No description available.

Yes / A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. Results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the environment and PEO molecular weight. / The research was funded by AstraZeneca, Sweden.

Die vorliegende Arbeit beschreibt die Herstellung und Charakterisierung der ersten Antikörper gegen Triacetontriperoxid (TATP), einem hoch empfindlichen und unkonventionellen (nicht-kommerziellen) Initialsprengstoff. Entscheidend dafür war die Synthese eines TATP-imitierenden Haptens, welches die typische nonagonale Struktur des TATP mit seinen drei Peroxid- und sechs Methylgruppen nahezu perfekt nachbildet, aber den Vorzug einer zusätzlichen Carboxygruppe zur kovalenten Kopplung an Proteine aufweist. Dadurch konnte das TATP-Hapten an Rinderserumalbumin (BSA) gebunden werden, um ein immunogenes Konjugat zu erzeugen, welches die erfolgreiche Immunisierung zweier Säugetierarten, Maus und Kaninchen, ermöglichte. Der Verlauf der In vivo-Immunisierungen wurde durch die Analyse der Tierseren in regelmäßigen Abständen mittels enzymgekoppeltem Immunoassay (ELISA) verfolgt. Die polyklonalen Antikörper beider Spezies waren ungewöhnlich selektiv gegenüber TATP. Jedoch unterschied sich die Affinität der Antikörper der zwei Spezies um das 5000-fache, wobei die Kaninchenseren den Mausseren überlegen waren. Entsprechend war auch die mit Kaninchenserum erreichbare TATP-Nachweisgrenze von 0.01 µg/L deutlich besser im Vergleich zu 50 µg/L, die mit Mausserum erzielt wurden. Der Messbereich des TATP-ELISA mit Kaninchenserum deckte zudem mehr als vier Zehnerpotenzen ab, wie mittels Präzisionsprofil bestimmt wurde. Die erhaltenen TATP-Antikörper aus Kaninchen stehen damit Anwendungen in Nachweissystemen für die sehr empfindliche Detektion von TATP zur Verfügung, die u. a. in sicherheitsrelevanten Bereichen zum Einsatz kommen könnten. Als erste Anwendung wurde ein TATP-ELISA realisiert, der im Rahmen dieser Arbeit ausführlich optimiert wurde. Außerdem wurden erste Schritte zur Entwicklung eines TATP-Schnelltests (LFA) unternommen. Weitere Biosensoren auf Grundlage der neu entwickelten TATP-Antikörper sind denkbar. / The present work decribes the production and characterization of the first antibodies against triacetone triperoxide (TATP), a highly sensitive and improvised (non-commercial) primary explosive. Crucial to this work was the synthesis of a TATP-related hapten that mimics almost perfectly the typical nonagonal structure of TATP with its three peroxide and six methyl groups. Advantageously, it has an additional carboxylic acid group, which provides a conjugation site for covalent attachment to proteins. Thus, the TATP hapten could be linked to bovine serum albumin (BSA) to produce an immunogenic conjugate, allowing the successful immunization of two different mammalian species, mouse and rabbit. The in vivo immunization progress was followed by periodically analyzing the animals’ sera using enzyme-linked immunosorbent assay (ELISA). The polyclonal antibodies of both species were remarkably selective to TATP. The affinity of these TATP-antibodies was, however, different between the two species, with the rabbit sera showing an affinity about 5000-fold superior than the murine one. Consequently, the TATP detection limit of 0.01 µg/L was considerably better using the sera from rabbit in contrast to 50 µg/L when mouse serum was used. The working range of the TATP-ELISA with rabbit sera covers more than four decades, calculated from a precision profile. The obtained TATP antibodies from rabbit are now available for applications in highly sensitive detection systems for TATP, which could be employed, among others, in security-relevant areas. The first application was the realization of a TATP-ELISA, which was extensively optimized within the course of this work. Furthermore, the first steps towards the development of a lateral flow assay (LFA) targeting TATP were taken, making conceivable further biosensor platforms based on the newly developed TATP antibodies.

No description available.

Made available in DSpace on 2016-04-25T16:45:04Z (GMT). No. of bitstreams: 1 Tiago Alves Costa.pdf: 830440 bytes, checksum: 40b830a47bb712666dd4a4ecfbcde61c (MD5) Previous issue date: 2008-04-29 / The finance science, as all sciences, shows an evolutionary line and according to Kuhn (1970), it is marked by shortly periods of knowledge accumulation. However, according to the author, such periods are inserted with scientific revolutions. In other words, the scientific evolution is stamped by revolutions which abandon oldfashioned paradigm and create new ones. The revolution is followed by a period where the researches are guided by the new paradigm and its purpose is strengthen the own paradigm. In other way, the finance science has today a central paradigm well-known by efficiency market hyperlink (EMH) which was witnessed and adopted by the entire scientific community around the 70 s. And since those times, almost entire research done in finance, mainly until the de 90 s, was leaded and done to validate the EMH. This dissertation attempted to evidence that the finance evolutionary line proposed by Haugen (2000) follows the same principle evidenced by Kuhn (1970), and in the present-day, the EMH find itself in a period which precede the scientific revolution which is called by time crisis by Kuhn (1970). This time crisis could weaken the EMH and open a space to create a new paradigm. This way, the proposal of dissertation is to prove how the revolutionary process will happen in finance too, soon after, to prove what would the candidates more inclined to replace the EMH be as a central paradigm in finance. To do so, this work considered only two candidates: the behavioral finance and the chaos theory. To do this analyze it was used the schooling principles nominated by Mckinley, Mone and Moon (2002). Such authors propose that a thought must display a combination of novelty, continuity, and scope to achieve school status in organizational theory. The purpose of this dissertation is to do a theory ransom which intends to show the fragility of the EMH as a central paradigm that orients the finance researches. The dissertation concludes that the current finance faces a crisis, and in this period, the behavioral finance displays the biggest chance to replace the EMH in the near future, however, the chaos theory provides the bigger promise considering a far future / A ciência das finanças, como toda ciência, apresenta uma linha evolutiva que de acordo com Kuhn (1970) é marcada por períodos de breve acumulação de conhecimento. Porém, de acordo com o autor, tais períodos são intercalados com revoluções científicas. Em outras palavras, a evolução científica é marcada por revoluções que abandonam antigos paradigmas e criam novos. Posteriormente à revolução, segue se um período onde as pesquisas são guiadas pelo novo paradigma com o propósito de fortalecer o próprio paradigma. De outra forma, a ciência financeira possui hoje um paradigma central conhecido como a hipótese de mercados eficientes (HME) que foi reconhecida e adotada pela comunidade científica por volta da década de 70. E desde aquela época, quase toda pesquisa feita na área, principalmente até a década de 90, foi guiada, e feita para validar e fortalecer a própria HME. Nesse sentido, este trabalho procurou evidenciar que a linha evolucionária das finanças proposta por Haugen (2000) segue o mesmo princípio evidenciado por Kuhn (1970), e que no momento atual, a HME encontra-se em um período que antecede a revolução científica e que é chamado de período de crise por Kuhn (1970). Esse período de crise, que antecede as revoluções, poderia enfraquecer a HME e abrir espaço para a criação de um novo paradigma. Sendo assim, o trabalho também propõe a evidenciar como que o processo de revolução poderá acontecer em finanças, e em seguida, também propõe quais seriam os candidatos mais propensos a substituir a HME como paradigma central em finanças. Para tanto, o trabalho considerou apenas dois candidatos: as finanças comportamentais e a teoria do caos. Para fazer tal análise, foram utilizados os princípios de escolarização propostos por Mckinley, Mone e Moon (2002). Tais autores propõem que um pensamento tem que possuir três características (novidade, continuidade e escopo) para ser considerado uma escola em teoria organizacional. O propósito do trabalho é de um resgate teórico básico que procura evidenciar a fragilidade da HME enquanto paradigma principal norteador das pesquisas em finanças. Assim sendo, o trabalho conclui que as finanças atuais enfrentam uma crise, e que nesse período, as finanças comportamentais apresentam a maior chance de substituir a HME em um futuro próximo, porém, a teoria do caos fornece uma promessa maior considerando um futuro mais distante

Applications of Hot Melt Extrusion (HME) in pharmaceuticals have become increasingly popular over the years but nonetheless a few obstacles still remain before wide scale implementation. In many instances these improvements are related to both processing and product performance. It is observed that HME process optimisation is majorly focused on the active pharmaceutical ingredient's (API) properties. Characterising polymeric properties for their suitability in HME should be equally studied since the impact of excipients on both product and process performance is just as vital. In this work, two well-established cellulose ester derivatives: Hydroxy Propyl Methyl Cellulose Acetate Succinate (HPMCAS) and Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP) are studied for their HME suitability. Their thermal, thermodynamic, rheological, thermo-chemical and degradation kinetic properties were evaluated with model plasticisers and APIs. It was found the thermal properties of HPMCP are severely compromised whereas HPMCAS is more stable in the processing zone of 150 to 200 °C. Thermodynamic properties revealed that both polymers share an important solubility parameter range (20-30 MPa P1/2P) where the majority of plasticisers and BCS class II APIs lie. Thus, greater miscibility/solubility can be expected. Further, the processability of these two polymers investigated by rheometric measurements showed HPMCAS possesses better flow properties than HPMCP because HPMCP forms a weak network of chain interactions at a molecular level. However, adding plasticisers such as PEG and TEC the flow properties of HPMCP can be tailored. The study also showed that plasticisers have a major influence on thermo-chemical and kinetic properties of polymers. For instance, PEG reduced polymer degradation with reversal in kinetic parameters whereas blends of CA produced detrimental effects and increased polymer degradation with reduction in onset degradation temperatures. Further, both polymers are observed to be chemically reactive with the APIs containing free -OH, -SOR2RN- and -NH2 groups. Finally, these properties prove that suitability of HPMCP is highly debated for HME and demands great care in use while that of HPMCAS is relatively better than HPMCP in many instances.

Cupriavidus metallidurans CH34 est une béta-protéobactérie, résistante aux métaux lourds, isolée des sédiments d'une usine de métallurgie non-ferreuse en Belgique. <p>Le génome de cette bactérie contient un chromosome (3.6 Mb), un mégaplasmide (2.6 Mb) et deux plasmides pMOL28 (171 kb) et pMOL30 (234 kb) déjà connus pour porter des gènes de résistance aux métaux lourds. <p>Nous avons d'abord fait le catalogue des gènes impliqués dans la résistance aux métaux lourds et, ensuite, cherché à mesurer leur expression par deux approches transcriptomiques :RT-PCR et puces à ADN.<p> L'analyse du génome montre au moins 170 gènes relatifs à la résistance aux ions métalliques localisés sur les 4 réplicons, principalement sur les deux plasmides. Ces gènes codent essentiellement pour des systèmes d'efflux tel que les HME-RND (transport chimioosmotique avec flux de protons à contresens), les ATPases de type P ou encore pour le système de résistance aux ions Cu(II). Dans le génome de C. metallidurans, nous avons identifié 13 opérons qui codent pour des systèmes HME-RND, seuls trois, localisés sur les plasmides, sont surexprimés en présence de métaux lourds. Huit gènes codent pour des ATPases de type P, dont deux appartiennent à une classe dont les substrats ne sont pas métalliques. Deux ATPases appartiennent à une famille spécialisée pour l'efflux du Cu(II) et les quatre autres à une autre grande famille impliquée dans l'efflux des ions Cd(II), Pb(II) et Zn(II). Les analyses transcriptomiques montrent la surexpression des deux premières classes d'ATPases P en présence des métaux lourds. La mutagenèse du gène zntA (mégaplasmide), codant pour l'une des ATPases, provoque une diminution de la viabilité en présence de Zn(II), Cd(II) et dans une moindre mesure de Pb(II), Tl(I) et Bi(III). <p>Sur pMOL30, la résistance au cuivre implique un groupe de 19 gènes cop codant pour la résistance au cuivre au niveau du périplasme et du cytoplasme, et vraisemblablement pour une forme de stockage du cuivre essentiel. Ces 19 gènes sont surexprimés en présence de cuivre, mais une quinzaine de gènes proches semblent aussi requis pour une expression optimale de la résistance au cuivre. <p>L'annotation des plasmides a mis en évidence la parenté du plasmide pMOL28 avec le plasmide pHG1 (hydrogénotrophie, fixation du CO2) de C. eutrophus H16 et le plasmide pSym (fixation de l'azote) de C. taiwanensis, et chez pMOL30, la présence de deux îlots génomiques concentrant la plupart des résistances aux métaux lourds. Les puces montrent la surexpression de 83 sur 164 gènes dans pMOL28, et de 143 sur 250 gènes dans pMOL30. Elles montrent aussi que les gènes présents sur les deux plasmides sont davantage surexprimés que ceux localisés sur les deux mégaréplicons. Parmi les gènes surexprimés les plus intéressants du plasmide pMOL30, il faut mentionner des transposases tronquées et des gènes impliqués dans la synthèse des membranes (glycosyltransférases). L'analyse de l'expression des gènes plasmidiens de résistance aux métaux lourds montre la surexpression en présence de plusieurs ions métalliques ajoutés indépendamment et pas seulement par les substrats métalliques de ces opérons, ce qui suggère l'intervention de deux types de régulation dont les gènes correspondants sont aussi localisés sur le chromosome et le mégaplasmide.<p>Ce travail met en évidence la spécialisation de la bactérie dans la réponse à un grand spectre de concentrations de métaux lourds, jusqu'à la limite majeure de la toxicité observée pour les bactéries mésophiles hétérotrophes. Cette spécialisation correspond bien aux biotopes industriels de divers continents dans lesquels on l'a trouvée. <p> / Doctorat en sciences, Spécialisation biologie moléculaire / info:eu-repo/semantics/nonPublished

Applications of Hot Melt Extrusion (HME) in pharmaceuticals have become increasingly popular over the years but nonetheless a few obstacles still remain before wide scale implementation. In many instances these improvements are related to both processing and product performance. It is observed that HME process optimisation is majorly focused on the active pharmaceutical ingredient's (API) properties. Characterising polymeric properties for their suitability in HME should be equally studied since the impact of excipients on both product and process performance is just as vital. In this work, two well-established cellulose ester derivatives: Hydroxy Propyl Methyl Cellulose Acetate Succinate (HPMCAS) and Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP) are studied for their HME suitability. Their thermal, thermodynamic, rheological, thermo-chemical and degradation kinetic properties were evaluated with model plasticisers and APIs. It was found the thermal properties of HPMCP are severely compromised whereas HPMCAS is more stable in the processing zone of 150 to 200 °C. Thermodynamic properties revealed that both polymers share an important solubility parameter range (20-30 MPa P1/2P) where the majority of plasticisers and BCS class II APIs lie. Thus, greater miscibility/solubility can be expected. Further, the processability of these two polymers investigated by rheometric measurements showed HPMCAS possesses better flow properties than HPMCP because HPMCP forms a weak network of chain interactions at a molecular level. However, adding plasticisers such as PEG and TEC the flow properties of HPMCP can be tailored. The study also showed that plasticisers have a major influence on thermo-chemical and kinetic properties of polymers. For instance, PEG reduced polymer degradation with reversal in kinetic parameters whereas blends of CA produced detrimental effects and increased polymer degradation with reduction in onset degradation temperatures. Further, both polymers are observed to be chemically reactive with the APIs containing free -OH, -SOR2RN- and -NH2 groups. Finally, these properties prove that suitability of HPMCP is highly debated for HME and demands great care in use while that of HPMCAS is relatively better than HPMCP in many instances.

No / A systematic identification of the degradation products of hydroxypropyl methylcellulose phthalate (HPMCP) during hot melt extrusion (HME) has been performed. A reverse phase HPLC method was developed for the extrudates of both hydroxypropyl methylcellulose acetate succinate (HPMCAS) and HPMCP polymers to quantify their thermal hydrolytic products: acetic acid (AA), succinic acid (SA) for HPMCAS and phthalic acid (PA) for HPMCP, without hydrolysing the polymers in strong alkaline solutions. The polymers were extruded in the temperature range of 160-190 degrees C at different screw rotation speeds and hydrolytic impurities were analysed. Investigation of extruded HPMCP showed an additional thermal degradation product, who is structural elucidation revealed to be phthalic anhydride (PAH). Moreover, two environmental analytical impurities, dimethyl phthalate and methyl benzoate formed in situ were recorded on GC-MS and their origin was found to be associated with PAH derivatization. Using the experimental data gathered during this study, a degradation mechanism for HPMCP is proposed.