Three-dimensional printing (3DP) has already found its way into the pharmaceutical industry and represents a promising technology for medication tailorization and combination (Chen et al., 2020, Dachtler et al., 2021, Dachtler et al., 2020, Huber et al., 2017). In contrast to conventional manufacturing methods such as powder compaction or encapsulation, 3DP products can be adapted to the individual needs of patients on-site and on-demand (Chandekar et al., 2019, Dachtler et al., 2020, Souto et al., 2019). For patient-centered therapy it is imperative to consider a wide range of variables and address factors such as gender, weight, age, disease progression, disease state, and numerous other parameters (Drumond, 2020, Trivedi et al., 2018, Wishart, 2016). When administering a precise dose of medications, a combination of separate dosage forms are used traditionally (Menditto et al., 2020). This leads to inconvenient or even challenging medication intake and puts treatment adherence at risk (Menditto et al., 2020, Robinson et al., 2008). Providing customized drug amounts in a single 3DP tablet offers a smart solution to overcome these issues.

The utilized FlexdoseTM 3D printer applies additive manufacturing by direct granules extrusion to produce oral dosage forms (ODF) (Pflieger et al., 2022). This particular device is fed by polymer granules containing active pharmaceutical ingredients (API), which are conveyed along an extrusion channel and dispensed from the nozzle in form of a polymer melt (Pflieger et al., 2022, Seoane-Viaño et al., 2021). Through movement of the printhead and bed according to a set 3D computer aided design (CAD) model, the object is gradually built up in horizontal layers (Pflieger et al., 2022, Seoane-Viaño et al., 2021).

TPH, a bronchodilator, has been used for the treatment of respiratory diseases such as bronchial asthma and chronic obstructive pulmonary disease (COPD) for over a century, establishing its position in the pharmaceutical field (Barnes, 2003, Karow and Lang-Roth, 2020). Due to its narrow therapeutic window, it is crucial to be able to precisely control both the absolute dosage and the release kinetics (Ratiopharm, 2020). Currently, TPH is administered in accordance with the patient’s body weight (BW), with initial recommendations starting from 11 to 13 mg/kg BW daily (Ratiopharm, 2020). In practice, the blood serum concentration is closely monitored throughout the course of the treatment and adjusted if necessary, which is where particularly pharmaceutical 3DP comes in handy (Barnes, 2003, Paloucek and Rodvold, 1988). In addition, it is noteworthy that currently available market products (MP) do not offer sufficient dose increments to cover a diverse spectrum of patients. Recent findings suggest that TPH helps treating various respiratory diseases and most interestingly Covid-19, in a progressive low-dose administration approach (Montaño et al., 2022, Pouya et al., 2020). As demonstrated by multiple studies, TPH has been shown to exhibit promising results in improving respiratory symptoms, particularly at low blood serum concentrations of 1–5 μg/mL (Barnes, 2003, Cosio et al., 2009, Devereux et al., 2019, Siddharthan et al., 2021). This innovative administration strategy shifts required absolute dosages and dose increment precision (Asmus et al., 1997). The typically available 100–125 mg increments of current TPH products do not facilitate the implementation of this new therapeutic strategy, necessitating a reevaluation by pharmaceutical 3DP (Asmus et al., 1997, Ratiopharm, 2020).

The first aim of our study was to resort to a Taguchi DOE, that serves as an initial evaluation of the impact of chosen design parameters and to establish an understanding of the stability of the printing process. To this end, tablets with varying drug concentrations in feeding granules (DC), printlet volumes (V), scale factors (SF), and tablet body infills (INF) were examined. In a second step, considerations regarding dose individualization are made, establishing a correlation between actual printed doses and the sustained drug release properties of selected tablet designs. Following this relationship and to complete the work, we have shown through IVIVC and PBPK modeling that a paradigm patient group could be covered according to the progressive low blood level approach.