Oral Delivery of Macromolecular Drugs: Where We Are After Almost 100years of Attempts

Adv Drug Deliv Rev. 2016 Jun 1;101:108-121. doi: 10.1016/j.addr.2016.01.010. Epub 2016 Jan 27.


Since the first attempt to administer insulin orally in humans more than 90years ago, the oral delivery of macromolecular drugs (>1000g/mol) has been rather disappointing. Although several clinical pilot studies have demonstrated that the oral absorption of macromolecules is possible, the bioavailability remains generally low and variable. This article reviews the formulations and biopharmaceutical aspects of orally administered biomacromolecules on the market and in clinical development for local and systemic delivery. The most successful approaches for systemic delivery often involve a combination of enteric coating, protease inhibitors and permeation enhancers in relatively high amounts. However, some of these excipients have induced local or systemic adverse reactions in preclinical and clinical studies, and long-term studies are often missing. Therefore, strategies aimed at increasing the oral absorption of macromolecular drugs should carefully take into account the benefit-risk ratio. In the absence of specific uptake pathways, small and potent peptides that are resistant to degradation and that present a large therapeutic window certainly represent the best candidates for systemic absorption. While we acknowledge the need for systemically delivering biomacromolecules, it is our opinion that the oral delivery to local gastrointestinal targets is currently more promising because of their accessibility and the lacking requirement for intestinal permeability enhancement.

Keywords: Biologics; High molecular weight; Oral bioavailability; Oral drug delivery; Permeation enhancers; Protease inhibitors.

Publication types

  • Review

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Excipients / adverse effects
  • Humans
  • Insulin / administration & dosage
  • Insulin / pharmacokinetics
  • Intestinal Absorption
  • Macromolecular Substances / administration & dosage*
  • Macromolecular Substances / pharmacokinetics*
  • Peptides / administration & dosage
  • Peptides / pharmacokinetics
  • Pharmaceutical Preparations / administration & dosage*
  • Risk Assessment


  • Excipients
  • Insulin
  • Macromolecular Substances
  • Peptides
  • Pharmaceutical Preparations