Avaliação do potencial de sistemas precursores de cristais líquidos mucoadesivos para administração nasal de rifampicina aplicáveis na terapia da tuberculose
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Data
2018-07-31
Autores
Santos, Karen Cristina dos
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Universidade Estadual Paulista (Unesp)
Resumo
A tuberculose (TB) é a principal doença infecciosa de origem bacteriana no mundo, levando anualmente à morte de milhares de pessoas e ocasionando prejuízos econômicos globais de aproximadamente 12 bilhões de dólares ao ano. Apenas um fármaco foi desenvolvido contra cepas multirresistentes desde 1960 (bedaquilina) e o surgimento de casos de TB multi-fármaco-resistente faz com que o tratamento atual seja ineficaz. A rifampicina (RIF) é um fármaco de primeira escolha usada no tratamento da TB utilizado desde 1966. Normalmente, este fármaco é administrado pela via oral, ficando assim susceptível à metabolização pré-sistêmica e interações medicamentosas com outros fármacos, o que reduz significativamente seus níveis séricos e de outros fármacos, podendo diminuir a eficácia do tratamento e aumentar o risco de resistências. Assim, o emprego de sistemas de liberação nanoestruturados e de vias alternativas de administração podem ser estratégias atraentes para a administração de RIF. A via nasal tem recebido especial atenção como rota promissora para liberação sistêmica de fármacos, uma vez que apresenta epitélio com numerosas microvilosidades e grande área de superfície, o que facilita a absorção de fármacos. Além disto, a anatomia da cavidade nasal oferece entrada para o Sistema Nervoso Central (SNC), aspecto extremamente interessante para casos de tuberculose meníngea. Dentre os sistemas nanoestruturados promissores para incorporação de RIF objetivando administração nasal, destacam-se os sistemas líquido cristalinos mucoadesivos. Devido à alta viscosidade de alguns domínios destes sistemas, eles podem promover a fixação da formulação num local de ação desejado após sua administração e formação in situ, o que pode ser interessante para a administração de RIF, de forma a aumentar a sua fixação na região nasal, facilitando sua absorção sistêmica e interface com o SNC. Dessa forma, o objetivo deste trabalho foi estudar o potencial de sistemas líquido cristalinos mucoadesivos para administração nasal de RIF na otimização da terapia da TB, com avaliação in vitro e in vivo da sua segurança e atividade. Após o desenvolvimento de 6 diagramas de fases, foram selecionadas 6 formulações fixando a concentração de tensoativo em 50%, sendo caraterizados por microscopia de luz polarizada, espalhamento de raio-X a baixo ângulo, reologia, análise de textura e bioadesão que demonstraram a presença de sistemas líquidos cristalinos constituídos de mesofases lamelar e hexagonal e também sistemas precursores de cristal líquido (microemulsão) que com a adição de soluções aquosas formaram mesofases significativamente mais estruturadas e mucoadesivas. Ensaios de citotoxicidade por difusão em Agar utilizando a linhagem celular L-929 revelaram citotoxicidade branda a moderada das formulações testadas. Dois sistemas líquido cristalinos foram selecionados, sendo eles 9D e 10D. No ensaio de cinética bacteriana os sistemas 9D e 10D carreando RIF apresentaram atividade bactericida sobre a cepa H37rv de Mycobacterium tuberculosis. Posteriormente ensaios farmacocinéticos foram realizados sugerindo que a absorção nasal da RIF carreada por tais sistemas é de 2 a 4 vezes maior utilizando a via nasal quando comparada à administração oral. Dessa forma. os sistemas desenvolvidos podem apresentar potencial para incorporação de RIF, com o objetivo de serem usados como plataforma tecnológica na liberação de fármacos na terapia contra a TB.
Tuberculosis (TB) is the world's leading bacterial infectious disease, causing thousands of people to die every year and causing global economic damage of about $ 12 billion a year. Only one drug has been developed against multiresistant strains since 1960 (bedaquilin) and the emergence of multidrug-resistant TB cases makes the current treatment ineffective. Rifampicin (RIF) is a first-line drug used in the treatment of TB used since 1966. This drug is commonly administered orally, thus being susceptible to pre-systemic metabolism and drug interactions with other drugs, which significantly reduces its serum levels and other drugs and may decrease the effectiveness of treatment and increase the risk of resistance. Thus, the use of nanostructured delivery systems and alternative routes of administration may be attractive strategies for administration of RIF. The nasal route has received special attention as a promising route for systemic drug delivery, since it presents epithelium with numerous microvilli and large surface area, which facilitates the absorption of drugs. In addition, the anatomy of the nasal cavity provides access to the Central Nervous System (CNS), an extremely interesting aspect for cases of meningeal tuberculosis. Among the promising nanostructured systems for the incorporation of RIF for nasal administration, we highlight the mucoadhesive liquid crystal systems. Due to the high viscosity of some domains of these systems, they can promote the fixation of the formulation at a desired site of action after administration and in situ formation, which may be of interest for the administration of RIF, in order to increase its fixation in the region nasal, facilitating its systemic absorption and interface with the CNS. Thus, the objective of this work was to study the potential of mucosal liquid crystal systems for nasal administration of RIF in the optimization of TB therapy, with in vitro and in vivo evaluation of its safety and activity. After the development of 6 ternary phase diagrams, 6 formulations were selected, fixing the concentration of surfactant in 50%, being characterized by polarized light microscopy, low angle X-ray scattering, rheology, texture analysis and bioadhesion that demonstrated the presence of liquid crystalline systems consisting of lamellar and hexagonal mesophases and also liquid crystal precursor systems (microemulsion) which with the addition of aqueous solutions formed significantly more structured and mucoadhesive mesofases. Agar diffusion cytotoxicity assays using the L-929 cell line revealed mild to moderate cytotoxicity of the formulations tested. In the bacterial kinetics assay the 9DR and 10DR systems showed bactericidal activity on the H37rv strain of Mycobacterium tuberculosis. Thus, the developed systems may have potential for incorporation of RIF, with the objective of being used as a technological platform in the release of drugs in the therapy against TB.
Tuberculosis (TB) is the world's leading bacterial infectious disease, causing thousands of people to die every year and causing global economic damage of about $ 12 billion a year. Only one drug has been developed against multiresistant strains since 1960 (bedaquilin) and the emergence of multidrug-resistant TB cases makes the current treatment ineffective. Rifampicin (RIF) is a first-line drug used in the treatment of TB used since 1966. This drug is commonly administered orally, thus being susceptible to pre-systemic metabolism and drug interactions with other drugs, which significantly reduces its serum levels and other drugs and may decrease the effectiveness of treatment and increase the risk of resistance. Thus, the use of nanostructured delivery systems and alternative routes of administration may be attractive strategies for administration of RIF. The nasal route has received special attention as a promising route for systemic drug delivery, since it presents epithelium with numerous microvilli and large surface area, which facilitates the absorption of drugs. In addition, the anatomy of the nasal cavity provides access to the Central Nervous System (CNS), an extremely interesting aspect for cases of meningeal tuberculosis. Among the promising nanostructured systems for the incorporation of RIF for nasal administration, we highlight the mucoadhesive liquid crystal systems. Due to the high viscosity of some domains of these systems, they can promote the fixation of the formulation at a desired site of action after administration and in situ formation, which may be of interest for the administration of RIF, in order to increase its fixation in the region nasal, facilitating its systemic absorption and interface with the CNS. Thus, the objective of this work was to study the potential of mucosal liquid crystal systems for nasal administration of RIF in the optimization of TB therapy, with in vitro and in vivo evaluation of its safety and activity. After the development of 6 ternary phase diagrams, 6 formulations were selected, fixing the concentration of surfactant in 50%, being characterized by polarized light microscopy, low angle X-ray scattering, rheology, texture analysis and bioadhesion that demonstrated the presence of liquid crystalline systems consisting of lamellar and hexagonal mesophases and also liquid crystal precursor systems (microemulsion) which with the addition of aqueous solutions formed significantly more structured and mucoadhesive mesofases. Agar diffusion cytotoxicity assays using the L-929 cell line revealed mild to moderate cytotoxicity of the formulations tested. In the bacterial kinetics assay the 9DR and 10DR systems showed bactericidal activity on the H37rv strain of Mycobacterium tuberculosis. Thus, the developed systems may have potential for incorporation of RIF, with the objective of being used as a technological platform in the release of drugs in the therapy against TB.
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Palavras-chave
rifampicina, tuberculose, cristal líquido, via nasal, rifampicin, tuberculosis, liquid crystal, nasal route