京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21345号 / 薬科博第95号 / 新制||薬科||10(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 髙倉 喜信, 教授 小野 正博, 教授 山下 富義 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H. P. M. C. ) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The 6-form, the cammerdiallý 4- available stable ýorm and the a and s metastable forr. s (nomenclature after Huller, 1978).. were isolated. The a form was found to be unstable on storage. A .7 fold increase in intrinsic dissolution rate was observed for the metastable s-polymorph compared with the stable 6-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H. P. M. C. and poloxamer 188 were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H. P. M. C. was f8und to form a "high energy" complex with phenylbutazone which melted 10 C lower than the parent drug. When prepared by spray drying H. P. M. C. inhibited the formation of the metastable a-polymorph of phenylbutazone. A2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex witý phenylbutazone and unlike H. P. M. C. did not inhibit thejgr gation of the a-polymorph. For both crystallised and spray fo0ld increase in dissolution rate was obtained at polymer levels oý 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of-selected phenylbutazone: polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compact. ion of phenylbu. tazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (67form), samples of spray dried phenylbutazone (a-form) and samples containing different concentrations of H. P. M. C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H. P. M. C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H. P. M. C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H. P. M. C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples. / Saudi Arabian Government

This study is an observation of the various physicochemical changes that occur in enzyme-modified cheese (EMC) during the incubation step of production. The purpose of this study was an attempt to gain a better understanding of the changes that occur due to enzymatic reactions during EMC production. A standard EMC batch was prepared with the addition of two exogenous enzymes, a lipase and a protease (LP). Two additional treatment batches had either only a lipase (L) or a protease (P) added individually. Batches were prepared in duplicate with each replicate performed on different days. Each batch was incubated at 42±0.5°C in a water bath and was monitored for changes in pH, water activity, viscosity, water-soluble nitrogen, water-soluble free amino acids, titratable acidity, and visual observations, every two hours over a standard incubation time of 24 hours. Changes in pH showed little to no change in the P batches, while both the LP and L batches showed a decrease over time, very similar to each other. Changes in water activity showed a slight decrease over time in all batches from 0.98 to 0.94-0.97. However, because these changes were so small and a considerable amount of variation was found between replicate batches, water activity was likely a less practically significant method for measuring enzyme hydrolysis. Changes in viscosity were significantly different between all batches at different points and the L batches produced some very unique changes in viscosity. Changes in water-soluble nitrogen showed unexpected higher levels in the LP batches than the P batches. Changes in water-soluble free amino acids showed a significant impact that the protease had on the liberation of free amino acids. Changes in titratable acidity showed an increase in the LP batches and an apparent additive effect from both enzymes when combined. Monitoring these physicochemical properties in the different treatments indicated the changes that were brought about by the enzymes and may be repeated by manufacturers to identify production end-points.

No description available.

<p dir="ltr"><i>Pseudomonas aeruginosa</i> (<i>P. aeruginosa</i>) is a Gram-negative bacterium responsible for many infections in immunocompromised humans. This multi-drug resistance human pathogen can form biofilms, which help protect it from not only clinical treatment but also from main homeostasis and metabolism. Understanding biofilm structures is critical to help combat biofilm formation and develop better ways to treat <i>P. aeruginosa</i> infections. A molecule that helps biofilm formation and virulence infections for <i>P. aeruginosa</i> is pyocyanin, which is believed to be correlated with the invasiveness of the bacteria and the stabilization of biofilms. To better understand the role of pyocyanin in assisting <i>P. aeruginosa</i> with survival, we applied optical imaging to study pyocyanin in biofilms and under blue light treatment. Using nonlinear optical imaging methods, we could successfully detect the aggregation of pyocyanin in biofilms. Furthermore, we discovered that pyocyanin protects <i>P. aeruginosa</i> from blue light inactivation. In addition, we found that blue light treatment alters the structure of pyocyanin, leading to irreversible changes that produce distinct spectra in UV-Vis and fluorescence signals. <i>These results provide new insights into how pyocyanin protects </i><i>P. aeruginosa</i> in blue light treatment. Further investigation would lead to better treatment strategies for more effective treatment of <i>P. aeruginosa</i> and biofilms for various infections.</p>

Yes / Lipid membrane-water partitions (e.g., immobilized artificial membrane systems where the lipid membrane is a neutral phospholipid monolayer bound to gel beads) were compared to various organic solvent-water partitions using linear free energy relationships. To this end, we also measured the retention factors of 36 compounds (including neutral and ionic species) from water to liposomes made up of 3-sn-phosphatidylcholine and 3-sn-phosphatidyl-l-serine (80:20, mol/mol), employing liposome electrokinetic chromatography in this work. The results show that lipid membranes exhibit a considerably different chemical environment from those of organic solvents. For both neutral species and ionic species, partitions into the more polar hydroxylic solvents are chemically closer to partition into the lipid membrane as compared to partitions into the less polar hydroxylic solvents and into aprotic solvents. This means that solutes partition into the polar parts of lipid membranes, regardless of whether they are charged or not. In addition, cerasome (i.e., liposome composed mainly of stratum corneum lipids) was compared with regular phospholipid liposomes as a possible model for human stratum corneum in partitions. It was found that the cerasome-water partition exhibits a better chemical similarity to skin permeation. This is probably due to the unique structures of ceramides that occur in cerasome and in the stratum corneum lipid domain. We further show that membranes in membrane-water partitions exhibit very different properties.

This thesis reports on the combined effects of toxicants and physicochemical factors on micro-organisms. The main objective of the project was to use multi-sensing systems such as mediated and non-mediated sensor systems, growth tests and physicochemical sensors to investigate novel stressor-toxicant-assay combinations. Screen-printed, disposable, developmental-phase, physicochemical sensor constructs (conductivity and dissolved oxygen) were validated under conditions compatible with microbial bioassays, to ascertain their potential role in toxicity testing. The conductivity sensor construct could be used to indirectly inform on the osmolality of the test samples, but the dissolved oxygen sensor construct was not found to give reproducible results. The results were thought to be compromised by in-house screen-printing using a complex carbon ink formulation for the working electrode. Escherichia coli and a consortium with ammonia oxidation capacity (CAOC) were used as the test species for the bioassays. The combined effects of four inorganic salts (NaCl, NaN03, KCl and KN03) and two toxicants (3,5-DCP and HgCh) on E. coli were investigated using the CellSense™ biosensor system, Clark oxygen electrode and microtitre plate growth assays. A variety of trends were observed with each salt-toxicantbioassay combination, emphasising a need for better understanding of the assay media and factors such as bioavailability, to interpret the toxicity data. The results also suggested the importance of using multiple bioassays with varied end points, for toxicity testing. The CAOC, which was isolated from the activated sludge, was tested for physicochemical stressor and toxicant effects using the mediated biosensors. The results were very different from those obtained with E. coli, indicating that each species reacts to toxicants and changes in physicochemical factors differently. Although the full potential of disposable, physicochemical sensors, at the point of toxicity testing was not achieved, the study did investigate previously uncharacterised, combined effects of salts and toxicants on microbial cells. It highlighted the need for development of hybrid systems and also offered a route towards integration of physicochemical and biological sensing systems for simultaneous monitoring of both environmental and biological elements.

Tendo em vista a natureza finita dos minerais naturais, torna-se evidente a necessidade de utilizarmos este recurso de maneira estratégica. Desta forma, diversas pesquisas vêm sendo desenvolvidas principalmente nas áreas químicas, metalúrgicas e mineralógicas desde as etapas de extração, beneficiamento, aplicação e reutilização dos resíduos de minérios. Portanto, é extremamente importante a intensificação dos estudos para aumentar o conhecimento quanto às características e propriedades físico-químicas destes minerais, visando melhorar o seu aproveitamento e longevidade das jazidas naturais, como as fontes de bauxita, que é a principal matéria-prima para a produção de óxido de alumínio fundido. Na sua forma cristalina mais comum, denominada coríndon, ou óxido de alumínio ?, sua baixa condutividade elétrica, baixo calor específico, alta condutividade térmica, alto ponto de fusão, elevada dureza e resistência mecânica, o torna adequado para uso em produtos refratários, cerâmicos e abrasivos tais como, lixas, rebolos, ferramentas de corte e de polimento. Na síntese deste produto as principais impurezas que afetam a qualidade dos grãos são Fe, Si, Ca, K, Na e Zr, oriundas da matéria prima bauxita e da carta de mistura, composta por ilmenita, limalha de ferro, carvão vegetal e coque de petróleo. Desta forma, o presente trabalho assumiu o objetivo de estudar a dispersão das propriedades físico-químicas em blocos de alumina fundida marrom obtida em fornos Higgins a arco por eletrofusão, produzidos na Saint-Gobain Abrasivos, unidade de Lorena, SP. Por fim, foram utilizadas técnicas de caracterização físico-químicas de difratometria de raios X (DRX), análises químicas de fluorescência de raios X (FRX), ensaio de dureza Knoop e caracterização microestrutural via (MEV/EDS). Desta forma, foi definido o mapeamento composicional nos blocos de alumina eletrofundida marrom, que servirão como referência técnico-científica para subsidiar ações de melhoria deste produto, em decorrência do avanço do estado da arte deste referido assunto. / The mineral ores are not renewable sources and we need to use it in the best way possible. In this way, a large number of researches are being developed around the world aiming the improvement of current methods of production mainly in chemical, metallurgy, mineralogical from the steps of extraction, processing, application and reuse of waste ore. Therefore, it is extremely important to intensify the studies to increase the knowledge about the characteristics and physicochemical properties of these minerals, in order to improve their utilization and longevity of natural deposits, such as sources of bauxite, which is the main raw material to product aluminum oxide fused. In its most common crystalline form, called corundum or ?-aluminum oxide, its low electrical conductivity, low specific heat, high thermal conductivity, high melting point, high hardness and mechanical strength, making it suitable for use as refractories, ceramics and fine or coarse abrasives. The synthesis of this product major impurities that affect quality of grain is Fe, Si, Ca, K, Na and Zr, derived from the raw material bauxite and the mixture chart consisting of ilmenite, iron filings, charcoal and coke oil. Thus, this shows the dispersion of physicochemical properties of brown fused alumina blocks produced by eletrocfusion at Higgins furnace process in the company Saint Gobain Abrasivos, Lorena- SP. Finally, the samples were physicochemical analyzed by X ray diffraction (XRD), chemical analyses by X ray fluorescence (XRF), hardnes using Knoop method, microstructural characterization by (SEM). The results of this work show a compositional gradient map of the fused alumina block; that shows the main physicochemical differences into the block, to support changes in the alumina production process; and it is also important to improve the actual state of art of this particular theme.

Com o objetivo de determinar as características físico-químicas e a origem floral de méis produzidos por Apis mellifera L., 1758, na região da Chapada do Araripe, município de Santana do Cariri/Ceará foram determinados no Laboratório de Apicultura do Setor de Entomologia da Escola Superior de Agricultura "Luiz de Queiroz", USP: os açúcares totais, açúcares redutores, sacarose, umidade, hidroximetilfurfural, proteína, cinzas, pH, acidez, índice de formol, condutividade elétrica, cor, viscosidade e análises polínicas de 21 amostras de méis colhidas em novembro e dezembro de 2001. Os resultados demonstraram que os valores médios dos parâmetros físico-químicos das amostras analisadas encontram-se dentro dos limites estabelecidos pela legislação brasileira. Pelas análises polínicas dos méis, foi verificada a presença do tipo Serjania (cipó-uva) em todas as amostras analisadas, aparecendo como pólen dominante na maioria delas. / This research deals with the determination of the physicochemical characteristics and floral origin of honeys produced by Apis mellifera L., 1758, in the region of Chapada do Araripe, municipality of Santana do Cariri, State of Ceará, Brazil. The experiments were set at the Laboratory of Apiculture, Department of Entomology, Plant Pathology and Agricultural Zoology, College of Agriculture "Luiz de Queiroz", University of São Paulo, in Piracicaba, State of São Paulo, Brazil. The following parameters were determined: total sugars, reducing sugars, sucrose, humidity, hydroxymethylfurfural, protein, ashes, pH, acidity, formaldehyde index, electrical conductivity, color, viscosity and pollen analysis of 21 samples of honeys collected in November and December, 2001. The results have indicated that the mean values of the physicochemical parameters of the samples are in between the limits required by the Brazilian legislation. The pollen analysis of the honeys showed the presence of the plant Serjania type ("cipó-uva") in all the honey samples.