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Compounded orodispersible films for rare paediatric diseases
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A deficiência da enzima estudada neste projeto é devida a um erro autossómico recessivo congénito que resulta em encefalopatia epilética nos estadios iniciais do recém-nascido tornando esses doentes dependentes da terapia com o fármaco X. Consequentemente, a terapêutica atual centra-se nos suplementos de fármaco X, o que pode pôr em causa a qualidade do tratamento dos doentes, uma vez que a sua regulamentação não é tão rigorosa como a da indústria farmacêutica, refletindo-se numa falta de qualidade generalizada. Os filmes orodispersíveis (ODF) são uma alternativa aos comprimidos e cápsulas tradicionais destinados a desintegrar-se rapidamente na cavidade oral. Esta investigação tem como objetivo desenvolver ODFs de fármaco X com diferentes doses de fármaco utilizando a base Orphyllo™ para otimizar o tratamento desta doença na população pediátrica. Os filmes desenvolvidas foram caracterizadas por inspeção visual, microscopia eletrónica de varrimento (SEM), calorimetria de varrimento diferencial (DSC), difração de raios X (XRD), espetroscopia de infravermelhos com transformada de Fourier (FT-IR) e análise de termogravimetria (TGA). Foi efetuado um estudo de libertação do fármaco, bem como um estudo de desintegração utilizando um modelo de cavidade oral (OCM) e carga de fármaco. Foi efetuada a otimização das amostras e foram desenvolvidos filmes contendo o agente complexante para melhorar a solubilidade do fármaco X. Para mascarar o sabor amargo, foi adicionada sucralose à formulação. Os ODFs apresentavam duas texturas em cada lado, uma superfície rugosa e uma superfície lisa. Os ODFs contendo o agente complexante foram as únicas amostras que apresentaram um aspeto liso em ambas as superfícies com uma textura quebradiça. A carga de fármaco apresentou resultados próximos de 100%. A caraterização físico-química mostrou a incorporação bem sucedida do fármaco X nos filmes na sua forma cristalina, quando o agente complexante não foi adicionado, e na sua forma amorfa, quando o agente complexante estava presente. A adição do agente complexante melhorou a solubilidade do fármaco X, o que, consequentemente, resultou numa melhoria do perfil de libertação do fármaco e do tempo de desintegração do filme.
The deficiency of a specific enzyme is characterised as an autosomal recessive inborn error which results in epileptic encephalopathy in the early new-born stages. Patients with this disease are chronically dependent on therapy with drug X. However, no marketing authorisation is available for this drug, and current therapies are centred on drug X supplements, with suboptimal quality, as their regulation is not as strict as the one applied by the pharmaceutical industry, leading to dose inaccuracy. Orodispersible films (ODFs) are proposed as an alternative to tablets and capsules as they disintegrate rapidly in the oral cavity when they come in contact with saliva without chewing or water. Orphyllo™ is a ready-to-use base that is intended to be easily adaptable to various APIs and used in compounding in pharmacies. This research aimed to develop drug X ODFs with different drug loadings using Orphyllo™ base to optimise the treatment for the paediatric population with this disease. The developed films were characterised by visual inspection, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR) and thermogravimetry analysis (TGA). A drug release study was conducted as well as a disintegration study using an oral cavity model (OCM), and drug loading. Optimisation of the samples was conducted, and films containing the complexing agent were developed to improve the solubility of drug X. To mask the bitter taste, sucralose was added to the formulation. ODFs displayed two textures on each side, a rough surface, and a smooth surface. ODFs containing the complexing agent were the only samples presenting a smooth appearance on both surfaces with a brittle texture. Drug loading presented results close to 100%. Physicochemical characterisation showed the successful incorporation of drug X within the films in its crystalline form when the complexing agent was not added, and in its amorphous form when the complexing agent was present. Furthermore, the addition of the complexing agent improved the solubility of drug X, which consequently resulted in an improved drug release profile and disintegration time of the film.
The deficiency of a specific enzyme is characterised as an autosomal recessive inborn error which results in epileptic encephalopathy in the early new-born stages. Patients with this disease are chronically dependent on therapy with drug X. However, no marketing authorisation is available for this drug, and current therapies are centred on drug X supplements, with suboptimal quality, as their regulation is not as strict as the one applied by the pharmaceutical industry, leading to dose inaccuracy. Orodispersible films (ODFs) are proposed as an alternative to tablets and capsules as they disintegrate rapidly in the oral cavity when they come in contact with saliva without chewing or water. Orphyllo™ is a ready-to-use base that is intended to be easily adaptable to various APIs and used in compounding in pharmacies. This research aimed to develop drug X ODFs with different drug loadings using Orphyllo™ base to optimise the treatment for the paediatric population with this disease. The developed films were characterised by visual inspection, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR) and thermogravimetry analysis (TGA). A drug release study was conducted as well as a disintegration study using an oral cavity model (OCM), and drug loading. Optimisation of the samples was conducted, and films containing the complexing agent were developed to improve the solubility of drug X. To mask the bitter taste, sucralose was added to the formulation. ODFs displayed two textures on each side, a rough surface, and a smooth surface. ODFs containing the complexing agent were the only samples presenting a smooth appearance on both surfaces with a brittle texture. Drug loading presented results close to 100%. Physicochemical characterisation showed the successful incorporation of drug X within the films in its crystalline form when the complexing agent was not added, and in its amorphous form when the complexing agent was present. Furthermore, the addition of the complexing agent improved the solubility of drug X, which consequently resulted in an improved drug release profile and disintegration time of the film.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Complexing agent Disintegration OCM ODF Orphyllo™ base Mestrado Integrado - 2024