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[Display omitted] Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of 'inhalation biopharmaceutics' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using 'simple' Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation. [ABSTRACT FROM AUTHOR]

[Display omitted] Inhalable formulations of medicines intended to act locally in the lung are therapeutically effective at lower doses with targeted delivery, compared to parenteral or oral administration. Meanwhile, different APIs, including biologics, have proven to be challenging regarding formulation and final bioavailability. This study focuses on the production, improved stability performance, and delivery of spray-dried, inhalable protein powders to the lungs. By spray-drying 11 aqueous formulations of proteinX with varying L-leucine content and by employing a Design of Experiment (DoE), two formulations have been selected for stability studies based on the highest fine particle fraction (FPF), highest monomer content, and lowest particle size. We found that 5 %w/w L-leucine (based on protein content) resulted in similar or higher FPF at 2–8 °C and 25 °C/60 %RH (67.12 % and 48.50 %) stored for six months than 10 %w/w L-leucine (68.49 % and 35.04 %). This indicates that less leucine may be sufficient to produce stable, spray-dried inhalable particles with an improved FPF, and by doubling the leucine content, the aerosolization stability can deteriorate. We have discussed the postulated hypothesis underlying the observed stability behavior based on solid-state and morphological analysis. Our results suggest that spray-dried proteinX-leu-powders can be delivered to the lung at a lower dose than for intravenous administration. [ABSTRACT FROM AUTHOR]

[Display omitted] The manufacturing of tablets containing biologics exposes the biologics to thermal and shear stresses, which are likely to induce structural changes (e.g., aggregation and denaturation), leading to the loss of their activity. Saccharides often act as stabilizers of proteins in formulations, yet their stabilizing ability throughout solid oral dosage processing, such as tableting, has been barely studied. This work aimed to investigate the effects of formulation and process (tableting and spray-drying) variables on catalase tablets containing dextran, mannitol, and trehalose as potential stabilizers. Non-spray-dried and spray-dried formulations were prepared and tableted (100, 200, and 400 MPa). The enzymatic activity, number of aggregates, reflecting protein aggregation and structure modifications were studied. A principal component analysis was performed to reveal underlying correlations. It was found that tableting and spray-drying had a notable negative effect on the activity and number of aggregates formed in catalase formulations. Overall, dextran and mannitol failed to preserve the catalase activity in any unit operation studied. On the other hand, trehalose was found to preserve the activity during spray-drying but not necessarily during tableting. The study demonstrated that formulation and process variables must be considered and optimized together to preserve the characteristics of catalase throughout processing. [ABSTRACT FROM AUTHOR]