Mesoporous materials constitute a promising class of nanomaterials for a number of applications due to their tunable pore structure. The synthesis of most mesoporous materials involves a surfactant liquid crystal structure to form the pores. As well as the many advantages associated with this method of synthesis, there are disadvantages such as high production costs and a substantial environmental impact which limit the possibilities for large scale production. Therefore there is a need for other synthesis routes. The aim of the work described herein was to contribute to this field by developing a synthesis route that does not rely on surfactants for pore formation. A mesoporous magnesium carbonate material was therefore formed by self-assemblage of the particles around carbon dioxide gas bubbles, which functioned as pore templates. It was also possible to vary the pore diameter between 3 and 20 nm. The biocompatibility of the formed magnesium carbonate material was evaluated in terms of in vitro cytotoxicity and hemocompatibility, in vivo skin irritation and acute systemic toxicity. The results from the in vitro cytotoxicity, in vivo skin irritation and acute systemic toxicity test using a polar extraction vehicle showed that the material was non-toxic. While signs of toxicity were observed in the acute systemic toxicity test using a non-polar solvent, this was attributed to injection of particles rather than toxic leachables. In the in vitro hemocompatibility test, no hemolytic activity was found with material concentrations of up to 1 mg/ml. It was further shown that the material had anticoagulant properties and induced moderate activation of the complement system. The anticoagulant properties were ascribed to uptake of Ca2+. Finally, the ability of the material to increase the dissolution rate of the poorly soluble drug itraconazole was analyzed.  Itraconazole was dissolved up to 23 times faster from the magnesium carbonate pores than when the free drug was used. The release rate from the delivery vehicle was dependent on the pore diameter. The work presented herein is expected to be useful for the development of alternative synthesis routes for mesoporous materials and also for encouraging the development of biomedical applications for these materials.

Amorphous solid dispersion (ASD) is a popular method to increase drug solubility and consequently poor drug bioavailability. Cellulose ω-carboxyesters were designed and synthesized specifically for ASD preparations in Edgar lab that can meet the ASD expectations such as high Tg, recrystallization prevention and pH-triggered release due to the free -COOH groups. Rifampicin (Rif), Ritonavir (Rit), Efavirenz (Efa), Etravirine (Etra) and Quercetin (Que) cellulose ester ASDs were investigated in order to increase drug solubility, prevent release at low pH and controlled release of the drug at small intestine pH that can improve drug bioavailability, decrease needed drug content and medication price to make it affordable in third world countries, and extent pill efficiency period to improve patient quality of life and adherence to the treatment schedule. The studies were compared with cellulose based commercial polymers to prove the impact of the investigation and potential for the application. Furthermore, the in vitro results obtained were further supported by in vivo studies to prove the significant increase in bioavailability and show the extended release. The need of new cellulose derivatives for ASD applications extended the research area, the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters for ASD formulations investigated and the efficiency of the polymers were summarized to show that they have the anticipated properties. The polymers were synthesized by the reaction of commercial cellulose alkyl ethers with benzyl ester protected, monofunctional hydrocarbon chain acid chlorides, followed by removal of protecting group using palladium hydroxide catalyzed hydrogenolysis to form the alkyl cellulose wcarboxyalkanoate. Having been tested for ASD preparation, it was proven that the polymers were efficient in maintaining the drug in amorphous solid state, release the drug at neutral pH and prevent the recrystallization for hours, as predicted. / Ph. D.

En raison de leur complexité croissante, la solubilité des nouvelles entités chimiques en milieu aqueux est de plus en plus faible. Ainsi, le développement de beaucoup de principes actifs échoue à cause d’une hydrosolubilité insuffisante. De nombreuses technologies existent pour améliorer la solubilité et/ou solubilisation de tels composés. Cette thèse est ciblée sur la formulation de dispersions solides amorphes par extrusion à chaud. En particulier, un principe actif d’intérêt industriel sera formulé en utilisant une extrudeuse bi-vis disponible sur la plateforme Gala®. Cette technologie autorise l’utilisation d’un grand nombre de matrices, ce qui peut nécessiter un grand nombre d’essais expérimentaux. Une attention particulière est donc portée à l’utilisation de méthodes prédictives de la miscibilité entre les composants qui peuvent ainsi permettre une première sélection des matrices. Sur la base de ces résultats, une étude sur le procédé de hot melt extrusion a ensuite été réalisée. / The aqueous solubility of new chemical entities is increasingly weak, due to their complex structure, and many API fail in development due to insufficient solubility. Many technologies exist to enhance the solubility and / or dissolution of such compounds in aqueous media. Among all of these methods, this thesis is focused on the formulation of amorphous solid dispersions by hot melt extrusion. A lot of matrix can be used to formulate with this technology, so few methods to estimate miscibility between API and matrices will also be presented in this thesis. Finally, a study about the hot melt extrusion process will also be presented.

La principale difficulté lors de l'administration orale d'un ingrédient pharmaceutique actif (API) est de garantir que la dose clinique de l’API sera dissoute dans le volume disponible de liquides gastro-intestinaux. Toutefois, environ 40% des API sur le marché et près de 90% des molécules en cours de développement sont peu solubles dans l’eau et présentent une faible absorption par voie orale, ce qui entraîne une faible biodisponibilité. Les dispersions solides amorphes (ASD) sont considérées comme l’une des stratégies plus efficaces pour résoudre des problèmes de solubilité des principes actifs peu solubles dans l’eau et, ainsi, améliorer leur biodisponibilité orale. En dépit de leur introduction il y a plus de 50 ans comme stratégie pour améliorer l’administration orale des API, la formation et la stabilité physique des ASD font toujours l'objet de recherches approfondies. En effet, plusieurs facteurs peuvent influer sur la stabilité physique des ASD pendant le stockage, parmi lesquels la température de transition vitreuse du mélange binaire API-polymère, la solubilité apparente de l'API dans le polymère, les interactions entre l'API et le polymère et le procédé de fabrication. Cette thèse consistait en deux parties qui avaient pour objectif le développement de nouvelles formulations sous forme d’ASD d'un antirétroviral, l'Efavirenz (EFV), dispersé dans un polymère amphiphile, le Soluplus, en utilisant deux procédés différents, le séchage par atomisation (SD) et l'extrusion à chaud (HME). EFV est l’API BCS de classe II de notre choix car c’est un API qui représente un défi pour les nouvelles formulations. En effet, il a besoin d’ASD plus fortement concentrées, pour lesquelles la stabilité chimique et physique pendant le stockage et la dissolution seront essentielles. Dans le but de développer de manière rationnelle les ASDs EFV- Soluplus à forte concentration, la première partie s'est concentrée sur la construction d'un diagramme de phases EFV-Soluplus en fonction de la composition et de la température. Le diagramme de phases a été construit à partir d'une étude thermique de recristallisation d'un ASD sursaturé (85 %m EFV), générée par séchage par atomisation. À notre connaissance, il s'agit de la première étude à présenter un diagramme de phase pour ce système binaire. Ce diagramme de phases est très utile et démontre que la solubilité de l'EFV dans les solutions varie de 20 %m (25 °C) à 30 %m (40 °C). Les ASD de EFV dans le Soluplus contenant plus de 30 %m d'EFV doivent être surveillées pendant le stockage dans des conditions typiques de température. Ce diagramme de phases peut être considéré comme un outil de pré-formulation pour les chercheurs qui étudient de nouvelles ASD d'EFV dans le Soluplus afin de prédire la stabilité (thermodynamique et cinétique). Les ASD préparées par différentes techniques peuvent afficher des différences dans leurs propriétés physicochimiques. La deuxième partie de cette thèse portait sur la fabrication d’ASD par des procédés HME et SD. Cette étude montre clairement que la formation d’ASD est une stratégie de formulation utile pour améliorer la solubilité dans l'eau et la vitesse de dissolution de l'EFV à partir de mélanges binaires EFV-Soluplus. Les procédés de fabrication (HME et SD) se sont révélés efficaces pour générer des ASD dans une large gamme de compositions en EFV. L'optimisation du ratio EFV-Soluplus peut être utilisée pour adapter la libération cinétique des ASD. Le choix d’une charge EFV élevée dépassant la solubilité thermodynamique de l’EFV dans le Soluplus est possible, mais il convient de prendre en compte sa stabilité cinétique dans le temps. / The main difficulty when an Active Pharmaceutical Ingredient (API) is orally administered is to guarantee that the clinical dose of the API will be dissolved in the available volume of gastrointestinal fluids. However, about 40% of APIs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble and exhibits a poor oral absorption, which leads to a weak bioavailability. Amorphous solid dispersions (ASD) are considered as one of the most effective strategies to solve solubility limitations of poorly-water soluble compounds and hence, enhance their oral bioavailability. Despite their introduction as technical strategy to enhance oral APIs bioavailability more than 50 years ago, ASD formation and physical stability remains a subject of intense research. Indeed, several factors can influence the physical storage stability of ASD, among them, the glass transition temperature of the API-carrier binary mixture, the apparent solubility of the API in the carrier, interactions between API and carrier, and the manufacturing process. This thesis consisted of two parts that aim on developing new formulations of ASD of an antiretroviral API, Efavirenz (EFV), dispersed in an amphiphilic polymer, Soluplus, by using two different processes, Spray-drying (SD) and Hot-melt extrusion (HME). EFV is the class II BCS API of our choice because it is a challenging API for new formulations. It needs higher-dosed ASDs, for which chemical and physical stability during storage and dissolution will be critical. Aiming a rational development of high-loaded EFV-Soluplus ASDs, the first part focused on the construction of a temperature- composition EFV-Soluplus phase diagram. The phase-diagram was constructed from a thermal study of recrystallization of a supersaturated ASD (85 wt% in EFV), generated by spray drying. To our knowledge, this is the first study reporting a phase-diagram for this binary system. This phase-diagram is very useful and demonstrated that the EFV solubility in Soluplus ranges from 20 wt% (25 °C) to 30 wt% (40 °C). ASD of EFV in Soluplus containing more than 30 wt% of EFV should be monitored over storage under typical temperature conditions. This phase-diagram might be considered as a preformulation tool for researchers studying novel ASD of EFV in Soluplus, to predict (thermodynamic and kinetic) stability. ASD prepared by different techniques can display differences in their physicochemical properties. The second part of this thesis focused on the manufacturing of ASD by HME or SD processes. This study clearly shows that ASD is a useful formulation strategy to improve the aqueous solubility and the dissolution rate of EFV from EFV-Soluplus binary mixtures. HME and SD manufacturing processes demonstrated to be efficient to generate ASDs in a large range of compositions and loads of EFV. The optimization of EFV to Soluplus ratio can be used to tailor the release kinetics from ASD. The choice of a high EFV load exceeding the thermodynamic solid solubility in Soluplus is possible but it needs the consideration of its kinetic stability over time.

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