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Previous issue date: 2009-09-21 === Known for thousands of years, tuberculosis (TB) is the leading cause of mortality by a single infectious disease due to lack of patient adherence to available treatment regimens, the rising of multidrug resistant strains of TB (MDR-TB) and co-infection with HIV virus. Isoniazid and rifampicin are the most powerful bactericidal agents against M. tuberculosis. Because of that, this couple of drugs becomes unanimity in anti-TB treatment around the world. However, the rifampicin in acidic conditions in the stomach can be degraded rapidly, especially in the presence of isoniazid, which reduces the amount of available drug for absorption, as well as its bioavailability, contributing to the growing resistance to tuberculostatic drugs. Rifampicin is well absorbed in the stomach because of its high solubility between pH 1 and 2 and the gastric absorption of isoniazid is considered poor, therefore it is mostly intestinal. This work has as objective the development of gastro-resistant multiple-systems (granules and pellets) of isoniazid aiming to prevent the contact with rifampicin, with consequent degradation in acid stomach and modulate the release of isoniazid in the intestine. Granules of isoniazid were obtained by wet method using both alcoholic and aqueous solutions of PVP K-30 as aggregating and binder agent, at proportions of 5, 8 and 10%. The influence of the excipients (starch, cellulose or filler default) on the physical and technological properties of the granules was investigated. The pellets were produced by extrusionesferonization technique using isoniazid and microcrystalline cellulose MC 101 (at the proportion of 85:15) and aqueous solution of 1% Methocel as platelet. The pellets presented advantages over granular, such as: higher apparent density, smaller difference between apparent and compaction densities, smoother surface and, especially, smaller friability, and then were coated with an organic solution of Acrycoat L 100 ? in a fluidized bed. Different percentages of coating (15, 25 and 50%) were applied to the pellets which had their behavior evaluated in vitro by dissolution in acidic and basic medium. Rifampicin dissolution in the presence of uncoated and coated isoniazid pellets was evaluated too. The results indicate that the gastro resistance was only achieved with the greatest amount of coating and isoniazid is released successfully in basic step. The amount of rifampicin in the dissolution medium when the isoniazid pellets were not coated was lower than in the presence of enteric release pellets. Therefore, the polymer Acrycoat L 100 ? was efficient for coating with gastro-resistant function and can solve the problem of low bioavailability of rifampicin and help to reduce its dosage === Conhecida h? milhares de anos, a tuberculose (TB) ? a principal causa de mortalidade por uma ?nica doen?a infecciosa devido ? falta de ades?o dos pacientes aos esquemas terap?uticos dispon?veis, o aparecimento de cepas multiresistentes e a co-infec??o com o v?rus HIV. A isoniazida e a rifampicina possuem o maior poder bactericida frente ao M. tuberculosis, sendo por isso unanimidade no tratamento anti-TB em todo o mundo. No entanto, a rifampicina em condi??es ?cidas do est?mago degrada-se rapidamente, principalmente na presen?a da isoniazida, diminuindo a quantidade de f?rmaco dispon?vel para absor??o bem como a sua biodisponibilidade, contribuindo para a resist?ncia crescente aos f?rmacos tuberculost?ticos. A rifampicina ? bem absorvida no est?mago devido ? sua alta solubilidade entre pH 1 e 2 e a absor??o g?strica da isoniazida ? considerada pobre, sendo ent?o, majoritariamente intestinal. O presente trabalho teve como objetivo o desenvolvimento de sistemas multiparticulados (granulados e p?letes) de isoniazida gastrorresistentes visando evitar contato da rifampicina com isoniazida e conseq?ente degrada??o no meio ?cido estomacal bem como modular a libera??o da isoniazida no intestino. Granulados de isoniazida foram obtidos por via ?mida utilizando solu??o alco?lica e solu??o aquosa de PVP K-30 como agente agregante/aglutinante, nas propor??es 5, 8 e 10%. A influ?ncia do excipiente (amido, celulose ou aus?ncia de diluente) sobre as propriedades f?sicas e tecnol?gicas dos granulados foi investigada. Os p?letes foram produzidos pela t?cnica de extrus?o-esferoniza??o utilizando isoniazida e Celulose MC 101 (na propor??o 85:15) e solu??o aquosa de Methocel 1% como agregante. Os p?letes apresentaram vantagens em rela??o aos granulados, como: maior densidade aparente, menor diferen?a entre as densidades aparente e de compacta??o, superf?cie mais lisa e, principalmente, menor friabilidade, sendo ent?o revestidos com uma solu??o org?nica de Acrycoat L 100? em leito fluidizado. Diferentes percentuais de revestimento (15, 25 e 50%) foram aplicados aos p?letes, os quais tiveram seus comportamentos avaliados in vitro por dissolu??o em meio ?cido e b?sico. Em seguida, a dissolu??o da rifampicina em meio ?cido na presen?a da isoniazida em p?letes n?o revestidos e p?letes revestidos foi avaliada tamb?m. Os resultados indicam que a gastrorresist?ncia foi obtida somente com a maior quantidade de revestimento, sendo a isoniazida liberada com sucesso na etapa b?sica. A quantidade de rifampicina dissolvida quando associada a p?letes de isoniazida n?o revestidos foi menor do que a observada na presen?a de p?letes de libera??o ent?rica. O pol?mero Acrycoat L 100? mostrou-se eficiente para o recobrimento com a fun??o de gastrorresist?ncia, podendo resolver o problema da baixa biodisponibilidade da rifampicina assim como ajudar a diminuir a dosagem utilizada
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