Development of a colonic release capsule dosage form and the absorption of insulin.

Since the colon is relatively low in peptidase activity and drainage into the lymphatics is maximized, a peroral dosage form was developed to deliver insulin to the colon. Microemulsions, used as a vehicle for insulin, were gelled using Cab-O-Sil, and filled into gelatin capsules pretreated with formaldehyde vapor. The capsules were coated with Eudragit NE 30 D, Eudragit S100 and cellulose acetate phthalate polymers of pH-dependent and time-controlled release mechanisms. In vitro dissolution profiles of the capsule coating, using sodium salicylate as the marker, show that dissolution of the capsule begins at 4 h, at pH 5.5, and is completed at 8 h, at pH 7.7, simulating the gastrointestinal transit and pH profile of the dog. An in vivo crossover study in beagle dogs was carried out employing the following treatments: i.v. insulin, p.o. insulin microemulsion and colonic release capsule dosage form without insulin (CRC), were used as controls, a colonic release capsule dosage form with insulin (CRI) and additionally with sodium laurylsulfate (CRIL) or aprotinin (CRIA) as sorption promoter and enzyme inhibitor, respectively. Evaluation was done by measuring the reduction in blood glucose concentration levels. The pharmacological availability (P.A.) is the ratio of the area under the baseline curve (AUC), expressed as percent glucose reduction from baseline vs time, of the p.o. dosage forms to i.v. insulin administration, corrected for body weight and dose size. The P.A. for the p.o. microemulsion, CRC, CRI, CRIL and CRIA were 2.1, 0.4, 5.0, 2.7 and 6.2%, respectively. Insulin release occurred throughout the GI tract, with the exception of the stomach. Tmax occurred at 6.4 h for CRIA; the majority of insulin is taken up after the colonic arrival time is reached in the dog (4-6 h). Duration of the reduction in blood glucose levels occurred for 14 h with the CRIA dosage form.