Combining SNAC and C10 in oral tablet formulations for gastric peptide delivery: A preclinical and clinical study

Abstract

Current oral formulations of macromolecules including peptides typically rely on single permeation enhancer (PE) to promote absorption and thus bioavailability. In this work, we combined two PEs, namely sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and sodium caprate (C10), in one tablet formulation to potentially gain a synergistic effect for enhanced gastric absorption of a GLP-1 analogue and a PCSK9 inhibitor. Permeability tests on a gastric organoids-based cell model showed that the combination of SNAC and C10 can significantly improve peptide permeability compared to either SNAC or C10 alone. Tablet formulations were then designed, adjusting the total PE amount, relative ratio between SNAC and C10, and the peptide dose. To facilitate drug and PE release, a diluent was added. Upon oral administration in beagle dogs, the lead formulations made of SNAC/C10/diluent demonstrated higher bioavailability than either SNAC, SNAC/diluent and C10/diluent formulations for both peptides. Finally, the SNAC/C10/diluent formulation with PCSK9 inhibitor was tested in human, where it displayed similar bioavailability to the SNAC/diluent reference, thereby suggesting a low translatability between pre-clinical and clinical data when C10 was involved. This may be attributed to the difference in physiology, gastric pH environment as well as C10 concentration and colloidal form in the gastric lumen between dogs and humans. Hence, additional studies are needed for a better understanding of the clinical translation of C10-based peptide formulations.

Introduction

Since recombinant DNA technology enabled the production of human insulin at a reasonable price in the 1980s, therapeutic peptides and proteins have been receiving growing attention [1]. Compared to traditional small molecules, peptides often offer greater potency and better specificity to target, thus resulting in fewer side effects. Accordingly, the regulatory approval rate of macromolecules such as peptides has been superior to small molecules over the last decades, and their global market value keeps increasing drastically [2]. However, the full clinical potential of peptides and proteins is restricted by their need for parenteral dosing. Subcutaneous or intramuscular injections remain the mainstream route of peptide administration, because oral delivery of peptides has been limited due to their enzymatic, chemical and physical instability in the gastrointestinal fluids and their poor permeability through the epithelial membranes [3]. This has resulted in a very limited number of marketed oral peptide drug products with systemic targets for patients.

To overcome these biological barriers, both pharmaceutical companies and academic groups have been exploring new strategies for oral peptide delivery, including innovative (pro)drug design, permeation enhancer-based formulations, and micro or nanoencapsulation [4]. Among the investigated permeation enhancers (PE), sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and medium-chain fatty acids, especially sodium caprate (C10) and sodium caprylate (C8), have shown the greatest potential in enabling oral absorption, and have been tested for oral delivery of multiple macromolecules in clinical trials [[5], [6], [7]]. SNAC enables gastric absorption of orally administered semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, and has also been clinically tested with a wide variety of biological drugs. It has been shown to act as a transcellular PE, promoting absorption of peptides by fluidisation of the epithelial membrane [8,9]. In contrast, C10 and C8 primarily act as paracellular PEs, which increase macromolecule permeation by opening of intercellular tight junctions [[10], [11], [12]]. They have also been involved in multiple clinical trials including oral insulin and octreotide [13]. However, the use of PEs still results in low absorption of the active pharmaceutical ingredient (API) with at most single-digit bioavailability via the oral route, leaving plenty of space for further innovation.

In addition to formulation challenges, the development of oral technologies for sufficiently soluble macromolecules with intrinsically low permeability (BCS III) is further hampered by the poor translation from rodents to large animals since the very early preclinical trials [[14], [15], [16], [17]]. Most work conducted by the academic community is limited to rodents due to practical reasons, e.g., cost and accessibility. Irreproducibility is not uncommon between research groups, which further complicates understanding of the underpinning mechanisms and prevents conclusive outcomes [18]. Moreover, the translatability of experimental results from large animals to humans is not fully known. Therefore, more clinical or clinically relevant studies are essential to improve fundamental understanding of the performance of oral peptide formulations.

In this work, we combined SNAC and C10 in oral peptide tablets to potentially achieve a synergistic permeability-enhancing effect, arising from concurrent transcellular and paracellular permeation. Simultaneous flux across the gastric epithelium via both permeation routes may result in increased absorption and thereby increased bioavailability of the API [19]. In vitro screening was employed for selection of the lead formulation with emphasis on securing increased API absorption, and fast API and PE release. The API absorption was assessed in presence of different SNAC/C10 ratios in a permeability model grown from gastric organoids resembling the gastric mucosa. Tablet disintegration was evaluated in a fast-screening set-up to discriminate between formulations. Lead candidates were then tested in beagle dogs due to their closer resemblance with the human gastrointestinal tract compared to rodents [20]. Ultimately, a clinical study in humans was conducted to evaluate the translatability of the in vivo dog readouts.

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Tablet Preparation

SNAC, C10 and APIs used in this study were from Novo Nordisk. The PEs and the diluent were granulated prior to tableting. PE and diluent granules were blended with the API by manual geometric mixing, followed by blending on a turbula mixer. Magnesium stearate was added in a secondary blending step prior to compression, also by manual geometric mixing followed by blending on a turbula mixer, to lubricate the blend. Tablets were produced on a STYL’One tableting press (MEDELPHARM, Beynost, France) 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.

Zhigao Niu, Damiano La Zara, Lasse Blaabjerg, Jenni Pessi, Konstantinos Raptis, Anders Toftlev, Max Sauter, Philip Christophersen, Pierre-Louis Bardonnet, Vincent Andersson, Jian Xiong Wu, Matthäus Brandt, Li Fan, Zhuoran Wang, Franta Hubálek, Per-Olof Wahlund, Mathias Norrman, Kateryna Breusova, Marie Stine Hjaltason, Nicolai Rytter Mortensen, Lars Bardtrum, Birgitte Nissen, Kaisa Naelapää, Philip Jonas Sassene, Combining SNAC and C10 in oral tablet formulations for gastric peptide delivery: A preclinical and clinical study, Journal of Controlled Release, Volume 378, 2025, Pages 92-102, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2024.11.078.