Oral administration is the most often used treatment for both systemic and local gastrointestinal diseases [1,2]. Despite the apparent advantages, oral drug delivery remains challenging due to the harsh gastrointestinal tract (GIT) microenvironment and a number of physiological barriers, including gastrointestinal anatomy factors, biochemistry factors, and physiology factors. The different parts of the GIT, including mouth cavity, esophagus, stomach, small intestine, and colon, play an important role in the digestion of food and absorption of medicine. The different anatomical characteristics, such as limited surface in oral cavity, gastric mucin–bicarbonate barrier, and enteral enzymes could also be obstacles for drug absorption. Considerable efforts have been made to overcome these issues, which are mainly based on improved comprehension of the healthy and diseased physiology characters of the GIT. Conventional drug delivery systems including normal tablets, capsules, or sterile drug preparations, are associated with limitations, including low site-specific accumulation of drugs, unfavorable body distribution, adverse side effects, etc. [3]. Therefore, the development of novel localized and systematic targeted drug delivery systems is urgent. The application of nanomedicines and novel drug delivery devices were considered as the most promising innovative pharmaceutical approaches in oral drug delivery systems [4].

On account of its easy application, being painless, low expense, wide drug assimilation/distribution, and high patient compliance, the oral route is the most common way for patients. However, the efficiency of many oral medicines is still limited due to various physiological barriers, resulting in low permeability, and drug degradation [20]. The limitations of oral drug delivery can be summarized by anatomy factors, biochemistry factors, and physiology factors in GIT.

Anatomically, the GIT consists of the oral cavity, esophagus, stomach, small intestine, and colon, each part having different factors that affect drug delivery [21]. The different anatomical characteristics of GIT show varying effects on drug absorption.

The oral cavity is covered by oral mucosa, it has a mild microenvironment, easy accessibility, facile access to circulation, good permeability, and absorption of drugs [20,22]. However, the limited surface of oral cavity, saliva, and enzymatic composition are the main barriers of drug delivery in mouth [20].

Due to the low permeability and short residence time of drugs, the esophagus is not a prime target for drug delivery [23,24].

The stomach exhibits a strong acid environment with a pH range of 1.0–2.5, which can break down food, ectogenic pathogens [25], and acid-labile drugs [26], which makes it the harshest barrier to drug absorption. In addition, the stomach possesses extrinsic epithelial cells [27] and a mucin–bicarbonate barrier [28]. The tight junctions beneath the intrinsic barrier also limit the drug absorption. Moreover, pepsins in the stomach can lead to the inactivation of protein drugs.

The small intestine has a huge surface area due to the villi and microvilli in the intestinal lumen [29,30]. The small intestine is regarded as a prime site for oral drug delivery due to the tremendous surface and diverse transport routes. The intestinal mucosa can recognize and transfer ectogenic antigens to the immune system [31,32]. However, there are still some challenges of small intestine drug delivery arising from its special physiology. The harsh stomach chemical microenvironment, pancreatic enzymes, bile salts, and the mucosal layer decrease the drug bioavailability. Drug delivery systems that can increase their retention time at villi and microvilli, improve lipid solubility, and interact with specific receptor or carrier are able to increase their overall bioavailability.

The colon exhibits a higher pH environment and much longer residence time compared with the upper GIT, and the enzyme activity in colon is relatively low [33,34]. Moreover, drugs can be metabolized by the gut microflora which effects the release characters of drugs. Targeting drugs to the colon is of great significance for treating bowel diseases with fewer side effects and lower drug dosage. However, the inherent difference of the gastric emptying time and microflora in different people remains a major drawback for colon targeting [35].

Different pH environments and digestive enzymes were regarded as the main biochemical barriers for oral drug delivery systems. The pH varies distinctly in different parts of the GIT, it rises gradually from the stomach to the colon in the range from 1 to 8 [36,37]. The variation from acidic to alkaline environment affects the drugs’ activities and bioavailability. pH variation not only affects drug delivery, but also a route for targeting the design of oral drugs.

The existence of various enzymes will critically influence the bioavailability of drugs in the GIT, especially for protein drugs. There are over 400 different species of aerobic and anaerobic microorganisms in the colon; they can produce hydrolytic and reductive metabolizing enzymes, which can catalyze the metabolism of xenobiotics and other biomolecules. Polysaccharides can only be metabolized in the colon by anaerobic bacteria and be stable in the stomach and intestine, making it possible for colon-targeted drug delivery.

Since drugs are also susceptible to colonic enzymes and generate biotransformation, the “prodrug” approach is often used for the colon-specific drug delivery [33].

The main anatomical and biochemical barriers of the oral administration are summarized in Table 1.

The GIT exerts a low permeability to the bloodstream and extraneous substances, which restricts the bioavailability and absorption of drugs. The physiological barriers mainly consist of epithelium cellular barrier and the mucus barrier.

The gastrointestinal epithelium is a phospholipid bilayer membrane, which allows the penetration and absorption of lipophilic macromolecules [38], while it is a primary absorption barrier for hydrophilicity and macromolecules [39]. The existence of tight junctions between adjacent cells also limits the paracellular pathway for hydrophilic drug [40].

Mucus is a dynamic semipermeable barrier, which restricts the direct interaction of drugs with epithelial cells [26]. Mucus is a viscous gel formed by mucins and glycoproteins; it can serve as a lubricant for ingested food and also a strong barrier to entrap foreign particles and eliminate potentially harmful compounds and bacteria [41,42,43,44,45]. Secreted mucins are linked together through disulfide bonds to form highly glycosylated macromolecules, which makes the mucin complex more stable and protects them from enzymatic degradation [28]. The mucus structure and intermolecular interactions dictate the permeation of peptides, large molecules, and microorganisms through the mucus layer [46,47].