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<p>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&#xa0;mg of PCSK9 inhibitor, 200&#xa0;mg of C10, 60&#xa0;mg of meglumine and 60&#xa0;mg of sorbitol showed a 57% increase in exposure compared to the benchmark SNAC formulation in animal studies 0.5&#xa0;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.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月23日

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  • Pierre-Louis Bardonnet,
  • Zhigao Niu,
  • Jenni Pessi,
  • Maria Kazakou,
  • Konstantinos Raptis,
  • Reece McCabe,
  • Anders Toftlev,
  • René Rebollo,
  • Zhuoran Wang,
  • Li Fan,
  • Nicolai Rytter Mortensen,
  • Lars Bardtrum,
  • Vincent Andersson,
  • Per-Olof Wahlund,
  • Mathias Norrman,
  • Andrew James Benie,
  • Jian Xiong Wu,
  • Max Sauter,
  • Damiano La Zara,
  • Philip Christophersen,
  • Philip Jonas Sassene

摘要

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.

Graphical abstract