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Advisor(s)
Abstract(s)
A ciclosporina A (CsA), um péptido hidrofóbico, é um potente imunomodulador utilizado para reduzir a inflamação e aumentar a produção de lágrimas em doentes com a Síndrome do Olhos Secos (SOS). No entanto, a sua baixa solubilidade aquosa apresenta desafios significativos de formulação. O Restasis® e o Ikervis®, as formas comerciais disponíveis no mercado com CsA, estão associados a efeitos secundários como ardor e irritação ocular devido à utilização de óleos ou tensioactivos irritantes, adicionados de forma a aumentar a solubilidade da CsA. As ciclodextrinas (CDs), oligossacarídeos cíclicos, são exploradas pela sua capacidade de formar complexos de inclusão solúveis em água com moléculas hidrofóbicas, aumentando assim a solubilidade e estabilidade das mesmas.
Este estudo tem como objetivo investigar a formulação de colírios aquosos de CsA, focando-se no aumento da solubilidade da mesma em água e, consequentemente no aumento da sua eficácia terapêutica no tratamento da SOS, através de estudos de solubilidade com CDs.
Foram examinadas três CDs: Sulfobutil-Éter-β-ciclodextrina (SBE-β-CD), hidroxipropil-β-ciclodextrina (HP-β-CD) e β-ciclodextrina aleatoriamente metilada (RM-β-CD), avaliando a sua eficácia no aumento da solubilidade da CsA, através de estudos de solubilidade de fase comparativos, utilizando um método de cromatografia líquida de alta eficiência (HPLC). A investigação envolve a preparação de soluções de CsA com as diferentes CDs e a análise das constantes de estabilidade (Ks) e dos seus diagramas de solubilidade.
Os resultados indicam que todas as CDs aumentam significativamente a solubilidade da CsA, sendo que a HP-β-CD e a RM-β-CD apresentam uma maior ação solubilizante e, por conseguinte, foram escolhidas para a futura formulação dos colírios. Em particular, o perfil tipo-AL do diagrama de solubilidade da RM-β-CD, indica um aumento consistente e linear da solubilidade com o aumento das concentrações de CD. Os resultados destacam o potencial das
CDs para ultrapassar as limitações atuais dos colírios de CsA disponíveis no mercado.
Recomendam-se estudos futuros para otimizar estas formulações e avaliar a sua segurança e eficácia clínica em populações. Esta investigação contribui para o desenvolvimento de sistemas avançados de administração de medicamentos oftálmicos, com o objetivo de melhorar a qualidade de vida dos doentes que sofrem da SOS.
Cyclosporine A (CsA), a hydrophobic peptide, is a potent immunomodulatory agent used to reduce inflammation and increase tear production in patients with Dry Eye Disease (DED). However, its low aqueous solubility presents significant formulation challenges. Restasis® and Ikervis®, the commercial forms containing CsA in the market, are associated with side effects like ocular burning and irritation due to the usage of irritating oils or surfactants added to improve CsA’s solubility. Cyclodextrins (CDs), cyclic oligosaccharides, are explored for their ability to form water-soluble inclusion complexes with hydrophobic molecules, thereby improving their solubility and stability. This study aims to investigate the formulation of aqueous-based CsA eye drops, focusing on enhancing CsA’s solubility and therapeutic efficacy for treating DED, through phase solubility studies with different CDs. Three modified CDs were examined: Sulfobutylether-β-CD (SBE-β-CD), Hydroxypropyl-β-CD (HP-β-CD), and Randomly Methylated β-CD (RM-β-CD), assessing their use in enhancing CsA’s solubility through comparative phase solubility studies, using a High-performance Liquid Chromatography (HPLC) method. The research involves preparing solutions of CsA with the different CDs and analyzing their stability constants (Ks) and their solubility diagrams. The findings indicate that all CDs significantly increase CsA’s solubility, with HP-β-CD and RM-β-CD showing the highest solubilizing efficiency and, therefore, were chosen for the future formulation of the eye drops. In particular, the AL-type phase solubility profile of RM-β-CD indicates consistent linear solubility enhancement with increasing CD concentrations, making it a promising candidate for CsA delivery systems. The results highlight the potential of CD based formulations to overcome the limitations of current CsA eye drops. By enhancing CsA’s aqueous solubility, CD-based eye drops could improve its bioavailability and offer a more effective and patient-friendly treatment for DED. Future studies are recommended to further optimize these formulations and evaluate their clinical efficacy and safety in animal and patient populations. This research contributes to the development of advanced ophthalmic drug delivery systems, aiming to improve the quality of life for patients suffering from DED.
Cyclosporine A (CsA), a hydrophobic peptide, is a potent immunomodulatory agent used to reduce inflammation and increase tear production in patients with Dry Eye Disease (DED). However, its low aqueous solubility presents significant formulation challenges. Restasis® and Ikervis®, the commercial forms containing CsA in the market, are associated with side effects like ocular burning and irritation due to the usage of irritating oils or surfactants added to improve CsA’s solubility. Cyclodextrins (CDs), cyclic oligosaccharides, are explored for their ability to form water-soluble inclusion complexes with hydrophobic molecules, thereby improving their solubility and stability. This study aims to investigate the formulation of aqueous-based CsA eye drops, focusing on enhancing CsA’s solubility and therapeutic efficacy for treating DED, through phase solubility studies with different CDs. Three modified CDs were examined: Sulfobutylether-β-CD (SBE-β-CD), Hydroxypropyl-β-CD (HP-β-CD), and Randomly Methylated β-CD (RM-β-CD), assessing their use in enhancing CsA’s solubility through comparative phase solubility studies, using a High-performance Liquid Chromatography (HPLC) method. The research involves preparing solutions of CsA with the different CDs and analyzing their stability constants (Ks) and their solubility diagrams. The findings indicate that all CDs significantly increase CsA’s solubility, with HP-β-CD and RM-β-CD showing the highest solubilizing efficiency and, therefore, were chosen for the future formulation of the eye drops. In particular, the AL-type phase solubility profile of RM-β-CD indicates consistent linear solubility enhancement with increasing CD concentrations, making it a promising candidate for CsA delivery systems. The results highlight the potential of CD based formulations to overcome the limitations of current CsA eye drops. By enhancing CsA’s aqueous solubility, CD-based eye drops could improve its bioavailability and offer a more effective and patient-friendly treatment for DED. Future studies are recommended to further optimize these formulations and evaluate their clinical efficacy and safety in animal and patient populations. This research contributes to the development of advanced ophthalmic drug delivery systems, aiming to improve the quality of life for patients suffering from DED.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Cyclosporine A Dry eye disease Cyclodextrins Phase solubility studies Eye drops Mestrado Integrado - 2024