Challenges and Opportunities in the Oral Delivery of Recombinant Biologics

Abstract

Recombinant biological molecules are at the cutting-edge of biomedical research thanks to the significant progress made in biotechnology and a better understanding of subcellular processes implicated in several diseases. Given their ability to induce a potent response, these molecules are becoming the drugs of choice for multiple pathologies. However, unlike conventional drugs which are mostly ingested, the majority of biologics are currently administered parenterally. Therefore, to improve their limited bioavailability when delivered orally, the scientific community has devoted tremendous efforts to develop accurate cell- and tissue-based models that allow for the determination of their capacity to cross the intestinal mucosa. Furthermore, several promising approaches have been imagined to enhance the intestinal permeability and stability of recombinant biological molecules. This review summarizes the main physiological barriers to the oral delivery of biologics. Several preclinical in vitro and ex vivo models currently used to assess permeability are also presented. Finally, the multiple strategies explored to address the challenges of administering biotherapeutics orally are described.

Keywords: biologics; ex vivo; in vitro; intestinal mucosa; oral delivery; permeability; stability.

Figure 7

Schematic representation of the gut-on-a-chip device. Reproduced from [144] with permission from the Royal Society of Chemistry.

Figure 1

Structure of the intestinal epithelium. AMPs: Antimicrobial Peptides; sIgA: Secretory Immunoglobulin A. Created with Biorender.com (accessed on 24 January 2023).

Figure 2

Schematic representation of intercellular junctions. Created with Biorender.com (accessed on 25 January 2023).

Figure 3

Different transport mechanisms across the intestinal epithelium. Created with Biorender.com (accessed on 24 January 2023).

Figure 4

Schematic representation of cells grown on a Transwell^® insert. Created with Biorender.com (accessed on 17 January 2023).

Figure 5

Schematic representation of Caco-2 cells grown on a Transwell^® insert. Cells were represented (a) at the beginning of the culture, (b), once confluent, and (c) structurally and functionally differentiated in mature enterocytes after 21 days. Created with Biorender.com (accessed on 17 January 2023).

Figure 6

Schematic representation of a well-differentiated Caco-2/HT-29/Raji B cells model. Created with Biorender.com (accessed on 12 February 2023).

Figure 8

Schematic representation of an intestinal organoid. Created with Biorender.com (accessed on 21 March 2023).

Figure 9

Schematic illustration of an Ussing chamber.

Figure 10

Schematic illustration of a Franz diffusion cell. Reproduced from [190] with permission from Permegear.

Figure 11

Schematic illustration of one chamber of the InTESTine™ model. Figure was adapted from [194].

Figure 12

Principle of a stimuli-responsive hydrogel targeting the small intestine. (1) Protection of the drug from the low pH and the proteolytic enzymes of the stomach thanks to (2) a complexation due to hydrogen bonding between the polymer chains; (3) drug release of the drug molecule in the small intestine thanks to (4) decomplexation and an increase in mesh size induced by ionic repulsion and swelling at a higher pH. Figure was adapted from [244]. The left part was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/ (accessed on 16 March 2023).

Figure 13

Schematic representation of the luminal unfolding microneedle injector (LUMI). Once the capsule is ingested, the LUMI is ejected in the small intestine and the arms press the patches on the gut wall. The microneedles dissolve and release the encapsulated drug. Then, the capsule breaks apart, and the device rapidly biodegrades before being eliminated from the body. Figure was adapted from [327]. The left part was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/ (accessed on 27 December 2022).