Recent advances in oral insulin delivery technologies

Abstract

With the rise in diabetes mellitus cases worldwide, oral delivery of insulin is preferred over subcutaneous insulin administration due to its good patient compliance and non-invasiveness, simplicity, and versatility. However, oral insulin delivery is hampered by various gastrointestinal barriers that result in low drug bioavailability and insufficient therapeutic efficiency. Numerous strategies have been developed to overcome these barriers and increase the bioavailability of oral insulin. Yet, no commercial oral insulin product is available to address all clinical hurdles because of various substantial obstacles related to the structural organization and physiological function of the gastrointestinal tract. Herein, we discussed the significant physiological barriers (including chemical, enzymatic, and physical barriers) that hinder the transportation and absorption of orally delivered insulin. Then, we showcased recent significant and innovative advances in oral insulin delivery technologies. Finally, we concluded the review with remarks on future perspectives on oral insulin delivery technologies and potential challenges for forthcoming clinical translation of oral insulin delivery technologies.

Keywords: Barriers; Bioavailability; Diabetes; Insulin; Oral delivery.

Fig. 1.

Schematic representation of physiological barriers in the gastrointestinal tract to oral drug delivery. Oral delivery faces three main barriers, including chemical barriers (highly acidic in the stomach with pH 1-3), enzymatic barriers (multiple enzymes such as pepsin and cathepsin in the stomach and trypsin, chymotrypsin and carboxypeptidase in small intestine), and physical barriers (mucus layer, epithelial layer, and their tight junction).

Fig. 2.

Strategies that have been used to overcome gastrointestinal barriers for improving oral peptide delivery, including enzyme inhibitors (a), permeation enhancers to enhance paracellular or transcellular transport (b), and physical insertion (such as microneedle injector) (c).

Fig. 3.

Mechanisms of tight junction opening for enhancing intestinal wall permeability. (a) Claudins (a family of proteins) make up the external barrier of the tight junctions and are expressed in tissue-specific combinations. (b-e) Potential mechanisms of action of different types of absorption enhancers: silica nanoparticles (b), Cell-permeable inhibitors of phosphatase (c), classical permeation enhancer caprate (d), and salcaprozate sodium (e). Reprinted with permission from ref [101], Copyright 2020, Springer Nature.

Fig. 4.

Zwitterionic micelles efficiently deliver oral insulin without opening tight junctions. (a) The schematic representation of DSPE-PCB micelles addresses both the mucus and the epithelial cell layer barriers without opening tight junctions for oral insulin delivery. (b) Representative TEM images of epithelial tissues at 1 h post ileum injection of different types of surfactants, indicating zwitterionic micelle/insulin treatment did not open intestinal tight junctions (indicated by arrows). (c,d) Pharmacological activity (blood glucose-lowering in c) and bioavailability (serum insulin concentration in d) of the DSPE-PCB/insulin capsule in diabetic rats through oral gavage, compared with the Polysorbate 80/insulin capsule and native insulin capsule. Adapted with permission from ref [102]. Copyright 2020, Springer Nature.

Fig. 5:

The luminal unfolding microneedle injector (LUMI) for oral delivery of macromolecules. (a) Overhead (top) and side-view (bottom) images of an unfolded LUMI. (b) LUMI actuation scheme. (c, d) Schematic timeline of LUMI devices for oral delivery of biologics in the gastrointestinal tract after administered in enteric capsules. a-c, adapted with permission from ref [109]. Copyright 2020, Springer Nature. d, adapted with permission from ref [110]. Copyright 2020, Springer Nature.

Fig. 6.

Schematic illustration of two smart ingestible devices for oral drug delivery. (a) The self-orienting millimeter-scale applicator (SOMA) localizes to the stomach lining, orients its injection mechanism toward the tissue wall, and injects a drug payload through the gastric mucosa. Adapted with permission from ref [111]. Copyright 2019, The American Association for the Advancement of Science. (b) The liquid-injecting SOMA (L-SOMA) for oral delivery of liquid formulations of pharmaceuticals into the gastric submucosa. Adapted with permission from ref [113]. Copyright 2021, Springer Nature.