Transmucosal Absorption Enhancers in the Drug Delivery Field

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Abstract

Drug delivery systems that safely and consistently improve transport of poorly absorbed compounds across epithelial barriers are highly sought within the drug delivery field. The use of chemical permeation enhancers is one of the simplest and widely tested approaches to improve transmucosal permeability via oral, nasal, buccal, ocular and pulmonary routes. To date, only a small number of permeation enhancers have progressed to clinical trials, and only one product that includes a permeation enhancer has reached the pharmaceutical market. This editorial is an introduction to the special issue entitled Transmucosal Absorption Enhancers in the Drug Delivery Field ( https://www.mdpi.com/journal/pharmaceutics/special_issues/transmucosal_absorption_enhancers). The guest editors outline the scope of the issue, reflect on the results and the conclusions of the 19 articles published in the issue and provide an outlook on the use of permeation enhancers in the drug delivery field.

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Most cited references 46

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Ionic liquids for oral insulin delivery

Amrita Banerjee, Christian Agatemor, Samir Mitragotri … (2018)

Insulin is currently available as an injectable formulation, but an oral product would enjoy higher patient compliance and would significantly improve the quality of life of diabetic patients worldwide. However, oral delivery of proteins such as insulin is challenging due to various gastrointestinal barriers to oral absorption of macromolecules. We have developed a safe and highly effective ionic liquid-based oral insulin formulation that significantly enhanced oral insulin absorption by efficiently circumventing the gastrointestinal barriers. Besides, the formulation demonstrated good stability at room temperature and under refrigeration. Evidence from cell and animal studies supports a promising prospect of development of the formulation into a clinical product. With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

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Orally Absorbed Cyclic Peptides.

Daniel Nielsen, Nicholas Shepherd, Weijun Xu … (2017)

Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol-water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.

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Intestinal permeation enhancers for oral peptide delivery.

Sam Maher, Randall J. Mrsny, David J. Brayden (2016)

Intestinal permeation enhancers (PEs) are one of the most widely tested strategies to improve oral delivery of therapeutic peptides. This article assesses the intestinal permeation enhancement action of over 250 PEs that have been tested in intestinal delivery models. In depth analysis of pre-clinical data is presented for PEs as components of proprietary delivery systems that have progressed to clinical trials. Given the importance of co-presentation of sufficiently high concentrations of PE and peptide at the small intestinal epithelium, there is an emphasis on studies where PEs have been formulated with poorly permeable molecules in solid dosage forms and lipoidal dispersions.

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Author and article information

Journal

Journal ID (nlm-ta): Pharmaceutics

Journal ID (iso-abbrev): Pharmaceutics

Journal ID (publisher-id): pharmaceutics

Title: Pharmaceutics

Publisher: MDPI

ISSN (Electronic): 1999-4923

Publication date (Electronic): 15 July 2019

Publication date Collection: July 2019

Volume: 11

Issue: 7

Electronic Location Identifier: 339

Affiliations

[1 ]School of Pharmacy, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland

[2 ]Department of Biomolecular Sciences, University of Urbino Carlo Bo, Piazza del Rinascimento 6, 61029 Urbino (PU), Italy

[3 ]IDentity, 19 Cavendish Crescent North, The Park, Nottingham NG7 1BA, UK

Author notes

[* ]Correspondence: sammaher@ 123456rcsi.com (S.M.); luca.casettari@ 123456uniurb.it (L.C.); lisbeth.illum@ 123456illumdavis.com (L.I.)

Author information

Sam Maher https://orcid.org/0000-0002-0856-1035

Luca Casettari https://orcid.org/0000-0001-6907-8904

Article

Publisher ID: pharmaceutics-11-00339

DOI: 10.3390/pharmaceutics11070339

PMC ID: 6680553

PubMed ID: 31311173

SO-VID: 8dc54b13-5d20-4b57-bed1-b70a5924e9ca

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Transmucosal Absorption Enhancers in the Drug Delivery Field

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RNA drug delivery

Most cited references 46

Ionic liquids for oral insulin delivery

Orally Absorbed Cyclic Peptides.

Intestinal permeation enhancers for oral peptide delivery.

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