Results We synthesized DMF-loaded ROS-responsive DSPE-TK-PEG@DMF liposomes (DTP@DMF NPs). DTP@DMF NPs had suitable size and negative zeta potential and excellent capability to rapidly release DMF in a high-ROS environment. We found that macrophage accumulation and polarization were closely related to fibrosis development, while DTP@DMF NPs could attenuate macrophage activity and fibrosis in mice. RAW264.7 and NIH-3T3 cells coculture revealed that DTP@DMF NPs could promote Nrf2 and downstream heme oxygenase-1 (HO-1) expression and suppress TGF-β and ROS production in macrophages, thereby reducing fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. In vivo experiments confirmed the above findings. Compared with direct DMF instillation, DTP@DMF NPs treatment presented enhanced antifibrotic effect. DTP@DMF NPs also had a prolonged residence time in the lung as well as excellent biocompatibility. Conclusions DTP@DMF NPs can reduce macrophage-mediated fibroblast-to-myofibroblast transition and extracellular matrix deposition to attenuate lung fibrosis by upregulating Nrf2 signaling. This ROS-responsive liposome is clinically promising as an ideal delivery system for inhaled drug delivery. Graphical Abstract

This retrospective population-based study investigated the impact of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on inhaled medication adherence in people with cystic fibrosis (pwCF). Prescription refill rate (PRR) for several inhaled medications were compared before and after ETI introduction in three major Italian CF centers. We found a significant decrease in PRR for most inhaled antibiotics and dornase-alpha after ETI implementation.This suggests that patients may be reducing their adherence to inhaled medications, potentially due to improved respiratory symptoms and quality of life. The study highlights the challenges of maintaining adherence to chronic inhaled medications in pwCF, even after the introduction of breakthrough therapies like ETI. Monitoring adherence remains crucial for optimizing patient outcomes, and the PRR emerges as a valuable tool for tracking adherence in real-world settings.

Inhaled corticosteroids (ICS) are the backbone of and primary choice for long-term asthma control therapy; however, the level of adherence to this regimen has not yet been investigated, particularly in the study area of Northwest Ethiopia. Therefore, this study aimed to examine the level of adherence to ICS treatment and its impact on adults living with asthma in Northwestern Ethiopian hospitals. A multicenter institution-based survey was conducted in asthma patients treated with ICS-based regimens in public hospitals in Northwest Ethiopia. Adherence to ICS was measured with the Medication Adherence Report Scale for Asthma. Descriptive statistics were used to present respondents' characteristics, and logistic regression was used to test associations between predictors and outcome variables. A level of <0.05 was used as a cut-off point for a significant association. Of a total of 422 approached subjects, 96.7% completed the survey. The mean (±SD) age of the participants was 49.82 (±16.1) years. The majority of participants (86.1%) had a low level of adherence to ICS treatment. A significant proportion (42%) of the respondents reported that they utilized ICS only before performing exercises that made them breathless. Around two-fifths of the participants used ICS either when they needed it or when they felt breathless. Furthermore, one-third of the study subjects reported that they either avoided or forgot to take ICS. Participants who had access to free healthcare services had better adherence to ICS ( =0.01), and non-adherence to ICS therapy was significantly associated with poor levels of asthma control ( ≤0.001). This study found that adult patients with asthma had low levels of adherence to ICS therapy. Future prospective research in a larger population, focusing on identifying the obstacles to ICS adherence in patients living with asthma and creating successful intervention options, is recommended.

In this review, an extensive analysis of dry powder inhalers (DPIs) is offered, focusing on their characteristics, formulation, stability, and manufacturing. The advantages of pulmonary delivery were investigated, as well as the significance of the particle size in drug deposition. The preparation of DPI formulations was also comprehensively explored, including physico-chemical characterization of powders, powder processing techniques, and formulation considerations. In addition to manufacturing procedures, testing methods were also discussed, providing insights into the development and evaluation of DPI formulations. This review also explores the design basics and critical attributes specific to DPIs, highlighting the significance of their optimization to achieve an effective inhalation therapy. Additionally, the morphology and stability of 3 DPI capsules (Spiriva, Braltus, and Onbrez) were investigated, offering valuable insights into the properties of these formulations. Altogether, these findings contribute to a deeper understanding of DPIs and their development, performance, and optimization of inhalation dosage forms.

In vitro dissolution and permeability testing aid the simulation of the in vivo behavior of inhalation drug products. Although the regulatory bodies have specific guidelines for the dissolution of orally administered dosage forms (e.g., tablets and capsules), this is not the case for orally inhaled formulations, as there is no commonly accepted test for assessing their dissolution pattern. Up until a few years ago, there was no consensus that assessing the dissolution of orally inhaled drugs is a key factor in the assessment of orally inhaled products. With the advancement of research in the field of dissolution methods for orally inhaled products and a focus on systemic delivery of new, poorly water-soluble drugs at higher therapeutic doses, an evaluation of dissolution kinetics is proving crucial. Dissolution and permeability testing can determine the differences between the developed formulations and the innovator’s formulations and serve as a useful tool in correlating in vitro and in vivo studies. The current review highlights recent advances in the dissolution and permeability testing of inhalation products and their limitations, including recent cell-based technology. Although a few new dissolution and permeability testing methods have been established that have varying degrees of complexity, none have emerged as the standard method of choice. The review discusses the challenges of establishing methods that can closely simulate the in vivo absorption of drugs. It provides practical insights into method development for various dissolution testing scenarios and challenges with dose collection and particle deposition from inhalation devices for dissolution tests. Furthermore, dissolution kinetic models and statistical tests to compare the dissolution profiles of test and reference products are discussed.

It is reported that pulmonary fibrosis has become one of the major long-term complications of COVID-19, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. Recently, inhalable nanocarriers have received more attention due to their ability to improve the solubility of insoluble drugs, penetrate biological barriers of the lungs and target fibrotic tissues in the lungs. The inhalation route has many advantages as a non-invasive method of administration and the local delivery of anti-fibrosis agents to fibrotic tissues like direct to the lesion from the respiratory system, high delivery efficiency, low systemic toxicity, low therapeutic dose and more stable dosage forms. In addition, the lung has low biometabolic enzyme activity and no hepatic first-pass effect, so the drug is rapidly absorbed after pulmonary administration, which can significantly improve the bioavailability of the drug. This paper summary the pathogenesis and current treatment of pulmonary fibrosis and reviews various inhalable systems for drug delivery in the treatment of pulmonary fibrosis, including lipid-based nanocarriers, nanovesicles, polymeric nanocarriers, protein nanocarriers, nanosuspensions, nanoparticles, gold nanoparticles and hydrogel, which provides a theoretical basis for finding new strategies for the treatment of pulmonary fibrosis and clinical rational drug use.

Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged. Graphical Abstract

The adoption of pulmonary vaccines to advantageously provide superior local mucosal protection against aerosolized pathogens has been faced with numerous logistical and practical challenges. One of these persistent challenges is the lack of effective vaccine adjuvants that could be well tolerated through the inhaled route of administration. Despite its widespread use as a vaccine adjuvant, aluminum salts (alum) are not well tolerated in the lung. To address this issue, we evaluated the use of porous aluminum (Al)-based metal–organic framework (MOF) nanoparticles (NPs) as inhalable adjuvants. We evaluate a suite of Al-based MOF NPs alongside alum including DUT-4, DUT-5, MIL-53 (Al), and MIL-101-NH 2  (Al). As synthesized, MOF NPs ranged between ~ 200 nm and 1 µm in diameter, with the larger diameter MOFs matching those of commercial alum. In vitro examination of co-stimulatory markers revealed that the Al-based MOF NPs activated antigen presenting cells more effectively than alum. Similar results were found during in vivo immunizations utilizing ovalbumin (OVA) as a model antigen, resulting in robust mucosal humoral responses for all Al MOFs tested. In particular, DUT-5 was able to elicit mucosal OVA-specific IgA antibodies that were significantly higher than the other MOFs or alum dosed at the same NP mass. DUT-5 also was uniquely able to generate detectable IgG2a titers, indicative of a cellular immune response and also had superior performance relative to alum at equivalent Al dosed in a reduced dosage vaccination study. All MOF NPs tested were generally well-tolerated in the lung, with only acute levels of cellular infiltrates detected and no Al accumulation; Al content was largely cleared from the lung and other organs at 28 days despite the two-dose regime. Furthermore, all MOF NPs exhibited mass median aerodynamic diameters (MMADs) of ~ 1.5–2.5 µm when dispersed from a generic dry powder inhaler, ideal for efficient lung deposition. While further work is needed, these results demonstrate the great potential for use of Al-based MOFs for pulmonary vaccination as novel inhalable adjuvants. Graphical Abstract