All4Nutra
Abstract
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.
Introduction
Peptide and protein drugs play an important role in several therapeutic areas in modern medicine, such as cardiometabolic diseases, oncology, immunology, and cardiovascular diseases, covering a growing number of patients worldwide. The high potency and specificity of these macromolecules offer great clinical advantages over traditional small molecules, yet their complex structures and labile nature in the gastrointestinal tract complicate their oral administration [1]. Although injectables remain the most common administration form for peptides and proteins, oral tablets are preferred by patients because of their convenience of administration [2]. Moreover, an oral modality may provide additional benefits in terms of safety, cost-effectiveness, and shelf-stability.
Extensive academic and industrial research has been carried out towards the development of oral peptide and protein formulations containing fatty acids or fatty acid-derived permeation enhancers (PE) such as salcaprozate sodium (SNAC), sodium caprylate (C8) and sodium caprate (C10). These efforts have led to the successful FDA registrations of SNAC-based oral semaglutide and C8-based oral octreotide [3,4,5,6]. The fatty acid PEs temporarily opens the intercellular tight junctions in the gastrointestinal epithelium and increase membrane fluidity [5, 7], thereby increasing the permeability of these drugs. Formulations containing C10 has shown potential in preclinical studies, but its translation into clinical use is currently limited due to challenges such as variable absorption, supply and processability issues. While C10 has mainly been studied as PE for intestinal delivery [8,9,10,11], recently Tran et al. reported the use of C10 for gastric delivery of a GIP/GLP-1 peptide [12]. Specifically, C10 was found as effective as SNAC in enhancing the gastric absorption of the peptide orally administered as an uncoated tablet in monkeys. For immediate-release oral peptide formulations, the stomach is the main site for tablet disintegration, dissolution and absorption, particularly in the case of molecules sensitive to intestinal proteases which would degrade once in the duodenum. Medium chain fatty acids can also be absorbed in the stomach [13, 14] as they are not incorporated into chylomicrons and can be absorbed by passive diffusion to the portal vein [15, 16].
Inadequate animal models for validating new formulation concepts represent a barrier for successful translation of C10-based formulations. Most in vivo readouts reported in literature are from rodents, where a poor correlation with clinical data is unsurprising considering the physiological differences between species. Moreover, even when larger animals such as dogs and pigs are employed due to the resemblance of their gastrointestinal (GI) tracts to humans [6], translational issues may arise in the case of C10-based formulations: for instance, our unpublished in-house data show that the exposure of two internal acylated peptides in C10-based formulations dosed in naive beagle dogs systematically overpredicts their clinical bioavailability (Fig. 1). A potential reason for the lack of translation may be the discrepancy in gastric pH between dogs and humans. In the fasted state, human gastric pH is reported to be around 2 for healthy volunteers [17,18,19], while beagle dog stomach commonly has higher and more variable pH [20, 21], with reported values ranging from 3 to 7 [22, 23]. The pH variability in dog stomach may be explained by a more significantly fluctuating gastric secretion rate in the fasted state, likely due to higher gastric responsiveness upon stimulation [24, 25]. Different gastric environments between species may affect tablet performance, ultimately altering bioavailability.
In this work we developed a novel C10-based tablet formulation containing a pH modifier and evaluated it preclinically in beagle dogs pre-treated with acid to reflect the human gastric pH. Different active pharmaceutical ingredients (APIs) were used for the preclinical exploration, and the one selected formulation was ultimately evaluated in a clinical trial.
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Tablet Preparation
SNAC, C10 and APIs used in this study were from Novo Nordisk. Sorbitol and Meglumine EMPROVE® were purchased from Merck (Darmstadt, Germany) and magnesium stearate from Sigma-Aldrich (Saint-Louis, USA).
The PEs were granulated prior to tableting. PE and other excipients were blended with the API by manual geometric mixing, followed by blending in a turbula mixer. Magnesium stearate was added in a secondary blending step prior to compression, also by manual geometric mixing followed by blending in a turbula mixer.
Tablets were produced on STYL’One Evo (Korsch AG) mounted with a single set of punches, and punch size was chosen according to the total tablet weight to well accommodate the powder blends. The press speed was set to 10%. The fill volume was adjusted to obtain tablets having target weights based on composition. Compression forces ranged from 3 to 25 kN to ensure the same apparent density.
Bardonnet, PL., Niu, Z., Pessi, J. et al. An effort to enhance the clinical translatability of caprate-based tablet formulations in gastric peptide delivery. Drug Deliv. and Transl. Res. (2025). https://doi.org/10.1007/s13346-025-01978-7
