Desarrollo y caracterización de un sistema de liberación controlada de capreomicina sulfato mediante formación de biocomplejos polielectrolíticos: un estudio exploratorio para aplicación terapéutica.
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Date
2026
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Universidad de Concepción
Abstract
Los complejos polielectrolitos (PECs) formados por polisacáridos catiónicos y aniónicos como los derivados de quitosano y carragenina, respectivamente, representan una alternativa prometedora para el desarrollo de sistemas de liberación controlada debido a su biocompatibilidad y biodegradabilidad. Estos sistemas pueden generar micropartículas capaces de encapsular y modular la liberación de activos de interés terapéutico como capreomicina sulfato (CAP), fármaco de segunda línea utilizado en tuberculosis multirresistente (TB-MDR), cuyo uso prolongado se asocia a toxicidad y baja adherencia terapéutica. El objetivo de este estudio fue desarrollar micropartículas núcleo–corona basadas en PECs de quitosano ariltrimetilamonio (TMACS) y λ-carragenina (LCG) capaces de encapsular CAP, modular su liberación y presentar un perfil de citotoxicidad compatible in vitro. Las micropartículas se obtuvieron mediante secado por aspersión y se caracterizaron fisicoquímica, estructural y biológicamente. Las micropartículas obtenidas con la relación TMACS/LCG de 3.0 presentaron un diámetro medio de 2.07 ± 0.61 μm y un potencial Zeta de −58.07 ± 3.16 mV, evidenciando la formación de micropartículas con predominio superficial del polianión. Además, alcanzaron una eficiencia de encapsulación fue de 91.53 ± 0.61 %, con una carga cercana al 20%. La caracterización fisicoquímica y estructural confirmó la incorporación de CAP en las micropartículas y sugirió la conservación parcial de su orden estructural dentro de la matriz polimérica. En los ensayos de liberación, las micropartículas redujeron significativamente la liberación de CAP. El análisis cinético mostró que el modelo de Korsmeyer–Peppas describe la liberación en las micropartículas núcleo-corona, confirmando que la composición y la arquitectura de la matriz influyen directamente en el mecanismo de transporte y liberación del fármaco. Finalmente, estas micropartículas mantuvieron una viabilidad celular superior al 80 % en fibroblastos HFF-1 a las concentraciones evaluadas.
Estos resultados demuestran que la arquitectura TMACS/LCG permite encapsular CAP y modular eficazmente su liberación, constituyendo una estrategia viable para terapias prolongadas en TB-MDR.
Polyelectrolyte complexes (PECs) formed by cationic and anionic polysaccharides, such as chitosan derivatives and carrageenan, respectively, represent a promising alternative for the development of controlled drug delivery systems due to their biocompatibility and biodegradability. These systems can generate microparticles capable of encapsulating and modulating the release of therapeutic agents such as capreomycin sulfate (CAP), a second-line drug used in multidrug-resistant tuberculosis (MDR-TB), whose prolonged use is associated with toxicity and poor therapeutic adherence. The aim of this study was to develop core–shell microparticles based on PECs of aryltrimethylammonium chitosan (TMACS) and λ-carrageenan (LCG) capable of encapsulating CAP, modulating its release, and exhibiting an in vitro cytotoxicity profile compatible with biomedical applications. The microparticles were produced by spray drying and characterized physicochemically, structurally, and biologically. The microparticles obtained at a TMACS/LCG ratio of 3.0 exhibited a mean diameter of 2.07 ± 0.61 μm and a zeta potential of −58.07 ± 3.16 mV, demonstrating the formation of microparticles with a polyanion-enriched surface. In addition, they achieved an encapsulation efficiency of 91.53 ± 0.61%, with a drug loading close to 20%. Physicochemical and structural characterization confirmed the incorporation of CAP into the microparticles and suggested the partial preservation of its structural order within the polymeric matrix. In the release assays, the microparticles significantly reduced CAP release. Kinetic analysis showed that the Korsmeyer–Peppas model describes drug release from the core–shell microparticles, confirming that the composition and architecture of the matrix directly influence the drug transport and release mechanism. Finally, these microparticles maintained cell viability above 80% in HFF-1 fibroblasts at the evaluated concentrations. These results demonstrate that the TMACS/LCG architecture enables efficient CAP encapsulation and release modulation, constituting a viable strategy for prolonged therapies in MDR-TB.
Polyelectrolyte complexes (PECs) formed by cationic and anionic polysaccharides, such as chitosan derivatives and carrageenan, respectively, represent a promising alternative for the development of controlled drug delivery systems due to their biocompatibility and biodegradability. These systems can generate microparticles capable of encapsulating and modulating the release of therapeutic agents such as capreomycin sulfate (CAP), a second-line drug used in multidrug-resistant tuberculosis (MDR-TB), whose prolonged use is associated with toxicity and poor therapeutic adherence. The aim of this study was to develop core–shell microparticles based on PECs of aryltrimethylammonium chitosan (TMACS) and λ-carrageenan (LCG) capable of encapsulating CAP, modulating its release, and exhibiting an in vitro cytotoxicity profile compatible with biomedical applications. The microparticles were produced by spray drying and characterized physicochemically, structurally, and biologically. The microparticles obtained at a TMACS/LCG ratio of 3.0 exhibited a mean diameter of 2.07 ± 0.61 μm and a zeta potential of −58.07 ± 3.16 mV, demonstrating the formation of microparticles with a polyanion-enriched surface. In addition, they achieved an encapsulation efficiency of 91.53 ± 0.61%, with a drug loading close to 20%. Physicochemical and structural characterization confirmed the incorporation of CAP into the microparticles and suggested the partial preservation of its structural order within the polymeric matrix. In the release assays, the microparticles significantly reduced CAP release. Kinetic analysis showed that the Korsmeyer–Peppas model describes drug release from the core–shell microparticles, confirming that the composition and architecture of the matrix directly influence the drug transport and release mechanism. Finally, these microparticles maintained cell viability above 80% in HFF-1 fibroblasts at the evaluated concentrations. These results demonstrate that the TMACS/LCG architecture enables efficient CAP encapsulation and release modulation, constituting a viable strategy for prolonged therapies in MDR-TB.
Description
Tesis presentada para optar al grado de Magíster en Ciencias Farmacéuticas.
Keywords
Medicamentos, Tuberculosis, Citotoxinas