A Chamomilla recutita L. é uma das plantas medicinais mais cultivadas no Brasil e no mundo. Os extratos da C. recutita são de interesse para as indústrias farmacêuticas e cosméticas, visto que estes apresentam atividades anti-inflamatória, antioxidante e adstringente. A ação terapêutica do extrato pode ser mais pronunciada que a ação terapêutica de um de seus ativos isolados. No entanto, a incorporação de um extrato em uma formulação pode ser difícil devido à baixa estabilidade dos extratos, bem como à possibilidade de gerarem instabilidade das formulações. Microencapsulando o extrato com um carreador é possível aumentar estabilidade do extrato quanto evitar instabilidade na formulação. Além disso, a microencapsulação é capaz de fornecer outras vantagens, como uma liberação controlada. Dois processos foram estudados como alternativas para a microencapsulação do óleo essencial e do extrato hidroalcoólico da C. recutita usando quitosana como carreador: o spray drying e o spray freeze drying. Planejamentos fatorais foram utilizados para determinar os fatores que mais influenciaram no diâmetro médio das micropartículas, eficiência de encapsulação e teor dos marcadores e rendimento do processo. A apigenina e a apigenina-7-glicosídeo foram usadas como marcadores do extrato hidroalcoólico e o óxido de bisabolol A foi usado como marcador do óleo essencial. Os processos de spray drying e spray freeze drying dos dois extratos foram otimizados e as micropartículas resultantes foram caracterizadas com relação ao diâmetro médio, rendimento do processo, teor e eficiência de encapsulação dos marcadores, atividade antioxidante in vitro, densidade, índice de Carr, fator de Hausner, umidade, morfologia, perfil de liberação n vitro e estabilidade. Os resultados mostraram que o processo de spray drying apresentou os melhores resultados para eficiência de encapsulação, com valores de aproximadamente 98%, 95% e 80% para apigenina, apigenina-7-glicosídeo e óxido de bisabolol A, respectivamente. As eficiências de encapsulação obtidas no processo de spray freeze drying foram de aproximadamente 59%, 58% e 38% para os mesmos marcadores, respectivamente. As micropartículas produzidas por spray freeze drying apresentaram formato irregular e poroso, enquanto as produzidas por spray drying apresentaram formato esférico e superfícies mais lisas, sem poros ou fissuras. Ao contrário do que ocorreu com o extrato hidroalcoólico, a perda do marcador do óleo foi elevada no processo de spray drying, com teor final de 35%. Os teores dos marcadores ficaram acima de 80% para o processo de spray freeze drying do óleo e acima de 90% para o extrato hidroalcoólico. As micropartículas produzidas por spray drying do extrato hidroalcoólico e do óleo e por spray freeze drying do extrato hidroalcoólico e do óleo apresentaram diâmetro médio de 5,1 ?m, 5,0 ?m, 31,0 ?m e 96,4 ?m, respectivamente. Ensaios de liberação in vitro mostraram que as micropartículas foram capazes de sustentar a liberação dos respectivos marcadores. Os estudos de permeação in vitro das micropartículas produzidas por spray drying do extrato hidroalcoólico também mostraram que estas foram capazes de sustentar a liberação. A microencapsulação proporcionou em todos os casos um aumento considerável da estabilidade. As micropartículas produzidas por spray drying do extrato hidroalcoólico apresentaram teores de marcadores no mínimo 50% maiores que o extrato puro após 90 dias. O spray freeze drying se mostrou como a melhor alternativa para produção de micropartículas de quitosana contendo o óleo essencial de C. recutita, enquanto o processo de spray drying se mostrou como uma ótima alternativa para microencapsulação do extrato hidroalcoólico da C. recutita. / Chamomilla recutita L. is one of the most cultivated medicinal plants in Brazil and around the world. Its extracts are important to both the pharmaceutical and cosmetics industries due to its therapeutic applications, such as an anti-inflammatory, antioxidant, and astringent. The therapeutic effects of an extract may be more pronounced than those of an isolated active compound. However, the incorporation of an extract in a formulation is difficult due to the low stability of extracts and the potential instabilities they may cause in formulations. Microencapsulating an extract in a carrier is a potential way of increasing the stability of an extract and avoiding instabilities in a formulation. Compound microencapsulation also brings other advantages, such as controlled release rates. Two processes were studied as alternatives to microencapsulating C. recutita essential oil and C. recutita hydroalcoholic extract using chitosan as a carrier: spray drying and spray freeze drying. Factorial designs were used to determine which process factors most influence the mean diameter, encapsulation efficiency and content of the chemical markers, and process yield. Apigenin and apigenin-7-glucoside were used as chemical markers for the hydroalcoholic extract and bisabolol oxide A was used as the chemical marker for the essential oil. The spray drying and spray freeze drying processes for both the oil and hydroalcoholic extract were optimized and the resulting microparticles were further characterized to determine mean diameter, process yield, marker encapsulation efficiency and content, in vitro antioxidant activity, density, Carr index, Hausner factor, water content, morphology, in vitro release profiles and stability. The results showed spray drying had the best encapsulation efficiency results, with about 98%, 95% e 80% of the apigenin, apigenin-7-glucoside and bisabolol oxide A content, respectively, inside the microparticles. The encapsulation efficiencies obtained in the spray freeze drying process were about 59%, 58% e 38% for the same chemical markers, respectively. Microparticles produced by spray freeze drying were irregular and porous, whereas microparticles produced by spray drying were spherical and fairly smooth, without porous or cracks. Contrary to what happened with the hydroalcoholic extract, oil marker content was low for spray dried microparticles, with final content at 35%. Chemical markers contents were above 80% for the oil and above 90% for the hydroalcoholic extract in spray freeze dried microparticles. Spray dried microparticles containing extract and oil and spray freeze dried microparticles containing extract and oil had mean diameter of 5.1 ?m, 5.0 ?m, 31.0 ?m and 96.4 ?m, respectively. In vitro release profiles showed all microparticles were able to sustain their respective marker release rates. In vitro permeation studies of spray dried microparticles containing hydroalcooholic extract also showed sustained release rates for the corresponding markers. Microencapsulation also provided considerable increase in C. recutita hydroalcoholic extract stability and C. recutita essential oil stability. After 90 days spray dried microparticles containing hydroalcoholic extract presented marker content 50% higher than the pure hydroalcoholic extract. Spray freeze drying was the best alternative to produce chitosan microparticles containing C. recutita essential oil, while spray drying was shown to be an excellent way to microencapsulate C. recutita hydroalcoholic extract in chitosan.

A Lippia sidoides é planta largamente difundida nas práticas da medicina popular no Brasil, sendo utilizada como anti-séptico de uso tópico, fato justificável pela presença de timol. Como estratégia para a obtenção de novos produtos com atividade antimicrobiana, a partir de fonte vegetal, o presente estudo visou o desenvolvimento tecnológico de extratos secos padronizados e a encapsulação do óleo essencial dessa planta, através da técnica de secagem por atomização (spray drying). Para obtenção dos extratos secos padronizados, utilizou-se metodologia capaz de avaliar a qualidade da matéria-prima vegetal, das ações de transformação, dos produtos intermediários e do produto final. A solução extrativa foi obtida a partir das folhas secas e moídas dessa planta, empregando-se o método de extração por maceração dinâmica, avaliando-se alguns fatores que influenciavam sua eficiência. A solução extrativa selecionada foi submetida à secagem por atomização, investigando-se a combinação de adjuvantes tecnológicos sobre o desempenho do equipamento e sobre características físico-químicas do produto obtido. Além disso, avaliou-se a atividade antifúngica in vitro dos extratos secos, confirmando-se o efeito antimicrobiano dos mesmos. Para a encapsulação do óleo essencial de Lippia sidoides, utilizou-se a técnica de spray drying (método físico) e a inclusão molecular com -ciclodextrina (método químico) com subseqüente secagem por spray drying. Na microencapsulação por spray drying foi utilizado um conteúdo de óleo de 20 e 25% em relação ao material de parede. Como material de parede foram empregadas diferentes proporções de maltodextrina DE 10 e goma-arábica, sendo as emulsões de alimentação atomizadas até à concentração de 60% de sólidos totais. A eficiência da encapsulação foi avaliada através da quantidade específica de óleo essencial encapsulado nas micropartículas, sendo obtido valor máximo de 65%, dependente das condições experimentais empregadas. Observou-se existir teor de sólidos ótimo (50%) e relação entre o aumento da retenção de óleo total e as maiores concentrações de goma-arábica nas emulsões de alimentação, sendo que todas as micropartículas demonstraram atividade antifúngica. A inclusão molecular do óleo essencial, através de sua complexação com moléculas de -ciclodextrina exibiu eficiência de encapsulação de até 70%. As diferentes proporções de óleo essencial e -ciclodextrina testadas influenciaram esses resultados, sendo que menores retenções foram observadas quando maiores quantidades de óleo foram adicionadas às suspensões de alimentação. Pelas análises térmicas foi possível demonstrar a mais alta estabilidade térmica dos produtos encapsulados (micropartícula/complexo de inclusão) comparados ao óleo essencial original. Os dados adquiridos durante os estudos de desenvolvimento de produtos secos, a partir de Lippia sidoides, indicaram o potencial desses como agentes antimicrobianos naturais para fins medicinais, representando assim, alternativa para o aproveitamento da espécie vegetal pelo setor farmacêutico. / Lippia sidoides is an aromatic shrub widely used in a folk medicine in Brazil as local antiseptic, justified by thymol presence as the major constituent of its essential oil. As strategy for production of new antifungal herbal products, the present study aimed the technological development of Lippia sidoides standardized spray dried extracts as well as the encapsulation of its essential oil by spray drying/ molecular inclusion. In order to obtain the standardized dried extract, process control parameters of manufacturing operations were established and they were continuously tracked to provide reproducibility from batch-to-batch and to assure productsquality. Extraction (maceration) from Lippia sidoides leaves was used to produce thymol-containing liquid extracts. Optimal extraction conditions were determined and the selected extractive solution was spray dried. Effect of different carrier ratios on physicochemical and antifungal properties of dried extracts was evaluated. Lippia sidoides dried extract showed an important antifungal effect against the tested strains. Lippia sidoides essential encapsulation was carried out by spray drying technique (physical method) and molecular inclusion within -cyclodextrin (chemical method) followed by spray drying of the slurries in order to produce inclusion complex in a powder form. For microencapsulation by spray drying, maltodextrin DE 10 and gum arabic in different were used as carrier. Content of essential oil related to carrier was 20 and 25% in weight and the emulsions were atomized from 30% up to 60% of total solid concentration. Encapsulation efficiency was estimated through determination of the content of essential oil in the microcapsules and a maximum value obtained was 65%, depending on experimental parameters adopted. An optimal solid content of the encapsulating composition (50%) was observed. The increase of gum arabic amount in the infeed emulsion was related to the increase in the total oil retention in the microparticles. Antifungal activities of microparticles were evaluated, evidencing their potential as important antifungal agent. For inclusion complex formation between essential oil and -cyclodextrin, the encapsulation efficiency was up to 70%. The entrapment ability was influenced by the different essential oil: -cyclodextrin ratios tested. A decreasing tendency in the total oil content was observed, when the initial amount of added oil was increased. The greater thermal stability of the encapsulated products (microparticles/ inclusion complexes) in comparison to the original oil was confirmed by thermal analysis. The finding acquired during the development of Lippia sidoides dried products indicated their potential as natural antimicrobial agent for medicinal propose and provided evidences which support the use of such plant specimen by pharmaceutical industry.

O chá verde (Camellia sinensis) é reconhecido mundialmente por seu alto teor de polifenóis, em especial as catequinas. As catequinas estão relacionadas à prevenção de várias doenças degenerativas, como o câncer e diabetes, devido ao grande potencial antioxidante. Contudo, vários incovenientes precisam ser superados para aprimorar o uso destes produtos, principalmente em relação à sua biodisponibilidade. O desenvolvimento de carreadores lipídicos na encapsulação de compostos bioativos é uma tecnologia recente capaz de resolver vários problemas de biodisponibilidade apresentadas pelos produtos naturais, produzindo uma estrutura capaz de proteger os compostos ativos. O objetivo deste trabalho foi o desenvolvimento de uma formulação utilizando carreador lipídico, empregando métodos de secagem para aumentar a estabilidade dos compostos bioativos, enfatizando-se processos de preparação, tipo de excipientes e procedimentos para a caracterização físico-química, estabilidade e avaliação da atividade antioxidante in vitro do produto final. Os compostos bioativos foram extraídos a partir das folhas secas e moídas de chá-verde através do processo de maceração dinâmica, sendo filtrado, concentrado e liofilizado. A formulação foi desenvolvida utilizando o sistema de balanço hidrófilo-lipófilo (EHL) com tensoativos nãoiônicos e co-solvente, e caracterizados pelas análises organolépticas, centrifugação, reologia, microscopia óptica, distribuição de tamanho e potencial zeta. Para a etapa de secagem, selecionou-se a formulação mais estável. As formulações foram secas em spray dryer de escala laboratorial a uma vazão de 4,0 g/min, e temperaturas de 100, 120 e 150 °C. O desempenho de secagem foi avaliado pela recuperação do produto. Os pós obtidos por spray drying foram caracterizados quanto ao teor de umidade, atividade da água, densidade, distribuição granulométrica, propriedades de fluxo, cristalinidade, morfologia e redispersibilidade. Após, se avaliou a atividade antioxidante do produto em óleo vegetal (óleo de soja) utilizando o teste acelerado de estabilidade oxidativa em Rancimat®. O EHL, o tipo de tensoativo e a técnica de preparo da formulação influenciaram diretamente na estabilidade do sistema. Para as formulações estudadas, o tensoativo que conferiu uma maior estabilidade foi o Gelucire® 44/14, sendo selecionado para prosseguimento com o processo de secagem das composições. O rendimento do processo atingiu em média 51,3 ±3,5 %, típico para secadores do tipo spray dryer em escala laboratorial. A maioria das partículas apresentou aparência arredondada, sem presença visível de porosidade, independente do adjuvante (lactose ou trealose). O produto apresentou baixa atividade de água (<= 0,22) e teor de umidade (<= 1,79). O aumento da temperatura de secagem provocou um ligeiro aumento no diâmetro médio de partícula quando a lactose foi utilizada como adjuvante de secagem (9,8 ± 5,9 ?m para 13,65 ± 8,4 ?m). Os pós obtidos tiveram baixa densidade, sendo menor em temperaturas mais altas. O índice de Carr e Fator de Hausner (15 % e < 1,25, respectivamente) indicaram boas propriedades de compressão e fluidez. O produto foi prontamente redispersível, recuperando facilmente sua consistência e características originais. A avaliação da estabilidade oxidativa acelerada utilizando Rancimat demonstrou que o processo de encapsulação conferiu uma maior solubilidade e proteção dos compostos bioativos, levando ao aumento da atividade antioxidante. Os resultados aqui relatados confirmam a viabilidade da encapsulação dos compostos bioativos de Camellia sinensis em carreadores lipídios empregando o processo de spray drying. O produto apresenta potencial de aplicação como matéria-prima para a produção de formas orais, inclusão em produtos nutracêuticos e cosméticos / Green tea, a product made from Camellia sinensis leaves, is recognized worldwide by its high polyphenol content, in special the catechins. Tea catechins are linked to the prevention of several degenerative diseases as cancer and diabetes. However, several drawbacks need to be overcome in order to increase the use of this products, being their bioavailability one of the upmost. The development of carrier lipid based containing bioproducts is a recent technology, which can solve several bioavailability problems presented by natural products, producing a structure which confer protection to active compounds. The aim of this work was the development of carrier lipid based compositions containing bioactive compounds of Camellia sinensis (green tea) by spray drying evaluating processes of preparation, type of excipients and characterization of physicochemical properties and evaluation the antioxidant activity in vitro of the product. Bioactive compounds from dried and milled green tea leaves was extracted by dynamic maceration, filtered, concentrated and freeze-dried. The formulation was developed through the utilization of Hydrophilic Lipophilic Balance System (HLB) using the non-ionic surfactants and a co-solvent and characterized by organoleptic analysis, centrifugation, rheology, optical microscopy, size distribution and zeta potential. The most stable compositions were submitted to spray drying. The compositions were dried in a labscale spray dryer at flow rate of 4.0 g/min at temperatures of 100, 120 and 150 °C. The spray drying performance was characterized by determination of the powder production yield. Spray dried powders were characterized by moisture content, water activity, density, size distribution, flow properties, crystallinity, morphology, and redispersibility. After, it was evaluated the antioxidant activity of the product in vegetable oil (soybean oil) using the accelerated oxidative stability test Rancimat®. The HLB, the type of surfactant and the preparation method of the formulation influenced the system stability. For the formulations studied, the surfactant which confers the greater stability was Gelucire® 44/14, which was selected to prepare composition for spray drying. The powder production yield falls around 51.3 ±3.5 %, typical for lab scale spray dryers. Wrinkled and rounded particles, without visible presence porosities were mostly generated, independent of the adjuvant (trehalose or lactose). The product presented low water activity (<= 0.20) and low moisture content (<= 1.79). Increasing in drying temperature caused a slight increase in mean particle diameter, when lactose was used as drying carrier (9.8 ±5.9 ?m to 13.65 ±8.4 ?m). Low density powders were generated, but density tends to be lower at high drying temperatures composition were submitted to spray drying. Carr index and Hausner ratio of the product (< 15% and < 1.25, respectively) were indicative of good compressive and flow properties. The product was promptly redispersible, regaining its original consistency straight forwardly. The accelerated oxidative stability using the Rancimat demonstrated that the encapsulation increased the solubility and protection of bioactive compounds, resulting to increased antioxidant activity of the product. The results here reported confirm the feasibility of entrapment of herbal bioactive compounds of Camellia sinensis in lipid carrier by spray drying. The product has potential to be used as raw material for production of oral dosage forms, inclusion in nutraceutical and cosmetic products.

Orientador: Miriam Dupas Hubinger / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-22T12:59:33Z (GMT). No. of bitstreams: 1 Garcia_LorenaCosta_D.pdf: 22115724 bytes, checksum: c861960aaac99c842236e9c6c73a593e (MD5) Previous issue date: 2013 / Resumo: No Brasil, o manjericão (Ocimum basilicum L.) é utilizado tanto in natura como para processamento industrial, visando a obtenção do óleo essencial, que possui como principais compostos aromáticos o linalol, 1,8-cineol (ou eucaliptol) e a cânfora. O objetivo neste trabalho foi microencapsular o óleo essencial de manjericão, através da secagem por atomização em spray-dryer, visando a proteção dos compostos aromáticos. Para isso, uma combinação de materiais de parede foi utilizada: goma arábica, maltodextrina (MD) + isolado proteico de soja (IPS) e maltodextrina + concentrado proteico de soro de leite (CPS). Numa primeira etapa foi realizado um planejamento experimental para o material de parede goma arábica (30% de sólidos) visando avaliar o efeito das variáveis (%) óleo:sólidos totais (10 ¿ 25 %) e pressão de homogeneização (0 ¿ 100 MPa) nas propriedades das emulsões e partículas obtidas. Na segunda etapa do trabalho foram produzidas emulsões e partículas com todos os materiais de parede, utilizando-se 10% de óleo em relação aos sólidos totais e pressões de homogeneização de 0 e 50 MPa, condições estas estabelecidas a partir dos resultados obtidos na primeira etapa do projeto. As partículas resultantes de emulsões homogeneizadas a 50 MPa apresentaram maior retenção de óleo, menor teor de óleo superficial e, consequentemente, maior eficiência de encapsulação, independentemente do material de parede utilizado, evidenciando o efeito positivo da homogeneização a alta pressão. Dentre os três compostos aromáticos avaliados, o linalol foi o retido em maior concentração, mostrando sua maior estabilidade quando comparado com o eucaliptol e a cânfora. Com base nos resultados obtidos nesta segunda etapa e também avaliando a questão econômica (custo dos materiais de parede), os materiais de parede goma arábica, MD:IPS (75:25) e MD:CPS (75:25) foram selecionados para a terceira etapa do trabalho. Avaliou-se a estabilidade das micropartículas ao serem armazenadas por 60 dias em potes herméticos à 25 ºC e 50 ºC e em umidade relativa de 50%, a 25 ºC. Concluiu-se que a microencapsulação de óleo essencial de manjericão é indicada quando a finalidade é o uso deste óleo em produtos nos quais há dificuldade de incorporação de materiais líquidos ou em produtos a serem armazenados em ambiente com elevada umidade relativa / Abstract: In Brazil, the basil (Ocimum basilicum L.) is used both fresh and for processing in order to obtain the essential oil, which has as main aromatic compounds linalool, 1,8-cineol (or eucalyptol) and camphor. The objective of this study was to microencapsulate basil essential oil by spray-drying, seeking the protection of aromatic compounds. For this, tree wall materials were studied: gum Arabic, maltodextrin (MD) + protein, that could be either soy protein isolate (SPI) or whey protein concentrated (WPC). In a first step an experimental design was used to evaluate the effect of the variables oil:total solids rate (10 ¿ 25 %) and homogenization pressure (0 ¿ 100 MPa), on emulsions and particles, using gum Arabic (30% solids) as wall material. On the second stage of the study, emulsions and particles were produced with all the wall materials, using 10% oil in relation to total solids content and emulsions homogenization pressures of 0 and 50 MPa, conditions established based on the results obtained in the first stage of this study. The particles obtained from emulsions homogenized at 50 MPa had higher oil retention, low surface oil, and hence higher encapsulation efficiency regardless of the wall material used, showing the positive effect of high pressure homogenization. Among the three compounds evaluated, linalool was retained in higher concentrations, indicating its higher stability when compared with eucalyptol and camphor. Based on the results obtained in this second stage and also evaluating the economic issue (wall materials costs), the wall materials gum Arabic, MD: IPS (75:25) and MD: CPS (75:25) were selected for the third stage of the study. The stability of the particles stored for 60 days at airtight recipients at 25 ºC and 50 ºC and at relative humidity of 50%, at 25ºC was evaluated. It was concluded that the microencapsulation of Basil essential oil is suitable when the purpose is the use of this oil in products in which the incorporation of liquid materials is difficult or products to be stored in an environment with high relative humidity / Doutorado / Engenharia de Alimentos / Doutora em Engenharia de Alimentos

L'objectif de ce travail de thèse consiste en l'étude de l'encapsulation, par des procédés d'atomisation, d'un adhésif sensible à la pression se présentant sous la forme d'une émulsion aqueuse. Des microparticules de diamètres moyens inférieurs à 50 μm et à base d'éthylcellulose plastifiée ont été élaborées par spray-drying ; la proportion d'adhésif incorporé a pu atteindre 25% en masse. L'encapsulation a également été réalisée par spraycooling avec des matières d'enrobage fusibles, notamment avec une huile de palme totalement hydrogénée. Un plan de criblage a été réalisé et a permis d'identifier des conditions optimales avec 50% d'adhésif et 2% d'un tensioactif lipophile : des tailles équivalentes aux précédentes et une adhésion maximale de l'ordre de 6 N après rupture des particules ont été obtenues. Le polymorphisme relatif aux matières grasses a été mis en évidence et des analyses couplées ont permis de mettre au point un traitement thermique adéquat pour s'en affranchir. Des tests de résistance mécaniques de microparticules unitaires de diamètres inférieures à 20 μm ont été menés et ont montré pour les deux types de particules des niveaux de forces de rupture de quelques centaines de micronewtons et une relation quasi linéaire entre ces forces et les tailles de particules / The aim of this work was to microencapsulate a water-based pressure sensitive adhesive by mechanical methods based on atomization. Microparticles having a mean diameter inferior to 50 μm have been produced by spray-drying with a wall material made up of plastified ethylcellulose; the proportion of adhesive incorporated reached 25% w/w. Besides, the microencapsulation of the adhesive was achieved by spray-cooling with fusible wall materials. A totally hydrogenated palm oil was especially selected. An experimental screening design was carried out: optimal formulation conditions were identified, namely 50% adhesive and 2% of a lipophilic emulsifier. Mean diameter size of the microparticles collected was equivalent to the spray-dried one and their adhesive forces reached 6 N after crushing. Polymorphism inherent in fats subjected to quenching was brought to light and coupled analyses enabled to set an appropriate thermal treatment to overcome it. Mechanical tests performed on unitary microparticles having diameters inferior to 20 μm and elaborated by both spray methods revealed that the order of magnitude of the crushing forces was about few hundreds micronewtons and the forces raised almost linearly with the particles size

Orientador: Lireny Aparecida Guaraldo Gonçalves / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-27T06:01:36Z (GMT). No. of bitstreams: 1 Mascarenhas_MariaCristinaChiarinelliNucci_D.pdf: 11179206 bytes, checksum: 71bb9c37c16718133e785f77c3b3fa2a (MD5) Previous issue date: 2015 / Resumo: O uso de gorduras vegetais em alimentos é amplo e muitas matérias primas, tecnologias e ingredientes são continuamente pesquisados em busca de funcionalidade e aspectos nutricionais mais adequados, ampliando o uso destas gorduras e melhorando a qualidade dos produtos finais. Uma das técnicas utilizadas para adequar a lenta cristalização do óleo de palma é o uso do processo de semeadura com óleos totalmente hidrogenados (OTH). O presente trabalho se refere à obtenção de cristais de OTH de soja ou de palma microencapsulados em material de parede amido de milho ¿OSA (AMM) ou maltodextrina (MD), em diversas proporções por spray drying. Estas micropartículas apresentaram tamanho de partícula (7,8-9,7µm), eficiência de encapsulação (61,8-89,6%) e morfologia características de produtos por spray dryer, além de manterem o polimorfismo original do material de recheio. Os OTH microencapsulados com quantidade de material de recheio superior (60%) apresentaram maior dificuldade de produção. Na aplicação em óleo de palma puro foram observadas a indução de cristalização e a formação de uma rede homogênea, densa e com poucos aglomerados. Os OTH de soja (45%) microencapsulados em MD e AMM inibiram a formação de polimorfos ? na mistura de óleo de palma. Os OTH microencapsulados com menor quantidade de recheio (30%), apresentaram comportamento de não liberação total do material de recheio nas aplicações, porém, atuaram como sementes de cristalização e influenciaram na transição polimórfica para forma ?. O OTH de soja (30%) microencapsulado em AMM, em sistemas de óleo de palma e açúcar auxiliou na textura e na redução de exsudação de óleo. Os OTH de soja (45%) microencapsulados em AMM e MD aplicados em emulsão A/O desempenharam papel de estruturantes e estabilizantes. Em geral, as micropartículas produzidas com AMM e OTH de soja apresentaram melhores desempenhos. A forma de dispersão ao meio dos cristais de OTH presentes nas micropartículas permitiu a formação de uma rede cristalina mais homogênea, acelerando o processo de cristalização, aumentando a consistência do óleo de palma no meio aplicado. E aos meios específicos, favoreceu a estabilidade em relação à separação de fase de emulsões, como margarinas e cremes, e reduziu a exsudação de óleo em sistemas anidros hidrofóbicos, a exemplo de recheios de biscoitos e de bombons, problemas de processo e qualidade de produto muito indesejável. Além disto, o uso destas micropartículas promove valores de consistência adequados e resistentes a oscilações térmicas, com ausência de ácidos graxos trans. Estas micropartículas podem servir como carreadoras de compostos lipofílicos com caráter nutracêutico se estes forem microencapsulados conjuntamente com o OTH, desempenhando função tecnológica e nutricional com facilidade de manuseio, estocagem e aplicação por estarem na forma de pó / Abstract: The technique of seeding is a option for the oils and fats industry to adapt to the physical characteristics of oils adding nutritional improvements and desirable consistency, expanding its application. This research refers to production of fully hydrogenated oils (FHO) by spray drying with maltodextrina (MD) and modified corn starch¿OSA (MCS) as wall materials to obtain possible seeds of crystallization. FHO of palm and soybean were used in different proportions. These particles were evaluated by mean diameter (7.8-9.7?m), efficiency of encapsulation (61.8-89.6%), polymorphism (maintained the original polymorphism corresponding material filling) and morphological characteristics (spherical form with some surface depression). In palm oil application, these particles induced crystallization and formed an homogeneous and dense crystal network with few agglomerates. FHO of soybean microencapsulated (45%) in MD and MCS inhibited the formation of the ? polymorph in palm oil. The FHO microencapsulated with smaller amount of filled material (30%) acted as seeding and polymorphic transition to influence the ? form, although it partially released the filled material in applications. FHO of soybean microencapsulated (30%) in MCS was applied in palm oil with sugar systems, enhancing the texture and the reduction of oil exudation. FHO of soybean microencapsulated (45%) with MCS and with MD were applied in W/O emulsion, in which these particles were structural network and stabilizers. In general, the particles produced using MCS as wall material and FHO of soybean as filling material showed better performance. The arrangement of the dispersion throughout the FHO crystals present in the particles allowed the formation of a more homogeneous crystal lattice, accelerating the crystallization process, increasing palm oil consistency in the applied mean. In specific means, it favored stability in relation to the separation of emulsions phase, such as margarines and creams, reducing exudation oil in hydrophobic anhydrous systems, such as fillings of cookies and candies, which is a very undesirable product quality problem. Furthermore, the use of these particles promotes consistency and temperature variation stability containing no trans fatty acids. These particles can serve as a carrier for nutraceutical lipophilic compounds if they were microencapsulated together with the FHO. Therefore these particles, which are in the powder form, can perform technological and nutritional functions allowing ease handling, storage and application / Doutorado / Tecnologia de Alimentos / Doutora em Tecnologia de Alimentos

Introdução e objetivos: As nanocápsulas, uma vez que são produzidas com polímeros, representam sistemas mucoadesivos promissores. O uso desse tipo de sistema é importante no delineamento de medicamentos que vislumbrem a membrana sublingual como via de administração, devido ao constante fluxo de saliva. Em vista disso, esse trabalho tem como objetivos: estudar o efeito da nanoestruturação em nanocápsulas de polímeros de diferentes características iônicas, quanto as suas propriedades mucoadesivas, quando veiculadas em suspensão, hidrogel ou pós, e frente a distintas superfícies mucoadesivas (discos de mucina, mucosa vaginal ou mucosa bucal); desenvolver nanocápsulas contendo carvedilol, avaliando as suas propriedades mucoadesivas e perfil de permeação do fármaco em diferentes modelos de membrana sublingual; e produzir, a partir das nanocápsulas secas, comprimidos sublinguais contendo carvedilol nanoencapsulado. Metodologia: Nanocápsulas formadas por Eudragit® RS100, Eudragit® S100 ou poly(ε-caprolactona) [PCL] foram produzidas pelo método de deposição interfacial do polímero. Suas propriedades mucoadesivas foram avaliadas empregando analisador de textura. As nanocápsulas contendo carvedilol foram produzidas pelo mesmo método citado acima, utilizando Eudragit® RS100 e a PCL. A mucoadesão dessas nanocápsulas foi avaliada quanto a sua interação com moléculas de mucina, além do efeito da sua interação com a mucosa sublingual de porco na permanência do fármaco sobre a mucosa e na sua permeação, em presença de um fluxo salivar mimetizado. O transporte de carvedilol através de uma monocamada celular de células de epitélio oral (SCC4) também foi estudado. As suspensões de nanocápsulas foram, então, secas por aspersão e as propriedades das nanocápsulas redispersas foram reavaliadas. Na última etapa, foram produzidos comprimidos sublinguais pelo método de compressão direta, a partir dos pós desenvolvidos. Resultados: A mucoadesividade dos polímeros Eudragit® RS100, Eudragit® S100 e PCL foi potencializada pela sua estruturação em nanocápsulas. Dentre as formulações analisadas, as nanocápsulas catiônicas, formadas por Eudragit® RS100, veiculadas em gel, foram as que apresentaram melhores propriedades adesivas. Além disso, o processo de secagem não interferiu na adesividade das nanocápsulas originais. Em relação a superfície utilizada, a mucina se mostrou uma superfície mais adesiva comparada as mucosas suínas. Entretanto, a mucina reproduziu as diferenças observadas entre as formulações. As nanocápsulas contendo carvedilol interagiram bem com moléculas de mucina, sendo essa interação mais intensa para as nanocápsulas catiônicas [Eudragit® RS100], que para as aniônicas [PCL]. No entanto, ambas as nanocápsulas melhoraram o contato do carvedilol com a mucosa sublingual suína, o que fez com que mais fármaco permeasse através da mucosa, na presença de um fluxo salivar mimetizado, em comparação com uma solução do fármaco. Além disso, as nanocápsulas controlaram a permeação do fármaco através de mucosa sublingual de porco, bem como através de monocamadas de células SCC4. A partir destes resultados, as suspensões de nanocápsulas foram secas por aspersão. As nanopartículas foram recuperadas após redispersão aquosa dos pós e mantiveram suas propriedades mucoadesivas e biofarmacêuticas. Na sequência, os comprimidos foram produzidos como forma farmacêutica final. A presença de nanoestruturas foi observada nos comprimidos, as quais foram liberadas após total desintegração destes em saliva artificial. Além disso, a liberação do fármaco partir dos comprimidos contendo as nanocápsulas apresentou um perfil controlado comparado aos comprimidos contendo o fármaco livre, reforçando a manutenção da estrutura supramolecular das nanocápsulas nos comprimidos. Conclusão: As nanocápsulas produzidas com Eudragit® RS100, Eudragit® S100 ou PCL apresentaram boas características mucoadesivas. As, nanocápsulas de Eudragit® RS100 e PCL também melhoraram a interação do carvedilol com a membrana sublingual de porco. Em ambos os estudos, um melhor desempenho mucoadesivo foi observado para as nanocápsulas catiônicas. Além disso, o carvedilol apresentou boa permeação através de mucosa sublingual suína e através de monocama celular de células de epitélio oral. Ainda, a secagem por aspersão das suspensões de nanocápsulas não alterou significativamente as suas propriedades. A compressão direta dos pós secos por aspersão produziu comprimidos inovadores contendo um sistema nanotecnológico mucoadesivo para administração sublingual de carvedilol, como um nanomedicamento. / Introduction and objectives: Nanocapsules may represent promissing mucoadhesive systems since they are produced with polymers. The use of these systems is very important for drug administration by the sublingual route due to the constantly salivary flux in the oral cavity. In view of this, the objectives of this study were: to study the effect of the nanostructuration in nanocapsules on the mucoadhesiveness of polymers with different charge surface and the effect of the vehicle (suspension, hydrogel, and powder) on the mucoadhesiveness of nanocapsules as well as the effect of different mucosal surfaces (mucin, vaginal mucosa, and buccal mucosa); to develop carvedilol-loaded nanocapsules and to evaluate their mucoadhesive properties and drug permeation profiles using different models of sublingual membrane; and to produce sublingual tablets using spray-dried carvedilol-loaded nanocapsules. Methods: Eudragit®RS100, Eudragit®S100 or poly(ε-caprolactone) [PCL] nanocapsules were produced by interfacial deposition of the polymer method. Their mucoadhesiveness were evaluated by tensile stress tester. Carvedilol-loaded nanocapsules were produced by the method cited above and using Eudragit® RS100 or PCL as polymers. Mucoadhesiveness of nanocapsules were studied analyzing their interaction with mucin molecules and analyzing the effect of their interaction with porcine sublingual mucosa on drug retention as well on the amount of drug permeated to the receptor fluid in the presence of simulated salivary flux. The transport of carvedilol across monolayers of oral epithelial cells (SCC4) was also evaluated. In the next step, nanocapsules suspensions were spray-dried and the properties of redispersed nanocapsules were evaluated. In the last step, sublingual tablets were produced by direct compression using the spray-dried nanocapsules. Results: Mucoadhesiveness of Eudragit® RS100, Eudragit® S100 and PCL were improved by their structuration in nanocapsules. Among the tested formulations, the cationic Eudragit® RS100 nanocapsules formulated as a hydrogel showed the best behavior. Moreover, the drying process did not interfer in the adhesiveness of original nanocapsules. Regarding the surface substrate, mucin discs were more adhesive than porcine mucosas. However, mucin was able to reproduce the differences observed between the formulations. Carvedilol-loaded nanocapsules interacted with mucin molecules and this interaction was more intense for cationic Eudragit® RS100 nanocapsules than for anionic PCL nanocapsules. However, both nanocapsules increased the amount of drug retained on porcine sublingual mucosa and improved the amount of drug permeated through mucosa, in comparison to the drug solution, in presence of a mimetic salivary flux was present. Furthermore, nanocapsules were able to control the drug permeation across porcine sublingual and through SCC4 monolayer. Subsequently, suitable powders were obtained by spray-drying. The original nanoparticles were recovered after aqueous redispersion of powders and the maintenance of their mucoadhesiveness and biopharmaceutics properties was observed. Moreover, sublingual tablets were produced as a final pharmaceutical form. The presence of nanometric particles in the tablets was observed and they were released after tablet disintegration in artififcial saliva. The drug was released by a controlled way from tablets containing nanocapsules when compared to tablets containing the non-encapsulated drug, reinforcing the maintenance of supramolecular structure of nanocapsules in the tablets. Conclusion: The Eudragit® RS100, Eudragit® S100 and PCL nanocapsules showed good mucoadhesive characteristics. Moreover, Eudragit® RS100 and PCL nanocapsules improved the carvedilol interaction with porcine sublingual mucosa. In both studies, cationic nanocapsules showed the best mucoadhesive performance. Additionally, carvedilol showed a good permeation across porcine sublingual mucosa and through oral epithelial cells monolayer. The spray-drying process did not change the properties of the original aqueous nanocapsules. Furthermore, their direct compression produced innovative tablets containing a mucoadhesive nanotechnological system for sublingual administration of carvedilol as a nanomedicine.

Crystal engineering study using spray dryer was performed for scale-up and rapid, continuous crystallisation of co-crystals from solution. The study emphasise on developing co-crystals of two structurally similar compounds, caffeine (CAF) and theophylline (THEO) with various di-carboxylic acids. The incongruently soluble pair of CAF and THEO with di-carboxylic acids acquires large solubility difference which is important to consider for its utility in product development. Based on previous assumption that maleic acid (MAL) elevates CAF’s solubility; solubility of the two similar compounds was tested in various dicarboxylic acids. Other solubility enhancement strategies such as introduction of surfactant and binary solvents were also scrutinised. A kinetically similar bench-scale technique, rotary evaporator (rotavap) was investigated as a pre-screening tool for the production of co-crystals via spray drying. Furthermore, various process parameters within the spray dryer were optimised to control the kinetic conditions which influence co-crystallisation and quality of the product. Another polymorphic co-crystal pair, CBZ (carbamazepine) and SAC (saccharin) was examined in various solvents and its degradation was evaluated over a period of few months. In this study, a two-step conversion of CBZ into its degradate was hypothesised. Rotavap delivered a true reflection of co-crystal favoured via spray drying apart from co-crystal pairs depicting polymorphism. Spray dryer offered a unique environment favouring metastable forms of co-crystals irrespective of the starting component stoichiometry; generating CAF:MAL 2:1. However, due to process limitation and solubility constraint, the impurity of CAF in CAF:MAL 2:1 co-crystals could not be abolished.

Enteric pathogens form a large part of infectious diseases which contribute to a bulk of the healthcare costs. Enteric infections are usually contracted via the faecal-oral route or through contact with contaminated surfaces. Treatment by antibiotics is becoming increasingly ineffective due to the growing number of antibiotic resistant strains. Anti-microbial resistance poses a serious threat to the future of healthcare worldwide and necessitates the search for alternate forms of therapy. Bacteriophages (phages), are viruses which specifically infect and lyse bacteria. To introduce phages as a viable form of therapy, route of administration needs to be considered carefully. Model phages with broad host ranges are ideal for therapy however oral delivery to the lower gastro-intestinal (GI) poses several challenges. The acidic stomach environment can be detrimental to phages, rendering them inactive during passage. To overcome this challenge and improve the stability of phage during encapsulation and storage, this PhD research has been conducted. pH responsive polymers, Eudragit and alginate were used to develop composite microparticles which protected phage from acidic pH (pH 1-3). A novel method of acidifying oil was developed for crosslinking droplets in vitro to avoid the use of harsh solvent systems that can cause phage inactivation. Platform microfluidic technology was employed for phage encapsulation for the first time. Monodispersed droplets and particles were produced, offering fine-tuning of droplet diameter to tailor the release and pH protection of encapsulated phage. Process scale-up was attempted using membrane emulsification (ME) to produce larger volumes of encapsulated phage. In vitro and in-situ models investigated the efficacy of encapsulated phage-bacterial killing. Industrial scale method of spray drying, and electrospinning were also used to demonstrate the versatility of the formulation. Tableting dry powder phage, showed an effective method for producing solid dosage forms for therapy. Additionally, electrospun phage fibres also showed the potential use of pH responsive formulations in addressing wound infections. Improvement in encapsulated phage storage stability was observed with the addition of trehalose in the formulation. This research underpins the need for testing phage encapsulation for site-specific delivery and offers insight into the potential use of commercially available technologies.

Face au manque de médicaments spécifiquement conçus et mis au point pour répondre aux besoins thérapeutiques de la population pédiatrique, les autorités nationales et européennes se sont vues dans l’obligation d’établir un cadre réglementaire visant à encourager le développement de médicaments à usage pédiatrique. Un médicament destiné à l’enfant nécessite une présentation galénique spécifique et adaptée à son âge, pour permettre une administration simple et sûre. L’Académie nationale de Pharmacie a également travaillé sur le sujet et élaboré un rapport en juin 2005 avec certaines propositions notamment favoriser les formes orales solides dispersibles ou orodispersibles. Cependant, les formes orales solides posent le problème de l’acceptabilité et de l’évaluation de la palatabilité, condition requise qui représente un véritable défi. L’objectif de ce travail était (i) de développer des techniques de masquage du goût d’un principe actif modèle, l'acétaminophène, (ii) de mettre au point des méthodes d’évaluation du masquage de goût et de caractérisation des particules obtenues et, (iii) d'élaborer un procédé de fabrication d’une forme dispersible : des minigranules à désintégration rapide. Le caséinate de sodium et la lécithine, excipients potentiellement tolérables et sans danger pour un usage pédiatrique, ont été utilisés pour encapsuler le principe actif par atomisation-séchage. Le masquage de goût est évalué in vitro de façon indirecte par des études de libération du principe actif. Nous avons développé une méthode simple avec une pompe à seringues qui utilise de faibles volumes et débits de tampon et simule le flux salivaire. La méthode d’évaluation de masquage de goût développée donne des résultats en accord avec ceux d’autres méthodes existantes comme la langue électronique. La caractérisation des particules obtenues, notamment grâce à la spectroscopie par Rayons X qui permet d’obtenir une cartographie de la composition à la surface des particules enrobées, a montré une différence de composition en fonction du ratio caséinate de sodium/lécithine utilisé lors de l’atomisation. Cette différence a pu être mise en relation avec l'efficacité de masquage de goût. Une étude a ensuite été menée pour évaluer l'effet des paramètres du procédé et de la formulation sur l'efficacité de masquage de goût. Un plan factoriel complet a permis de déterminer les variables les plus importantes influant sur la quantité de principe actif libéré durant les premières minutes, soit la quantité de caséinate de sodium et de lécithine. L’optimisation par la méthode du simplex a permis d’obtenir une formulation optimisée pour laquelle la quantité libérée était 7 fois inférieure à celle du principe actif initial durant les deux premières minutes de l’essai de libération. Une autre approche visant à améliorer l'effet de masquage de goût incluait l'utilisation de caséinate de calcium à la place de caséinate de sodium. Le caséinate de calcium a été montré capable de retarder la libération du principe actif de façon plus importante lors de son association avec de la lécithine, ce qui améliore le masquage de goût. En effet, le masquage de goût est obtenu quand sur une courte période de temps (1 à 2 minutes), soit le principe actif n’est pas détecté, soit la quantité détectée est sous le seuil de perception du patient. Une forme galénique multiparticulaire à base de minigranules à désintégration rapide a ensuite été élaborée par extrusion-sphéronisation suivie d’une lyophilisation. Les minigranules présentent des qualités appropriées à savoir, une bonne sphéricité, une faible friabilité, la capacité d’incorporer une quantité élevée de principe actif et de plus, ces minigranules sont presque immédiatement désintégrés en présence d'eau lors de la mesure du temps de désagrégation avec l'analyseur de texture. Ce type de minigranules promet une forme galénique adaptée à la population pédiatrique grâce à la facilité d’administration et la flexibilité de dosage. / The development of paediatric formulations involves an urgent need but also presents many difficulties, e.g. the safety data of existing and new excipients in children stay restrictive; the development of palatable formulations for better compliance is requisite and challenging; the appropriateness of dosage form faces to dysphagia issue and flexibility of dosing for a large range of age. The aim of this work was (i) to develop a taste-masking formulation of a model drug (acetaminophen) on the one hand, and (ii) to elaborate a process for manufacture of fast disintegrating minigranules on the other hand. Sodium caseinate and lecithin, potentially tolerable and safe excipients for paediatric use, were utilized in order to encapsulate the drug through spray-drying. Taste-masking effect was demonstrated by in vitro drug release study and electronic tongue analysis. The characterization of spray-dried particles showed a difference in the surface composition according to the sodium caseinate/lecithin ratio, which related to the taste-masking efficiency. A study was subsequently undertaken to evaluate the effect of process and formulation parameters on the taste-masking efficiency. A full factorial design allowed screening for the most important variables that affect the released amount of drug during the early minutes, i.e. quantity of sodium caseinate and lecithin. An optimized formulation was successfully achieved by simplex design that released the drug 7-fold less than the unmasked drug during the first two minutes. Another approach to improve the taste-masking effect included the use of calcium caseinate rather than sodium caseinate. Calcium caseinate was showed to be more effective in delaying the drug release to a higher extent in association with lecithin. Indeed, the lower the released amount, the better the taste-masking. A multiparticulate dosage form of fast disintegration was developed through extrusion-spheronization followed by freeze-drying. The pellets exhibited suitable quality, e.g. good sphericity, low friability, ability of high drug loading, and moreover, almost immediately disintegrated in contact with water during measurement of disintegration by texture analyzer. This type of pellets promises age-appropriate dosage form for pediatric population thank to facility of administration and flexibility of dosing.