Simulações em computador aplicadas ao desenvolvimento de formulações farmacêuticas sólidas de uso oral contendo fexofenadina
Arquivos
Data
2021-08-23
Autores
Faturi, Amanda Isis de Souza [UNIFESP]
Orientadores
Duque, Marcelo Dutra [UNIFESP]
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A fexofenadina é um fármaco empregado em tratamentos de estados alérgicos. Pertence à classe 4 do Sistema de Classificação Biofarmacêutica, sendo, portanto, de baixa solubilidade e baixa permeabilidade, cuja absorção é ainda dependente de transportadores intestinais como OATP e P-gp. Considerando a complexidade envolvida no seu processo de absorção e a existência, atualmente, de ferramentas computacionais para prever a dissolução e a absorção de fármacos, o objetivo deste estudo foi desenvolver uma formulação de comprimidos de liberação imediata contendo 180 mg de cloridrato de fexofenadina por meio de métodos in silico, utilizando o programa de computador GastroPlus®, e realizar estudo de bioequivalência em população simulada. Foi desenvolvida uma formulação de comprimido de liberação imediata contendo 180 mg de fexofenadina. Comprimidos dessa formulação teste e o do medicamento referência Allegra® 180 mg foram submetidos ao ensaio de dissolução empregando aparato 2 a 50 rpm e 900 mL de HCl 0,001M a 37°C. Um modelo farmacocinético de três compartimentos foi desenvolvido no GastroPlus® e verificado com dados da literatura. O modelo de dissolução Z-factor, disponível no GastroPlus®, foi utilizado para calcular os valores desse parâmetro, os quais permitiram ao programa diferenciar entre as formulações e perfis de dissolução. As curvas plasmáticas simuladas utilizando os valores de Z-factor para o medicamento referência e a formulação teste apresentaram valores dos parâmetros farmacocinéticos próximos aos da curva plasmática do medicamento Allegra® 180 mg proveniente da literatura. Por meio de estudo de bioequivalência virtual, foi demonstrada a bioequivalência entre a formulação teste e o medicamento referência Allegra® 180 mg com intervalo de confiança de 90% para o Cmax e ASC entre o intervalo de 80-125%. Dessa forma, foi possível, por meio de simulações em computador, desenvolver uma formulação de comprimidos de liberação imediata contendo 180 mg de fexofenadina, bioequivalente ao medicamento referência quando testada em população simulada.
Fexofenadine is a drug used in treatments of allergic states. It belongs to class 4 of the Biopharmaceutical Classification System, being therefore of low solubility and low permeability, and which intestinal absorption is also dependent on intestinal transporters such as OATP and P-gp. Considering the complexity involved on its absorption process and the existence, currently, of computational methods to predict the dissolution and absorption of drugs, the aim of this study was to develop one formulation of immediate-release tablets containing 180 mg of fexofenadine by in silico methods, using the GastroPlus® computer program, and run a bioequivalence study in a simulated population. An immediate release tablet formulation containing 180 mg of fexofenadine was developed. Tablets of this test formulation and Allegra® 180 mg were submitted to dissolution test using apparatus 2 at 50 rpm and 900 mL of 0.001M HCl at 37°C. A three-compartment pharmacokinetic model was developed in the GastroPlus® and verified with literature data. The Z-factor dissolution model, available in the software, was used to calculate the values of this parameter, which allowed the program to differentiate between formulations and dissolution profiles. The simulated plasma curves using the Z-factor values for the reference product and the test formulation showed pharmacokinetic parameter values close to those of the plasma curve for the drug Allegra® 180 mg from the literature. Through a virtual bioequivalence study, the bioequivalence between the test formulation and the reference product Allegra® 180 mg was demonstrated, with a 90% confidence interval for Cmax and AUC between the interval of 80-125%. Thus, it was possible, through computer simulations, to develop an immediate-release tablet formulation containing 180 mg of fexofenadine, bioequivalent to the reference drug when tested in a simulated population.
Fexofenadine is a drug used in treatments of allergic states. It belongs to class 4 of the Biopharmaceutical Classification System, being therefore of low solubility and low permeability, and which intestinal absorption is also dependent on intestinal transporters such as OATP and P-gp. Considering the complexity involved on its absorption process and the existence, currently, of computational methods to predict the dissolution and absorption of drugs, the aim of this study was to develop one formulation of immediate-release tablets containing 180 mg of fexofenadine by in silico methods, using the GastroPlus® computer program, and run a bioequivalence study in a simulated population. An immediate release tablet formulation containing 180 mg of fexofenadine was developed. Tablets of this test formulation and Allegra® 180 mg were submitted to dissolution test using apparatus 2 at 50 rpm and 900 mL of 0.001M HCl at 37°C. A three-compartment pharmacokinetic model was developed in the GastroPlus® and verified with literature data. The Z-factor dissolution model, available in the software, was used to calculate the values of this parameter, which allowed the program to differentiate between formulations and dissolution profiles. The simulated plasma curves using the Z-factor values for the reference product and the test formulation showed pharmacokinetic parameter values close to those of the plasma curve for the drug Allegra® 180 mg from the literature. Through a virtual bioequivalence study, the bioequivalence between the test formulation and the reference product Allegra® 180 mg was demonstrated, with a 90% confidence interval for Cmax and AUC between the interval of 80-125%. Thus, it was possible, through computer simulations, to develop an immediate-release tablet formulation containing 180 mg of fexofenadine, bioequivalent to the reference drug when tested in a simulated population.