Abstract
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.Graphical abstract
Highlights
The increasing attention that therapeutic proteins and peptides are gaining in the pharmaceutical field is illustrated by the hundreds of them that have been approved by the FDA during the last decades [1, 2]
The goal of this work was the rational design, development, and characterization of a nanoemulsion that fulfills the main requirements for an efficient oral peptide administration, namely, (i) possibility of producing a mono-dispersed population of carrier with nanometric size in a reproducible way, (ii) efficient HM-insulin loading, (iii) colloidal stability in simulated intestinal fluids and appropriate miscibility with them, (iv) mucodiffusive properties, (v) ability to interact with the intestinal cells without causing cytotoxic effects, and (vi) ability to lead an adequate pharmacological response once administered in vivo
Using the HM-insulin, we expected that its hydrophobic domains (GRAVY ≈ − 0.0333) would favor its entrapment within the nanoemulsion
Summary
The increasing attention that therapeutic proteins and peptides are gaining in the pharmaceutical field is illustrated by the hundreds of them that have been approved by the FDA during the last decades [1, 2] The attractiveness of these macromolecular drugs, which have opened up doors to many new and powerful therapies, relies on their specificity and potency. Despite of this, these macromolecules exhibit severe biopharmaceutical limitations, i.e., instability, short half-life, and limited oral bioavailability, which restrict their efficient clinical exploitation. In recent years, an important number of phase III clinical trials [5,6,7] have been initiated, which in addition to the already approved products, i.e., salmon calcitonin on 2012 [8], octreotide on 2015 [9], and semaglutide on 2019 [10, 11], will stimulate new oral peptide delivery strategies
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