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.

Development andin vitroevaluation of an oral SEDDS for desmopressin

“…Oral peptide delivery still remains one of the ultimate challenges in the pharmaceutical-technological field (Fosgerau & Hoffmann, 2015;Wang et al, 2015). Orally administered peptides are facing various obstacles concerning the ADME process.…”

“…For instance, peptides must avoid acidic or enzymatic degradation, pass mucus barriers and, in case of drugs containing one or more disulfide bonds, also the socalled sulfhydryl barrier (Leonaviciute & Bernkop-Schnürch, 2015). Human physiology with highly acidic conditions in the stomach, secreted enzymes like trypsin, a-chymotrypsin, and elastase along with poor intestinal membrane permeability contribute to an overall low oral peptide bioavailability (Wang et al, 2015). However, some oral peptide formulations are yet available on the market (Shen, 2003;Fosgerau & Hoffmann, 2015;Wang et al, 2015), whereby peptide drugs like vancomycin (Vancocin Õ ) and linaclotide (Linzess Õ ) are targeted only for local intestinal delivery.…”

“…However, some oral peptide formulations are yet available on the market (Shen, 2003;Fosgerau & Hoffmann, 2015;Wang et al, 2015), whereby peptide drugs like vancomycin (Vancocin Õ ) and linaclotide (Linzess Õ ) are targeted only for local intestinal delivery. In contrast, the lipophilic peptide cyclosporine (Neoral Õ ) and the highly potent vasopressin structural analog desmopressin (DDAVP Õ , DesmoMelt Õ , Minirin Õ , Octim Õ , Stimate Õ ) exhibit sufficient systemic effects after oral administration (Wang et al, 2015).…”

“…Additionally, it contains a disulfide bond and a cleavage site for a-chymotrypsin. This results in an extensive presystemic degradation and peptide inactivation via a-chymotrypsin and sulfhydryl compounds after oral administration (Kahns et al, 1993;Fredholt et al, 1999;Wang et al, 1999Wang et al, , 2015. Consequently, the oral bioavailability of the above mentioned formulations is less than 1% (Kahns et al, 1993;Ilan et al, 1996;Fredholt et al, 1999;Wang et al, 2015).…”

“…This results in an extensive presystemic degradation and peptide inactivation via a-chymotrypsin and sulfhydryl compounds after oral administration (Kahns et al, 1993;Fredholt et al, 1999;Wang et al, 1999Wang et al, , 2015. Consequently, the oral bioavailability of the above mentioned formulations is less than 1% (Kahns et al, 1993;Ilan et al, 1996;Fredholt et al, 1999;Wang et al, 2015). Thus, several attempts to develop alternative oral delivery systems such as mucoadhesive submicron emulsions (Ilan et al, 1996), solid lipid particles (Christophersen et al, 2014) as well as prodrugs (Kahns et al, 1993;Wang et al, 1999Wang et al, , 2002 have been undertaken to increase its bioavailability.…”