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The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.

One of the main limitations of protein drugs is their restricted capacity to cross biological barriers. We have previously reported nanostructured complexes of insulin and modified octaarginine (C12-r8), enveloped by a polyethyleneglycol-polyglutamic acid (PEG-PGA) protective shell, and showed their capacity to overcome different barriers associated to the oral modality of administration. The objective of this work was to produce the said nanocomplexes with structurally diverse PEG-PGA shells, i.e. with different chain lengths and PEG substitution degrees, and comparatively analyze their PEG surface density and subsequent impact on their interaction with mucus glycoproteins and Caco-2 cells. The new PEG-PGA enveloped C12-r8-insulin nanocomplexes (ENCPs) exhibited a narrow size distribution (average size of 210-239 nm), a neutral surface charge and a 100% insulin association efficiency (final insulin loading of 16.5-29.6% w/w). Proton nuclear magnetic resonance ( 1 H NMR) analysis indicated the possibility to modulate the PEG density on the ENCPs from 6.7 to 44.5 PEG chains per 100 nm 2 . This increase in the ENCPs PEG surface density resulted in their reduced interaction with mucins in vitro, while their interaction with Caco-2 cells in vitro remained unaltered. Overall, these data indicate the capacity to tune the surface characteristics of the ENCPS in order to maximize the capacity of these nanocarriers to overcome barriers associated to mucosal surfaces.

Despite the convenience of the oral route for drug administration, the existence of different physiological barriers associated with the intestinal tract greatly lowers the bioavailability of many active compounds. We have previously suggested the potential polymeric nanocapsules, consisting of an oily core surrounded by a polymer shell, as oral drug delivery carriers. Here we present a systematic study of the influence of the surface properties of these nanocapsules on their interaction with the intestinal barriers. Two different surfactants, Pluronic®F68 (PF68) and F127 (PF127), and two polymeric shells, chitosan (CS) and polyarginine (PARG) were chosen for the formulation of the nanocapsules. We analyzed nine different combinations of these polymers and surfactants, and studied the effect of each specific combination on their colloidal stability, enzymatic degradation, and mucoadhesion/mucodiffusion. Our results indicate that both, the polymer shell and the surfactants located at the oil/water interface, influence the interaction of the nanocapsules with the intestinal barriers. More interestingly, according to our observations, the shell components of the nanosystems may have either synergic or disruptive effects on their capacity to overcome the intestinal barriers., (Copyright © 2018. Published by Elsevier B.V.)