(T1230-08-54) Development of 3D-Printed Bicompartmental Tablets by Dual Fused Deposition Modelling (FDM) for Site-Specific Colon Drug Delivery

Purpose: The 3D-printing technique Fused Deposition Modelling (FDM) with dual-nozzle offers important advantages to develop, in a single step, compartmental Drug Delivery Systems (DDS) with complex architectures and specific drug distributions. Hence, the drug release profile can be modulated by changes in the formulation and/or 3D-printed design. The main objective of this study was to design and manufacture 3D-printed bicompartmental tablets by dual FDM to get a colonic delivery of the model drug 5-amino salicylic acid (5-ASA, mesalamine), first-line therapy in inflammatory bowel disease. For this purpose, made-in-house filaments were prepared from pH-dependent and water-soluble thermoplastic pharmaceutical polymers.

Methods: Preparation of HPMCAS and drug-loaded PVA filaments: Two made-in-house filaments were prepared as feeding materials for the dual-nozzle FDM printer. The first formulation was composed of the enteric polymer hydroxypropyl methylcellulose acetate succinate HPMCAS-HG (pH threshold 6.5), the plasticizer triethyl citrate (TEC) and the lubricant magnesium stearate (88:10:2 wt/wt ratio). The second formulation was composed of the hydrophilic polymer polyvinyl alcohol (milled PVA 4-88), the plasticizer sorbitol, the model drug 5-ASA and the glidant colloidal silicon dioxide (51:27:20:2 wt/wt ratio). The physical blends were extruded in a single-screw extruder using heating temperatures and screw speeds of 150 ºC/20 rpm and 180 ºC/30 rpm, respectively, for each formulation. Thermal analysis of raw materials and extruded filaments was performed by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Tablet design and 3D printing: The extruded filaments were printed using a dual-extruder FDM printer with 0.4 mm printing nozzles. Cylindrical tablets (14 mm diameter, 5 mm thickness) were prepared using the HPMCAS-HG filament for the design of the external pH-dependent compartment and the drug-loaded PVA filament for the internal water-soluble compartment (spiral shape). The printing settings were as follows: printing temperature (195 ºC for HPMCAS-HG filament and 190 ºC for PVA filament), platform temperature 60 ºC and rectilinear infill pattern (100% density). Scanning Electron Microscopy (SEM) was used to evaluate the morphology of the extruded filaments and 3D-printed tablets. In vitro drug release studies of 3D-printed systems were conducted in a USP dissolution apparatus II at 37 ± 0.5 °C and 50 rpm using the following dissolution media (500 mL) and residence times (sequential pH change method): Simulated Gastric Fluid (pH 1.2) for 2h, Simulated Intestinal Fluid (pH 6.8) for 2h, and phosphate buffer (pH 7.4) up to 8h. Samples (5 mL) were withdrawn at predetermined time intervals, filtered and analysed by UV–Vis spectrophotometry.

Results: DSC thermographs (Fig. 1a) show that HPMCAS-HG is an amorphous polymer with an exothermic peak at 180°C indicative of crystallization. PVA is a semi-crystalline polymer with a glass transition temperature (T_g) at 40 ºC and a broad melting endotherm at 178 ºC. Pure 5-ASA exhibits sharp endothermic peaks at 269 °C and 280 °C that corresponds to melting and decomposition temperatures, respectively. The DSC scans of the filaments show the conversion of the polymers to the amorphous state while 5-ASA remains crystalline in the PVA filament. The obtained TGA thermographs (Fig. 1b) demonstrate that the raw materials and filaments are stable at the extrusion (150-180 ºC) and printing (190-195 ºC) temperatures. The extruded filaments have appropriate characteristics in terms of aspect homogeneity and diameter (1.79 ± 0.05 and 1.77 ± 0.04 mm for HPMCAS and PVA filaments, respectively). SEM images (Fig. 2a) of the HPMCAS-HG filament demonstrated a reasonable smooth appearance, while the surface of PVA filament was rougher due to the dispersion of 5-ASA as crystalline particles. 3D-printed tablets with uniform weight (811.3 ± 31.2 mg) and dimensions (14.06 ± 0.07 x 5.09 ± 0.16 mm) were obtained. SEM images (Fig. 2b) of the 3D-printed tablet revealed an external uniform layer-by-layer deposition and a consistently printed spiral channel throughout the internal structure. The in vitro drug release profile (Fig. 3) shows only 5.7 wt% and 8.2 wt% drug released at pH_s 1.2 and 6.8, respectively, due to the slow water uptake in the PVA compartment. The drug release rate increased when the pH was changed to 7.4, due to the solubilisation of the HPMCAS compartment, reaching 63.6 wt% drug released after 8h.

Conclusion: HPMCAS-HG and drug-loaded PVA filaments were successfully obtained using a single-screw extruder. Bicompartmental tablets were printed by dual FDM combining an enteric external compartment and an internal soluble compartment to reach specific release of 5-ASA in the colonic region.

Acknowledgements: This research was part of the project US-1380923 funded by Consejería de Economía, Conocimiento, Empresas y Universidad (Junta de Andalucía, Spain).

Fig. 1. Thermal analysis of raw materials and filaments: a) DSC and b) TGA scans.

Fig. 2. Digital pictures and SEM images of: a) HPMCAS-HG and drug-loaded PVA filaments; b) 3D-printed tablet perimeter and internal compartment with spiral shape.

Fig. 3. In vitro drug release profile of 3D-printed bicompartmental tablets (mean ± SD, n =3).