Table 2.
Strategies to overcome the absorption barriers.
| Barrier | Strategy employed | Example of agents | Primary function | Ref. |
|---|---|---|---|---|
| pH and enzyme degradation | Colon targeting; Enteric coating; Microcapsules; |
HPMC; Eudragit; Gelatin; α-cyclodextrin |
Preventing denaturation and the low level of proteases | 44, 45, 46, 47 |
| Protease inhibitors | Aprotinin; Na-glycocholate; Bacitracin; Camostat mesylate |
Enzyme inhibition | 48, 49, 50 | |
| Natural degradable polymer shell; | Chitosan; Dextran; Alginate |
Low toxicity and enhanced sustained release | 51, 52, 53 | |
| Nanorobots; | – | Rapid passage through the stomach under propulsive forces; | 54, 55, 56, 57 | |
| Microneedles | Physically piercing tissue barriers to evade the gastrointestinal tract | 58, 59, 60 | ||
| Mucus barrier | Mucus adhesion | Natural/synthetic biodegradable polymer NPs | Facilitate close contact through electrostatic interactions, thereby increasing drug residence time | 60,61 |
| PEGylation | Increase hydrophilicity to enhance adhesive capabilities | 62,63 | ||
| Virus-mimicking | The surface charge is slightly negative, and the outer shell is hydrophilic | 64,65 | ||
| Hydrogels | The swollen hydrogel adheres to the intestinal mucosa | 38,66,67 | ||
| Mucus penetration | NPs with small size | Diffusing faster in the mucus by having a diameter smaller than the average pore size of the mucous mesh structure | 38,68 | |
| Hydrophilic modification | Hydrophilic surface helps reduce hydrophobic interactions and promotes mucus penetration | 69, 70, 71, 72 | ||
| Epithelial barrier | Absorption enhancers | Fatty acids; Surfactants; EDTA |
Perturbed cell membranes, improved cell bypass transport, and selectively opened tight junctions | 73, 74, 75 |
| Hydrogels | Super porous hydrogel; pH-sensitive hydrogels | The expansion of the hydrogel exerts mechanical pressure to open the tight junctions | 38,67,75 | |
| NP carrier systems | Liposomes; Nanospheres; SLN; SNEDDS |
Selectively opening tight junctions | 76, 77, 78 | |
| Modification of specific groups | Ligands (immunoglobulins, transferrin, lectins, biotin, folate, and vitamin B12); | Ligands can be recognized, thereby improving cell internalization | 74,79,80 | |
| CPP (penetratin, transportan, oligoarginine, and TAT) | Endocytosis, cell membrane perturbation and channel generation may be the potential modes of action | 77,81, 82, 83 |
‒, not applicable. HPMC, hydroxypropyl methyl cellulose; NPs, nanoparticles; SLN, solid lipid nanoparticles; SNEDDS, self-nanoemulsifying drug delivery systems; CPP, cell-penetrating peptides; TAT, transactivator of transcription.