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)-Bowman-Birk inhibitor and CMC-elastatinal were homogenized with polycarbophil-cysteine conjugate, insulin, and mannitol, compressed to 2 mg microtablets and enteric coated with a polymethacrylate. The protective effect of this delivery system for insulin towards enzymatic degradation, as well as the release profile, was evaluated in vitro. In addition, the effect of the dosage form on glucose levels of diabetic mice was determined. RESULTS: Tablets containing the CMC-inhibitor conjugates showed a strong protective effect for insulin. Whereas 91.6 +/- 7.4% (mean +/- SD, n = 3) of insulin in the dosage form without the inhibitor conjugates has been degraded within 3 h of incubation in an artificial intestinal fluid containing physiological concentrations of trypsin, chymotrypsin, and elastase, 49.7 +/- 5.5% (mean +/- SD, n = 3) of insulin remained stable in the delivery system containing the polymer-inhibitor conjugates. Additionally, polycarbophil-cysteine (PCP-Cys) provides high cohesiveness of the dosage form, due to the formation of interas well as intramolecular disulfide bonds within the polymer matrix. According to this, a controlled release of insulin could be achieved over a time period of 10 h. Furthermore, in vivo studies in diabetic mice showed a decrease in basal glucose levels of 20% to 40% during a time period of 80 h. CONCLUSIONS: Mucoadhesive polymer-inhibitor conjugates might represent a promising excipient in delivery systems for oral (poly)peptide delivery.