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 90 years ago, the oral delivery of macromolecular drugs (> 1000 g/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.

Introduction

The first attempt to deliver insulin orally in humans was undertaken as early as 1922, only 1 year after the discovery of insulin by Drs. Frederick Banting and Charles Best [1], when increasing doses of insulin were given orally to a single diabetes patient. The results were negative, and already in this first study, the critical challenges of oral protein delivery became apparent: poor and variable absorption, and low efficacy compared with subcutaneous injection. Although the interest and efforts in the oral delivery of biomacromolecules have intensified over the past two decades, safely and effectively delivering high-molecular-weight substrates via the oral route remains highly challenging for formulation scientists [2], [3].

The gastrointestinal (GI) tract is a hostile environment for biomacromolecules because it is evolutionarily optimized to break down nutrients and deactivate pathogens. The highly acidic pH in the stomach results in the protonation of proteins and their unfolding, which exposes more motifs that are recognized by protein-degrading enzymes [4]. The enzymes in the stomach (pepsin) and small intestine (e.g., chymotrypsin, amino- and carboxypeptidases, RNases and DNases) cleave proteins and nucleic acids into smaller fragments and single units [4]. In the colon, enzymatic fermentation processes further degrade biomacromolecules [4]. Because therapeutically active biomacromolecules are equally affected by these processes, the fraction surviving these degradation processes is generally low and variable, especially in the presence of food [5]. The macromolecular drug needs to overcome multiple barriers designed to prevent the entry of dietary and bacterial antigens in order to reach the systemic compartment. To access the epithelial cell layer, the biomacromolecule firstly needs to diffuse through the mucus layer covering the intestinal epithelium [5]. The latter is another important barrier, as the tight junctions which seal the epithelial cells restrict the paracellular transport (i.e., the passage between cells) to small molecules and ions (< 600 Da) [6]. The transcytotic pathway (i.e., the passage across the cell in an endocytotic vesicle) is mediated by luminally expressed endocytotic receptors (e.g., vitamin B12 receptor, transferrin receptor), and therefore necessitates conjugation to the respective ligands in order to be exploited in drug delivery [7]. Another access point to the systemic compartment is the phagocytotic M-cells of Peyer's patches which sample luminal antigens and can take up particular substrates in the low micrometer range [8]. However, the proportion of M-cells in the gut epithelium is small and varies greatly between species, which complicates predictions of absorption in humans based on animal data [9].

Not surprisingly, only six biomacromolecules have been approved by the Food and Drug Administration (FDA) for oral delivery: two locally and two systemically delivered peptides, one locally delivered non-peptidic macrocycle, and one locally delivered protein mixture. However, several orally applied formulations of proteins, peptides, and nucleic acids are currently under clinical evaluation. Often, these formulations contain at least one of the following excipients (Fig. 1): an enteric coating and/or protease inhibitors to prevent drug degradation and permeation enhancers to enable paracellular transport of macromolecules [10], [11]. Mechanistically, absorption enhancement can be achieved by mechanically disrupting tight junctions or the plasma membrane, lowering mucus viscosity, and modulating tight junction-regulating signaling pathways [2]. Additional strategies for the oral delivery of biomacromolecules under clinical development include buccal delivery, utilizing carrier-mediated transcytosis, and local delivery to GI targets.

The overwhelming majority of currently approved oral drugs and clinical candidates exhibit a molecular weight of < 1000 Da [12]. Above this threshold, low bioavailability, inter- and intraindividual variability, food effects, and long-term safety concerns of bioavailability-enhancing excipients remain important challenges of oral delivery despite clear advances in knowledge after nearly 90 years of trial and error. In this review, we address orally applied biomacromolecular therapeutics (> 1000 Da) already marketed or under clinical investigation for local or systemic delivery with an emphasis on the drug formulations and the biopharmaceutical aspects. The oral delivery of vaccines will not be covered in this manuscript, and the readers are referred to other recent reviews for more information on this topic [13], [14], [15], [16].