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Development of a Non-Aqueous Dispersion to Improve Intestinal Epithelial Flux of Poorly Permeable Macromolecules

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Abstract

Intestinal permeation enhancers (PEs) offer an attractive strategy to enable oral peptide administration. However, optimal presentation of peptide and PE from solid-dosage forms is offset by slow dissolution rates in the small intestine, which reduces the likelihood that the PE can reach the threshold concentration for sufficient permeability enhancement. The purpose of this study was to design a PE-based liquid dispersion that can improve intestinal permeation of macromolecules across Caco-2 monolayers and isolated rat/human intestinal mucosae mounted in Ussing chambers. An enhancer screen in monolayers based on permeability (TEER, Papp [14C]-mannitol) and cytotoxicity (MTT assay) initially identified methyl 10-hydroxydecanoate (10-OHC10CH3) as a candidate. 10-OHC10CH3 (20 mM) increased the Papp of fluorescent dextran of 4 kDa (FD4) (167-fold), 10 kDa (FD10) (429-fold), and 40 kDa (FD40) (520-fold) across monolayers. Blends of 10-OHC10CH3 with low molecular weight PEGs (0.2–1 kDa) formed liquid dispersions in which enhancement capacity across monolayers of 10-OHC10CH3 was increased over 10-OHC10CH3 alone in the order PEG200 < PEG400 < PEG600 < PEG1000. Finally, a 1:5 ratio of 10-OHC10CH3 (10–20 mM)/PEG600 (50–100 mM) increased the Papp of [14C]-mannitol across rat and human intestinal mucosae. This study highlights the potential future role for non-aqueous, PE-based liquid dispersions in oral delivery of macromolecules.

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Acknowledgments

The study was supported by Enterprise Ireland (Grant Number TC20130001) and by SFI Center grant (CURAM Medical Devices) grant number 13-RC-20273.

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Authors and Affiliations

  1. School of Pharmacy, Royal College of Surgeons in Ireland, St. Stephen’s Green, Dublin 2, Ireland

    Sam Maher

  2. Department of Surgery, St. Vincent’s University Hospital, Elm Park, Merrion Road, Dublin 4, Ireland

    Mekki Medani & Desmond C. Winter

  3. Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, 00931-3346, Puerto Rico

    Nestor N. Carballeira

  4. School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

    Alan W. Baird & David J. Brayden

Authors
  1. Sam Maher
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  2. Mekki Medani
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  3. Nestor N. Carballeira
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  4. Desmond C. Winter
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  5. Alan W. Baird
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  6. David J. Brayden
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Corresponding author

Correspondence to Sam Maher.

Ethics declarations

Studies involving dissected rodent tissue were carried out in accordance with the approved UCD Animal Research Ethics Committee protocol [AREC-14-28 Brayden]. Approval for the use of human colonic specimens was obtained from the Ethics Committee of St. Vincent’s University Hospital (Dublin, Ireland) following informed patient consent.

Glossary

10-OHC10CH3

Methyl 10-hydroxydecanoate

C8

Sodium caprylate

C10

Sodium caprate

CCh

Carbachol

DMSO

Dimethyl sulfoxide

EDTA

Ethylenediaminetetraacetic acid

ER

Enhancement ratio

FD4 FD10 and FD40

Fluorescent dextran of 4 kDa, 10 kDa, and 40 kDa

HLB

Hydrophilic lipophilic balance

ISC

Short circuit current

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Papp

Apparent permeability coefficient

PdI

Polydispersity index

PE

Permeation enhancer

PEG

Polyethylene glycol

SNAC

(sodium N-[8-(2-hydroxybenzoyl)amino] caprylate)

TEER

Transepithelial electrical resistance

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Maher, S., Medani, M., Carballeira, N.N. et al. Development of a Non-Aqueous Dispersion to Improve Intestinal Epithelial Flux of Poorly Permeable Macromolecules. AAPS J 19, 244–253 (2017). https://doi.org/10.1208/s12248-016-9996-9

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  • DOI: https://doi.org/10.1208/s12248-016-9996-9

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