Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised lysosomal levels of cystine in the cells of almost all organs. It is treated by regular oral and topical administration of the aminothiol, cysteamine(Cystagon™), which possesses an offensive taste and smell. The oral form frequently causes emesis,and should be administered every six hours to be maximally effective. The topical eye drop treatment requires hourly application to be most effective.In an attempt to reduce this frequency and improve the treatment, the preparation and evaluation of three alternative cysteamine containing formulations (suppositories, long-acting ophthalmic gels and an inhaler) was undertaken. The physiochemical properties, stability and release profiles of the active (cysteamine or phe conjugate) from the formulations were evaluated. The suppositories released cysteamine over a 20-40 minute period with a T75= 10-13minutes. They were most stable at 4°C. The analysis of the ophthalmic gels demonstrated that a weak gel network was formed at low shear stress, the bioadhesion of the gel was increased with inclusion of a cysteamine derivative (e.g.mean force of 0.067N compared to 0.107N with compound included) and eight-hour, first order release from the gel was observed. There was significant adhesion observed between the ophthalmic gels and bovine corneal tissue. The pulmonary microspheres were spherical and within the optimum size range for deep lung delivery (1-5μm). However, Andersen Cascade Impactor analysis revealed poor deep lung penetration. In conclusion, these results demonstrated that more development work was required to produce a useful pulmonary formulation of cysteamine, however, formulation of an ocular applicable gel or suppository was readily achievable. The suppository preparations may be particularly beneficial for the treatment of infants, whilst the ophthalmic gel preparations could be developed for daily or overnight use. With respect to pulmonary delivery, microspheres in the optimum size range were produced. However, deep lung targeting was prevented by static agglomeration, which requires further investigation.

Made available in DSpace on 2016-08-10T10:29:43Z (GMT). No. of bitstreams: 1 Fritz Eduardo Kasbaum.pdf: 8675531 bytes, checksum: fd4de7b5752ef941286dcf268c9d38da (MD5) Previous issue date: 2010-01-25 / The present work show the pharmaceutical development of new release systems of drugs, specifically dapsona's (DDS) prolonged release tablets, a sulfon with bacteriostatic action used on the leprosy treatment and several other skin diseases and also in the treatment of the other pathologies as malaria and pneumonia caused by Pneumocystis carinii. This drug, depending on the pathology, can be managed in doses trat vary between 25 to 300m/day, and the administration frequency added to the high doses is responsible for the sprouting of serious collateral effect in the hematologic system, amongst them the methemoglobinemia and in some cases hemolysis. Systems of modified release aim to optimize the medicines therapy by reduction of the usually managed doses, attainment of plasmatic levels more uniforms of the drug for bigger period of time in administrations frequency and also reduction of the observed collateral effect. Eight formulations of DDS were prepared using as excipients the microcrystalline cellulose, the monohydrated lactose spray dryer and magnesium stearate. To compose a matricial system of asset release it was formulated tablets sometimes contending matrix with hydrophilic characteristic and sometimes lipofilic, respectively, hidroxipropilmetilcelulose (HPMC) and gliceril monostearate (MEG). The prepared formulations were submitted to dissolution tests in medium that simulated the stomachal and enteric conditions and the respective profiles or release were evaluated the Kinetic of DDS release to elucidate the mechanisms that controls it. The results of release throughout the time had been treated in accordance with model zero-order, first-order, Higuchi and exponential model. The gotten coefficients of correlation indicate that DDS release from the chosen formulation follows exponential model. / O presente trabalho tem como objetivo o desenvolvimento farmacotécnico de novos sistemas de veiculação de fármacos, especificamente comprimidos de liberação prolongada de dapsona (DDS), uma sulfona com ação bacteriostática utilizada no tratamento da hanseníase e diversas afecções da pele e também no tratamento de outras patologias como a malária a pneumonia causada por Pneumocystis carinii. Esse fármaco, dependendo da patologia, poder ser administrado em doses que variam de 25 a 300mg/dia, e a frequencia de administração somada às altas doses são responsáveis pelo surgimento de efeitos colaterais graves no sistema hematológico, dentre eles a metemoglobinemia e em alguns casos hemólise. Sistemas de liberação modificada visam a otimização da terapia medicamentosa por redução das doses usualmente administradas e obtenção de níveis plasmáticos mais uniformes do fármaco por maior período de tempo em relação às formas de liberação imediata. Isso geralmente promove a redução na frequência de administração e também redução dos efeitos colaterais observados. Foram preparados oito formulações de DDS utilizando-se como excipientes a celulose microcristalina, a lactose monohidratada spray dryer e estearato de magnésio. Para compor o sistema matricial de liberação do fármaco, formularam-se comprimidos ora contendo matriz com caractéristica hidrofílica, ora lipofílica, respectivamente, hidroxipropilmetilcelulose (HPMC) e monoesterato de glicerila (MEG). As formulações preparadas foram submetidas a ensaios de dissolução em meios que simulavam as condições estomacal e entérica e os respectivos perfis de liberação avaliados por meio de análise de vâriancia (ANOVA). Para a formulação de escolha também avaliou-se a cinética de liberação da DDS de forma a elucidar os mecanismos que a controlam. Os resultados de liberação ao longo do tempo foram tratados de acordo com modelo cinéticos zero-ordem, primeira ordem, Higuchi e modelo exponencial. Os coeficientes de correlação obtidos indicam que a liberação da DDS a partir da formulação escolhida é governada modelo exponencial.

Made available in DSpace on 2017-07-21T14:13:03Z (GMT). No. of bitstreams: 1 Mona Lisa S Gomes.pdf: 2596723 bytes, checksum: cad81f365e93a147f44fe76b57ed4640 (MD5) Previous issue date: 2015-02-24 / Cilostazol is a selective inhibitor of phosphodiesterase III. It acts as a vasodilator and antiplatelet agent. It is the main drug for the treatment of intermittent claudication related to peripheral arterial occlusive disease. This drug belongs to the class II of the Biopharmaceutical Classification System (BCS) and shows low solubility and high permeability in gastrointestinal tract. The usual oral dose is 100 mg twice a day, which represents a disadvantage in treatment compliance. Cilostazol is a lipophilic drug and the development of controlled drug delivery systems can improve its bioavailability. The aim this study was to obtain and characterize nanocapsules suspensions prepared from poly(caprolactone) (PCL), poly(D,L-lactic-co-glycolic acid) (PLGA) and blends using polyethylene glycol (PEG), PCL/PEG and PLGA/PEG containing 0 to 3.0 mg.mL-1cilostazol. The analytical method was developed and validated for the quantification of cilostazol into the nanocápsulas by high performance liquid chromatography. All formulations had suitable encapsulation efficiencies (≥99.6%). Nanocapsules showed pH values between 6.0 and 6.4, average size lower than 137 nm, polydispersity index lower than 0.22 and average negative zeta potential of -35.34 mV. The images observed by electron transmission microscopy and scanning electron microscopy, revealed spherical shape with smooth surface. The results achieved by X-ray diffraction demonstrated no crystallinity which indicated the drug amorphization compared to the raw materials. Analyses performed by Fourier transform infrared spectroscopy showed no chemical reactions between drug and polymers. The formulations prepared from blends of PCL/PEG showed the best stability parameters after 60 days of storage. The use of nanoparticles can be a promising strategy for increasing the apparent solubility of cilostazol leading to better dissolution profiles and therapeutical effect. / O cilostazol é um inibidor seletivo da fosfodiesterase III, atuando como antiagregante plaquetário e vasodilatador. É o medicamento de primeira escolha para o tratamento clínico da claudicação intermitente por doença arterial obstrutiva periférica. O fármaco pertence à classe II do Sistema de Classificação Biofarmacêutica, apresentando baixa solubilidade e alta permeabilidade no trato gastrointestinal. A dose usual é de 100 mg, via oral, duas vezes ao dia, o que representa uma desvantagem à adesão ao tratamento. O cilostazol tem característica lipofílica, podendo ser utilizado no desenvolvimento de sistemas de liberação modificada de fármaco, com a finalidade de melhorar sua biodisponibilidade. Assim, com o propósito de se elaborar sistemas de liberação modificada, o objetivo deste trabalho foi obter e caracterizar suspensões de nanocápsulas, a partir do uso dos polímeros poli(caprolactona) (PCL), poli(D,L-ácido lático-co-ácido glicólico) (PLGA) e de blendas com polietilenoglicol (PEG), PCL/PEG e PLGA/PEG, contendo concentrações de 0 a 3,0 mg.mL-1 de cilostazol. O método analítico por cromatografia líquida de alta eficiência foi desenvolvido e validado para a quantificação do cilostazol presente nas nanocápsulas. Todas as formulações apresentaram valores de eficiência de encapsulação adequados (≥99,6%). As nanocápsulas obtidas apresentaram valores de pH entre 6,0 e 6,4, com tamanho médio de partículas inferior a 137 nm, índice de polidispersão menor que 0,22 e potencial zeta negativo de -35,34 mV, devido aos polímeros aniônicos empregados. As imagens obtidas por microscopia eletrônica de transmissão e microscopia eletrônica de varredura revelaram formato esférico com superfície lisa e homogeneidade das nanocápsulas. Os resultados obtidos por difração de raios X revelaram a ausência de cristalinidade das nanocápsulas, evidenciando sua característica amorfa, em comparação aos polímeros e ao fármaco. As análises efetuadas por espectroscopia na região do infravermelho com transformada de Fourier demonstraram que não ocorreram reações químicas entre o fármaco e os polímeros. Em geral, as formulações de cilostazol obtidas a partir de blendas PCL/PEG foram as que apresentaram os melhores parâmetros de estabilidade após 60 dias de armazenamento. O uso de nanopartículas pode ser uma estratégia promissora na promoção do aumento da solubilização aparente do cilostazol melhorando seu perfil de dissolução e, consequentemente, sua ação farmacológica.

The aim of the present study was to formulate oral modified release matrices of diclofenac sodium, using the Eudragit® polymers. In addition to the formulation processes, numerous variables had to be investigated, which included dissolution variables, formulation variables, and processing variables. The application of the tabletting technique as well as the use of Eudragit® polymers to modify the release of diclofenac sodium is motivated at the outset. A comprehensive review of modified drug release, the use of the tabletting methodologies and the application of Eudragit® polymers are presented. In-process quality control tests as well as the mechanisms and interpretation of the dissolution process are outlined. Diclofenac sodium, a potent nonsteroidal anti-inflammatory drug, was used in the present study, hence a brief review of this drug is also presented. The direct compression as well as the wet granulation tabletting methods were investigated. The major limitation of the direct compression method was found to be the lack of suitable flow properties of the powder blend. The wet granulation technique however, was successfully employed to prepare various diclofenac sodium Eudragit® matrix tablets. All tablets were prepared to contain 100 mg diclofenac sodium. The optimisation process was shown to be an integral procedure in influencing the matrix characteristics. In addition, it was shown that drug release was significantly influenced by different types and concentrations of Eudragit® polymers. A specific formulation was selected to investigate the integrity of the matrices produced by the wet granulation technique. The drug release profile of a commercially available modified release preparation containing diclofenac sodium viz. Veltex® 100 CR (reference standard) was also obtained. A comparison of the drug release profiles of Veltex® 100 CR capsules and the selected formulation showed them to be markedly dissimilar. Hence, a strong motivation is provided for rationalising the selection of the particular formulation in the present study, that was shown to release diclofenac sodium optimally. The selected formulation was prepared using a combination of the Eudragit® RL and Eudragit® RS polymers. In vitro dissolution studies on the selected as well as various other formulations demonstrated the wet granulation method to be both predictable and reproducible. However, absolute drug release independency of dissolution methods, media and agitation rates was unattainable. Furthermore, drug release was shown to be pH dependent. The selected formula was subjected to certain formulation and processing variables. An increase in the concentrations of lactose and starch was shown to increase drug release. Different types of diluents were also shown to influence drug release from the tablets. The method of incorporation of the lubricant, magnesium stearate, was investigated. Compression studies demonstrated the susceptibility of the tablets to changes in drug release behaviour and morphological characteristics as the hardness was varied. X-ray diffraction studies demonstrated that the processes of granulation and compression did not promote any atomic rearrangement of the drug and Eudragit® polymers. Scanning electron microscopy was useful in investigating the integrity and surface morphology of newly formulated as well as stored samples, while energy dispersive x-ray microprobe analysis adequately revealed the elemental composition of the tablets. The selected formulation was shown to be stable at room temperature (21 ±1°C) and low temperature (5± 1°C), while storage at 37°C with 80% relative humidity and 40°C demonstrated significantly decreased drug release behaviour during short term (3 months) stability testing. Tablet hardness evaluated during the stability testing showed that there were virtually no differences in tablet hardness between the room temperature and low temperature samples, while tablets stored at 37°C with 80% relative humidity and 40°C hardened considerably. However, tablet potencies and the moisture content of the samples were not significantly influenced during the storage period. In addition to usual observations and mathematical manipulation, some of the data generated from this study were also evaluated statistically. / Thesis (M.Sc.)-University of Durban-Westville, 1998.

The motivation for the present study is systematically presented and the aims and objectives of the study are clearly defined. A comprehensive review on modified release drug delivery has been presented to provide the basis for the meltable aqueous dispersion technique as an approach to the formulation of a multiple-unit oral modified release drug delivery system. In addition, a brief discussion on the theory of dissolution testing and the mechanisms and interpretation of the dissolution process has been presented. Naproxen sodium, a potent non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic activity employed in the study, has been briefly discussed. In the present study, the coacervation phase separation technique utilizing ethylcellulose was initially investigated but proved unsuccessful in producing a formulation displaying suitable drug release characteristics. Subsequently, the meltable aqueous dispersion technique utilizing cetostearyl alcohol was successfully employed to formulate a multipleunit modified release naproxen sodium preparation containing 550 mg of naproxen sodium. The use of cetosteary!alcohol, as·a·retarding material, generated modified ·drug release characteristics as a function of its content. Magnesium stearate (anti-tackiness agent) and Span 20 and Tween 60· (surfactants) were incorporated in the formulation to optimize particle size and sphericity. The influence. of various formulation variables on drug release characteristics were investigated: An optimized formulation displaying a desirable modified release profile of naproxen sodium was achieved employing a 1:1 ratio of naproxen sodium:cetostearyl alcohol, 2% m/m .. .. magnesium stearate, and 1%m/m Span 20 dispersed in a liquid manufacturing vehicle of pH 0.6 containing 2% m/m Tween 60. In vitro dissolution studies on the selected formulation showed drug release to be predictable and reproducible, dependent on the dissolution method, agitation rate, and the pH of the dissolution media (i.e. pH-dependent drug release). The density of the microspheres was shown to decrease as the concentration of cetostearyl alcohol increased whilst the mean specific surface area increased with increasing concentrations of cetostearyl alcohol. Differential scanning calorimetric studies reveals a change in the thermograms which is suggestive of eutectic formation. Scanning electron microscopy proved useful in evaluating the integrity and surface morphology of the microspheres as well as in elucidating the drug release characteristics of the formulation. Energy dispersive x-ray microprobe analysis revealed the elemental composition of the microspheres to be a composite of the pure ingredients. X-ray mapping and the line scan depicted the homogenous distribution of drug within the microspheres and confirmed that the formulation is a matrix-type modified release I' preparation. Stability studies were performed on the selected formulation at room temperature (21 :t 1°C), 40°C, 37°C with 80% relative humidity, and at low temperature (5 :t 1°C). The shelf-life of the selected formulation was determined to be 1.29 years. Applying the data to five different kinetic models to investigate the drug release mechanisms showed that first order and cube-root release characteristics were exhibited by the microspheres. / Thesis (M.Sc.)--University of Durban-Westville, 1997.

Os médicos têm solicitado grande número de formulações diferenciadas, sob a forma de cápsulas de liberação lenta ou prolongada, aos farmacêuticos magistrais, com o objetivo de atender as necessidades específicas dos pacientes. Considerando que, praticamente, não há estudos sobre a liberação de fármacos a partir de formas magistrais de liberação prolongada, neste estudo, cápsulas de liberação modificada com 100 mg de teofilina foram preparadas com diferentes polímeros como os derivados celulósicos (Methocel® K100MPRCR, K15MPRCR e E4MCR) em diferentes concentrações, 15-35%. As cápsulas foram manipuladas, empregando o método volumétrico de enchimento de cápsulas. A lactose, de natureza hidrofílica, foi utilizada como diluente, quando necessário. Para o controle de qualidade das cápsulas, determinações de peso médio e teor de fármaco foram realizados nas 17 formulações desenvolvidas. A avaliação da dissolução das cápsulas foi feita de acordo com a Farmacopéia Americana 26 ed., para cápsulas de liberação prolongada (Teste 8), empregando aparato 1 (cesta), rotação de 100 rpm e temperatura mantida a 37ºC ± 0,5 em 900 mL de meio fluido intestinal sem enzimas (pH 7,5). Os perfis de dissolução foram comparados ao de duas especialidades farmacêuticas, sob a forma de cápsulas liberação prolongada. A formulação obtida com 35% da capacidade em volume de Methocel® E4MCR para cápsulas de tamanho 01 e lactose como diluente, evidenciou perfil de liberação de acordo com as especificações estabelecidas, sendo possível obter resultados reprodutíveis com 10 lotes da mesma formulação, através da padronização dos procedimentos adotados durante a manipulação dos mesmos. Por outro lado, as formulações comerciais de cápsulas de liberação prolongada contendo 100 mg de teofilina sob a forma de microgrânulos, quando submetidas ao mesmo ensaio de dissolução, apresentaram rápida liberação do fármaco, indicando que nestas formulações a liberação do fármaco não é fator limitante para a absorção. Para a avaliação da cinética de liberação do fármaco foram aplicados os modelos matemáticos de ordem zero, primeira ordem e Higuchi. Concluiu-se que as matrizes obtidas com os polímeros foram capazes de modular a liberação de teofilina envolvendo os mecanismos de difusão e erosão, prevalecendo o modelo de ordem um. / Pharmacists are called upon by physicians to compound a wide range of different products, including extended-release and slow-release capsules, when patients require specific individualized therapy. Considering that, practically, there aren\'t studies about compounded extended-release dosage forms, in this study, extended-release capsules of theophylline (100 mg) were prepared with different polymers as cellulose (Methocel® K100MPRCR, K15MPRCR e E4MCR) at different concentrations (15-35%). A hand filling relative volume process was used to prepare the matrix capsules. Lactose was used as hydrophilic diluent. For the quality control of capsules, average weight and assay were performed in 17 formulations. Dissolution rate of these capsules were evaluated according to United States Pharmacopeia 26 ed., dissolution method for theophylline extended-release capsules (Test 8). Determinations were performed with apparatus 1 (basket), agitation at 100 rpm and 900 mL of intestinal medium without enzimes (pH 7,5) were kept at 37ºC ± 0,5ºC. Dissolution profiles were compared to two other commercial extended-release capsules. The batch of capsules compounded with 35% volume capacity to capsules size number 1 of Methocel® E4MCR and with lactose as excipient showed dissolution profile according to the especifications and it was possible to reproduce the same results with more ten batches, through the standardized compounding procedure. On the other hand, commercial extended-release capsules containing theophylline pellets (100 mg) showed quick drug release, indicating that the drug release is not a limitant factor to the absorption. Mathematical models like zero¬-order, first-order and Higuchi were applied in kinetic studies of theophylline release from the capsules. The evaluation indicated that the polymers were efficient to control the release of theophylline in capsules and the involved mechanisms were diffusion and erosion and first-order was the model that better fitted for theophylline matrix capsules.

Os médicos têm solicitado grande número de formulações diferenciadas, sob a forma de cápsulas de liberação lenta ou prolongada, aos farmacêuticos magistrais, com o objetivo de atender as necessidades específicas dos pacientes. Considerando que, praticamente, não há estudos sobre a liberação de fármacos a partir de formas magistrais de liberação prolongada, neste estudo, cápsulas de liberação modificada com 100 mg de teofilina foram preparadas com diferentes polímeros como os derivados celulósicos (Methocel® K100MPRCR, K15MPRCR e E4MCR) em diferentes concentrações, 15-35%. As cápsulas foram manipuladas, empregando o método volumétrico de enchimento de cápsulas. A lactose, de natureza hidrofílica, foi utilizada como diluente, quando necessário. Para o controle de qualidade das cápsulas, determinações de peso médio e teor de fármaco foram realizados nas 17 formulações desenvolvidas. A avaliação da dissolução das cápsulas foi feita de acordo com a Farmacopéia Americana 26 ed., para cápsulas de liberação prolongada (Teste 8), empregando aparato 1 (cesta), rotação de 100 rpm e temperatura mantida a 37ºC ± 0,5 em 900 mL de meio fluido intestinal sem enzimas (pH 7,5). Os perfis de dissolução foram comparados ao de duas especialidades farmacêuticas, sob a forma de cápsulas liberação prolongada. A formulação obtida com 35% da capacidade em volume de Methocel® E4MCR para cápsulas de tamanho 01 e lactose como diluente, evidenciou perfil de liberação de acordo com as especificações estabelecidas, sendo possível obter resultados reprodutíveis com 10 lotes da mesma formulação, através da padronização dos procedimentos adotados durante a manipulação dos mesmos. Por outro lado, as formulações comerciais de cápsulas de liberação prolongada contendo 100 mg de teofilina sob a forma de microgrânulos, quando submetidas ao mesmo ensaio de dissolução, apresentaram rápida liberação do fármaco, indicando que nestas formulações a liberação do fármaco não é fator limitante para a absorção. Para a avaliação da cinética de liberação do fármaco foram aplicados os modelos matemáticos de ordem zero, primeira ordem e Higuchi. Concluiu-se que as matrizes obtidas com os polímeros foram capazes de modular a liberação de teofilina envolvendo os mecanismos de difusão e erosão, prevalecendo o modelo de ordem um. / Pharmacists are called upon by physicians to compound a wide range of different products, including extended-release and slow-release capsules, when patients require specific individualized therapy. Considering that, practically, there aren\'t studies about compounded extended-release dosage forms, in this study, extended-release capsules of theophylline (100 mg) were prepared with different polymers as cellulose (Methocel® K100MPRCR, K15MPRCR e E4MCR) at different concentrations (15-35%). A hand filling relative volume process was used to prepare the matrix capsules. Lactose was used as hydrophilic diluent. For the quality control of capsules, average weight and assay were performed in 17 formulations. Dissolution rate of these capsules were evaluated according to United States Pharmacopeia 26 ed., dissolution method for theophylline extended-release capsules (Test 8). Determinations were performed with apparatus 1 (basket), agitation at 100 rpm and 900 mL of intestinal medium without enzimes (pH 7,5) were kept at 37ºC ± 0,5ºC. Dissolution profiles were compared to two other commercial extended-release capsules. The batch of capsules compounded with 35% volume capacity to capsules size number 1 of Methocel® E4MCR and with lactose as excipient showed dissolution profile according to the especifications and it was possible to reproduce the same results with more ten batches, through the standardized compounding procedure. On the other hand, commercial extended-release capsules containing theophylline pellets (100 mg) showed quick drug release, indicating that the drug release is not a limitant factor to the absorption. Mathematical models like zero¬-order, first-order and Higuchi were applied in kinetic studies of theophylline release from the capsules. The evaluation indicated that the polymers were efficient to control the release of theophylline in capsules and the involved mechanisms were diffusion and erosion and first-order was the model that better fitted for theophylline matrix capsules.

Orientador: Prof. Dr. Eraldo José Madureira Tavares / Tese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, 2015. / Atualmente, sistemas de liberação de fármacos usando nanotecnologia tem despertado grande interesse, entretanto, uma área frequentemente ignorada pelos pesquisadores de formulações de liberação controlada é o combate de ectoparasitas em gado. Para superar essa deficiência, foram desenvolvidas neste estudo formulações de nanopartículas visando a aplicações para uso tópico. As nanopartículas foram sintetizadas e caracterizadas através da avaliação da taxa de associação, tamanho, potencial zeta e pH. A cinética de permeação de ivermectina na pele foi simulada em células de Franz. As formulações (doze) apresentaram estabilidade adequada e taxas de associação próximas a 100%. Os ensaios de permeação mostraram que a liberação da ivermectina foi alterada e os perfis de liberação variaram entre as formulações. Duas formulações, nanocápsulas de PLA e de PLGA, ambas obtidas por nanoprecipitação, iniciaram a liberação dentro das 32 h de ensaio de permeação. Essas duas nanocápsulas também apresentaram bons resultados de estabilidade, apresentando tamanho relativamente constante, potenciais zeta normalmente abaixo de -30 mV, índice de polidispersão (IPD) abaixo de 0,2 e diminuição de pH aproximadamente dentro de 1 unidade de pH. A cinética de permeação das duas formulações foi avaliada utilizando-se modelos matemáticos tais como Higuchi, difusão em esferas sólidas e cápsulas, cinética de ordem zero, modelos de dissolução e a equação generalizada de Korsmeyer-Peppas. O perfil de liberação dessas nanocápsulas sugere o possível acúmulo do fármaco no miristato de isopropila, que simula o estrato córneo da pele. As demais formulações requerem estudos adicionais para detectar seus perfis de liberação, e poderiam ser úteis para liberações extremamente longas e depender bastante da erosão dos polímeros. Os resultados obtidos nesta pesquisa são promissores como sistema alternativo para o tratamento de ectoparasitas, visando a aplicações veterinárias. / Drug release systems using nanotechnology are currently among the research programs which have aroused great interest, however, a field being frequently ignored by controlled release formulation researches is the fight against cattle ectoparasites. In order to overcome that deficiency, nanoparticle formulations for topical usage were developed in this research. The nanoparticles were synthetized and characterized with respect to association rate, size, zeta potential and pH. Ivermectin permeation kinetics in skin was simulated in Franz cells. The formulations (12) presented adequate stability and rate of association of about 100%. The release assays have shown that the release of ivermectina was modified and the release profiles varied among the formulations. Two formulations, PLA and PLGA nanocapsules, both prepared by nanoprecipitation, started the release during the 32h of the permeation assay. Both nanocapsules also had good stability results, having relatively constant size, zeta potentials usually below -30 mV, polydispersity index (PDI) below 0.2 and pH decrease within 1 pH unit. The release kinetics of both formulations was assessed using mathematical models such as Higuchi, diffusion in solid spheres and in capsules, zero order, dissolution models, and Korsmeyer-Peppas¿s generalized equation. The release profile of these nanocapsules suggests the possible accumulation of the drug in the isopropyl myristate, which simulates de stratum corneum of the skin. The remaining formulations require additional studies to detect their release profiles, and could be useful for extremely long releases and might depend quite a lot on the polymers erosion. The results of this research are promising as an alternative system for the treatment of ectoparasites, aiming for veterinary usage.

Nesta Dissertação de Mestrado foram estudadas as respostas inflamatórias e de reparo de tecido muscular de ratos a implantes de hidróxidos duplos lamelares (HDL) contendo íon cloreto e sulindaco (fármaco anti-inflamatório não-esteroidal - FAINE) em seu espaço interlamelar. As técnicas empregadas nesta investigação foram as espectroscopias Raman e de absorção no infravermelho (FTIR), a difratometria de raios X (XRD) e a análise histomorfológica dos tecidos corados pelas técnicas de Hematoxilina e Eosina (HE) (Michalany, 1990)(Michalany, 1990)(Michalany, 1990) e Picrosirius Red (Picro). Simulações do espectro vibracional foram feitas por DFT usando o pacote computacional Gaussian 09 e as análises estatísticas foram feitas usando o pacote Unscrambler X.10.1. Os experimentos in vivo foram realizados fazendo-se a implantação das pastilhas de HDL por microcirurgia entre as camadas do músculo externo oblíquo de ratos (Wistar) e como experimento controle foi feita a separação de tais camadas simulando um implante. Os tecidos foram coletados após 7, 21, 28 e 35 dias de pós operatório, divididos em duas porções (uma para análise histomorfológica e outra para análise por espectroscopia Raman). Inicialmente foram feitos os cálculos teóricos e a caracterização espectroscópica do sulindaco, que possibilitou melhorar sua atribuição vibracional encontrada na literatura. O mesmo ocorreu com as matrizes de HDL, de Zn(II) e de Mg(II), intercaladas com íons cloreto, o que também resultou em um aprimoramento da atribuição que é encontrada na literatura. Os dois HDLs intercalados com sulindaco também foram caracterizados espectroscopicamente e os espectros Raman mostraram grande semelhança com a espécie do fármaco desprotonado. O difratograma obtido dos intercalatos mostra expansão do espaçamento basal (de 7 Å para 26 Å) compatível com a intercalação do sulindaco inclinado em relação ao plano das lamelas. Os espectros Raman do tecido controle mostram alterações mais significativas nas banda amida I e amida III com o tempo de pós-operatório e por PCA foi possivel observar a nítida separação do grupo que apresenta um processo inflamatório agudo (7 dias). Os tecidos expostos à pastilha de HDL intercalada com íons cloreto, mostraram resposta inflamatória reduzida em relação ao tecido controle e as alterações espectrais observadas evidenciam a presença de colágenos, o que indica uma aceitação da pastilha por parte do organismo (biocompatibilidade). As pastilhas também foram analisadas espectroscopicamente e mostraram que houve incorporação de íons CO32- no espaço interlamelar, indicado pela presença da banda Raman em 1060 cm-1 (estiramento simétrico C-O nesse íon), mas não foi possivel determinar se eventuais variações no pH local exerceram efeitos na resposta inflamatória. No caso dos tecidos expostos à pastilha de HDL com sulindaco, a análise por microscopia Raman mostrou que o processo inflamatório foi significativamente reduzido, evidenciando uma ação local do fármaco, além do crescimento de colágenos do tipo III. A pastilha de HDL com sulindaco implantado foi analisada por FT-Raman e a liberação do fármaco foi confirmada. Os resultados de espectroscopia Raman de tecidos foram confirmados pela análise histomorfológica, que mostrou haver de fato um acúmulo de colágeno do tipo III nas regiões próximas às pastilhas implantadas, assim como a formação de invaginações e neovascularização. / In this Master\'s Thesis the inflammatory responses and tissue repair of rat muscles caused by implants of Lamellar Double Hydroxides (LDH) containing chloride ion and sulindac (anti-inflammatory non-steroidal drug - NSAID) in its interlayer space was studied. The techniques used in this research were the Raman spectroscopy and infrared absorption spectroscopy (FTIR), the X-ray diffraction (XRD) and the histomorphological analysis of tissues stained by techniques of Hematoxylin and Eosin (HE) and Picrosirius Red (Picro). Simulations of vibrational spectrum were made by DFT using the computational package Gaussian 09 and the statistical analyzes were performed using the Unscrambler X.10.1 package. In vivo experiments were performed by making the implantation of HDL tablets by microsurgery between the layers of the external oblique muscle of rats (Wistar) and as a control experiment the separation of the layers to simulate an implant was conducted. The tissues were collected after 7, 21, 28 and 35 days postoperatively, divided into two parts (one for histomorphological analysis and the other for analysis by Raman spectroscopy). Initially, theoretical calculations and spectroscopic characterization of sulindac where made, which enabled improving its vibrational assignment in the literature. The same happened for the LDH matrices, Zn(II) and Mg(II), both with chloride ions in the interlamelar space, which also resulted in an improving of it vibrational assignment found in the literature. Both LDH intercalated with sulindac were also characterized spectroscopically and their Raman spectra showed great agreement to the deprotonated species of thedrug. The diffraction pattern obtained from intercalated compounds shows an expansion of the basal spacing (7 Å to 26 Å) compatible with the hypothesis of the sulindac inclined relative to the lamelar plane. The Raman spectra control tissues show the most significant changes in the band amide I and amide III after diferente surgery times and through PCA was possible to observe the clear separation of the group that presenting an acute inflammatory process (at 7 days). Tissues exposed to LDH pellet intercalated with chloride ions showed a reduced inflammatory response relative to control tissue and the spectral changes demonstrate the presence of collagen, which indicates an acceptance of the insert by the body (biocompatibility). The pellets were also analyzed spectroscopically and showed that there was incorporation of CO32- ions in the interlayer space, indicated by the presence of the Raman band at 1060 cm-1 (symmetric stretch C-O of this ion), but it was not possible to determine if changes in local pH affect the inflammatory response. In the case of tissues exposed to LDH tablet with sulindac, analysis by Raman microscopy showed that inflammation was significantly reduced, indicating a local action of the drug, in addition, the collagen type III growth has been observed. The implanted LDH pellet with sulindac was analyzed by FT-Raman and the drug release was confirmed. The results of Raman spectroscopy of tissues were confirmed by histomorphological analysis, which showed that there is indeed an accumulation of collagen type III in the tissue regions near to the implanted pellets, as well as the formation of invagination and neovacularization.

Submitted by Eunice Novais (enovais@uepg.br) on 2018-09-06T16:39:14Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Nubia Nascimento.pdf: 1296891 bytes, checksum: 1fb7f4ddd43a4591eeb9f1b8e95bb14f (MD5) / Made available in DSpace on 2018-09-06T16:39:14Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Nubia Nascimento.pdf: 1296891 bytes, checksum: 1fb7f4ddd43a4591eeb9f1b8e95bb14f (MD5) Previous issue date: 2018-05-28 / O cilostazol é um inibidor seletivo da fosfodiesterase III que atua como antiagregante plaquetário e vasodilatador. Faz parte do tratamento clínico da doença aterosclerótica carotídea extracraniana,apresentando benefícios para o adequado fluxo sanguíneo local.Devido à suacaracterística lipofílica,é um excelente fármaco para o estudo do desenvolvimento de sistemas de liberação modificada, que objetivam melhorar a disponibilidade biológica. A aplicação de tecnologias em formulações, como nanosuspensões, caracteriza uma estratégia atrativa para melhorar a ação de compostos pouco solúveis em água como o Cilostazol. Este trabalho avalioua ação do Cilostazolnanoencapsulado na túnica média da artéria carótida esquerda e no perfil lipídico de ratos Wistar. Os animais foram divididos em 4 grupos, que receberam soluções de nanocápsulas contendo cilostazol, nanocápsulas sem cilostazol, solução de propilenoglicol e cilostazol pesado.Foi observada diferença entre a espessura da carótida em micrômetros, entre os grupos que receberam o cilostazolnanoencapsulado e o grupo que recebeu a solução de propilenoglicol [70.22(9.2±47-81)IC95% 62-72] (P 0,019), sendo a maior espessura observada no grupo que recebeu o cilostazolnanoencapsulado. Não houve diferença em relação à celularidade em números absolutos, entre os grupos. Em relação ao perfil lipídico, o grupo que recebeu propilenogicol apresentou valores maiores de HDL comparativamente ao grupo que recebeu a solução de cilostazolnanoencapsulado [56.85(10.5±37.7-83.7)IC95% 52.56-61.38] (P0,01). O nível de triglicerídeos em mg/dL foi maior no grupo que recebeu o cilostazolpesado em relação ao grupo que recebeu a solução de nanocápsulas [116,92(56.37±45-266)IC95% 74.15-132.33] (P0,01). O cilostazol pesado apresentou melhores resultados em relação ao perfil lipídico. A apresentação do cilostazolnanoecapsulado não demonstrou ser adequada para o tratamento da doença carotídea extracraniana devido ao fato de aumentar o perfil lipídico dos animais estudados. A estrutura da nanocápsula, por conter lipídios em seu interior, piorou o perfil lipídico. Os achados laboratoriais foram condizentes com os achados histopatológicos. / Cilostazol is a selective inhibitor of phosphodiesterase III that acts as a platelet antiaggregant and vasodilator. It is part of the clinical treatment of extracranial atherosclerotic carotid disease, presenting benefits for adequate local blood flow. Due to its lipophilic characteristics, it is an excellent drug for the study of the development of modified release systems, which aim to improve biological availability. The application of technologies in formulations, such as nanosuspensions, characterizes an attractive strategy to improve the action of compounds little soluble in water like Cilostazol. This study evaluated the effect of nanoencapsulated Cilostazol on the left carotid artery layers and in the lipid profile of Wistar rats. The animals were divided into 4 groups, which received solutions of nanocapsules containing cilostazol, nanocapsules without cilostazol, solution of propylene glycol and heavy cilostazol. Differences were observed between carotid thickness in micrometers between groups receiving nanoencapsulated cilostazol and the group receiving the propylene glycol solution (70.22 (9.2 ± 47-81) 95% CI 62-72) (P <0.019), with the highest thickness observed in the group receiving nanoencapsulated cilostazol. There was no difference in cellularity in absolute numbers between the groups. Regarding the lipid profile, the group receiving propylene glycol had higher values of HDL in mg/dL, compared to the group that received the nanoencapsulated cilostazol solution [56.85 (10.5 ± 37.7-83.7) 95% CI 52.56-61.38] (P 0.01). The level of triglycerides in mg/dL was higher in the group that received the heavy cilostazol compared to the group that received the nanocapsule solution [116 (56.37 ± 45-116.92) CI95% 74.15-132.33] (P 0.01). The heavy cilostazol presented better results in relation to the lipid profile. The presentation of nanoecapsulated cilostazol has not been shown to be adequate for the treatment of extracranial carotid disease due to the fact that it increases the lipid profile of the animals studied. The structure of the nanocapsule, as it contained lipids, worsened the lipid profile. Laboratory findings were consistent with histopathological findings.