Ce travail porte sur la préparation, la caractérisation physico-chimique et l'évaluation biopharmaceutique de Microparticules Lipidiques Solides Composites (MLSC) innovantes assurant la gastrorétention et la libération progressive d'un principe actif modèle hydrophobe, l'ibuprofène. Une méthode d'émulsification à chaud est utilisée pour préparer ces MLSC, stabilisées par des nanoparticules de silice Aérosil® d'hydrophobie variée, selon le principe des « émulsions de Pickering », en remplacement de surfactifs organiques. Ces nanoparticules inorganiques se retrouvent en surface et dispersées au coeur des MLSC dans tous les cas. L'utilisation d'Aérosil® hydrophobe permet la formation de MLSC homogènes de plus de 100 µm de diamètre. Il est à noter que la présence de silice, en fonction de la charge en ibuprofène, a une influence certaine sur les cinétiques de libération du principe actif, que ce soit dans le PBS de pH 7.4 ou le milieu gastrique simulé de pH 1.2, principalement en modulant la taille des microparticules. Elle permet aussi de stabiliser sur une période de 6 mois les propriétés physico-chimiques et biopharmaceutiques des MLSC, d'améliorer leurs propriétés d'usage, comme l'écoulement, la résistance à l'écrasement et la flottaison dans un milieu gastrique simulé. Enfin, le recouvrement des MLSC par des polysaccharides assure la bioadhésion sur des membranes biologiques simulées à base de mucine en accélérant le plus souvent la libération de l'ibuprofène. Néanmoins, la stabilisation de MLSC avec des nanoparticules de silice dispersées au sein de matrices d'alginate gélifiées au CaCl2 avant lyophilisation constitue une nouvelle voie prometteuse pour la libération prolongée de principe actif hydrophobe dans l'estomac car ce polymère assure leur bioadhésion sur plus de 4h sans toutefois modifier le profil de libération de l'ibuprofène. / The aim of this work consists in the preparation, physic-chemical characterization and biopharmaceutical evaluation of innovative Composite Solid Lipid Microparticles (CSLM), allowing gastroretention and extended-release of a model hydrophobic drug, ibuprofen. Hot Melt emulsification's method is used to prepare these CSLM, stabilized by Aerosil® nanoparticles of various hydrophobicity as “emulsion of Pickering” instead of using an organic surfactant. Nanoparticles of silica take place on surface and are dispersed into CSLM in all cases. Using hydrophobic Aerosil allow the preparation of homogeneous over 100µm size CSLM. Presence of silica depending on the charge of ibuprofen influences the ibuprofen kinetics of release in both PBS ph 7.4 and simulated gastric fluid pH 1.2 by modulating the size of microparticles. Silica nanoparticles are also able to stabilize on a period of over 6 months the physic-chemical and biopharmaceuticals properties of CSLM, to improve their use properties, as helping free-flowing, enhancing crushing strength, and floating of CSLM in simulated gastric fluid. Finally CSLM coating with polysaccharides allows their bioadhesion on mucine simulated biological membrane, with an increased ibuprofen kinetics of release in most of the cases. Nevertheless, silica nanoparticles stabilized CSLM dispersed in CaCl2 gelified alginate matrices before freeze drying represent a new promising way for the extended release of hydrophobic drugs in stomach because this polymer can promote their bioadhesion for more than 4h without any change in the kinetics of ibuprofen release.

The self-assembly of isotropic and anisotropic colloidal particles into higher-ordered structures has been of great interest recently due to the promise of creating metamaterials with novel macroscopic properties. The physicochemical properties of these metamaterials can be tailored to achieve composites with tunable functionalities. The formation of these metamaterials can be used as a pathway to emulating advanced biological systems. In particular, synthetically mimicking the surface of a moth’s eye, which consists of arrays of ellipsoidal protuberances, can be used as a strategy for fabricating antireflective coatings. To enable this technology, it is necessary to design a synthesis scheme that produces micron-sized composite particles with tunable refractive index. In the future, the resulting composite microparticles can then undergo geometric and spatial modifications to form self-assemblies that have unique macroscopic material properties. This research work delineates a strategy of developing microparticles with a hybrid configuration that constitutes an inorganic and an organic part. The inorganic part comprises ~30 nm diameter titania (TiO2) nanoparticles, which are embedded within an organic polymer particle comprised of diethyl methylene malonate polymer [p(DEMM)]. Anionic polymerization is modified to controllably incorporate TiO2 nanoparticles into the polymer matrix. A design of experiments was identified and carried out to identify the major process variables that influence the final particle size. In particular, since DEMM polymerization may be initiated entirely by the presence of hydroxyl anions, pH was found to control the final overall particle diameter between 300 nm and 1 micrometer. The overall inorganic particle loading can be readily modified and is confirmed by thermogravimetric analysis, allowing for the desired macroscopic refractive index to be controlled. Light scattering, scanning electron microscopy and zeta potential analysis reveals that the colloidal stability of the hybrid microparticles is dependent on the ligand coating the inorganic constituent. In addition, this synthetic scheme is applied to different inorganic constituents that have interesting functionalities, such as fluorescent CdTe quantum dots, in order to show the methods versatility method to produce composite particles for a wide spectrum of applications. These initial investigations provide a the synthetic groundwork to evaluating the coating properties of the microparticles and their self-assembly into novel materials in the future.