Impact of dosage form on the pharmacokinetics of octreotide after oral administration with permeation enhancers

The permeation enhancers (PEs) sodium salcaprozate (SNAC) and sodium decanoate (C10) are reported to enhance gastric and intestinal absorption of different macromolecules. While previous preclinical and clinical studies report effects of these PEs, no head-to-head comparison between their effect in different dosage forms administered by oral gavage in rats is reported. For that purpose, we developed mini-tablets containing octreotide and SNAC or C10 as the PE. The disintegration behavior of the mini-tablets was evaluated using biorelevant liquid volumes of 0.1–0.5 mL in different experimental setups. The efficacy of the PEs co-administered in solution and the in solid dosage form was compared in rats after oral gavage and subsequent assessment of the octreotide pharmacokinetics (PK).

While the type of PE and the volume only slightly affected the disintegration time for the mini-tablets, significant differences were observed to depend on the exact experimental setup. Upon oral gavage, plasma octreotide concentrations were enhanced in presence of PE for both solution and mini-tablet formulations compared to control formulations without PEs, as reflected by the higher area under the plasma concentration curves (AUC). SNAC produced a significantly greater relative bioavailability than both the control and the C10-containing formulations. The relative bioavailability increased 2.0- and 9.4-fold for C10 and SNAC solutions, respectively. Notably, the mini-tablets both with and without PE showed higher numerical octreotide absorption than their solution counterparts and the mini-tablets resulted in a 1.6- and 1.8-fold increase for C10, and a 4.8- and 5.4-fold increase for SNAC in relative bioavailability after co-administering with low and high liquid volumes, respectively. In conclusion, the study shows that the PK profiles for octreotide are different after oral gavage administration of solutions compared to mini-tablets containing the PEs SNAC and C10 and that SNAC outperformed C10 as a permeation enhancer when administered by oral gavage.