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Open AccessArticle

An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer

1
UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
2
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
3
School of Medicine, Trinity College Dublin, Dublin 2, Ireland
4
ECSIN Laboratory–Ecamricert Srl, Corso Stati Uniti 4, I-35127 Padova, Italy
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(3), 259; https://doi.org/10.3390/pharmaceutics12030259
Received: 29 January 2020 / Revised: 3 March 2020 / Accepted: 10 March 2020 / Published: 12 March 2020
(This article belongs to the Special Issue Peptide-Based Drug Delivery Systems)
The use of nanocarriers is being researched to achieve oral peptide delivery. Insulin-associated anionic polyelectrolyte nanoparticle complexes (PECs) were formed that comprised hyaluronic acid and chitosan in an optimum mass mixing ratio of 5:1 (MR 5), followed by coating with a pH-dependent polymer. Free insulin was separated from PECs by size exclusion chromatography and then measured by HPLC. The association efficiency of insulin in PECs was >95% and the loading was ~83 µg/mg particles. Dynamic light scattering and nanoparticle tracking analysis of PECs revealed low polydispersity, a negative zeta potential range of −40 to −50 mV, and a diameter range of 95–200 nm. Dissolution studies in simulated small intestinal fluid (FaSSIF-V2) revealed that the PECs were colloidally stable. PECs that were coated with Eudragit® L-100 delayed insulin release in FaSSIF-V2 and protected insulin against pancreatin attack more than uncoated PECs. Uncoated anionic PECs interacted weakly with mucin in vitro and were non-cytotoxic to Caco-2 cells. The coated and uncoated PECs, both concentrated further by ultrafiltration, permitted dosing of 50 IU/kg in rat jejunal instillations, but they failed to reduce plasma glucose or deliver insulin to the blood. When ad-mixed with the permeation enhancer (PE), sucrose laurate (100 mM), the physicochemical parameters of coated PECs were relatively unchanged, however blood glucose was reduced by 70%. In conclusion, the use of a PE allowed for the PEC-released bioactive insulin to permeate the jejunum. This has implications for the design of orally delivered particles that can release the payload when formulated with enhancers. View Full-Text
Keywords: insulin; hyaluronic acid; chitosan; oral peptide delivery; intestinal permeation enhancers; nanomedicine insulin; hyaluronic acid; chitosan; oral peptide delivery; intestinal permeation enhancers; nanomedicine
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MDPI and ACS Style

Sladek, S.; McCartney, F.; Eskander, M.; Dunne, D.J.; Santos-Martinez, M.J.; Benetti, F.; Tajber, L.; Brayden, D.J. An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer. Pharmaceutics 2020, 12, 259.

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