Publication: Desarrollo farmacotécnico de nano- y microformulaciones de liberación controlada de anfotericina B para mejorar su biodisponibilidad y actividad terapéutica
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2021-02-15
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Universidad Complutense de Madrid
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Abstract
“Introducción “
La elevada incidencia y prevalencia de las infecciones fúngicas y parasitarias supone un grave problema de salud pública a nivel global debido a la complejidad de dichos tratamientos, así como a la aparición de resistencias. Los tratamientos existentes actualmente engloban desde la administración parenteral de anfotericina B (AmB), con efectos nefrotóxicos y hemolíticos, hasta el uso oral de miltefosina, que puede resultar elevadamente tóxica a nivel gastrointestinal y además es teratogénica. AmB es el fármaco de referencia en la terapia antifúngica y antiparasitaria desde hace décadas, aunque afortunadamente el uso de la presentación Fungizona® ha sido desplazado por la formulación liposomal de AmB (AmBisome®) y otras presentaciones lipídicas, reduciendo su toxicidad. Además, la AmB presenta tres estados de agregación en solución y desarrolla su actividad a través de dos mecanismos de acción. La modulación del estado de agregación para desencadenar uno u otro mecanismo de acción es una estrategia prometedora en el tratamiento de estas infecciones. Los mecanismos de acción que permiten la actividad antiinfecciosa de la AmB consisten en la ruptura de la membrana plasmática y la inducción del estrés oxidativo. La ruptura de la membrana plasmática se produce debido a la unión del fármaco al ergosterol presente en células fúngicas y parasitarias, que dan lugar a la formación de poros que liberan iones, produciendo una alteración electrolítica que finaliza con la muerte celular; mientras que la inducción del estrés oxidativo tiene lugar debido a un aumento de la concentración de radicales libres que provocan daños en la célula, conllevando la pérdida de la actividad metabólica de ésta. Actualmente, sólo existen formulaciones de AmB de administración intravenosa disponibles en el mercado debido a la baja biodisponibilidad del fármaco a través de otras vías. Por ello, es necesario desarrollar formulaciones que permitan incrementar su biodisponibilidad. Así, la administración tópica u oral de formulaciones de AmB supone una alternativa terapéutica, incrementando la permeabilidad a través de la piel y la absorción a nivel gastrointestinal, respectivamente. Así, se permite una vectorización del fármaco hacia los tejidos diana. En los últimos años, se han desarrollado formulaciones similares a los liposomas para mejorar la permeabilidad transdérmica de fármacos, de la misma forma que la utilización de terapias combinadas para tratar infecciones. Estos sistemas permitirían, por lo tanto, un incremento de la biodisponibilidad de AmB a través de diferentes vías. “Objetivos” El objetivo principal de este trabajo fue el desarrollo de nuevas formulaciones de AmB teniendo en cuenta su tamaño de partícula y estado de agregación. En la elaboración de estos sistemas, se utilizaron excipientes naturales y bioactivos para incrementar la tolerabilidad a estas 6 formulaciones. Las técnicas que se emplearon para la obtención de estas formulaciones fueron el método de hidratación en capa fina seguido de sonicación, así como granulación por vía húmeda seguida de recubrimiento en lecho fluido. Los objetivos específicos se describen a continuación: 1. Evaluación fisicoquímica y estudio in vitro de los estados de agregación de AmB. Para ello, se emplearon excipientes, como la γ-ciclodextrina o el desoxicolato sódico, y cambios en el pH para obtener los tres estados de agregación del fármaco. 2. Desarrollo y caracterización de transferosomas de AmB para administración transdérmica, combinando la utilización de microagujas. 3. Elaboración y caracterización de sistemas combinados de AmB, itraconazol, miltefosina y alopurinol en forma de pellets recubiertos para administración oral...
“Introduction” An increase in the incidence and prevalence of fungal and parasitic infections has been reported, causing a global health problem due to the complexity of treatments, as well as the appearance of resistances. Current treatments involve parenteral administration of amphotericin B (AmB), with nephrotoxic and hemolytic effects, and also, the oral utilization of miltefosine, which can result highly toxic and teratogenic. AmB has been the reference drug in antifungal and anti-parasitic therapy for decades. The use of the Fungizone® has been downgraded by the liposomal formulation of AmB (AmBisome®) and other lipid formulations, decreasing its toxicity. Moreover, it is well-known that AmB presents three different aggregation states in solution and its activity takes place through two mechanisms of action. Modulating its aggregation state to trigger one or another mechanism of action is a promising strategy in the treatment of these infections. The mechanisms of actions that enable the anti-infective activity of AmB consist on the disruption of plasma membrane and producing oxidative stress. Membrane disruption is produced by the binding of AmB to ergosterol in fungal and parasitic cells, triggering the formation of pores that generate the leakage of ions, resulting in an electrolytic disturbance which finalizes with cell death; while oxidative stress induction is produced due to an increase in the concentration of free radicals which cause cell damage, and hence a loss in the metabolic activity. Nowadays, only intravenous formulations containing AmB are available in the market due to its low bioavailability through other pathways. Thus, there is an increased clinical need to engineer formulations that promote and enhance its bioavailability. Thereby, topical or oral administration of AmB formulations could be a therapeutic alternative to parenteral formulations. In the last few years, formulations based on liposomes have been developed to improve transdermal permeability of drugs, as well as the use of fixed-dose combinations to treat infections. The optimization of AmB topical and oral formulations would therefore open the therapeutic window for this drug and its clinical use in practice. “Aims” The main aim of this project was to engineer novel AmB formulations considering particle size and aggregation state. In the manufacturing of these systems, natural and bioactive excipients were selected to improve tolerance towards these formulations. The utilised techniques to obtain these formulations were film-thin hydration followed by sonication, as well as wet granulation followed by spray-coating. The specific aims of the project are described below: 1. Physicochemical characterization and manufacturing of the three AmB aggregation states, including several excipients such as γ-cyclodextrin and sodium deoxycholate, as well as a pH switch. 2. Development and characterization of AmB-transferosomes for transdermal delivery, combined with microneedles. 3. Engineering and characterization of fixed-dose combination products containing AmB, itraconazole, miltefosine and allopurinol, consisting of coated pellets with an AmB core coated by the other three drugs above mentioned...
“Introduction” An increase in the incidence and prevalence of fungal and parasitic infections has been reported, causing a global health problem due to the complexity of treatments, as well as the appearance of resistances. Current treatments involve parenteral administration of amphotericin B (AmB), with nephrotoxic and hemolytic effects, and also, the oral utilization of miltefosine, which can result highly toxic and teratogenic. AmB has been the reference drug in antifungal and anti-parasitic therapy for decades. The use of the Fungizone® has been downgraded by the liposomal formulation of AmB (AmBisome®) and other lipid formulations, decreasing its toxicity. Moreover, it is well-known that AmB presents three different aggregation states in solution and its activity takes place through two mechanisms of action. Modulating its aggregation state to trigger one or another mechanism of action is a promising strategy in the treatment of these infections. The mechanisms of actions that enable the anti-infective activity of AmB consist on the disruption of plasma membrane and producing oxidative stress. Membrane disruption is produced by the binding of AmB to ergosterol in fungal and parasitic cells, triggering the formation of pores that generate the leakage of ions, resulting in an electrolytic disturbance which finalizes with cell death; while oxidative stress induction is produced due to an increase in the concentration of free radicals which cause cell damage, and hence a loss in the metabolic activity. Nowadays, only intravenous formulations containing AmB are available in the market due to its low bioavailability through other pathways. Thus, there is an increased clinical need to engineer formulations that promote and enhance its bioavailability. Thereby, topical or oral administration of AmB formulations could be a therapeutic alternative to parenteral formulations. In the last few years, formulations based on liposomes have been developed to improve transdermal permeability of drugs, as well as the use of fixed-dose combinations to treat infections. The optimization of AmB topical and oral formulations would therefore open the therapeutic window for this drug and its clinical use in practice. “Aims” The main aim of this project was to engineer novel AmB formulations considering particle size and aggregation state. In the manufacturing of these systems, natural and bioactive excipients were selected to improve tolerance towards these formulations. The utilised techniques to obtain these formulations were film-thin hydration followed by sonication, as well as wet granulation followed by spray-coating. The specific aims of the project are described below: 1. Physicochemical characterization and manufacturing of the three AmB aggregation states, including several excipients such as γ-cyclodextrin and sodium deoxycholate, as well as a pH switch. 2. Development and characterization of AmB-transferosomes for transdermal delivery, combined with microneedles. 3. Engineering and characterization of fixed-dose combination products containing AmB, itraconazole, miltefosine and allopurinol, consisting of coated pellets with an AmB core coated by the other three drugs above mentioned...
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Tesis inédita de la Universidad Complutense de Madrid. Facultad de Farmacia, leída el 28-04-2020