The pursuit of targeted therapies for cytokine-dependent diseases has led to the discovery of Janus kinase (JAK) inhibitors, a promising class of drugs. Among them, CPL409116, a selective dual JAK and rho-associated protein kinase inhibitor (ROCK), has demonstrated potential for treating conditions such as pulmonary fibrosis exacerbated by the COVID-19 pandemic. This study investigated the feasibility of delivering CPL409116 via inhalation, with the aim of minimizing the systemic adverse effects associated with oral administration. Two micronization methods, jet milling and spray drying, were assessed for CPL409116, with spray drying chosen for its ability to produce an amorphous form of the compound. Moreover, parameters such as the mixing energy, drug load, and force control agent significantly influenced the fine particle fraction (FPF), a critical parameter for pulmonary drug delivery. This study provides insights into optimizing the formulation parameters to enhance the delivery efficiency of CPL409116 to the lungs, offering potential for improved therapeutic outcomes in cytokine-dependent pulmonary diseases.

The development of dry powder inhalers (DPIs) for pulmonary drug delivery is complex, requiring optimization of variable factors to ensure effective lung deposition. This study investigates the factors influencing the dispersibility of glycopyrronium bromide (GLP) and indacaterol maleate (IND) in adhesive mixtures using both in vitro and in silico approaches. The formulation was designed to match the reference listed drug (RLD), using lactose and magnesium stearate as excipients. Key variables examined included mixing energy, carrier particle size distribution (PSD), and active pharmaceutical ingredient (API) particle size characteristics across multiple suppliers. A Next Generation Impactor (NGI) was employed to assess the aerodynamic particle size distribution (APSD) of 67 formulations. The collected impactor data were analyzed using machine learning (ML) models, leveraging the h2o AutoML framework. Stacked ensemble models demonstrated high predictive accuracy (R ² : 0.940 for GLP, 0.969 for IND), identifying key formulation parameters affecting dispersibility. SHAP analysis revealed that GLP dispersibility was influenced primarily by GLP PSD (d90, d50, SPAN), lactose d10, and mixing energy, while IND was more dependent on lactose PSD and its own particle size. The findings confirm that both APIs interact with each other within the formulation, significantly impacting their reciprocal deposition profiles. These insights highlight the challenge of developing bioequivalent DPI formulations and emphasize the importance of PSD control, mixing energy optimization, and advanced ML modeling in predicting therapeutic equivalence. The study provides a predictive framework to support the development of generic inhalation products, improving regulatory approval pathways and ensuring effective pulmonary drug delivery. Graphical Abstract

Magnesium stearate (MgSt), although well established as a pharmaceutical lubricant in solid oral dosage forms, plays a more complex role in carrier-based dry powder inhalers (DPIs), where it functions as a surface modifier and force control agent (FCA). In DPI formulations, MgSt can influence powder rheology, moisture resistance, interparticulate interactions, and aerosolization efficiency; however, these effects depend not simply on its presence or concentration, but on whether effective surface modification is achieved. This review critically evaluates experimental evidence on MgSt-mediated particle coating in carrier-based DPIs, with particular emphasis on how material attributes, particle cohesion and surface area, process energy, coating strategy, and MgSt concentration interact to determine coating efficiency and formulation performance. By integrating these factors, the review aims to provide a mechanistic framework for selecting and optimizing MgSt coating strategies and to identify methodological priorities for future research. The available evidence indicates that process energy is a major determinant of coating efficiency. High-energy techniques, particularly mechanofusion, can effectively modify highly cohesive micronized particles that are difficult to coat using conventional blending, whereas high-shear blending may provide sufficient energy for surface modification of larger, coarse lactose carriers. Mechanical milling represents a distinct strategy in which particle-size reduction and surface modification occur simultaneously. Direct comparison between coating approaches remains difficult because studies differ in MgSt grade, carrier and API properties, particle size distribution, processing conditions, and methods used to assess coating efficiency. MgSt generally improves aerosolization by modifying cohesive and adhesive interactions, but the magnitude of this effect is formulation-specific. Improvements in fine-particle delivery depend on MgSt particle size and specific surface area, the properties and surface area of the particles being coated, process energy, and the resulting coating efficiency. Consequently, increasing MgSt concentration does not necessarily improve performance, and excessive amounts may lead to overlubrication or MgSt agglomeration. Despite considerable progress, important knowledge gaps remain regarding how MgSt coating translates into improved DPI performance. Further studies integrating material properties, processing conditions, surface modification, and formulation performance are needed to establish more robust relationships between coating strategy and functional outcomes. Such knowledge may support more rational and formulation-specific use of MgSt in carrier-based DPIs.