Combinations of Drugs for Pulmonary Inhalation: A Review of Novel Technologies and Toxicological Evaluation Using Cellular Models

This review summarizes innovative co-formulation strategies for non-marketed dry powder inhalers (DPIs), enabling the simultaneous pulmonary delivery of multiple active pharmaceutical ingredients (APIs). Key approaches include co-amorphous systems (COAMS) and co-crystals, which combine two APIs into a single particle, improving aerodynamic properties, solubility, dissolution, and patient compliance while reducing manufacturing complexity. Core–shell microparticles, produced via spray drying, allow spatial separation and controlled release of APIs, minimizing drug–drug interactions and enabling tailored pharmacokinetics. Co-spray drying of dual APIs can yield particles with superior aerosolization and stability, though examples remain limited. Nanoparticle-based systems offer enhanced lung deposition and cellular uptake but face challenges in device compatibility, scalability, and regulatory approval. Each technology presents unique advantages and limitations regarding manufacturability, dose flexibility, and clinical translation. This review also highlights advances in in vitro toxicity testing, including air–liquid interface cultures, organoids, lung-on-chip models, and precision-cut lung slices, which are increasingly important as alternatives to animal studies. The importance of using an aerosol exposure system for the testing is highlighted. Ultimately, the choice of co-formulation platform should balance scientific innovation with practical considerations of manufacturing and regulatory requirements to maximize therapeutic benefit and commercial viability for future DPI combination products.