Design of experiment approach for formulating multi-unit colon-targeted drug delivery system: in vitro and in vivo studies

Objective: The objective of the present investigation was to develop systematically optimized multiunit formulation for colon targeted delivery of metronidazole (MTZ) by employing design of experiment (DoE) and evaluate it for in vitro as well as in vivo drug release study. Methods: Core of mini-tablets of MTZ was prepared using drug along with suitable swelling agents to provide pH sensitive pulsatile drug delivery. Eudragit (R) S 100 (ES) and ethyl cellulose (EC) were used as coating polymers to prevent initial drug release in gastric region. The coating composition was systematically optimized using 3(2)-full factorial design and optimized formulation was evaluated in vitro and then in vivo, to confirm colon targeting ability of the developed system. Stability study of optimized formulation was performed for 6 months as per ICH guidelines. Results: The optimized coating composition was selected from the results of design batches. The optimized formulation showed 6.99 +/- 1.5% drug release up to 5 h and 100% drug release within 7.2 +/- 0.2 h indicating pH sensitive pulsatile behavior of formulation. Similar drug release profile was observed while performing in vivo study in rabbits with a lag time of 4 h and C-max of 190 +/- 4.9 ng/ml being achieved after 7 h. Stability study indicated insignificant difference in properties of tablets and their drug release patterns. Conclusion: Optimization of coating composition (EC and ES) and thickness could offer pH sensitive pulsatile release of drugs at colon. Furthermore, in vivo results confirmed the successful development of colon targeted formulation of MTZ.