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|Título:||Production of laminar extrudates containing particles of a model drug processed by supercritical fluids|
|Autor:||Oliveira, Gonçalo Emanuel Rodrigues da Cunha Correia de, 1983-|
|Orientador:||Pinto, João Fernandes de Abreu, 1963-|
Wahl, Martin A.
|Palavras-chave:||Teses de doutoramento - 2015|
|Data de Defesa:||2015|
|Resumo:||The aim of this work was to test the hypothesis that laminar extrudates and co-extrudates, containing particles of drugs processed by supercritical fluids, can be manufactured at room temperature and in the absence of solvents, to deliver drugs by the oral or transdermal routes of administration. Particles of coumarin (drug) were manufactured by Rapid Expansion of Supercritical Solutions (RESS), which is a supercritical fluid micronization technique, using both a discontinuous and a continuous mode of operation. The manufactured particles of coumarin obtained from different RESS experiments, in which there were tested different experimental conditions, presented reduced sizes (between 20-40 μm, mean values) and similar properties in terms of morphology, surface area, thermal behavior, amorphous and crystalline contents, density and porosity. It was observed that specific experimental conditions of the RESS influenced the size of the manufactured drug particles, namely the pre-expansion pressure, the initial amount of solute, and the post-expansion pressure, amongst others. In parallell, several excipients and different formulations were developed and tested in order to manufacture extrudates with a laminar shape, at room temperature, and without including solvents in the formulations. The lipid-based materials were the excipients that better contributed for the aim of the study, as the formulations with these excipients in high proportions presented suitable physical and mechanical properties and, in consequence, a satisfactory quality. After identifying the best formulation, the extrusion processing parameters and their influence in the properties of the manufactured extrudates, namely the extrusion rate, were properly studied. Additionally, for each extrudate, there were analyzed the dissolution profiles, the thermal behaviors of the raw materials before extruding and of the extrudates after extrusion and over the storage period, as well as the evolution of the density, of the porosity and of the mechanical properties of the extrudates such as the bending strength, the deformation, the stiffness, and the elasticity (Young’s modulus). It was studied the release of the drug from extrudates containing particles of drugs with different sizes in order to assess the impact of the particle size of the drug on its release from the extrudates previously manufactured. It was concluded that the manufacture of extrudates at room temperature and without including solvents in the formulation is a promising technology for the manufacture of new pharmaceutical dosage forms. All the analysis performed both to the starting materials and to the obtained extrudates showed that after extrusion occurs an aging phenomenon of the extrudates, which is visible by the evident changes in their physical and mechanical properties over storage. This phenomenon is similar to the previously observed and described for the glycerides and triglycerides that mainly compose the lipid-based excipients selected for this study. The formulations composed by different excipients originated extrudates with different properties such as the mechanical properties. Also, the bending strength, the stiffness, the deformation, the elasticity, the density and the porosity changed over time, and the observed changes were related to the composition of the formulations and of the extrusion processing conditions. It was observed that the properties of the extrudates, namely their physical and mechanical properties, needed to be stabilized over time in order to maintain unaffected the release of the drug performance expected for certain drug and extrudate. Additionally, the extrudates including particles of drugs with smaller sizes presented higher release rates when compared with particles with higher dimensions. The formulations and the components selected for the manufacture of extrudates at room temperature and in the absence of solvents were in the majority composed by lipid-based materials, which can sustain the release of the drug. Therefore, it was concluded that the release rate of a certain drug can be modified by changing the composition of the formulatons and/or by changing the size of the particles of drug. The entire approach for the formulation development and for the study of the extrusion process and of the properties of the extrudates was replicated for the development of the laminar co-extrudates (with two or three layers). The properties and results obtained were similar to those observed for the extrudates with a single layer. The particles of coumarin micronized by RESS were included in laminar extrudates manufactured without changing the temperature during processing and avoiding the inclusion of solvents in the formulation. The release of coumarin from these extrudates was assessed and it was concluded that this pharmaceutical dosage form could successfully transport and release coumarin. Those laminar extrudates were also tested for its ability in delivering coumarin obtained by RESS and levothyroxine by both the oral and the transdermal routes of administration. The particles of both drugs, in separate, were included in formulations of extrudates and its in-vitro release, ex-vivo permeation and in-vivo absorption / permeation were properly assessed. Several portions of extrudates containing coumarin or levothyroxine were placed in the donor compartments of diffusion cells (Franz cells) containing a barrier composed by human skin (ex-vivo experiment) and it was observed that both drugs were successfully released and permeated through the skin. Also, several portions of extrudates containing levothyroxine were delivered to Wistar rats by both routes of administration (oral and transdermal) and it was observed that levothyroxine was respectively absorbed and permeated, being detected in the blood mainstream of the mice. All the findings described in this work allowed to conclude that the hypothesis was valid and that it is possible to manufacture extrudates and co-extrudates at room temperature, without including solvents containing particles of a drug manufactured by supercritical fluids.|
|Descrição:||Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2015|
|Designação:||Doutoramento em Farmácia|
|Aparece nas colecções:||FF - Teses de Doutoramento|
Ficheiros deste registo:
|ulsd071233_td_Goncalo_Oliveira.pdf||2,9 MB||Adobe PDF||Ver/Abrir|
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