Oral Delivery Of Macromolecules Research Articles

Fully Biodegradable Elastomer-Based Device for Oral Macromolecule Delivery.

Oral devices, such as foil-type devices, show great potential for the delivery of poorly permeable macromolecules by enabling unidirectional release of the loaded pharmaceutical composition in close proximity to the epithelium in the small intestine or colon. However, one of the primary concerns associated with the use of foil-type devices so far has been the utilization of nonbiodegradable elastomers in the fabrication of the devices. Therefore, research into biodegradable substitute materials with similar characteristics enables drug delivery in a sustainable and environmentally friendly manner. In this study, a biodegradable elastomer, polyoctanediol citrate (POC), was synthesized via a one-pot reaction, with subsequent purification and microscale pattern replication via casting. The microstructure geometry was designed to enable fabrication of foil-type devices with the selected elastomer, which has a high intrinsic surface free energy. The final elastomer was demonstrated to have an elastic modulus ranging up to 2.2 ± 0.1 MPa, with strain at failure up to 110.1 ± 1.5%. Devices were loaded with acetaminophen and enterically coated, demonstrating 100% release at 2.5 h, following dissolution for 1 h in 0.1 M hydrochloric acid and 1.5 h in pH 6.8 phosphate-buffered saline. The elastomer demonstrated promising properties based on mechanical testing, surface free energy evaluation, and degradation studies.

More Than Metal–Organic Frameworks: Intestinal Villi‐Inspired Device as a Therapeutic Platform for Oral Enzyme Delivery

AbstractMacromolecules are fragile when orally administered. An intestinal villi‐inspired metal–organic frameworks (MOFs)‐based smart pill with multiple advantages is developed to offer a salubrious solution for oral delivery of enzymes. In the pill, MOFs accommodate enzymes as carriers exhibit excellent in vitro and in vivo catalytic activities with good oral biosafety, displaying supreme protection from degradation or inhibition in simulated gastrointestinal tract and high tolerance in simulated gastric acid and intestinal fluid. Moreover, the bioinspired pill possesses the morphology of the small intestinal villi obtained via an in situ moulding strategy for enhancing biocatalysis, which is attributed to the increase of surface area. Collaboratively, the adhesive layer renders increased smart pill in vivo retention, which is verified in pigs, providing a clinically translational and versatile platform for long‐term oral macromolecule delivery.

Mucus-penetrating and permeation enhancer albumin-based nanoparticles for oral delivery of macromolecules: Application to bevacizumab

The oral administration of therapeutic proteins copes with important challenges (mainly degradation and poor absorption) making their potential therapeutic application extremely difficult. The aim of this study was to design and evaluate the potential of the combination between mucus-permeating nanoparticles and permeation enhancers as a carrier for the oral delivery of the monoclonal antibody bevacizumab, used as a model of therapeutic protein. For this purpose, bevacizumab was encapsulated in PEG-coated albumin nanoparticles as a hydrophobic ion-pairing complex with either sodium deoxycholate (DS) or sodium docusate (DOCU). In both cases, complex formation efficiencies close to 90% were found. The incorporation of either DS or DOCU in PEG-coated nanoparticles significantly increased their mean size, particularly when DOCU was used. Moreover, the diffusion in mucus of DOCU-loaded nanoparticles was significantly reduced, compared with DS ones. In a C. elegans model, DS or DOCU (free or nanoencapsulated) disrupted the intestinal epithelial integrity, but the overall survival of the worms was not affected. In rats, the relative oral bioavailability of bevacizumab incorporated in PEG-coated nanoparticles as a complex with DS (B-DS-NP-P) was 3.7%, a 1000-fold increase compared to free bevacizumab encapsulated in nanoparticles (B-NP-P). This important effect of DS may be explained not only by its capability to transiently disrupt tight junctions but also to their ability to increase the fluidity of membranes and to inhibit cytosolic and brush border enzymes. In summary, the current strategy may be useful to allow the therapeutic use of orally administered proteins, including monoclonal antibodies.Graphical

A self-unfolding proximity enabling device for oral delivery of macromolecules

Oral delivery of macromolecules remains highly challenging due to their rapid degradation in the gastrointestinal tract and poor absorption across the tight junctions of the epithelium. In the last decade, researchers have investigated several medical devices to overcome these challenges using various approaches, some of which involve piercing through the intestine using micro and macro needles. We have developed a new generation of medical devices called self-unfolding proximity enabling devices, which makes it possible to orally deliver macromolecules without perforating the intestine. These devices protect macromolecules from the harsh conditions in the stomach and release their active pharmaceutical ingredients in the vicinity of the intestinal epithelium. One device version is a self-unfolding foil that we have used to deliver insulin and nisin to rats and pigs respectively. In our study, this device has shown a great potential for delivering peptides, with a significant increase in the absorption of solid dosage of insulin by ∼12 times and nisin by ∼4 times in rats and pigs, respectively. With the ability to load solid dosage forms, our devices can facilitate enhanced absorption of minimally invasive oral macromolecule formulations.

Rocket-Inspired Effervescent Motors for Oral Macromolecule Delivery.

Oral administration is among the most convenient ways with good patient compliance for drug delivery; while it remains a challenge to achieve desirable bioavailability of most macromolecules due to the complex gastrointestinal barriers. Here, inspired by the structure and function of rocket, a novel micromotor delivery system is presented with scaled-down rocket-like architecture and effervescent-tablets-derived fuel for efficient oral macromolecule delivery by penetrating intestinal barrier. These rocket-inspired effervescent motors (RIEMs) are composed of sharp needle tips for both loading cargoes and efficient penetrating, and tail wings for loading effervescent powders and avoiding perforation. When exposed to a water environment, the effervescent fuel generates intensive CO2 bubbles to propel the RIEMs to move at high speed. Thus, the RIEMs with their sharp tip can inject into the surrounding mucosa for effective drug release. Furthermore, benefiting from their tail-wing design, perforation can be effectively avoided during the injection process, ensuring the safety of the RIEMs in gastrointestinal active delivery. Based on these advantages, it is demonstrated that the RIEMs can efficiently move and stab into the intestinal mucosa for insulin delivery, exhibiting efficacy in regulating blood sugar glucose in a diabetic rabbit model. These features indicate that these RIEMs are versatile and valuable for clinical oral delivery of macromolecules.

Quality by Design-Based Development of Solid Self-Emulsifying Drug Delivery System (SEDDS) as a Potential Carrier for Oral Delivery of Lysozyme.

For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: -4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (-0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.

In Vivo Mechanism of Action of Sodium Caprate for Improving the Intestinal Absorption of a GLP1/GIP Coagonist Peptide

Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect in vivo remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs. Furthermore, we investigated the mechanism of action (MoA) of C10 for improving the intestinal absorption of the LY peptide in vivo via live imaging of the rat intestinal epithelium and tissue distribution of the LY peptide in minipigs. The LY peptide showed higher proteolytic stability in pancreatin and was a monomer in solution compared to that in semaglutide. C10 increased in vitro permeability in the minipig intestinal organoid monolayer to a greater extent for the LY peptide than for semaglutide. In the rat jejunal closed-loop model, C10 increased the absorption of LY peptide better than that of semaglutide, which might be attributed to higher in vitro proteolytic stability and permeability of the LY peptide. Using confocal live imaging, we observed that C10 enabled the rapid oral absorption of a model macromolecule (FD4) in the rat intestine. In the duodenum tissues of minipigs, C10 was found to qualitatively reduce the tight junction protein level and allow peptide uptake to the intestinal cells. C10 decreased the transition temperature of the artificial lipid membrane, indicating an increase in membrane fluidity, which is consistent with the above in vivo imaging results. These data indicated that the LY's favorable physicochemical properties combined with the effects of C10 on the intestinal mucosa resulted in an ∼2% relative bioavailability in minipigs.

Aptamer-modified M cell targeting liposomes for oral delivery of macromolecules

There is an urgent demand for non-invasive and high compliance delivery systems of macromolecules for long-term therapy. However, oral administration of macromolecules is hindered by low permeability and instability in the gastrointestinal (GI) tract. Therefore, we developed a novel aptamer-modified liposomes (Apt-Lip) with M cell targeting for oral delivery of exenatide (EXT). Firstly, we optimized aptamers to M cells by Cell-SELEX and aptamer truncations. The selected aptamer T-M3 (Apt-T-M3) with high binding affinity (Kd = 176 ± 108 nM) and specificity was modified on the surface of liposomes for targeting M cells. Liposomes were formulated by microfluidics system and characterized in terms of morphology, hydrodynamic diameter, zeta potential, and the efficiency of encapsulation. In comparison with non-targeting liposomes, cell uptake in M cells was significantly enhanced by Apt-Lip. Similarly, the transport efficiency of EXT was 2-fold increase using Apt-Lip in M cells. Additionally, the transepithelial electrical resistance (TEER) of M cell monolayers is significantly reduced. In ex vivo intestinal absorption study, Apt-Lip was proved to possess significantly high intestinal absorption in Peyer’s patches (PPs) and M cells-specific targeting capacity. Consequently, Apt-Lip promoted the EXT transport could base not only on M cell mediated transport, but also on enhancement of paracellular permeability. In conclusion, the present study supported Apt-Lip as a promising M cell targeted delivery system for oral delivery of macromolecules.

Dynamic omnidirectional adhesive microneedle system for oral macromolecular drug delivery.

Oral drug administration remains the preferred route for patients and health care providers. Delivery of macromolecules through this route remains challenging because of limitations imposed by the transport across the gastrointestinal epithelium and the dynamic and degradative environment. Here, we present the development of a delivery system that combines physical (microneedle) and nonphysical (enhancer) modes of drug delivery enhancement for a macromolecule in a large animal model. Inspired by the thorny-headed intestinal worm, we report a dynamic omnidirectional mucoadhesive microneedle system capable of prolonged gastric mucosa fixation. Moreover, we incorporate sodium N-[8-(2-hydroxybenzoyl) amino] caprylate along with semaglutide and demonstrate enhanced absorption in swine resistant to physical displacement in the gastric cavity. Meanwhile, we developed a targeted capsule system capable of deploying intact microneedle-containing systems. These systems stand to enable the delivery of a range of drugs through the generation and maintenance of a privileged region in the gastrointestinal tract.

Dip-Printed Microneedle Motors for Oral Macromolecule Delivery

Micromotors have demonstrated values in drug delivery, and recent attempts focus on developing effective approaches to generate functional micromotors to improve this area. Here, with the integration of microfluidic droplet printing and wettability-induced drawing photolithography, we present an innovative spatiotemporal serial multistep dip-printing strategy to generate novel independent microneedle motors (IMNMs) for orally delivering macromolecular drugs. As the strategy combines the advantages of the hydrophilic wettability, extension effects, and capillary effects, the IMNMs with an oblate basement and a needle-shaped head or a core-shell structured multicomponent head can be created by simply printing pregel droplets layer by layer, following with simultaneous wiredrawing and solidification. Owing to the polarized magnetic particles in the bottom basement and the rapidly dissolvable polymers as the middle basement, the resultant IMNMs can respond to magnetic fields, move to desired places under a magnet, penetrate tissue-like substrates, induce head-basement separation, and leave only the needles for cargo release. Based on these features, we have demonstrated that these IMNMs can deliver insulin via intestinal tracts to realize effective blood glucose control of diabetic rabbit models. These results indicate the practical values and bright future of the dip-printing stratagem and these IMNMs in clinical applications.

Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery

The efficacy of oral insulin drug delivery is seriously hampered by multiple gastrointestinal barriers, especially transepithelial barriers, including apical endocytosis, lysosomal degradation, cytosolic diffusion and basolateral exocytosis. In this study, a functional nanoparticle (PG-FAPEP) with dual-modification was constructed to sequentially address these important absorption obstacles for improved oral insulin delivery. The dual surface decorations folate and charge-convertible tripeptide endowed PG-FAPEP with the ability to target the apical and basolateral sides of enterocytes, respectively. After fast diffusion across the mucus layer, PG-FAPEP could be efficiently internalized into epithelial cells via a folate receptor-mediated pathway and subsequently became positively charged in acidic lysosomes due to the surface tripeptide, triggering the proton sponge effect to escape lysosomes. When entering the cytosolic medium, PG-FAPEP was converted to neutral charge again, attenuating intracellular adhesion, and gained improved motility toward the basolateral side. Finally, the tripeptide helped PG-FAPEP recognize the proton-coupled oligopeptide transporter (PHT1) in the basolateral membrane, boosting intact exocytosis across intestinal epithelial cells. The in vivo studies further verified that PG-FAPEP could traverse the intestinal epithelium by folate receptor-mediated endocytosis, lysosomal escape, and PHT1-mediated exocytosis, exhibiting a high oral insulin bioavailability of 14.3% and a prolonged hypoglycemic effect. This formulation addresses multiple absorption barriers on demand with a simple dual-modification strategy. Therefore, these features allow PG-FAPEP to unleash the potential of oral macromolecule delivery.

Bacteria-Based Microdevices for the Oral Delivery of Macromolecules.

The oral delivery of macromolecules is quite challenging due to environmental insults and biological barriers encountered along the gastrointestinal (GI) tract. Benefiting from their living characteristics, diverse bacterial species have been engineered as intelligent platforms to deliver various therapeutics. To tackle difficulties in oral delivery, innovative bacteria-based microdevices have been developed by virtue of advancements in synthetic biology and nanotechnology, with aims to overcome the instability and short half-life of macromolecules in the GI tract. In this review, we summarize the main classes of macromolecules that are produced and delivered through the oral ingestion of bacteria and bacterial derivatives. Furtherly, we discuss the engineering strategies and biomedical applications of these living microdevices in disease diagnosis, bioimaging, and treatment. Finally, we highlight the advantages as well as the limitations of these engineered bacteria used as platforms for the oral delivery of macromolecules and also propose their potential for clinical translation. The results summarized in this review article would contribute to the invention of next-generation bacteria-based systems for the oral delivery of macromolecules.

The Centenary of the Discovery of Insulin: An Update on the Quest for Oral Delivery

Not many topics in drug delivery science have exercised so many pharmaceutical, formulation, and bioengineering minds than the oral delivery of macromolecules, especially when insulin is the focus. The year 2021 marks a hundred years since the discovery of insulin by Banting and Best to treat Type 1 diabetes. Repeated efforts to deliver it orally since then have met with failure, with particular disappointment resulting from encouraging preclinical studies in the 1980s. Here, the barriers to synthesizing successful oral inulin formulations are discussed. It is apparent that this peptide has chemistry and pharmacology features that make its oral delivery one of the toughest challenges in delivery science. At this seminal point in its history, the question is whether oral delivery of insulin will ever be possible, or even if this quest is still desirable?

Design of a self-unfolding delivery concept for oral administration of macromolecules

Delivering macromolecular drugs, e.g. peptides, to the systemic circulation by oral administration is challenging due to their degradation in the gastrointestinal tract and low transmucosal permeation. In this study, the concept of an oral delivery device utilizing an elastomeric material is presented with the potential of increasing the absorption of peptides, e.g. insulin. Absorption enhancement in the intestine is proposed as a result of self-unfolding of a polydimethylsiloxane foil upon release from enteric coated capsules. A pH-sensitive polymer coating prevents capsule disintegration until arrival in the small intestine where complete unfolding of the elastomeric foil ensures close contact with the intestinal mucosa. Foils with close-packed hexagonal compartments for optimal drug loading are produced by casting against a deep-etched silicon master. Complete unfolding of the foil upon capsule disintegration is verified in vitro and the insulin release profile of the final delivery device confirms insulin protection at gastric pH. In vivo performance is evaluated with the outcome of quantifiable plasma insulin concentrations in all rats receiving duodenal administration of the novel delivery device. By taking advantage of elastomeric material properties for drug delivery, this approach might serve as inspiration for further development of commercially viable biocompatible devices for oral delivery of macromolecules.

Hydrophilic and Electroneutral Nanoparticles to Overcome Mucus Trapping and Enhance Oral Delivery of Insulin.

The oral delivery of macromolecules using nanoparticles is limited by secreted mucus, resulting in low contact or internalization via intestinal cells and, thus, both mucus trapping and further low cellular uptake need to be overcome. Here, hydrophilic and electroneutral nanoparticles were developed to overcome mucus trapping and enhance the oral delivery of macromolecules. Mesoporous silica nanoparticles (MSNs) were synthesized and modified with a hydrophilic block polymer (poly(lactic acid)-methoxy poly(ethylene glycol), PLA-PEG), and then an overall electroneutrality and promoted cellular uptake were achieved by sequential modification with cell-penetrating peptides (CPPs). Reduced hydrophobic and electrostatic interactions of MSN@PLA-PEG-CPP with mucus decreased mucus trapping by 36.0%, increased the cellular uptake of MSN@PLA-PEG-CPP by 2.3-folds in mucous conditions via active heparan sulfate proteoglycan receptor (HSPG)-mediated and caveolae-mediated endocytosis and electrostatic interactions. Furthermore, insulin, a model macromolecular drug, was successfully loaded into the nanoparticles (INS@MSN@PLA-PEG-CPP). Compared with insulin solution, in vitro cellular uptake in mucous conditions and in vivo pharmacodynamic effects were significantly increased by 9.1- and 14.2-folds, respectively. As well, all nanoparticles with or without insulin loading presented negligible in vitro and in vivo toxicity. Herein, hydrophilic and electroneutral nanoparticles with sequential PEG and CPP modification could promote cellular uptake against mucus trapping and finally show good prospects for oral insulin delivery.

Design and characterization of chitosan/citrate films as carrier for oral macromolecule delivery

The oral delivery of biopharmaceuticals requires the including of absorption enhancer, protease inhibitor and a suitable carrier system. The aim of the present work was to formulate and characterize chitosan solutions/films incorporating citric acid (CA) as potential excipient in comparison to the well-known acetic acid (AA)-based films as a reference. Films were made by the solvent casting method with/without glycerol (G), propylene glycol (PG) and polyethylene glycol (PEG-400) as plasticizers. The minimum film forming temperature (MFFT) of the prepared solutions, film thickness, hardness/deformation, mucoadhesivity, moisture content, FT-IR spectra and surface free energy (SFE) were investigated. Chitosan has been reported as a safe and effective paracellular absorption enhancer for hydrophilic macromolecules, therefore there would be more rationale for incorporating CA as a solubility enhancer, a permeation enhancer and an enzyme inhibitor. CA shows good cross-linking, an ideal plasticizing property and increases both tensile strength and mucoadhesivity, thus its incorporation simplifies the formulation while improving effectiveness. We concluded that CA (3.5, 4 and 5 w/v %)-based chitosan solution could be used as a novel coating/subcoating polymer for oral macromolecule delivery, or as oral mucoadhesive films.

Materials for oral delivery of proteins and peptides

Throughout history, oral administration has been regarded as the most convenient mode of drug delivery, as it requires minimal expertise and invasiveness. Although oral delivery works well for small-molecule drugs, oral delivery of macromolecules (particularly proteins and peptides) has been limited by acidic conditions in the stomach and low permeability across the intestinal epithelium. Accordingly, the large numbers of biologic drugs that have become available in the past 10 years typically require administration by injection or infusion. As such, a renewed emphasis has been placed on the development of novel materials that overcome the physiological challenges of oral delivery for macromolecular agents. This Review provides an overview of physiological barriers to the oral delivery of biologics and highlights the advances made in materials across various length scales, from small molecules to macroscopic devices. This Review also describes the current status of materials for oral delivery of protein and peptide drugs. New materials, beyond those that have already obtained regulatory approval, are needed to improve the bioavailability of orally administered proteins. In this Review, barriers to the oral delivery of protein-based therapies are discussed, along with the current translational landscape and state of the art of materials for oral protein delivery.

Evaluation of Sucrose Laurate as an Intestinal Permeation Enhancer for Macromolecules: Ex Vivo and In Vivo Studies.

Oral delivery of macromolecules requires permeation enhancers (PEs) adaptable to formulation. Sucrose laurate (SL) (D1216), a food grade surfactant, was assessed in Caco-2 monolayers, isolated rat intestinal tissue mucosae, and rat intestinal instillations. Accordingly, 1 mM SL increased the apparent permeability coefficient (Papp) of [14C]-mannitol and reduced transepithelial electrical resistance (TEER) across monolayers. It altered expression of the tight junction protein, ZO-1, increased plasma membrane potential, and decreased mitochondrial membrane potential in Caco-2 cells. The concentrations that increased flux were of the same order as those that induced cytotoxicity. In rat colonic tissue mucosae, the same patterns emerged in respect to the concentration-dependent increases in paracellular marker fluxes and TEER reductions with 5 mM being the key concentration. While the histology revealed some perturbation, ion transport capacity was retained. In rat jejunal and colonic instillations, 50 and 100 mM SL co-administered with insulin induced blood glucose reductions and achieved relative bioavailability values of 2.4% and 8.9%, respectively, on a par with the gold standard PE, sodium caprate (C10). The histology of the intestinal loops revealed little damage. In conclusion, SL is a candidate PE with high potential for emulsion-based systems. The primary action is plasma membrane perturbation, leading to tight junction openings and a predominant paracellular flux.

A luminal unfolding microneedle injector for oral delivery of macromolecules.

Insulin and other injectable biologic drugs have transformed the treatment of patients suffering from diabetes1,2, yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications3-5. Compared with subcutaneously administered drugs, oral formulations create less patient discomfort4, show greater chemical stability at high temperatures6, and do not generate biohazardous needle waste7. An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract8. We developed an ingestible capsule, termed the luminal unfolding microneedle injector, which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies, the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug, we showed that, when actuated, the luminal unfolding microneedle injector provided a faster pharmacokinetic uptake profile and a systemic uptake >10% of that of a subcutaneous injection over a 4-h sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.

Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10).

Salcaprozate sodium (SNAC) and sodium caprate (C10) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C10 acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small intestinal epithelia based on increased lipophilicity arising from non-covalent macromolecule complexation. More recently, an additional mechanism for SNAC associated with a pH-elevating, monomer-inducing, and pepsin-inhibiting effect in the stomach for oral delivery of semaglutide was advocated. Comparing the two surfactants, we found equivocal evidence for discrete mechanisms at the level of epithelial interactions in the small intestine, especially at the high doses used in vivo. Evidence that one agent is more efficacious compared to the other is not convincing, with tablets containing these PEs inducing single-digit highly variable increases in oral bioavailability of payloads in human trials, although this may be adequate for potent macromolecules. Regarding safety, SNAC has generally regarded as safe (GRAS) status and is Food and Drug Administration (FDA)-approved as a medical food (Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA), whereas C10 has a long history of use in man, and has food additive status. Evidence for co-absorption of microorganisms in the presence of either SNAC or C10 has not emerged from clinical trials to date, and long-term effects from repeat dosing beyond six months have yet to be assessed. Since there are no obvious scientific reasons to prefer SNAC over C10 in orally delivering a poorly permeable macromolecule, then formulation, manufacturing, and commercial considerations are the key drivers in decision-making.