Orientador: Nelson Eduardo Durán Caballero / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-27T11:57:43Z (GMT). No. of bitstreams: 1 BerniNeto_EliasAntonio_D.pdf: 2747484 bytes, checksum: 572541fe31adfbc199cbcb02da6c1cbe (MD5) Previous issue date: 2014 / Resumo: O Brasil se destaca por ter uma das maiores pecuárias bovinas do mundo,movimentando cerca de R$ 164 bilhões ao ano. Contudo, este setor apresenta ainda algumas dificuldades, principalmente relacionadas com a sanidade dos animais. Dentre as principais patologias responsáveis por perdas podemoscitar o ataque de ectoparasitas,como o Boophilumicroplus, que gera perdas da ordem de US$ 4 bilhão ao ano, e a mastite bovina (inflamação no ubre de vacas) causada por microorganismos como Staphylococcus aureus e a Escherichia colie que gera perdas nos valores de U$ 185 por animal ao ano. Baseado nesses fatos, a área de nanoliberação ou drug release foi escolhida como alternativa para aumentar a eficácia dos carrapaticidas e dos medicamentos usados no combate a mastite. Com o uso de nanopartículas poliméricas de poli(?-caprolactona) (PCL) eutilizando a técnica de nanoprecipitação ou deslocamento do solvente recobertas com o polímero quitosana, foi possível aumentar tanto a estabilidade como asolubilidade dos ativos, bem como diminuir sua toxicidade contra células 3T3. Foram estudados 4 sistemas distintos, QS_PCLnp (sem ativo), QS_PCLnp _ami (contendo o ativo amitraz), QS_PCLnp_flu (contendo o ativo fluazuron) e QS_PCLnp_vio (contendo o ativo violaceína). O sistema QS_PCLnp_vioapresentou um tamanho de 260±10 nm e carga superficial de +30±2 mV, com uma concentração final de violaceína de 180 ?g mL-1eeficiência de 91±1% para uma capacidade de encapsulamento de 11±1% em relação a massa de PCL, sendo testado contra as bactérias E. coli e S. aureus no combate a Mastite bovina. O sistemaQS_PCLnp_amiapresentou o tamanho de 275±30 nm e carga superficial de +43±7 mV, com uma concentração final de amitraz de 1,0 mg mL-1e eficiência de 77±1% para uma capacidade de encapsulamento de 39±1% com relação a massa de PCL. Já o sistema QS_PCLnp_flu apresentou o tamanho de 295±35nm com um potencial zeta de +44±10econcentração de 0,5 mg mL-1 de fluazurono, onde obteve-se uma eficiência de 89±1% para uma capacidade de encapsulamento de 22±1% com relação a massa de PCL. Sendo que os sistemas QS_PCLnp_ami e QS_PCLnp_flu foram usados no combate ao carrapato B. microplus. Em todos os sistemas contendo ativos foi observado que os mesmos estavam dispersos molecularmente na matriz polimérica interna de PCL bem como na camada superficial de quitosana, influenciando na estabilidade estérica das nanopartículas no pH acima de 7. Todos os sistemas se mostraram estáveis em soluções salinas deconcentração de 1,25 mol L-1de NaCl e com o aumento da temperatura até 50°C. No estudo da mastite,o sistema QS_PCLnp_vio mostrou uma maior ação contra a S. aureus, enquanto que a violaceína pura se mostrou mais eficaz contra a E. coli,resultados que possibilitam um estudo de um sistema híbrido contendoQS_PCLnp_vio e violaceína pura. No caso do combate ao carrapato B. microplus o uso dos sistemas QS_PCLnp_ami e QS_PCLnp_flu em conjunto, possibilitou uma dose menor do ativo fluazuron do que a praticada comercialmente, deixando o animal livre de carrapatos por um período de 28 dias, necessitando de espaços maiores entre os banhos daqueles praticados atualmente / Abstract: Brazil plays a pivotal role in livestock market, moving around R$ 164 billions per year. However, this market shows yet some difficulties, mainly related to the health of animals being the main pathologies which affect the ectoparasites such as Boophilus microplus that generates losses of US$ 4 billion per year, and bovine mastitis (inflammation of the udders of cows) caused by microorganisms such as Staphylococcus aureus and Escherichia coli, that generates losses in the amounts of US$ 185 per cow per year. For this reason the drug release was chosen as an alternative to increase the effectiveness of acaricides and drugs used against bovine mastitis. Using polymeric nanoparticles of poly (?-caprolactone) (PCL) coated with the polymer chitosan, and synthesized by displacement solvent technique was possible to increase both stability and solubility assets as well as decreasing its toxicity against 3T3 cells. In this work, 4 different systems were studied, QS_PCLnp (without assets), QS_PCLnp_vio (containing the active violacein) QS_PCLnp_ami (containing the active amitraz) and QS_PCLnp_flu (containing the active fluazuron). The QS_PCLnp_vio system showed a size of 260±10 nm and surface charge of +30±2 mV, with a final concentration of 180 mg mL-1 of violacein and efficiency of 91±1% for a loading capacity of 11±1% compared with PCL mass, this system were being tested against the bacteria S. aureus and E. coli against bovine mastitis. The QS_PCLnp_ami system shows a size of 275±30 nm and surface charge of +43±7 mV, with a final concentration of 1.0 mg mL-1 of amitraz, and an efficiency of 77±1% for a loading capacity of 39±1 % compared with PCL mass, while QS_PCLnp_flu shows a size of 295±35 nm and surface charge of +44±10 mV and 0.5 mg ml-1 of fluazuron, which gave an efficiency of 89±1% for a loading capacity of 22±1% compared with PCL mass. Both system QS_PCLnp_ami and QS_PCLnp_flu were used against B. microplus. All systems shows molecularly dispersed active compound in the polymer matrix of PCL inside and the surface layer of chitosan influencing the steric stability of nanoparticles in pH above 7. All systems were stable in saline concentration of 1.25 mol L-1 of NaCl and with temperature increase up to 50°C. In the study of mastitis, the QS_PCLnp_vio system showed greater activity against S. aureus, while the pure violacein is more effective against E. coli. This result motivates a study of a hybrid system contain QS_PCLnp_vio and pure violacein. In the case of B. microplus tick were used QS_PCLnp_ami and QS_PCLnp_flu together, which provided a lower dose of the active fluazuron than commercially practiced, leaving the animal free of ticks for a period of 28 days, requiring larger spaces between the bathing those currently practiced nowadays / Doutorado / Físico-Química / Doutor em Ciências

Orientador: Nelson Eduardo Durán Caballero / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-27T13:02:52Z (GMT). No. of bitstreams: 1 Bueno_CamilaPedrosoSilveira_M.pdf: 80017692 bytes, checksum: afdb5714b60ba879bf69cbd031077a1d (MD5) Previous issue date: 2015 / Resumo: Um dos principais problemas da quimioterapia, atualmente, é o uso de fármacos extremamente citotóxicos, cuja falta de especificidade acarreta na ação sob todos os tipos de células, incluindo as saudáveis, gerando efeitos colaterais intensos, que prejudicam a terapia em si. Nesse sentido, os nanomateriais oferecem uma opção terapêutica valiosa, pois podem conjugar especificidade e liberação sustentada do fármaco, prevenindo-o de ser degradado prematuramente e permitindo o uso de menores doses. A fim de desenvolver um sistema do tipo drug depot que servisse como plataforma para a liberação sustentada de fármacos, foram produzidas, neste trabalho, formulações baseadas em nanopartículas mesoporosas de sílica e hidrogel de Pluronic F-127, associadas a dois fármacos individualmente: doxorrubicina e sildenafila. As nanopartículas mesoporosas de sílica são boas alternativas para uso médico, pois são biocompatíveis e possuem grande volume de poros, atuando como carreadoras, promovendo a liberação sustentada do fármaco. O Pluronic F-127 atua como agente gelificante e promove uma liberação prolongada das nanopartículas e do fármaco incorporado, uma vez que é um polímero termo-reversível que permite a formação de um hidrogel à temperatura ambiente. A doxorrubicina é um antibiótico antitumoral de largo espectro, amplamente usada no tratamento de diversos cânceres, que atua ligando-se ao DNA e induzindo apoptose celular. Por sua vez, a sildenafila faz parte de uma classe de inibidores da enzima fosfodiesterase-5, cuja expressão aparece aumentada em diversos carcinomas e, por isso, seu papel na progressão tumoral vem sendo amplamente estudado. Após estudar os aspectos físico-químicos envolvendo os componentes dos sistemas, como estabilidade coloidal e interações entre as nanopartículas e biomoléculas presentes no meio biológico, as formulações foram testadas contra câncer de próstata quimicamente induzido em ratos. Os resultados mostram que as nanopartículas possuem um papel determinante no quadro de melhora de tumor, minimizando, também, a toxicidade do antitumoral / Abstract: One of the largest problems of chemotherapy currently is the use of highly cytotoxic drugs with lack of specificity, thus damaging all kinds of tissues, including healthy cells. This leads to aggressive side effects that jeopardize the therapy itself. In this context, nanomaterials emerge as a valuable therapeutic option, as they can provide the specificity to target tumor tissues and a sustained release of the drug, preventing the drugs premature degradation and allowing lower doses. Aiming to develop a drug depot system that would act as platform for the sustained release of drugs, this project proposed to develop formulations based on mesoporous silica nanoparticles and Pluronic F-127 hydrogels, associated with two drugs individually: doxorubicin and sildenafil. The mesoporous silica nanoparticles are good alternatives for biomedical use because of their biocompatible features and their great pore volume, acting as carriers and providing sustained release. Pluronic F-127 acts as the gelling agent and provides a prolonged release of the nanoparticles and the loaded drug, since it is a thermo-reversible polymer that allows the formation of a hydrogel at room temperature. Doxorubicin is an antibiotic and antitumor of large spectra, largely used to treat several types of cancer and acts binding the DNA and inducing cell apoptosis. Sildenafil, in turn, is part of a class of inhibidors of the enzyme phosphodiesterase-5, which expression is increased in many carcinomas and which role in tumor progression has been largely studied. After studying physico-chemical aspects involving the systems produced, such as the colloidal stability, release profile, and the interactions of the nanoparticles with the biomolecules present in biological medium. The formulations were also tested in rats with chemically induced prostate cancer. The results show that the nanoparticles play a determinant role on the improvement of tumor conditions, also reducing doxorubicin's toxicity / Mestrado / Físico-Química / Mestra em Química

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18133号 / 医博第3853号 / 新制||医||1001(附属図書館) / 30991 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂田 隆造, 教授 瀬原 淳子, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13051号 / 論医博第2117号 / 新制||医||1017(附属図書館) / 33141 / (主査)教授 別所 和久, 教授 椛島 健治, 教授 開 祐司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20807号 / 医博第4307号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 瀬原 淳子, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Ibrutinib is the first Bruton`s tyrosine kinase (BTK) inhibitor for oral administration approved by FDA in 2014. It is the first-line treatment for B-cell malignancies, which are the most common hematologic neoplasia. Ibrutinib is a relatively safe alternative for currently used treatment modalities that are associated with long-term toxicity and resistance. However, ibrutinib is considered as BCS class II drug and has very low solubility in an aqueous medium (13 μg/ml at PH 8.0) and has six different polymorphic forms. Furthermore, recommended daily dose of ibrutinib is about 420 mg to 560 mg, which causes severe GI disturbances, with poor patient compliance. This represent a major critical concern because drug is used chronically. Increasing drug solubility and controlling rate of drug release may improve both bioavailability at significantly lower daily administered doses and by implication could minimize GI side effects and improve patient compliance.The objective of this study is to utilize Hot Melt Extrusion (HME) to develop a stable amorphous solid dispersion (ASD) of ibrutinib using Copovidone (PlasdoneTM S-630 Ultra) as a carrier for inclusion into a hydrating matrix for sustained release delivery. Development of ASD based on HME is an efficient method to overcome poor solubility problem and stabilize the drug`s metastable polymorphic states. It is known that amorphous systems are energetically at a higher thermodynamic state and can dissolve to a much greater extent relative to their crystalline counterpart. A stable sustained-release ASD based system may offer many advantages, including reduction in frequency of administration and GI disturbances with propensity to enhance solubilization while suppressing recrystallization. The ASD systems prepared in this study was stable, amorphous, and single-phase systems up to 60% API load as confirmed by X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC), and rheological analysis. Supersaturated micro-dissolution testing of melt-extruded powder in fasted state simulated intestinal fluid demonstrated up to 70% increase in supersaturation solubility than the saturation solubility of crystalline counterparts. In addition, dissolution data based on the standard USP paddle method for the formulated SR tablets demonstrated a prolonged release up to six hours and a maximum of 53% higher drug release than crystalline ibrutinib. In conclusion, the results of this study indicate that ibrutinib amorphous solid dispersion developed utilizing hot-melt extrusion technology and Copovidone (PlasdoneTM S-630 Ultra) as a carrier is able to produce stable and homogeneous single-phase ASD system with enhanced solubility and desirable sustained drug release rate. / Pharmaceutical Sciences

Nanoparticles are important tools in biotechnology and biomedical research. Gold nanoparticles (AuNPs) have emerged as a particularly important class of nanobiotechnological tools as a result of a number of unique and useful attributes. These attributes include the high degree of biocompatibility of AuNP cores, the similarity in size of AuNPs and biomacromolecules, and the great chemical flexibility of AuNP surface design. One of the most promising applications of AuNPs in biotechnology and biomedicine is their use as drug delivery vehicles. Drug delivery vehicles provide therapeutics with desired delivery properties by targeting them specifically to the environments in which their therapeutic activity is sought and by overcoming solubility barriers. The drug delivery properties of AuNPs are a function of their sizes and surface chemistries. The nanometer scale of AuNPs allows these three-dimensional and diffusible self-assembled monolayers to act as substructures for supramolecular assemblies, to extravasate from tumor-supplying endothelia, and to undergo cellular uptake by endocytosis. AuNPs have become a versatile platform for the creation of multifunctional delivery vehicles. This work represents a collection of studies in which AuNPs have been used as probes in fundamental biological research and delivery systems for small molecules and biologics. In these studies, precision control of surface chemistry on the nanometer scale, made possible by AuNPs, has been used to find solutions to the problems of unraveling the role of hydrophobicity in immune system activation, delivering proteins past mammalian cell membranes, development of a sustained release drug delivery platform, and condensation and cellular delivery of siRNA.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24794号 / 医博第4986号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 寺田 智祐, 教授 武藤 学, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

As Formas Farmacêuticas de Liberação Prolongada (FFLP) têm sido uma alternativa eficaz na terapia, pois proporcionam maior adesão do paciente ao tratamento em função da redução da frequência de dosagem ao longo do dia, sendo sua principal característica, a modulação da liberação/dissolução do fármaco. Entretanto, esta etapa pode ser influenciada por diferentes fatores, dentre eles: os físico-químicos relacionados ao fármaco; os farmacêuticos, principalmente relacionados aos excipientes empregados e às técnicas de obtenção da forma farmacêutica (FF) e os fisiológicos do trato gastrintestinal (TGI), como por exemplo, o pH dos líquidos do TGI, o tempo de esvaziamento gástrico, a motilidade intestinal, entre outros. Desse modo, a avaliação do trânsito da FF no TGI, após a sua administração, permite uma melhor compreensão dos fatores que podem afetar as etapas de liberação/dissolução do fármaco in vivo. Dentre as técnicas empregadas com esse objetivo, destacam-se: a cintilografia e os métodos biomagnéticos. A Biosusceptometria de Corrente Alternada (BAC) é um método biomagnético que tem se mostrado promissor para este tipo de estudo, por ser não invasivo, portátil, livre de radiação ionizante, e por apresentar acurácia e versatilidade. Diante do exposto, o presente trabalho teve como objetivos, desenvolver e caracterizar sob o aspecto biofarmacotécnico in vitro, um sistema de liberação prolongada contendo nimesulida (fármaco-modelo) e marcador magnético (ferrita), visando obtenção de ferramenta para avaliação do trânsito gastrintestinal por meio de técnica biomagnética. Para isto foram desenvolvidas quatro formulações de comprimidos de liberação prolongada contendo nimesulida, ferrita e diferentes concentrações de hidroxipropilmetilcelulose (HPMC): NF1 (30% HPMC); NF2 (23% HPMC); NF3 (17% HPMC) e NF4 (10% HPMC). Essas foram avaliadas quanto ao comportamento de dissolução por meio de ensaios com aparato 4 e avaliação da cinética e da eficiência de dissolução (ED%). Posteriormente, estudos biomagnéticos, in vitro e in vivo, foram conduzidos com emprego da técnica de BAC para a formulação selecionada. Os resultados obtidos mostraram que as 04 formulações desenvolvidas apresentaram porcentagens de dissolução distintas em função das diferentes concentrações de HPMC (NF1 = 13,2%; NF2 = 40,1%; NF3 = 72,5% e NF4 = 91,5%). A formulação NF4, com menor concentração de HPMC, foi escolhida para os estudos por meio de BAC em função dos resultados de ED% (54,3%) e por apresentar comportamento mais próximo de uma formulação de liberação prolongada. Em relação aos resultados de BAC in vitro, destaca-se que a formulação NF4 (10%HPMC) apresentou aumento de área magnética de forma independente do pH do meio, sugerindo que a hidratação/intumescimento da HPMC independe do pH. Em relação à avaliação do trânsito intestinal (estudo in vivo) foram obtidos os seguintes dados: Tempo médio de Residência Gástrica (TTR) - 89 minutos; Tempo médio do Trânsito Orocecal (TTO) - 313 minutos e Tempo médio do Trânsito Intestinal (TTI) - 224 minutos. Os dados de BAC in vivo permitiram observar que o aumento de área magnética atingiu um platô em cerca de 80 minutos após a administração da formulação NF4. A comparação dos dados de BAC in vitro e BAC in vivo, relacionados ao trânsito gastrintestinal, indica que a formulação NF4, após apresentar o ápice de intumescimento, foi capaz de manter sua estrutura permanente ao longo do TGI, favorecendo assim a liberação modulada do fármaco. Os resultados obtidos demonstraram que a formulação desenvolvida foi eficiente para avaliar e caracterizar o trânsito no TGI por meio da técnica de BAC e também permitiram uma estimativa do comportamento do fármaco em relação a solubilidade em cada porção do TGI, proporcionando assim uma ferramenta adequada para avaliação do trânsito do TGI e desenvolvimento de FFLP. / Extended Release (ER) dosage forms have been an effective alternative in therapy, since they provide greater patient adherence to treatment as a function of the reduction of the frequency of dosing throughout the day, its main characteristic being the release / dissolution modulation of the drug. However, this stage can be influenced by different factors, among them: the physical and chemical related to the drug; the pharmacists, mainly related to the excipients employed and the techniques of obtaining the form dosage and the physiological ones of the gastrointestinal tract (GI tract), as for example, the pH of the liquid of the GI tract, gastric emptying time, intestinal motility, among others. Thus, assessment of dosage forms transit in GI tract after its administration allows a better understanding of the factors that may affect the drug release / dissolution steps in vivo. Among the techniques used for this purpose, the following stand out: scintigraphy and biomagnetic methods. Alternating Current Biosensiometry (ACB) is a biomagnetic method that has shown promise for this type of study, since it is non-invasive, portable, free of ionizing radiation, and because of its accuracy and versatility. In view of the above, the aim of this work was to develop and characterize a sustained release system containing nimesulide (study drug) and magnetic marker (ferrite) under the in vitro biopharmaceutical aspect, aiming to obtain a tool to evaluate the GI tract transit through means of biomagnetic technique. For this, four formulations of extended release tablets containing nimesulide, ferrite and different concentrations of hydroxypropylmethylcellulose (HPMC): NF1 (30% HPMC) were developed; NF2 (23% HPMC); NF3 (17% HPMC) and NF4 (10% HPMC). These were evaluated for dissolution behavior by apparatus 4, assays and kinetics and dissolution efficiency (ED%). Subsequently, biomagnetic studies, in vitro and in vivo, were conducted using the ACB technique for the selected formulation. The results showed that the formulations developed showed different percentages of dissolution as a function of the different concentrations of HPMC (NF1 = 13.2%, NF2 = 40.1%, NF3 = 72.5% and NF4 = 91.5%). The NF4 formulation, with a lower concentration of HPMC, was chosen for the ACB studies as a function of ED% results (54,3%) and because of the behavior of a sustained release formulation. In relation to the in vitro ACB results, the NF4 formulation (10% HPMC) showed an increase in magnetic area independently of the pH of the medium, suggesting that the HPMC hydration / swelling is independent of pH. In relation to intestinal transit evaluation (in vivo study) the following data were obtained: Mean Time of Gastric Residency (TTR) - 89 minutes; Mean Time of Orocecal Transit (OCTT) - 313 minutes and Mean Time of lntestinal Transit (TTI) - 224 minutes. ACB data in vivo showed that the increase in magnetic area reached a plateau in about 80 minutes after administration of the NF4 formulation. Comparison of in vitro ACB and ACB data in vivo, related to gastrointestinal transit, indicates that the NF4 formulation, after showing the swelling apex, was able to maintain its permanent structure throughout the GI tract, thus favoring the modulated release of the drug. The obtained results demonstrated that the developed formulation was efficient to evaluate and characterize the transit in the GI tract by means of the ACB technique and allowed a prediction of the behavior of the drug in relation to the solubility in each portion of the GI tract, thus providing a suitable tool for evaluation of the GI tract transit and the development of sustained release formulation.