Development of an immediate release excipient composition for 3D printing via direct powder extrusion in a hospital

1. Introduction

With further advancements in medicine, the need for individually dosed medications is becoming increasingly apparent. Additive manufacturing (AM), which is often referred to as 3D printing (3DP), is a computer-controlled process that comprises several different technologies. Some of these offer the possibility to be used in the manufacturing of pharmaceutics, for example, binder jetting, fused deposition modeling (FDM), direct powder extrusion (DPE) and semi solid extrusion (SSE).

Current pharmaceutical literature on material extrusion techniques is focused on FDM (Chamberlain et al., 2022, Goyanes et al., 2015a, Hoffmann et al., 2022, Kissi et al., 2021, Krueger et al., 2023, Windolf et al., 2021) and SSE (Díaz-Torres et al., 2023, Liang et al., 2023, Rodríguez-Pombo et al., 2022, Seoane-Viaño et al., 2021a, Tagami et al., 2021, Yan et al., 2020, Yu and Chen, 2020, Zhu et al., 2022). Both technologies are readily available and offer the possibility of producing relatively small batches, which limits the amounts of active pharmaceutical ingredient (API) and excipients needed to conduct formulation studies.

In addition to the printer, FDM requires a hot melt extruder to manufacture the drug-loaded filament that serves as a feedstock in the printing process. This not only limits the selection of excipients, as the filaments need to match specific mechanical properties in order to be usable as feedstock, but also increases thermal stress on the API. As an alternative, SSE enables the use of pre-filled syringes from which a gel or paste is extruded but often requires a post-printing solidification process.

In contrast, DPE can be viewed as a single-step process in which the powder blend is directly added to the printhead, fed towards the heated nozzle by a single screw and subsequently extruded in order to print the designed object in a layer-by-layer fashion (Goyanes et al., 2019). It has been reported that the powder flow exhibits a considerable influence on the printing process in DPE (Boniatti et al., 2021). This could pose a challenge for the implementation in hospital pharmacies as it limits the formulation options. Hospital pharmacies are often not equipped to granulate powders quickly and efficiently and are therefore dependent on commercially available product qualities or additives to increase powder flow. Other than that, DPE poses a viable option for the manufacturing of extemporaneous formulations in hospital pharmacies, since there is no need for a complex and time consuming, preceding feedstock preparation or post-printing process. Moreover, the printer can be used with only a few grams of the powder blend, which allows a more cost-efficient formulation development and enables the manufacturing of very small batch sizes in clinical practice. However, using DPE to manufacture solid oral dosage forms in a clinical setting has not been established yet.

In general, AM is an intriguing technology for the implementation in hospital pharmacies. At times, the medication for specific therapeutic approaches or patient groups is not commercially available and therefore needs to be manufactured by (hospital) pharmacies. Most commonly, if there is the need for individually dosed solid oral dosage forms, capsules are prepared. To achieve an adequate level of content uniformity, large numbers of capsules with a fixed dose need to be prepared, which makes frequent dose changes based on the measurement of drug levels, biomarkers or current symptom control challenging. In contrast, AM facilitates the manufacturing of individually dosed solid oral dosage forms since it offers the possibility of printing different doses on demand with a high level of precision and accuracy of the doses (Seoane-Viaño et al., 2021b, Vaz and Kumar, 2021).

Furthermore, the digital nature of 3DP makes the integration of manufacturing personalized medicines into an existing digital medication process in hospitals, such as the closed-loop medication management (CLMM) (Baehr and Melzer, 2018), feasible and might therefore contribute to improving medication safety for inpatients (Berger et al., 2022). However, there are no findings regarding the integration of compounding personalized solid oral dosages by AM into a digital medication process in a clinical setting.

Due to a shift towards precision dosing for numerous indications (Vinks et al., 2019) coupled with recent advancements in digital health monitoring systems (Bayoumy et al., 2021, Bruno et al., 2020, Kim et al., 2020, Pahwa et al., 2020, Powers et al., 2021), the benefits of personalized pharmacotherapy are becoming increasingly apparent. For instance, patients with Parkinson’s disease often require more than four doses of Levodopa (LD) / Carbidopa monohydrate (CD) per day in different dosages (Fox et al., 2018) that are often compiled from fragmented, marketed drug products (Forough et al., 2018). However, due to the symptoms (e.g., tremor and dysphagia) of the disease, patients often have problems handling and swallowing (Buhmann et al., 2019) tablets and therefore may benefit from the flexibility of AM to print individual doses and tablet geometries on demand. This might reduce the potential of medication errors, as it eliminates the need to compile the intended dose with fragmented tablets, which poses a two-fold risk. First, the wrong tablet might be split or some fragments could be lost due to disease-related motor symptoms of the patient. Secondly, it has been shown that quarters of tablets with a score-line are often not dose equivalent and the standard deviation (SD) of the dose is relatively high (up to 19.3%) (Madathilethu et al., 2018), whereas in comparison, DPE often reaches SDs below 5% (Ong et al., 2020, Pflieger et al., 2022). In addition, the therapy of Parkinson’s disease with LD / CD often requires an immediate drug release to achieve adequate symptom control. However, there is no data on a rapidly disintegrating DPE formulation without an elaborate feedstock preparation, of doses up to 200 mg, which is integral for the intended use of the tablets.

Therefore, this study aimed to demonstrate the feasibility of developing an excipient composition that enables an immediate drug release and reliable printing properties within DPE, in a hospital setting. Additionally, the resulting tablets should exhibit high hardness values and a storage stability sufficient for our CLMM. For that purpose, LD and CD were identified as model APIs of high clinical interest (Langebrake et al., 2023). The study presented here is a part of a larger project that comprises the tablet formulation, manufacturing process development and analytics as well as the development of a digital infrastructure and a machine learning based decision-support-system, which will be published separately.

2. Materials and Methods