Purpose: The main objective of this present investigation was to develop an oral pulsatile drug delivery system using hot melt extrusion technology (HME) coupled with three-dimensional (3D) printing and to tailor the drug release characteristics to meet the needs of an individualized pharmacotherapy.
Methods: Filaments for 3D printing were prepared using hydroxypropyl methylcellulose acetate succinate (AquaSolve™), an enteric polymer. Ketoprofen was selected as a model drug. A ThermoFisher Scientific Process 11 twin screw extruder was used for HME and fused-deposition model-based 3D printer for printing shell-core modified release tablets. Different concentrations of polyethylene glycol (PEG) 8000 (0%, 5%, and 10%) was used to enable 3D printing at lower temperatures. Composition and processing parameters are provided in Table 1. Initially, a hollow shell was printed, and the 3D printer was paused to insert an immediate release core tablet. Printing was resumed to close the hollow structure to form a tablet-shaped device as demonstrated in Fig. 1. Design and dimensions of the 3D printed tablet are shown in Fig. 2. The core tablet was prepared by direct compression of drug and excipients on a single punch press (MCTMI, GlobePharma Inc., New Brunswick, NJ). Thermal stability of HPMC-AS was assessed using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). A three-stage dissolution study was performed to investigate in-vitro drug release characteristics. Mechanical properties of the extruded filaments were determined using a Texture Analyzer (TA-XT2i analyzer, Texture Technologies, Hamilton, MA, USA).
Results: Filaments suitable for 3D printing were successfully extruded by optimizing the amount of plasticizer. Filaments with 0-5% plasticizer were not able to print due to the high glass transition temperature of the polymer, thus inhibiting the flow of the polymer through the 3D printer nozzle resulting in irregularly shaped tablets. Filaments with 10% plasticizer had good mechanical properties suitable for 3D printing and were printed into tablets at 195 C. TGA and DSC results indicated that HPMC-AS is stable at the temperatures employed for HME and 3D printing. In-vitro dissolution results exhibited the desired lag time of 6 hours followed by a pulsatile release of 100% of the drug.
Conclusion: Filaments suitable for 3D printing using HPMC-AS and 10% PEG 8000 were successfully extruded using HME. Desired shell-core tablets were printed using the extruded filaments. HME coupled with 3D printing is a feasible technique for developing dosage forms necessary for patient-centric pharmacotherapy.
The authors wish to thank Ashland Specialty Ingredients for its generous supply of polymers. This study was also supported by Grant Number P20GM104932 from the National Institute of General Medical Sciences and the Biopharmaceutics-Clinical and Translational Core E of the COBRE, a component of the National Institutes of Health.
Jiaxiang Zhang– Student, University of Mississippi, Oxford
Suresh Bandari– Post-doc, University of Mississippi, OXFORD, Mississippi
Sandeep Sarabu– University of Mississippi, oxford, Mississippi
Michael. A Repka– Professor, University of Mississippi, Mississippi