Les nanosphères " furtives " comme nouvelles formes galéniques injectables : espoirs et réalités.

Abstract

L’amélioration de la biodisponibilité de substances thérapeutiques est un objectif poursuivi depuis plusieurs années par de nombreuses équipes. Les bénéfices attendus sont évidents : optimisation de l’effet thérapeutique, amélioration du confort du malade par la réduction du nombre de prises, diminution de la toxicité, des coûts de santé, etc. L’encapsulation de biomolécules actives dans des nanosphères « furtives », c’est-à-dire invisibles visà- vis des macrophages du « système des phagocytes mononucléés », permet d’envisager le développement de nouvelles formes injectables, à persistance intra-vasculaire prolongée et à libération contrôlée. De tels systèmes nanoparticulaires peuvent être élaborés à partir de polymères dégradables, encapsuler des biomolécules instables, y compris des protéines thérapeutiques, avec de bons rendements et influer sur leur libération.

The improvement of drug delivery is a major challenge in pharmacology, and a great number of studies have aimed toward this goal during the last years. The main expected benefits are: the optimisation of the therapeutic effect, the improvement of the patient comfort, a toxicity decrease... Among the various approaches which have been investigated, one of them relies on encapsulating active molecules in nanospheres (of about 100-200 nm) prepared from appropriate polymers, especially when intravenous injection is required. Poly lactic acid (PLA) is a good candidate for this purpose, since it is well tolerated by the organism, and slowly degraded in vivo into non-toxic compounds. Many examples of drug encapsulation in PLA nanospheres have been described in the literature, and the emulsion/solvent evaporation procedure is often used for this nanosphere encapsulation. However, when nanoparticles are injected into an organism, their surface properties (both hydrophobicity and charge) provoke the adsorption of opsonines, and consequently their phagocytosis by the macrophages of the Mononuclear Phagocyte System (MPS). As a result, the particles quickly disappear from the blood stream and accumulate in the MPS organs. To overcome these setbacks, nanospheres can be covered by a neutral hydrophilic layer to generate corona-core particles in which the corona is made of polyoxyethylene (POE) or polysaccharide chains. These particles can be prepared directly from amphiphilic copolymers (consisting of hydrophilic and hydrophobic segments) through various different methods, the most common being the emulsion/solvent evaporation procedure. POE coverage leads to the decrease of phagocytosis by macrophages, which parallels that of the nanosphere zeta potential and protein adsorption. In this paper, examples of hydrophobic drug and protein encapsulation are presented, and the release kinetics discussed with respect to the nanosphere size and composition.