An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer
by
Svenja Sladek 1, Fiona McCartney 1
, Mena Eskander 2, David J. Dunne 2, Maria Jose Santos-Martinez 2,3, Federico Benetti 4, Lidia Tajber 2 and 
David J. Brayden 1,*
Svenja Sladek 1, Fiona McCartney 1, Mena Eskander 2, David J. Dunne 2, Maria Jose Santos-Martinez 2,3, Federico Benetti 4, Lidia Tajber 2 and David J. Brayden 1,*
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.
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Keywords:
insulin; hyaluronic acid; chitosan; oral peptide delivery; intestinal permeation enhancers; nanomedicine
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
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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