Oral delivery of proteins and peptides: Challenges, status quo and future perspectives

Abstract

Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.

Keywords: ASBT, apical sodium-dependent bile acid transporter; BSA, bovine serum albumin; CAGR, compound annual growth; CD, Crohn's disease; COPD, chronic obstructive pulmonary disease; CPP, cell penetrating peptide; CaP, calcium phosphate; Clinical; DCs, dendritic cells; DDVAP, desmopressin acetate; DTPA, diethylene triamine pentaacetic acid; EDTA, ethylene diamine tetraacetic acid; EPD, empirical phase diagrams; EPR, electron paramagnetic resonance; Enzyme inhibitor; FA, folic acid; FDA, U.S. Food and Drug Administration; FcRn, Fc receptor; GALT, gut-associated lymphoid tissue; GI, gastrointestinal; GIPET, gastrointestinal permeation enhancement technology; GLP-1, glucagon-like peptide 1; GRAS, generally recognized as safe; HBsAg, hepatitis B surface antigen; HPMCP, hydroxypropyl methylcellulose phthalate; IBD, inflammatory bowel disease; ILs, ionic liquids; LBNs, lipid-based nanoparticles; LMWP, low molecular weight protamine; MCT-1, monocarborxylate transporter 1; MSNs, mesoporous silica nanoparticles; NAC, N-acetyl-l-cysteine; NLCs, nanostructured lipid carriers; Oral delivery; PAA, polyacrylic acid; PBPK, physiologically based pharmacokinetics; PCA, principal component analysis; PCL, polycarprolacton; PGA, poly-γ-glutamic acid; PLA, poly(latic acid); PLGA, poly(lactic-co-glycolic acid); PPs, proteins and peptides; PVA, poly vinyl alcohol; Peptides; Permeation enhancer; Proteins; RGD, Arg-Gly-Asp; RTILs, room temperature ionic liquids; SAR, structure–activity relationship; SDC, sodium deoxycholate; SGC, sodium glycocholate; SGF, simulated gastric fluids; SIF, simulated intestinal fluids; SLNs, solid lipid nanoparticles; SNAC, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate; SNEDDS, self-nanoemulsifying drug delivery systems; STC, sodium taurocholate; Stability; TAT, trans-activating transcriptional peptide; TMC, N-trimethyl chitosan; Tf, transferrin; TfR, transferrin receptors; UC, ulcerative colitis; UEA1, ulex europaeus agglutinin 1; VB12, vitamin B12; WGA, wheat germ agglutinin; pHPMA, N-(2-hydroxypropyl)methacrylamide; pI, isoelectric point; sCT, salmon calcitonin; sc, subcutaneous.