Design and in vivo evaluation of an oral delivery system for insulin

Purpose. To develop an oral controlled release system for insulin. Methods. The polymer-inhibitor conjugates carboxymethylcellulose (CMC)-Bowm an-Birk inhibitor and CMC-elastatinal were homogenized with polycarbophil-c ysteine: conjugate, insulin, and mannitol, compressed to 2 mg microtablets and enteric coated with a polymethacrylate. The protective effect of this d elivery system for insulin towards enzymatic degradation, as well as the re lease profile, was evaluated in vitro. In addition, the effect of the dosag e form on glucose levels of diabetic mice was determined. Results. Tablets containing the CMC-inhibitor conjugates showed a strong pr otective effect for insulin. Whereas 91.6 +/- 7.4% (mean +/- SD, n = 3) of insulin in the dosage form without the inhibitor conjugates has been degrad ed within 3 h of incubation in an artificial intestinal fluid containing ph ysiological concentrations of trypsin, chymotrypsin, and elastase, 49.7 +/- 5.5% (mean +/- SD, n = 3) of insulin remained stable in the delivery syste m containing the polymer-inhibitor conjugates. Additionally, polycarbophil- cysteine (PCP-Cys) provides high cohesiveness of the dosage form, due to th e formation of inter-as well as intramolecular disulfide bonds within the p olymer matrix. According to this, a controlled release of insulin could be: achieved over a time period of 10 h. Furthermore, in vivo studies in diabe tic mice showed a decrease in basal glucose levels of 20% to 40% during a t ime period of 80 h. Conclusions, Mucoadhesive: polymer-inhibitor conjugates might represent a p romising excipient in delivery systems for oral (poly)pep tide delivery.