The purpose was to show, using destructive/nondestructive methods, that the interplay between water, tablet structure, and composition determine the unique spatiotemporal hydration pattern of polymer-based matrices. The tablets containing a 1:1 w/w mixture of sodium alginate with salicylic acid (ALG/SA) or sodium salicylate (ALG/SNA) were studied using Karl Fischer titration, differential scanning calorimetry, X-ray microtomography, and magnetic resonance imaging. As the principal results, matrix specific features were detected, e.g., “locking” of the internal part of the matrix (ALG/SA); existence of lamellar region associated with detection of free/freezing water (ALG/SA); existence of water penetrating the matrix forming specific region preceding infiltration layer (ALG/SNA); switch in the onset temperature of endothermic water peak associated with an increase in the fraction of non-freezing water weight per dry matrix weight in the infiltration layer (ALG/SNA). The existence of complicated spatiotemporal hydration patterns influenced by matrix composition and molecular properties of constituents has been demonstrated.

Methods of spatiotemporal characterization of nonequilibrated polymer based matrices are still immature and imperfect. The purpose of the study was to develop the methodology for the spatiotemporal characterization of water transport and properties in alginate tablets under hydration. The regions of low water content were spatially and temporally sampled using Karl Fisher and Differential Scanning Callorimetry (spatial distribution of freezing/nonfreezing water) with spatial resolution of 1 mm. In the regions of high water content, where sampling was infeasible due to gel/sol consistency, magnetic resonance imaging (MRI) enabled characterization with an order of magnitude higher spatial resolution. The minimally hydrated layer (MHL), infiltration layer (IL) and fully hydrated layer (FHL) were identified in the unilaterally hydrated matrices. The MHL gained water from the first hour of incubation (5–10% w/w) and at 4 h total water content was 29–39% with nonfreezing pool of 28–29%. The water content in the IL was 45–47% and at 4 h it reached ~50% with the nonfreezing pool of 28% and T₂ relaxation time < 10 ms. The FHL consisted of gel and sol layer with water content of 85–86% with a nonfreezing pool of 11% at 4 h and T₂ in the range 20–200 ms. Hybrid destructive/nondestructive analysis of alginate matrices under hydration was proposed. It allowed assessing the temporal changes of water distribution, its mobility and interaction with matrices in identified layers.

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.

Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the present study, we describe the development of a robust SR matrix tablet with a novel G-protein-coupled receptor 40 (GPR40) agonist for first-in-human studies and introduce a general workflow for the successful development of SR formulations for innovative APIs. The hydrophilic matrix tablets containing the labeled API dose of 5, 30, or 120 mg were evaluated with several methods: standard USP II dissolution, bio-predictive dissolution tests, and the texture and matrix formation analysis. The standard dissolution tests allowed preselection of the prototypes with the targeted dissolution rate, while the subsequent studies in physiologically relevant conditions revealed unwanted and potentially harmful effects, such as dose dumping under an increased mechanical agitation. The developed formulations were exceptionally robust toward the mechanical and physicochemical conditions of the bio-predictive tests and assured a comparable drug delivery rate regardless of the prandial state and dose labeled. In conclusion, the introduced development strategy, when implemented into the development cycle of SR formulations with innovative APIs, may allow not only to reduce the risk of formulation-related failure of phase I clinical trial but also effectively and timely provide safe and reliable medicines for patients in the trial and their further therapy.

Aim: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G‐protein‐coupled receptor 40 agonist developed to treat type 2 diabetes (T2D). Methods: The phase 1 study in healthy volunteers (White, age 18–55 years, body mass index 18.5–29.9 kg/m ² ) was performed after single (24 subjects, 5–480 mg) and multiple (32 subjects, 60–480 mg) once‐daily administration of CPL207280. The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C‐peptide, proinsulin, glucagon levels) observed during the 14‐day treatment period. Results: No deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration ( C _max ) or area under the plasma concentration–time curve up to 24 h. However, dose‐normalized C _max decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half‐life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed. Conclusions: CPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single‐daily administration and justifies further development of this therapy for patients with T2D.

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