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Toward oral delivery of biopharmaceuticals: an assessment of the gastrointestinal stability of 17 peptide drugs.

Molecular pharmaceutics (2015-01-24)
Jie Wang, Vipul Yadav, Alice L Smart, Shinichiro Tajiri, Abdul W Basit
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Trifluoroacetic acid, suitable for HPLC, ≥99.0%
Sigma-Aldrich
Trifluoroacetic acid, ReagentPlus®, 99%
Sigma-Aldrich
Trifluoroacetic acid, puriss. p.a., suitable for HPLC, ≥99.0% (GC)
Sigma-Aldrich
Trifluoroacetic acid, ≥99%, for protein sequencing
Supelco
Trifluoroacetic acid, analytical standard
Sigma-Aldrich
Oxytocin
Sigma-Aldrich
Oxytocin, lyophilized powder, ~15 IU/mg solid (Prepared from synthetic oxytocin)
Sigma-Aldrich
Octreotide, ≥98% (HPLC)
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Sodium trichloroacetate, 97%
Oxytocin, European Pharmacopoeia (EP) Reference Standard
USP
Oxytocin, United States Pharmacopeia (USP) Reference Standard
Desmopressin, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Goserelin acetate, ≥99% (HPLC), white powder
Goserelin, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
[des-Gly10, D-His(Bzl)6]-LH-RH ethylamide, ≥97% (HPLC), powder
Goserelin for NMR identification, European Pharmacopoeia (EP) Reference Standard

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