(M1130-07-42) Fabrication of a Core-Shell Model for Combinational Drug Delivery via Hot Melt-Extrusion Paired with 3D Printing

Purpose: The combined utilization of hot-melt extrusion and 3D printing has several advantages for the development of solid oral dosage forms such as producing complex structure formulations, personalized medication, and enhanced patient compliance. In this study, an immediate release shell and a delayed release core model were designed and fabricated using hot-melt extrusion (HME) paired 3D printing. The drug in the shell was immediately released after administration, while another drug in the core started to release after a 0.5-1.5h lag time. The lag time decreased the retention time of the second drug in stomach which protected it from the chemical degradation caused by the acid gastric fluid. The ‘core-shell model’ drug delivery system developed in this work exhibits a huge potential for improved absorption of the encapsulated drug and reduced drug-drug interactions after administration.

Methods: The core-shell models were designed using 3D design software shown in Figure 1 (Tinker cad, Autodesk Inc., CA, USA). For the shell parts, theophylline was used as the model drug. Klucel™ HPC EF (HPC, Ashland Inc. USA) and Kollidon^® VA 64 (VA 64, BASF, Germany) were used as the main matrix. Polyethylene glycol 4000 (PEG 4000, Fisher Scientific. USA) was employed as the plasticizer. For the core formulation, acetaminophen (APAP) was used as the model drug. Methocel™ K4M (HPMC Colorcon Inc. USA), HPC and Eudragit® RS PO (RSPO, Evonik Industries, Germany) were used as the printing excipients. The polymers and APIs for different formulations were combined at various weight ratios. A co-rotating twin-screw extruder, (11 mm Process 11™, ThermoFisher Scientific, Germany) was used to produce the filaments. The physical mixture was extruded with a speed of 50 rpm at 130°C and 165°C for shell and core, respectively. A 2.0-mm round-shaped die was used to obtain filaments for 3D printing. A differential scanning calorimetry (DSC) system (TA Instruments, New Castle, DE, USA) was used to investigate the crystallinity of the drug. The dissolution studies were conducted using a United States Pharmacopeia (USP)-I dissolution apparatus (Hanson SR8-plusTM; Hanson Research, CA, USA) at 37 °C with a basket speed at 100 rpm. Samples were collected at predetermined time intervals and analyzed using HPLC at the wavelength of 243 nm and 278 nm.

Results: The obtained Shell 1 and Shell 2 filaments were difficult to print due to the soft texture when loaded into the 3D printer feeder. However, the produced Shell 3, Shell 4, and Shell 5 filaments composed of PEG 4000 were successfully printed (Figure 1). The upper and lower parts could successfully be assembled forming the final external shell with a good sealing performance.The core filaments also showed adequate printability. The final formulations F3, F4 and F5 were obtained after the cores were loaded into the different shells. The DSC thermograms of theophylline and APAP exhibited endothermic melting peaks at around 270°C and 170°C, respectively (Figure 2). However, the peaks were absent in both of the extrudates which indicated the transformation of theophylline and APAP from the crystalline to amorphous state. The dissolution profile of theophylline in the shells showed immediate release characteristics. As shown in Figure 3a, all three printed shells achieved 100% drug release within 60-90 min. The contents of VA 64 affected the dissolution rate of the shell. The drug release was faster as the amount of VA 64 increased. Shell 5 (50% VA 64) exhibited the quickest drug release compared to Shell 4 (40% VA 64) and Shell 3 (30% VA 64). Moreover, the amount of VA 64 would affect the delayed release characteristics of the shell. For the APAP in the core components, the different outer-surrounding shell played an important role to protect them from contacting the release medium. The increase of the VA 64 could decrease the lag time for the core-loaded drug. Shell 3 (30% VA 64) delayed the drug release for 1.5h, while Shell 4 (40 % VA 64) and Shell 5 (50% VA 64) have a lag time of 1h and 0.5h, respectively (Figure 3b, c, d). All of the APAP in the core components realized 100% drug release in 12h.

Conclusion: The drug-loaded filaments can be successfully fabricated using HME. APAP and theophylline were dispersed in the polymer excipients forming an amorphous solid dispersion during the HME process. The dissolutions of the shell perform immediate release characterizations and the dissolution of the encapsulated core exhibit delayed release characterizations. The dissolution rate of the shell can be governed by the content of the VA 64, thereby influencing the delayed release profiles of the shell model and similarly reducing the lag time for the release of the core drug. Further printing experiments and dissolution studies are warranted.

Figure 1. (a.) The three-dimensional model of the designed upper part of the shell (b.) The three-dimensional model of the designed lower part of the shell (c.) The three-dimensional model of core (d.) The printed shells and core.



Figure 2. The DSC thermograms of the pure excipients and the shell and core filaments. (a.) The DSC thermograms of the shell filaments (b.) The DSC thermograms of the core filaments.



Figure 3. In vitro dissolution study of the designed core-shell model. (a.) The dissolution profile of different shell model. (b.) The dissolution profile of F3. (c.) The dissolution profile of F4. (d.) The dissolution profile of F5.