Cette thèse a été consacrée à la mise au point de deux systèmes d'administration destinés à la voie orale, pour deux molécules différentes.Dans la première partie, des microparticules (MPs) à base de xylane et d'Eudragit® S-100 ont été produites pour encapsuler l’acide 5-aminosalicylique et permettre son absorption au niveau du colon. Le xylane a été extrait à partir de rafles de maïs et caractérisé selon ses propriétés physico-chimiques, rhéologiques et toxicologiques. Par la suite, les MPs ont été préparées soit par réticulation interfaciale, soit par séchage par atomisation et caracterisés quant à leur morphologie, leur taille moyenne et leur distribution, leur stabilité thermique, leur cristallinité, leur efficacité et leur profil de libération du médicament in vitro. Des MPs de caractéristiques physiques appropriées avec des rendements satisfaisants ont été préparées par ces deux méthodes, bien que les systèmes séchés par pulvérisation aient montré une plus grande stabilité thermique. En général, ces derniers systèmes étaient plus prometteurs en raison de leur stabilité thermique et de l'absence d'agents réticulants toxiques. Toutefois, la méthodologie doit être optimiser afin d’améliorer le chargement de principe actif ainsi que sa libération.Dans la deuxième partie de cette thèse, des microémulsions huile-dans-l’eau (ME H/E) à base de triglycérides à chaîne moyenne ont été preparées afin de vectoriser et d’augmenter la solubilité de l'amphotéricine B (AmB). Des diagrammes de phases ont été construits en utilisant des mélanges de tensioactifs dont les valeurs de la balance hydrophile-lipophile variaient entre 9,7 et 14,4. Les MEs H/E sans et avec AmB étaient composées de gouttelettes sphériques non agrégées de diamètre moyen autour de 80 et 120 nm, respectivement, et avec une faible polydispersité. L'incorporation de l'AmB était élevée et dépendait de la fraction volumique de la phase dispersée. La viabilité des cellules J774.A1 n’était pas diminuée par l’exposition aux concentrations d’AmB encapsulée allant jusqu’à 25μg/mL. Par conséquent, les MEs H/E à base d’esters de propylèneglycol et d'acide caprylique peuvent être considéré comme des vecteurs adaptés pour l’AmB. / This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit® S-100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spray-dried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on medium-chain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophilic-lipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 µg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB.

This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit® S-100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spray-dried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on medium-chain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophilic-lipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 µg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB.

O fruto da bocaiúva pertence à família Palmae, espécie Acrocomia aculeata (Jacq.) Lodd.Ex Martius abundante e nativa no Estado do Mato Grosso do Sul, Pará, São Paulo e Minas Gerais. O óleo da polpa da fruta constitui de alto teor de ácidos graxos insaturados, com uma predominância de ácido oleico, chegando a 60% de sua composição e o óleo da amêndoa da bocaiúva apresenta além do oleico, aproximadamente 40% o ácido láurico (13%) e ácido palmítico (12,6%). O óleo da polpa é rico em fenóis totais (2,69 g por 100g de amostra), carotenóides (55mg eq β- caroteno/100g de amostra) e possui alta atividade ORAC (283,93 µmol/g de amostra). Foram obtidos quatro novos sistemas nanoestruturados que estão apresentados a seguir com seus respectivos valores de potencial zeta e diâmetro médio: 1) carreador lipídico nanoestruturado contendo o óleo da polpa (-22,4 mV e 192,55 nm); 2) carreador lipídico nanoestruturado contendo o óleo da amêndoa (-23,95 mV e 227,75 nm); 3) nanopartículas poliméricas contendo o óleo da polpa (-47,5 mV e 127,70 nm) e 4) nanopartícula polimérica contendo o óleo da amêndoa da bocaiúva (-44,74 mV e 131,3 nm). O sistema nanoestruturado contendo o óleo de polpa de bocaiuva e o sistema contendo triglicérides de ácido cáprico e caprílico apresentaram a primeira concentração não-citotóxica igual a 0,098% (p/v). O sistema lipídico nanoestruturado contendo óleo de polpa de bocaiúva e os filtros químicos octocrileno e avobenzona revelou citotoxicidade maior quando comparado aos sistemas ipídicos nanoestruturados, isentos de filtros, conforme esperado. Os sistemas carreadores lipídicos nanoestruturados contendo o óleo da amêndoa e o óleo da polpa da bocaiuva quando adicionados na formulação base (FPS 14), em concentração de 20% p/p, apresentou aumento respectivamente de 92,8% e 35,7 % no FPS. Tais resultados demonstraram interação sinérgica entre a formulação fotoprotetora e o sistema lipídico nanoestruturado contendo o óleo de amêndoa. Dessa maneira, esse sistema carreador lipídico nanoestruturado, aditivado com os filtros químicos constitui inovação com aplicação industrial. A obtenção dos sistemas nanoestruturados proposto no presente projeto permitirá o desenvolvimento de uma nova plataforma nanotecnológica farmacêutica e cosmética contendo os óleos vegetais do fruto da bocaiúva, de maior segurança, eficácia e de elevado valor agregado. / Acrocomia aculeata (Jacq.) Lodd. ex Martius, known as bocaiuva is an oleaginous species of the family Arecaceae, a widely distributed palm in America. Pulp and almond oils were extracted by cold-pressed method. The oil from the pulp is rich in phenolics (2.69 g per 100 g of sample), carotenoids (beta-carotene 55 mg eq / 100g sample) and has high ORAC activity (283.93 umol/g of sample). Four new nanostructured systems were obtained which are shown below with their respective values zeta potential and average diameter: 1) nanostructured lipid carrier containing the pulp oil (-22.4 mV and 192.55 nm); 2) nanostructured lipid carrier containing the almond oil (-23.95 mV and 227,75nm); 3) polymeric nanoparticles containing the pulp oil (-47.5 mV and 127,70nm) and 4) polymeric nanoparticle containing the almond oil (-44.74 mV and 131.3 nm). The nanostructured system containing the bocaiuva pulp oil and the system containing oil and capric caprylic triglyceride presented the first non-cytotoxic concentration equal to 0.098% (w/v). The nanostructured lipid system containing bocaiuva pulp oil and chemical filters octocrylene and avobenzone showed a higher cytotoxicity when compared to the nanostructured lipid systems, free of filters. The nanostructured lipid carriers systems containing bocaiuva almond oil and pulp oil when added to the base formulation (SPF 14), in a concentration of 20% (w/w), increased respectively 92.8% and 35.7% the SPF. These results demonstrated a synergic interaction between the sunscreen formulation and nanostructured lipid system containing almond oil. Thus, the lipid carrier system nanostructured, spiked with the chemical filters is innovation with industrial application. The obtaining nanostructured systems proposed in the present design will allow the development of a new pharmaceutical nanotechnology platform and cosmetics containing oils from the fruit of bocaiuva, increased safety, efficiency and high added value. Thus, bocaiuva pulp and almond oils present interesting composition, consistent for the use in pharmaceutical and cosmetic topical products due to its moisturizing, emollient and anti-aging potential properties.

Made available in DSpace on 2014-12-17T14:13:48Z (GMT). No. of bitstreams: 1 AcariliaES_TESE.pdf: 9221805 bytes, checksum: 71876e327362584aeb9dcac7d3652c4d (MD5) Previous issue date: 2013-04-05 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit? S- 100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spraydried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on mediumchain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophiliclipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 μg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB / Esta tese teve como objetivo o desenvolvimento de novos sistemas de libera??o para duas mol?culas distintas. Na primeira parte, micropart?culas ? base de xilana e Eudragit? S-100 foram produzidas para encapsular ?cido 5-aminosalic?lico visando ? libera??o c?lonespec?fica. A xilana foi extra?da de sabugos de milho e caracterizada quanto ?s suas propriedades f?sico-qu?micas, reol?gicas e toxicol?gicas. Em seguida, dois m?todos de microencapsula??o foram utilizados: reticula??o interfacial polim?rica e secagem por aspers?o. Os sistemas produzidos foram caracterizados quanto ? morfologia, tamanho m?dio e distribui??o, estabilidade t?rmica, cristalinidade, taxa de encapsula??o e libera??o do f?rmaco in vitro. Foram obtidas micropart?culas com adequadas caracter?sticas f?sicas e rendimentos satisfat?rios atrav?s dos dois m?todos, embora os sistemas aspergidos tenham apresentado maior estabilidade t?rmica e sejam considerados mais interessantes devido a sua maior estabilidade t?rmica e aus?ncia de agentes t?xicos. No entanto, ajustes precisam ser feitos para melhorar a encapsula??o e libera??o do f?rmaco. Na segunda parte, microemuls?es do tipo ?leo em ?gua (MEs O/A) com base em triglicer?deos de cadeia m?dia (MCT) foram produzidas visando ao carreamento de anfotericina B (AmB) e aumento da sua solubilidade. Foram obtidas MEs O/A sem e com AmB com got?culas em torno de 80 e 120 nm, respectivamente, e ?ndices de polidispers?o de 0,25 e 0,31, respectivamente. A taxa de incorpora??o da AmB foi alta e dependente do volume da fase dispersa. A viabilidade celular n?o foi afetada at? 25 μg/mL da AmB. Portanto, MEs O/A a partir de MCT podem ser promissores sistemas de libera??o para AmB

O fruto da bocaiúva pertence à família Palmae, espécie Acrocomia aculeata (Jacq.) Lodd.Ex Martius abundante e nativa no Estado do Mato Grosso do Sul, Pará, São Paulo e Minas Gerais. O óleo da polpa da fruta constitui de alto teor de ácidos graxos insaturados, com uma predominância de ácido oleico, chegando a 60% de sua composição e o óleo da amêndoa da bocaiúva apresenta além do oleico, aproximadamente 40% o ácido láurico (13%) e ácido palmítico (12,6%). O óleo da polpa é rico em fenóis totais (2,69 g por 100g de amostra), carotenóides (55mg eq β- caroteno/100g de amostra) e possui alta atividade ORAC (283,93 µmol/g de amostra). Foram obtidos quatro novos sistemas nanoestruturados que estão apresentados a seguir com seus respectivos valores de potencial zeta e diâmetro médio: 1) carreador lipídico nanoestruturado contendo o óleo da polpa (-22,4 mV e 192,55 nm); 2) carreador lipídico nanoestruturado contendo o óleo da amêndoa (-23,95 mV e 227,75 nm); 3) nanopartículas poliméricas contendo o óleo da polpa (-47,5 mV e 127,70 nm) e 4) nanopartícula polimérica contendo o óleo da amêndoa da bocaiúva (-44,74 mV e 131,3 nm). O sistema nanoestruturado contendo o óleo de polpa de bocaiuva e o sistema contendo triglicérides de ácido cáprico e caprílico apresentaram a primeira concentração não-citotóxica igual a 0,098% (p/v). O sistema lipídico nanoestruturado contendo óleo de polpa de bocaiúva e os filtros químicos octocrileno e avobenzona revelou citotoxicidade maior quando comparado aos sistemas ipídicos nanoestruturados, isentos de filtros, conforme esperado. Os sistemas carreadores lipídicos nanoestruturados contendo o óleo da amêndoa e o óleo da polpa da bocaiuva quando adicionados na formulação base (FPS 14), em concentração de 20% p/p, apresentou aumento respectivamente de 92,8% e 35,7 % no FPS. Tais resultados demonstraram interação sinérgica entre a formulação fotoprotetora e o sistema lipídico nanoestruturado contendo o óleo de amêndoa. Dessa maneira, esse sistema carreador lipídico nanoestruturado, aditivado com os filtros químicos constitui inovação com aplicação industrial. A obtenção dos sistemas nanoestruturados proposto no presente projeto permitirá o desenvolvimento de uma nova plataforma nanotecnológica farmacêutica e cosmética contendo os óleos vegetais do fruto da bocaiúva, de maior segurança, eficácia e de elevado valor agregado. / Acrocomia aculeata (Jacq.) Lodd. ex Martius, known as bocaiuva is an oleaginous species of the family Arecaceae, a widely distributed palm in America. Pulp and almond oils were extracted by cold-pressed method. The oil from the pulp is rich in phenolics (2.69 g per 100 g of sample), carotenoids (beta-carotene 55 mg eq / 100g sample) and has high ORAC activity (283.93 umol/g of sample). Four new nanostructured systems were obtained which are shown below with their respective values zeta potential and average diameter: 1) nanostructured lipid carrier containing the pulp oil (-22.4 mV and 192.55 nm); 2) nanostructured lipid carrier containing the almond oil (-23.95 mV and 227,75nm); 3) polymeric nanoparticles containing the pulp oil (-47.5 mV and 127,70nm) and 4) polymeric nanoparticle containing the almond oil (-44.74 mV and 131.3 nm). The nanostructured system containing the bocaiuva pulp oil and the system containing oil and capric caprylic triglyceride presented the first non-cytotoxic concentration equal to 0.098% (w/v). The nanostructured lipid system containing bocaiuva pulp oil and chemical filters octocrylene and avobenzone showed a higher cytotoxicity when compared to the nanostructured lipid systems, free of filters. The nanostructured lipid carriers systems containing bocaiuva almond oil and pulp oil when added to the base formulation (SPF 14), in a concentration of 20% (w/w), increased respectively 92.8% and 35.7% the SPF. These results demonstrated a synergic interaction between the sunscreen formulation and nanostructured lipid system containing almond oil. Thus, the lipid carrier system nanostructured, spiked with the chemical filters is innovation with industrial application. The obtaining nanostructured systems proposed in the present design will allow the development of a new pharmaceutical nanotechnology platform and cosmetics containing oils from the fruit of bocaiuva, increased safety, efficiency and high added value. Thus, bocaiuva pulp and almond oils present interesting composition, consistent for the use in pharmaceutical and cosmetic topical products due to its moisturizing, emollient and anti-aging potential properties.