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P155. In-vitro dissolution testing of 5-aminosalicylic acid release from pH dependent mesalazine formulations

S. Tenjarla, A. Abinusawa

Shire Pharmaceuticals Inc., Wayne, PA, United States

Aims: To be effective, oral 5-aminosalicylic acid (5-ASA) treatment for patients with ulcerative colitis (UC) must protect the drug from absorption in the stomach and small intestine, yet ensure availability of the drug throughout the colon. Many formulations use a release mechanism that depends on the pH gradient in the human gut. We investigate the release of mesalazine from currently available pH-dependent mesalazine formulations in simulated physiological pH conditions.

Methods: The release of 5-ASA from five mesalazine formulations (Apriso®, Salix Pharmaceuticals Inc., USA; Asacol® MR 800 mg; Warner Chilcott, USA; Mezavant® XL, Shire Pharmaceuticals Inc., USA; Salofalk® tablets and Granu-Stix®; Dr. Falk Pharma GmbH, Germany and Axcan Pharma, Canada) was monitored over time in two separate in vitro experiments. In experiment A, dissolution of 5-ASA was monitored in a pH 6.8 solution. In experiment B, drug release from individual tablets was monitored over three stages designed to simulate the pH conditions to which the tablets are exposed in vivo: pH 1 for 2 hr; pH 6 for 1 hr; and pH 6.8 for 8 hr. In both experiments six tablets of each formulation were tested separately; percentage of dissolution is presented as a mean. All tablets were tested using standard United States Pharmacopeia dissolution apparatus, with a paddle speed of 50–100 rpm. Samples were collected every 30min and analysed by UV spectroscopy at 330 nm.

Results: Experiment A: Apriso: 70% of 5-ASA was released in 3 hr and 95% was released in 8 hr. Asacol MR 800 mg: 5-ASA release was incomplete (65%) after 8 hr, with high tablet-to-tablet variability. Mezavant XL: release was complete (100%) and sustained over 5 hr. Salofalk tablets: drug release completed (100%) within 2.5 hr. Granu-stix: after 8 hr, less than 20% of the total drug was released.

Experiment B: The dissolution results for each formulation, over three pH stages, are summarized in the Table.

Table: 5-ASA release from mesalazine formulations (Experiment B)
 Mezavant XLAprisoAsacol MR 800SalofalkGranu-Stix
pH 1.0No releaseNo releaseNo releaseNo releaseNo release
pH 6.0No release40% released in 1 hrNo release11% released in 1 hr2% released in 1 hr
pH 6.8100% release in 5 hr in sustained fashion100% release in 3 hr in sustained fashion100% release in 7.5 hr with tablet variability100% release in 1 hr32% release in 8 hr in sustained fashion

Conclusions: Although currently available pH dependent mesalazine formulations are designed to deliver the drug to the colon, the results of this in vitro study suggest that the release profiles vary between formulations across a physiologic pH range. As delivery of 5-ASA to the colon is important in treating patients with UC, consideration of the potential release profiles may be a useful tool in choosing the most appropriate treatment.

This research was funded by Shire Pharmaceuticals Inc.