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Challenges for the oral delivery of macromolecules

Nature Reviews Drug Discovery volume 2, pages 289–295 (2003)Cite this article

Key Points

  • Macromolecules comprise a growing group of new pharmaceutical products with the potential to treat diseases that heretofore have had no effective therapeutic options.

  • To date, the therapeutic application of these drugs has been limited because they are effective only when administered parenterally.

  • Since the discovery of insulin and heparin in the early 1900s, there has been keen interest in solving the problem of orally delivering macromolecules safely and effectively. Various approaches have been investigated including altering the intestinal membrane, targeting intestinal transport mechanisms, chemically altering the drug and carrier-assisted transport mechanisms.

  • To date, the most promising approach has been the carrier-assisted approach, which has advanced seven different macromolecules or highly charged small molecules human proof-of-concept testing.

Abstract

The rapid integration of new technologies by the pharmaceutical industry has resulted in numerous breakthroughs in the discovery, development and manufacturing of pharmaceutical products. In particular, the commercial-scale production of high-purity recombinant proteins has resulted in important additions to treatment options for many large therapeutic areas. In addition to proteins, other macromolecules, such as the animal-derived mucopolysacharide heparins, have also seen dramatic growth as injectable pharmaceutical products. To date, macromolecules have been limited as therapeutics by the fact that they cannot be orally delivered. This article will address the current status and future possibilities of oral macromolecular drug delivery.

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Figure 1: Schematic representation of drug diffusion across a transport barrier.
Figure 2: Pathways of oral drug absorption.
Figure 3: Structure of insulin and hexyl-insulin monoconjugate 2 (HIM2).
Figure 4: Effect of oral insulin, formulated using eligen technology, on fasting plasma glucose in a Phase I clinical study (N = 8).
Figure 5: Results from a Phase I clinical study with Emisphere oral heparin (N = 10).

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Authors and Affiliations

  1. Emisphere Technologies Inc, 765 Old Saw Mill River Road, Tarrytown, 10591, New York, USA

    Michael Goldberg & Isabel Gomez-Orellana

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  1. Michael Goldberg
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Correspondence to Michael Goldberg or Isabel Gomez-Orellana.

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DATABASES

LocusLink

Insulin

tissue plasminogen activator

FURTHER INFORMATION

Encyclopedia of Life Sciences

History of insulin

Glossary

BIOAVAILABILITY

The extent to which a drug becomes available in the bloodstream, or at the target tissue, after administration.

LIPOPHILICITY

The extent of insolubility in water or resistance to hydration of a molecule or chemical entity.

HYDROPHILICITY

The extent of solubility in water or the ability to be hydrated of a molecule or chemical entity.

TRANSCYTOSIS

The process by which polarized cells transport certain molecules by engulfing them into vesicles that are released at the opposite side of the cells.

ENTEROCYTES

Epithelial cells that form the gastrointestinal wall.

TIGHT JUNCTION

An intercellular junction that seals together adjacent epithelial cells, preventing the passage of substances through the spaces in between cells.

FUNCTIONAL GROUP

A chemical group with specific properties attached to a molecule.

PHARMACOKINETICS

The way in which drugs are absorbed, distributed, localized in tissues, metabolized and excreted over a period of time.

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Goldberg, M., Gomez-Orellana, I. Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov 2, 289–295 (2003). https://doi.org/10.1038/nrd1067

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