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From molecules to manufacture : an analytical portfolio definition for enhanced Dry Powder Inhaler (DPI) screening
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A administração terapêutica de fármacos por inalação desempenha um papel fundamental no tratamento de doenças respiratórias, sendo os inaladores de pó seco um dos principais sistemas de administração. A otimização das formulações para inalação requer um conhecimento avançado das várias interações entre partículas, de modo a maximizar a deposição nos alvéolos pulmonares. Este estudo desenvolveu uma abordagem analítica para prever o desempenho aerodinâmico, analisando atributos-chave da formulação, como o tamanho das partículas, a energia de superfície, a agregação e a dinâmica de desaglomeração. Foi desenvolvida uma nova metodologia de Calorimetria de Solução (Solcal) para avaliar a coesão das partículas, demonstrando que a entalpia de dissolução é um preditor da fração de partículas finas (FPF). Para além disso, foi desenvolvido um modelo matemático que correlaciona, com elevada precisão, as propriedades das partículas e formulações com o desempenho aerodinâmico para sistemas homogéneos (um componente) Os resultados demonstraram que a concentração de ingrediente farmacêutico ativo e o teor de excipientes finos influenciam significativamente a performance aerodinâmica, com concentrações ótimas de excipientes finos a favorecer a desaglomeração até a um limite, que a partir do qual a coesão entre partículas prejudica a performance. As técnicas de engenharia de partículas, como a micronização por jet-milling e o wet-polishing, modificaram as forças de adesão e as propriedades de dispersão. Além disso, a incorporação de leucina em formulações sem carreador melhorou a dispersão e a performance aerodinâmica, reduzindo a coesão e estabilizando a energia de superfície. Este estudo desenvolveu um modelo preditivo e metodologias analíticas para otimizar formulações de DPIs. Estudos futuros deverão incluir a melhoria do modelo, através da inclusão de fatores específicos que tenham em conta o inalador e formulações mais complexas, contribuindo para o desenvolvimento de sistemas inovadores de administração pulmonar de fármacos.
The therapeutic administration of inhaled drugs plays a crucial role in treating respiratory disorders, with dry powder inhalers (DPIs) being a widely used delivery system. However, optimizing DPI formulations requires a comprehensive understanding of their composition and behavior to enhance drug deposition efficiency in the lungs. This study aimed to develop an analytical framework capable of predicting the aerodynamic performance of DPI formulations by investigating key formulation attributes, including particle size, surface energy, aggregation behavior, and de-agglomeration dynamics. A novel Solution Calorimetry (Solcal) methodology was introduced to assess particle cohesion, demonstrating that dissolution enthalpy is a reliable predictor of fine particle fraction (FPF). Additionally, a mathematical model correlating particle and formulation properties with aerodynamic performance was developed, showing high accuracy for single-component formulations. Key findings indicated that drug load and excipient content significantly impact dispersion efficiency, with optimal fine excipient concentrations enhancing de-agglomeration up to a threshold beyond which cohesion reduced performance. Particle engineering techniques, such as jet milling and wet polishing, were found to influence adhesion forces and dispersion properties. Furthermore, carrier-free formulations incorporating leucine improved particle dispersion and lung deposition by reducing cohesion and stabilizing surface energy. This study successfully established predictive models and analytical methodologies to support DPI formulation optimization. Future research should focus on refining these models to account for device-specific factors and other drug models, further advancing inhaled drug delivery systems.
The therapeutic administration of inhaled drugs plays a crucial role in treating respiratory disorders, with dry powder inhalers (DPIs) being a widely used delivery system. However, optimizing DPI formulations requires a comprehensive understanding of their composition and behavior to enhance drug deposition efficiency in the lungs. This study aimed to develop an analytical framework capable of predicting the aerodynamic performance of DPI formulations by investigating key formulation attributes, including particle size, surface energy, aggregation behavior, and de-agglomeration dynamics. A novel Solution Calorimetry (Solcal) methodology was introduced to assess particle cohesion, demonstrating that dissolution enthalpy is a reliable predictor of fine particle fraction (FPF). Additionally, a mathematical model correlating particle and formulation properties with aerodynamic performance was developed, showing high accuracy for single-component formulations. Key findings indicated that drug load and excipient content significantly impact dispersion efficiency, with optimal fine excipient concentrations enhancing de-agglomeration up to a threshold beyond which cohesion reduced performance. Particle engineering techniques, such as jet milling and wet polishing, were found to influence adhesion forces and dispersion properties. Furthermore, carrier-free formulations incorporating leucine improved particle dispersion and lung deposition by reducing cohesion and stabilizing surface energy. This study successfully established predictive models and analytical methodologies to support DPI formulation optimization. Future research should focus on refining these models to account for device-specific factors and other drug models, further advancing inhaled drug delivery systems.
Descrição
Tese de doutoramento em Bioquímica (Bioquímica Farmacêutica e Toxicológica), Universidade de Lisboa, Faculdade de Ciências, 2025.
Palavras-chave
DPIs aerodynamic performance de-agglomeration model pós seco para inalação performance desaglomeração modelo