Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: In vitro permeability and in vivo oral absorption of salmon calcitonin (sCT)

Purpose. To evaluate a biopharmaceutical approach for selecting formulation additives and establishing the performance specifications of an oral pepti de delivery system using sCT as a model peptide. Methods. The effect of formulation additives on sCT effective permeability and transepithelial electrical resistance (TEER) was evaluated in side-by-s ide diffusion chambers using rat intestinal segments. Baseline regional ora l absorption of sCT was evaluated in an Intestinal and Vascular Access Port (IVAP) dog model by administration directly into the duodenum, ileum, and colon by means of surgically implanted, chronic catheters. The effect of va rying the input rate and volume of the administered solution on the extent of sCT absorption was also evaluated. Citric acid (CA) was utilized in all studies to cause a transient reduction in local pH. In vitro samples and pl asma samples were analyzed by radioimmunoassay (RIA). Two oral delivery sys tems were prepared based on the results of the in vitro and IVAP studies, a nd evaluated in normal dogs. Results. Maximal permeability enhancement of sCT was observed using taurode oxycholate (TDC) or lauroyl carnitine (LC) ill vitro. Ileal absorption of s CT was higher than in other regions of the intestine. Low volume and bolus input of solution formulations was selected as the optimal condition for th e IVAP studies since larger volumes or slower input rates resulted in signi ficantly lower sCT bioavailability (BA). Much lower BA of sCT was observed when CA was not used in the formulation. The absolute oral bioavailability (mean +/- SD) in dogs for the control (sCT + CA) and two proprietary sCT de livery systems was 0.30% +/- 0.05%, 1.10 +/- 0.18%, and 1.31 +/- 0.56%, res pectively. Conclusions. These studies demonstrate the utility of in vitro evaluation a nd controlled in vivo studies for developing oral peptide delivery strategi es. Formulation additives were selected, the optimal intestinal region for delivery identified, and the optimal release kinetics of additives and acti ves from the delivery system were characterized. These methods were success fully used for devising delivery strategies and fabricating and evaluating oral sCT delivery systems in animals. Based on these studies, sCT delivery systems have been fabricated and tested in humans with favorable results.