An effort to enhance the clinical translatability of caprate-based tablet formulations in gastric peptide delivery.

Sodium caprate (C10) is the most investigated permeation enhancer to promote oral peptide absorption. However, the clinical translation of C10-based formulations is possibly affected by low gastric pH. Here, we developed a C10-based immediate-release tablet containing meglumine as a pH modifier to mitigate stomach acidity and evaluated it both in dogs and clinically. To mitigate the difference in gastric pH between species, the C10-based formulations were evaluated in acid pre-treated dogs. The exposure was compared to results with sodium salcaprozate (SNAC)-based tablets previously tested in clinical trials. The benefit of meglumine in improving gastric peptide absorption in dogs was demonstrated for several peptide modalities. Ultimately, an oral PCSK9 inhibitor was chosen for test clinical trials. The lead formulation containing 40 mg of PCSK9 inhibitor, 200 mg of C10, 60 mg of meglumine and 60 mg of sorbitol showed a 57% increase in exposure compared to the benchmark SNAC formulation in animal studies 0.5 h post dosing. However, this benefit was not observed in humans to the same extent, where the C10-based formulations provided similar bioavailability to the SNAC-based formulation. Other factors than pH which are likely to influence the relative performance of C10- and SNAC-based formulations are also discussed in this article.