Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies

Abstract

The past few years has witnessed a booming market of protein and peptide drugs, owing to their superior efficiency and biocompatibility. Parenteral route is the most commonly employed method for protein and peptide drugs administration. However, short plasma half-life protein and peptide drugs requires repetitive injections and results in poor patient compliance. Oral delivery is a promising alternative but hindered by harsh gastrointestinal environment and defensive intestinal epithelial barriers. Therefore, designing suitable oral delivery systems for peptide and protein drugs has been a persistent challenge. This review summarizes the main challenges for oral protein and peptide drugs delivery and highlights the advanced formulation strategies to improve their oral bioavailability. More importantly, major intestinal cell types and available targeting receptors are introduced along with the potential strategies to target these cell types. We also described the multifunctional biomaterials which can be used to prepare oral carrier systems as well as to modulate the mucosal immune response. Understanding the emerging delivery strategies and challenges for protein and peptide drugs will surely inspire the production of promising oral delivery systems that serves therapeutic needs in clinical settings.

Recent Advances in Oral and Transdermal Protein Delivery Systems

“…Chemical modifications can improve the enzymatic stability of proteins, as well as membrane permeability to enhance the absorption of proteins, thus increasing the bioavailability [2, 26] . One common strategy is to introduce extra groups for their structural modification, including vitamin B 12 conjugation, [27] lipidization, [28] PEGylation, [29] prodrug design, [30] and protein fusion [13, 31] .…”

“…Since the discovery of insulin in 1921, the development of therapeutic proteins and peptides has made great progress in the last century, including antibodies, hormones, cytokines, enzymes, and vaccines [1] . Currently, there are more than 240 protein and peptide drugs approved by U.S. Food and Drug Administration (FDA) for treating diseases [2] . Compared to small‐molecule drugs, protein therapeutics display highly specific and complex biological functions due to their unique structures [1b] .…”

Soft robot-enabled controlled release of oral drug formulations

“…However, they encounter additional resistance during FDA approval due to potential toxicity and risks associated with introducing new compounds into the body. 18,19 Furthermore, a lack of entrapment efficiency, stability, 20 in vivo retention mechanism, 21 and easy manufacturing processes 22 pose additional barriers to clinical translation.…”

The efficacy of anti‐proteolytic peptide R7I in intestinal inflammation, function, microbiota, and metabolites by multi‐omics analysis in murine bacterial enteritis

“…According to the report, the global peptide therapeutics market was valued at US$ 25.0 Bn in 2018 and is anticipated to expand at a CAGR of 7.9% from 2019 to 2027 (https://www.transparencymarketresearch.com/peptide-therapeutics-market.html). However, most peptide drugs, including AMPs, are difficult to administer orally due to an enzymatic barrier that limits systemic bioavailability, yet oral administration is the recommended technique for treating gastrointestinal inflammatory illnesses 15–17 . Accordingly, improving AMPs' protease resistance was crucial to substituting antibiotics in IBD treatment.…”

“…However, most peptide drugs, including AMPs, are difficult to administer orally due to an enzymatic barrier that limits systemic bioavailability, yet oral administration is the recommended technique for treating gastrointestinal inflammatory illnesses. [15][16][17] Accordingly, improving AMPs' protease resistance was crucial to substituting antibiotics in IBD treatment.…”