Versatile Oral Insulin Delivery Nanosystems: From Materials to Nanostructures

Abstract

Diabetes is a chronic metabolic disease characterized by lack of insulin in the body leading to failure of blood glucose regulation. Diabetes patients usually need frequent insulin injections to maintain normal blood glucose levels, which is a painful administration manner. Long-term drug injection brings great physical and psychological burden to diabetic patients. In order to improve the adaptability of patients to use insulin and reduce the pain caused by injection, the development of oral insulin formulations is currently a hot and difficult topic in the field of medicine and pharmacy. Thus, oral insulin delivery is a promising and convenient administration method to relieve the patients. However, insulin as a peptide drug is prone to be degraded by digestive enzymes. In addition, insulin has strong hydrophilicity and large molecular weight and extremely low oral bioavailability. To solve these problems in clinical practice, the oral insulin delivery nanosystems were designed and constructed by rational combination of various nanomaterials and nanotechnology. Such oral nanosystems have the advantages of strong adaptability, small size, convenient processing, long-lasting pharmaceutical activity, and drug controlled-release, so it can effectively improve the oral bioavailability and efficacy of insulin. This review summarizes the basic principles and recent progress in oral delivery nanosystems for insulin, including physiological absorption barrier of oral insulin and the development of materials to nanostructures for oral insulin delivery nanosystems.

Keywords: absorption barrier; bioavailability; nanodrug delivery system; oral insulin.

Figure 1

(A) Materials and nanostructures of oral insulin delivery systems. (B) The physiological absorption barrier of oral administration of insulin. (a) Destruction by gastric acid. (b) Degradation by digestive enzyme. (c) Retention by the mucus layer barrier. (d) Retardation by intestinal epithelial cell layer.

Figure 2

The chemical structures of the carrier materials for oral insulin delivery nanosystems. (A) PLA, (B) PLGA, (C) chitosan, (D) MOFs, and (E) alginate acid.

Figure 3

(A) The structure of liposomes. (B) TEM images of CLs and PcCLs, and schematic diagram for the process of the transport of the PcCLs through the mucus layers and epithelial barrier. (C) Schematic diagram of IPUL-CST and its intestinal uptake and lymphatic transport. (D) Schematic representation of the glucose-responsive oral insulin delivery liposomes for postprandial glycemic regulation.

Figure 4

(A) Structure of micelles. (B) Schematic representation of Ins-loaded PCPMs and its pH-triggered release. (C) Schematic representation of DSPE-PCB micelles for oral delivery of insulin.

Figure 5

(A) Structure of SLNs. (B) Schematic representation of possible structures of VEN. (C) Schematic diagram of SLN and its behavior in intestinal epithelium.

Figure 6

(A) Structures of organic nanospheres/nanocapsules. (B) Schematic representation of sequential FNC platform for preparation of the CPP/insulin nanoparticles. (C) The structure and the preparation process of NC-HTCC. (D) The structure of virus-like P-R8-Pho NPs and diagram of P-R8-Pho NPs to sequentially overcome mucus layer and intestinal epithelial cell layer.

Figure 7

(A) Structure of nanogel. (B) Schematic representation of insulin-loaded glucose-responsive nanocarriers further encapsulated into hyaluronic acid (HA) hydrogel for oral delivery of insulin. (C) Schematic diagram of pH and glucose dual-responsive nanogels for protein delivery. (D) Synthetic process and its pH responsiveness of CMS/PiBAA hybrid microgel.

Figure 8

(A) Structure of inorganic/organic hybrid. (B) Structure of penetration behavior of virus-mimicking nanoparticles (MSN-NH2@COOH/CPP5). (C) Structure of HAP-PEG-GA-INS NPs and schematic diagram of insulin delivery to the effector cells by HAP-PEG-GA-INS NPs. (D) Structure and synthesis of the MSNs core–shell nanoparticles (a) and its pH- and glucose-sensitive behavior (b).