Orientador: Ângela Maria Moraes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Agrícola / Made available in DSpace on 2018-08-25T01:12:46Z (GMT). No. of bitstreams: 1 Souza_FernandaCarlaBombaldide_M.pdf: 2498035 bytes, checksum: f26cf0a46c0249d60c3316fd94c93e91 (MD5) Previous issue date: 2014 / Resumo: A quitosana, a goma guar e a policaprolactona são exemplos de polímeros muito usados na obtenção de curativos para a terapia de lesões de pele devido ao fato de serem biocompatíveis e biodegradáveis. A fim de aumentar a atividade biológica destes curativos, a incorporação de compostos bioativos que estimulam o processo de cura das lesões pode ser feita. Neste contexto, este trabalho teve como objetivo a obtenção de curativos biologicamente ativos, por meio da incorporação do alfa-bisabolol, um composto antioxidante e anti-inflamatório de origem natural, a membranas constituídas de quitosana combinada com goma guar (Q-G) e de policaprolactona (PCL). Dois métodos de incorporação foram utilizados: adição direta do composto ativo à mistura polimérica (AD) e impregnação do composto nas membranas por imersão em solução etanólica (IE). As membranas produzidas foram caracterizadas quanto ao seu aspecto visual, cor e opacidade, morfologia, ângulo de contato com água, propriedades mecânicas e espessura em diferentes umidades, capacidade de absorção e perda de massa em etanol e em soluções aquosas, taxa de transmissão de vapor d¿água e espectro FTIR. A eficiência de incorporação do alfa-bisabolol às membranas e a atividade antioxidante deste composto foram determinadas, e sua cinética de liberação estudada. Os resultados mostraram que tanto os filmes de Q-G como de PCL apresentaram comportamento mais adequado para a aplicação no tratamento de lesões pouco exsudativas. As propriedades mecânicas dos filmes sofreram variação significativa apenas quando estes foram expostos a condições de umidade elevada. O alfa-bisabolol utilizado nos ensaios apresentou elevado grau de pureza, porém atividade antioxidante relativamente baixa. A inserção do composto na matriz ocasionou mudanças significativas em sua aparência e alterações em sua microestrutura. Para Q-G, baixas eficiências de incorporação foram obtidas, sendo o valor máximo atingido pelo método AD igual a 1,65%, o equivalente a 4,96 mg/g, enquanto que para o método IE atingiu-se cerca de 18%, com uma retenção de aproximadamente 1080 mg/g. Já no caso da PCL, alta eficiência de incorporação foi observada (100%). A liberação mostrou-se relativamente lenta em ambos os casos e a percentagem máxima de alfa-bisabolol liberado ficou em torno de 6% e 30%, o equivalente a 12 e 300 mg/g para filmes de PCL e de Q-G, respectivamente. O tempo prolongado de liberação permitiria a troca do curativo com intervalos de tempo maiores, tornando o tratamento menos incômodo para o paciente / Abstract: Chitosan, guar gum and polycaprolactone are polymers widely used to obtain wound dressings due to their biocompatibility and biodegradability. To increase the biological activity of these dressings, bioactive compounds which accelerate wound healing can be incorporated. In this context, this work aimed the development of biologically active dressings, through the incorporation of alpha-bisabolol, a natural antioxidant and anti-inflammatory compound, to membranes made of chitosan associated with guar gum (C-G) and of polycaprolactone (PCL). The incorporation of alpha-bisabolol was performed by two distinct methods: addition directly to the polymeric mixture (AD) and absorption of the active compound from an ethanolic solution (AS). The membranes were characterized regarding to visual appearance, color and opacity, morphology, water contact angle, water vapor transmission rate, swelling capacity in ethanol and in aqueous solutions as well as mass loss in the same media, strain at break, tensile strength and thickness in different humidities conditions and FTIR spectrum. Alpha-bisabolol incorporation efficiency and its antioxidant activity were determined and the release kinetics was studied. Results showed that both films are more suitable for the use in the treatment of lesions with low exudate levels. Mechanical properties suffered significant change only after exposure of the films to high humidity conditions. The alpha-bisabolol used in this study exhibits high purity, but relatively low antioxidant activity. The addition of the compound to the matrix led to significant changes in the appearance and to modifications in the microstructure of the films. The C-G membranes presented low incorporation efficiencies, with the maximum value of 1.65%, equivalent to 4.96 mg/g, for the AD method, and 18%, approximately 1080 mg/g, for the AS method. In the case of PCL, high incorporation efficiency (100%) was observed. The release of alpha-bisabolol from the matrices was relatively slow and the maximum percentage of compound released reached about 6% and 30%, equivalent to 12 and 300 mg/g for PCL and C-G films, respectively. A prolonged release would allow less frequent dressing changes, turning the treatment more comfortable for the patient / Mestrado / Engenharia Química / Mestra em Engenharia Química

Orientador: Pedro Luiz Onófrio Volpe / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-25T19:42:54Z (GMT). No. of bitstreams: 1 Fozia_D.pdf: 5148812 bytes, checksum: 468649b9d5c06383a0fcd0b39c0fc098 (MD5) Previous issue date: 2014 / Resumo: Híbridos polisilsesquioxanos arranjados em pontos, foram sintetizados e caracterizados por análise elementar, espectroscopia de absorção na região do infravermelho, ressonância magnética nuclear no estado sólido, difração de raios X, microscopia eletrônica de varredura e transmissão eletrônica. Os dados de sorção/dessorção de nitrogênio para sílica pura, SBA-15 e os híbridos funcionalizados resultaram na isoterma do tipo IV com histerese do tipo H1. A estrutura da sílica mesoporosa ficou preservada após a pós-funcionalização com cadeias orgânicas. Pos-funcionalização da superfície com amina e outros grupos orgânicos contendo estrutura hidrofóbica, resultou numa diminuição da área da superfície 802,4-63,0 m2g-1 e volume de poros de 0,09 nm e aumento capacidade de carga de ibuprofeno a partir de 18,0 até 29% e um muito lento taxa de liberação ao longo do período de 72,5 h. Para investigar a taxa de liberação e o mecanismo a partir desses materiais híbridos sintetizados, zero-ordem, primeira ordem, Higuchi, Hixson-Crowell, Peppas e Korsmeyer-Peppas modelos cinéticos foram aplicados. Os materiais foram utilizados para a liberação controlada do fármaco ibuprofeno. Estes também foram avaliados quanto à capacidade de remover o corante aniônico azul reativo-15 e o corante catiônico verde brilhante de soluções aquosas. As sílicas modificadas apresentaram alta capacidade de carregamento do fármaco ibuprofeno e de sorção seletiva para o corante azul reativo 15. A sílica não modificada, SBA-15, apresentou alta capacidade de remover o corante verde brilhante. As isotermas de equilíbrio obtidas foram ajustadas aos modelos de Langmuir, Freundlich e Sips e os dados cinéticos foram ajustados aos modelos de pseudo-primeira-ordem e pseudo-segunda-ordem. Os resultados sugerem que os compostos organofuncionalizados de sílica podem ser um método simples, eficiente, barato e conveniente para a liberação controlada de fármacos e também para a remoção eficaz e seletiva de poluentes orgânicos tais como, corantes em soluções aquosas / Abstract: Bridged polysilsesquioxane silica hybrids, synthesized by the combination of SBA-15 type silica with new synthesized silylating agents containing bridged chains, were characterized by elemental analysis, absorption spectroscopy in the infrared region, nuclear magnetic resonance in the solid state, X-ray diffraction, scanning/transmission electron microscopy and thermogravimetry. The sorption/desorption of nitrogen to pure silica, SBA-15 and functionalized hybrids resulted in the isotherms of type IV with type H1 hysteresis. The structure of the precursor mesoporous silica was preserved after post-functionalization with bridged organic bridged chains. The precursor and its derivative silicas were ibuprofen-loaded for controlled delivery in simulated biological fluids. Surface functionalization with amine and other organic groups containing bridged hydrophobic structure resulted in significantly decreased surface area from 802.4 to 63.0 m2g-1 and pore volume to 0.09 nm, which ultimately increased the drug-loading capacity from 18.0 up to 29 % and a very slow release rate of ibuprofen over the period of 72.5 h. To investigate the release rate and mechanism from these synthesized hybrid materials, Zero-order, first-order, Higuchi, Hixson-Crowell and Peppas and Korsmeyer-Peppas kinetic models were applied. The synthesized materials were also evaluated for their ability to remove the anionic dye reactive blue-15 and cationic dye brilliant green from aqueous solutions. The hybrid silica showed selective sorption capacity for the anionic dye, reactive blue 15. The unmodified silica, SBA -15 showed high ability to remove the cationic dye, brilliant green from the aqueous medium. The obtained equilibrium isotherms were fitted to Langmuir, Freundlich and Sips models and the kinetic data were used to fit pseudo-first-order and pseudo-second-order. The results suggest that the organo-functionalized hybrid silicates could be a simple, efficient, inexpensive and convenient for the controlled release of drugs and for effective and selective removal of organic pollutants such as dyes from the aqueous solutions / Doutorado / Quimica Inorganica / Doutora em Ciências

Submitted by Gabriela Lopes (gmachadolopesufpel@gmail.com) on 2017-03-09T15:58:23Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertação _Thaís Antolini Veçozzi (para impressão).pdf: 2198036 bytes, checksum: 0b6a9f3bfafdc322a425a6d9fd27a705 (MD5) / Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2017-03-10T19:34:35Z (GMT) No. of bitstreams: 2 Dissertação _Thaís Antolini Veçozzi (para impressão).pdf: 2198036 bytes, checksum: 0b6a9f3bfafdc322a425a6d9fd27a705 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-03-10T19:34:35Z (GMT). No. of bitstreams: 2 Dissertação _Thaís Antolini Veçozzi (para impressão).pdf: 2198036 bytes, checksum: 0b6a9f3bfafdc322a425a6d9fd27a705 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-05-13 / Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul - FAPERGS / A eficiência dos fertilizantes nitrogenados utilizados no cultivo de arroz é baixa, reflexo da susceptibilidade do N a perdas no sistema solo-planta, destacando aquelas originadas da produção de óxido nitroso (N2O). O N2O, juntamente com o metano (CH4) e o dióxido de carbono (CO2), são os principais gases de efeito estufa e suas emissões para a atmosfera são apontadas como a principal causa das mudanças climáticas globais. No Brasil, grande parte da emissão desses gases advém da agricultura e do desmatamento, caracterizando estas atividades como potenciais para reduzir suas emissões. Os fertilizantes nitrogenados de liberação controlada (FLC) são utilizados visando aumentar o aproveitamento de N, em função de sua propriedade de liberar gradativamente o nutriente ao solo. Este trabalho buscou avaliar a eficiência agronômica de fertilizante de liberação controlada e seus efeitos nas emissões de CH4 e N2O no arroz irrigado. O Estudo 1 foi realizado através de um experimento delineado em blocos casualizados, com quatro repetições, em casa de vegetação e composto pelos tratamentos: T1: testemunha sem aplicação de N; T2: ureia aplicada de acordo com a recomendação para a cultura; T3: ureia incorporada; T4: FLC 1; T5: FLC 2. Foram analisadas as concentrações de NH4+e NO3- na solução do solo ao longo do alagamento do solo e o N mineral das plantas. O Estudo 2 foi realizado em condições de campo, com três repetições e os tratamentos: T0: testemunha sem a aplicação de N; T1: ureia aplicada de acordo com a recomendação; T2: FLC em cobertura na semeadura; T3: FLC no sulco de plantio. Foram avaliadas as emissões de CH4 e N2O, o Potencial de Aquecimento Global parcial (PAGp), as concentrações de compostos minerais na solução do solo ao longo do período de alagamento, a eficiência dos fertilizantes e o rendimento de grãos. De acordo com os resultados, a solubilização dos fertilizantes de liberação controlada ocorreu mais rapidamente do que o esperado, não ultrapassando 23 dias de alagamento. A eficiência agronômica no uso de N foi de 17,20 kg kg-1 para o tratamento com uréia, 13,55 kg kg-1 no tratamento com FLC em superfície e 11,51 kg kg-1 para o FLC aplicado incorporado ao solo, resultados que não mostraram diferença estatística. A emissão de CH4 não foi influenciada pelas fontes e formas de aplicação de N. A emissão total de N2O foi de 0,44 kg/ha no tratamento sem N, de 1,09 kg/ha no tratamento com ureia, 2,09 kg/ha no tratamento com FLC em superfície e de 2,94 kg/ha no tratamento com FLC incorporado ao solo. O potencial de aquecimento global parcial não foi afetado pelo manejo da adubação nitrogenada. A aplicação de FLC não tem potencial para reduzir as emissões de CH4 e N2O do solo cultivado com arroz irrigado. O uso de FLC no arroz irrigado não eleva o rendimento de grãos. As contradições e variações observadas nos estudos com fertilizantes de liberação controlada demostram a necessidade de pesquisas amplas que avaliem seu comportamento no solo e a rentabilidade econômica. / Nitrogen use efficiency of the fertilizers used is low, as a result of its loss susceptibility in plant-soil system, highlighting among these those originated of the production of N2O. N2O, along with methane (CH4) and carbon dioxide (CO2) are the main greenhouse gases and these gases emissions to the atmosphere are seen as the main cause of possible climate change. In Brazil, much of the greenhouse gas emissions comes from agriculture and deforestation, featuring such activities as potential to reduce air pollution. Controlled-release nitrogen fertilizers (CRF) are used to increase the use of N by plants, due to its property to gradually release nutrients to the soil. This study aimed to evaluate the controlled release fertilizer agronomic efficiency and its effects on CH4 and N2O emissions in irrigated rice cultivation. Study 1 was conducted through an experiment in randomized block design with four replications, conducted in a greenhouse and composed for the treatments: T1: control without N fertilization; T2: application of urea according to Southern Brazil recommendation; T3: all dose of urea incorporated; T4: CRF 1; T5: CRF 2. NH4 + and NO3 - concentration were analyzed in the soil solution along the soil flooding and mineral N in plant aerial part. Study 2 was conducted by experiment under field conditions, with three replications and the treatments: T0: control without N application; T1: urea applied in according with the recommendation; T2: CRF in coverage at sowing; T3: CRF in the furrow. Were evaluated CH4 and N2O emissions along the cultivation, Global Warming Potential partial (GWPp), concentrations of mineral compounds in the soil solution along the soil flooding, efficiency of fertilizers and grain yield. According to the results, the solubilization of the controlled release fertilizer is occurs more faster than expected, not exceeding 23 days flooding. The agronomic N use efficiency was 17,20 kg kg -1 for treatment with urea, 13,55 kg kg-1 in the treatment with CRF in coverage at sowing and 11,51 kg kg-1 for CRF in the furrow, results statistically not difference. The CH4 emission was not influenced by sources and N forms of application. The N2O emission total was 0,44 kg/ha treatment without N, 1,09 kg/ha of treatment with urea, 2,09 kg/ha of treatment with CRF in coverage at sowing and 2,94 kg/ha on treatment with CRF in the furrow. Global Warming Potential partial was not affected by nitrogen fertilization management. The application of CRF has no potential to reduce CH4 and N2O emissions in soil cultivated with rice. The use of CRF in the rice does not increase the yield. Contraventions and variations observed in studies with controlled-release fertilizers demonstrate the need for extensive research to assess the behavior in soil and the economic profitability of these products.

Ce travail de thèse a pour objectif de formuler un emballage comestible à base d’un mélange de chitosan et de gélatine (bœuf ou poisson), de mieux comprendre l’influence d’irradiations par faisceaux d’électrons et de l’incorporation d’antioxydants naturels sur les propriétés physico-chimiques et fonctionnelles des films. Une étude de l’effet de l’irradiation sur la cinétique de libération des antioxydants dans un milieu liquide simple a été étudiée pour validation. Une étude préliminaire a montré d’abord que la densification de la solution filmogène puis du gel pendant le séchage ne dépend ni de l’épaisseur, ni de la concentration, ni du temps et laisse supposer une diffusion Fickienne de l’eau dans la matrice. La perméabilité à la vapeur d’eau augmente linéairement avec l’épaisseur de films et d’autant plus lorsque l’étendue du différentiel d’humidités relatives est élevé. Ce phénomène est attribué à un mécanisme de gonflement et de plastification du réseau de gélatine-chitosan par l’eau. L’effet du taux de mélange de deux biopolymères a montré une amélioration des propriétés mécaniques et barrières à l’eau et à l’oxygène des films de chitosan. Ces gains de performances sont dus à la bonne miscibilité des deux macromolécules et aux interactions moléculaires établies suite à la formation d’un complexe polyélectrolytique, confirmé par analyse FTIR. L’irradiation des films après séchage accroit la polarité de surface et l’hydrophilie des films et ainsi induit une augmentation des propriétés barrières à la vapeur d’eau et à l’oxygène, mais aussi des mécaniques et thermiques des films. Toutefois, l’irradiation ne modifie pas la cristallinité des films. L’incorporation des antioxydants (acide férulique, coumarine, quercétine et tyrosol) avec ou sans irradiation agit différemment, selon leur nature, sur l’organisation du réseau macromoléculaire et donc sur les propriétés des films. Ainsi, l’acide férulique et le tyrosol réduise la perméabilité à la vapeur d’eau mesurée à un gradient de 0-30% d’humidité relative, alors qu’ils l’augmentent jusqu’à 90 fois avec un gradient 30-84% et un traitement d’irradiation. La perméabilité à l’oxygène diminue d’une façon significative après ajout de quercétine ou de tyrosol et après irradiation. L’acide férulique et la coumarine augmente la force à la rupture des films alors que ce sont la quercétine et l’acide férulique qui permettent d’accroitre la résistance thermique des films. Ces résultats mettent ainsi en évidence la complexité des interactions mises en jeu entre les antioxydants et les chaînes de chitosan et/ou de gélatine, leur dépendance au niveau d’hydratation du système et à l’impact du traitement de réticulation par irradiation. Il faut noter que l’irradiation a permis de protéger les molécules actives contre l’oxydation durant une longue période de stockage des films. La libération en milieu aqueux de l’acide férulique est la plus ralentie avec une rétention dans les films la plus élevée à l’équilibre (27%). Les coefficients de diffusion des antioxydants, déterminés à partir des cinétiques de libération ont pu être modulés (50%) grâce à l’irradiation. / This thesis aims to develop an edible packaging made of a mixture of chitosan and gelatin (beef or fish), to better understand the influence of the electron beam irradiation and of the incorporation of natural antioxidants on the physico-chemical and functional properties of the films. A study of the effect of irradiation on antioxidants release kinetics in a simple liquid medium was studied for validation. A preliminary study first showed that the densification of the film-forming solution and the gel during drying does not depend on the thickness or concentration or time and suggests a Fickian diffusion of water in the matrix. The permeability to water vapor increases linearly with film thickness and especially when the extent of the relative humidity differential is high. This phenomenon is attributed to a swelling mechanism and plasticization of the gelatin-chitosan network by the water. The effect of the chitosan-gelatin ratio showed an improvement of the mechanical properties and barrier to water and oxygen of the films compared to chitosan films. These performance gains are due to the good miscibility of the two macromolecules and to the molecular interactions established after the formation of a polyelectrolyte complex, as confirmed by FTIR analysis. Irradiation of films after drying increases the polarity of the surface and the film hydrophilicity, and thus induces an increase in barrier properties to water vapor and oxygen, and also of the mechanical and thermal films. However, irradiation does not change the crystallinity of the films. The incorporation of antioxidants (ferulic acid, coumarin, quercetin and tyrosol) with or without irradiation acts differently on the organization of the macromolecular network and thus on the film properties. Thus, ferulic acid and tyrosol reduce the permeability of water vapor measured in a gradient of 0-30% relative humidity, while it increases up to 90 times with a gradient 30-84 % and an irradiation treatment. The oxygen permeability decreases significantly after addition of quercetin or tyrosol and after irradiation. Ferulic acid and coumarin increases the tensile strength of the films while they are quercetin and ferulic acid which allow to increase the thermal resistance of the films. These results thus demonstrate the complexity of the interactions involved between antioxidants and the chains of chitosan and/or gelatin, their dependence on the moisture level of the system and on the impact of cross-linking treatment by irradiation. It is noticed that the irradiation has protected the active molecules against oxidation for a long period of storage of the films. Release in aqueous medium of ferulic acid is the more delayed with the highest retention in the film at equilibrium (27%). The antioxidants diffusion coefficients, determined from the release kinetics, could be modulated (about 50%) by the irradiation treatments.

Therapeutics based on siRNA represent a promising hope for the treatment of many congenital and acquired disorders. This method is based on posttranscriptional silencing of pathological gene or set of genes (RNAi process), which are responsible for the actual cause of the disease. Access is therefore based on the assumption of treatment options for the disease at the point of origin of the defect intervention at the molecular level, which is different from the conventional, so-called symptomatic therapy, which focuses only on the treatment or suppression of symptoms. Despite rapidly increasing understanding of gene function and cause a number of genetic diseases, the expansion of siRNA therapeutics limited the development of efficient and safe transport systems (vectors). In order to ensure efficient transport of siRNA in vivo conditions, the vectors must sufficiently reduce the size of the siRNA, protect it against degradation during transport, and release in the cytoplasm of the target cell. For this purpose they were developed sophisticated transport systems based on viral and non-viral origin. This diploma thesis is focused on the preparation of new transport systems, siRNA-based synthetic hydrophilic polymers, such as non-viral vectors. For in vitro testing the effectiveness during transport of siRNA...

Les études de libération de substance active à partir de système polymériques tels que des microparticules à base d’acide poly(lactique-co-glycolique) (PLGA) ont été largement explorées au cours de ces dernières décennies . L’objectif principal de ce travail consiste à mieux comprendre les mécanismes de transport de masse contrôlant la libération de substance active à partir des microparticules de PLGA. Un nouvel aperçu devait être acquis sur la base de suivi expérimental de la cinétique de gonflement de microparticules. Dans un premier temps, des microparticules à base de PLGA chargées de différents types de substances actives (acide, base et neutre), tels que kétoprofen, prilocaine base libre et dexamethasone ont été préparées par simple émulsion (huile dans eau) en utilisant une méthode d'extraction/évaporation du solvant. Les microparticules obtenues avaient des taux d’efficacité d’encapsulation qui sont variables selon la substance active utilisée. Une caractérisation des propriétés clés des microparticules obtenues a été réalisée en utilisant différentes techniques (microscopie optique, microscopie électronique). La chromatographie par permeation de gel a été utilisé pour déterminer le poids moléculaire du PLGA après exposition des microparticules au milieu de libération à différents temps afin d’évaluer la cinétique de dégradation du polymère. La diffraction des rayons X et la calorimétrie différentielle à balayage étaient utilisés pour étudier l’état physique du polymère, de la substance active pure ainsi que les microparticules chargées en substance active. Les études de libération ont montré deux types de profils de libération : un profil tri-phasique et un profil plus ou moins mono-phasique. Le profil tri-phasique observé est constitué de trois phases : une phase de libération initiale rapide suivie d’une libération constante qui est suivie ; à son tour ; par une seconde phase de libération rapide. En revanche, les différentes phases étaient difficilement distinguées pour le deuxième type de profil obtenu, du fait de la libération rapide de substance active ce qui permet de dire que les profils obtenus étaient plus ou moins mono-phasique. L’élucidation des mécanismes de libération de substance active était basée sur le suivi expérimental de la cinétique de gonflement des microparticules. Comme pour les cinétiques de libération obtenues à partir des microparticules à base de PLGA, différentes phases peuvent être distinguées pour les profils de gonflement. Les transitions d’une phase à une autre semblent s’accorder entre le profil de libération et celui du gonflement. Ainsi, le gonflement des microparticules pourrait contribuer au contrôle de la libération de la substance active à partir des microparticules à base de PLGA. / The drug release studies from polymeric system such as Poly(lactic-co-glycolic) acid (PLGA)-based microparticles have been widely investigated during recent decades. The main objective of this work is to better understand the mass transport mechanisms controlling the drug release kinetics from PLGA microparticles. New insight was to be gained based on the experimental monitoring of the swelling kinetics of single microparticle. Initially, PLGA microparticles containing different type of drugs (acidic, basic and neutral), such as ketoprofen, prilocaine free base and dexamethasone were prepared using simple oil in water emulsion extraction/evaporation solvent technique. The characterization of the key properties of microparticles was performed using different techniques (optical microscopy, electron microscopy). The gel permeation chromatography was used to determine the molecular weight of PLGA following exposure of microparticles to the release medium at various times to assess the kinetic degradation of the polymer. The X-ray diffraction and differential scanning calorimetry were used to study the physical state of the polymer, drug and drug-loaded microparticles. Release studies have shown two types of release profiles: tri-phasic and more or less mono-phasic profile. The tri-phasic profile is composed of three phases: an initial rapid release phase followed by a constant release which is followed by a second phase of rapid release. In contrast, at the investigated higher initial drug loadings, different release phases could hardly be distinguished: The profiles were more or less mono-phasic. The elucidation of drug release mechanisms was based on the experimental results of the swelling kinetics of single microparticles. As for drug release, distinct phases can be distinguished for microparticles swelling. The transition from one phase to another seem to coincide for microparticle swelling and drug release. Thus also microparticle swelling might contribute to a significant extent to the control of drug release.

L’oreille interne est l’organe responsable pour la perception auditive et le maintien de l’équilibre. L’OMS estime que 360 millions personnes dans le monde (plus que 5 % de la population) souffrent d’une perte auditive handicapante, soit 40 dB dans l’oreille qui entend le mieux. Une des principales stratégies de traitement est l’administration systémique de stéroïdes, ex : la dexaméthasone. Ces stéroïdes sont utilisés pour prévenir les inflammations ou œdèmes pouvant endommager les très sensibles cellules ciliées de l’oreille interne.La libération contrôlée de principes actifs (PA) est un vrai challenge car l’oreille interne est protégée par la barrière hémato-cochléaire qui ressemble à la barrière hémato-encéphalique et protège l’oreille de substances toxiques. Par conséquent, il est nécessaire d’utiliser de fortes doses pour obtenir des concentrations thérapeutiques dans l’oreille interne. Ainsi, une libération locale et contrôlée semble une approche prometteuse pour limiter la survenue d’effets secondaires.D’un point de vue clinique, un deuxième obstacle doit être surmonté: la taille minuscule de la cochlée et sa difficulté anatomique d’accès. Les deux membranes semi-perméables (la fenêtre ronde et ovale) qui relient l’oreille moyenne avec l’oreille interne sont une voie possible –mais challenging -pour libérer le PA dans l’oreille interne. L’injection de solutions ou de gels chargés en PA dans l’oreille moyenne à travers la membrane tympanique semble être une méthode fiable et économique pour un traitement à court ou moyen terme. Malheureusement, ces formulations risquent d’être éliminées ou dégradées rapidement et par conséquent requièrent des applications répétées. Un autre désavantage est que l’anatomie varie énormément d’un patient à l’autre menant à des concentrations très diverses dans l’oreille interne.Pour un traitement à long terme une libération à partir d’implants cochléaires semble prometteuse : l’implant étant inséré directement dans l’oreille interne, il permet de libérer le PA de manière contrôlée pendant des mois ou des années. Néanmoins, cette intervention est très invasive et le bénéfice pour chaque patient doit être évalué en détail.L’objectif de cette étude est de développer un implant miniaturisé pour la libération contrôlée de dexaméthasone dans l’oreille interne.Dans un premier temps, de fins films de silicone chargés en PA ont été préparés et caractérisé in vitro. La libération à partir de ces films peut être ajustée en modifiant le type de silicone (ex : le type des chaînes latérales, degré de réticulation) ou en ajoutant différents quantités de PEG 400 ou 1000. Une solution analytique de la seconde loi de Fick a pu être utilisée pour décrire les cinétiques de la libération à partir des films et prédire théoriquement la libération du PA à partir de matrices de taille et de forme diverses.Ensuite, deux types d’implants ont été préparés en se basant sur les systèmes les plus prometteurs. Le premier est l’implant « Ear Cube » ayant une forme prédéfinie avec un cube lié à un cylindre. Ce cylindre est en contact avec la périlymphe de l’oreille interne. Le second est un implant se formant in situ qui s’adapte parfaitement à l’anatomie de l’oreille moyenne en réticulant directement dans l’oreille moyenne. Cet implant est en contact avec l’oreille interne par un orifice. Les deux types d’implants ont été caractérisés in vitro.In vivo, la libération de dexaméthasone à partir d’implant se formant in situ a été évaluée avec des gerbilles. Le PA peut être détecté déjà 20 min après l’implantation et ce jusqu’à au moins 30 jours.Ainsi, les deux implants semblent prometteurs pour contrôler à long terme la libération de dexaméthasone directement dans l’oreille interne. A l’avenir, des études pour évaluer les effets des implants « Ear Cube » seront menées. De plus, ces systèmes pourraient être adaptés pour délivrer d’autres PA, ex : la gentamicine, pour traiter d’autres maladies. / The ear is the organ responsible for the perception of sound and the sense of balance. The WHO estimated that worldwide 360 million people (over 5 % of the population) are suffering from disabling hearing loss, meaning a loss of 40 dB in the better hearing ear in adults. One of the major strategies to treat hearing loss is to administer steroids, e.g. dexamethasone, systemically. Steroids are used to prevent inflammation and oedema damaging the highly sensitive inner ear hair cells.Unfortunately, drug delivery to the inner ear is very challenging due to the blood-cochlea barrier which is similar to the blood-brain barrier and protects the inner ear from drugs or toxic substances from the blood stream. High doses are often required to reach therapeutic drug concentrations in the inner ear. Thus, local drug delivery seems to be a more promising approach to limit adverse effects due to high systemic blood levels.Nevertheless, a second major hurdle has to be overcome in clinical practice: the small dimensions of the cochlea and its difficult anatomical access. The two semipermeable membranes connecting the middle with the inner ear (the round and oval window) are one possible - but challenging - route to deliver drugs locally to the inner ear. Drug loaded solutions or gels administered with an intra-tympanic injection into the middle ear seem to be a relatively safe and economical therapy for a short or mid-term treatment. Unfortunately, they might be washed away or degraded rapidly and, though, often require repeated applications. Additionally, the anatomy of the ear varies from patient to patient leading to different drug concentrations in the inner ear.For long term treatment, intra-cochlear implants seem to be promising: Since the device is inserted directly into the inner ear, the drug concentration is better controlled and – depending on the formulation – the drug can be released over prolonged periods of time. Nevertheless, this approach is rather invasive so that the benefit for the patient has to be discussed in detail.The purpose of this study was to develop a miniaturized implant being able to deliver dexamethasone directly to the inner ear.To facilitate the development of silicone-based implants loaded with dexamethasone, thin drug loaded films have been prepared and thoroughly characterized in vitro as a model system. Drug release can easily be adjusted by varying the type of silicone used (e.g. type of side chain, degree of crosslinking), or by adding various amounts of PEG 400 or 1000. An analytical solution of Fick’s second law could be used to describe the drug release kinetics from the films and to theoretically predict drug release from dosage forms of arbitrary size and shape.Subsequently, two types of implants have been prepared using the most promising silicone systems. The first system, the Ear Cube implant with a predefined shape consists of a cube on top of a cylinder which stays in contact with the perilymph of the inner ear. The second system, the in situ forming implant adapts perfectly to middle ear anatomy because it cures directly in vivo. It also stays in contact with the inner ear fluids via a hole. Both systems have been characterized in vitro.In vivo, the dexamethasone loaded in situ forming silicone-based implants have been evaluated in mongolian gerbils. Interestingly, dexamethasone was detected within the explanted gerbil cochleae already 20 min after implant formation until at least 30 days.Thus, both implants seem to be a good tool to administer dexamethasone locally to the inner ear in a prolonged and time controlled manner. Further studies should be performed to characterize the Ear Cube implants in vivo. Additionally, both systems could be tested with different types of drug, e.g. gentamicin, to treat also other diseases with this new promising inner ear implants.

Orientador : Eliana Aparecida de Rezende Duek / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Mecanica / Made available in DSpace on 2018-08-04T01:54:38Z (GMT). No. of bitstreams: 1 Bernatavicius_SergioTadeu_M.pdf: 9386061 bytes, checksum: 9e736c52e1042de3187574f10e183c68 (MD5) Previous issue date: 2004 / Resumo: Um dos pontos que deve ser considerado de difícil solução no Brasil, é a perda dentinária. Vários materiais tem sido estudados para minimizar o problema, mas nenhum atende às necessidades de tal aplicação. Nesse sentido, o objetivo do presente avaliar a biocompatibilidade do Poli (L-ácido-Iático), PLLA, contendo vancomicina e piroxicam no tratamento de grandes perdas de dentina onde pode ou não ocorrer a exposição da polpa dental, casos onde a exposição leva ao tratamento endodontico ou exodontia. Para tanto, foram realizados estudos in vivo em coelhos e humanos, ambos aprovados pelo Comitê de Ética em Pesquisa da Universidade Estadual de Campinas parecer número 490/2003.Os estudos em coelhos foram realizados utilizando-se de um modelo experimental onde foi implantado as microesferas contendo medicamento nos incisivos centrais e após 20, 40, e 60 dias os dentes foram cortados e submetidos à análise histológica. Após 20 dias de implante, verificou-se regiões centrais de hipocalcificações em relação ao implante e formação de pontos de dentina. Não foi localizado processo inflamatório em função da utilização dos medicamentos. Após 40 dias verificou-se a que a calcificação começa por áreas globulosas que crescem e se fundem, porém o processo muitas vezes é imperfeito, resultando áreas de matriz orgânica não calcificada; são as áreas interglobulares. Após 60 dias, verificou-se a formação de tecido de normalidade o que demonstra a eficácia das microesferas com medicamento como material reparador. A análise in vivo em humanos se fez necessária para avaliar a resposta frente à aplicação do material, seu efeito antiinflamatório e analgésico em casos de exposição pulpar e grande perda dentinária, além da avaliação do retomo da função ao elemento dental, ou seja, controle da dor e possibilidade de mastigação normal. Observou-se após 60 dias que todos os pacientes implantados não apresentaram dor a nenhum dos testes realizados e mantinham a vitalidade pulpar, as microesferas com medicamento aqui também se mostraram eficazes no controle antiinflamatório e infeccioso. O estudo in vivo indicou que as microesferas de PLLA contendo vancomicina e piroxicam apresentam grande potencial para serem utilizadas para aplicação em questão, já que o material favorece a formação de uma neodentina e controla os processos inflamatório e infeccioso / Abstract: One of the points that it should be considered of difficult solution in Brazil, is the loss dentine. Several materials have been studied to minimize the problem, but none assists to the needs of such application. In that sense, the objective of the present to evaluate the biocompatibility of the Poly (L-lactide acid), PLLA, contends vancomicina and piroxicam in the treatment of great dentin losses where cannot or not to happen the exhibition of the dental pulp, cases where the exhibition takes to the treatment endodontic or exodontia. For so much, studies in was accomplished In vivo in rabbits and humans, both approved by the Comitê de Ética em Pesquisa da Universidade Estadual de Campinas to seem number 490/2003. The studies in rabbits were accomplished being used of an experimental model where it was implanted the microesferas contends medication in the incisive central and after 20, 40, and 60 days the teeth were cut and submitted to the analysis histological. After 20 days of it implants, it was verified central areas of hipocalcification in relation to the it implants and formation of dentin points. Inflammatory process was not located in function of the use of the medications. After 40 days the one was verified that the calcification begins for areas interglobules that grow and they are founded, even so the process a lot of times it is imperfect, not resulting areas of organic matrix not calcified; they are the areas interglobules. After 60 days, the formation of normality tissue was verified that demonstrates the effectiveness of the microspheres with medication as reparative material. The analysis in vivo in humans if made necessary to evaluate the answer front to the application of the material, its effect antiinflammatory and analgesic in cases of exhibition pulp and great loss dentine, besides the evaluation of the return of the function to the dental element, that is to say, control ofthe pain and possibility of normal mastication. It was observed after 60 days that ali the implanted patients didn't present pain to none of the accomplished tests and they maintained the vitality pulpar, the microspheres with medication here was shown also effective in the control antiinflammatory and infectious. The study in vivo it indicated that the microspheres of PLLA contends vancomicina and piroxicam they present great potential for they be used for application in subject, since the material favors the formation of a neodentine and it controls the inflammatory and infectious processes / Mestrado / Materiais e Processos de Fabricação / Mestre em Engenharia Mecânica

La presente tesis doctoral, que lleva por título “Diseño de nuevos nanomateriales híbridos con puertas moleculares como nanodispositivos para aplicaciones terapéuticas” está centrada en el desarrollo de nuevos materiales funcionales híbridos orgánico-inorgánicos para aplicaciones de liberación controlada. Los dos capítulos de la presente tesis en los que se describen los resultados obtenidos (el segundo y el tercer capítulos) están directamente relacionados con el uso de las nanopartículas mesoporosas de sílice como matriz inorgánica en el desarrollo de nuevos materiales híbridos orgánico-inorgánicos para aplicaciones en liberación controlada. Aun así, los resultados se han dividido en dos capítulos, dependiendo del estímulo aplicado para la liberación de la molécula encapsulada. En uno de los capítulos, los diferentes materiales desarrollados se basan en nanodispositivos controlados enzimáticamente, mientras que en el otro capítulo es un cambio de pH o de fuerza electroestática (en los dos casos debido a la presencia de un microorganismo patógeno) el que causa la consecuente liberación de la carga. En el caso de los nanodispositivos controlados enzimáticamente, los cuales se describen en el Capítulo 2, se desarrollaron tres sólidos diferentes. El primer ejemplo se basó en el diseño, síntesis y caracterización de nanopartículas mesoporosas de sílice recubiertas con sales de azopiridinio, que se hidrolizan en presencia de esterasas y reductasas, las cuales se encuentran en la microflora del colon. Estas sales, que contienen un enlace azoico, se seleccionaron para una posible liberación selectiva en el colon. Los estudios de viabilidad celular e internalización se llevaron a cabo con células HeLa, así como los estudios de liberación del agente quimioterapéutico camptotecina. Un segundo ejemplo se centró en el diseño, síntesis, caracterización y aplicaciones de un nuevo nanodispositivo que responde a la presencia de proteasas para liberación controlada, empleando nanopartículas de sílice cubiertas con el polímero -poli-L-lisina. En este caso, se pretendía evaluar dos mecanismos diferentes de anclaje del polímero y los dos dieron resultados positivos, aunque presentaron diferentes perfiles de liberación en cada caso. También se realizaron estudios de viabilidad e internalización celular con este nuevo nanodispositivo, así como la liberación de camptotecina en células HeLa. Finalmente, el último nanodispositivo que responde a la acción de un enzima; incluye el diseño y aplicación de un “scaffold” 3D inteligente con puertas moleculares, el cual consiste en la combinación de nanopartículas mesoporosas de sílice con puertas y biomateriales porosos clásicos. En este caso, las nanopartículas mesoporosas de sílice se cubrieron con poliaminas y ATP. Estas nanopartículas se incorporaron durante la síntesis de un “scaffold” de gelatina, el cual se preparó mediante técnicas de prototipado rápido (RP). En presencia de fosfatasa ácida se induce la liberación del colorante encapsulado en los poros de las nanopartículas. La fosfatasa ácida se seleccionó como estímulo activador de este material diseñado, ya que es un enzima cuya concentración se emplea para evaluar la actividad de los osteoclastos en procesos de remodelación ósea y como marcador en metástasis de huesos. Estas propiedades abren posibilidades de uso de esta combinación en el diseño de materiales funcionales para la preparación de numerosos “scaffolds” avanzados con puertas moleculares, que puedan ayudar en aplicaciones de medicina regenerativa y terapias de cáncer de huesos. Con respecto al otro tipo de nanodispositivos, que se muestra en el Capítulo 3, se ha evaluado el posible uso de las nanopartículas mesoporosas de sílice con puertas moleculares como posibles vehículos para la liberación controlada de fármacos cuando un microorganismo patógeno está presente. En este caso, el diseño y desarrollo de nuevos materiales híbridos orgánico-inorgánicos se ha basado en el uso de nanopartículas mesoporosas de sílice como matriz inorgánica, cubiertas con entidades moleculares orgánicas que podrían responder a un cambio en el pH del ambiente o a un cambio en la fuerza electroestática, debido a la presencia de un microorganismo patógeno, tales como hongos o bacterias. Uno de estos nanodispositivos desarrollados demuestra las aplicaciones y propiedades antifúngicas de un soporte cargado con tebuconazol y cubierto con moléculas que actúan de puerta molecular dirigida mediante un cambio de pH. El otro material presenta aplicaciones antibacterianas contra bacterias gram-positivas y gram-negativas, ya que se utiliza un nanodispositivo cargado con vancomicina y funcionalizado con -poli-L-lisina. En los dos casos, se ha demostrado que el uso de la nanoformulación puede mejorar la efectividad del fármaco encapsulado, mejorando y ampliando el espectro de acción del mismo, lo cual abre un gran abanico de posibilidades en aplicaciones de estos nanodispositivos en el tratamiento de infecciones. En resumen, se puede concluir que en la presente tesis se han desarrollado nuevos sólidos híbridos orgánico-inorgánicos, así como se han descrito las aplicaciones de estos nanodisposotivos como sistemas de liberación controlada. Los resultados obtenidos podrían ser útiles en futuros diseños de materiales híbridos avanzados en biotecnología, biomedicina y, concretamente, en aplicaciones terapéuticas (como terapias contra el cáncer, tratamiento de infecciones, medicina regenerativa, etc.) / Mas Font, N. (2014). Design of new hybrid nanomaterials with molecular gates as nanodevices for therapeutic applications [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/48491 / TESIS

This thesis is focused on description of superabsorbents with controlled released of nutrients, specifically macronutrients nitrogen, phosphorus and kalium. Superabsorbents are polymers, mostly acrylic acid polymers, that can absorb huge amount of water without dissolving in it. In its structure they can hold water and thanks to this they are very perspective materials for agricultural usage. Experimental part was focused on growing corn with use of superabsorbents and control samples without use of superabsorbents. Plants were growth for 3 time periods, specifically 46, 60 and 74 days. During the experiments, plats were growth without water stress and in controlled conditions in growing box under UV lamp that simulated day and night by turning on and off after 12 hours. At the end, an image analysis was performed in HARFA program, from which we got information about branching of the roots. Results were supplemented by soil and plants analysis.