Pharmacokinetics and Safety of a New 1200 mg Single-Dose Delayed Release Mesalazine Microgranule Formulation

Abstract

The treatment of Inflammatory Bowel Diseases (IBDs) requires a relative high therapeutic daily dose of mesalazine and thus, the drug formulation need to be well tolerate and safe. A new pH-dependent controlled release 5-ASA microgranule formulation in 1.2 g sachets has been developed. The plasma levels of both the active principle 5-ASA and the main metabolite N-Acetyl-5-ASA, after oral administration of the new formulation or after an equimolar dose of three separated enteric coated 400 mg tablets administered in the same time (Pentacol® 400, SOFAR, Milan, ITALY), were measured with a validated high performance liquid chromatography-tandem mass spectrometry method. C max , t max and AUC values were considered as primary variables and the drug safety was the secondary one. The plasma 5-ASA concentration appearance was faster after microgranule administration ( tmax of 8.1 hours) than after the reference tablets assumption (tmax of 10.6 hours). The Cmax and AUC values were similar for both formulations and the kinetic of plasma disappearance of the test formulation was slight faster. The intersubject variability was lower after administration of the microgranules with a %CV of 17.5% vs 40.4% for the tablets (n=23), due to a more controlled homogeneous drug release from the granule format. The N-Acetyl-5ASA metabolite presents a similar plasma profile of the 5-ASA for both formulations. The use of microgranules is safe and will allow to reduce the daily dosages, by improving the patients compliance also in presence of difficulty to swallow large tablets.