Enteral insulin delivery by microspheres in 3 different formulations using Eudragit L100 and S100

Abstract

Three types of insulin microspheres (IMS) were prepared in order to deliver insulin selectively in the intestinal tract using copolymers having pH-dependent solubility, Eudragit L100 (L), Eudragit S100 (S) and a 1:1 mixture of these (LS). In a release study, the insulin release rate from S-IMS was much slower than that from L-IMS at a pH below 7.0. At a pH of 7.5, all the IMS released more than 90% of the insulin within 60 min. Thus, the three types of IMS were expected to release insulin at different sites through the small intestine. To confirm this distribution in the intestinal tract, the amount of insulin in the residual IMS in the stomach and several parts of the small intestine was measured. L-IMS emptied from the stomach seemed to release insulin immediately in the upper parts of the small intestine. In contrast, many of the S-IMS appeared in the lower area of the small intestine (corresponding to the ileum). From these results, insulin released from L-IMS may exist in the jejunum to upper ileum at higher concentration compared with the cases of LS- or S-IMS. The hypoglycemic effect was observed to be the greatest after administration of L-IMS. The biological effect of each IMS was significantly amplified by a protease inhibitor, aprotinin (AP). The most remarkable effect of AP was seen in L-IMS. Our results suggest that L-IMS has the advantage of carrying insulin to the optimum sites for absorption and that AP effectively enhances its absorption.