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Open AccessArticle

In Vitro, Ex Vivo and In Vivo Evaluation of Microcontainers for Oral Delivery of Insulin

1
Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
2
The Danish National Research Foundation and Villum Foundation’s Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics, 2800 Kgs. Lyngby, Denmark
3
Department of Health Technology, Technical University of Denmark, Ørsteds Plads, 2800 Kgs. Lyngby, Denmark
4
Center for Biopharmaceuticals and Biobarriers in Drug Delivery, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
5
Bioneer:FARMA, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(1), 48; https://doi.org/10.3390/pharmaceutics12010048 (registering DOI)
Received: 10 December 2019 / Revised: 31 December 2019 / Accepted: 3 January 2020 / Published: 7 January 2020
Enhancing the oral bioavailability of peptides has received a lot of attention for decades but remains challenging, partly due to low intestinal membrane permeability. Combining a permeation enhancer (PE) with unidirectionally releasing microcontainers (MCs) has previously been shown to increase insulin permeation across Caco-2 cell monolayers. In the present work, this setup was further employed to compare three common PEs—sodium caprate (C10), sodium dodecyl sulfate (SDS), and lauroyl carnitine. The concept was also studied using porcine intestinal tissue with the inclusion of 70 kDa fluorescein isothiocyanate-dextran (FD70) as a pathogen marker. Moreover, a combined proteolysis and Caco-2 cell permeation setup was developed to investigate the effect of soybean trypsin inhibitor (STI) in the MCs. Lastly, in vivo performance of the MCs was tested in an oral gavage study in rats by monitoring blood glucose and insulin absorption. SDS proved to be the most potent PE without increasing the ex vivo uptake of FD70, while the implementation of STI further improved insulin permeation in the combined proteolysis Caco-2 cell setup. However, no insulin absorption in rats was observed upon oral gavage of MCs loaded with insulin, PE and STI. Post-mortem microscopic examination of their gastrointestinal tract indicated lack of intestinal retention and optimal orientation by the MCs, possibly precluding the potential advantage of unidirectional release. View Full-Text
Keywords: oral peptide delivery; microdevices; permeation enhancers; protease inhibitors; Caco-2 cells; Franz diffusion cells; oral gavage oral peptide delivery; microdevices; permeation enhancers; protease inhibitors; Caco-2 cells; Franz diffusion cells; oral gavage
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MDPI and ACS Style

Jørgensen, J.R.; Yu, F.; Venkatasubramanian, R.; Nielsen, L.H.; Nielsen, H.M.; Boisen, A.; Rades, T.; Müllertz, A. In Vitro, Ex Vivo and In Vivo Evaluation of Microcontainers for Oral Delivery of Insulin. Pharmaceutics 2020, 12, 48.

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