(173f) Toward Next Level of Pharmaceutical 3D-Printing through Advanced Lipid-Based Excipients

The opportunities and challenges faced by three-dimensional (3D-) printing in the pharmaceutical field are not based solely on the process itself, but also associated with the material attributes. Until now, polymer-based excipients remain the principal materials employed for dosage formulation and printing of medicine, with very limited trials on lipid-based excipients (LBEs). The high amorphous content of polymers provides them with high flexibility which impacts their 3D printability. LBEs, unlike polymers, are characterized by a crystalline nature which contributes to their brittleness, making their 3D-printing very challenging. Considering the advantages of LBEs compared to polymers, e.g. being naturally occurring materials, predominantly digestible with “Generally Recognized as Safe” (GRAS) status, it is of significant importance to investigate their functionality for 3D-printing of pharmaceutical dosage forms. Recently, polyglycerol esters of fatty acids (PGFAs), also known commercially as Witepsol^® PMF, were introduced as the next generation lipid-based excipients offering plenty of potentials for pharmaceutical applications ^[1]. The broad functionality based on their composition make PGFAs an appealing material for investigation. The synthesis of this group of excipients typically yields a mixture of PGFA as the main component (>80% w/w) and two more species, namely free polyglycerins (PGs) and mono acid fractions (MAF). Tuning the ratio between the three species can influence the material attributes and hence their processability and printability. In this study, we are investigating PGFAs, based on variations in their composition, as an advanced LBE for manufacturing lipid-based drug delivery systems via extrusion-based 3D-printing.

Due to the high number of polyglycerol moieties and free hydroxyl groups per molecule associated with the significant number of hydrogen bonds, and hence higher flexibility, the PG6-C16 partial ester (Witepsol PMF166) was selected as the starting material in this study. Beside the raw material, different blends of PG6-C16 partial esters composed of different ratios of its three components were prepared; either by adding PGs, MAF or both to the raw material. The materials were prepared for extrusion by melting, re-solidifying, crushing and sieving (<800 µm). Filaments of the PG6-C16 partial ester and its blends were manufactured using solid lipid extrusion at temperatures below the melting onset. The extrusion process parameters were adjusted in order to achieve 3D-printable filaments with targeted diameter and ovality using a 1.8 mm-diameter nozzle. By modifying the gear wheels of the printer, the force induced on the filament during 3D-printing was reduced to a minimum, enabling a flawless processability. A drug delivery matrix in the shape of a solid oral tablet (10×10×4 mm³) was then printed using the produced filaments. In addition, extrudability and printability of other conventional lipids such as behenoyl polyoxyl-8 glycerides (containing PEG-8 esters) and polyethylene glycol monostearate (containing PEG-32 esters) were compared.

The printability was strongly impacted by the filament flexibility. The flexibility was assessed in terms of the critical bending diameter (CBD), which is the smallest bending diameter at which the material breaks under a bending load. The smaller the CBD, the more flexible is the filament. All LBEs were found extrudable, however, behenoyl polyoxyl-8 glycerides was not processable below its melting onset. The CBD of PG6-C16 partial ester, behenoyl polyoxyl-8 glycerides and polyethylene glycol monostearate were 100, 125, and >223 mm, respectively. The filaments of PG6-C16 partial ester were more flexible, hence easier to handle for printing than other tested lipids. Polyethylene glycol monostearate was unprintable with the present set-up. Varying the composition of PG6-C16 partial ester in terms of PGs and MAF, displayed upgraded performance in extrudability and printability. The highest flexibility was found at the highest ratio of PGs and MAF corresponding to a CBD of 1.8 mm(50 folds lower than that of PG6-C16 partial ester). Higher flexibility led to a more efficient process. The filaments were spoolable during extrusion and less prone to breakage, which, in turn, allowed simultaneous printing of multiple tablets.

In conclusion, PG6-C16 partial ester was effectively extruded and 3D-printed via tuning its composition. This approach is an essential step towards using LBEs as natural and biodegradable alternatives to polymer-based excipients, expanding the pallet of materials that can be used for 3D-printing of medicines. Nevertheless, more opportunities and new functionalities can be enabled through optimizing PGFAs properties.

_References

_{[1] Corzo, C., Lopes, D. G., Lochmann, D., Reyer, S., Stehr, M., & Salar-Behzadi, S. (2020). Novel approach for overcoming the stability challenges of lipid-based excipients. Part 1: Screening of solid-state and physical properties of polyglycerol esters of fatty acids as advanced pharmaceutical excipients. European journal of pharmaceutics and biopharmaceutics, 148, 134–147. https://doi.org/10.1016/j.ejpb.2020.01.012}

Acknowledgments: The Austrian Funding Agency (FFG)

This work was funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation, and Technology (BMVIT), the Austrian Federal Ministry of Economy, Family, and Youth (BMWFJ), and by the State of Styria (Styrian Funding Agency SFG)