Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches

Brayden, David J.; Hill, Timothy A.; Fairlie, David P.; Maher, Sam; Mrsny, Randy

doi:10.1016/j.addr.2020.05.007

Cited by 157 publications

(99 citation statements)

References 242 publications

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“…The vast majority of marketed peptides are administered via injection [ 1 ], which is not a convenient route for patients, especially those suffering from chronic illnesses requiring daily injections. Subcutaneous (s.c.) injections are also not the safest route for some peptides, like insulin, which is associated with many adverse effects due to the unphysiological nature of this delivery route [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

et al. 2021

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For many diabetics, daily, lifelong insulin injections are required to effectively manage blood glucose levels and the complications associated with the disease. This can be a burden and reduces patient quality of life. Our goal was to develop a more convenient oral delivery system that may be suitable for insulin and other peptides. Insulin was entrapped in 1.5-mm beads made from denatured whey protein isolate (dWPI) using gelation. Beads were then air-dried with fumed silica, Aerosil®. The encapsulation efficiency was ~61% and the insulin loading was ~25 µg/mg. Dissolution in simulated gastric-, and simulated intestinal fluids (SGF, SIF) showed that ~50% of the insulin was released from beads in SGF, followed by an additional ~10% release in SIF. The omission of Aerosil® allowed greater insulin release, suggesting that it formed a barrier on the bead surface. Circular dichroism analysis of bead-released insulin revealed an unaltered secondary structure, and insulin bioactivity was retained in HepG2 cells transfected to assess activation of the endogenous insulin receptors. Insulin-entrapped beads were found to provide partial protection against pancreatin for at least 60 min. A prototype bead construct was then synthesised using an encapsulator system and tested in vivo using a rat intestinal instillation bioassay. It was found that 50 IU/kg of entrapped insulin reduced plasma glucose levels by 55% in 60 min, similar to that induced by subcutaneously (s.c.)-administered insulin (1 IU/kg). The instilled insulin-entrapped beads produced a relative bioavailability of 2.2%. In conclusion, when optimised, dWPI-based beads may have potential as an oral peptide delivery system.

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Section: Introductionmentioning

confidence: 99%

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

et al. 2021

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“…The historical development of oral peptide drugs and the current status of candidates in end-stage clinical trials have been reviewed extensively recently. 5,21,22 Here we instead focus on the four peptide drugs currently approved for use in the clinic. We focus on the mechanisms involved in their successful transport across cell barriers and discuss instances where fluorescence imaging has helped elucidate these mechanisms.…”

Section: Oral Peptide Drugs For Systemic Applications Used In the Clinicmentioning

confidence: 99%

“…Despite the potent ability of microbial toxins to modulate TJ biology, their clinical use as PEs has remained sparse, mainly due to concerns about toxicity. 21 The most clinically advanced paracellular PEs are EDTA (ethylenediaminetetraacetic acid)…”

Section: Elucidating Permeation Enhancers' Modes Of Action Using Fluorescence Imagingmentioning

confidence: 99%

“…All evidence suggested that C 10 increased paracellular permeability via a membrane-perturbation induced alteration in intracellular calcium levels, which leads to TJ opening through a MLC regulated mechanism. 30,40 Additionally C 10 has been shown to have a direct effect on membrane fluidity above its critical micelle concentration 41 , illustrating how PEs, like C 10 , can affect numerous different pathways simultaneously. 21 The perceived mechanism of the main member of the acetylated amino acid class, SNAC, has also recently been updated.…”

Section: Elucidating Permeation Enhancers' Modes Of Action Using Fluorescence Imagingmentioning

confidence: 99%

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Imaging therapeutic peptide transport across intestinal barriers

et al. 2021

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“…In fact, the proof of concept of oral absorption of intact particles has been inadvertently verified by observation of oral absorption of labile biomacromolecules, such as insulin. The fact that free biomacromolecules are readily broken down in the GIT but absorbed partly in encapsulated form implies probable absorption as integral particles 3,4 . The recovery of nondegradable inorganic nanoparticles in the systemic circulation and remote tissues after oral administration adds more convincing evidence 5,6 …”

Section: Figurementioning

confidence: 99%

Peroral targeting of drug micro or nanocarriers to sites beyond the gastrointestinal tract

Zhang

Lü

et al. 2021

Medicinal Research Reviews

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Targeted delivery of drug micro or nanocarriers has been attained via parenteral routes, especially the intravenous route. Conventionally, oral targeting refers to site‐specific delivery and triggered drug release at local sites within the gastrointestinal tract (GIT), or targeting to the enteric epithelia through ligand‐receptor or transporter interactions. Beyond that barrier, the concept of peroral targeting has not been clarified. Nevertheless, this is possible as long as drug carriers are able to be absorbed into the systemic circulation intact. Recent findings on in vivo translocation of drug micro or nanocarriers shed light on potential peroral targeting to remote sites beyond the GIT. Sequential processes of penetration across the enteric epithelia, transportation via the lymphatics and ultimate convergence with the systemic circulation are involved in the underlying mechanisms. The microfold cell (M cell) pathway plays a leading role in breaking through the enteric epithelial barrier. Accumulating evidence confirms primary targeting of a series of lipid and polymeric micro or nanocarriers to organs and tissues of the mononuclear phagocyte systems (MPS), such as the liver, spleen, lungs and kidneys. The total amount of lymph‐bound particles could reach 8%, as evidenced by quantification of glucan microparticles that specifically bind M cell. Migration or translocation of micro or nanocarrier‐bearing macrophages attains secondary targeting of the engulfed micro or nanocarriers to distant sites far beyond the MPS. The current findings foresee a probability of targeting to sites beyond the GIT. However, the content of exposure of micro or nanocarriers at target sites and potential therapeutic or diagnostic promises are yet to be unraveled.

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Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches

Cited by 157 publications

References 242 publications

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

Imaging therapeutic peptide transport across intestinal barriers

Peroral targeting of drug micro or nanocarriers to sites beyond the gastrointestinal tract

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