La presente investigación busca determinar los factores que influenciaron en la evolución de las exportaciones de las tablillas y frisos para parqué sin ensamblar del Perú a la República Popular de China durante los años 2009 - 2017. En el primer capítulo, se estudiarán conceptos relacionados al comercio exterior, desde las teorías de liberalización hasta acuerdos comerciales como el de Perú con China; aspectos relacionados a las tablillas y frisos para parqué, factores críticos de éxito, internos y externos. Entendemos que la firma del Tratado de Libre Comercio origina la desgravación, lo cual significa que los productos de ambos países tendrán una eliminación progresiva, parcial o total de los aranceles para ambos mercados. De acuerdo a lo mencionado anteriormente y relacionándolo con la teoría del liberalismo comercial, entendemos que luego de 9 años desde la entrada en vigencia del Tratado, encontramos en base al modelo de estudio cualitativo que existen otros factores que tienen más relevancia con respecto a la firma del TLC, los cuales se desarrollarán más adelante. Asimismo, en el segundo capítulo se expondrá el planteamiento de la investigación tanto como el problema, hipótesis y objetivos principales y específicos. En el tercer capítulo se expondrá el método de investigación cualitativo exploratorio porque se quiere conocer mediante datos empíricos, cuales eran para los entrevistados los factores determinantes en la evolución de las exportaciones de las tablillas y frisos para parqués sin ensamblar, todo ello con a través del recojo y el análisis sistemático de datos. Además, mediante esta investigación cualitativa se determinará la muestra, categorías, procedimiento, procesamiento de los resultados, la clasificación de las categorías y las limitaciones que se presentaron en la investigación. En el cuarto capítulo se presentan los hallazgos de la investigación en relación con las entrevistas realizadas a cada participante. Se analizó de manera empírica la información y se plasmó en tablas de acuerdo con el número de menciones por factor para determinar a los que tuvieron mayor influencia en la evolución de las exportaciones. Finalmente, en las conclusiones se presenta el factor que tuvo mayor impacto para luego determinar si se cumplieron los objetivos de la investigación y la hipótesis. / The present investigation seeks to determine the factors that influenced the evolution of the exports of the slats and friezes for parquet without assembling from Peru to Popular Republic of China during the years 2009 - 2017. In the first chapter, concepts related to foreign trade will be studied, from liberalization theories to trade agreements such as Peru with China; Aspects related to the slats and friezes for parquet, critical success factors, internal and external. We understand that the signing of the Free Trade Agreement results in the elimination of tariffs, which means that the products of both countries will have a progressive, partial or total elimination of tariffs for both markets. According to the aforementioned and related to the theory of commercial liberalism, we understand that after 9 years since the entry into force of the Treaty, we find based on the qualitative study model that there are other factors that have more relevance with respect to the signature of the FTA, which will be developed later. Also, in the second chapter the research approach will be exposed as well as the main and specific problem, hypothesis and objectives. In the third chapter the method of exploratory qualitative research will be exposed because we want to know through empirical data, which were for the interviewees the determining factors in the evolution of the exports of the slats and friezes for parquet without assembling, all with the I collect and systematic data analysis. In addition, this qualitative research will determine the sample, categories, procedure, processing of the results, the classification of the categories and the limitations that were presented in the investigation. In the fourth chapter, the findings of the research are presented in relation to the interviews conducted with each participant. The information was analyzed in an empirical way and was reflected in tables according to the number of mentions by factor to determine those that had the greatest influence on the evolution of exports. Finally, in the conclusions, the factor that had the greatest impact is presented to determine if the objectives of the research and the hypothesis were met. / Tesis

Les environnements multi-surfaces (MSE) combinent plusieurs surfaces dans une variété d'arrangements physiques pour former un espace d'information continu. Les grandes surfaces, telles que les tables et les écrans muraux, sont souvent utilisées comme espace partagé pour coordonner les efforts, et les périphériques portables, tels que les tablettes et les smartphones sont considérés comme des espaces personnels prenant en charge les tâches individuelles. Les MSE ont montré des avantages pour soutenir les activités co-implémentées, en particulier celles impliquant une exploration de données riches, telles que des activités collaboratives complexes de résolution de problèmes et de prise de décision. Cependant, la diversité des MSE soulève également des questions et des défis, car différents facteurs de configuration et dispositifs de MSE peuvent être adaptés à différents types d'activités, et le développement d'activités de collaboration dans les MSE reste complexe. Cette dissertation étudie comment les MSE peuvent soutenir la collaboration des utilisateurs en général et l'apprentissage collaboratif en particulier. Elle fournit des informations sur la façon dont la configuration et les facteurs de forme des périphériques des MSE façonnent les comportements collaboratifs des utilisateurs et propose des implications pour la conception d'activités collaboratives dans des MSE. Elle offre également un outil de prototypage rapide, qui peut être facilement utilisé par des non-experts, tels que des enseignants, afin de créer des activités de prise de décision collaboratives dans des MSE. / Multi-surface environments (MSEs) combine several of surfaces in a variety of physical arrangements to form a seamless information space. The large surfaces, such as tabletops and wall-displays are often used as a shared space to coordinate efforts, and handheld devices, such as tablets and smartphones are regarded as personal space supporting individual tasks. MSEs have shown benefits for supporting co-located activities, especially the ones involving rich data exploration, such as complex collaborative problem-solving and decision-making activities. However, the diversity of MSE also raises questions and challenges, as different configuration and devices factors of MSE can be suited for different kinds of activities, and developing collaborative activities in MSE remains complex. This dissertation studies how MSE can support users' collaboration in general, and collaborative learning specifically. It provides insights on how the configuration and form factors of devices in MSE shape users' collaborative behaviors, and offers implications on designing collaborative activities in MSE. It also contributes with a rapid prototyping tool, which can be easily used by non-experts, such as teachers, to create collaborative decision-making activities in MSE.

O uso de ferramentas estatísticas no ciclo de vida de um produto farmacêutico permite verificar e controlar o processo tendo como objetivo a sua melhoria contínua. No presente estudo foi avaliada a estabilidade e a capacidade estatística do processo de fabricação dos comprimidos revestidos de lamivudina 3TC e zidovudina AZT (150 + 300 mg) fabricados pela Fundação para o Remédio Popular \"Chopin Tavares de Lima\" (FURP). Esse medicamento, distribuido gratuitamente pelo programa DST/AIDS do Ministério da Saúde, e fabricado por compressão direta, processo rápido que permite a implementação futura da tecnologia analítica de processo (Process Analytical Technology - PAT). No Capítulo I foi realizada avaliação retrospectiva da variabilidade de atributos criticos da qualidade de 529 lotes dos comprimidos fabricados de acordo com a RDC ANVISA 17/2010 e as monografias oficiais, sendo tais atributos: peso médio, uniformidade de dose unitária e % m/v de fármaco dissolvido, antes e após o revestimento. O objetivo foi identificar eventuais causas especiais de variabilidade dos processos que permitam melhorias contínuas. No Capitulo II foi desenvolvida metodologia analítica empregando a espectroscopia no infravermelho próximo com transformada de Fourier para a avaliação da homogeneidade da mistura dos pós. Nesse estudo foram analisadas amostras de misturas dos fármacos lamivudina 3TC e zidovudina AZT e mistura excipiente, empregando como método de referência a CLAE, para a quantificação desses dois fármacos. No Capitulo I, a avaliação do processo para o peso médio revelou a necessidade de investigação das causa especiais de variabilidade, evidenciada por meio das cartas de controle. Os resultados do ano de 2015 indicaram necessidade de centralização e de consistência do processo, com redução de probabilidade de falha. As cartas de controle para uniformidade de dose unitária, no ano de 2013, revelaram menor variabilidade do processo. Porem, nesse ano, a análise estatística para a dissolução revelou processo descentralizado e sem consistência, com maior evidência para o fármaco 3TC que demonstrou menor desempenho, Cpk<1,0. A avaliação da estabilidade e da capacidade do processo de fabricação de comprimidos de lamivudina + zidovudina (150+300 mg), no período de 2012 a 2015, permitiu o maior entendimento de suas fontes de variação. Foi possível detectar e determinar o grau dessa variação e seu impacto no processo e nos atributos críticos de qualidade do produto com evidentes oportunidades de melhoria do processo, reduzindo os riscos para o paciente. No capítulo II, no desenvolvimento do método, as estatísticas de validação revelaram que os menores valores de BIAS foram observados para a 3TC, 0,000116 e 0,0021, respectivamente para validação cruzada e validação. Os valores de BIAS próximos a zero indicaram reduzida porcentagem de variabilidade do método. O presente estudo demonstrou a viabilidade do uso do modelo desenvolvido para a quantificação da 3TC e AZT por FT-NIR apos ajustes que contribuam para a elevação de R, R2 e RPD para valores aceitáveis. Valores de RPD acima de 5,0 que permitem o uso do modelo para uso em controle de qualidade. / The use of statistical tools in the life cycle of a pharmaceutical product allows verifying and controlling the process aiming at its continuous improvement. In the present study, the stability and statistical capacity of the lamivudine coated tablets 3TC and zidovudine AZT (150 + 300 mg) manufactured by the Chopin Tavares de Lima Foundation (FURP) were evaluated. This drug, distributed free of charge by the Ministry of Health\'s DST/AIDS program, is manufactured by direct compression, a rapid process that allows the future implementation of Process Analytical Technology (PAT). In Chapter I, a retrospective evaluation of the variability of critical quality attributes of 529 batches of tablets manufactured was carried out, such attributes being: mean weight, unit dose uniformity and % m/v of dissolved drug substances, before and after coating. The objective was to identify possible special causes of variability of the processes that allow continuous improvements. In Chapter II an analytical methodology was developed employing the near infrared spectroscopy with Fourier transform for the evaluation of the homogeneity of the powder mixture. In this study, samples of mixtures of the drugs lamivudine 3TC and zidovudine AZT and excipient mixture were analyzed, using as reference method the HPLC, for the quantification of these two drugs. In Chapter I, the evaluation of the process for the mean weight revealed the need to investigate the special cause of variability, as evidenced by the charts. The results of the year 2015 indicated the need for centralization and process consistency, with a reduction in the probability of failure. The control charts for unit dose uniformity, in the year 2013, revealed less process variability. However, in that year, the statistical analysis for dissolution revealed a decentralized process with no consistency, with greater evidence for the 3TC drug that showed lower performance, Cpk<1.0. The evaluation of the stability and capacity of the lamivudine + zidovudine tablet manufacturing process (150 + 300 mg) in the period from 2012 to 2015 allowed a better understanding of its sources of variation. It was possible to detect and determine the degree of this variation and its impact on the process and the critical quality attributes of the product with evident opportunities to improve the process, reducing risks for the patient. In Chapter II, in the development of the method, the validation revealed that the lowest values of BIAS were observed for 3TC, 0.000116 and 0.0021, respectively for cross validation and validation. BIAS values close to zero indicated a reduced percentage of variability of the method. The present study demonstrated the feasibility of using the model developed for the quantification of 3TC and AZT by FT-NIR after adjustments that contribute to the elevation of R, R2 and RPD to acceptable values. RPD values above 5.0 that allow the use of the model for use in quality control.

Com o aumento da expectativa de vida temos um maior contingente de pessoas portadoras de próteses totais, contudo não temos um protocolo bem estabelecido para higienização/desinfecção dessas próteses pelo paciente após a sua instalação. O objetivo desta pesquisa foi avaliar a ação antimicrobiana de diferentes meios de higienização de próteses totais, afim de se estabelecer um protocolo eficaz para a manutenção das próteses e com isso prevenir futuras estomatites protéticas. Para tanto foi testada a ação antimicrobiana dos agentes químico - a pastilha efervescente; e físico - o ultra-som, contra leveduras do gênero Candida, freqüentemente associadas à estomatite protética e contra os estreptococos do grupo mutans, responsáveis pela consolidação e progressão de alguns tipos de biofilme. 113 indivíduos participaram desta pesquisa, distribuídos aleatoriamente em 4 grupos, a saber: A- controle (25 pacientes) - apenas escovaram suas próteses com água, 3 vezes ao dia; B- (29 pacientes) utilizaram 1 pastilha efervescente ao dia por 5 minutos, durante 21 dias; C- (28 pacientes) fizeram o mesmo procedimento que o grupo A, com exceção de que, após 21 dias, as próteses foram submetidas ao ultra-som por 15 minutos; D-(31 pacientes) fizeram o mesmo que o grupo B, com exceção de que, após 21 dias, as próteses foram submetidas ao ultra-som por 15 minutos. Todos os procedimentos foram realizados por 21 dias e todos os grupos realizaram escovação da prótese com escovas dentais de cerdas macias Bitufo® e água. As colheitas do material das próteses ocorreram durante o exame inicial e após 21 dias da realização dos procedimentos de higienização listados acima. Antes do início dos procedimentos de higienização, todas as próteses receberam profilaxia profissional, afim de remover completamente o biofilme existente. As colheitas foram feitas por meio de escovação das próteses com PBS (salina tamponada fosfatada). Estas amostras foram submetidas a diluição decimal seriada e semeadas em placas contendo BHIA (Brain Heart Infusion Agar), Chromagar-Candida e SB20 (Ágar Sacarose Bacitracina) para a quantificação de aeróbios totais, Candida sp e estreptococos do grupo mutans, respectivamente. Após incubação em aerobiose por 24 horas; em aerobiose por 48 horas e em microaerofilia por 48-72 horas respectivamente, era realizada a quantificação dos microrganismos pesquisados e a verificação da eficácia dos procedimentos testados. Os resultados entre os tratamentos foram comparados por espécie, por meio de ANOVA para um fator de variação; ou por meio do teste de Kruskal-Wallis (?=0,05), a depender da aderência à distribuição normal. Pôde-se verificar que, frente à C. albicans (ANOVA, P=0,761), C. tropicalis (Kruskal-Wallis, P=0,944) e. C. glabrata (Kruskal-Wallis, P=0,803), os 3 tratamentos testados (pastilha efervescente, ultra-som e associação pastilha efervescente e ultra-som) não diferiram significativamente do controle (escovação e água), quanto à ação antimicrobiana. Por outro lado, o tratamento com pastilha efervescente e a associação pastilha efervescente e ultra-som, mostraram-se altamente eficientes em relação às cepas de estreptococos do grupo mutans (ANOVA, P<0,001). Em relação aos aeróbios totais, o tratamento com pastilhas efervescentes mostrou uma significante ação antimicrobiana, enquanto que a associação pastilha efervescente e ultra-som apresentou uma moderada ação sobre estes microrganismos (ANOVA, P=0,011). / With the increase of life expectation there is a greater number of people denture wearers. However, there isn\'t any protocol properly established about good oral hygiene/ disinfection these dentures by patient after its installation. The aim of this survey was evaluate the antimicrobial action of different hygiene methods to full maxillary dentures in order to establish some efficient protocol to maintenance of dentures and with this to prevent from future denture stomatitis. In this way, the antimicrobial action of a physical-chemical agent, effervescent tablets and of a physical agent, the ultrasonic were tested against Candida sp yeast which are frequently associated with denture stomatitis and against mutans streptococci which are responsible for consolidation and progression of some types of biofilm. 113 individuals who took part in this study were randomly assigned to one of 4 groups: A - Control (25 individuals): They just brushed their dentures with water, three times per day; B - (29 individuals): used of one effervescent tablet per day during five minutes; C - (28 individuals): the same of the group A, with exception of that after 21 days they had had their dentures submitted to ultrasonic for 15 minutes; D - (31 individuals): the same of the group B, with exception of that after 21 days they had had their dentures submitted to ultrasonic for 15 minutes. All procedures were carried out for 21 days and all groups brushed the dentures with dental brushes of soft bristles and water. The samples of dentures material were collected at baseline before any treatment after 21 days of treatment listed above. Prior to the beginning of these hygiene procedures, all dentures received professional prophylactic brushing in order to remote entirely the biofilm existent. The samples were collected by brushing the dentures with PBS, and sent to seriate decimal dilution and plated in BHIA (Brain Heart Infusion Agar), in Chromagar-Candida and in SB20 (Agar Sacarose Bacitracina) to quantification total aerobics, Candida sp and mutans streptococci, respectively. After incubation in aerobiosis for 24 hours, in aerobiosis for 48 hours and in microaerofilic for 48-72 hours, respectively. The outcomes among the treatments were compared by species, using ANOVA test to one factor of variation; or using Kruskal-Wallis test (=0,05), depending on adherence to normal distribution. It was verified that the antimicrobial action of the three treatments tested (effervescent tablets, the ultrasonic and the association between effervescent tablets and ultrasonic) weren\'t statistically different of the Control (brushing and water), against C. albicans (ANOVA, P=0,761), C. tropicalis (Kruskal-Wallis, P=0,944) e. C. glabrata (Kruskal-Wallis, P=0,803). However, the effervescent tablets treatment and the association between effervescent tablets and ultrasonic were highly efficient in relation to mutans streptococci (ANOVA, P<0,001). As for to total aerobics, the treatment with effervescent tablets showed a significant antimicrobial action, whereas the association between effervescent tablets and ultrasonic showed a moderate action against these microorganisms (ANOVA, P=0,011).

No presente trabalho, foram desenvolvidos e avaliados comprimidos de liberação convencional de hidroclorotiazida 50mg: 6 por granulação úmida e 8 por compressão direta. Na etapa de pré-formulação, foram realizados estudos termoanalíticos (TG/DTG e DSC) para seleção de excipientes compatíveis com o fármaco e estudos micromeríticos para avaliação das propriedades de fluxo e compressibilidade das matérias-primas empregadas, dos granulados e das misturas para compressão direta obtidos. As formulações foram avaliadas quanto ao diâmetro, espessura, dureza, friabilidade, desintegração, dissolução, teor, uniformidade de conteúdo, perfil e eficiência de dissolução, empregando-se métodos analíticos devidamente validados. As melhores formulações obtidas por granulação úmida (formulação B1) e compressão direta (formulação J) foram comparadas com o produto referência para comprimidos de hidroclorotiazida, quanto à eficiência de dissolução e demonstraram ser estatisticamente semelhantes entre si e superiores ao produto referência, nas condições empregadas. / In this work, conventional liberation of hydrochlorothiazide 50 mg: 6 for wet granulation and 8 for direct compression - were developed and valuated. In the pre-formulation stage, thermoanalytical studies (TG/DTC and DSC) were realized to select compatible excipients with the drug; as well as micromeritical studies were realized to value the flow and compressibility properties of the used raw materials, granulates and obtained mixtures for direct compression. The prescriptions were valuated in relation to diameter, thickness, hardness, friability, disintegration, dissolution, assay, uniformity of contents, profile and efficiency of dissolution, using analytical methods property validated. The best formulations obtained by wet granulation (B1 formulation) and direct compression (J formulation) were compared with the reference product to tablet of hydrochlorothiazide, concerning to the efficiency of dissolution and they demonstrated to be statistically similar to each other and to be superior to the reference product, in the used conditions.

袁國華. / 論文(博士) -- 香港中文大學硏究院中國語言及文學學部, 1995. / 參考文献 : leaves 536-569. / Yuan Guohua. / 序 / Chapter 第一章 --- 緒論 --- p.1 / Chapter 第一節 --- 包山楚簡的發現 --- p.1 / Chapter 第二節 --- 包山楚簡的內容 --- p.4 / Chapter 一 --- 「文書」的內容 --- p.4 / Chapter (一) --- 「集箸」「集箸言」簡的內容 --- p.4 / Chapter (二) --- 「受□」簡的內容 --- p.6 / Chapter (三) --- 「疋獄」簡的內容 --- p.7 / Chapter (四) --- 欠標題簡的內容 --- p.9 / Chapter 二 --- 「卜筮祭禱紀錄」的內容 --- p.12 / Chapter 三 --- 「遣策」的內容 --- p.15 / Chapter 第三節 --- 包山楚簡的價值 --- p.19 / Chapter 一 --- 補充文獻的不足 --- p.19 / Chapter 二 --- 証明史書的可信 --- p.21 / Chapter 三 --- 印證其他楚簡的內容 --- p.22 / Chapter 四 --- 保存器物的名實 --- p.23 / Chapter 五 --- 有助古文字的考釋 --- p.25 / Chapter 第四節 --- 本文的研究範疇與目的 --- p.27 / Chapter 第二章 --- 包山楚簡所見名籍編制考 --- p.37 / Chapter 第一節 --- 「□典」意義的商榷 --- p.40 / Chapter 一 --- 「□」字的字形、讀音及意義 --- p.40 / Chapter 二 --- 「典」字的意義及其相關問題 --- p.55 / Chapter 三 --- 與「□典」有關簡文的釋讀 --- p.64 / Chapter 四 --- 釋「□典」 --- p.80 / Chapter 第二節 --- 名籍的種類 --- p.95 / Chapter 一 --- 玉□之典 --- p.99 / Chapter 二 --- □典 --- p.103 / Chapter 三 --- 陳豫之典 --- p.106 / Chapter 四 --- 某瘽之典 --- p.109 / Chapter 第三節 --- 名籍的編造與保管 --- p.112 / Chapter 一 --- 《周禮》所載名籍的編造與保管 --- p.112 / Chapter 二 --- 春秋戰國所載名籍的編造與保管 --- p.116 / Chapter 三 --- 包山楚簡所載名籍的編造與保管 --- p.120 / Chapter 第四節 --- 名籍的用途 --- p.123 / Chapter 一 --- 登除生死 --- p.123 / Chapter 二 --- 查證身分 --- p.127 / Chapter 三 --- 明別歸屬 --- p.130 / Chapter 第三章 --- 包山楚簡「受□」意義考 --- p.143 / Chapter 第一節 --- 「受□」意義的商榷 --- p.144 / Chapter 一 --- 「受□」即「受賄」說的商榷 --- p.144 / Chapter 二 --- 「受□」即「受稽」說的商榷 --- p.159 / Chapter 三 --- 「受□」即「接受年度考核」說的商榷 --- p.168 / Chapter 第二節 --- 釋「受□」 --- p.186 / Chapter 第三節 --- 「受□」簡的釋讀 --- p.191 / Chapter 第四節 --- 海外「受□」遺簡述要 --- p.202 / Chapter 一 --- 有一簡記二事者 --- p.202 / Chapter 二 --- 簡文內容有重覆出現者 --- p.206 / Chapter 三 --- 大事紀年所記地名有別者 --- p.208 / Chapter 第四章 --- 包山楚簡遣策所見「□」、「房□」、「鑐」等器物形制考 --- p.220 / Chapter 第一節 --- 「□」器形制考 --- p.220 / Chapter 一 --- 釋「□」 --- p.220 / Chapter 二 --- 釋「□」 --- p.232 / Chapter 三 --- 論「□」器的形制 --- p.248 / Chapter 第二節 --- 「房□」形制考 --- p.264 / Chapter 一 --- 釋「一房□」 --- p.264 / Chapter 二 --- 釋「房□」形制 --- p.274 / Chapter 第三節 --- 「鑐」鼎形制考 --- p.285 / Chapter 一 --- 釋「亥」 --- p.285 / Chapter 二 --- 釋「鑐」鼎的形制 --- p.293 / Chapter 第五章 --- 包山楚簡文字考釋 --- p.322 / Chapter 1 --- □ --- p.324 / Chapter 2 --- 頸 --- p.325 / Chapter 3 --- 戌 --- p.327 / Chapter 4 --- □ --- p.328 / Chapter 5 --- □、□、□ --- p.332 / Chapter 6 --- 主 --- p.336 / Chapter 7 --- □ --- p.340 / Chapter 8 --- 天 --- p.342 / Chapter 9 --- □ --- p.344 / Chapter 10 --- □ --- p.345 / Chapter 11 --- □ --- p.346 / Chapter 12 --- □ --- p.348 / Chapter 13 --- □ --- p.352 / Chapter 14 --- □ --- p.354 / Chapter 15 --- 受 --- p.355 / Chapter 16 --- □ --- p.359 / Chapter 17 --- □ --- p.360 / Chapter 18 --- □、□ --- p.361 / Chapter 19 --- □ --- p.362 / Chapter 20 --- 齊 --- p.362 / Chapter 21 --- 已 --- p.364 / Chapter 22 --- □ --- p.366 / Chapter 23 --- □ --- p.367 / Chapter 24 --- 常 --- p.367 / Chapter 25 --- 衣 --- p.371 / Chapter 26 --- □ --- p.372 / Chapter 27 --- □ --- p.373 / Chapter 28 --- □ --- p.375 / Chapter 29 --- 伬 --- p.376 / Chapter 30 --- □ --- p.379 / Chapter 附錄一： --- 重訂「包山楚簡」釋文 --- p.389 / Chapter 附錄二： --- 包山楚簡文字諸家考釋一覽表(一)(二) --- p.485 / 主要參考書目及其簡稱 --- p.536

Dans le domaine pharmaceutique, la voie orale demeure la voie d’administration de prédilection, car plus simple et mieux acceptée par les patients. Cependant, ce mode d’administration pose problème pour de nombreux principes actifs (PA) présentant une faible solubilité, une faible perméabilité et/ou une instabilité dans l’environnement gastro-intestinal. Leur micro-encapsulation dans des matrices polymériques peut permettre d’y répondre, notamment si les microparticules générées résistent aux environnements rencontrés lors du tractus gastro-intestinal et jouent alors un rôle protecteur, tant pour le principe actif que pour les muqueuses rencontrées. La recherche de nouveaux excipients, issus des agro-ressources tels que les polymères naturels, est en plein essor. Les protéines végétales, grâce à leurs propriétés fonctionnelles telles qu’une bonne solubilité, une viscosité relativement basse, et des propriétés émulsifiantes et filmogènes, représentent des candidats privilégiés. De plus, la grande diversité de leurs groupements fonctionnels permet d’envisager des modifications chimiques ou enzymatiques variées. L’objectif de ce travail était d’étudier l’intérêt de la protéine de soja en tant que matériau enrobant de principes actifs pharmaceutiques destinés à la voie orale, et plus particulièrement en tant que candidat pour l’élaboration de formes gastro-résistantes. Un isolat protéique de soja (SPI) été utilisé comme matière enrobante et l’atomisation comme procédé. L’ibuprofène, anti-inflammatoire non stéroïdien, a été choisi comme molécule modèle du fait de sa faible solubilité nécessitant une amélioration de sa biodisponibilité, et de ses effets indésirables gastriques nécessitant une mise en forme entérique. Deux modifications chimiques des protéines (l’acylation et la succinylation) ont été étudiées dans le but de modifier la solubilité de la protéine de soja. Ces modifications ont été effectuées dans le respect des principes de la Chimie Verte, notamment en absence de solvant organique. Les microcapsules obtenues par atomisation ont été caractérisées en termes de taux et efficacité d'encapsulation, morphologie et distribution de tailles des particules, état physique du PA encapsulé et capacité de libération en milieu gastrique et intestinal simulé. Les résultats obtenus ont permis de valider l’intérêt des modifications chimiques de la protéine de soja pour moduler les cinétiques de libération d’actif. Les modifications chimiques sont apparues particulièrement adaptées pour l’encapsulation de principes actifs hydrophobes, et ont permis de l’obtention de cinétiques de libération d’ibuprofène ralenties à pH acide (gastrique). La dernière partie de ce travail a permis de valider cette dernière hypothèse par la réalisation de formes gastro-résistantes sur le modèle des comprimés MUPS (multiple unit pellet system). Les résultats de ce travail exploratoire démontrent que les protéines de soja, associées à un procédé de mise en forme multi-particulaire couplé à de la compression directe, peuvent constituer une alternative biosourcée, respectueuse de l’environnement (manipulation en solvant aqueux, temps de séchage et étapes de compression réduits) et sûre à l’enrobage utilisé dans les formes gastro-résistantes traditionnelles. / In the pharmaceutical field, the oral route remains the preferred route of administration because it is simpler and better accepted by patients. However, this mode of administration is problematic for many active pharmaceutical ingredients (API) with low solubility, low permeability and/or instability in the gastrointestinal environment. Their microencapsulation in polymeric matrices can make them able to respond to these factors, especially if the microparticles generated resist the environments encountered during the gastrointestinal tract and then play a protective role, both for the API and for the mucous membranes encountered. The search for new excipients, from agroresources such as natural polymers, is booming. Vegetable proteins, thanks to their functional properties such as good solubility, relatively low viscosity, and emulsifying and film-forming properties, are preferred candidates. In addition, the great diversity of their functional groups makes it possible to envisage various chemical or enzymatic modifications. The aim of this work was to study the interest of soy protein as a coating material for API intended for the oral route, and more particularly as a candidate for the development of gastro-resistant forms. A soy protein isolate (SPI) was used as a coating material and the atomization as a process. Ibuprofen, a nonsteroidal anti-inflammatory drug, was chosen as a model molecule because of its low solubility requiring an improvement in its bioavailability, and its gastric side effects requiring an enteric shaping. Two chemical modifications of proteins (acylation and succinylation) have been studied in order to modify the solubility of the soy protein. These modifications were carried out in accordance with the principles of Green Chemistry, especially in the absence of organic solvent. The microcapsules obtained by spray-drying were characterized in terms of rate and encapsulation efficiency, morphology and size distribution of the particles, physical state of the encapsulated API and capacity of release in simulated gastric and intestinal medium. The results obtained validated the interest of the chemical modifications of the soy protein to modulate the release kinetics of API. The chemical modifications appeared particularly suitable for the encapsulation of hydrophobic active ingredients, and allowed to obtain ibuprofen release kinetics decreased to acidic pH (gastric). The last part of this work allowed to validate this last hypothesis by the realization of gastro-resistant forms on the model of MUPS tablets (multiple unit pellet system). The results of this exploratory work demonstrate that soy protein, combined with a multiparticle shaping process coupled with direct compression, can be a biosourced, environmentally friendly alternative (aqueous solvent handling, drying and compression steps reduced) and confident to the coating used in traditional gastroresistant forms.

This master dissertation "Czech Electronic Book Market -- Obstacles and Opportunities" analyzes Czech market with e-books. The aim is to provide a comprehensive overview of the current situation on the market in terms of technologies, distribution models and legal issues. It describes commercial, free and illegal sources in the market, including a description of digitisation projects in Czech libraries. The thesis also includes a theoretical introduction to e-books and their development in the past. Details are discussed, focusing on technology, modern electronic readers with electronic ink. For comparison, the thesis also analyzes the U.S. market with e-books. In analytical part the individual portals with e-books on the market, their supply and user interfaces are compared. The real example analyzes the costs of an e-book and its comparison to costs of a printed book. At the end of the thesis, alternative models of distribution requirements for establishment of a new portal with e-books are characterised, the Creative Commons licenses are described and the current trend of e-journals is mentioned. Finally, I suggest recommendations especially for sellers on the Czech market describe the advantages and disadvantages of e-books in terms of individual roles in the distribution model and estimate the future market development. More detailed information related to the comparison of different types of electronic ink, a list of electronic readers that are available on the Czech e-book market at this time and specific examples of various users' interfaces that are being used on Czech e-books portals can be found in Appendix.

No presente trabalho, foram desenvolvidos e avaliados comprimidos de liberação convencional de hidroclorotiazida 50mg: 6 por granulação úmida e 8 por compressão direta. Na etapa de pré-formulação, foram realizados estudos termoanalíticos (TG/DTG e DSC) para seleção de excipientes compatíveis com o fármaco e estudos micromeríticos para avaliação das propriedades de fluxo e compressibilidade das matérias-primas empregadas, dos granulados e das misturas para compressão direta obtidos. As formulações foram avaliadas quanto ao diâmetro, espessura, dureza, friabilidade, desintegração, dissolução, teor, uniformidade de conteúdo, perfil e eficiência de dissolução, empregando-se métodos analíticos devidamente validados. As melhores formulações obtidas por granulação úmida (formulação B1) e compressão direta (formulação J) foram comparadas com o produto referência para comprimidos de hidroclorotiazida, quanto à eficiência de dissolução e demonstraram ser estatisticamente semelhantes entre si e superiores ao produto referência, nas condições empregadas. / In this work, conventional liberation of hydrochlorothiazide 50 mg: 6 for wet granulation and 8 for direct compression - were developed and valuated. In the pre-formulation stage, thermoanalytical studies (TG/DTC and DSC) were realized to select compatible excipients with the drug; as well as micromeritical studies were realized to value the flow and compressibility properties of the used raw materials, granulates and obtained mixtures for direct compression. The prescriptions were valuated in relation to diameter, thickness, hardness, friability, disintegration, dissolution, assay, uniformity of contents, profile and efficiency of dissolution, using analytical methods property validated. The best formulations obtained by wet granulation (B1 formulation) and direct compression (J formulation) were compared with the reference product to tablet of hydrochlorothiazide, concerning to the efficiency of dissolution and they demonstrated to be statistically similar to each other and to be superior to the reference product, in the used conditions.

O uso de ferramentas estatísticas no ciclo de vida de um produto farmacêutico permite verificar e controlar o processo tendo como objetivo a sua melhoria contínua. No presente estudo foi avaliada a estabilidade e a capacidade estatística do processo de fabricação dos comprimidos revestidos de lamivudina 3TC e zidovudina AZT (150 + 300 mg) fabricados pela Fundação para o Remédio Popular \"Chopin Tavares de Lima\" (FURP). Esse medicamento, distribuido gratuitamente pelo programa DST/AIDS do Ministério da Saúde, e fabricado por compressão direta, processo rápido que permite a implementação futura da tecnologia analítica de processo (Process Analytical Technology - PAT). No Capítulo I foi realizada avaliação retrospectiva da variabilidade de atributos criticos da qualidade de 529 lotes dos comprimidos fabricados de acordo com a RDC ANVISA 17/2010 e as monografias oficiais, sendo tais atributos: peso médio, uniformidade de dose unitária e % m/v de fármaco dissolvido, antes e após o revestimento. O objetivo foi identificar eventuais causas especiais de variabilidade dos processos que permitam melhorias contínuas. No Capitulo II foi desenvolvida metodologia analítica empregando a espectroscopia no infravermelho próximo com transformada de Fourier para a avaliação da homogeneidade da mistura dos pós. Nesse estudo foram analisadas amostras de misturas dos fármacos lamivudina 3TC e zidovudina AZT e mistura excipiente, empregando como método de referência a CLAE, para a quantificação desses dois fármacos. No Capitulo I, a avaliação do processo para o peso médio revelou a necessidade de investigação das causa especiais de variabilidade, evidenciada por meio das cartas de controle. Os resultados do ano de 2015 indicaram necessidade de centralização e de consistência do processo, com redução de probabilidade de falha. As cartas de controle para uniformidade de dose unitária, no ano de 2013, revelaram menor variabilidade do processo. Porem, nesse ano, a análise estatística para a dissolução revelou processo descentralizado e sem consistência, com maior evidência para o fármaco 3TC que demonstrou menor desempenho, Cpk<1,0. A avaliação da estabilidade e da capacidade do processo de fabricação de comprimidos de lamivudina + zidovudina (150+300 mg), no período de 2012 a 2015, permitiu o maior entendimento de suas fontes de variação. Foi possível detectar e determinar o grau dessa variação e seu impacto no processo e nos atributos críticos de qualidade do produto com evidentes oportunidades de melhoria do processo, reduzindo os riscos para o paciente. No capítulo II, no desenvolvimento do método, as estatísticas de validação revelaram que os menores valores de BIAS foram observados para a 3TC, 0,000116 e 0,0021, respectivamente para validação cruzada e validação. Os valores de BIAS próximos a zero indicaram reduzida porcentagem de variabilidade do método. O presente estudo demonstrou a viabilidade do uso do modelo desenvolvido para a quantificação da 3TC e AZT por FT-NIR apos ajustes que contribuam para a elevação de R, R2 e RPD para valores aceitáveis. Valores de RPD acima de 5,0 que permitem o uso do modelo para uso em controle de qualidade. / The use of statistical tools in the life cycle of a pharmaceutical product allows verifying and controlling the process aiming at its continuous improvement. In the present study, the stability and statistical capacity of the lamivudine coated tablets 3TC and zidovudine AZT (150 + 300 mg) manufactured by the Chopin Tavares de Lima Foundation (FURP) were evaluated. This drug, distributed free of charge by the Ministry of Health\'s DST/AIDS program, is manufactured by direct compression, a rapid process that allows the future implementation of Process Analytical Technology (PAT). In Chapter I, a retrospective evaluation of the variability of critical quality attributes of 529 batches of tablets manufactured was carried out, such attributes being: mean weight, unit dose uniformity and % m/v of dissolved drug substances, before and after coating. The objective was to identify possible special causes of variability of the processes that allow continuous improvements. In Chapter II an analytical methodology was developed employing the near infrared spectroscopy with Fourier transform for the evaluation of the homogeneity of the powder mixture. In this study, samples of mixtures of the drugs lamivudine 3TC and zidovudine AZT and excipient mixture were analyzed, using as reference method the HPLC, for the quantification of these two drugs. In Chapter I, the evaluation of the process for the mean weight revealed the need to investigate the special cause of variability, as evidenced by the charts. The results of the year 2015 indicated the need for centralization and process consistency, with a reduction in the probability of failure. The control charts for unit dose uniformity, in the year 2013, revealed less process variability. However, in that year, the statistical analysis for dissolution revealed a decentralized process with no consistency, with greater evidence for the 3TC drug that showed lower performance, Cpk<1.0. The evaluation of the stability and capacity of the lamivudine + zidovudine tablet manufacturing process (150 + 300 mg) in the period from 2012 to 2015 allowed a better understanding of its sources of variation. It was possible to detect and determine the degree of this variation and its impact on the process and the critical quality attributes of the product with evident opportunities to improve the process, reducing risks for the patient. In Chapter II, in the development of the method, the validation revealed that the lowest values of BIAS were observed for 3TC, 0.000116 and 0.0021, respectively for cross validation and validation. BIAS values close to zero indicated a reduced percentage of variability of the method. The present study demonstrated the feasibility of using the model developed for the quantification of 3TC and AZT by FT-NIR after adjustments that contribute to the elevation of R, R2 and RPD to acceptable values. RPD values above 5.0 that allow the use of the model for use in quality control.