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

Wilson's disease is a hereditary disorder of copper metabolism, which causes copper accumulation in organism, especially in the liver, kidneys and brain. Current treatment is based on using low-molecular weight copper chelators and high doses of zinc salts. Unfortunately, they can induce some severe side effects due to systemic action. The aim of this thesis is to improve the treatment of Wilson's disease by using of polymeric drug delivery systems. The size of polymer particles in tens of microns should provide non-resorbability of the drug after oral administration. Synthetic microparticles of poly(glycidyl methacrylate-co- ethylene dimethacrylate), natural microcrystalline cellulose and cross-linked chitosan were used as polymer matrices. N,N-di(2-pyridylmethyl)amine, triethylenetetraamine and 8-hydroxyquinoline were selected as specific copper chelators, which can complex copper cations with high efficiency. The principle of the proposed treatment is that the polymeric carrier-bound chelator complex copper directly from the food in digestive tract of the organism. Because of non-resorbability, the entire complex should be eliminated from the body together with stools. This virtually eliminates systemic side effects. The ability of adsorption of copper and the stability of polymer complex under...

Abstract Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. The main features of the syndrome include menstrual irregularities and hyperandrogenism. In addition to symptoms related to fertility, some women also suffer from an unfavourable metabolic profile including impaired glucose tolerance, dyslipidaemia and low-grade chronic inflammation. In the present studies we aimed to investigate the role of age on adrenal and ovarian androgen secretion in 79 women with PCOS and 98 healthy women, with special focus on the menopause. Furthermore, we studied the effects of combined hormonal contraceptives (CHCs) administered orally, transdermally and vaginally (n=42, healthy women, 9 weeks) and atorvastatin treatment (n=28, women with PCOS, 6 months) on androgen levels and metabolic factors. Androgen secretion capacity was analysed by using adrenal and ovarian stimulation tests and glucose tolerance by using oral and intravenous glucose tolerance tests. Furthermore, chronic inflammation was assessed via assay of C-reactive protein and pentraxin-3. Basal and stimulated adrenal and ovarian androgen production was elevated and levels remained higher in women with PCOS compared with healthy women even after the menopause. Furthermore, women with PCOS presented with enhanced insulin resistance and chronic inflammation, which persisted beyond menopausal transition. During CHC treatment, the route of administration was insignificant, and all treatments impaired insulin sensitivity and increased chronic inflammation. In women with PCOS, treatment with atorvastatin improved chronic inflammation and the lipid profile as expected, but worsened glucose tolerance and did not affect testosterone levels. Regardless of strict exclusion criteria, where only relatively healthy women with PCOS were recruited, the results showed that enhanced androgen secretion and unfavourable metabolic alterations associated with PCOS persist through menopausal transition. The findings emphasize the importance of monitoring glucose metabolism during the use of CHCs, especially in women with known risks of type 2 diabetes. Atorvastatin treatment exacerbates insulin resistance in women with PCOS and therefore the treatment should only be considered after individual risk assessment of cardiovascular disease and not just because of PCOS. / Tiivistelmä Monirakkulainen munasarjaoireyhtymä (PCOS) on hedelmällisessä iässä olevien naisten yleisin hormonaalinen ongelma. Tyypillisiä PCOS:n oireita ovat munarakkuloiden epäsäännöllisestä kypsymisestä johtuvat kuukautiskierron häiriöt ja miessukuhormonien eli androgeenien liikatuotanto. Hedelmällisyyttä heikentävien oireiden lisäksi PCOS:än liittyy aineenvaihdunnan ongelmia, kuten heikentynyttä sokerinsietoa sekä taipumus rasva-aineenvaihdunnan häiriöihin ja krooniseen tulehdukseen. Tutkimuksessa selvitettiin ikääntymisen ja vaihdevuosien vaikutuksia lisämunuais- ja munasarjaperäiseen androgeenieritykseen 79 PCOS-naisella ja 98 terveellä naisella. Lisäksi tutkittiin eri yhdistelmäehkäisyvalmisteiden antoreittien (suu, iho, emätin) (n=42, terveet naiset, 9 viikkoa) ja atorvastatiinihoidon (n=28, PCOS-naiset, 6 kuukautta) vaikutuksia androgeenitasoihin ja aineenvaihdunnallisiin muuttujiin. Androgeenieritystä tutkittiin lisämunuaisten ja munasarjojen stimulaatiotesteillä ja sokeriaineenvaihdunnan muutoksia suun kautta ja suonensisäisesti tehtävillä sokerirasituskokeilla. Tulehduksellista tilaa mitattiin määrittämällä C-reaktiivisen proteiinin ja pentraksiini-3:n pitoisuuksia. Lisämunuaisten ja munasarjojen androgeenieritys oli PCOS-naisilla lisääntynyt terveisiin naisiin verrattuna, ja ero säilyi vaihdevuosi-iän jälkeen. PCOS-naisilla esiintyi myös enemmän heikentynyttä sokerinsietoa ja kroonista tulehdusta vielä vaihdevuosi-iän jälkeenkin. Hormonaalinen yhdistelmäehkäisy heikensi insuliiniherkkyyttä sekä pahensi pitkäaikaista tulehdusta annostelureitistä riippumatta. Atorvastatiinihoito puolestaan paransi pitkäaikaista tulehdusta sekä rasva-aineenvaihduntaa PCOS-naisilla, mutta huononsi sokerinsietoa ja insuliiniherkkyyttä eikä sillä ollut vaikutusta testosteronitasoihin. Koska poissulkukriteerit olivat tiukat, tutkimuksiin valikoitui varsin terveitä PCOS-naisia. Siitä huolimatta osoittautui, että PCOS:än liittyvä lisääntynyt androgeenituotanto sekä epäedulliset aineenvaihdunnan muutokset jatkuvat vielä vaihdevuosi-iän jälkeen. Hormonaalisen yhdistelmäehkäisyn käytön aikana olisi hyvä seurata sokeriaineenvaihdunnan muutoksia erityisesti niillä naisilla, joilla on kohonnut riski sairastua aikuistyypin diabetekseen. Atorvastatiinihoito huonontaa PCOS-naisilla insuliiniherkkyyttä, minkä vuoksi hoito tulisi aloittaa vain yksilöllisen riskiarvion perusteella.