Development of a pH Gradient Dissolution Condition to Predict the Behavior of Delayed Release Formulations under Fed In Vivo Condition

To deliver Mesalamine (MSA) in the treatment of Ulcerative Colitis (UC) at the targeted site of action, numerous modified release formulations have been developed to release the drug in colon that are coated with pH dependent delayed release (DR) polymer. Such pH dependent formulations have a significant degree of unpredictability in terms of their drug release as the intraluminal pH varies with population. Also, postprandial administration of such formulations pose unpredictable drug release patterns when compared to the fasted state. Available in vitro methods overlook physiological aspects impacting drug release and lack the ability to predict the in vivo performance of a test formulation. Here, we have developed a discriminatory/ bio-predictive dissolution (DBD) method for a DR formulation of MSA that considers postprandial GI pH gradient, ionic strength and surfactant concentration to discriminate test formulations based on their in vivo behaviour. The required pH gradient, time of treatment, use of osmotic agent and bio-relevant surfactants was optimized based on comparative in vivo observations of reference and test formulations. A linear relationship between formulation variable (amount of release controlling polymer) and in vitro drug release in the developed dissolution condition was observed (regression coefficient > 0.99). Further, a Level A in vitroin vivo correlation (IVIVIC) was developed using in vivo pharmacokinetic data (PK) from a bioequivalence (BE) study and in vitro drug release from the developed dissolution method to predict the behavior of test formulations with average prediction error less than 10%.