(T1130-02-13) Rapid Production of Personalized Medicines Using Tomographic Volumetric 3D Printing

Purpose: 3D printing (3DP) has the potential to disrupt the traditional one-size-fits-all approach of pharmaceutical manufacturing by enabling on-demand production of personalized medicines [1]. Amongst the array of 3D printing technologies, vat photopolymerization offers the highest resolution and does not involve the use of heat. However, existing vat photopolymerization technologies, such as stereolithography and digital light processing, suffer from relatively slow printing speeds and mechanical anisotropy. To be integrated into fast-paced clinical environments, 3D printers must afford both dimensional accuracy and high throughput. Volumetric 3DP is a novel vat photopolymerization-based additive manufacturing technology that possess these attributes. In volumetric 3DP, the entire object is simultaneously created within seconds by irradiating the photosensitive resin from multiple angles, as opposed to the conventional layer-by-layer approach [2]. Through the superposition of these 2D images, the 3D structure is fabricated in a single step, greatly reducing printing time. This study reports, for the first time, the use of tomographic volumetric 3DP for simultaneously fabricating multiple oral pharmaceutical dosage forms.

Methods: Formulation preparation: Three formulations comprising paracetamol, LAP, PEGDA (Mn 575), and water (Table 1) were prepared. The formulations were thoroughly mixed at room temperature until all components dissolved. Tomographic volumetric printing process: Geometric figures (torus and cylinder) were created using Microsoft Paint, exported in .jpg format, and loaded onto an in-house software. The software projects the image of the object in two dimensions on the resin container, which coupled by the rotating motion of the resin container results in the desired 3D structure. Specifically, by projecting an image of two circles or a rectangle, the shape of a torus or a cylinder was obtained, respectively. The volumetric printer comprised of a 385 nm digital light projector, and a cylindrical resin container suspended by a rotating axis 23 cm away from the light source. The prepared formulations were loaded into the resin container, set to rotate, and irradiated with light. Subsequently, the printed objects were washed with isopropanol for 10 s and then post-cured in an oven at 20 ºC for 1 hour under UV light. Characterization of printlets: The printlets were characterized by ESEM, DSC, XRPD, X-ray micro-CT, and FTIR. Drug content was quantified by HPLC, and in vitro dissolution test was performed to obtain the drug release profiles. In vitro dissolution test was performed using a USP-II apparatus, with paddle speed set at 50 rpm and temperature set at 37 ± 0.5 ºC. Printlets were dropped in 750 mL of 0.1 M HCl for 2 h, after which 250 mL of 0.2 M trisodium phosphate solution was added to adjust pH to 6.8. Dissolution tests were conducted over 24 hours in total.

Results: All formulations were successful printed with uniformity in weight and size (Figure 1). Printing times ranged between 12.5 to 32 s, with PW65-35 printing the fastest and PP90-10 printing the slowest. Printlets with lower concentrations of PEGDA were noticeably more opaque, due to microphase separation occurring between PEGDA and water. DSC and XRD results suggested that the drug was completely dissolved in the initial PEGDA solutions and remained molecularly dispersed in the printlets. ESEM images showed a core-shell structure, and X-ray micro-CT images also showed an internal structure that was less dense in the core and denser on the surface. This was due to post-curing under UV-irradiation, which induced a higher degree of photopolymerization on the surface of the object compared to the internal core. All printlets exhibited a sustained drug release profile and were insoluble in the dissolution media, suggesting that the printlets behaved like inert matrix tablets. The in vitro drug release profiles revealed that the ratio of monomer to non-reactive diluent influenced the drug release rate, wherein a lower ratio (i.e., higher proportion of diluent) led to faster drug release (Figure 2). This is because the presence of diluents decreased the cross-linking density of the matrices, permitting greater molecular mobility and faster drug diffusion out of the solid matrix. The torus shape released drug faster than the cylinder shape, as it possessed a higher surface area to volume ratio.

Conclusion: Tomographic volumetric 3D printing was successfully used, for the first time, to simultaneously produce paracetamol-loaded torus-shaped and cylindrical tablets within 12 to 32 s. Multiple printlets could be fabricated at the same time, which further increases the throughput of the printing technology. Future work will focus on optimizing printing parameters, such as mitigating the inconsistent refraction of light, to advance this technology for personalised pharmaceutical manufacturing.

References: 1. Seoane-Viaño, I., et al., Translating 3D printed pharmaceuticals: from hype to real-world clinical applications. Advanced Drug Delivery Reviews, 2021.
2. Brett E. Kelly, et al., Volumetric additive manufacturing via tomographic reconstruction. Science 363,1075-1079 (2019).

Acknowledgements: The work was partially supported by MCIN [PID 2020-113881RB-I00/AEI/10.13039/501100011033], Spain, Xunta de Galicia [ED431C 2020/17], and FEDER. LRP acknowledges the predoctoral fellowship [FPU20/01245] provided by the Ministerio de Universidades [Formación de Profesorado Universitario (FPU 2020)].

Table 1. Compositions of the formulations.

Figure 1. Photographs of the torus and cylinder Printlets obtained with different formulations. (A) From left to right: Torus of PW35-65, PW65-35 and PW90-10 formulations. (B) From left to right: Cylinder of PW35-65, PW65-35 and PW90-10 formulations.

Figure 2. Paracetamol dissolution profiles from PEGDA 575–Water Printlets