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The oral route of administration is by far the most convenient route, especially in the treatment of chronic conditions. However, many therapeutics present formulation difficulties which make them unsuitable for oral delivery. Recently, we synthesized a denatured whey protein isolate (dWPI) bead entrapped with insulin. Our present goal was to assess the suitability of this delivery system to the delivery of other potential molecules, both hydrophilic and hydrophobic. Beads of 1.2–1.5 mm in diameter were entrapped with four payloads representing a range of solubilities. The water-soluble payloads were sodium fluorescein (SF) and FITC dextran 4000 Da (FD4), while the hydrophobic ones were Fast Green and curcumin. Encapsulation efficiency (EE) was 73%, 84%, 70%, and 83% for SF, FD4, Fast Green, and curcumin-loaded beads, respectively. The corresponding loading capacity for each bead was 0.07%, 1.1%, 0.75%, and 1.1%, respectively. Each payload produced different release profiles in simulated gastric fluid (SGF) and simulated intestinal fluids (SIF). SF released steadily in both SGF and SIF. FD4 and curcumin release was not substantial in any buffers, while Fast Green release was low in SGF and high in SIF. The differences in release behaviour were likely due to the varying properties of the payloads. The effect of proteolysis on beads suggested that enzymatic degradation of the whey bead may promote payload release. The beads swelled rapidly in SGF compared to SIF, which likely contributed to the release from the beads, which was largely governed by solvent diffusion and polymer relaxation. Our results offer a systematic examination of the behaviour of hydrophilic and hydrophobic payloads in a dWPI delivery system. These beads may be further designed to orally deliver poorly permeable macromolecules and poorly soluble small molecules of pharmaceutical interest.

In addition to their solubilizing properties, excipients used in lipid-based formulations can improve intestinal permeability of macromolecules. We determined whether admixing of medium-chain fatty acid (MCFA) permeation enhancers with a lipoidal excipient (Labrasol®) could potentiate transepithelial flux of a poorly permeable macromolecule (fluorescein isothiocyanate dextran 4 kDa [FD4]) across rat intestinal mucosae mounted in Ussing chambers. Low concentrations of sodium caprate (C10), sodium undecylenate (C11:1), or sodium laurate (C12) combined with Labrasol® increased the apparent permeability coefficient (Papp) of FD4 to values typically seen with higher concentrations of MCFAs or Labrasol® alone. For example, combination of C11:1 (0.5 mg/mL) with Labrasol® (1 mg/mL) increased the Papp of FD4 by 10- and 11-fold over the respective individual agents at the same concentrations where no enhancement was evident. The increased enhancement ratios seen with the combinations were associated with some perturbation in intestinal histology and with attenuation of an epithelial functional measure, carbachol-stimulated inward short-circuit current. In conclusion, combining three MCFAs separately with Labrasol® increased the Papp of FD4 to values greater than those seen for MCFAs or Labrasol® alone. Ultimately, this may permit lower concentrations of MCFA to be used in combination with other excipients in oral formulations of poorly permeable molecules. European Commission - European Regional Development Fund Irish Research Council Science Foundation Ireland AnaBio Technologies Ltd The Centre for Medical Devices (CURAM) European Regional Development Fund

Surfactant-based intestinal permeation enhancers (PEs) are constituents of several oral macromolecule formulations in clinical trials. This study examined the interaction of a test panel of surfactant-based-PEs with isolated rat colonic mucosae mounted in Ussing chambers in an attempt to determine if increases in transepithelial permeability can be separated from induction of mucosal perturbation. The aim was to establish assess if increases in permeability (i) intestinal permeability (the apparent permeability coefficient (Papp) of [14C]-mannitol), (ii) epithelial histology, and (iii) short-circuit current (ΔIsc) responses to a cholinomimetic (carbachol, CCh). Enhancement ratio increases for Papp values followed the order: C10 > C9 = C11:1 > a bile salt blend > sodium choleate > sucrose laurate > Labrasol® >C12E8 > C12 > Cremophor® A25 > C7 > sucrose stearate > Kolliphor® HS15 > Kolliphor® TPGS. Exposures that increased the Papp by ≥2-fold over 120 min were accompanied by histological damage in 94% of tissues, and by a decreased ΔIsc response to CCh of 83%. A degree of separation between the increased Papp of [14C]-mannitol, histological damage, and diminution of the ΔIsc response to CCh was observed at selected PE concentrations (e.g. Labrasol® at 2 mg/mL). Overall, this surfactant-based PE selection caused transcellular perturbation at similar concentrations to those that enhanced permeability. European Commission - European Regional Development Fund Irish Research Council Science Foundation Ireland AnaBio Technologies Ltd

In addition to their solubilizing properties, excipients used in lipid-based formulations can improve intestinal permeability of macromolecules. We determined whether admixing of medium-chain fatty acid (MCFA) permeation enhancers with a lipoidal excipient (Labrasol

Two food-derived ACE inhibitory peptides, Ile-Pro-Pro (IPP) and Leu-Lys-Pro (LKP), may have potential as alternative treatments for treatment of mild- or pre-hypertension. Lack of stability to secretory and intracellular peptidases and poor permeability across intestinal epithelia are typical limiting factors of oral delivery of peptides. The stability of IPP and LKP was confirmed in vitro in rat intestinal washes, and intestinal and liver homogenates over 60min. A positive protein control for peptidases, insulin, was significantly digested in each format over the same period. Neither tripeptide showed cytotoxic activity on Caco-2 and Hep G2 cells using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, even after chronic exposure. The basal Papp of fluorescein isothiocyanate (FITC)-labeled IPP and FITC-LKP across isolated rat jejunal and colonic mucosae were low, but were significantly increased in each tissue type by the medium chain fatty acids (MCFA) permeation enhancers, sodium caprate (C10) and the sodium salt of 10-undecylenic acid (uC11). IPP and LKP were therefore stable against intestinal and liver peptidases and were non-cytotoxic; their Papp values across rat intestinal mucosae were low, but could be increased by MCFA. There is potential to make on oral dosage form once in vivo pharmacology is confirmed. Department of Agriculture, Food and the Marine

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. European Commission Horizon 2020 Science Foundation Ireland SANOFI-AVENTIS Recherche & Development French National Agency of Research and Technology CÚRAM Center for Medical Devices