Influência do omeprazol sobre processos de dissolução e desintegração gástrica de comprimidos pH-dependente
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2020-03-12
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Universidade Estadual Paulista (Unesp)
Resumo
A via oral de administração de fármacos é a mais utilizada devido a maior aceitação pelo paciente e sua fácil administração. Dentre as estratégias de sistema de liberação de fármacos estão os comprimidos revestidos com polímero pH-dependente, da qual o Eudragit E-100 é um polímero de revestimento protetor solúvel em pH <5, utilizado em formas farmacêuticas sólidas para liberação do fármaco no ambiente gástrico. Para que ocorra a liberação do fármaco é necessário que o comprimido revestido passe por processos que antecedem a absorção, tal como a dissolução do revestimento e desintegração. Sendo assim, se ocorrer mudanças no pH fisiológico o processo de dissolução do revestimento gastrossolúvel pode ser comprometido e consequentemente alterar a biodisponibilidade do fármaco. Diante deste cenário, é de grande importância realizar pesquisas que explorem a influencia do aumento do pH gástrico na biodisponibilidade de um fármaco, contido em comprimido com revestimento pH-dependente administrado concomitantemente. Nesta proposta consiste em empregar a Magnetofarmacocinética (MgPK) para avaliar a influencia da alteração do pH gástrico provocado pelo tratamento com omeprazol no processo de liberação de um fármaco modelo administrado pela via oral em comprimidos revestidos com Eudragit® E-100. Foi produzido um lote de comprimidos magnéticos revestidos com Eudragit® E -100 contendo 500 mg de ferrita e 100 mg de metronidazol. O lote foi avaliado através de testes farmacotécnicos e avaliados segundo o perfil de dissolução. Para os experimentos in vivo, cada voluntário foi submetido a duas fases de estudos (placebo e omeprazol), em dias distintos, para avaliar a biodisponibilidade do metronidazol. Os sistemas BAC multissensor e monossensor foram empregados para a avaliação em tempo real in vivo o processo de desintegração do comprimido e avaliar os parâmetros de início da desintegração ou tempo de retenção. As curvas do perfil de dissolução do Metronidazol em função do tempo demostram um deslocamento à direita no eixo do tempo, na medida em que o pH da solução aumenta. Ao analisar os parâmetros farmacotécnicos observa-se que em pH 4,5 e pH 6,0 ocorreu um atraso na dissolução do Metronidazol, mostrando que o aumento do pH interfere nos processos de liberação de comprimidos revestidos com Eudragit® E-100. Nos ensaios in vitro com o sistema BAC, na medida em que o pH do meio de dissolução aumenta, o tempo necessário para pág. 9 dissolver o revestimento aumenta, confirmando que a dissolução do polímero de revestimento utilizado neste estudo é dependente do pH. Nas medidas magnéticas realizadas nos voluntários, foi possível identificar dois perfis distintos: um grupo de participantes (n = 5) nos quais não foi possível caraterizar o processo de desintegração no tratamento com omeprazol, e outro grupo (n = 7) nos quais o processo foi quantificado. Para os participantes elencados no grupo I (n=5), os parâmetros farmacocinéticos obtidos após a administração do omeprazol foram nulos, ou seja, não foi possível obter o perfil de concentração plasmática do metronidazol. Por outro lado, nos participantes elencados no grupo 2 (n=7), foi possível obter valores de tlag, tmax e Início da Desintegração com diferenças significativas, indicando um possível atraso na liberação do fármaco. A abordagem magnetofarmacocinética (MgPK) empregada neste estudo, de forma inédita, contribui para avaliar criticamente o comportamento de uma forma farmacêutica sólida frente a um meio complexo como o TGI do homem.
The oral route of drug administration is the most used due to the greater acceptance by the patient and its easy administration. Among the drug delivery system strategies are tablets coated with pH-dependent polymer, which aim to improve the stability of the drug, mask taste and odor. Eudragit E-100 is a protective coating polymer soluble at pH <5, used in solid dosage forms to release the drug into the gastric environment. For the drug to release, it is necessary that the coated tablet undergo processes that precede absorption, such as the dissolution of the coating and disintegration. Therefore, if changes in physiological pH occur, the dissolution process of the gas-soluble coating may be compromised and consequently change the bioavailability of the drug. In view of this scenario, it is of great importance to conduct research that explores the influence of the increase in gastric pH on the bioavailability of a drug, contained in a tablet with a pH-dependent coating administered concomitantly. In this proposal, it consists of using Magnetopharmacokinetics (MgPK) to evaluate the influence of gastric pH changes caused by treatment with omeprazole in the process of releasing a model drug administered orally in tablets coated with Eudragit® E-100. Batch of magnetic tablets coated with Eudragit® E-100 containing 100 mg of metronidazole was produced. The batch was evaluated through pharmacotechnical tests and evaluated according to the dissolution profile. For in vivo experiments, each volunteer underwent two phases of study (placebo and omeprazole), on different days, to assess the bioavailability of metronidazole. The multisensor and monosensor BAC systems were used for the real time in vivo evaluation of the tablet disintegration process and to evaluate the parameters of onset of disintegration or retention time. The batch of magnetic tablets containing ferrite and Metronidazole was approved in all quality control tests. The curves of the dissolution profile of Metronidazole as a function of time show a shift to the right on the time axis, as the pH of the solution increases. When analyzing the pharmacotechnical parameters, it is observed that at pH 4.5 and pH 6.0 there was a delay in the dissolution of Metronidazole, showing that the pH increase interferes in the release processes of the solid pharmaceutical form coated with Eudragit® E-100. In in vitro tests with the BAC system, as the pH of the dissolution medium increases, the time required to dissolve the coating increases, confirming that the dissolution of the coating polymer used in this study is dependent on pH. In the magnetic measurements performed on the volunteers, it was possible to identify two distinct profiles: a group of pág. 11 participants (n = 5) in whom it was not possible to characterize the disintegration process in the treatment with omeprazole, and another group (n = 7) in which the process has been quantified. For the participants listed in group I (n = 5), the pharmacokinetic parameters obtained after the administration of omeprazole were null, that, it was not possible to obtain the plasma concentration profile of metronidazole. On the other hand, in the participants listed in group 2 (n = 7), it was possible to obtain values of tlag, tmax and start of disintegration with significant differences, indicating a possible delay in the release of the drug. The magnetopharmacokinetic approach (MgPK) used in this study, in an unprecedented way, contributes to critically evaluate the behavior of a solid pharmaceutical form in face of a complex environment such as the human TGI.
The oral route of drug administration is the most used due to the greater acceptance by the patient and its easy administration. Among the drug delivery system strategies are tablets coated with pH-dependent polymer, which aim to improve the stability of the drug, mask taste and odor. Eudragit E-100 is a protective coating polymer soluble at pH <5, used in solid dosage forms to release the drug into the gastric environment. For the drug to release, it is necessary that the coated tablet undergo processes that precede absorption, such as the dissolution of the coating and disintegration. Therefore, if changes in physiological pH occur, the dissolution process of the gas-soluble coating may be compromised and consequently change the bioavailability of the drug. In view of this scenario, it is of great importance to conduct research that explores the influence of the increase in gastric pH on the bioavailability of a drug, contained in a tablet with a pH-dependent coating administered concomitantly. In this proposal, it consists of using Magnetopharmacokinetics (MgPK) to evaluate the influence of gastric pH changes caused by treatment with omeprazole in the process of releasing a model drug administered orally in tablets coated with Eudragit® E-100. Batch of magnetic tablets coated with Eudragit® E-100 containing 100 mg of metronidazole was produced. The batch was evaluated through pharmacotechnical tests and evaluated according to the dissolution profile. For in vivo experiments, each volunteer underwent two phases of study (placebo and omeprazole), on different days, to assess the bioavailability of metronidazole. The multisensor and monosensor BAC systems were used for the real time in vivo evaluation of the tablet disintegration process and to evaluate the parameters of onset of disintegration or retention time. The batch of magnetic tablets containing ferrite and Metronidazole was approved in all quality control tests. The curves of the dissolution profile of Metronidazole as a function of time show a shift to the right on the time axis, as the pH of the solution increases. When analyzing the pharmacotechnical parameters, it is observed that at pH 4.5 and pH 6.0 there was a delay in the dissolution of Metronidazole, showing that the pH increase interferes in the release processes of the solid pharmaceutical form coated with Eudragit® E-100. In in vitro tests with the BAC system, as the pH of the dissolution medium increases, the time required to dissolve the coating increases, confirming that the dissolution of the coating polymer used in this study is dependent on pH. In the magnetic measurements performed on the volunteers, it was possible to identify two distinct profiles: a group of pág. 11 participants (n = 5) in whom it was not possible to characterize the disintegration process in the treatment with omeprazole, and another group (n = 7) in which the process has been quantified. For the participants listed in group I (n = 5), the pharmacokinetic parameters obtained after the administration of omeprazole were null, that, it was not possible to obtain the plasma concentration profile of metronidazole. On the other hand, in the participants listed in group 2 (n = 7), it was possible to obtain values of tlag, tmax and start of disintegration with significant differences, indicating a possible delay in the release of the drug. The magnetopharmacokinetic approach (MgPK) used in this study, in an unprecedented way, contributes to critically evaluate the behavior of a solid pharmaceutical form in face of a complex environment such as the human TGI.
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Biosusceptometria AC, Comprimido revestido, Eudragit E-100, Inibidor de Bomba de Próton, Magnetofarmacocinética, AC Biosusceptometry, Coated tablet, Eudragit E-100, Proton Pump Inhibitor, Magnetopharmacokinetics