Nanocarriers for the oral administration of therapeutic macromolecules

Resumo

The high specificity and potency of therapeutic proteins/peptides have increasingly attracted the attention of the pharmaceutical research in the last decades. However, their efficient oral administration remains generally unviable due to their biopharmaceutical limitations (e.g., instability, limited bioavailability…). A strategy to overcome these drawbacks has relied on the design of biocompatible lipid-based nanocarriers able to protect their peptide cargo and enhance its absorption. According to these research challenges, the main goal of this work has been the generation of knowledge that could potentially contribute to make feasible the oral administration of peptides using lipid-based nanocarriers. The specific objective has been to study how the composition and surface properties of a lipid-based nanocarrier influence their capacity to load hydrosoluble peptides and their ability to overcome the biological barriers associated to the oral modality of administration. The first chapter provides an overview of the nanotechnologies mostly explored to produce lipid-based nanocarriers for protein/peptide delivery. The basic principles and the advantages/disadvantages of the most relevant techniques are discussed. Additionally, the main factors involved in their drug association capacity, along with the release profile of their cargo, are briefly analyzed. The second chapter describes a systematic study intended to elucidate what are the critical formulation parameters that influence the physicochemical properties of chitosan nanocapsules and their capacity to associate insulin glulisine, used as model peptide drug. The results obtained within the range of formulation conditions investigated, showed the interference of the polymer shell layers on the association of insulin to the nanocapsules. Other formulation parameters, e.g., type and concentration of surfactants had a minor effect on their physicochemical properties and loading capacity. Chapter 3 describes a systematic study aimed at investigating the influence of the nanocarriers’ surface properties on their interaction with several intestinal barriers. For this purpose, we selected a set of 9 lipid-based nanosystems comprising both, uncoated nanoemulsions and polymeric nanocapsules, which were obtained through the combination of different polymers (chitosan and polyarginine) and surfactants (poloxamer 188 and 407). Our results indicated that both, the polymer shell and the surfactants located at the oil/water interface may have either synergic or disruptive effects on the nanosystems’ capacity to overcome the intestinal barriers. For example, while the presence of the non-ionic surfactant poloxamer 407 in the uncoated nanoemulsion contributed to its stabilization, and improved its mucodiffusion, its use together with either chitosan or polyarginine had a limited effect on the nanocapsules performance. In Chapter 4 the specific objective was to develop and fully characterize a new nanoemulsion aimed to the oral administration of peptides using as model cargo a hydrophobically-modified insulin. The results showed that the nanoemulsion co-existed with a population of micelles (mixed system) and exhibited a 100 % of insulin association efficiency. In brief, this nanosystem showed a great stability and miscibility in bio-relevant media, acceptable mucodiffusive properties and ability to interact and enter the intestinal cells without remarkable cytotoxic effects. Finally, the promising behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate hypoglycemic response (≈ 20−30 %) following intestinal administration to rats. Overall, the knowledge disclosed in this thesis is expected to contribute to the rational design of delivery carriers intended to overcome the biological barriers associated to the oral administration of peptides.