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Previous issue date: 2013-02-28 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / The benznidazole (BNZ) is the only alternative for Chagas disease
treatment in Brazil. This drug has low solubility, which restricts its dissolution
rate. Thus, the present work aimed to study the BNZ interactions in binary
systems with beta cyclodextrin (?-CD) and hydroxypropyl-beta cyclodextrin
(HP-?-CD), in order to increase the apparent aqueous solubility of drug. The
influence of seven hydrophilic polymers, triethanolamine (TEA) and 1-methyl-2-
pyrrolidone (NMP) in benznidazole apparent aqueous solubility, as well as the
formation of inclusion complexes was also investigated. The interactions in
solution were predicted and investigated using phase solubility diagram
methodology, nuclear magnetic resonance of protons (RMN) and molecular
modeling. Complexes were obtained in solid phase by spray drying and
physicochemical characterization included the UV-Vis spectrophotometric
spectroscopy in the infrared region, scanning electron microscopy, X-ray
diffraction and dissolution drug test from the different systems. The increment
on apparent aqueous solubility of drug was achieved with a linear type (AL) in
presence of both cyclodextrins at different pH values. The hydrophilic polymers
and 1-methyl-2-pyrrolidone contributes to the formation of inclusion complexes,
while the triethanolamine decreased the complex stability constant (Kc). The
log-linear model applied for solubility diagrams revealed that both
triethanolamine and 1-methyl-2-pyrrolidone showed an action cosolvent (both
solvents) and complexing (1-methyl-2-pyrrolidone). The best results were
obtained with complexes involving 1-methyl-2-pyrrolidone and hydroxypropylbeta-
cyclodextrin, with an increased of benznidazole solubility in 27.9 and 9.4
times, respectively. The complexes effectiveness was proven by dissolution
tests, in which the ternary complexes and physical mixtures involving 1-methyl-
2-pyrrolidone and both cyclodextrins investigated showed better results,
showing the potential use as novel pharmaceutical ingredient, that leads to
increased benznidazole bioavailability / A doen?a de Chagas tem como ?nica alternativa para tratamento, no Brasil, o
benznidazol (BNZ). Este f?rmaco possui baixa solubilidade, o que restringe sua
velocidade de dissolu??o. Diante disto, o presente trabalho teve como objetivo
o estudo das intera??es do BNZ em sistemas bin?rios com a beta-ciclodextrina
(?-CD) e a hidroxipropil-beta-ciclodextrina (HP-?-CD), com o intuito de
aumentar a solubilidade aquosa do f?rmaco. A influ?ncia de sete pol?meros
hidrof?licos, da trietanolamina (TEA) e da metil-1-pirrolidona-2 (NMP) na
solubilidade aquosa aparente do benznidazol, assim como na forma??o dos
complexos de inclus?o, tamb?m foi investigada. As intera??es em solu??o
foram previstas e investigadas usando os diagramas de solubilidade de fases,
espectroscopia de ressonancia magn?tica nuclear de pr?tons (RMN) e
modelagem molecular. Diferentes complexos foram obtidos em fase s?lida por
secagem por atomiza??o em aparelho de spray dryer e a caracteriza??o
f?sico-qu?mica destes incluiu a espectrofotometria UV-Vis, a espectroscopia na
regi?o do infravermelho, a microscopia eletr?nica de varredura, a difra??o de
raios-X e os ensaios de dissolu??o do f?rmaco a partir das diferentes amostras.
O aumento da solubilidade aquosa aparente do f?rmaco foi alcan?ada de forma
linear (perfil AL) na presen?a de ambas as ciclodextrinas em diferentes valores
de pH. A presen?a dos pol?meros hidrof?licos e da metil-1-pirrolidona-2 contribui
para a estabiliza??o dos complexos formados, enquanto a trietanolamina
diminuiu a constante de estabilidade (Kc) dos complexos formados. O modelo
do log linear aplicado aos diagramas de solubilidade revelou que a
trietanolamina e a metil-1-pirrolidona-2 mostraram uma a??o cossolvente
(ambos solventes) e complexante (metil-1-pirrolidona-2). Os melhores
resultados foram obtidos com os complexos envolvendo a metil-1-pirrolidona-2
e a hidroxipropil-beta-ciclodextrina, com um aumento de solubilidade do
f?rmaco em 27,9 e 9,4 vezes, respectivamente. A efic?cia dos complexos foi
comprovada pelos ensaios de dissolu??o, nos quais os complexos tern?rios e
misturas f?sicas envolvendo a metil-1-pirrolidona-2 e as ciclodextrinas
investigadas apresentaram os melhores resultados, demonstrando a
possibilidade de uso como um novo insumo farmac?utico, que leve ao aumento
da biodisponibilidade do benznidazol / 2020-01-01
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/13488 |
| Date | 28 February 2013 |
| Creators | Melo, Polyanne Nunes de |
| Contributors | CPF:00840406452, http://lattes.cnpq.br/2593509584288129, Pereira, M?rcia Rodrigues, CPF:83115951787, http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4788568T8, Silva J?nior, Arn?bio Ant?nio |
| 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/embargoedAccess |
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