In-vitro and in-vivo characteristics of a modified-release double-pulse formulation for a water soluble drug.

OBJECTIVE: The aim of the present study was to evaluate the in-vitro dissolution and in-vivo pharmacokinetic profile of a novel two-phase modified-release formulation for diltiazem hydrochloride, as a water-soluble drug. MATERIALS AND METHODS: The delivery system consisted of two tablets inserted into a capsule. Both tablets comprised a coated drug core-matrix. The coating of the first tablet was intended to produce a first phase with a relatively fast release profile, while that of the second tablet included a unique controlling membrane designed to achieve a delayed controlled-release profile. Three different formulations were tested for their dissolution profiles both in water media and in buffer with a pH of 6.8. These formulations were also evaluated for their pharmacokinetic profile in healthy volunteers after single administration of a 240 mg dose. Serial venous blood samples were collected over 36 h post administration to measure diltiazem levels by HPLC. In addition the in-vivo /in-vitro correlation (IVIVC) was calculated for these formulations. RESULTS: The in-vitro characteristics of these formulations demonstrated a controlled release profile in both media but with different characteristics, as in Formulation 3 where faster dissolution profile obtained in water but slower one in pH 6.8 buffer. In-vivo the pharmacokinetic profile of these formulations showed that arabinogalactan containing formulations achieved plasma levels which allow a once daily administration. IVIVC calculation demonstrated that dissolution tested in buffer 6.8 media better correlates with the percent absorbed in-vivo and the best results were achieved with the formulation containing the highest amount of polysaccharide in the coating. CONCLUSION: It is concluded that the developed formulations achieved a controlled release profile both in-vitro and in-vivo which are suitable for once-daily administration.