Development of Colon Targeting Tablet of a JAK Inhibitor to Combat Chronic Ulcerative Colitis: A Novel Approach for Local Drug Delivery

Abstract:

Background: Tofacitinib, a pan-Janus kinase (JAK) inhibitor, initially used for the treatment of rheumatoid arthritis, was later found to have robust efficacy in Phase 2 and Phase 3 ulcerative colitis clinical trials. It had been approved by FDA for its use in the treatment of moderate to severe ulcerative colitis, in 2018. Objectives: The main objective of the present work was to develop a new colonic drug delivery system for tofacitinib using combined approaches of formulating an extended release matrix tablet along with a pH sensitive polymer coating of Eudragit® S100. Methods: The core tablets of tofacitinib were prepared by wet granulation method containing sodium carboxymethyl cellulose (CMC) as rate controlling polymer. Formulation variables used in the matrix system and pH dependent coating were optimized. Results: Negligible drug release was obtained in 0.1 N HCl and 6.4 pH phosphate buffer media, where as in 7.2 pH phosphate buffer media, the drug release increased up to 94.2±2.0%. Minimum concentration of sodium CMC was 11% (w/w) to ensure6 h’s extended release of drug from the matrix tablet. While, the minimum functional coating percentage, was found to be 13% in order to obtain an adequate lag time. Conclusion: The study showed that, the lag time of the drug release was highly affected by the coating percentage of Eudragit S 100 and product temperature during coating. After the lag time, extended drug release was observed, and rate of drug release was found to be depended on the concentrations of sodium CMC used in the core tablet. The final colon targeted formulation showed no change in either its physical appearance, drug content or in dissolution pattern even after three months of storage at 40±2°C/75±5% RH.

Key words: Colon targeted matrix tablet, Controlled release, Lag period, Ulcerative colitis, Tofacitinib, JAK inhibitor, Immunosuppressant.