Post-COVID syndrome or long COVID is defined as the persistence of symptoms after confirmed SARS-CoV-2 infection, the pathogen responsible for coronavirus disease. The content herein presented reviews the reported long-term consequences and aftereffects of COVID-19 infection and the potential strategies to adopt for their management. Recent studies have shown that severe forms of COVID-19 can progress into acute respiratory distress syndrome (ARDS), a predisposing factor of pulmonary fibrosis that can irreversibly compromise respiratory function. Considering that the most serious complications are observed in the airways, the inhalation delivery of drugs directly to the lungs should be preferred, since it allows to lower the dose and systemic side effects. Although further studies are needed to optimize these techniques, recent studies have also shown the importance of in vitro models to recreate the SARS-CoV-2 infection and study its sequelae. The information reported suggests the necessity to develop new inhalation therapies in order to improve the quality of life of patients who suffer from this condition.

Purpose: The purpose of this study was to investigate multi-fluid spray drying as a formulation strategy to engineer inhalable microparticles containing levofloxacin and mucolytic agents, and to evaluate how formulation and process parameters influence particle properties, aerosol performance, and drug release under mucus-relevant conditions. Methods: Microparticles containing levofloxacin in combination with mucolytic agents were produced using a mini spray dryer equipped with a triple-fluid nozzle. Different compositions and particle architectures were obtained by varying formulation and excipient allocation. The resulting powders were characterized in terms of morphology, bulk, tapped and true density, aerodynamic performance, and in vitro drug release evaluated both in the absence and presence of a mucus layer. Results: Ambroxol showed greater suitability for spray drying than N-acetylcysteine, resulting in markedly higher process yields (up to 74%). The incorporation of L-leucine as a functional excipient reduced particle agglomeration and improved powder handling and aerosolization, with fine particle fractions exceeding 38% for leucine containing formulations. Drug release experiments demonstrated that spray drying altered release behaviour under diffusion limiting conditions imposed by a mucus layer compared to dissolution under sink conditions. Conclusions: Overall, the results indicate that multi-fluid spray drying enables effective modulation of the physicochemical and aerodynamic properties of inhalable microparticles. This study provides mechanistic insight into how formulation composition and process design influence particle behaviour in mucus-relevant environments, supporting the use of this approach as a flexible platform for the development of inhalable formulations.

Background/Objectives: Dry powder inhalation (DPI) is a promising strategy for the treatment of respiratory diseases such as cystic fibrosis (CF), where thick and viscous mucus limits drug penetration and contributes to persistent infection and inflammation. Although inhalation allows rapid drug action with reduced systemic exposure, its efficacy depends on the ability of inhaled drugs to achieve and maintain therapeutic concentrations in the lungs and to overcome airway barriers. This study aimed to develop and characterize effervescent dry powder formulations designed to enhance mucus permeabilization through mechanical disruption while delivering an antibiotic. Methods: Effervescent microparticles containing sodium bicarbonate, an organic acid (citric or tartaric acid), and levofloxacin were produced by spray drying using a triple-fluid nozzle to control component distribution and prevent premature effervescence. The influence of functional excipients, including L-leucine and mannitol, on particle formation, aerosol performance, and process yield was evaluated. Microparticles were characterized in terms of morphology, fine particle fraction (FPF), and effervescence-related properties. Results: Formulations containing L-leucine and citric acid reduced particle agglomeration and achieved a fine particle fraction of up to approximately 18%, although with a lower process yield. In contrast, formulations based on tartaric acid and mannitol improved both production yield and aerosol performance, with FPF values increasing up to 27.3% and more efficient CO₂ release. The resulting microparticles exhibited spherical, hollow, and partially fragmented morphology, consistent with premature CO₂ generation during spray drying. Conclusions: The effervescent approach, combined with controlled spray drying parameters, represents a promising formulation strategy to modulate particle behavior and drug release in mucus-relevant environments. These findings support further investigation of effervescent DPI systems for improved pulmonary drug delivery in CF.