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.

Inhaled drug delivery is a unique administration route known for its ability to directly target pulmonary or brain regions, facilitating rapid onset and circumventing the hepatic first-pass effect. To characterize current global trends and provide a visual overview of the latest trends in inhaled drug delivery research, bibliometric analysis of data acquired from the Web of Science Core Collection database was performed via VOSviewer and CiteSpace. Inhaled drug delivery can not only be utilized in respiratory diseases but also has potential in other types of diseases for both fundamental and clinical applications. Overall, we provide an overview of present trends, collaborations, and newly discovered frontiers of inhaled drug delivery.

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The severe course of COVID-19 leads to the long-terming pulmonary diseases, such as bacterial pneumonia and post-COVID-19 pulmonary fibrosis. Thus, the essential task of biomedicine is a design of new effective drug formulations, including those for inhalation administration. In this work, we propose an approach to the creation of lipid-polymer delivery systems for fluoroquinolones and pirfenidone based on liposomes of various compositions decorated with mucoadhesive mannosylated chitosan. A generalizing study on the physicochemical patterns of the interactions of drugs with bilayers of various compositions was carried out, and the main binding sites were identified. The role of the polymer shell in the stabilization of vesicles and the delayed release of the contents has been demonstrated. For the liquid-polymer formulation of moxifloxacin, a prolonged accumulation of the drug in lung tissues was found after a single endotracheal administration to mice, significantly exceeding the control intravenous and endotracheal administration of the drug.

The aim of this research was to chemically analyse the distribution of drugs and excipients in pharmaceutical dry powder inhalation (DPI) aerosol particles of various sizes in solid state. The conventional wet assay of the chemical composition of particles after collection in a cascade impactor lacks the capability to differentiate spatially resolved morphology and chemical composition of particles in complex DPI formulations. In this proof-of-concept study, we aim to demonstrate the feasibility of using optical photothermal infrared spectroscopy (O-PTIR) to characterize micro- to nano-scale chemical composition of size-segregated particles of pharmaceutical DPI formulations. These formulations were prepared by spray drying a solution or a suspension comprising an inhaled corticosteroid fluticasone propionate, a long-acting β2-agonist salmeterol xinafoate, and excipient lactose. The active ingredients fluticasone propionate and salmeterol xinafoate are widely used for the treatment of asthma and chronic obstructive pulmonary disease. Spatially resolved O-PTIR spectra acquired from the particles collected from stages 1-7 of a Next Generation Impactor (NGI) for both formulations confirmed the presence of peaks related to fluticasone propionate (1746 cm-1, 1702 cm-1, 1661 cm-1 and 1612 cm-1), salmeterol xinafoate (1582 cm-1), and lactose (1080 cm-1). There was no significant difference in the drug to lactose peak ratio among various size fractions of particles spray dried from solution indicating a homogeneity in drug and lactose content in the aerosol formulation. In contrast, the suspension-spray dried formulation showed the drug content increased while the lactose content decreased in the particles collected down the NGI from stage 1 to stage 7, indicating heterogeneity in the ratio of drug-excipient distribution. The qualitative chemical compositions from O-PTIR were comparable to conventional wet chemical assays of various size fractions, indicating the suitability of O-PTIR to serve as a valuable analytical platform for screening the physicochemical properties of DPIs in solid state.

A lethal condition at the arterial-alveolar juncture caused the exhaustive remodeling of pulmonary arterioles and persistent vasoconstriction, followed by a cumulative augmentation of resistance at the pulmonary vascular and, consequently, right-heart collapse. The selective dilation of the pulmonary endothelium and remodeled vasculature can be achieved by using targeted drug delivery in PAH. Although 12 therapeutics were approved by the FDA for PAH, because of traditional non-specific targeting, they suffered from inconsistent drug release. Despite available inhalation delivery platforms, drug particle deposition into the microenvironment of the pulmonary vasculature and the consequent efficacy of molecules are influenced by pathophysiological conditions, the characteristics of aerosolized mist, and formulations. Uncertainty exists in peripheral hemodynamics outside the pulmonary vasculature and extra-pulmonary side effects, which may be further exacerbated by underlying disease states. The speedy improvement of arterial pressure is possible via the inhalation route because it has direct access to pulmonary arterioles. Additionally, closed particle deposition and accumulation in diseased tissues benefit the restoration of remolded arterioles by reducing fallacious drug deposition in other organs. This review is designed to decipher the pathological changes that should be taken into account when targeting the underlying pulmonary endothelial vasculature, especially with regard to inhaled particle deposition in the alveolar vasculature and characteristic formulations.

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.

While the inhalation route has been used for millennia for pharmacologic effect, the biological barriers to treating lung disease created real challenges for the pharmaceutical industry until sophisticated device and formulation technologies emerged over the past fifty years. There are now several inhaled device technologies that enable delivery of therapeutics at high efficiency to the lung and avoid excessive deposition in the oropharyngeal region. Chemistry and formulation technologies have also emerged to prolong retention of drug at the active site by overcoming degradation and clearance mechanisms, or by reducing the rate of systemic absorption. These technologies have also been utilized to improve tolerability or to facilitate uptake within cells when there are intracellular targets. This paper describes the biological barriers and provides recent examples utilizing formulation technologies or drug chemistry modifications to overcome those barriers.

Mucociliary clearance is an essential airway defense mechanism dependent predominantly on the proper ciliary function and mucus rheology. The crucial role of cilia is evident in `a variety of respiratory diseases, as the ciliary dysfunction is associated with a progressive decline in lung function over time. The activity of cilia is under supervision of multiple physiological regulators, including second messengers. Their role is to enable a movement in coordinated metachronal waves at certain beat frequency. Ciliary function can be modulated by various stimuli, including agents from the group of beta2 agonists, cholinergic drugs, and adenosine triphosphate (ATP). They trigger cilia to move faster in response to elevated cytoplasmic Ca2+ originated from intracellular sources or replenished from extracellular space. Well-known cilia-stimulatory effect of Ca2+ ions can be abolished or even reversed by modulating the phosphodiesterase (PDE)-mediated breakdown of cyclic adenosine monophosphate (cAMP) since the overall change in ciliary beating has been dependent on the balance between Ca2+ ions and cAMP. Moreover, in chronic respiratory diseases, high ATP levels may contribute to cAMP hydrolysis and thus to a decrease in the ciliary beat frequency (CBF). The role of PDE inhibitors in airway cilia-driven transport may help in prevention of progressive loss of pulmonary function often observed despite current therapy. Furthermore, administration of selective PDE inhibitors by inhalation lowers the risk of their systemic effects. Based on this review we may conclude that selective (PDE1, PDE4) or dual PDE inhibitors (PDE3/4) increase the intracellular level of cyclic nucleotides in airway epithelial cells and thus may be an important target in the development of new inhaled mucokinetic agents. Further research is required to provide evidence of their effectiveness and feasibility regarding their cilia-modulating properties.

The discovery of drugs to treat tuberculosis (TB) was a major medical milestone in the twentieth century. However, from the outset, drug resistance was observed. Currently, of the 10 million people that exhibit TB symptoms each year, 450,000 have multidrug or extensively drug resistant (MDR or XDR) TB. While greater understanding of the host and pathogen (Mycobacterium tuberculosis, Mtb) coupled with scientific ingenuity will lead to new drugs and vaccines, in the meantime 4000 people die daily from TB. Thus, efforts to improve existing TB drugs should also be prioritized. Improved efficacy and decreased dose and associated toxicity of existing drugs would translate to greater compliance, life expectancy and quality of life of Mtb infected individuals. One potential strategy to improve existing drugs is to deliver them by inhalation as aerosols to the lung, the primary site of Mtb infection. Inhaled drugs are used for other pulmonary diseases, but they have yet to be utilized for TB. Inhaled therapies for TB represent an untapped opportunity that the pharmaceutical, clinical and regulatory communities should consider.