Trata-se de uma investigação sobre a influência de alguns fatores no comportamento mecânico de misturas asfálticas densas quanto à estabilidade e à flexibilidade. Foram testados três tipos de ligantes, asfalto convencional, modificado com 4,5% de SBS e modificado com 20% de borracha reciclada de pneu; duas distribuições granulométricas do agregado, centros das faixas B e C do DNER (1997); quatro teores de ligante, escolhidos com base nos valores de volumes de vazios e espessuras de película almejados; três condições de envelhecimento a longo prazo, mistura não envelhecida, envelhecida em estufa ventilada a 85ºC por 5 dias e envelhecida por exposição ao tempo por 4 meses; e duas condições de envelhecimento a curto prazo, mistura não envelhecida e envelhecida em estufa ventilada a 135ºC por 4 horas. A técnica de planejamento e análise de experimentos fatoriais fracionários assimétricos foi utilizada para a consideração simultânea dos fatores citados. O comportamento mecânico das misturas foi avaliado através dos ensaios de resistência à tração, módulo de resiliência e fluência por compressão uniaxial estática e dinâmica. A análise de variância dos resultados permitiu a identificação dos fatores com influência significativa nas respostas dos ensaios. O modo como cada fator interferiu nas propriedades apresentadas pelas misturas foi estabelecido através da construção de modelos estatísticos de comportamento. Os resultados mostraram que a adição de modificadores ao asfalto melhora a resistência das misturas à fadiga e à deformação permanente. Os processos de envelhecimento aumentaram os módulos de resiliência das misturas mas diminuíram sua capacidade de recuperação elástica, o que significa queda de resistência à fadiga. Por outro lado, a resistência a deformações permanentes das misturas, inclusive daquelas compostas por asfaltos modificados, aumentou com o envelhecimento. / This work deals with the influence of some factors in the mechanical behavior of asphalt mixtures stability and flexibility. Three types of binders were tested, conventional one, modified with 4,5% of SBS and modified with 20% of recycled tire rubber. Two aggregate gradations were tested, center of B and C gradations of DNER (1997). Four binder contents were chosen based on the air voids and film thickness. Three types of long-term aging were tested, not aged, aged in a forced-draft oven for 5 days at 85ºC and aged through weather exposition for the period of 4 months. Two types of short-term aging were tested; not aged and aged in a forced-draft oven for 4 hours at 135ºC. The technique of design and analysis of asymmetric fractional factorial experiments was used for the simultaneous analysis of the factors. The mechanical behavior of the mixtures was evaluated based on indirect tensile strength test, resilient modulus test and static and dynamic creep tests. The results of the analysis of variance allowed the identification of factors with significant influence in the answers. The influence of the factors in the mixtures properties was established through statistical models of behavior. The results showed that modified binders improves the mixtures resistance in relation to fatigue and to permanent deformation. The aging processes increased the resilient modulus of the mixtures, but also decreased its capacity of elastic return, resulting in a lost of fatigue resistance. On the other hand, the permanent deformation resistance of the aging mixtures increased, including the mixtures with modified binders cases.

O ensaio de fluência e recuperação sob tensão múltipla (MSCR) é resultado do aperfeiçoamento do ensaio de fluência repetida e recuperação (RCRT) pela Administração Rodoviária Federal dos Estados Unidos (FHWA) e tem por objetivo avaliar o percentual de recuperação, a compliância não-recuperável e a dependência dos ligantes asfálticos, especialmente os modificados, quanto ao nível de tensão. O MSCR foi utilizado neste estudo para caracterizar o comportamento fluência-recuperação de diversos ligantes asfálticos modificados virgens e envelhecidos a curto prazo. Foi empregado o procedimento da norma ASTM D7405, que prescreve os tempos de fluência e recuperação de 1 e 9 s, e avaliada a influência do aumento dos tempos de fluência e recuperação de 1 e 9 s para 2 e 18 s nas propriedades dos ligantes asfálticos envelhecidos a curto prazo. Além dos resultados destes ensaios, foram utilizados os valores de penetração, ponto de amolecimento, viscosidade rotacional, penetração retida, incremento do ponto de amolecimento, incremento de viscosidade e perda de massa para verificar quais ligantes asfálticos apresentam melhor comportamento à luz das propriedades e parâmetros considerados. Foram preparados doze materiais modificados e de classificação PG 76-XX tendo como base um CAP 50/70 de classificação PG 64-XX: CAP+PPA, CAP+Elvaloy+PPA, CAP+borracha, CAP+borracha+PPA, CAP+SBS, CAP+SBS+PPA, CAP+EVA, CAP+EVA+PPA, CAP+PE, CAP+PE+PPA, CAP+SBR e CAP+SBR+PPA. O CAP+Elvaloy+PPA apresenta, em um contexto geral, o melhor desempenho nas propriedades e parâmetros analisados em virtude dos bons resultados do percentual de recuperação e da compliância não-recuperável e das menores sensibilidades à tensão. O CAP+PE apresenta o pior desempenho geral dentre os materiais estudados, na medida em que os resultados do percentual de recuperação e da compliância não-recuperável deste ligante asfáltico são ruins e as sensibilidades ao aumento nos tempos de fluência e recuperação de 1 e 9 s para 2 e 18 s são elevadas. Ao ordenar os ligantes asfálticos do melhor para o pior à luz das propriedades e parâmetros considerados, o resultado é: CAP+Elvaloy+PPA, CAP+EVA, CAP+EVA+PPA, CAP+PPA, CAP+borracha+PPA, CAP+SBR+PPA, CAP+SBS+PPA, CAP+SBS, CAP+PE+PPA, CAP+borracha, CAP+SBR, CAP 50/70 e CAP+PE. / The multiple stress creep and recovery (MSCR) test is the result of a refinement of the repeated creep and recovery test (RCRT). This refinement was performed by the United States Federal Highway Administration (FHWA) with the aim of evaluating the percent recovery, the non-recoverable compliance and the stress dependency of asphalt binders, especially the modified ones. The MSCR test was applied in this study in order to characterize the creep-recovery behavior of unaged and short-term aged modified asphalt binders. The test procedure prescribed in ASTM D7405 specification was adopted and, to evaluate the influence of a greater creep-recovery time in the behavior of asphalt binders, the creep and recovery times of 2 and 18 s were also adopted in additional tests. The results of these tests, as well as the penetration, softening point, rotational viscosity, retained penetration, softening point increase, viscosity increase and mass loss data and mixing and compaction temperatures, were used with the objectives of ranking the asphalt binders and checking the ones with the best results in the parameters and properties considered. By using a PG 64-XX base asphalt-binder of 50/70 penetration grade, the following PG 76-XX odified asphalt binders were prepared: AC+PPA, AC+Elvaloy+PPA, AC+crumb rubber, AC+crumb rubber+PPA, AC+SBS, AC+SBS+PPA, AC+EVA, AC+EVA+PPA, AC+PE, AC+PE+PPA, AC+SBR and AC+SBR+PPA. In general, AC+Elvaloy+PPA has the best results in the parameters and properties considered in this study, especially due to the good results in the percent recovery and non-recoverable compliance and the lower stress sensitivity. In general, AC+PE has the worst results among the asphalt binders considered in this work, due to the facts that the percent recovery and non-recoverable compliance results are not good and the sensitivities to the creep-recovery times are high. By taking the results of this study and ranking the asphalt binders from the best to the worst, the following sequence is obtained: AC+Elvaloy+PPA, AC+EVA, AC+EVA+PPA, AC+PPA, AC+crumb rubber+PPA, AC+SBR+PPA, AC+SBS+PPA, AC+SBS, AC+PE+PPA, AC+crumb rubber, AC+SBR, neat AC and AC+PE.

O envelhecimento dos ligantes asfálticos possui uma grande influência sobre as propriedades mecânicas das misturas asfálticas. As especificações atuais limitam determinados índices ou parâmetros de envelhecimento, visando contornar o endurecimento excessivo do ligante asfáltico, porém, não levam em conta o efeito da radiação ultravioleta (UV). O objetivo deste trabalho é avaliar o efeito dos envelhecimentos termo-oxidativo e foto-oxidativo sobre as propriedades reológicas de um CAP puro e 11 ligantes asfálticos modificados, incluindo polímeros elastoméricos e plastoméricos, borracha moída de pneus e ácido polifosfórico, incluindo também combinações destes aditivos. Os ligantes asfálticos, com classificação por grau de desempenho PG 76-XX, preparados com base em um CAP 50-70 com classificação PG 64-22, foram previamente envelhecidos a curto prazo na estufa RTFO e posteriormente submetidos ao envelhecimento foto-oxidativo em uma estufa UV sob dois níveis de radiação, 0,68 W/m² e 1,00 W/m², por um período de 240 h. Para efeitos de comparação dos resultados, as mesmas amostras foram submetidas ao envelhecimento termo-oxidativo na estufa PAV. As amostras virgens e envelhecidas a curto prazo foram caracterizadas por meio de ensaios empíricos. Os resíduos obtidos nos envelhecimentos foram submetidos a ensaios no reômetro de cisalhamento dinâmico (DSR). Propriedades reológicas dos ligantes asfálticos foram analisadas por meio de curvas-mestre e do ensaio de fadiga LAS. Algumas amostras foram caracterizadas quimicamente por meio de espectroscopia no infravermelho (FTIR), cromatografia por permeação em gel (GPC) e do fracionamento SARA. Para a maioria das amostras os procedimentos PAV e UV a 0,68 W/m² apresentam certa equivalência, em termos da capacidade de alterar as propriedades reológicas analisadas. O ligante asfáltico que mostrou ser menos sensível ao envelhecimento PAV foi o CAP+SBR, o que demonstrou ser menos sensível ao envelhecimento UV a 0,68 W/m² foi o CAP+EVA, e o que demonstrou menor sensibilidade ao envelhecimento UV a 1,00 W/m² foi o CAP+SBS. O CAP+SBS+PPA foi a amostra que apresentou maior sensibilidade ao envelhecimento PAV e UV a 1,00 W/m². / Aging of the asphalt binders has a great influence on the mechanical properties of asphalt mixtures. The current specifications establish limits for some indexes or aging parameters in an attempt to avoid the excessive hardening of the asphalt binder; however, they do not take into account the effects of ultraviolet (UV) irradiation. The objective of this study is to analyze the impact of thermo-oxidative and UV aging methods on the rheological properties of a base asphalt cement (AC) and 11 formulations prepared with additives, i. e., elastomeric and plastomeric polymers, ground tire rubber and polyphosphoric acid. Combinations these additives were also included in the study. The modified asphalt binders are graded as PG-76 XX in the Superpave specification, whereas the 50-70 base AC is graded as PG 64-22 in the same specification. The materials were first aged in the rolling thin-film oven (RTFO), and then submitted to photo-oxidative aging in an UV oven at two irradiation levels (0.68 W/m² and 1.00 W/m²) for 240 h. For comparison purposes, these formulations were also subjected to thermo-oxidative aging in the pressurized aging vessel (PAV). The unaged and short-term aged samples were characterized by means of empirical tests. The residues obtained in the RTFOT, PAV e UV aging methods were tested in the dynamic shear rheometer (DSR). The rheological properties of asphalt binders were analyzed by means of master curves and the linear amplitude sweep (LAS) fatigue test. Some samples were chemically characterized by the Fourier transform infrared spectroscopy (FTIR), the gel permeation chromatography (GPC) and the SARA fractionation techniques. The PAV and the UV procedures at 0.68 W/m² show some similarities for many formulations in terms of the ability to change their rheological properties. The AC+SBR was found to be less sensitive to PAV aging than the other studied binders, whereas the AC+EVA was the less sensitive material to UV aging at 0.68 W/m² and the AC+SBS showed the lowest sensitivity to UV aging at 1.00 W/m². The AC+SBS+PPA was the most sensitive formulation to PAV and UV aging at 1.00 W/m².

A adição de modificadores no ligante asfáltico visando melhorar o seu comportamento é uma prática comum atualmente. Existem vários tipos de modificadores, entre eles o mais utilizado nas rodovias federais brasileiras é o copolímero SBS. Além dos polímeros, o ácido polifosfórico (PPA) é outro tipo de modificador que produz boas características quando adicionado ao ligante asfáltico. Apesar do efeito positivo, sabe-se que este material é importado, o que dificulta sua aquisição e pode tornar o produto final muito caro. Tendo em vista a possibilidade de se trabalhar com um produto de mesma base, mas de origem nacional, o que o tornaria o modificador mais acessível, optou-se por verificar o comportamento da adição de ácido fosfórico (PA85) ao ligante asfáltico. Sendo assim, o propósito desta tese é analisar o efeito da adição de ácidos fosfóricos no comportamento reológico de ligantes asfálticos puros e modificados com o copolímero SBS. Para tanto, realizou-se ensaios empíricos e reológicos com o intuito de verificar o comportamento destes materiais. Na primeira parte da pesquisa, dois ligantes asfálticos de base, CAP50/70 de classificação PG64-XX, (Replan e Lubnor), foram modificados somente com a adição dos dois ácidos (PPA e PA85), enquanto na segunda parte esses ligantes asfálticos de base foram modificados com o copolímero SBS com ou sem a presença dos ácidos. Os ensaios avaliados foram penetração, ponto de amolecimento, viscosidade rotacional, ensaio de fluência e recuperação sob tensão múltipla (MSCR), LAS modificado, e estabilidade à estocagem. De maneira geral, a adição dos modificadores melhora o comportamento dos ligantes asfálticos, tendo em vista que melhoram a recuperação, ficam menos sensíveis à deformação permanente e são mais tolerantes à fadiga. Pode-se constatar que o tipo de ligante asfáltico de base influencia diretamente o comportamento dos materiais, independente dos modificadores adicionados. A adição dos modificadores foi mais expressiva no ligante asfáltico proveniente da Replan. Em relação aos ácidos, conclui-se que a adição do PA85 foi satisfatória, uma vez que apresentou comportamento semelhante ao do ácido PPA, porém com efeito um pouco menos expressivo. A adição dos ácidos melhorou a estabilidade à es tocagem dos ligantes asfálticos modificados, e pode-se constatar que a adição de um destes modificadores permite a redução do teor do copolímero SBS. Quanto à capacidade de suporte de tráfego, a adição de altos teores desses modificadores não é viável, devido ao fato de apresentarem suporte similar a ligantes asfálticos modificados com teores baixos e intermediários. / The addition of modifiers in asphalt binder to improve its behavior is a common practice nowadays. There are many types of modifiers, among them the most used in the Brazilian federal highways is the SBS copolymer. In addition to polymers, polyphosphoric acid (PPA) is another type of modifier that produces good characteristics when added to asphalt binder. Despite the positive effects, it is known that this material is imported, which makes its purchase as well as the final product very expensive. Considering the opportunity to work with a product with the same basic component, but of national origin, which would make it the most affordable modifier, the present study decided to verify the behavior of the addition of phosphoric acid (PA85) to the asphalt binder. Therefore, the purpose of this thesis is to analyze the effect of the addition of phosphoric acid to the rheological behavior of pure and modified asphalt binders with the SBS copolymer. For both, empirical and rheological tests were conducted in order to verify the behavior of these materials/substances. In the first part of the research, two asphalt binders base CAP50/70 asphalt binder graded PG64-XX (Replan and Lubnor) were modified only with the addition of the two acids (PPA and PA85), while in the second part of these asphalt binders base were modified with SBS copolymer with or without the presence of acids. The tests evaluated penetration, softening point, rotational viscosity, multiple stress creep and recovery (MSCR), LAS modified, and storage stability. In general, the addition of the modifiers enhances the behavior of the asphalt binders, for they improve recovery, are less susceptible to rutting and are more resistant to fatigue. It was found that the type of asphalt binder base directly influences the behavior of materials, regardless of added modifiers. The addition of modifiers was greater in the asphalt binder from the Replan. Compared to acids, it is concluded that the addition of PA85 was satisfactory, since the performance was similar to the PPA acid behavior, but with slightly less significant effect. The addition of acid improved the storage stability of the modified asphalt binders, and it was found that the addition of such modifiers allows reducing the content of the SBS copolymer. Regarding the ability to support traffic, the addition of high levels of these modifiers is not feasible because they show similar support for modified asphalt binders with low and intermediate levels.

Trata-se de uma investigação sobre a influência de alguns fatores no comportamento mecânico de misturas asfálticas densas quanto à estabilidade e à flexibilidade. Foram testados três tipos de ligantes, asfalto convencional, modificado com 4,5% de SBS e modificado com 20% de borracha reciclada de pneu; duas distribuições granulométricas do agregado, centros das faixas B e C do DNER (1997); quatro teores de ligante, escolhidos com base nos valores de volumes de vazios e espessuras de película almejados; três condições de envelhecimento a longo prazo, mistura não envelhecida, envelhecida em estufa ventilada a 85ºC por 5 dias e envelhecida por exposição ao tempo por 4 meses; e duas condições de envelhecimento a curto prazo, mistura não envelhecida e envelhecida em estufa ventilada a 135ºC por 4 horas. A técnica de planejamento e análise de experimentos fatoriais fracionários assimétricos foi utilizada para a consideração simultânea dos fatores citados. O comportamento mecânico das misturas foi avaliado através dos ensaios de resistência à tração, módulo de resiliência e fluência por compressão uniaxial estática e dinâmica. A análise de variância dos resultados permitiu a identificação dos fatores com influência significativa nas respostas dos ensaios. O modo como cada fator interferiu nas propriedades apresentadas pelas misturas foi estabelecido através da construção de modelos estatísticos de comportamento. Os resultados mostraram que a adição de modificadores ao asfalto melhora a resistência das misturas à fadiga e à deformação permanente. Os processos de envelhecimento aumentaram os módulos de resiliência das misturas mas diminuíram sua capacidade de recuperação elástica, o que significa queda de resistência à fadiga. Por outro lado, a resistência a deformações permanentes das misturas, inclusive daquelas compostas por asfaltos modificados, aumentou com o envelhecimento. / This work deals with the influence of some factors in the mechanical behavior of asphalt mixtures stability and flexibility. Three types of binders were tested, conventional one, modified with 4,5% of SBS and modified with 20% of recycled tire rubber. Two aggregate gradations were tested, center of B and C gradations of DNER (1997). Four binder contents were chosen based on the air voids and film thickness. Three types of long-term aging were tested, not aged, aged in a forced-draft oven for 5 days at 85ºC and aged through weather exposition for the period of 4 months. Two types of short-term aging were tested; not aged and aged in a forced-draft oven for 4 hours at 135ºC. The technique of design and analysis of asymmetric fractional factorial experiments was used for the simultaneous analysis of the factors. The mechanical behavior of the mixtures was evaluated based on indirect tensile strength test, resilient modulus test and static and dynamic creep tests. The results of the analysis of variance allowed the identification of factors with significant influence in the answers. The influence of the factors in the mixtures properties was established through statistical models of behavior. The results showed that modified binders improves the mixtures resistance in relation to fatigue and to permanent deformation. The aging processes increased the resilient modulus of the mixtures, but also decreased its capacity of elastic return, resulting in a lost of fatigue resistance. On the other hand, the permanent deformation resistance of the aging mixtures increased, including the mixtures with modified binders cases.

Les structures avec des lieurs sont très communes en informatique. Les langages de programmation et les systèmes logiques sont des exemples de structures avec des lieurs. La manipulation de lieurs est délicate, de sorte que l’écriture de programmes qui ma- nipulent ces structures tirerait profit d’un soutien spécifique pour les lieurs. L’environ- nement de programmation Beluga est un exemple d’un tel système. Nous développons et présentons ici un compilateur pour ce système. Parmi les programmes pour lesquels Beluga est spécialement bien adapté, plusieurs peuvent bénéficier d’un compilateur. Par exemple, les programmes pour valider les types (les "type-checkers"), les compilateurs et les interpréteurs tirent profit du soutien spécifique des lieurs et des types dépendants présents dans le langage. Ils nécessitent tous également une exécution efficace, que l’on propose d’obtenir par le biais d’un compilateur. Le but de ce travail est de présenter un nouveau compilateur pour Beluga, qui emploie une représentation interne polyvalente et permet de partager du code entre plusieurs back-ends. Une contribution notable est la compilation du filtrage de Beluga, qui est particulièrement puissante dans ce langage. / In computer science, structures with variable binders are very common. Program- ming languages and logical frameworks are examples of structures with binders. Thus writing programs that deal with these kinds of data benefits with explicit support for data binding. The Beluga programming environment is an example of such a system. In this work we develop and present a compiler for the system. Many of the programs that Beluga is specially well suited for writing can benefit from a compiler. For example, some of the kinds programs that would benefit more are type-checkers, compilers and interpreters that take advantage of the binder support and dependent types present in the language, and also require a reasonably fast run-time. Our goal in this work, is to present a compiler for the Beluga system, that uses a very versatile internal representation that helps with the development of the system, and allows a sharing of code between several back-ends. Furthermore, we present a way of compiling the uniquely powerful pattern language supported by Beluga.

La maladie cœliaque ou sprue cœliaque est une intolérance au gluten. Il s’agit d’une maladie inflammatoire de l’intestin liée à l’ingestion de gluten chez des personnes génétiquement susceptibles. Ce désordre présente une forte prévalence puisqu’il touche 1 % de la population mondiale. En l’état actuel des choses, il n’existe aucun outil pharmacologique pour traiter ou pallier à cette maladie. Cependant, grâce aux avancées dans la compréhension de sa pathogenèse, de nouvelles cibles thérapeutiques ont été identifiées. À l’heure actuelle, le seul traitement efficace consiste à suspendre la consommation de l’agent pathogène, à savoir le gluten. Le gluten est un ensemble de protéines de stockage des céréales contenu dans le blé, l’orge et le seigle. Le gluten du blé se subdivise en gluténines et gliadines. Ce sont ces dernières qui semblent les plus impliquées dans la maladie cœliaque. Les gliadines et ses protéines apparentées (i.e. sécalines et hordéines, respectivement dans le seigle et l’orge) sont riches en prolines et en glutamines, les rendant résistantes à la dégradation par les enzymes digestives et celles de la bordure en brosse. Les peptides résultant de cette digestion incomplète peuvent induire des réponses immunitaires acquises et innées. L’objectif principal de cette thèse était de tester un nouveau traitement d’appoint de la maladie cœliaque utile lors de voyages ou d’évènements ponctuels. Dans les années 80, une observation italienne montra l’inhibition de certains effets induits par des gliadines digérées sur des cultures cellulaires grâce à la co-incubation en présence de mannane: un polyoside naturel composé de mannoses. Malheureusement, ce traitement n’était pas applicable in vivo à cause de la dégradation par les enzymes du tractus gastro-intestinales du polymère, de par sa nature osidique. Les polymères de synthèse, grâce à la diversité et au contrôle de leurs propriétés physico-chimiques, se révèlent être une alternative attrayante à ce polymère naturel. L’objectif de cette recherche était d’obtenir un polymère liant la gliadine, capable d’interférer dans la genèse de la maladie au niveau du tube digestif, afin d’abolir les effets délétères induits par la protéine. Tout d’abord, des copolymères de type poly (hydroxyéthylméthacrylate)-co-(styrène sulfonate) (P(HEMA-co-SS)) ont été synthétisés par polymérisation radicalaire contrôlée par transfert d’atome (ATRP). Une petite bibliothèque de polymères a été préparée en faisant varier la masse molaire, ainsi que les proportions de chacun des monomères. Ces polymères ont ensuite été testés quant à leur capacité de complexer la gliadine aux pH stomacal et intestinal et les meilleurs candidats ont été retenus pour des essais cellulaires. Les travaux ont permis de montrer que le copolymère P(HEMA-co-SS) (45:55 mol%, 40 kDa) permettait une séquestration sélective de la gliadine et qu’il abolissait les effets induits par la gliadine sur différents types cellulaires. De plus, ce composé interférait avec la digestion de la gliadine, suggérant une diminution de peptides immunogènes impliqués dans la maladie. Ce candidat a été testé in vivo, sur un modèle murin sensible au gluten, quant à son efficacité vis-à-vis de la gliadine pure et d’un mélange contenant du gluten avec d’autres composants alimentaires. Le P(HEMA-co-SS) a permis de diminuer les effets sur les paramètres de perméabilité et d’inflammation, ainsi que de moduler la réponse immunitaire engendrée par l’administration de gliadine et celle du gluten. Des études de toxicité et de biodistribution en administration aigüe et chronique ont été réalisées afin de démontrer que ce dernier était bien toléré et peu absorbé suite à son administration par la voie orale. Enfin des études sur des échantillons de tissus de patients souffrants de maladie cœliaque ont montré un bénéfice therapeutique du polymère. L’ensemble des travaux présentés dans cette thèse a permis de mettre en évidence le potentiel thérapeutique du P(HEMA-co-SS) pour prévenir les désordres reliés à l’ingestion de gluten, indiquant que ce type de polymère pourrait être exploité dans un avenir proche. / Celiac Disease or celiac sprue is identified as a gluten intolerance. It is an inflammatory disorder of the intestine triggered by the ingestion of gluten in genetically susceptible individuals. This condition is highly prevalent because it affects up to 1% of the worldwide population. Nowadays, there is no pharmacological treatment available to treat or off set to the disease. Due to the huge progress in the understanding of the pathogenesis, new therapeutic targets have been discovered. At the present time, the only effective treatment remains the strict lifelong abandonment of the pathogen agent, gluten. Gluten encompasses the storage proteins in wheat, rye and barley. The wheat gluten is divided into glutenins and gliadins. The latter seem to be the most important trigger in the celiac disease. Gliadins and the related proteins (i.e. secalins and hordeins, respectively in rye and barley) are rich in prolin and glutamin residues, conferring them to be resistant by enzymatic digestion. The resulting peptides of the incomplete process may set off the inflammatory reaction. The main objective of this thesis was to test a new supportive therapy in treating celiac disease, useful in punctual occasion (i.e. during travel or social event when the gluten-free property cannot be ascertained). In the 1980’s, inhibition of some gliadin-induced effects on cell cultures were observed owing to mannan co-incubation. However, this compound, due to his osidic nature, may be cleaved by digestive enzymes in vivo. Synthetic polymers prove to be an attracting alternative owing to the tunability of their physical and chemical properties. The goal of this study was to obtain a polymeric gliadin-binder, interferring with the pathogenesis of the celiac disease in the gastro-intestinal tract, to abrogate the gliadin induced effects. Atom transfer radical polymerization was used to synthesize copolymers of the type poly (hydroxyethylméthacrylate)-co-(styren sulfonate) (P(HEMA-co-SS)). A small library of polymers varying in their molecular weight and in their constituting monomers ratio was prepared. The ability of these polymers to sequester gliadin was assessed at stomacal and intestinal pH. The best candidates were further evaluated in cell cultures. Our results revealed that a selective binding was obtained with the P(HEMA-co-SS) (45:55 mol%, 40 kDa). This compound abolished gliadin-induced effects on various cell lines. In addition, gliadin digestion was hindered, suggesting a decrease in the formation of immunogenic peptides known to trigger the diseases. In vivo experiments were additionally carried out on a murine model of gluten-sensitivity with this polymeric candidate. Its efficacy towards pure gliadin and gluten containing food was tested. P(HEMA-co-SS decreased gliadin–induced effect on permeability and inflammatory parameters and modulated the immune response due to gliadin/gluten gavage. Toxicity and biodistribution studies following acute and chronic administration were performed on murine to demonstrate that the polymer was well tolerated and not absorbed after oral administration. Finally, biopsies of patients suffering from CD disease exhibited therapeutic benefit of the polymer. Altogether, the results presented in this thesis evidenced the potential of P(HEMA-co-SS) to prevent the gluten-induced disorder, indicating that this type of polymer may be useful in a near future.

Direct compression has gained significant interest since its advent in the late 1950's due to its potential ease compared to wet granulation. The primary prerequisites for powders used in direct compression are (i) good flow properties (ii) good compressibility and (iii) an acceptable dilution potential to accommodate a relative high percentage of active ingredient. Several filler/binders have been manufactured especially for direct compression and co–processing is one of the recent methods used to produce good compressible excipients with acceptable flow properties. In this study, lactose–based filler/binders were used which included simple and modified lactose materials (Granulac, Lactopress, Flowlac and Tablettose) as well as co–processed excipients (Starlac, Cellactose and Microcelac). A comprehensive literature study on direct compression revealed the importance of the physical properties of filler/binders such as interparticle forces, particle shape, particle size and distribution, powder density, particle surface structure and particle packing geometry which influence the flow of powders. All the materials were subjected to the various tests available to evaluate powder flow, namely (i) angle of repose (AoR), (ii) critical orifice diameter (COD), (iii) flow rate and percentage compressibility (%C) in terms of the powders' bulk and tap densities. The results of these tests confirmed the expected flow properties of the various filler/binders, with only one material exhibiting extremely poor flow properties. The following rank order in terms of all flow tests conducted was established; Starlac >> Microcelac ~ Flowlac >> Cellactose > Tablettose > Lactopress >>> Granulac. The co–processed filler/binders presented with superior flow compared to the other lactose–based materials. During the next phase of the study, the compaction properties of the various fillers were evaluated, employing direct compression. Compacts of pure filler were tabletted on an eccentric tablet press at different compression pressures (manipulated by the upper punch setting of the tablet press). The modified lactose filler/binders (Lactopress, Flowlac and Tablettose) exhibited unexpectedly poor compression profiles, where the co–processed filler/binders (Starlac, Cellactose and Microcelac) produced compacts with acceptable appearance and compact properties. Two lubricants (Mg–St or Pruv), which were tested separately in formulations were added since no compacts could be produced from the pure filler/binders. None of the modified lactose filler/binders, in combination with a lubricant, were able to produce an acceptable compact, since lamination occurred during compression. The co–processed filler/binders produced satisfactory compacts with the addition of a lubricant, but lactose–cellulose fillers (Cellactose and Microcelac) also required the inclusion of a disintegrant (Ac–Di–Sol) to induce satisfactory compact disintegration. Poor compressible active ingredients (paracetamol), which exhibit very poor flow properties, are usually difficult to use during direct compression. Many excipients (tested in this study) are formulated to accommodate these drugs and produce acceptable functional tablets. After identifying the best filler/binders (co–processed fillers), according to their flow and compressible properties, paracetamol was added to the formulations. During a pilot study, the percentage paracetamol these fillers could accommodate in a 400 mg tablet was determined. Both Microcelac and Cellactose could accommodate 24.5% w/w paracetamol, whilst Starlac could only accommodated 19.5% w/w. Paracetamol is well known for its tendency to cause tablet capping and lamination. An acceptable upper punch setting range (20–22) was chosen for tabletting, followed by quality control tests done. All three formulations produced suitable tablets for testing and exhibited good tablet properties. All tablets disintegrated within two minutes, with hardness profiles between 120 N and 148 N and friability percentages less than 1%. Dissolution studies, however, are probably the ultimate test to distinguish between the capability of filler/binders to release the optimum percentage drug after disintegration. Dissolution studies were done on all three formulations using the AUC (area under the curve) and IDR (initial drug release) as parameters to evaluate drug release. All tablets exhibited high initial dissolution rates (between 0.018 - 0.023 mg/min/ml) and 100% drug release was observed. Starlac presented with a lower amount of drug released compared to the other two, but can be explained by the lower percentage (19.5%) paracetamol present in the formulation. It was once again confirmed that the physical and compressible properties of potential directly compressible filler/binders play a major role in direct compression. It was concluded that co–processed filler/binders (Starlac, Microcelac and Cellactose) definitely exhibited better tabletting properties during direct compression. They were able to accommodate a certain percentage of paracetamol, although it was expected that they would accommodate a higher amount (at least 50% of total tablet weight). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Direct compression has gained significant interest since its advent in the late 1950's due to its potential ease compared to wet granulation. The primary prerequisites for powders used in direct compression are (i) good flow properties (ii) good compressibility and (iii) an acceptable dilution potential to accommodate a relative high percentage of active ingredient. Several filler/binders have been manufactured especially for direct compression and co–processing is one of the recent methods used to produce good compressible excipients with acceptable flow properties. In this study, lactose–based filler/binders were used which included simple and modified lactose materials (Granulac, Lactopress, Flowlac and Tablettose) as well as co–processed excipients (Starlac, Cellactose and Microcelac). A comprehensive literature study on direct compression revealed the importance of the physical properties of filler/binders such as interparticle forces, particle shape, particle size and distribution, powder density, particle surface structure and particle packing geometry which influence the flow of powders. All the materials were subjected to the various tests available to evaluate powder flow, namely (i) angle of repose (AoR), (ii) critical orifice diameter (COD), (iii) flow rate and percentage compressibility (%C) in terms of the powders' bulk and tap densities. The results of these tests confirmed the expected flow properties of the various filler/binders, with only one material exhibiting extremely poor flow properties. The following rank order in terms of all flow tests conducted was established; Starlac >> Microcelac ~ Flowlac >> Cellactose > Tablettose > Lactopress >>> Granulac. The co–processed filler/binders presented with superior flow compared to the other lactose–based materials. During the next phase of the study, the compaction properties of the various fillers were evaluated, employing direct compression. Compacts of pure filler were tabletted on an eccentric tablet press at different compression pressures (manipulated by the upper punch setting of the tablet press). The modified lactose filler/binders (Lactopress, Flowlac and Tablettose) exhibited unexpectedly poor compression profiles, where the co–processed filler/binders (Starlac, Cellactose and Microcelac) produced compacts with acceptable appearance and compact properties. Two lubricants (Mg–St or Pruv), which were tested separately in formulations were added since no compacts could be produced from the pure filler/binders. None of the modified lactose filler/binders, in combination with a lubricant, were able to produce an acceptable compact, since lamination occurred during compression. The co–processed filler/binders produced satisfactory compacts with the addition of a lubricant, but lactose–cellulose fillers (Cellactose and Microcelac) also required the inclusion of a disintegrant (Ac–Di–Sol) to induce satisfactory compact disintegration. Poor compressible active ingredients (paracetamol), which exhibit very poor flow properties, are usually difficult to use during direct compression. Many excipients (tested in this study) are formulated to accommodate these drugs and produce acceptable functional tablets. After identifying the best filler/binders (co–processed fillers), according to their flow and compressible properties, paracetamol was added to the formulations. During a pilot study, the percentage paracetamol these fillers could accommodate in a 400 mg tablet was determined. Both Microcelac and Cellactose could accommodate 24.5% w/w paracetamol, whilst Starlac could only accommodated 19.5% w/w. Paracetamol is well known for its tendency to cause tablet capping and lamination. An acceptable upper punch setting range (20–22) was chosen for tabletting, followed by quality control tests done. All three formulations produced suitable tablets for testing and exhibited good tablet properties. All tablets disintegrated within two minutes, with hardness profiles between 120 N and 148 N and friability percentages less than 1%. Dissolution studies, however, are probably the ultimate test to distinguish between the capability of filler/binders to release the optimum percentage drug after disintegration. Dissolution studies were done on all three formulations using the AUC (area under the curve) and IDR (initial drug release) as parameters to evaluate drug release. All tablets exhibited high initial dissolution rates (between 0.018 - 0.023 mg/min/ml) and 100% drug release was observed. Starlac presented with a lower amount of drug released compared to the other two, but can be explained by the lower percentage (19.5%) paracetamol present in the formulation. It was once again confirmed that the physical and compressible properties of potential directly compressible filler/binders play a major role in direct compression. It was concluded that co–processed filler/binders (Starlac, Microcelac and Cellactose) definitely exhibited better tabletting properties during direct compression. They were able to accommodate a certain percentage of paracetamol, although it was expected that they would accommodate a higher amount (at least 50% of total tablet weight). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / It is certain that most of Brazilian highways are under unfavorable conditions of trafficability. Technological developments led to a large increase in load capacity of trucks, resulting in higher impacts on the highways. Another factor to be considered in this degradation process of pavements is climatic variations, very common in Brazil. Among many types of defects found on Brazilian highways, one deserves special attention, the fatigue cracking. Aiming to investigate this problem, this study aimed to study the fatigue phenomenon in laboratory for asphalt mixture used in the field (Av. Hélvio Basso, Santa Maria-RS) and evaluate in laboratory its possible improvement using polymer modified binder before to fatigue performance at three different temperatures: 10°C, 25°C and 35°C. Three asphalt mixtures were prepared in the la, two conventional binder used in the monitored section (CACAMPO asphalt content in the field, and CALAB 50/70 asphalt content obtained in laboratory dosage), and a third polymer modified binder with (CALAB 60/85-E). Mixtures reproduced in the laboratory were prepared according to the Marshall methodology and the materials were characterized according to traditional experiments. For all mixtures, the volumetric parameters were determined, stability, fluency, adhesion, Indirect Tensile Streght, Total Resilience Moduli and performance to fatigue by indirect tensile stress under controlled mode. These last three were held at the three test testing temperatures. In the laboratory, it was evident the improvement in thermal susceptibility properties and stability of the mixture by using the modified binder polymer, providing a blend less susceptible to variations in temperature and stable at high temperatures. The results obtained in the laboratory demonstrated the superiority of the mixture CALAB 60/85 E, for the three temperatures studied, with emphasis on the destructive tests at the higher temperature. The rigidity of the mixtures, measured by the resilience module, showed little influence by the use of the modified binder, however, showed very different behavior with variation in temperature. Regarding the fatigue performance, the modified blends proved to be far superior than the conventional mix, ensuring an increase in service life for the three temperatures studied, specially for the temperature of 35°C. The temperature variation of the test proved to be very crucial in the fatigue performance of the asphalt mixture, which is inversely proportional to the temperature increase. At the end of the study, it is concluded that the use of polymer modified binders for can be a great option to improve the performance of asphalt mixtures against the fatigue rupture mechanism and it can be used successfully in regions with large temperature variations. Thus, it is possible to ensure an increase in the service life of the asphalt layer and therefore to the pavement as a whole. / É notório que grande parte das rodovias brasileiras encontram-se em condições desfavoráveis de trafegabilidade. A evolução tecnológica permitiu um grande aumento da capacidade de carga dos caminhões, refletindo em maiores solicitações nas rodovias. Outro fator a ser considerado neste processo degradativo dos pavimentos são as variações climáticas, muito presentes no Brasil. Dentre tantos tipos de defeitos encontrados nas rodovias brasileiras, um deles merece destaque especial, a degradação por fadiga. Com intuito de investigar tal problema, o presente trabalho teve como propósito estudar o fenômeno de fadiga em laboratório para uma mistura asfáltica utilizada em campo (Av. Hélvio Basso, Santa Maria-RS) e avaliar, em laboratório, a sua possível melhora pelo uso de ligante modificado por polímero perante o seu desempenho à fadiga, em três temperaturas distintas: 10°C, 25°C e 35°C. Foram preparadas em laboratório três misturas asfálticas, duas com o ligante convencional utilizado no trecho monitorado (CACAMPO, teor de asfalto de campo, e CALAB 50/70, teor de asfalto obtido em dosagem de laboratório) e uma terceira, com ligante modificado por polímero (CALAB 60/85-E). As misturas foram preparadas conforme a Metodologia Marshall e os insumos foram caracterizados de acordo com ensaios tradicionais. Para todas as misturas, determinram-se os parâmetros volumétricos, estabilidade, fluência, adesividade, Resistência à Tração indireta, Módulo de Resiliência total e desempenho à fadiga por tração indireta à tensão controlada. Estes três últimos foram realizados nas três temperaturas de ensaio. Em laboratório, ficou evidente a melhora das propriedades de suscetibilidade térmica e estabilidade da mistura pelo uso do ligante modificado por polímero, proporcionando uma mistura menos suscetível às variações de temperatura e mais estável a temperaturas elevadas. Os resultados obtidos em laboratório demonstraram a superioridade da mistura CALAB 60/85-E, para as três temperaturas analisadas, com ênfase para os ensaios destrutivos à temperatura mais elevada. A rigidez das misturas, medida pelo Módulo de Resiliência, mostrou-se pouco influenciável pela utilização do ligante modificado, porém, apresentou comportamentos bem distintos com a variação da temperatura. Quanto ao desempenho à fadiga, as misturas modificadas apresentaram-se muito superiores às convencionais, garantindo um incremento na vida de serviço para as três temperaturas analisadas, sendo este, mais evidente para a temperatura de 35°C. A variação da temperatura de ensaio mostrou-se bastante determinante no desempenho à fadiga das misturas asfálticas, sendo este, inversamente proporcional ao aumento de temperatura. Ao término do estudo, conclui-se que o emprego de ligantes modificados por polímero pode ser uma ótima opção de melhora do desempenho de misturas asfálticas frente ao mecanismo de ruptura por fadiga, podendo ser utilizado com sucesso em regiões que apresentam grandes variações térmicas. Desta forma, garantindo um incremento na vida de serviço do revestimento asfáltico e consequentemente ao pavimento como um todo.