UNIVERSIDADE DE SÃO PAULO
FACULDADE DE CIÊNCIAS FARMACÊUTICAS DE RIBEIRÃO PRETO
Encapsulação de compostos bioativos de
Syzygium aromaticum
em
carreadores lipídicos sólidos
Tese de doutorado apresentada ao programa de Pós-Graduação em Ciências Farmacêuticas para obtenção do título de Doutor em Ciências.
Área de concentração: Medicamentos e Cosméticos
Orientado: Diego Francisco Cortés Rojas
Orientador: Prof. Dr. Wanderley P. Oliveira
Co-orientadora: Dra. Cláudia R. F. Souza
Versão corrigida da Tese de Doutorado apresentada ao programa de Pós-Graduação em Ciências Farmacêuticas em 04/09/2015. A versão original encontra-se disponível na Faculdade de Ciências Farmacêuticas de Ribeirão Preto/USP
Trabalho realizado no Departamento de
Ciências Farmacêuticas da Faculdade de
Ciências Farmacêuticas de Ribeirão Preto da
Universidade de São Paulo, no Laboratório de
P&D em Processos Farmacêuticos, sob a
supervisão do Prof. Dr. Wanderley Pereira de
Oliveira e Dra Cláudia R. Fernandes Souza.
Apoio Financeiro:
FAPESP
AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE.
Cortés-Rojas, Diego Francisco
Encapsulação de compostos bioativos de Syzygium aromaticum
em carreadores lipídicos sólidos. Ribeirão Preto, 2015. 160 p. : il. ; 30 cm
Tese de Doutorado, apresentada à Faculdade de Ciências Farmacêuticas de Ribeirão Preto/USP - Área de concentração: Medicamentos e Cosméticos.
Orientador: Oliveira, Wanderley Pereira. Co-orientadora: Souza,Claudia R. Fernandes.
RESUMO
Cortés-Rojas, D.F. Encapsulação de compostos bioativos de Syzyguim aromaticum em
carreadores lipídicos sólidos. 2015. 157 f. Tese (Doutorado). Faculdade de Ciências Farmacêuticas de Ribeirão Preto – Universidade de São Paulo, Ribeirão Preto, 2015.
Compostos de origem vegetal podem apresentar inúmeros efeitos benéficos à saúde, havendo, entretanto, uma necessidade de desenvolver formulações que permitam viabilizar seu uso farmacêutico, alimentício, nutracêutico ou cosmecêutico. Syzygium aromaticum, conhecido popularmente como cravo da Índia, é uma espécie vegetal aromática com marcada atividade antioxidante, analgésica e antimicrobiana. A baixa solubilidade e estabilidade química, assim como a volatilidade dos principais compostos associados às atividades biológicas da planta justificam o desenvolvimento de formulações que melhorem suas propriedades físico-químicas e características de liberação. Formulações lipídicas têm sido cada vez mais usadas para o aumento da solubilidade de compostos no trato gastrointestinal e para o aumento da biodisponibilidade. O principal objetivo deste projeto foi investigar a produção de formulações lipídicas sólidas contendo compostos bioativos de S. aromaticum e avaliar o efeito da composição da formulação e das variáveis operacionais nas propriedades físico-químicas das partículas, estabilidade e permeação intestinal in vitro. O processo de extração dos compostos a partir da matéria-prima vegetal também foi estudado. A formulação lipídica foi otimizada com respeito ao tipo e a proporção dos lipídeos, do emulsificante e dos carreadores de secagem. Os processos de emulsificação e secagem também foram criteriosamente estudados. Os resultados mostraram que a composição da formulação teve efeitos significativos nas propriedades físico-químicas do produto e no desempenho da secagem. A formulação lipídica otimizada mostrou ser mais estável que a formulação não lipídica em condições de armazenamento de alta umidade. Com relação à permeação intestinal in vitro, utilizando eugenol como marcador, não foram observadas diferenças significativas entre estas duas formulações. Este projeto permitiu obter informações relevantes sobre a secagem por spray drying de formulações lipídicas contendo extratos vegetais. Esta rota tecnológica representa uma estratégia interessante na obtenção de formulações lipídicas estáveis que promovam o aumento da biodisponibilidade oral de compostos bioativos.
ABSTRACT
Cortés Rojas, D.F. Encapsulation of bioactive compounds from Syzygium aromaticum in
solid lipid carriers. 2015. 157 f. Thesis (Doctoral). School of Pharmaceutical Sciences of Ribeirão Preto – University of São Paulo, Ribeirão Preto, 2015.
Plant-derived compounds can provide important benefits to human health. However, these compounds should be properly formulated in order to facilitate their pharmaceutical, nutraceutical, food or cosmetic applications. Syzygium aromaticum commonly known as Indian clove, is an aromatic tree with antioxidant, antimicrobial and analgesic properties. The poor water solubility and the volatility of the compounds associated to the biological activities, justify the development of formulations that improve its physicochemical and release properties. Lipid based formulations have gained special attention for oral delivery due to the improvement of solubility in the intestinal tract and increase of bioavailability. The main objective of this project was to investigate the production of solid lipidic formulations containing bioactive compounds of S. aromaticum and to test the effect of the formulation composition and the process variables on the physhicochemical properties of the particles, stability and in vitro intestinal permeation. The extraction methods of the compounds from the plant were also studied. The lipid formulation was optimized with regard to the type and proportion of the solid lipid, the surfactant and the drying carrier. The emulsification and the drying processes were carefully evaluated. Results showed that the formulation composition had significant effects on the physicochemical properties of the product and on the drying performance. The optimized lipid formulation was more stable than the formulation without lipids in high humidity stress storage conditions. With regard to the in vitro intestinal permeation using eugenol as marker compound, not significant differences were observed between the samples. This project allowed to obtain relevant information about the spray drying process of lipid formulations containing plant extracts. This technique could be an interesting strategy to obtain stable lipid formulations than enhance the oral bioavailability of bioactive compounds.
RESUMEN
Cortés-Rojas, D.F. Encapsulación de compostos bioactivos de Syzygium aromaticum em
sistémas lipídicos sólidos. 2015. 157 f. Tesis (Doctorado). Faculdad de Ciencias Farmaceuticas de Ribeirão Preto – Universidad de São Paulo, Ribeirão Preto, 2015.
Compuestos de origen vegetal pueden presentar diversos efectos benéficos para la salud, sin embargo, existe la necesidad de desarrollar formulaciones que permitan viabilizar su uso farmacéutico, alimentício, nutracéutico o cosmético. Syzygium aromaticum, conocida popularmente como clavo de la India, es una espécie vegetal aromática con elevada actividad antioxidante, analgésica y antimicrobiana. La poca solubilidad y estabilidad química así como la alta volatilidad de los principales compuestos de la planta asociados a la actividad biológica justifican el desarrollo de formulaciones que mejoren sus propiedades fisicoquímicas y características de liberación. Formulaciones lipidias están siendo cada vez más usadas para aumentar a solubilidad de los compuestos en el tracto gastrointestinal y para aumentar la biodisponibilidad. El principal objetivo de este proyecto fue investigar la producción de formulaciones lipídicas sólidas de compuestos bioactivos de S. aromaticum y evaluar el efecto de la composición de la formulación y de las variábles operacionales en las propiedades fisicoquímicas de las partículas, estabilidad y permeación intestinal in vitro. El proceso de extracción de los compuestos a partir del material vegetal también fue estudiado. La formulación lipídica fue optimizada con respecto al tipo y proporción de los lípidos, tensoactivos y adjuvantes de secado. Los procesos de emulsificación y secado también fueron críticamente estudiados. Los resultados mostraron que la composición de la formulación tuvo efectos significativos en las propiedades fisicoquímicas del producto y en el desempeño del proceso de secado. La formulación lipídica optimizada fue mas estable que la formulación sin lípidos cuando fue almacenada en condiciones de alta humedad. Con respecto a la permeación intestinal in vitro, utilizando eugenol como marcador, no fueron observadas diferencias significativas entre estas dos formulaciones. Este proyecto permitió obtener informaciones relevantes sobre el proceso de secado por spray drying de formulaciones lipídicas conteniendo extractos vegetales. Esta ruta tecnológica representa una estrategia interesante en la obtención de formulaciones lipídicas estables que promuevan el aumento de la biodisponibilidad oral de compuestos bioactivos.
1. Introdução
Historicamente, a maioria dos fármacos tem surgido de metabólitos secundários de produtos naturais ou seus derivados (Li & Vederas, 2009). As plantas medicinais e aromáticas têm representado importantes fontes de compostos de elevado valor terapêutico e nutricional para o tratamento e prevenção de diversas doenças. Dentre os medicamentos que tiveram grande impacto na medicina e que foram obtidos a partir de fontes naturais estão a vimblastina, placitaxel, podofilotoxina, campotecina, avermectina, quinina, artemisinina, lovastatina, doxorubicina, captopril e taxol entre outros.
O cravo da Índia, em particular, é uma especiaria que tem sido usada por séculos por suas propriedades antimicrobianas, anestésicas e antioxidantes, comprovadas em diversos trabalhos científicos e associadas a compostos como o eugenol, β-cariofileno e α-humuleno
(Cortes-Rojas, Souza, & Oliveira, 2014). Entretanto, varias limitações relacionadas à estabilidade, volatilidade, baixa solubilidade e biodisponibilidade dos seus compostos bioativos representam um desafio e tornam o cravo uma matéria-prima vegetal de grande interesse para o desenvolvimento deste projeto.
A encapsulação de princípios ativos vegetais é uma técnica que vem sendo empregada para solucionar problemas relacionados com a volatilidade, baixa estabilidade, solubilidade e baixa biodisponibilidade. Esta técnica consiste na inclusão do agente ativo em um invólucro protetor utilizando diferentes tipos de materiais de parede. Os métodos de encapsulação podem ser divididos em processos físicos como spray drying, químicos como a polimerização interfacial ou físico-químicos como a coaservação (Fang & Bhandari, 2010). Os compostos bioativos encapsulados são protegidos frente a fatores externos (oxidação, luz) e são conferidas algumas propriedades fisico-químicas desejadas.
Sistemas lipídicos micro e nanoestruturados representam uma nova tendência de sistemas de liberação por via oral aumentando a biodisponibilidade do fármaco por diversos mecanismos os quais serão abordados na revisão da literatura. Este tipo de formulações também têm sido utilizados para a proteção e liberação de compostos de origem vegetal como a quercetina (Chen-yu et al., 2012), luteína (Liu & Wu, 2010), silibina (Jia et al., 2010), psoralenos (Fang, Fang, Liu, & Su, 2008), β-caroteno (Hung et al., 2011) entre outros. A
simplicidade de preparo e de ampliação de escala tem contribuído para o aumento do interesse das indústrias farmacêuticas e de alimentos.
ser realizado um estudo detalhado de cada etapa do processo visando conhecer os mecanismos de formação das partículas e alcançar as características desejadas do produto.
Por outro lado, as formas fitofarmacêuticas secas são preferidas devido à maior estabilidade, facilidade de manuseio e armazenamento. A técnica de spray drying tem sido utilizada com sucesso na secagem e microencapsulação de extratos vegetais, entretanto, a secagem de formulações lipídicas contendo extratos vegetais por esta técnica é uma nova abordagem que ainda carece de informações. Nesse sentido, este projeto de pesquisa teve por objetivo desenvolver formulações secas de emulsões e sistemas lipídicos visando a melhora da solubilidade e o aumento da estabilidade dos principais compostos ativos presentes em extratos de cravo da Índia (Syzygium aromaticum).
Conclusões 11
6. CONCLUSÕES
A partir dos resultados obtidos nas condições experimentais analisadas, foram geradas informações relevantes sobre a influência dos componentes da formulação etapas de processamento e condições de secagem por spray drying na obtenção de sistemas particulados de base lipídica incorporando compostos bioativos de S. aromaticum. A seguir são apresentadas as conclusões obtidas em de cada etapa do desenvolvimento deste trabalho.
6.1. Extração micelar
Os resultados obtidos em esta etapa demonstraram que a extração de eugenol e de compostos antioxidantes dos botões florais de S.aromáticum utilizando tensoativos representa uma alternativa interessante ao uso de solventes orgânicos. Foi demonstrado que a eficiência da extração depende do EHL dos tensoativos e sua concentração, obtendo-se melhores resultados quando foram utilizados valores de EHL maiores que 10. Da mesma forma, foi observado que a extração em meio básico foi mais eficiente e que a atividade antioxidante, assim como o teor de polifenóis totais, estão diretamente correlacionados com o teor de eugenol extraído. Deste modo, é possível dizer que a extração usando solventes reconhecidos como seguros (GRAS), pode facilitar o desenvolvimento de formulações fitofarmacêuticas ou de grau alimentício sem a necessidade de um processo posterior de eliminação do solvente. Entretanto, foi obtida baixa retenção de eugenol quando as composições foram submetidas a secagem em spray drying.
6.2. Influência da composição da formulação
Conclusões 12
6.3. Influência do EHL e temperatura de secagem da formulação
Esta etapa do projeto mostrou que o sistema de tensoativos (caracterizado pelo valor de HLB) e a temperatura de secagem, influenciam na retenção de eugenol e acetato de eugenol após secagem. As perdas de eugenol e acetato de eugenol foram em torno de 25 a 30 % maiores, quando as formulações foram atomizadas utilizando temperatura de secagem de 140 °C. Por outro lado nas formulações preparadas com o tensoativo de EHL 13 as perdas de eugenol e acetato de eugenol foram menores.
6.4. Influência da proporção dos componentes na formulação
Esta etapa do projeto mostrou que mudanças nas proporções dos componentes têm grande influência na viscosidade das formulações o que por sua vez, tem relação com a estabilidade e retenção dos compostos ativos. Dentre as duas formulações selecionadas para secagem por spray drying, a formulação com menor viscosidade, contendo goma arábica como carreador de secagem e com menor proporção de fase lipídica teve maior retenção de eugenol.
6.5. Comparação formulação lipídica e não lipídica
A partir da comparação da formulação lipídica com a formulação sem a adição de lipídeos foi possível determinar que a adição de lipídeos à formulação aumenta a adesão das partículas às paredes do secador, ocasionando um menor rendimento de produção de pó. Além disso a formulação sem lipídeos (CSD5) apresentou maior retenção de eugenol e da atividade antioxidante do que a formulação lipídica (CSD4).
Em relação ao estudo de estabilidade, a formulação lipídica mostrou ser mais estável do que a formulação não lipídica em condições de alta umidade relativa. Da mesma forma, a formulação lipídica teve menor variação de peso e menor ganho de umidade média do que a formulação sem lipídeo em todas as condições de armazenamento avaliadas.
Conclusões 13
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