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Previous issue date: 2010-02-26 / According to the global framework regarding new cases of tuberculosis, Brazil
appears at the 18th place. Thus, the Ministry of Health has defined this disease as a
priority in the governmental policies. As a consequence, studies concerning
treatment and prevention have increased. Fixed-dose combination formulations
(FDC) are recognized as beneficial and are recommended by WHO, but they present
instability and loss on rifampicin bioavailability. The main purpose of this work was to
carry out a pre-formulation study with the schedule 1 tuberculosis treatment drugs:
rifampicin, isoniazid, pyrazinamide and ethambutol and pharmaceutical excipients
(lactose, cellulose, magnesium stearate and talc), in order to develop an FDC
product (150 mg of rifampicin + 75 mg of isoniazid + 400 mg of pyrazinamide + 250
mg of ethambutol). The studies consisted of the determination of particle size and
distribution (Ferret s diameter) and shape through optical microscopy, as well as
rheological and technological properties (bulk and tapped densities, Hausner Factor,
Carr s Index, repose angle and flux rate) and interactions among drugs and drug
excipient through thermal analysis (DSC, DTA, TG and your derivate). The results
showed that, except isoniazid, the other drugs presented poor rheological properties,
determined by the physical characteristics of the particles: small size and rod like
particles shape for rifampicin; rectangular shape for pyrazinamide and ethambutol,
beyond its low density. The 4 drug mixture also not presented flowability, particularly
that one containing drug quantity indicated for the formulation of FDC products. In
this mixture, isoniazid, that has the best flowability, was added in a lower
concentration. The addition of microcrystalline cellulose, magnesium stearate and
talc to the drug mixtures improved flowability properties. In DSC analysis probable
interactions among drugs were found, supporting the hypothesis of ethambutol and
pyrazinamide catalysis of the rifampicin-isoniazid reaction resulting in 3-
formylrifamycin isonicotinyl hydrazone (HYD) as a degradation product. In the
mixtures containing lactose Supertab? DSC curves evidenced incompatibility among
drugs and excipient. In the DSC curves of mixtures containing cellulose MC101?,
magnesium stearate and talc, no alterations were observed comparing to the drug
profiles. The TG/DTG of the binary and ternary mixtures curves showed different
thermogravimetrics profiles relating that observed to the drug isolated, with the
thermal decomposition early supporting the evidences of incompatibilities showed in
the DSC and DTA curves / De acordo com o quadro mundial da tuberculose, o Brasil ocupa o 18? lugar
em n?mero de casos novos, assim o Minist?rio da Sa?de definiu a doen?a como
prioridade entre as Pol?ticas Governamentais de Sa?de. Desde ent?o se
intensificaram os estudos relacionados ao tratamento e preven??o desta doen?a. As
formula??es em dose fixa combinada (DFC) s?o reconhecidas como ben?ficas e
apoiadas pela OMS, mas apresentam problemas de instabilidade e queda na
biodisponibilidade da rifampicina. O objetivo principal desse trabalho foi realizar
estudo de pr?-formula??o com os f?rmacos que integram o esquema 1 para o
tratamento da tuberculose: rifampicina, isoniazida, pirazinamida e etambutol e
excipientes farmac?uticos (lactose, celulose, estearato de magn?sio e talco),
visando o desenvolvimento de um produto em dose fixa combinada (150 mg de
rifampicina + 75 mg de isoniazida + 400 mg de pirazinamida + 250 mg de
etambutol). Os estudos consistiram na determina??o do tamanho e distribui??o das
part?culas (di?metro de Ferret) e forma por microscopia ?ptica, al?m das
propriedades reol?gicas e tecnol?gicas (densidades aparente e de compacta??o,
Fator de Hausner, ?ndice de Carr, ?ngulo de repouso e velocidade de escoamento) e
das intera??es entre os f?rmacos e f?rmacos-excipientes por an?lise t?rmica (DSC,
DTA, TG e sua derivada). Os resultados mostraram que ? exce??o da isoniazida, os
demais f?rmacos apresentaram propriedades reol?gicas pobres, determinadas pelas
caracter?sticas f?sicas das part?culas: tamanho reduzido e forma de agulhas da
rifampicina; forma retangular da pirazinamida e etambutol, al?m da baixa densidade
deste ?ltimo. A mistura dos quatro ativos tamb?m n?o apresentou fluxo,
especialmente a prepara??o contendo a quantidade de f?rmacos preconizada para a
formula??o de produtos em dose fixa combinada, uma vez que nessa mistura, a
isoniazida, que possui o melhor fluxo, foi adicionada a uma concentra??o menor. A
adi??o de celulose microcristalina, estearato de magn?sio e talco ?s misturas dos
f?rmacos, melhorou as propriedades de fluxo. Nas an?lises por DSC foram
encontradas prov?veis intera??es entre as subst?ncias ativas, refor?ando a hip?tese
de cat?lise por etambutol e pirazinamida para a rea??o entre rifampicina e isoniazida
que resulta no produto de degrada??o 3-(isonicotinoilhidrazinometil)rifamicina. Nas
curvas de DSC das misturas contendo lactose Supertab? foi evidenciada a
ocorr?ncia de incompatibilidade entre os f?rmacos e o excipiente. As curvas de DSC
das misturas contendo celulose MC101?, estearato de magn?sio e talco n?o
apresentaram altera??es em rela??o ao perfil dos f?rmacos. As curvas de TG/DTG
das misturas bin?rias e tern?rias apresentaram perfis termogravim?tricos diferentes
em rela??o ao observado para os f?rmacos isoladamente, com in?cio da
decomposi??o t?rmica antecipada, dando suporte as evid?ncias de
incompatibilidades encontradas nas curvas de DSC e DTA
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/13458 |
| Date | 26 February 2010 |
| Creators | Lavor, Edilene Pereira |
| Contributors | CPF:13138863434, http://lattes.cnpq.br/4452581275123481, Arag?o, C?cero Fl?vio Soares, CPF:62001728468, http://lattes.cnpq.br/9657118649043311, Macedo, Rui Oliveira, CPF:16622553491, http://lattes.cnpq.br/8326594695097434, Moura, T?lio Fl?vio Accioly Lima e |
| Publisher | Universidade Federal do Rio Grande do Norte, Programa de P?s-Gradua??o em Ci?ncias Farmac?uticas, UFRN, BR, Bioan?lises e Medicamentos |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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