Oral peptide delivery: Translational challenges due to physiological effects

Tyagi, Puneet; Pechenov, Sergei; Subramony, J. Anand

doi:10.1016/j.jconrel.2018.08.032

Cited by 106 publications

(53 citation statements)

References 110 publications

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“…The apical membrane surface pH of the small intestinal epithelium has been suggested to be between 5 and 7. 17 A→B transport across primary human intestinal epithelium in vitro was observed to be approximately twice as efficient when the apical media was pH 7 compared to pH 5, while the basal pH of 7 or 5 did not have an effect (Figure 1f). The greater variability observed for outcomes where the apical pH of 5 was tested on ntChx transport may have been due to partial neutralization of the apical compartment during the course of the study.…”

Section: Resultsmentioning

confidence: 96%

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

et al. 2020

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Cholix (Chx) is expressed by the intestinal pathogen Vibrio cholerae as a single chain of 634 amino acids (~70.7 kDa protein) that folds into three distinct domains, with elements of the second and third domains being involved in accessing the cytoplasm of nonpolarized cells and inciting cell death via ADP-ribosylation of elongation factor 2, respectively. In order to reach nonpolarized cells within the intestinal lamina propria, however, Chx must cross the polarized epithelial barrier in an intact form. Here, we provide in vitro and in vivo demonstrations that a nontoxic Chx transports across intestinal epithelium via a vesicular trafficking pathway that rapidly achieves vesicular apical to basal (A→B) transcytosis and avoids routing to lysosomes. Specifically, Chx traffics in apical endocytic Rab7 + vesicles and in basal exocytic Rab11 + vesicles with a transition between these domains occurring in the ER-Golgi intermediate compartment (ERGIC) through interactions with the lectin mannose-binding protein 1 (LMAN1) protein that undergoes an intracellular redistribution that coincides with the reorganization of COPI + and COPII + vesicular structures. Truncation studies demonstrated that domain I of Chx alone was sufficient to efficiently complete A→B transcytosis and capable of ferrying genetically conjoined human growth hormone (hGH). These studies provide evidence for a pathophysiological strategy where native Chx exotoxin secreted in the intestinal lumen by nonpandemic V. cholerae can reach nonpolarized cells within the lamina propria in an intact form by using a nondestructive pathway to cross in the intestinal epithelial that appears useful for oral delivery of biopharmaceuticals. One-Sentence Summary: Elements within the first domain of the Cholix exotoxin protein are essential and sufficient for the apical to basal transcytosis of this Vibrio cholerae-derived virulence factor across polarized intestinal epithelial cells.

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Section: Resultsmentioning

confidence: 96%

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

et al. 2020

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“…Peptide drugs with a very low intestinal stability and/or permeability are, with a few exceptions, not administered orally because of their low intestinal absorption. Their low stability can be related to stomach pH denaturation, the high concentrations of luminal gastric and pancreatic peptidases and proteinases, and the high peptidase activity in the brush border membrane of the enterocytes [7]. These issues can be partly circumvented by the formulation approaches.…”

Section: Blood-to-lumen CL Cr-edta Ratiomentioning

confidence: 99%

“…The rat SPIP model may also be used to investigate regional intestinal differences in how pharmaceutical excipient(s) affect drug permeation and overall absorption rate. This is especially relevant because of the renewed interest in permeation enhancers (PE), also called absorption-modifying excipients (AME), for enabling oral administration of low-permeation compounds, for example, peptides [6,7]. Some advocates of this formulation approach propose the colon as a potential target for PEs, because the colon has a longer residence time, its mucosa may be more easily affected, and it does not have the higher peptidase activity of the upper GI tract [8,9].However, few comparisons of the small and large intestine in rat have been made on the direct permeability effects of PEs in the same laboratory.…”

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confidence: 99%

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

et al. 2020

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Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.Pharmaceutics 2020, 12, 242 2 of 14 frequently used in pharmaceutical development to evaluate the potential success of a drug, for instance with oral modified-release (MR) dosage forms. In MR dosage forms, the drug is released throughout the gastrointestinal (GI) tract prior to absorption so the regional intestinal permeability needs to be sufficiently high in both the small and large intestine. The rat and human small intestine have similar drug intestinal absorption profiles and transporter expression patterns, but differ in their enzymatic metabolism [2]. Differences in absorption from the rat and human colon have not been extensively compared, but a recent meta-analysis of rat SPIP data reports regional differences in drug permeability for 42 drugs in this species [3].How relevant for humans are the regional intestinal drug permeability values determined in the rat SPIP model? It is difficult to answer this because of the limited amount of human reference permeability data from the lower GI trac...

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“…Despite the abundant resources allocated to that line of research, its fruits have been relatively sparse . Besides the harsh, acid, gastric environment, the oral delivery of proteins and peptides is primarily hampered by the physical barrier represented by the intestinal epithelial cells, by the intestinal mucus covering the epithelium, and by various chemical components of the gastrointestinal tract, including bile salts, gastric acids and proteases . Alternative methods of proteins and peptides administration, which do not require injections or intravenous access, including the use of permeation enhancers, cell‐penetrating peptides, protease inhibitors, conjugation or enteric coating of the proteins and peptides, and drug delivery using degradable, polymeric or mucoadhesive carriers have all been described and implemented .…”

Section: Introductionmentioning

confidence: 99%

“…Besides the harsh, acid, gastric environment, the oral delivery of proteins and peptides is primarily hampered by the physical barrier represented by the intestinal epithelial cells, by the intestinal mucus covering the epithelium, and by various chemical components of the gastrointestinal tract, including bile salts, gastric acids and proteases . Alternative methods of proteins and peptides administration, which do not require injections or intravenous access, including the use of permeation enhancers, cell‐penetrating peptides, protease inhibitors, conjugation or enteric coating of the proteins and peptides, and drug delivery using degradable, polymeric or mucoadhesive carriers have all been described and implemented . While these methods have been at least partially successful at maintaining the stability and bioactivity of certain drugs, have increased the intestinal permeability, reduced the degradation of proteinic substances, and extended their half‐life in the bloodstream, they may also damage the intestinal epithelium and lower its immune‐protective function, and display considerable variability in diffusion, absorption and localization of the delivery within the gastrointestinal tract, as well as between fasting and postprandial states …”

Section: Introductionmentioning

confidence: 99%

Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine—A pharmacokinetic and pharmacodynamic study

Hashim

Korupolu

Syed

et al. 2019

Pharmacology Res & Perspec

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Biotherapeutic agents must be administered parenterally to obtain therapeutic blood concentrations, lowering patient compliance and complicating care. An oral delivery platform (ODP) was developed to deliver drugs into the small intestinal wall. This proof‐of‐concept study was performed in 17 anesthetized, laparotomized swine. In 8 swine weighing 17.4 ± 1.2 kg (mean ± SEM), 20 IU of recombinant human insulin (RHI) were auto‐injected into the jejunal wall by placing the ODP inside the jejunum via an enterotomy. In 9 control swine weighing 17.0 ± 0.4 kg, 20 IU of RHI were injected subcutaneously. In both groups, under a 60‐80 mg/dL euglycemic glucose clamp, blood glucose was measured with a handheld glucometer and serum insulin was measured using ELISA, at 10‐minute intervals between −20 and +420 minutes after RHI delivery. The peak serum concentration of RHI was 517 ± 109 pmol/L in the ODP and 342 ± 50 pmol/L in the subcutaneous group (ns). The areas under the insulin concentration curves (83 ± 18 and 81 ± 10 nmol/L·min) were also similar in both groups. The mean time to peak serum concentration of insulin was 139 ± 42 minutes in the ODP and 227 ± 24 minutes in the subcutaneous group (ns). In conclusion, (a) The bioactivity of RHI was preserved after its delivery into the jejunal wall, (b) the intrajejunal route delivered insulin as rapidly and physiologically as the subcutaneous route, and (c) these pharmacokinetic and pharmacodynamic characteristics of RHI after intrajejunal delivery suggest that drugs currently administered parenterally, such as basal insulin, could be successfully delivered into the proximal intestinal wall via the ingestible capsule.

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Oral peptide delivery: Translational challenges due to physiological effects

Cited by 106 publications

References 110 publications

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine—A pharmacokinetic and pharmacodynamic study

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