title: Toward oral delivery of biopharmaceuticals: an assessment of the gastrointestinal stability of 17 peptide drugs.
abstract: A major barrier to successful oral delivery of peptide and protein molecules is their inherent instability in the lumen of the gastrointestinal tract. The aim of this study was to determine the stability of 17 disparate peptide drugs (insulin, calcitonin, glucagon, secretin, somatostatin, desmopressin, oxytocin, [Arg(8)]-vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, [d-Ser](4)-gonadorelin, deslorelin, and goserelin) in gastric and small intestinal fluids from both humans and pigs, and in simulated gastric and intestinal fluids. In human gastric fluid, the larger peptides including somatostatin, calcitonin, secretin, glucagon, and insulin were metabolized rapidly, while the smaller peptides showed good stability. In human small intestinal fluid, however, both small and large peptides degraded rapidly with the exception of the cyclic peptide ciclosporin and the disulfide-bridge containing peptides octreotide and desmopressin, which showed good stability. The stability of peptides in both simulated gastric fluid and pig gastric fluid correlated well with stability in human gastric fluid. However, it was not possible to establish such a correlation with the small intestinal fluids because of the rapid rate of peptide degradation. This work has identified the molecular features in the structure of a wide range of peptides that influence their stability in the environment of the gastrointestinal tract, which in turn will allow for better selection of peptide candidates for oral delivery.
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London , WC1N 1AX London, U.K.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Vipul
authors.initials: V
authors.lastname: Yadav
authors.forename: Alice L
authors.initials: AL
authors.lastname: Smart
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Tajiri
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Basit
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001702:Biopharmaceutics; D001826:Body Fluids / Q000378:metabolism; D004355:Drug Stability; D005750:Gastric Juice / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D059748:Proteolysis; D034421:Sus scrofa
chemical_list: D010455:Peptides; D010447:Peptide Hydrolases
keywords: Biopharmaceuticals; gastrointestinal fluids; metabolism; oral delivery; peptides and proteins