Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems

Abstract

Oral delivery of therapeutics is the preferred route of administration due to ease of administration which is associated with greater patient medication adherence. One major barrier to oral delivery and intestinal absorption is rapid clearance of the drug and the drug delivery system from the gastrointestinal (GI) tract. To address this issue, researchers have investigated using GI mucus to help maximize the pharmacokinetics of the therapeutic; while mucus can act as a barrier to effective oral delivery, it can also be used as an anchoring mechanism to improve intestinal residence. Nano-drug delivery systems that use materials which can interact with the mucus layers in the GI tract can enable longer residence time, improving the efficacy of oral drug delivery. This review examines the properties and function of mucus in the GI tract, as well as diseases that alter mucus. Three broad classes of mucus-interacting systems are discussed: mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems. For each class of system, the basis for mucus interaction is presented, and examples of materials that inform the development of these systems are discussed and reviewed. Finally, a list of FDA-approved mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems is reviewed. In summary, this review highlights the progress made in developing mucus-interacting systems, both at a research-scale and commercial-scale level, and describes the theoretical basis for each type of system.

Keywords: Gastrointestinal tract; Mucoadhesive; Mucus; Mucus penetration; Oral delivery.

Fig. 1

Schematic of the mucus layers in the GI tract as a whole (A), as well as tissue histology of the mucin MUC5B in the submucosal glands of the esophagus (B) as shown by Arul et al. [23], the mucins MUC5AC/MUC6 in the stomach (C) as shown by Ho et al. [24], and the mucin MUC2 in the small intestine (D) as shown by Gustafsson et al. [25]. The schematic (A) shows the esophagus (left), stomach (left middle), small intestine (right middle), and colon (right). The esophagus contains a thin layer of mucin MUC5B. The stomach contains two layers of mucin MUC5AC: a thin layer firmly attached to the epithelium and a thicker, loosely attached layer above. This outer layer also contains “bands” of mucin MUC6. The small intestine and colon both contain the mucin MUC2, but the small intestine only contains a thin, loosely bound layer. The colon is organized similarly to the stomach, with a thin, firmly attached layer and a thicker, loosely attached layer above

Fig. 2

Schematic showing a crosslinked mucin structure. The image on the left shows the multimeric structure of the gel, in which individual mucin chains are connected via either their N-terminal D domains (in the trans-Golgi compartments of goblet cells) or through disulfide bonds formed between the cysteine knot regions. The image on the right shows the general structure of each of the three major GI mucins MUC2, MUC5AC, and MUC5B, with the indicated regions shown below in the legend. Figure adapted from Moran et al. [40]

Fig. 3

Schematic for the contact (left) and consolidation (middle) steps in forming a successful mucoadhesive bond (right) between a nanoparticle and the surface of the mucus layer (A), as well as a histological image of the mucoadhesion process for electrospun fibers (B) [119]. In this paper, the mucoadhesive bonds represent bonds with the mucus layers (composed of GI mucins) rather than with the GI mucosa (such as epithelial cells in the small and large intestines)

Fig. 4

Illustration of the mucus-interacting methods employed for successful oral drug delivery: mucoadhesive, mucus-penetrating (densely layered uncharged surface coating and evenly distributed positive/negative surface charges) and mucolytic (conjugated and released mucolytic enzymes)