Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: In vitro permeability and in vivo oral absorption of salmon calcitonin (sCT)
Pj. Sinko et al., Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: In vitro permeability and in vivo oral absorption of salmon calcitonin (sCT), PHARM RES, 16(4), 1999, pp. 527-533
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.