This thesis aimed to investigate and document the potential of applying ceramics in two specific drug delivery applications: tamper-resistant opioid formulations and transdermal enhancement protrusions. Geopolymers were developed into the matrix for a tamper-resistant formulation, aiming to protect drug substances from non-medical abuse. The synthesis conditions and excipients composition of the geopolymer-based formulation were modified in this work to facilitate a stable and extended drug delivery. Results showed that 37ºC 100% humidity for 48 hours were applicable conditions to obtain geopolymer with suitable mechanical strength and porosity. Moreover, it was found that the integration of poly(methyl acrylate) into the geopolymer-based formulation could reduce the drug release at low pH and, meanwhile, maintain the mechanical strength. Therefore, the geopolymer-based drug formulations concluded from these studies were applied in oral and transdermal delivery systems. Evidence of the tamper-resistance of geopolymer-based oral and transdermal formulations was documented and compared to the corresponding commercial opioid formulations. The results provided experimental support for the positive effects of geopolymers as drug carriers for the tamper-resistance of oral and transdermal delivery systems. Self-setting bioceramics, calcium phosphate and calcium sulfate were fabricated into transdermal enhancement protrusions in this work for the first time. Results showed that, under mild conditions, both bioceramics could form pyramid-shaped needles in the micron size. The drug release from these needles could be controlled by the bulk surface area, porosity and degradation of the bioceramics. An in vitro insertion test showed that the bioceramic microneedles had enough mechanical strength to insert into skin. Further optimization on the geometry of needles and the substrate material was also performed. The higher aspect-ratio needles with a flexible and self-swellable substrate could release most of the drug content within 4 hours and could penetrate through the stratum corneum by manual insertion. This study explored the potential application of bioceramics in transdermal enhancement protrusions and showed promising indication of their future developments.

Les benzoxaboroles sont des dérivés cycliques d'acides boroniques, récemment développés en médecine comme agents thérapeutiques. Dans cette thèse, une étude fondamentale de la formulation des benzoxaboroles dans des matériaux a été effectuée, utilisant le benzoxaborole le plus simple ainsi qu'un dérivé fluoré, l'AN2690 (antifongique approuvé par la FDA). L'étude a commencé par la détermination des données spectroscopiques de ces molécules à l'état solide, sous leur forme acide (à partir des molécules cristallisées), et basique (utilisant des matériaux modèles à base de benzoxaborolates) ; une variété de paramètres RMN a ainsi été établie pour chaque forme de la molécule. Par la suite, une première formulation a été développée par association de benzoxaborolates à un matériau inorganique de type « hydroxyde double lamellaire » (HDL Mg/Al-NO3). Un taux de charge à ~30 % massique en benzoxaboroles a pu être atteint, et des cinétiques de libérations rapides ont été observées. Cependant, une sensibilité des molécules au caractère basique de la matrice a été mise en évidence, et la structure de ces matériaux s'est avérée complexe, évoluant d'un mode d'intercalation normale à une structure de type « staging », en fonction du taux d'hydratation de l'espace interlamellaire. Dans une deuxième formulation, nous avons incorporé les benzoxaboroles, à divers taux de charge (jusqu'à 25% en masse), dans un polymère biorésorbable, l'acide poly-L-lactique (PLLA), avec une mise en forme en films et fibres, ces dernières étant formées par électrospinning. Dans ce cas, plusieurs vitesses de libération ont été obtenues, en modulant la composition et les conditions de préparation des matériaux, et les tests cellulaires réalisés (migration de cellules cancéreuses et tests antifongiques) sont en bonne corrélation avec ces cinétiques. Cette étude, dans son ensemble, permet d'élargir la gamme de formulations envisageables pour les benzoxaboroles, mais souligne aussi les enjeux associés à leur formulation dans des matériaux, du fait de la réactivité intrinsèque de la fonction benzoxaborole / Benzoxaboroles are cyclic derivatives of boronic acids, which have recently been developed as therapeutic agents. In this thesis, a fundamental study was carried out on the formulation of benzoxaboroles in materials, using the simplest benzoxaborole molecule and its fluorinated derivative, AN2690 (an antifungal agent approved by the FDA). The spectroscopic signatures of these molecules were first determined in the solid state, by looking at their acid form (using the crystallized molecules) and their basic form (using model materials based on benzoxaborolates), and this led to the establishment of the NMR parameters of each form of the molecules. A first formulation was then performed by association of benzoxaborolates with an inorganic material, a “layered double hydroxide” (Mg/Al-NO3 LDH). A loading capacity of ~ 30 wt% could be reached for this system and fast release kinetics were observed. However, the molecules were found to be sensitive to the basic character of the matrix. The resulting structure of these materials was also complex, due to the evolution from a normal mode of intercalation to a “staging” structure by dehydration of the interlamellar space. In a second formulation, the benzoxaboroles were incorporated at different loadings (up to 25 wt %), in a bioresorbable polymer, poly L lactic acid (PLLA), and shaped under the form of films and also fibers (which were obtained by electrospinning). Different release rates were achieved by varying the composition or the preparation conditions of the materials. Cellular assays investigating the migration of cancer cells and the inhibition of fungi showed a good correlation between these release rates and the cellular responses. Overall, this study allowed not only to increase the span of possible formulations of the benzoxaboroles, but also to highlight the issues related to their formulation in materials, due to the inherent reactivity of the benzaxoborole function.

Nous décrivons dans ce manuscrit la synthèse et l'étude de surfactifs à base de poly(2-méthyl-2-oxazoline) et de corps gras. Pour cela, deux voies de synthèse ont été réalisées. La première qui consiste à amorcer la polymérisation avec un alcool gras tosylé. La deuxième voie de synthèse a été réalisée en amorçant la polymérisation par un alcane iodé. Les surfactifs ainsi obtenus ont une chaîne grasse saturée ayant douze ou dix-huit atomes de carbone et des longueurs de chaînes polymères variables.Ces surfactifs sont examinés afin d'évaluer leur aptitude à la formulation. Ainsi, la valeur de leur concentration micellaire critique a été déterminée par tensiométrie et spectrofluorimétrie. Ensuite, l'évaluation de leurs pouvoirs mouillant et moussant, de leur HLB, de leur température de point de trouble… ont été déterminés afin de les comparer avec leurs homologues POE, les Brij®. Dans l'optique d'une application à la formulation, des tests d'évaluation de leur toxicité ont également été réalisés. Enfin, des préparations cosmétiques ont été formulées, à base de ces surfactifs et des Brij®. Parallèlement, une étude a été menée démontrant l'intérêt du carbonate de glycérol tosylé comme amorceur de la polymérisation de la 2-méthyl-2-oxazoline. Cet amorceur a permis de fonctionnaliser les polyoxazolines en extrémité de chaîne par des fonctions terminales (hydroxy)uréthane. / In this manuscript, we describe the synthesis and the study of surfactants based on poly(2-methyl-2-oxazoline) and vegetable oil derivatives. Two ways for the synthesis are realized. The first path consists to initiate the polymerization with a tosylate fatty alcohol. The second synthetic route was realized by initiating the polymerization by an iodoalkane. The obtained surfactants have au saturated fatty chain with twelve or eighteen carbon atoms and various lengths of polymeric chain. This surfactants are reviewed to assess their suitability for the formulation. Thus, the value of their critical micelle concentration was determined by tensiometry and spectrofluorimetry. After, the evaluation of their wetting and foaming powers, their HLB, their cloud point temperature… was determinded in order to compare with their homologous POE, the Brij®. In the context of an application in the formulation, evaluation tests of toxicity were also made. Next, cosmetic preparations were realized, based on this surfactants and Brij®. In parallel, a study was conducted to demonstrate the tosylate gycerol carbonate interest as initiator in the 2-methyl-2-oxazoline polymerization. This initiator enable to fonctionalize the polyoxazoline in the chain end with (hydroxy)uréthane terminal function.

The objective of this study was to develop soy concept foods with potential marketability in the food industry for health conscious consumers. Fourteen commercial soy protein isolate samples were obtained from various processors. The flavor profiles of the soy protein isolates were evaluated by five expert panelists. The three soy protein isolate samples with the most acceptable flavor profiles were utilized for further analysis and the development of soy concept foods including cranberry nut soy pudding, two bean soy dip and a soy based meal replacer. Based on consumer acceptability studies, it appears that two bean soy dip may have the most potential for success in the food industry. Although, no differences (P>0.05) existed in acceptability among soy protein products in any of the soy concept foods, ISP may have the most potential for utilization in the development of new products since numerical values were slightly higher when this soy protein was incorporated into the various concept foods.

This dissertation is based on the theory and applications of the most commonly used solubilization techniques: pH adjustment, cosolvency, micellization, complexation, and the combinations of pH adjustment with one of the other techniques.Chapter 1 provides an overview for the methods which are available to formulate a poorly water-soluble drug based on its administration route.Chapter 2 applies these commonly used techniques to solubilize two structurally related anticancer drugs. The efficiency of each technique is compared for both drugs side by side. It is observed that each technique is more efficient on the drug which has less polarity. However, the achievable final drug concentration in a formulation depends not only on the efficiency of the applied technique, but also on the drug's water solubility.Chapter 3 emphasizes the overall effectiveness of each technique on drugs which have different physicochemical properties. Solubilization profiles for the above techniques are generated for twelve compounds, eight of which are ionizable and studied under both unionized and ionized conditions. This chapter illustrates that the efficiency of the cosolvency, micellization, and complexation on both unionized and ionized drug species can be predicted from their polarities. Thus, the solubility of an ionizable drug can be estimated by using a given solubilizing excipient at any pH to meet the dose requirement.Chapter 4 studies the effect of cosolvent on complex stability. A series of alcohols were used to illustrate the effect of cosolvent size and polarity on the solubilization of a compound. It is proposed that a ternary drug-ligand-cosolvent complex is formed in these combined systemsThis dissertation provides guidance for the selection of a solubilization technique for a compound based on the physicochemical properties and the dose requirement.

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Ce travail s’intéresse à la résolution numérique par éléments finis des équations de Maxwell en régime quasi-stationnaire et en formulations potentielles. L’objectif poursuivi consiste à développer des estimateurs d’erreur a posteriori résiduels, afin de contrôler l’erreur de discrétisation spatiale, dans le cadre d’applications en régime statique ou en régime dynamique harmonique.La première partie de cette thèse est composée de deux chapitres. Le premier est consacré à la modélisation des phénomènes physiques étudiés et à l’obtention des équations mathématiques en résultant. Dans le second, on présente les estimateurs a posteriori et leur intérêt dans le cadre de la mise en oeuvre de la méthode des éléments finis. On détaille notamment les notions de fiablité et d’efficacité d’un estimateur. La deuxième partie se décompose en trois chapitres. Le premier développe l’estimateur a posteriori dans le cas de la magnétostatique en formulation potentielle vecteur A. Les outils mathématiques nécessaires à l’étude sont en particulier détaillés. L’estimateur obtenu est alors validé sur quelques cas tests académiques. Le deuxième traite de l’estimateur a posteriori pour la formulation magnétodynamique en potentiel A/φ en régime harmonique. Un soin particulier est apporté pour générer une décomposition de Helmholtz ad hoc permettant d’obtenir la fiabilité de l’estimateur. Plusieurs configurations sont traitées en fonction de la position du domaine conducteur dans le domaine de calcul et des conditions aux limites associées. Un test numérique est ensuite effectué. Le troisième chapitre est consacré à l’estimateur d’erreur a posteriori pour la formulation T/Ω en régime harmonique pour le problème de la magnétodynamique, en supposant le domaine conducteur simplement connexe. Similairement à la formulation A/φ, une décomposition de Helmholtz est développée pour établir la fiabilité. Une validation numérique est proposée. Enfin, la troisième partie présente une batterie de tests numériques applicatifs et industriels permettant de tester les estimateurs développés dans des conditions réelles. Celle-ci se termine notamment par une application de EDF R&D ayant pour objet le contrôle non destructif par courant de Foucault de tubes générateurs de vapeur. / We are interested in resolving the Maxwell equations in the case of quasi-stationary and potential formulations when the finite element method is used. The aim of this work is to develop residual-based a posteriori estimators to control the spatial discretization error in magnetostatic and magnetodynamic problems. The first part is decomposed in two chapters. In the first one, the modeling of the physical phenomena involved are proposed and the mathematical equations are derived. Then, in the second one, the definition of the a posteriori estimators and their interest are presented in the context of the finite element method. The particular notions of reliability and efficiency of an estimator are presented. The second part can be decomposed into three chapters. In the first one, a residualbased a posteriori estimator for the vector potential formulation A in the case of magnetostatic problems is developed. Some necessary mathematical tools for the study are particularly detailed. The estimator is then validated by some academic tests. In the second chapter, a residual-based a posteriori estimator for the A/φ magnetodynamic harmonic formulation is developed. An ad-hoc Helmholtz decomposition is derived to obtain the reliability of the estimator. Several configurations are considered according to the position of the conductor domain in the computational domain as well as boundary conditions used. A numerical test is then performed. In the third chapter, a residual-based a posteriori estimator is derived for the T/Ω magnetodynamic harmonic formulation, when the conductor domain is simply connected. Similarly to the A/φ formulation, an ad-hoc Helmholtz decomposition is developed to establish the reliability. A numerical validation is proposed.Finally, in the third part, a set of numerical experiments and industrial applications are presented to evaluate our estimators. It ends with a particular application of EDF R&D focusing on the eddy current non-destructive evaluation of steam generator tubes.

>Magister Scientiae - MSc / Introduction: Nanoparticles (NPs) are gaining increased popularity for cancer treatment, especially the multifunctional nanoparticles like Quantum dots (QDs) which have a wide range of applications in nanotheranostics, cell imaging and targeted drug delivery to cancerous tissue. QDs comprise of very tiny crystals of a semiconductor material (diameter: 2-10 nm) capable of producing bright, intensive and size-tuneable near-infrared fluorescence emissions. In particular, 3-mercaptopropionic acid -capped Cadmium Telluride Quantum Dots with a zinc sulphide shell (MPA-capped CdTe/ZnS QDs), are known to be very stable, highly photoluminescent, less toxic with long-lasting “fluorophore” effects, thus making them the preferred QDs for this study. Aims: To synthesize and characterize biocompatible MPA-capped CdTe/ZnS QDs to determine size range, polydispersity index (PdI), zeta (ζ) potential, photoluminescence (PL) spectra, stability in various milieus as well as to evaluate the effects of the synthesized QDs on the viability and morphology of neuroblastoma (NB) and glioblastoma (GB) cell lines using the WST-1 cell viability assay, imaging and cell cycle analysis. Materials and methods: MPA-capped CdTe/ZnS QDs were synthesized and analysed with the Zetasizer to determine ζ-potential, hydrodynamic (hd) size and PdI, while high resolutiontransmission electron microscopy (HR-TEM) was used to validate the hd size and elemental composition using energy dispersive X-ray (EDX) spectra. Pl absorption and emission spectra were obtained with a fluorometer and stability studies were done using UV-Vis spectroscopy, permitting further biological evaluation. A concentration range of 5-20μg/ml QDs was exposed to U87 and SH-SY5Y cancer cell lines to determine biological effects at different time points, using the WST-1 assay. Confocal fluorescence microscopy was used to establish uptake and cellular localization of the QDs, cell morphology was visualized with an inverted microscope while cell cycle distribution analysis was done using the C6 flow cytometer.

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