Formulation and dosage form design in drug-induced topical irritation of the gastrointestinal tract.

To test drugs for topical effects on gastrointestinal mucosa, a new in situ rabbit colon model was used that permits direct application of drugs in suspensions from gel cups, solutions, or commercially available tablets and capsules onto rabbit colonic mucosa for up to 8 hr. For each agent tested an irritation index was calculated--the product of the area of the mucosa affected by drug exposure and a numerical score for observed effect. Irritation indices ranged from 0 (no effect) to 25.6 (maximal irritation measurable). In general, the immediate release of drug onto tissue elicited the greatest effect, whereas slow or controlled release of drug produced the least response. Topical irritation was found to be a function of (1) the drug, (2) the formulation, (3) the delivery rate, and (4) the concentration. The gastrointestinal therapeutic system (GITS) of potassium chloride and of brompheniramine/pseudoephedrine produced far less irritation than current commercial formulations of these drugs. The rabbit colon model is proposed as a useful screening tool during drug development to aid in selecting the formulation of an oral dosage form that will minimize topical irritation.