Dispersões sólidas de ácido ursólico veiculadas em hidrogéis para administração cutânea: desenvolvimento, caracterização e avaliação biológica in vitro e in vivo
Carregando...
Data
2019-05-30
Autores
Pironi, Andressa Maria
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
RESUMO A inflamação cutânea envolve a liberação de vários mediadores inflamatórios, os quais quando em excesso podem ser nocivos e causar o desenvolvimento de doenças inflamatórias e crônicas de pele. O fator nuclear kappa B (NF-κB) exerce um papel fundamental na produção de citocinas e outras proteínas pró-inflamatórias, portanto, o desequilíbrio dessa via celular está associado à patogênese dos distúrbios inflamatórios na pele. O ácido ursólico é um triterpenóide de ocorrência natural com propriedades anti-inflamatórias que resultam na supressão de mediadores inflamatóriosvia inibição da ativação doNF-κB, sendo um candidato para o tratamento de inflamações cutâneas. Entretanto, essa molécula apresenta baixa solubilidade em água o quelimita sua aplicação terapêutica.Neste contexto, o desenvolvimento de dispersões sólidas (DS)constituídas de polivinilpirrolidona k-30 e tensoativos, como poloxamer 407 ou D-α-tocoferol polietilenoglicol 1000 succinato (TPGS) representa uma estratégiapara aumentar a sua solubilidade.Além disso, a veiculação das DS em um hidrogel à base de poloxamer pode viabilizara administração tópica do fármaco. O objetivo deste trabalho foi desenvolver e caracterizar DS de ácido ursólico constituídas por PVP K-30 e TPGS/P407 incorporadas em um hidrogel, além de avaliar a citotoxicidadein vitro e a atividade anti-inflamatória in vivo desses sistemas. Os resutados obtidos revelaram que ambas as DS aumentaram significativamente a solubilidade aquosa do fármaco. Conforme os dados obtidos a partir das análises de difração de raios-X e calorimetria exploratória diferencial, o aumento da solubilidade demonstrou estar relacionado com a dispersão do AU na matriz polimérica na forma molecular ou no estado amorfo. Os hidrogéis de poloxamer demonstraram adequadas propriedades mecânicas e bioadesivas para administração cutânea. Ainda, as análises reológicas evidenciaram comportamento pseudoplástico para os hidrogéis, o que é desejável para formulações de uso tópico. Além disso, as DS e os hidrogéis contendo ambas as DS retardaram o perfil de liberação do ácido ursólico. A partir do estudo de permeação cutânea in vitro e quantificação do fármaco nas camadas da pele, verificou-se que aDS16 ao ser incorporada no hidrogel, proporcionou um menor fluxo de fármaco(12,48±1,48 μg/cm²/ h) atravé da pele, enquanto para o hidrogel contendo a DS2 não houve a permeação após 30 horas de ensaio. Ainda, foi observado para todas as formulações desenvolvidas que o AU se acumulou mais na epiderme do que no estrato córneo, isto é particularmente evidente para as DS16. O ácido ursólico bem com os hidrogéis com as dispersões sólidas demonstraram-se biocompatíveis frente à linhagem celular L929 (fibroblastos). Os resultados da avaliação do efeito anti-inflamatório in vivo revelaram que para as DS a atividade anti-inflamatória foi significativamente maior quando ambas foram aplicadas incorporadas nos hidrogéis de poloxamer, reduzindo 41,87% e 56,64% do edema induzido por aplicação tópico de óleo de cróton. Portanto a partir dos resultados obtidos pode-se concluir que os sistemas desenvolvidos demonstram ser uma abordagem interessante e inovadora para o tratamento de doenças inflamatórias crônicas de pele.
Cutaneous inflammation involves the release of several inflammatory mediators, which when excess can be harmful and cause the development of inflammatory and chronic skin diseases. Nuclear factor kappa B (NF-κB) plays a key role in the production of cytokines and other proinflammatory proteins, so imbalance of this cellular pathway is associated with the pathogenesis of inflammatory skin disorders. Ursolic acid (UA) is a naturally-occurring triterpenoid with anti-inflammatory properties that result in the suppression of inflammatory mediators via inhibition of NF-κB activation and is a promising candidate for the treatment of cutaneous inflammations. However, this molecule presents low solubility in water, which limits its therapeutic application. In this context, the development of solid dispersions (SD) consisting of polyvinylpyrrolidone k-30 and surfactants, such as poloxamer 407 or D-α- tocopherol polyethylene glycol 1000 succinate (TPGS) appears as a strategy to improve their solubility. In addition, SD conveyed in a poloxamer-based hydrogel may enable topical administration of the drug present in SD. The objective of this work was to develop and characterize and SD of ursolic acid constituted by PVP K-30 and TPGS / P407 carried in a hydrogel, in addition to evaluate the in vitro cytotoxicity and in vivo anti-inflammatory activity of these systems. The results obtained revealed that both solid dispersions significantly increased the aqueous solubility of the UA. According to the data obtained from X-ray diffraction and differential scanning calorimetry, the increase in solubility has been shown to be related to the dispersion of UA in the polymer matrix in molecular or amorphous form. Poloxamer hydrogels and subsequent incorporation of DS demonstrated adequate mechanical and bioadhesive properties for skin delivery. Furthermore, rheological analyzes showed a pseudoplastic behavior for all hydrogels, whose performance is desirable for topical formulations. In addition,SD, hydrogels with the drug, and hydrogels containing SD controlled release of the ursolic acid. In vitro cutaneous permeation study and quantification of the drug in the skin layers, it was found that SD16, when formulated in hydrogel, provided a lower drug flow (12.48 ± 1.48 μg / cm² / h) through the skin, whereas for the hydrogel containing SD2 there was no permeation after 30 hours of test. Furthermore, it has been observed for all formulations developed that UA has accumulated more in the epidermis than in the stratum corneum, this is particularly evident for the SD16. Free ursolic acid and hydrogels with the solid dispersions were shown to be biocompatible against the L929 cell line (fibroblasts). The results of the evaluation of the anti-inflammatory effect in vivo revealed that for the SD the anti-inflammatory activity was significantly higher when both were applied incorporated in the poloxamer hydrogels, reducing 41.87% and 56.64% of the edema induced by topical application of croton oil. Therefore from the results obtained it can be concluded that the systems developed prove to be an interesting and innovative approach for the treatment of chronic inflammatory skin diseases.
Cutaneous inflammation involves the release of several inflammatory mediators, which when excess can be harmful and cause the development of inflammatory and chronic skin diseases. Nuclear factor kappa B (NF-κB) plays a key role in the production of cytokines and other proinflammatory proteins, so imbalance of this cellular pathway is associated with the pathogenesis of inflammatory skin disorders. Ursolic acid (UA) is a naturally-occurring triterpenoid with anti-inflammatory properties that result in the suppression of inflammatory mediators via inhibition of NF-κB activation and is a promising candidate for the treatment of cutaneous inflammations. However, this molecule presents low solubility in water, which limits its therapeutic application. In this context, the development of solid dispersions (SD) consisting of polyvinylpyrrolidone k-30 and surfactants, such as poloxamer 407 or D-α- tocopherol polyethylene glycol 1000 succinate (TPGS) appears as a strategy to improve their solubility. In addition, SD conveyed in a poloxamer-based hydrogel may enable topical administration of the drug present in SD. The objective of this work was to develop and characterize and SD of ursolic acid constituted by PVP K-30 and TPGS / P407 carried in a hydrogel, in addition to evaluate the in vitro cytotoxicity and in vivo anti-inflammatory activity of these systems. The results obtained revealed that both solid dispersions significantly increased the aqueous solubility of the UA. According to the data obtained from X-ray diffraction and differential scanning calorimetry, the increase in solubility has been shown to be related to the dispersion of UA in the polymer matrix in molecular or amorphous form. Poloxamer hydrogels and subsequent incorporation of DS demonstrated adequate mechanical and bioadhesive properties for skin delivery. Furthermore, rheological analyzes showed a pseudoplastic behavior for all hydrogels, whose performance is desirable for topical formulations. In addition,SD, hydrogels with the drug, and hydrogels containing SD controlled release of the ursolic acid. In vitro cutaneous permeation study and quantification of the drug in the skin layers, it was found that SD16, when formulated in hydrogel, provided a lower drug flow (12.48 ± 1.48 μg / cm² / h) through the skin, whereas for the hydrogel containing SD2 there was no permeation after 30 hours of test. Furthermore, it has been observed for all formulations developed that UA has accumulated more in the epidermis than in the stratum corneum, this is particularly evident for the SD16. Free ursolic acid and hydrogels with the solid dispersions were shown to be biocompatible against the L929 cell line (fibroblasts). The results of the evaluation of the anti-inflammatory effect in vivo revealed that for the SD the anti-inflammatory activity was significantly higher when both were applied incorporated in the poloxamer hydrogels, reducing 41.87% and 56.64% of the edema induced by topical application of croton oil. Therefore from the results obtained it can be concluded that the systems developed prove to be an interesting and innovative approach for the treatment of chronic inflammatory skin diseases.
Descrição
Palavras-chave
ácido ursólico, atividade anti-inflamatória, hidrogéis, dispersões sólidas, Ursolic acid, Hydrogels