• Langue : Anglais, Français
• Discipline : Sciences de la vie et de la santé
• Identifiant : 2011LIL2S054
• Type de thèse : Doctorat
• Date de soutenance : 22/09/2011

Résumé en langue originale

Les effets de la résistance mécanique, de l'uniformité de l'épaisseur et de la vulnérabilité à l'éthanol des revêtements à libération prolongée sur les propriétés du film et le comportement de libération du médicament sont examinés dans ce travail. Tout d'abord, des films minces et libres ont été préparés en coulant ou en pulvérisant des dispersions aqueuses de mélanges Kollicoat® SR:Eudragit® NE, et ont été minutieusement caractérisés en ce qui concerne leur comportement d'absorption d'eau, leur perméabilité à l'eau, leur cinétique de perte de masse sèche, leurs propriétés mécaniques et leurs schémas de libération de médicaments. En outre, un modèle mathématique mécaniste basé sur la loi de diffusion de Fick a été utilisé pour quantifier la libération du succinate de métoprolol mesurée expérimentalement à partir de différents types de systèmes. Il a été constaté que les films devenaient plus hydrophobes avec l'augmentation de la teneur en Eudragit® NE, ce qui entraîne une diminution de la perméabilité à l'eau ainsi que des taux et de l'étendue de l'absorption d'eau. En outre, la perte de masse sèche lors de l'exposition au milieu de libération a diminué. Par conséquent, la perméabilité des films au médicament a diminué. Il est important de noter que la libération du succinate de métoprolol par les films minces était principalement contrôlée par la diffusion pure, ce qui a permis de déterminer le coefficient de diffusion apparent du médicament dans les différents systèmes polymères. En connaissant ces valeurs, la libération du médicament à partir des granulés enrobés a pu être prédite quantitativement, en supposant que l'enrobage des films était intact pendant toute la période d'observation. Cependant, la comparaison avec des résultats expérimentaux indépendants a montré que la formation de fissures s'est produite très rapidement dans les membranes polymériques lors de l'exposition à l'acide sulfurique [...]

Résumé traduit

The effects of mechanical strength, thickness uniformity and ethanol vulnerabilityof sustained release coatings on the film properties and respective drug release behavior arediscussed in this work. First of all, thin, free films were prepared by casting or sprayingaqueous dispersions of Kollicoat® SR:Eudragit® NE blends, and thoroughly characterizedwith respect to their water uptake behavior, water permeability, dry mass loss kinetics,mechanical properties and drug release patterns. Furthermore, a mechanistic mathematicalmodel based on Fick’s law of diffusion was used to quantify the experimentally measuredrelease of metoprolol succinate from various types of systems. It has been found that filmsbecame more hydrophobic with increasing Eudragit® NE content, resulting in decreased waterpermeability as well as water uptake rates and extents. In addition, the dry mass loss uponexposure to the release medium decreased. Consequently, the films’ permeability for the drugdecreased. Importantly, metoprolol succinate release from thin films was mainly controlled bypure diffusion, allowing for the determination of the apparent diffusion coefficient of the drugin the different polymeric systems. Knowing these values, drug release from coated pelletscould be quantitatively predicted, assuming intact film coatings throughout the observationperiod. However, comparison with independent experimental results showed that crackformation set on very rapidly in the polymeric membranes upon exposure to the releasemedium in the case of sugar starter cores, irrespective of the polymer:polymer blend ratio andinvestigated coating level. Thus, drug release occurred not only via diffusion through theintact film coating but through generated pores in the membrane (convection), created by asignificant hydrostatic pressure in the device. In contrast, the onset of crack formation (andthus drug release through convection) was delayed as a function of the blend ratio and coatingthickness in the case of microcrystalline cellulose starter cores, attracting less water into thepellets core and, thus, decreasing the osmotic pressure acting against the membrane. This has also been found for pellet starter cores layered with other drug types exhibiting varioussolubilities.Secondly, the film coating thickness (uniformity) and terahertz electric field peakstrength (TEFPS) of sustained release film coatings were determined using a non-destructivetool: terahertz pulsed imaging (TPI). Pellets consisting of theophylline-layered sugar coresand coated with Kollicoat® SR:Kollicoat® IR blends were specially prepared and investigatedwith regard to the effects of coating thickness, drug layer uniformity and optional curing onthe respective drug release behavior. Prior to release measurements the pellets were imagedwith TPI and analysed for their coating morphology (depicted in TEFPS) and coatingthickness. As expected, the results showed significantly higher TEFPS values for pellets witha smooth drug layer than for those with a coarse one. This indicates less uniform film coatingthicknesses of the latter, which was supposed to result in increased drug release rates withbroad ranges. Surprisingly, the resulting drug release kinetics was very similar, irrespective ofthe major differences in TEFPS. Also, a 36 μm coating thickness difference was not releaserate determining. Thus, it was suggested that drug release for the pellets studied was notpredominately governed by drug diffusion through the polymeric film coating but probably toa large extent limited by drug solubility. Nevertheless, drug release from pellets layered withthe more soluble drug metoprolol succinate was found to be as well rather insensitive to thecore surface morphology [...]