Multiple dose regimens are frequently required to optimize therapy; however, such therapy is frequently undermined by poor patient adherence. In fact, patient adherence is inversely related to the number of doses a patient is asked to take each drug. Consequently, great efforts are under way to develop drug delivery systems that are able to release drugs over an extended time interval; this could offer considerable benefits including reducing administration frequency. This dissertation describes multiple dose platforms designed to deliver a variety of drugs as a single oral administration are described in this dissertation. We believe these drug delivery systems can be used to enhance patient compliance and achieve better therapeutic outcomes. We developed and tested a novel gastroretentive pulsatile drug delivery platform. This platform could deliver multiple unit doses of a drug in a pulsatile pattern and be controlled by dissolution/erosion of a lag-time interval layer. The platform was designed to be retained in the stomach whilst pulsing drug at various timed intervals. This would allow each dose of the drug to release above or within an optimized absorption window over an extended period of time. To assure the robustness and reproducibility of the platform, various in vitro dissolution studies and physical stability tests were performed and evaluated through drug release characteristics, buoyancy, and structural integrity evaluations. The applicability of the novel multiple dose platform was demonstrated by providing repeated release profiles of ciprofloxacin and verapamil in a single, once-daily delivery system. Ultimately, this dissertation demonstrates that a novel multiple dose platform could be a suitable alternative dosing strategy for a variety of drugs to improve patient adherence and treatment efficacy. / text

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.