Modelagem biofarmacêutica baseada em fisiologia aplicada ao desenvolvimento de comprimidos de liberação prolongada contendo cetoprofeno
Arquivos
Data
2022-07-20
Autores
Viezzer, Caio Domingues 
Orientadores
Duque, Marcelo Dutra
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Recentemente, vem havendo um aumento no emprego de métodos computacionais (in silico) para o desenvolvimento de medicamentos e/ou aplicações regulatórias. Entre os principais desafios encontrados pelas indústrias farmacêuticas, está o desenvolvimento de formas farmacêuticas de liberação prolongada que possam liberar o fármaco adequadamente. O objetivo deste trabalho foi construir um modelo biofarmacêutico baseado em fisiologia (PBBM) e aplicá-lo ao desenvolvimento de comprimidos de cetoprofeno (CTP) de liberação prolongada. Para isso, foi utilizado o programa de computador GastroPlus®. O modelo PBBM para o CTP foi construído usando dados farmacocinéticos, in silico e in vitro. Os perfis de dissolução in vitro de quatro formulações de comprimidos matriciais de liberação prolongada de CTP (FM1, FM2, FM3 e FM4) e do produto referência (Profenid® Retard 200 mg), bem como a curva de concentração plasmática deste, foram obtidos da literatura. Foi estabelecida relação in vitro-in vivo (RIVIV) para cada perfil de dissolução in vitro. FM1 exibiu o melhor valor de coeficiente de determinação (R2 = 0,809) na RIVIV. A composição desta formulação foi reproduzida no programa de computador DDDPlus™. Foram obtidos 25 perfis de dissolução virtuais (VT), correspondentes a variações da quantidade de hidroxipropilmetilcelulose (HPMC) K4M. O perfil VT1, que corresponde à formulação com 24,90 mg (5,38%) do polímero, foi o que mostrou maior R2 = 0,836 na RIVIV. Essa formulação foi submetida a um estudo de bioequivalência virtual, mostrando ser bioequivalente ao medicamento referência Profenid Retard® 200 mg no estado de jejum. Portanto, foi possível aplicar um modelo PBBM ao desenvolvimento de comprimidos de liberação prolongada contendo cetoprofeno, de forma a obter uma formulação bioequivalente ao medicamento referência, demonstrando o grande potencial desse tipo de tecnologia para as indústrias farmacêuticas.
Recently, there has been an increase in the use of computational methods (in silico) for drug development and/or regulatory applications. Among the main challenges faced by the pharmaceutical industries is the development of extended-release dosage forms that can release the drug properly. The purpose of this work was to build a physiologically based biopharmaceutics modeling (PBBM) and apply it in the development of extended-release ketoprofen (KTP) tablets. For this, the software GastroPlus® was used. A PBBM for KTP was constructed using pharmacokinetic data, both in silico and in vitro. The in vitro dissolution profiles of four KTP extended-release matrix tablet formulations (FM1, FM2, FM3 and FM4) and the reference product (Profenid® Retard 200 mg), as well as its plasma concentration curve, were obtained from literature. In vitro-in vivo relationship (IVIVR) was established for each in vitro dissolution profile. FM1 exhibited the best coefficient of determination value (R2 = 0.809) in IVIVR. The composition of this formulation was reproduced in the software DDDPlus™. Twenty five virtual dissolution (VT) profiles were obtained, corresponding to variations in the amount of hydroxypropyl methylcellulose (HPMC) K4M. The VT1 profile, which corresponds to the formulation with 24.90 mg (5.38%) of the polymer, was the one that showed the highest R2 = 0.836 in IVIVR. This formulation was submitted to a virtual bioequivalence study, showing to be bioequivalent to the reference drug Profenid Retard® 200 mg in the fasting state. In this way, it was possible to apply a PBBM to the development of extended-release tablets containing ketoprofen, in order to obtain a formulation that is bioequivalent to the reference drug, demonstrating the great potential of this type of technology for the pharmaceutical industries.
Recently, there has been an increase in the use of computational methods (in silico) for drug development and/or regulatory applications. Among the main challenges faced by the pharmaceutical industries is the development of extended-release dosage forms that can release the drug properly. The purpose of this work was to build a physiologically based biopharmaceutics modeling (PBBM) and apply it in the development of extended-release ketoprofen (KTP) tablets. For this, the software GastroPlus® was used. A PBBM for KTP was constructed using pharmacokinetic data, both in silico and in vitro. The in vitro dissolution profiles of four KTP extended-release matrix tablet formulations (FM1, FM2, FM3 and FM4) and the reference product (Profenid® Retard 200 mg), as well as its plasma concentration curve, were obtained from literature. In vitro-in vivo relationship (IVIVR) was established for each in vitro dissolution profile. FM1 exhibited the best coefficient of determination value (R2 = 0.809) in IVIVR. The composition of this formulation was reproduced in the software DDDPlus™. Twenty five virtual dissolution (VT) profiles were obtained, corresponding to variations in the amount of hydroxypropyl methylcellulose (HPMC) K4M. The VT1 profile, which corresponds to the formulation with 24.90 mg (5.38%) of the polymer, was the one that showed the highest R2 = 0.836 in IVIVR. This formulation was submitted to a virtual bioequivalence study, showing to be bioequivalent to the reference drug Profenid Retard® 200 mg in the fasting state. In this way, it was possible to apply a PBBM to the development of extended-release tablets containing ketoprofen, in order to obtain a formulation that is bioequivalent to the reference drug, demonstrating the great potential of this type of technology for the pharmaceutical industries.