Oral peptide delivery: challenges and the way ahead

Dubey, Sunil Kumar; Parab, Shraddha; Dabholkar, Neha; Agrawal, Mukta; Singhvi, Gautam; Alexander, Amit; Bapat, Ranjeet; Kesharwani, Prashant

doi:10.1016/j.drudis.2021.01.001

Cited by 52 publications

(17 citation statements)

References 187 publications

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“…Increasing the absorption window of a drug by targeting the colon offers advantages in terms of frequency of dosing, where controlled or extended release (XR) formulations can be used to enable once daily dosing (improving patient convenience [ 8 ], maintaining therapeutic concentrations [ 13 ] and reducing the risk of administration errors [ 14 ]). The low proteolytic activity and the potential of intact peptide absorption [ 15 ] (as demonstrated for insulin [ 16 ] or linaclotide [ 17 ]) enables the large intestine (with emphasis on the proximal colon) as an appropriate absorption site [ 5 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

et al. 2021

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Previous studies have used magnetic resonance imaging (MRI) to quantify the fluid in the stomach and small intestine of children, and the stomach, small intestine and colon of adults. This is the first study to quantify fluid volumes and distribution using MRI in the paediatric colon. MRI datasets from 28 fasted (aged 0–15 years) and 18 fluid-fed (aged 10–16 years) paediatric participants were acquired during routine clinical care. A series of 2D- and 3D-based software protocols were used to measure colonic fluid volume and localisation. The paediatric colon contained a mean volume of 22.5 mL ± 41.3 mL fluid, (range 0–167.5 mL, median volume 0.80 mL) in 15.5 ± 17.5 discreet fluid pockets (median 12). The proportion of the fluid pockets larger than 1 mL was 9.6%, which contributed to 94.5% of the total fluid volume observed. No correlation was detected between all-ages and colonic fluid volume, nor was a difference in colonic fluid volumes observed based on sex, fed state or age group based on ICH-classifications. This study quantified fluid volumes within the paediatric colon, and these data will aid and accelerate the development of biorelevant tools to progress paediatric drug development for colon-targeting formulations.

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Section: Introductionmentioning

confidence: 99%

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

et al. 2021

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“…Despite such low oral bioavailability, both oral formulations are effective due to their high potency and the structural modifications that increase their half-life (t 1/2 ). Other strategies for oral peptide delivery include micro and nanoparticle carries for protection and controlled release, enzyme inhibitors to prevent degradation, and microneedle-based devices to bypass the intestinal epithelium, reviewed in [ 6 ].…”

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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“…The route of administration is one of the critical factors that govern the formulation of a bioactive. For oral peptide delivery, intestinal permeation, luminal, brush border and cytosolic metabolism, and hepatic clearance mechanism, are all typical limiting factors for poor bioavailability [ 45 , 46 ]. It has previously been reported that IPP and LKP are stable in low pH, intestinal and liver peptidase, indicating their ability to withstand first pass metabolism [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Formulation, Characterisation and Evaluation of the Antihypertensive Peptides, Isoleucine-Proline-Proline and Leucine-Lysine-Proline in Chitosan Nanoparticles Coated with Zein for Oral Drug Delivery

Danish

Gleeson

Brayden

et al. 2022

IJMS

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Isoleucine-Proline-Proline (IPP) and Leucine-Lysine-Proline (LKP) are food-derived tripeptides whose antihypertensive functions have been demonstrated in hypertensive rat models. However, peptides display low oral bioavailability due to poor intestinal epithelial permeability and instability. IPP and LKP were formulated into nanoparticles (NP) using chitosan (CL113) via ionotropic gelation and then coated with zein. Following addition of zein, a high encapsulation efficiency (EE) (>80%) was obtained for the NP. In simulated gastric fluid (SGF), 20% cumulative release of the peptides was achieved after 2 h, whereas in simulated intestinal fluid (SIF), ~90% cumulative release was observed after 6 h. Higher colloidal stability (39–41 mV) was observed for the coated NP compared to uncoated ones (30–35 mV). In vitro cytotoxicity studies showed no reduction in cellular viability of human intestinal epithelial Caco-2 and HepG2 liver cells upon exposure to NP and NP components. Administration of NP encapsulating IPP and LKP by oral gavage to spontaneously hypertensive rats (SHR) attenuated systolic blood pressure (SBP) for 8 h. This suggests that the NP provide appropriate release to achieve prolonged hypotensive effects in vivo. In conclusion, chitosan-zein nanoparticles (CZ NP) have potential as oral delivery system for the encapsulation of IPP and LKP.

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Oral peptide delivery: challenges and the way ahead

Cited by 52 publications

References 187 publications

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

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

Formulation, Characterisation and Evaluation of the Antihypertensive Peptides, Isoleucine-Proline-Proline and Leucine-Lysine-Proline in Chitosan Nanoparticles Coated with Zein for Oral Drug Delivery

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