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Desenvolvimento de um medicamento genérico através de engenharia reversa
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Orientador(es)
Resumo(s)
Apesar do avanço da tecnologia que observamos dentro da indústria farmacêutica e
da pressão por parte das autoridades responsáveis pela aprovação da autorização de
introdução no mercado, o desenvolvimento de genéricos ainda é baseado, na maioria
dos casos, em conhecimento empírico ou tentativa e erro invés do uso de métodos
robustos, lógicos e mais rápidos para a descoberta da formulação e do método de fabrico
do medicamento de referência.
Este trabalho surge da necessidade de desenvolver um destes métodos de
desenvolvimento de genéricos. Neste caso é usada a engenharia reversa e a
espectroscopia de infravermelho médio de modo a, com um delineamento experimental
metódico, analisar um conjunto de possíveis formulações e compará-las ao
medicamento de referência em estudo, neste caso, o Dermovate®, um creme de
propionato de clobetasol (0.5 mg/g). Este creme não possui a descrição completa da sua
formulação qualitativa em bibliografia, sendo uma das finalidades deste trabalho a
confirmação do tipo monoestearato de glicerilo e de álcool cetoestiarílico (ambos
excipientes com caracterização dúbia), assim como a sua formulação quantitativa. O
trabalho partiu de alguns estudos realizados previamente pelos Laboratórios Basi que
forneceram os dados relativos ao produto e as concentrações conhecidas de alguns
excipientes, assim como a produção de todas as formulações experimentais traçadas ao
longo do projeto. Estas formulações foram analisadas através de tecnologia FTIR,
caracterizando os dados recolhidos com análise visual e através de métodos
matemáticos como a aglomeração hierárquica.
Foi assim possível determinar, ao longo dos resultados, a composição qualitativa da
formulação em estudo (incluindo a caracterização dos excipientes em dúvida) assim
como a concentração em que os diferentes excipientes se encontram no creme. Esta
abordagem mostrou-se assim um método eficaz, robusto e rápido na formulação de
genéricos, permitindo a melhor justificação da formulação em contexto do dossier de
AIM perante as entidades competentes, podendo assim ser aplicado a outras
substâncias, assim como a outras formas farmacêuticas.
Despite all the technological advances seen in the pharmaceutical industry and the pressure from the regulatory authorities that are responsible for market introduction authorization approval, the development of generic drugs is still based on either empiric knowledge or on try and error methods instead of the use of robust, logical, and faster methods for formulation and fabrication method development. This work was developed based on the necessity of improving one of this development methods for generic drugs. In this case, reversed engineering along with near infrared spectroscopy and tools for design of experiences were used to analyze several experimental formulations and to compare them to the reference drug, Dermovate®, a cream of clobetasol propionate (0.5 mg/g). This drug is not well described (qualitative or quantitative) in any literature, so, one of the objectives of this work is to characterize the grade of glycerol monostearate and cetostearyl alcohol and quantify every excipient in the formulation studied during the research stage of this thesis. This project was based on studies performed by “Laboratórios Basi”, who gave us all the data needed relative to the drug and some known concentrations of the final drug formulation, and the production of all the experimental formulations designed during the project. These formulations were analyzed with FTIR technology, reading the obtained data with visual analyses and with mathematical methods like cluster analyses. With this method, it was possible to confirm, based on the acquired results, the qualitative composition of this formulation (including the characterization of the dubious excipients grades) and to determine the concentration of all the excipients present in the reference drug. So, this approach showed to be a fast and robust method in the development of generic drugs, allowing for a better foundation when justifying the obtained formulation, in the AIM dossier, to the competent authorities, and giving ground to the premise that this method should be used in the development of other drugs and pharmaceutical forms.
Despite all the technological advances seen in the pharmaceutical industry and the pressure from the regulatory authorities that are responsible for market introduction authorization approval, the development of generic drugs is still based on either empiric knowledge or on try and error methods instead of the use of robust, logical, and faster methods for formulation and fabrication method development. This work was developed based on the necessity of improving one of this development methods for generic drugs. In this case, reversed engineering along with near infrared spectroscopy and tools for design of experiences were used to analyze several experimental formulations and to compare them to the reference drug, Dermovate®, a cream of clobetasol propionate (0.5 mg/g). This drug is not well described (qualitative or quantitative) in any literature, so, one of the objectives of this work is to characterize the grade of glycerol monostearate and cetostearyl alcohol and quantify every excipient in the formulation studied during the research stage of this thesis. This project was based on studies performed by “Laboratórios Basi”, who gave us all the data needed relative to the drug and some known concentrations of the final drug formulation, and the production of all the experimental formulations designed during the project. These formulations were analyzed with FTIR technology, reading the obtained data with visual analyses and with mathematical methods like cluster analyses. With this method, it was possible to confirm, based on the acquired results, the qualitative composition of this formulation (including the characterization of the dubious excipients grades) and to determine the concentration of all the excipients present in the reference drug. So, this approach showed to be a fast and robust method in the development of generic drugs, allowing for a better foundation when justifying the obtained formulation, in the AIM dossier, to the competent authorities, and giving ground to the premise that this method should be used in the development of other drugs and pharmaceutical forms.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Engenharia reversa Espectroscopia de infravermelho Forma farmacêutica semissólida Monoestearato de glicerilo Álcool cetoestiarílico Mestrado integrado - 2021