Influence of the surface properties of nanocapsules on their interaction with intestinal barriers

Abstract

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.

Introduction

The oral route is one of the most accepted routes for the administration of drugs, especially in the case of chronic treatments. Despite having an adequate patient compliance, this route of administration has several well-known physiological barriers that hamper the administration of many drugs. When administrated orally, the drugs must overcome several hurdles, such as their potential degradation by the intestinal enzymes, their instability in the presence of high ionic forces at different pHs, and their difficulty to pass through the intestinal mucosa [1], [2]. The existence of all these physiological barriers influences particularly the bioavailability of certain active substances (e.g., peptides and proteins) after oral administration and, hence, their potential therapeutic effect [3], [4], [5], [6].

Some of the strategies proposed to improve the oral bioavailability of peptides and proteins refer to the incorporation into their formulation of absorption enhancers or enzyme inhibitors [7], [8], [9], [10], [11], [12], [13], [14]. This variety of formulation strategies has opened new avenues for the increasing number of peptidic drugs in industry pipelines [15], [16]. However, despite the improved bioavailability of some drugs when associated with nanocarriers [17], advances in this area have been hampered by the limited knowledge about the effect of the physicochemical properties and composition of the nanocarriers in their interaction with the intestinal tract [13], [18].

The high concentration of electrolytes and enzymes in the intestinal environment is a major obstacle for the maintenance of the integrity of the nanocarriers and of their associated active compounds, since they can undergo degradation even before reaching the intestinal epithelium. In this scenario, the role of pancreatin, a combination of amylases, lipases and proteases enzymes, is particularly relevant [19], [20], [21]. Consequently, to understand the influence that the properties and composition of these nanocarriers have on their interaction with these enzymes is crucial to further advance in this field.

Additionally, the intestinal epithelium is covered by a mucus layer whose biological function is to keep the epithelium lubricated and protected from pathogens and exogenous substances [22]. The mucus layer, with a thickness that varies along the intestinal tract [23], [24], consists of a first layer firmly attached to the cellular epithelium and a second layer that is constantly being replaced [25], [26], [27]. This is why, mucoadhesive colloidal systems, specially designed to interact with the intestinal mucus [28], [29], [30], may become immobilized in the superficial mucus layer, and eventually removed [26], [31], [32]. Therefore, the nanocarriers intended for oral drug delivery must exhibit an adequate mucoadhesive/mucodiffusive balance.

Based on this information, the objective of this work was to evaluate the effect of the surface composition of different oily-based nanocarriers (nanoemulsions and nanocapsules) on their capacity to overcome specific barriers associated to the oral modality of administration. The basis for the selection of the nanocarriers relies of previous activity from our group showing the potential of chitosan (CS) nanocapsules (NCs) and polyarginine (PARG) NCs for the oral administration of salmon and insulin, respectively [33], [34], [35], [36], [37], [38], [39]. These nanocarriers are composed of an oily core and a polymeric shell, which is the main determinant for the interaction with the surrounding medium. Overall, the behaviour of nine nanosystems containing different surfactants and polymer shells was investigated (Fig. 1). A nanoemulsion (NE) consisting of Miglyol®812 N and Epikuron®145 V lecithin was used as reference in order to study the effect of the Pluronic® surfactant F68 and F127 , as well as that of the cationic polymers CS and PARG. In total, 3 different NEs and 6 different NCs were systematically analyzed for their capacity to overcome specific intestinal barriers. Namely, we evaluated the nanosystems for (i) their stability, both colloidal and chemical, in simulated intestinal fluid and (ii) their interaction (adhesion and diffusion) with mucus, while mimicking the physiological conditions [27], [40].