Oral delivery of macromolecular drugs: Where we are after almost 100 years of attempts

Abstract

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.

A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

“…Oral delivery of proteins and peptides has attracted great attention in recent years, 1 and new breakthroughs in the field of nanotechnology and biology have opened a new avenue to meet this goal. Among the large number of peptides and hydrophilic compounds, insulin is the main peptide whose oral delivery has been the dream of many accredited universities and pharmaceutical companies around the world.…”

“…1 H NMR studies revealed the successful cross-linking of CS with PEG as well as the attachment of the peptide sequence to the polysaccharide structure of CS polymer ( Figure 5). The chemical shift at δ 7.2 is related to the aromatic protons of the phenylalanine moiety in the structure of CPP confirming the presence of CPP in the structure of CPP-conjugated CS NPs.…”

Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials

“…In making assessments of the clinical data, we note that many of the companies claiming clinical progress have not actually published the data in peer-reviewed journals or have even have updated the Clinical Trials.gov website, so accurate interpretation is difficult; this problem was also remarked upon in a recent oral insulin review [194]. Finally, we note that a similar but complementary review [195] has just been published following our submission; its focus was primarily on oral macromolecule formulation compositions, but with a greater emphasis formulations designed for localization in intestinal regions and less on the clinical aspects.…”

Exploration of the Key Factors for Optimizing the <i>in Vivo</i> Oral Delivery of Insulin by Using a Noncovalent Strategy with Cell-Penetrating Peptides

“…[1][2][3] Diabetes patients can appropriately choose injectable types of insulin formulations; however, more convenient forms of insulin that can be administered via noninvasive routes, such as oral administration, have not yet been developed because of poor absorption through mucosal regions. [4][5][6][7] To further improve the QOL and compliance of patients, we aimed to develop a noninvasive form of insulin by using pharmaceutical technologies and drug delivery systems. Moreover, the oral route of insulin absorption has another advantage as insulin absorbed from the intestine first passes through the liver, similarly to endogenous insulin secreted to the portal vein; therefore, oral insulin can circumvent the risk of hypoglycemia.…”