Pharmaceutical approach to subcutaneous dosage forms of insulin.

The present studies were undertaken to describe the dynamic nature of the degradation and absorption of insulin in the subcutaneous injection site and to develop agents which would stabilize this dosage form. [125I]Insulin with 0.2-U/kg of unlabeled insulin in 10 microliters of aqueous solution was injected subcutaneously in rats under the depilated skin of the back. At various times, radioactive skin tissue was extracted and assayed for insulin and/or its metabolites by gel filtration. Using these data, absorption and degradation rate constants of these substances were estimated according to a one-compartment model. Absorption rate constants of insulin and its metabolite of low molecular weight (monoiodotyrosine) were 0.021 min-1 and 0.107 min-1, respectively, while the degradation rate constant for insulin to monoiodotyrosine was 0.013 min-1. Thus, the bioavailability of insulin injected subcutaneously was lower than expected, suggesting the necessity of stabilizing methods. The protection of insulin from degradation at the site of injection was examined by the addition of various peptides. It was found that benzyloxycarbonyl-Gly-Pro-Leu-Gly was a good stabilizing agent, and remarkably inhibited insulin degradation. This inhibition was confirmed by the increase of immunoreactive insulin level and the decrease of the blood glucose level. We postulated that this peptide protects the injected insulin from degradation by inhibiting the peptidase present in subcutaneous tissue.