Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals

Abstract

Recently, two oral-administered peptide pharmaceuticals, semaglutide and octreotide, have been developed and are considered as a breakthrough in peptide and protein drug delivery system development. In 2019, the Food and Drug Administration (FDA) approved an oral dosage form of semaglutide developed by Novo Nordisk (Rybelsus^®) for the treatment of type 2 diabetes. Subsequently, the octreotide capsule (Mycapssa^®), developed through Chiasma's Transient Permeation Enhancer (TPE) technology, also received FDA approval in 2020 for the treatment of acromegaly. These two oral peptide products have been a significant success; however, a major obstacle to their oral delivery remains the poor permeability of peptides through the intestinal epithelium. Therefore, gastrointestinal permeation enhancers are of great relevance for the development of subsequent oral peptide products. Sodium salcaprozate (SNAC) and sodium caprylate (C8) have been used as gastrointestinal permeation enhancers for semaglutide and octreotide, respectively. Herein, we briefly review two approved products, Rybelsus^® and Mycapssa^®, and discuss the permeation properties of SNAC and medium chain fatty acids, sodium caprate (C10) and C8, focusing on Eligen technology using SNAC, TPE technology using C8, and gastrointestinal permeation enhancement technology (GIPET) using C10.

Keywords: medium chain fatty acids; oral delivery; peptides; permeation enhancers; sodium salcaprozate.

Figure 1

The historical chart of the octreotide formulation development process.

Figure 2

Structures of sodium caprate (C10) and sodium caprylate (C8).

Figure 3

Hypotheses on the mechanism of C10. The diagram shows the simple classification of the mechanisms of C10 proposed to date. It is essentially divided into tight junction (TJ) modulation (left) and membrane perturbation mechanisms [68]. The TJ modulation hypothesis is divided into a Ca²⁺-dependent PLC-PKC pathway mechanism (a) and a Ca2+-independent TJ protein modulation (b). As per the membrane perturbation hypothesis, the mechanism of action of C10 can be its insertion into the membrane to fluidize the membrane and enhance absorption into the transcellular pathway (c), and an unknown TJ modulation signal due to membrane perturbation (d).

Figure 4

Schematic diagram of the mechanism of the Eligen™ technology (carrier mechanism). Emisphere researchers have argued that small carrier molecules with hydrophobic moieties increase lipophilicity through the formation of weak non-covalent bonds with drug molecules [120].

Figure 5

Structures of (a) SNAC, (b) 5-CNAC, and (c) 4-CNAB.

Figure 6

Formulation design of the Rybelsus^® tablet and schematic diagram of the semaglutide absorption enhancement mechanism of SNAC (published by the Novo Nordisk research team) [61]. The Rybelsus^® tablet (A) is completely eroded from the gastric mucosal surface (B,C) and SNAC increases the local pH to prevent the degradation of semaglutide from pepsin (C). Moreover, it indirectly weakens the self-association of semaglutide and helps to maintain the monomer state (D), and increases transcellular absorption by increasing membrane fluidity (E,F). Reprinted with permission from ref. [61]. Copyright 2018 Science.