Simulações em computador aplicadas ao desenvolvimento de suspensões de uso oral contendo fexofenadina
Data
2021-08-25
Autores
Ferreira, Marina Machado da Mata 
Orientadores
Duque, Marcelo Dutra
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A fexofenadina é fármaco empregado em tratamentos de estados alérgicos, pertencente à classe IV do Sistema de Classificação Biofarmacêutica. O presente trabalho teve como objetivo avaliar a influência da dissolução na absorção e a bioequivalência em população virtual simulada, de formulações de suspensões pediátricas de uso oral contendo fexofenadina, por meio de simulações em computador. Foram preparadas quatro formulações contendo 0,6 % de fexofenadina, 0,25% de carboximetilcelulose sódica e água purificada, sendo que a F1 continha apenas essa composição. Além destes componentes, o propilenoglicol (PPG) e o lauril sulfato de sódio (LSS) também foram empregados em F2 (5% de PPG), F3 (0,02% de LSS) e F4 (5% PPG + 0,02% de LSS). O percentual de fexofenadina dissolvida em 45 minutos de ensaio de dissolução foi de 51,52% (F1), 77,57% (F2), 42,01% (F3) e 95,89% (F4). Utilizando simulações em computador por meio do programa GastroPlus®, um modelo farmacocinético de três compartimentos foi desenvolvido utilizando o módulo PKPlus™ empregando a curva plasmática do medicamento referência Allegra® pediátrico suspensão oral (Sanofi-Aventis Farmacêutica Ltda.), proveniente da literatura. O modelo de dissolução utilizado para descrever os perfis de dissolução foi o Z-factor. O modelo farmacocinético foi verificado por meio de ensaios de bioequivalência virtual simulada e comparação com dados in vivo da literatura, onde foi confirmada a adequabilidade do modelo. Após verificação do modelo, simulações das curvas plasmáticas das suspensões F1-F4 desenvolvidas, foram conduzidas, sendo possível estabelecer uma relação entre os perfis de dissolução com a absorção do fármaco. Além disso, foi construído um safe-space (espaço seguro) para os valores de Z-factor capaz de predizer o atendimento aos critérios de bioequivalência em perfis de dissolução com quantidade dissolvida de fexofenadina maior que 80% após 20 minutos. A formulação F4 demonstrou ser bioequivalente in silico ao medicamento referência Allegra® suspensão oral (Sanofi-Aventis Farmacêutica Ltda.), por meio de estudo de bioequivalência virtual.
Fexofenadine is a drug used in the treatment of seasonal allergies and it belongs to class IV on the Biopharmaceutical Classification System. The aim of this work was to evaluate the influence of dissolution on absorption and bioequivalence in a virtual population in formulations of fexofenadine pediatric suspensions for oral use using computer simulations. Four formulations were prepared containing 0.6% of fexofenadine, 0.25% sodium carboxymethylcellulose and purified water (F1 contained only this composition). In addition to these components, propylene glycol (PPG) and sodium lauryl sulfate (LSS) were also used in F2 (5% PPG), F3 (0.02% LSS), and F4 (5% PPG + 0.02% of LSS). The percentage of fexofenadine dissolved in 45 minutes of dissolution test were 51.52% (F1), 77.57% (F2), 42.01% (F3), and 95.89% (F4). A three-compartment pharmacokinetic model was developed using the PKPlus™ module in the GastroPlus® software, based on the plasma concentration-time curve from the literature of the reference drug product Allegra® oral pediatric suspension (Sanofi-Aventis Farmacêutica Ltda.). Z-factor was the dissolution model used to describe the dissolution profiles. The pharmacokinetic model was verified by running virtual bioequivalence studies and by comparison with in vivo data from the literature, where the suitability of the model was confirmed. After verifying the model, simulations of the plasma concentration-time curves of the F1-F4 suspensions developed, were carried out, making it possible to establish a correlation between the dissolution profiles and drug absorption. Additionally, a safe-space for the Z-factor values capable to predict the bioequivalence criteria from the dissolution profiles with percent dissolved of fexofenadine greater than 80% in 20 minutes. Formulation F4 proved to be in silico bioequivalent to the reference drug product Allegra® oral suspension (Sanofi-Aventis Farmacêutica Ltda.), tested using a virtual bioequivalence study.
Fexofenadine is a drug used in the treatment of seasonal allergies and it belongs to class IV on the Biopharmaceutical Classification System. The aim of this work was to evaluate the influence of dissolution on absorption and bioequivalence in a virtual population in formulations of fexofenadine pediatric suspensions for oral use using computer simulations. Four formulations were prepared containing 0.6% of fexofenadine, 0.25% sodium carboxymethylcellulose and purified water (F1 contained only this composition). In addition to these components, propylene glycol (PPG) and sodium lauryl sulfate (LSS) were also used in F2 (5% PPG), F3 (0.02% LSS), and F4 (5% PPG + 0.02% of LSS). The percentage of fexofenadine dissolved in 45 minutes of dissolution test were 51.52% (F1), 77.57% (F2), 42.01% (F3), and 95.89% (F4). A three-compartment pharmacokinetic model was developed using the PKPlus™ module in the GastroPlus® software, based on the plasma concentration-time curve from the literature of the reference drug product Allegra® oral pediatric suspension (Sanofi-Aventis Farmacêutica Ltda.). Z-factor was the dissolution model used to describe the dissolution profiles. The pharmacokinetic model was verified by running virtual bioequivalence studies and by comparison with in vivo data from the literature, where the suitability of the model was confirmed. After verifying the model, simulations of the plasma concentration-time curves of the F1-F4 suspensions developed, were carried out, making it possible to establish a correlation between the dissolution profiles and drug absorption. Additionally, a safe-space for the Z-factor values capable to predict the bioequivalence criteria from the dissolution profiles with percent dissolved of fexofenadine greater than 80% in 20 minutes. Formulation F4 proved to be in silico bioequivalent to the reference drug product Allegra® oral suspension (Sanofi-Aventis Farmacêutica Ltda.), tested using a virtual bioequivalence study.