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This work aimed to develop a three-dimensional printed (3DP) tablet containing glimepiride (GLMP) and/or rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes. Curcumin oil was extracted from the dried rhizomes of Curcuma longa and utilized to develop a self-nanoemulsifying drug delivery system (SNEDDS). Screening mixture experimental design was conducted to develop SNEDDS formulation with a minimum droplet size. Five different semi-solid pastes were prepared and rheologically characterized. The prepared pastes were used to develop 3DP tablets using extrusion printing. The quality attributes of the 3DP tablets were evaluated. A non-compartmental extravascular pharmacokinetic model was implemented to investigate the in vivo behavior of the prepared tablets and the studied marketed products. The optimized SNEDDS, of a 94.43 ± 3.55 nm droplet size, was found to contain 15%, 75%, and 10% of oil, polyethylene glycol 400, and tween 80, respectively. The prepared pastes revealed a shear-thinning of pseudoplastic flow behavior. Flat-faced round tablets of 15 mm diameter and 5.6–11.2 mm thickness were successfully printed and illustrated good criteria for friability, weight variation, and content uniformity. Drug release was superior from SNEDDS-based tablets when compared to non-SNEDDS tablets. Scanning electron microscopy study of the 3DP tablets revealed a semi-porous surface that exhibited some curvature with the appearance of tortuosity and a gel porous-like structure of the inner section. GLMP and RSV demonstrated relative bioavailability of 159.50% and 245.16%, respectively. Accordingly, the developed 3DP tablets could be considered as a promising combined oral drug therapy used in treatment of metabolic disorders. However, clinical studies are needed to investigate their efficacy and safety.

Binder jetting has the potential to revolutionize the way we produce medicine. However, tablets produced by binder jetting technology can be quite fragile and hard to handle. In this study, the printing process and ink composition were examined to optimize the mechanical properties of tablets. A model formulation containing the ketoprofen drug was developed and used as a base for optimization. Firstly, important printing parameters were identified with a fractional factorial design. Saturation and layer height critically influenced selected tablet properties. Relevant process parameters were optimized for tablet mechanical strength by using the D-optimization DoE approach. The best mechanical properties were achieved when saturation was set to 1 and layer height to 150 µm. On the other hand, binder ink composition did not appear to impact tablet mechanical strength as much as process parameters did. Three ethanol-water mixtures were tested at three tablet strength levels and no definitive conclusions could be drawn. The binder jetting process can be wasteful, especially if the unbound powder cannot be reused. To determine the suitability of powder blend recycling, the ketoprofen content was measured for 27 subsequent batches of tablets. While the trendline did indicate a slight reduction in ketoprofen content, the powder blend reuse can nevertheless be employed.

Fused deposition modeling (FDM) 3D printing was used to produce 3D printed tablets with the thermo-sensitive model peptidomimetic drug enalapril maleate (EM). Two different formulations were prepared to investigate the degradation of enalapril maleate during the FDM 3D printing process. Soluplus® and Eudragit® E PO were chosen as polymers. After hot-melt extrusion (HME) and FDM 3D printing, both formulations were characterised regarding their solid-state properties using DSC and XRD. The degradation of the drug was analysed by determination of the content in the extrudates and 3D printed tablets, and dissolution was assessed. Various approaches have been attempted to prevent degradation of enalapril maleate, including utilization of a larger nozzle diameter and higher printing speeds to reduce heat exposition. None of these approaches were successful in preventing drug degradation. However, significant differences in the amount of degradation between the two formulations with different polymers could be observed. Thus, the FDM 3D printing process was not feasible without any degradation for the thermo-sensitive drug enalapril maleate. A maximum of 85.55 ± 1.48% enalapril was recovered in Eudragit® E PO tablets printed with a 0.4 mm nozzle at a temperature of 180 °C and with a speed of 30 mm/s.

Despite the importance of process parameters in the printing of solid dosage forms using fused deposition modelling (FDM) technology, the field is still poorly explored. A design of experiment study was conducted to understand the complete set of process parameters of a custom developed FDM 3D printer and their influence on tablet disintegration time. Nine settings in the Simplify 3D printing process design software were evaluated with further experimental investigation conducted on the influence of infill percentage, infill pattern, nozzle diameter, and layer height. The percentage of infill was identified as the most impactful parameter, as increasing it parabolically affected the increase of disintegration time. Furthermore, a larger nozzle diameter prolonged tablet disintegration, since thicker extruded strands are generated through wider nozzles during the printing process. Three infill patterns were selected for in-depth analysis, demonstrating the clear importance of the geometry of the internal structure to resist mechanical stress during the disintegration test. Lastly, layer height did not influence the disintegration time. A statistical model with accurate fit ( = 0.928) and predictability ( = 0.847) was created. In addition, only the infill pattern and layer height influenced both the uniformity of mass and uniformity of the disintegration time, which demonstrates the robustness of the printing process.

In this study, 3D-printed tablets with a constant surface area were designed and fabricated using polylactic acid (PLA) in the outer compartment and polyvinyl alcohol and felodipine (FDP) in the inner compartment. The influences of different surface geometries of the inner compartment, namely, round, hexagon, square, and triangle, on drug release from 3D-printed tablets were also studied. The morphology and porosity of the inner compartment were determined using scanning electron microscopy and synchrotron radiation X-ray tomographic microscopy, respectively. Additionally, drug content and drug release were also evaluated. The results revealed that the round-shaped geometry seemed to have the greatest total surface area of the inner compartment, followed by square-shaped, hexagon-shaped, and triangle-shaped geometries. FDP-loaded 3D-printed tablets with triangle and hexagon surface geometries had the slowest drug release (about 80% within 24 h). In the round-shaped and square-shaped 3D-printed tablets, complete drug release was observed within 12 h. Furthermore, the drug release from triangle-shaped 3D-printed tablets with double the volume of the inner compartment was faster than that of a smaller volume. This was due to the fact that a larger tablet volume increased the surface area contacting the medium, resulting in a faster drug release. The findings indicated that the surface geometry of 3D-printed tablets with a constant surface area affected drug release. This study suggests that 3D printing technology may be used to develop oral solid dosage forms suitable for customized therapeutic treatments.

The objective of this study was to investigate the effects of thermal crosslinking on the properties of 3D-printed poly-vinyl alcohol (PVA) tablets loaded with fluorescein sodium (NaFl). The PVA filaments were selected for the fabrication of 3D-printed tablets. Different infill densities (80% and 100%) of the tablets were applied. The tablets were crosslinked at different temperatures and times. The physiochemical properties of the tablets and the release profiles of fluorescein from the 3D-tablets were investigated. The 3D-printed PVA tablets were successfully produced with favorable physical and mechanical properties. A smooth surface with a mesh pattern was obtained with a yellow color of NaFl. The 100% infilled tablets provided slightly greater loading efficiency and loading capacity in comparison with the 80% infilled tablets. The release of NaFl increased with an increase in crosslinking time and temperature. However, crosslinking at 140 °C for 4 h (80% CFT4 and 100%CFT4) showed similar release characteristic compared to the non-crosslink one. The release kinetics of 3D-printed tablets were observed to be Quasi-Fickian diffusion mechanism.

This work was aimed to develop a Curcuma oil-based self-nanoemulsifying drug delivery system (SNEDDS) 3D-printed polypills containing glimepiride (GMD) and rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes as a model for metabolic syndrome (MS). Compartmentalized 3D printed polypills were prepared and studied in streptozotocin/poloxamer induced diabetic/dyslipidemic rats. The pharmacokinetic parameters of GMD and RSV in the prepared polypills were evaluated. Blood glucose level, lipid profile, antioxidant, and biochemical markers activities were investigated. Also, histopathological examination of the liver and pancreas was carried out. The atherosclerotic index, the area of islets of Langerhans, and liver steatosis lesion scores were calculated. The developed SNEDDS-loaded GMD/RSV polypills showed acceptable quality control characteristics with a high relative bioavailability of 217.16% and 224.28% for GMD and RSV, respectively, when compared with the corresponding non-SNEDDS pills. The prepared polypills showed dramatic lowering in blood glucose levels and substantial improvement in lipid profile and hepatic serum biomarkers as well as remarkable decrease in serum antioxidants in response to Poloxamer 407 intoxication. The prepared polypills decreased the risk of atherosclerosis and coronary disease by boosting the level of high-density lipoprotein and lowering both triglyceride and low-density lipoprotein. Microscopic examination showed normal hepatic sinusoids and high protection level with less detectable steatosis in the examined hepatocytes. Normal size pancreatic islets with apparently normal exocrine acini and pancreatic duct were also noticed. This formulation strategy clearly shows the potential of the developed polypills in personalized medicine for treatment of patients with MS.

The purpose of this study was to investigate the impact of the drug loading method on drug release from 3D-printed tablets. Filaments comprising a poorly water-soluble model drug, indomethacin (IND), and a polymer, polyvinyl alcohol (PVA), were prepared by hot-melt extrusion (HME) and compared with IND-loaded filaments prepared with an impregnation (IMP) process. The 3D-printed tablets were fabricated using a fused deposition modeling 3D printer. The filaments and 3D printed tablets were evaluated for their physicochemical properties, swelling and matrix erosion behaviors, drug content, and drug release. Physicochemical investigations revealed no drug–excipient interaction or degradation. IND-loaded PVA filaments produced by IMP had a low drug content and a rapid drug release. Filaments produced by HME with a lower drug content released the drug faster than those with a higher drug content. The drug content and drug release of 3D-printed tablets containing IND were similar to those of the filament results. Particularly, drug release was faster in 3D-printed tablets produced with filaments with lower drug content (both by IMP and HME). The drug release of 3D-printed tablets produced from HME filaments with higher drug content was extended to 24 h due to a swelling-erosion process. This study confirmed that the drug loading method has a substantial influence on drug content, which in turn has a significant effect on drug release. The results suggest that increasing the drug content in filaments might delay drug release from 3D-printed tablets, which may be used for developing dosage forms suited for personalized medicine.

The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions on the printability of formulations, since they significantly affect the properties of the raw materials, whose control is crucial to enable three-dimensional printing (3DP). Hence, the objective of this work was to investigate the correlation between the environmental settings and the properties of paroxetine (PRX)-loaded filaments, previously produced by HME, which affect printability by FDM. The influence of different drying methods of the physical mixtures (PMs) and HME-filaments (FILs) on the quality and printability of these products was also assessed. The printability of FILs was evaluated in terms of the water content, and the mechanical and thermal properties of the products. Stability studies and physicochemical, thermal, and in vitro dissolution tests were carried out on the 3D-printed tablets. Stability studies demonstrated the high ductility of the PRX loaded FILs, especially under high humidity conditions. Under low humidity storage conditions (11% RH), the FILs became stiffer and were successfully used to feed the FDM printer. Water removal was slow when carried out passively in a controlled atmosphere (desiccator) or accelerated by using active drying methods (heat or microwave). Pre-drying of the PRX/excipients and/or PMs did not show any positive effect on the printability of the FIL. On the contrary, dry heat and, preferably, microwave mediated drying processes were shown to reduce the holding time required for successful FDM printing, enabling on-demand production at the point of care.

Three-dimensional printing (3DP) has demonstrated great potential for multi-material fabrication because of its capability for printing bespoke and spatially separated material conformations. Such a concept could revolutionise the pharmaceutical industry, enabling the production of personalised, multi-layered drug products on demand. Here, we developed a novel stereolithographic (SLA) 3D printing method that, for the first time, can be used to fabricate multi-layer constructs (polypills) with variable drug content and/or shape. Using this technique, six drugs, including paracetamol, caffeine, naproxen, chloramphenicol, prednisolone and aspirin, were printed with different geometries and material compositions. Drug distribution was visualised using Raman microscopy, which showed that whilst separate layers were successfully printed, several of the drugs diffused across the layers depending on their amorphous or crystalline phase. The printed constructs demonstrated excellent physical properties and the different material inclusions enabled distinct drug release profiles of the six actives within dissolution tests. For the first time, this paper demonstrates the feasibility of SLA printing as an innovative platform for multi-drug therapy production, facilitating a new era of personalised polypills.