A high strenght mesalamine multiple-unit dosage form intended for ileo-colonic delivery

Purpose: To develop an oral multi-particulate drug delivery system (DDS) containing a high dose (i.e.> 1,000 mg) of 5-aminosalicylic acid (5-ASA, mesalamine) for the treatment of Inflammatory Bowel Disease (IBD). Gastric protection, followed by a prolonged and pH-independent release of 5-ASA were sought, aiming to potentially meet the IBD therapeutic needs. Methods: Highly-loaded (95 wt%) 5-ASA pellets were prepared by extrusion-spheronisation (Nica® System, model E140) and characterised in terms of size distribution, shape, bulk density and mechanical resistance. Pellets of the selected 710-1,000 m size fraction were coated (Glatt® GPCG-1) with increasing amounts of a polyvinyl acetate (Kollicoat® SR) dispersion to achieve different sustained-release profiles. Moreover, to avoid unwanted 5-ASA release under acidic conditions, an outer layer of an acrylate-based polymer (Kollicoat® MAE) was applied. Drug release performance of 5-ASA pellets was assessed according to the USP 34-NF 29 Monograph for delayed- and extended-release mesalamine products. Pellets with the desired in-vitro release profile were filled into 000 size gelatine capsules to deliver the final multi-particulate dosage form, the drug release performance of which was then compared to that of two commercial reference products (i.e. LialdaTM and Pentasa®). Results: 5-ASA pellets containing more than 95 wt% drug loading and a bulk density value of 0.9 g/mL were successfully prepared. A prolonged and relatively pH-independent release of 5-ASA, throughout 18 hours dissolution testing, was achieved from multiple-units coated with Kollicoat® SR up to 2 w.g.%. In addition, a complete enteric protection under 2 hours simulated gastric conditions was attained. Conclusions: An oral high strength multi-particulate DDS containing not less than 1,000 mg 5-ASA able, in-vitro, to avoid gastric release and afford a continuous 5-ASA release within the simulated small and large intestinal fluids was successfully developed.