Desenvolvimento de comprimidos de liberação imediata contendo amiodarona por meio de simulações em computador
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Data
2021-07-21
Autores
Santos, Juliane Cristina Mercadante dos [UNIFESP]
Orientadores
Duque, Marcelo Dutra [UNIFESP]
Tipo
Dissertação de mestrado
Título da Revista
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Resumo
A amiodarona é relatada na literatura como um fármaco pertencente à classe II do Sistema de Classificação Biofarmacêutica. O objetivo desse trabalho foi empregar a tecnologia de simulações em computador por meio do uso do programa GastroPlus® no desenvolvimento de comprimidos de liberação imediata contendo cloridrato de amiodarona. Inicialmente, foram realizados ensaios de solubilidade do fármaco em função do pH. Foi construído no programa, um modelo farmacocinético baseado em fisiologia (PBPK), utilizando dados de administração intravenosa da amiodarona provenientes da literatura. Tal modelo foi verificado empregando outros dados intravenosos da literatura e aplicado a dados de administração via oral, sendo obtida uma equação de relação in vitro-in vivo. A qual foi utilizada para prever a dissolução in vivo do medicamento Cordarone® 200 mg e para estimar o perfil de dissolução in vitro alvo. Foi desenvolvida uma formulação teste de comprimidos de liberação imediata contendo 200 mg de amiodarona que apresentou perfil de dissolução in vitro semelhante ao do Cordarone® 200 mg. Após a realização de um estudo de bioequivalência do tipo cruzada em população virtual no GastroPlus®, a formulação teste se apresentou bioequivalente in sílico ao medicamento Cordarone® 200 mg. Foi possível, dessa forma, desenvolver uma formulação de comprimidos de liberação imediata contendo 200 mg de amiodarona bioequivalente in sílico ao medicamento referência, com uma avaliação detalhada da absorção do fármaco.
Amiodarone is reported in the literature as a drug that belongs to class II of the Biopharmaceutical Classification System. The objective of this work was to employ computer simulation technology through the use of the GastroPlus® program in the development of immediate release tablets containing amiodarone hydrochloride. Initially, drug solubility tests were performed as a function of pH. A physiology-based pharmacokinetic model (PBPK) was built in the program, using data from the intravenous administration of amiodarone from the literature. This model was verified using other intravenous data from the literature and applied to data from oral administration, obtaining an in vitro-in vivo relationship equation. Which was used to predict the in vivo dissolution of the Cordarone® 200 mg drug and to estimate the target in vitro dissolution profile. A test formulation of immediate-release tablets containing 200 mg of amiodarone was developed and presented an in vitro dissolution profile similar to that of Cordarone® 200 mg. After conducting a cross-type bioequivalence study in a virtual population in GastroPlus®, the test formulation was found to be bioequivalent to the drug Cordarone® 200 mg. Thus, it was possible to develop a formulation of immediate-release tablets containing 200 mg of amiodarone in silico bioequivalent to the reference drug, with a detailed assessment of the drug's absorption.
Amiodarone is reported in the literature as a drug that belongs to class II of the Biopharmaceutical Classification System. The objective of this work was to employ computer simulation technology through the use of the GastroPlus® program in the development of immediate release tablets containing amiodarone hydrochloride. Initially, drug solubility tests were performed as a function of pH. A physiology-based pharmacokinetic model (PBPK) was built in the program, using data from the intravenous administration of amiodarone from the literature. This model was verified using other intravenous data from the literature and applied to data from oral administration, obtaining an in vitro-in vivo relationship equation. Which was used to predict the in vivo dissolution of the Cordarone® 200 mg drug and to estimate the target in vitro dissolution profile. A test formulation of immediate-release tablets containing 200 mg of amiodarone was developed and presented an in vitro dissolution profile similar to that of Cordarone® 200 mg. After conducting a cross-type bioequivalence study in a virtual population in GastroPlus®, the test formulation was found to be bioequivalent to the drug Cordarone® 200 mg. Thus, it was possible to develop a formulation of immediate-release tablets containing 200 mg of amiodarone in silico bioequivalent to the reference drug, with a detailed assessment of the drug's absorption.