Colon-Targeted Delayed Release Drug Delivery Tablet Fabricated by MED® 3D Printing Technology

Background: Ulcerative colitis is a multifactorial chronic inflammatory bowel disease of mostly unknown etiology. The resulting pathogenesis involves mucosal inflammation initiating in the rectum and extending proximally in the colon in a continuous fashion. Delivery of therapeutic agents to the lower GI tract to provide local drug exposure in the colon may be beneficial for intestinal inflammatory treatment. A (3D)-printed, delayed release colon-targeted tablet fabricated with Melt Extrusion Deposition (MED)® three-dimensional (3D) printing technology can be programmed to deliver drug to the inflammatory region. 3D printed tablets are designed and fabricated with sequential two-step (pH- and time-based) control mechanism. The candidate tablet contains an enteric layer to prevent drug release within the stomach to minimize inter-and intra-patient variation in stomach transit time. Beneath the enteric layer resides a time-based layer of appropriate thickness. The drug release is delayed until the tablet reaches the colon. Methods: Two 3D printed tablets of model drug with different delay layer were investigated in healthy subjects to validate the colon-targeted drug delivery in vivo. The tracking layers consisted of contrast agent barium sulfate were incorporated into the drug layer by structural design, to make the candidate tablet could be visible under X-ray and to inform the drug release. The study was an open label, randomized, single dose, three period, three sequence, three-way crossover X-ray imaging and pharmacokinetic study in healthy subjects. Twelve healthy volunteers were enrolled into the study. Candidate tablet 1 and 2, and the reference of the model drug were administered in the morning under fasted condition according to randomization plan. There was at least 4 days’ wash-out between each treatment. X-ray images and PK samples were collected at the predetermined timepoints. Tablet intestinal transit and drug release property were evaluated based on X-ray images. The drug plasma concentration was determined by the LC-MS/MS analytical method. Results: The X-ray imaging results showed that the tablet could be tracked in the gastrointestinal tract based on the contrast agent. Majority subjects (each 8 out of n=12 for both test treatments) suggested that both candidate tablets released the drug to the colon regions: Tablet 1 (3 subjects at ascending colon, 2 subjects at transverse colon, 1 subject at transverse to descending colon, 1 subject at descending colon, 1 subject at descending to sigmoid colon) while tablet 2 (7 subjects at ascending colon, 1 subject at transverse colon). The pharmacokinetic results demonstrated the delayed release property of the candidate tablets and median (range) absorption Tlag was 8.0h (7.0-11.0h), 7.0 h (5.0-8.0h) and 0.0h (0.0-0.0h) for tablet 1, 2 and the reference tablet, respectively, which confirmed the colon release property of test formulations. Conclusions: The MED®3D printed tablets with sequential two-step control mechanism can precisely deliver drug to the colon in human. The drug release and tracking agent images demonstrated the release location/time for the 3D printed tablets perform as designed.