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Dry Powder Inhaler (DPI) could offer a propellant-free, easy-to-use powder form ensuring better stability than liquid dosage forms. Therefore the development of traditional carrier-based and carrier-free new generation systems is a determinative factor in the field of DPI formulation. The purpose of our research work was to combine these two systems, utilizing their beneficial properties to produce a novel pulmonary drug delivery system containing ciprofloxacin hydrochloride (CIP). Co-spray drying, surface smoothing and the preparation of an interactive physical mixture were applied as the technological procedures of sample preparation. The carrier-based and carrier-free formulations, as well as the developed novel product were compared to each other. Structural investigations were made by X-ray powder diffraction and micrometric properties (habit, bulk density) were determined. Particle interactions were also evaluated to investigate surface free energy, cohesive-adhesive forces, and spreading coefficient. In vitro aerodynamic properties (mass median aerodynamic diameter), fine particle fraction (FPF) and emitted dose of DPIs were measured using Andersen Cascade Impactor. A novel in silico Stochastic Lung Model was also used to quantify the amount of particles deposited at the target area. The novel-formulated composition presented amorphous spherical particles with an average size of about 2 μm. The in vitro aerodynamic investigations showed a variance in FPF as a function of formulation method (carrier-based: 24%, carrier-free: 54% and applying the novel combination method: 63%). The in silico deposition results were in line with the in vitro measurements and yielded increased lung doses for the sample prepared by the combined technology. This novel DPI formulation provides an opportunity for a more effective therapy with deeper deposition of CIP.