Cancer is one of the leading causes of death in the world. For women in the U.S. and the European countries, breast cancer is the most common type and it continuously threatens the lives of the patients and causes huge economic losses. Chemotherapy and endocrine therapy are the common treatments for recurrence prevention and metastatic cancer symptom palliation. However, the uses of these therapies are meanwhile largely limited because their toxic side effects and non-specificity usually lead to low quality lives of the patients. Low aqueous solubility, multi-drug resistance, degradation of drug, limited intra-tumor diffusion and etc. are other limitations of conventional chemotherapies and endocrine therapies. Nanoparticle based drug carriers were extensively studied for therapeutic drug delivery. Many carriers could be loaded with high dose of hydrophobic and hydrophilic drugs, protect the drug from the surrounding in vivo environment during the transportation, specifically target and enter the tumor cells and slowly release the drug thereafter. Advanced nanoparticle drug carriers are studied driven by the need of a more efficient drug delivery. The 3rd generation of nanoparticle based drug carriers are recently developed. They usually consist of more than one type of nanoparticles. Different part of the particle has more specialized functions. Therefore, by carefully selecting from the conventional nanoparticle carriers, a 3rd generation particle could have the properties such as high loading capacity of multiple drugs, prolonged half-life in circulation, higher tendency of accumulating at the tumor site, improved specificity to the tumor cells, higher cell uptake rate and accurately triggered controlled release, and combination of the above-mentioned properties. In our study, a paclitaxel loaded nanoparticle supported immunoliposome was assembled for metastatic breast cancer drug delivery. Functionalized single walled carbon nanohorn or poly(lactic-co-glycolic acid) was encapsulated in the polyethylene glycol (PEG) coated liposome for high drug loading and controlled release. Anti-Her2 antibody or Herceptin® was grafted onto the surface of the liposome for a higher affinity to the Her2 overexpressing breast cancer cells. Firstly, the conjugation of protein to the surface of liposome and PEGylated liposomes were investigated. Proteins with or without membrane binding domain were conjugated to liposome and PEGylated liposomes through covalent and non-covalent binding for comparison. A modified enzyme-linked immune sorbent assay was developed for surface grafted protein quantification. Secondly, the encapsulation of solid nanoparticle into PEGylated immunoliposome was investigated. Results showed a new structure of solid nanoparticle in PEGylated immunoliposome at a 1:1 ratio was formed during the repeated freeze-thawing process. Supported immunoliposomes with high homogeneity in size and structure were purified by sucrose density gradient centrifugation. Thirdly, the drug loading, triggered release, cell binding, cell uptake and cell toxicities of the supported immunoliposome were studied. Release results showed a minimum drug leakage in serum at body temperature from the particle. The release was initiated with a minor burst trigged by low pH inside the tumor cell and followed with a long term linear pattern. Cell assay results showed the highest binding affinity of the antibody or Herceptin® grafted nanoparticles to Her2 overexpressing cell lines and a lysosomal intracellular distribution of the endocytosised particles. In the final study, a fabrication process for polymeric material nanoparticles was established. The process was capable of providing accurate control of the particle size with significant high output rates, thus largely extends the scope of materials for supporting the immunoliposome. / Ph. D.

Tesis por compendio / [EN] The present PhD thesis, entitled "Encapsulation of folic acid in silica porous supports: a nutritional and technological approach", focuses on the development of new smart systems for the controlled delivery of folic acid for nutritional applications. The first part of the thesis shows folic acid encapsulation in polyamines-functionalized silica porous matrices from a nutritional approach. The first part evaluates not only the influence of the loading method and the type of silica support employed (MCM-41, SBA-15, UVM-7 and Hollow Silica) on the efficacy of folic acid encapsulation, but also the influence of the morphology and porous system on the folic acid delivery profile from different supports. Folic acid release studies from different supports with various pH values have demonstrated that the designed systems are capable of smartly modulating the delivery of the folic acid dependent on the pH of the medium (inhibition of the release at an acidic pH -stomach-, controlled release at a neutral pH -intestine-). This capacity makes these developed delivery systems an excellent alternative to direct fortification to successfully modulate the bioaccessibility of folic acid along the gastrointestinal tract. The stability of the supports during an in vitro digestive process was evaluated, and demonstrated that not only small particles can be attacked during the digestion process, but also the functionalization with organic molecules, which act as molecular gates, prevents this attack. Finally, the cell viability studies carried out with four different cell lines revealed that neither the supports nor their degradation products caused any specific toxicity during the in vitro digestive process. The second part evaluates the influence of adding different silica supports to two food matrices: gelatin gels and yoghurts. This technological approach enabled us to know that the capacity of these smart systems to deliver folic acid in a controlled manner during an in vitro digestive process is mantained even after their incorporation in stirred yoghurt. The effect of the matrices on the gel's physical properties depends on the particle size, functionalization and concentration. Finally, this thesis tested that the optimization of folic acid loading, achieved in the first part of the thesis, allowed the fortification of yoghurt with 100% of the recommended daily allowance of folic acid with a very low amount of the system. This fortification affected neither the physico-chemical properties of the yoghurt, nor bacterial viability. In summary, it was concluded that the present thesis globally deals with folic acid encapsulation in silica porous matrices to be used in nutritional and food applications, which include the optimization of loading, release studies at diferent pH, in vitro digestions, stability studies of the employed matrixes, biocompatibility studies, and studies into the influence of their addition to food matrixes. The obtained results positively exhibit that the developed smart folic acid delivery systems open up a new way of fortifying food without endangering the properties of the food to which they are added. / [ES] La presente tesis doctoral que lleva por título "Encapsulación de ácido fólico en soportes porosos de óxido de silicio: una aproximación nutricional y tecnológica" está centrada en el desarrollo de nuevos sistemas inteligentes de liberación controlada de ácido fólico para aplicaciones nutricionales. La primera parte de la tesis muestra la encapsulación de ácido fólico en matrices porosas de óxido de silicio funcionalizadas con poliaminas desde una aproximación nutricional. En ella se ha evaluado la influencia del método de cargado y del tipo de soporte de óxido de silicio utilizado (MCM-41, SBA-15, UVM-7 y Hollow Silica) en la eficacia de encapsulación de ácido fólico. En esta primera parte, también se ha evaluado la influencia de la morfología y el sistema de poros de los diferentes soportes en el perfil de liberación del ácido fólico desde los mismos. Los estudios de liberación de ácido fólico desde los diferentes soportes a diferentes valores de pH han demostrado que los sistemas diseñados son capaces de modular inteligentemente la liberación de ácido fólico en función del pH del medio (inhibición de la liberación a pH ácido -estómago-, liberación controlada a pH neutro -intestino-). Esta capacidad convierte a los sistemas liberación desarrollados en una alternativa excelente a la fortificación directa para modular exitosamente la bioaccesibilidad del ácido fólico a lo largo del tracto gastrointestinal. Por otra parte, se ha evaluado la estabilidad de los soportes durante un proceso de digestión in vitro, demostrando que si bien algunos soportes pueden ser atacados durante la digestión, la funcionalización con moléculas que actúan como puertas moleculares previene este ataque. Por último, los estudios de viabilidad celular llevados a cabo en cuatro tipos de líneas celulares demuestran que ni los soportes, ni los productos de degradación de los mismos durante el proceso de digestión in vitro promueven ningún tipo de toxicidad inespecífica. En la segunda parte se ha evaluado la influencia de la adición de diferentes soportes de óxido de silicio a dos matrices alimentarias, geles de gelatina y yogures. Esta aproximación tecnológica ha permitido conocer que la capacidad de estos sistemas inteligentes para liberar controladamente el ácido fólico a lo largo de un proceso de digestión in vitro se mantiene incluso tras su incorporación en yogures batidos. Por otra parte, se ha comprobado que el efecto de las matrices sobre las propiedades físicas de los geles, es dependiente tanto del tamaño de las partículas, como de su funcionalización y concentración. Por último, se ha comprobado que debido a la optimización del cargado de ácido fólico alcanzada en la primera parte de la tesis, se puede lograr una fortificación de un yogur con el 100% de la cantidad diaria recomendada de ácido fólico con una cantidad tan pequeña de sistema que ni las propiedades físico-químicas de un yogur, ni la viabilidad bacteriana se ven comprometidas. En resumen, se puede concluir que la presente tesis ha abordado de una manera global la encapsulación de ácido fólico en matrices porosas de óxido de silicio para ser utilizados en aplicaciones nutricionales y alimentarias incluyendo estudios de optimización de cargado, estudios de liberación en función del pH, digestiones in vitro, estudios de estabilidad de las matrices utilizadas, estudios de biocompatibilidad, así como estudios de la influencia de la adición de estos sistemas inteligentes en matrices alimentarias. Los resultados obtenidos han puesto de manifiesto que los sistemas inteligentes de liberación de ácido fólico desarrollados abren la puerta a una nueva manera de fortificar los alimentos sin comprometer sus características. / [CA] La present tesi doctoral, que porta per títol "Encapsulació d'àcid fòlic en suports porosos d'òxid de silici: una aproximació nutricional i tecnològica" està centrada en el desenvolupament de nous sistemes intel·ligents de lliberació controlada d'àcid fòlic per a aplicacions nutricionals. La primera part de la tesi mostra l'encapsulació d'àcid fòlic en matrius poroses d'òxid de silici funcionalitzades amb poliamines des d'una aproximació nutricional. En esta part, s'ha avaluat la influència del mètode de carrega i del tipus de suport d'òxid de silici que s'ha emprat (MCM-41, SBA-15, UVM-7 i Hollow Silica) en l'eficàcia de l'encapsulació d'àcid fòlic. En esta primera part, també s'ha avaluat la influència de la morfologia i el sistema de porus dels diferents suports en el perfil d'alliberament de l'àcid fòlic des dels mateixos. Els estudis d'alliberament d'àcid fòlic des dels diferents suports a diferents valors de pH han demostrat que els sistemes dissenyats són capaços de modular intel¿ligentment l'alliberament d'àcid fòlic en funció del pH del medi (inhibició de l'alliberament a pH àcid -estómac-, alliberament controlat a pH neutre -intestí-). Esta capacitat fa dels sistemes desenvolupats una excel·lent alternativa a la fortificació directa per a modular amb èxit la bioaccessibilitat de l'àcid fòlic a través del tracte gastrointestinal. D'altra banda, s'ha avaluat l'estabilitat dels suports en un procés de digestió in vitro, demostrant que mentre que les partícules menudes poden ser atacades durant la digestió, la funcionalització amb molècules orgàniques que actuen com a portes moleculars prevé aquest atac. Per últim, els estudis de viabilitat cel·llular duts a terme en quatre tipus de línies cel·lulars demostren que ni els soports, ni els productes de degradació dels mateixos durant el procés de digestió in vitro promouen cap tipus de toxicitat inespecífica. En la segona part, s'ha avaluat la influència de l'addició de diferents sopors d'òxid de silici a dos matrius alimentàries, gels de gelatina i iogurts. Esta aproximació tecnològica ha permés conéixer que la capacitat d'aquests sistemes intel·ligents per alliberar controladament àcid fòlic durant un procés de digestió in vitro es manté fins i tot després de ser incorporats en iogurts batuts. D'altra banda, s'ha comprovat que l'efecte de les matrius sobre les propietats físiques dels gels, és dependent tant de la grandària de les partícules, com de la seua funcionalització i concentració. Per últim, s'ha comprovat que a causa de l'optimització del carregat d'acid fòlic alcançada en la primera part de la tesi, es pot aconseguir una fortificació d'un iogurt amb el 100% de la quantitat diària recomanada d'àcid fòlic amb una quantitat tan baixa del sistema que ni les propietats físico-químiques d'un iogurt, ni la viabilitat bacteriana se'n veuen compromeses. En resum, es pot concluir que en la present tesi s'ha abordat d'una manera global l'encapsulació d'àcid fòlic en matrius poroses d'òxid de silici per a ser utilitzades en aplicacions nutricionals i alimentàries, que inclouen estudis d'optimització de carregat, estudis d'alliberament en funció del pH, digestions in vitro, estudis d'estabilitat de les matrius utilitzades, estudis de biocompatibilitat, així com estudis de la influència de l'addició d'aquests sistemes en matrius alimentàries. Els resultats obtesos han posat de manifest de forma positiva que els sistemes intel·ligents d'àcid fòlic que s'han desenvolupat obrin una porta a una nova manera de fortificar els aliments sense comprometre les seues caracterísitiques. / Pérez Esteve, E. (2015). ENCAPSULATION OF FOLIC ACID IN MESOPOROUS SILICA SUPPORTS: A NUTRITIONAL AND TECHNOLOGICAL APPROACH [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/58613 / Premios Extraordinarios de tesis doctorales / Compendio

Yes / Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach is employed to fabricate highly modular 3D printed “polypill” capsules with bespoke release patterns for multiple drugs. Complex structures are devised using combined fused deposition modeling 3D printing aligned with hot-filling syringes. Two unibody highly modular capsule skeletons with four separate compartments are devised: i) concentric format: two external compartments for early release while two inner compartments for delayed release, or ii) parallel format: where nondissolving capsule shells with free-pass corridors and dissolution rate-limiting pores are used to achieve immediate and extended drug releases, respectively. Controlling drug release is achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles are achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules reveal how the developed approach can be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.

This thesis investigates the feasibility of utilizing biodegradable polymeric microspheres loaded with the anticancer drug 5-fluorouracil (5FU) and superparamagnetic iron oxide nanoparticles (SPIONs) to magnetically deliver the cancer therapeutic 5FU to a target tumor in the human body. The primary method of material loading consisted of a w/o/w double emulsion mechanism which 1) loads and protects 5FU in the inner water phase consisting of distilled water and polyvinyl alcohol (PVA), 2) dispersed SPIONs in the biodegradable polymeric organic phase consisting of methylene chloride (MeCl2) for eventual magnetic transport, and 3) suspended these w/o emulsion droplets in an outer aqueous phase comprised of water and PVA and then evaporating the solvent by convection. This procedure produced dried double emulsion microspheres below 2 µm in diameter. They were characterized using scanning electron microscopy (SEM), and magnetometry, which demonstrated their size and superparamagnetic properties. The encapsulation efficiency of 5FU into these polymeric microspheres was above 95%. Drug release of 5FU from dried double emulsion microspheres was significant over 63 days in water and phosphate buffered saline (PBS). Drug release was faster at 37 °C compared to room temperature (21 °C). The medium of PBS at pH 7.4 and 5.4 promoted faster release than distilled water at pH 7.0. Release was faster from PLGA than from PLA. Antibiotic potency of 5FU remained effective after drug release and degradation of carrier. Application of these microspheres in future clinical trials may present a noninvasive, low-risk method to treating malign tumors in nonresectable regions while demonstrating more effective results than systemic administration of chemotherapy. This research presents a significant innovation in therapeutic drug delivery technology for nonresectable cancerous tumors, particularly in the head and neck regions.

Master of Science / Department of Agronomy / David B. Mengel / Nitrogen fertilizers play an essential role in agricultural production in Kansas, particularly in row crops such as corn (Zea mays L.) and grain sorghum (Sorghum bicolor (L.) Moench). A good portion of the corn and grain sorghum grown in Kansas is typically grown using no-till production systems. These systems leave a large amount of surface residue on the soil surface, which can lead to ammonia volatilization losses from surface applied urea-containing fertilizers and immobilization of N fertilizers placed in contact with the residue. Leaching and denitrification can also be a problem on some soils. Current nitrogen prices, as well as concerns over environmental stewardship, are forcing producers to make smarter choices in the fertilizer products used as well as when and how the materials are applied, to optimize their nitrogen use efficiency. A common practice throughout Kansas is to apply N fertilizers prior to planting, sometimes up to 6 month prior to planting. What affect does this practice have on nitrogen availability to the growing crop? Current Kansas State University (KSU) soil test fertilizer recommendations assume 50% nitrogen use efficiency. This means of every pound of nitrogen applied only half will be utilized by the plant and turned into valuable grain. Possible solutions to help increase nitrogen use efficiency are the use of nitrogen additives which are currently on the market and claim to reduce nitrogen loss through denitrification and volatilization as well as the use of timing and application of fertilizers to further increase nitrogen use efficiency. The objective of this study is to evaluate different N fertilizer products, as well as additives and application practices and determine whether specific combinations can improve yield and N use efficiency of no-till corn and grain sorghum. The long-term goal of this study is to quantify some of these relationships to assist farmers in selecting specific combinations that could enhance yield and profitability. In this study five tools for preventing N loss were examined: fertilizer placement, or placing N below the soil surface or in bands on the residue-covered soil surface to reduce immobilization and/or volatilization; use of a urease inhibitor Agrotain (NBPT) that blocks the urease hydrolysis reaction that converts urea to ammonia and potentially could reduce ammonia volatilization; the use of a commercially available additive, Agrotain Plus, that contains both a nitrification inhibitor (DCD) and a urease inhibitor to slow both urea hydrolysis and the rate of ammonium conversion to nitrate and subsequent denitrification or leaching loss; use of a commercial product NutriSphere-N, which claims urease and nitrification inhibition; and the use of a polyurethane plastic-coated urea to delay release of urea fertilizer until the crop can use it. The ultimate goal of using these practices or products is to increase N uptake by the plant and enhance yield. An important measurement that was developed for this research was the use of a greenleaf firing index which used the number of green leaves below the ear at pollination as a key measurement in determining the effectiveness of fertilizer placement, application method, application timing and the use of nitrogen additives. If significant differences in lower leaf nitrogen stress are found, the potential exists to further develop this index and correlate differences observed with key parameters of nitrogen uptake such as ear-leaf nitrogen concentration, total nitrogen uptake and grain yield. Results observed from this research show that the potential to increase nitrogen use efficiency and reduce nitrogen loss do exist with the use of certain nitrogen additives, application methods and application timing. When conditions are conducive for nitrogen loss the use of currently available tools to protect nitrogen from volatilization, immobilization and/or denitrification loss significantly increased yields in the corn experiments. Results from the grain sorghum research indicate that when N losses limit yield, the use of products and practices enhance yield. In locations where nitrogen loss is minimal or low yields limit nitrogen response, the use of these practices was not found to be helpful.

Inflammatory processes are infamous for their destructive effects on tissues and joints in a variety of diseases. Within the body, inflammation is a highly regulated biological response whose purpose is to promote tissue regeneration following injury. However, in certain settings, inflammation persists and leads to progressive tissue destruction. This thesis focused on modulating inflammatory signaling in both contexts. Part I investigated the effects of a model pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), on the in vitro osteogenic differentiation of mesenchymal stem cells (MSCs). In contrast, Part II describes the development and in vivo evaluation of the first intra-articular controlled release system for the temporomandibular joint (TMJ), which silences inflammatory signaling and thus mitigates the painful joint damage seen in inflammatory TMJ disease. The following specific aims were addressed: (1) to determine the concentration of TNF-α that enhances in vitro osteogenic differentiation of MSCs; (2) to determine the temporal pattern of TNF-α delivery that enhances in vitro osteogenic differentiation of MSCs; (3) to determine the impact of bone-like extracellular matrix (ECM) on the concentration and temporal pattern of TNF-α delivery that enhances in vitro osteogenic differentiation of MSCs; (4) to evaluate the biocompatibility of intra-articular microparticles in the rat TMJ; (5) to develop a microparticle-based formulation for sustained release of a model anti-inflammatory small interfering ribonucleic acid (siRNA); and (6) to evaluate the therapeutic efficacy of intra-articular microparticles delivering siRNA in an animal model of TMJ inflammation. These studies led to the development of powerful strategies to rationally control inflammation to promote bone regeneration and mitigate joint damage in the setting of disease, both of which will ultimately improve the quality and specificity of therapies available in modern medicine. / Only volume 2 has been digitized.

MSc (Eng) dissertation - Faculty of Engineering and the Built Environment / Fertilizers are defined in the broadest sense as products that improve the levels of available plant nutrients or chemical and physical components that directly or indirectly enhance plant growth, yield and quality. The aim of this study was to produce slow controlled release fertilizers from oxidised coal. Two types of coals namely, Waterberg and Twistdraai (products, middlings) were utilised for the production of humic acids through slurry phase oxidation. The highest yields of humic acids were obtained in Waterberg and Twistdraai products samples. Subsequent to that, a nitrogen element was successfully inserted into the humic acid substrate. Humic acids are potential feedstock for modern manufacturing of organic fertilizers. The chemical substances regarded as hazardous to human consumption or those elements that negatively impact on the soil were significantly less detectable.

O presente trabalho teve como objetivo produzir comprimidos de liberação controlada de difosfato de primaquina baseados em polímeros hidrofílicos e otimizar a liberação do fármaco por meio do planejamento estatístico de mistura (DOE). Na seleção dos componentes da formulação foram realizados estudos de calorimetria exploratória diferencial (DSC) para verificar a compatibilidade entre o fármaco/excipientes e avaliação do fluxo dos pós das formulações por meio da determinação do ângulo de repouso. As 20 formulações obtidas no planejamento experimental continham misturas de hidroxipropilmetilcelulose de diferentes graus de viscosidade (K15M, K4M e K100LV) e polietilenoglicol 4000 como polímeros para controle da liberação. Os comprimidos de 30 mg de primaquina foram produzidos por compressão direta em máquina de punção simples de 9 mm e foram avaliados quanto à dureza, friabilidade, peso médio, teor do fármaco e dissolução. A cinética de liberação do fármaco foi estudada segundo os modelos de ordem zero, Higuchi e Korsmeyer-Peppas. Os ensaios de DSC permitiram verificar algum tipo de interação entre o fármaco e os excipientes lactose e estearato de magnésio. Os pós das formulações demonstraram boas propriedades de fluxo de acordo com os valores de ângulo de repouso. Os dados de regressão obtidos pelos modelos matemáticos aplicados com o DOE não permitiram verificar se a mistura de polímeros influenciou no ângulo de repouso dos pós e nas características físicas como dureza, friabilidade e peso médio dos comprimidos. No entanto, foi observada influência significativa da composição polimérica na dissolução dos comprimidos nos intervalos de 2, 4, 6 e 8 horas de ensaio. A partir desses dados e dos gráficos de superfície de resposta gerados pelo programa Design Expert® 6.0, foi possível otimizar as formulações restringindo a quantidade de cada polímero de forma a obter uma formulação com mecanismo de liberação duplo, por difusão e relaxamento das cadeias de polímero. O transporte anômalo foi o mecanismo de liberação de fármaco apresentado pela maioria das formulações, inclusive da formulação otimizada. / The objective of the present work was to produce primaquine diphosphate controlled release tablets based on hydrophilic polymers and use the mixture statistical experimental design (DOE) to optimize drug release. In selecting the components of the formulations, differential scanning calorimetry (DSC) were carried out to verify the compatibility between drug/excipients and evaluating flow properties of the powders by determining the angle of repose. The 20 formulations obtained in the experimental design contained mixtures of hydroxylpropylmethylcellulose of different degrees of viscosity (K15M, K4M and K100LV) and polyethylene glycol 4000 as polymers to control drug release. Tablets containing 30 mg of primaquine were produced by direct compression in a 9 mm single punch tablet press and were evaluated for hardness, friability, average weight, drug content and dissolution. The kinetics of drug release was studied applying Zero Order, Higuchi and Korsmeyer-Peppas models. DSC tests allowed verifying some kind of interaction between the drug and the excipients lactose and magnesium stearate. The values of angle of repose obtained demonstrated that the powders of the formulations presented good flow properties. The regression data obtained by the mathematical models failed to verify the influence of the mixture of polymers in the angle of repose of the powders and physical characteristics such as hardness, friability and average weight of the tablets. However, there was a significant influence of polymers composition in the dissolution of the tablets at intervals of 2, 4, 6 and 8 hours of testing. Most formulations showed anomalous transport as the mechanism of drug release. From these data and response surface plots generated by Design Expert® 6.0 software, it was possible to optimize the formulations by restricting the amount of each polymer to obtain a formulation with a double release mechanism, diffusion and relaxation of the hydrated matrix chains.

A zidovudina (AZT) ainda é o fármaco mais empregado no tratamento da AIDS, isoladamente ou em associação a outros antirretrovirais, porém é um fármaco administrado em altas doses e que apresenta efeitos adversos que comprometem a adesão do paciente ao tratamento. Assim, um novo sistema de liberação de zidovudina composto por nanopartículas de poli (n-butil-cianoacrilato) (PBCA) revestidas por ácido hialurônico (AH) foi desenvolvido e caracterizado com o objetivo de prolongar a liberação do fármaco e diminuir sua toxicidade. As nanopartículas têm sido amplamente estudadas como veículo para fármacos por permanecer na circulação por um tempo maior e, portanto, liberar o fármaco de forma prolongada. Para polimerização e, portanto, obtenção das nanopartículas, n-butil-cianoacrilato e Dextran® foram adicionados a HCl 0,1 M (pH 2,5), sob agitação a 800 rpm, por 1 h. O AZT foi adicionado e o processo foi neutralizado com adição de NaOH 0,1M após mais 3 h de agitação. Após filtração as partículas foram revestidas pela adição de uma dispersão aquosa de ácido hialurônico (AH) a baixa rotação. O diâmetro hidrodinâmico médio das nanopartículas não revestidas foi de 152,3 nm, com um índice de polidispersividade médio igual a 0,055. O potencial zeta médio dessas partículas foi -0,678 mV. O diâmetro hidrodinâmico médio das nanopartículas revestidas com AH obtido foi de 196,9 nm, com um índice de polidispersividade médio igual a 0,440. O potencial zeta médio dessas partículas foi de -25,6 mV. Os valores resultantes dessas análises são indicativos da estabilidade das nanopartículas obtidas e da boa reatividade dos monômeros dos cianoacrilatos. Ainda, pelos resultados é possível confirmar a ocorrência do revestimento. Assim, a eficiência do processo de revestimento das nanopartículas pode ser comprovada por meio dos resultados das análises de calorimetria exploratória diferencial (DSC) e pelos resultados das análises de espectroscopia de absorção na região do infravermelho. Para quantificar o fármaco associado às nanopartículas, um método empregando espectrofotometria derivada (ED1) no UV aplicando a técnica do ponto de anulação foi desenvolvido e validado. Tal método possibilitou a eliminação da interferência dos excipientes, o que permitiu a quantificação do AZT na suspensão de nanopartículas com precisão e exatidão adequadas. A porcentagem de fármaco associado às nanoestruturas obtidas pelo método foi de 64%, considerado satisfatório. As nanopartículas foram incorporadas a uma formulação base de gel de Carbopol® 940 que, apresentou estabilidade após ser submetida a diferentes condições de armazenamento, com incidência de luz e variação da temperatura. / Zidovudine (AZT) is still the most widely used drug in the treatment of AIDS, alone or in combination with other antiretroviral drugs, however it is indicated in high doses and has adverse effects that compromise patient compliance to treatment. Thus, a new zidovudine delivery system made of poly (n-butyl-cyanoacrylate) nanoparticles coated with hyaluronic acid (HA) was developed and characterized in order to extend the drug release and reduce its toxicity. The nanoparticles have been widely studied as drug carriers once they remain in circulation for a longer period and, consequently, release the drug gradually. For the polymerization, and, therefore synthesis of nanoparticles, n-butyl-cyanoacrylate and Dextran® were added to 0.1 M HCl (pH 2.5) and stirred at 800 rpm for 1 hour. AZT was added and the reaction was neutralized by the addition of 0.1 M NaOH after 3 more hours of agitation. After filtration the particles were coated by addition of an aqueous dispersion of hyaluronic acid (HA) at low revs. The mean hydrodynamic diameter of non-coated nanoparticles was 152.3 nm with an average polydispersity index of 0.055. The average zeta potential of these particles was -0.678 mV. The average hydrodynamic diameter of the coated nanoparticles was 196.9 nm, presenting an average polydispersity index of 0.440. The average zeta potential of these particles was -25.6 mV. The resulting values of these tests are indicative not only of the stability of the obtained nanoparticles but also the good reactivity of the monomers of cyanoacrylates. Moreover, the results can confirm the occurrence of coating. Thus, the efficiency of the coating process of the nanoparticles can be demonstrated by the results of the analysis of differential scanning calorimetry (DSC) and the results of the absorption spectroscopy in the infrared region. In order to quantify the drug associated with the nanoparticles, a method employing derivative spectrophotometry (ED1) UV applying the zero-crossing technique was developed and validated. This method allowed the elimination of interference of excipientes, allowing the quantification of AZT nanoparticles in suspension with adequate accuracy and precision. The percentage of the drug associated with the obtained nanostructures by the method was 64%. The nanoparticles were incorporated into a Carbopol® 940 gel formulation, which was stable after being subjected to different storage conditions, with incidence of light and temperature variation.

Made available in DSpace on 2017-07-21T14:13:11Z (GMT). No. of bitstreams: 1 MARTINHA ANTUNES ALMEIDA1.pdf: 2864603 bytes, checksum: 067120c01fd21002ee39713f2ce0f36c (MD5) Previous issue date: 2013-02-27 / Capsaicinoids show several therapeutic uses. However they cause pungency in contact with skin and mucosae. In that sense, the aim of this study was to obtain microparticles of poly (-caprolactone) (PCL) containing capsaicinoids for prolonged release through the gastrointestinal tract in order to improve the treatment of obesity. Formulations containing 3, 5 and 10% capsaicinoids were successfully prepared by simple emulsion/solvent evaporation. Values of encapsulation efficiency above 90% were observed for these vanillylamide-loaded microparticles. Microparticles showed spherical shape and smooth surface. The size was suitable for oral use in order to provide a release through the gastrointestinal tract. No chemical bonds were observed between drug and polymer. Microencapsulation led to drug amorphization. Formulations prolonged the release of capsaicinoids without changing the release kinetics (biexponential model). Microencapsulation increased the gastric tolerability of capsaicin and dihydrocapsaicin because it prevented inflammatory processes in the stomach of rats. Microparticles containing 5% capsaicinoids had an effect similar to ranitidine and omeprazole in preventing ulcerative lesions induced by ethanol. This same formulation demonstrated a statistically significant reduction of Lee index, mesenteric fat and retroperitoneal fat in rats with obesity induced by hypothalamic lesion using monosodium L-glutamate. These rats also showed a remarkable improvement in lipid profile and glucose level compared to the control groups. Based on the experimental results, it is possible to suggest that capsaicinoids-loaded PCL microparticles are feasible approaches for the treatment of obesity. / Os capsaicinoides apresentam diversas aplicações terapêuticas, entretanto causam elevada pungência quando em contato com a pele e com as mucosas. Nesse sentido, o objetivo do presente trabalho foi desenvolver micropartículas de poli(-caprolactona) (PCL) contendo capsaicinoides para a liberação prolongada ao longo do trato gastrointestinal, com o propósito de otimizar o tratamento da obesidade. As formulações foram obtidas com sucesso pelo método de emulsão simples e evaporação do solvente, nas concentrações teóricas de 3, 5 e 10% de capsaicinoides. Valores de eficiência de encapsulação acima de 90% foram observados para todas as micropartículas contendo essas vanililamidas. As micropartículas apresentaram formato esférico e superfície lisa. O tamanho foi adequado para uso oral, a fim de permitir uma liberação ao longo do trato gastrointestinal. Não foi verificada a formação de ligações químicas entre o fármaco e o polímero. A microencapsulação promoveu a amorfização do fármaco. As formulações prolongaram a liberação dos capsaicinoides, sem alterar a cinética de liberação (modelo biexponencial). A microencapsulação foi capaz de aumentar a tolerância gástrica da capsaicina e da di-hidrocapsaicina, prevenindo a formação de processos inflamatórios no estômago dos ratos. As micropartículas contendo 5% de capsaicinoides tiveram efeito comparável à ranitidina e ao omeprazol na prevenção de lesões ulcerativas induzidas por etanol. Essa mesma formulação promoveu a redução estatisticamente significativa do índice de Lee, da gordura mesentérica e da gordura retroperitonial de ratos com obesidade induzida por lesão hipotalâmica utilizando L-glutamato monossódico. Esses ratos também apresentaram uma melhora expressiva no perfil lipídico e na glicemia, em comparação aos grupos controle. Com base nos resultados experimentais, é possível sugerir que as micropartículas de PCL contendo capsaicinoides são alternativas viáveis para o tratamento da obesidade.