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PLGA in situ forming microparticles loaded with nanosized dexamethasone as long-term drug delivery carriers
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O ácido polilático-co-glicólico (PLGA) é um co-polímero sintético de ácido polilático (PLA) e ácido poliglicólico (PGA). Devido à sua biodegradabilidade e biocompatibilidade, tem sido extensivamente estudado para o desenvolvimento de novos e avançados sistemas de liberação de Substâncias ativas. O PLGA é frequentemente empregue para a administração direcionada e regulada de compostos terapêuticos usados para tratar uma variedade de doenças e distúrbios, como cancro, doenças cardiovasculares, cirurgia ortopédica e cosméticos.
Devido à baixa biodisponibilidade oral de alguns medicamentos, há um interesse crescente na administração parenteral para potenciar a absorção do fármaco diretamente na corrente sanguínea, ignorando a barreira gastrointestinal e a metabolização hepática. Apesar das desvantagens das injeções necessárias nos sistemas de formação in situ (ISF), o método de preparação fácil, menos doses administradas e a adesão do paciente tornam- nas técnicas populares para a administração controlada de medicamentos de libertação prolongada. Outros métodos de administração (por exemplo, transdérmico, nasal e retal) mostram problemas na absorção e degradação de enzimas.
Nesta tese, são estudados vários ensaios de liberação prolongada de dexametasona em partículas e implantes de formação in situ. Os estudos foram elaborados com diferentes formulações, contendo um solvente solúvel (NMP em diferentes concentrações 20% e 100%), um solvente insolúvel (Triacetina) e um aditivo básico (Mg(OH)2). O objetivo foi avaliar a validade do método de preparação das partículas, o efeito do tamanho das partículas e do estado físico no perfil de liberação e estabilidade das partículas resultantes e, por último, o impacto de um aditivo básico (Mg(OH)2) no perfil de libertação. Para atingir esses objetivos, as partículas e os implantes foram caracterizados medindo a percentagem de libertação cumulativa, o pH do meio, o tamanho das partículas e a variação da massa húmida.
Através das experiências observou-se que o método “back-forth” para preparação de partículas formadas in situ resultou em emulsões estáveis e na formação de partículas estáveis após a precipitação. As partículas com Substância ativa (AS) na forma Micronizada mostraram-se as mais estáveis, seguidas das micropartículas com AS na forma Nanosizada e por último as partículas com 20% de NMP dissolvido. Por outro lado, as partículas 100% dissolvidas em NMP não foram viáveis. Através da adição de Mg(OH)2 com NMP como co-solvente, não houve alteração significativa no perfil de libertação. No entanto, na formulação com Mg(OH)2 e Triacetina, observou-se uma correlação entre o aumento da concentração de Mg(OH)2 e o aumento da taxa de libertação da substância ativa.
Polylactic-co-glycolic acid (PLGA) is a synthetic copolymer of poly lactic acid (PLA) and poly glycolic acid (PGA). Due to its biodegradability and biocompatibility, it is extensively studied for the development of novel and advanced drug delivery systems. PLGA is frequently employed for the targeted and regulated administration of therapeutic compounds used to treat a variety of illnesses and disorders, like cancer, cardiovascular disease, orthopedic surgery, and cosmetics. Due to the low oral bioavailability of some medications, there is increased interest in parenteral delivery to target drug absorption directly into blood stream, bypassing the delayed gastrointestinal route and hepatic processing. Despite the drawbacks of the necessary injections of in situ forming (ISF), the easy preparation method, fewer doses administered, and patient compliance make them popular techniques for administering controlled long-acting drug administration. In this thesis, it is studied several long-term release studies of dexamethasone in in situ forming particles and implants. The studies were prepared with different formulations, containing a soluble solvent (NMP in different concentrations 20% and 100%), an insoluble solvent (Triacetin), and a basic additive (Mg(OH)2). The goal was to evaluate the validity of the particle’s preparation method, the effect of the particle size and solid state on the release profile and stability of the resulting particles, and lastly, the impact of a basic additive (Mg(OH)2) to the release profile. To accomplish these objectives the particles and implants, were characterized by measuring the cumulative release percentage, the pH of the release medium, particle size, and wet mass change. Through the experiments it was observed that the back-forth method for preparing in situ forming particles resulted in stable emulsions and the formation of stable particles after precipitation. The Micronized particles showed to be the more stable, followed by the Nanosized and lastly the particles with 20% dissolved NMP. While the 100% dissolved particles were not viable. Through the addiction of Mg(OH)2 with NMP as co-solvent, there was no significant change in the release profile. However, in the formulation with Mg(OH)2 and Triacetin, a correlation was observed between the increase of Mg(OH)2 concentration and an increase in the burst release rate.
Polylactic-co-glycolic acid (PLGA) is a synthetic copolymer of poly lactic acid (PLA) and poly glycolic acid (PGA). Due to its biodegradability and biocompatibility, it is extensively studied for the development of novel and advanced drug delivery systems. PLGA is frequently employed for the targeted and regulated administration of therapeutic compounds used to treat a variety of illnesses and disorders, like cancer, cardiovascular disease, orthopedic surgery, and cosmetics. Due to the low oral bioavailability of some medications, there is increased interest in parenteral delivery to target drug absorption directly into blood stream, bypassing the delayed gastrointestinal route and hepatic processing. Despite the drawbacks of the necessary injections of in situ forming (ISF), the easy preparation method, fewer doses administered, and patient compliance make them popular techniques for administering controlled long-acting drug administration. In this thesis, it is studied several long-term release studies of dexamethasone in in situ forming particles and implants. The studies were prepared with different formulations, containing a soluble solvent (NMP in different concentrations 20% and 100%), an insoluble solvent (Triacetin), and a basic additive (Mg(OH)2). The goal was to evaluate the validity of the particle’s preparation method, the effect of the particle size and solid state on the release profile and stability of the resulting particles, and lastly, the impact of a basic additive (Mg(OH)2) to the release profile. To accomplish these objectives the particles and implants, were characterized by measuring the cumulative release percentage, the pH of the release medium, particle size, and wet mass change. Through the experiments it was observed that the back-forth method for preparing in situ forming particles resulted in stable emulsions and the formation of stable particles after precipitation. The Micronized particles showed to be the more stable, followed by the Nanosized and lastly the particles with 20% dissolved NMP. While the 100% dissolved particles were not viable. Through the addiction of Mg(OH)2 with NMP as co-solvent, there was no significant change in the release profile. However, in the formulation with Mg(OH)2 and Triacetin, a correlation was observed between the increase of Mg(OH)2 concentration and an increase in the burst release rate.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2022, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
In situ forming systems PLGA Dexamethasone Biodegradable Solvent exchange Mestrado integrado - 2022