Micropartículas gastrorretentivas de curcumina constituídas por hidroxipropilmetilcelulose e quitosana aplicadas ao tratamento de úlceras gástricas
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Data
2021-12-17
Autores
Souza, Maurício Palmeira Chaves de
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Universidade Estadual Paulista (Unesp)
Resumo
As úlceras gástricas são patologias causadas por bactérias ou uso de medicamentos especialmente os antiinflamatórios não esteroidais (AINES), sendo que a falta de tratamento dessa condição pode levar ao agravamento da lesão e até mesmo ao câncer gástrico. A curcumina é um composto natural obtido a partir dos rizomas da planta Curcuma longa e é utilizada na medicina tradicional indiana há muitos séculos. Entretanto, por apresentar baixa solubilidade em meios aquosos, seu uso é limitado. Atrelado a isso, o tratamento de doenças gástricas demanda que o fármaco permaneça em contato com a área, porém o tempo de permanência de formas farmacêuticas convencionais neste órgão é limitado pelo tempo de esvaziamento gástrico, que é de cerca de 2h. Uma estratégia que pode ser utilizada para contornar essas limitações é o uso de um sistema de entrega gastrorretentivo, mucoadesivo e de liberação controlada para o estômago. Nesse sentido, o desenvolvimento de micropartículas poliméricas utilizando polímeros mucoadesivos, capazes de controlar a liberação de fármacos e permitir que essa liberação somente aconteça em meios ácidos, como a hidroxipropilmetilcelulose (HPMC) e a quitosana, pode ser extremamente vantajosa. Assim, o objetivo desse estudo foi desenvolver e caracterizar micropartículas poliméricas constituídas de quitosana e HPMC para veiculação de curcumina e avaliar in vivo o seu potencial antiúlcera. As micropartículas puderam ser selecionadas usando uma metodologia de ‘quality by design”, as quais foram obtidas por meio de geleificação ionotrópica e processo de liofilização. As micropartículas apresentaram forma esférica e exibiam diâmetros entre 620 e 820 µm. A microscopia eletrônica de varredura mostrou que as partículas contendo curcumina possuem grandes poros em seu interior, enquanto aquelas sem curcumina apresentam uniformidade em todo o seu interior. Espectroscopia no infravermelho com transformada de Fourier (FTIR) indicada como as principais regiões de interação polimérica; A difração de raios-X (DRx) foi capaz de mostrar que o processo de microencapsulação levou à amorfização da curcumina. A eficiência de encapsulação foi superior a 50% e as micropartículas liberaram completamente a curcumina após 24h, enquanto as liofilizadas apresentaram maiores taxas de liberação do que as não liofilizadas, o que evidenciou o impacto do processo de secagem. O mesmo comportamento foi observado nos testes de absorção de líquidos. As análises térmicas e gravimétricas mostaram que mudanças na estrutura dos polímeros e do curcumina e confirmaram uma interação polimérica, por meio majoritariamente de ligações de hidrogênio e forças de van der Waals. A análise de mucoadesão mostraram que todas as micropartículas obtidas apresentaram adesão no disco de mucina. E os resultados do estudo in vivo apontam na direção de que esses sistemas são ferramentas promissoras na prevenção de lesões gástricas associadas ao uso de AINES, apresentando índice de gastroproteção semelhante à conferida pelo ao omeprazol. A partir desses resultados, os MPs desenvolvidos podem ser explorados como um sistema de liberação controlada de fármacos com mecanismo duplo, um desencadeado pela presença de ácidos, destinados à liberação gastroespecífica e outro mucoadesivo, com potencial para aplicação em gastroproteção, principalmente em pacientes que fazem uso crônico de AINES.
Gastric ulcers are pathologies caused by bacteria or use of medication, especially non steroidal anti inflammatory drugs (NSAIDs).The lack of treatment for this condition can lead to aggravation of the lesion and cause gastric cancer. Curcumin is a natural compound extracted from the rhizomes of the long turmeric plant and has been used in traditional Indian medicine for many centuries. However, due to its low solubility in aqueous media, its use is limited. The treatment of gastric diseases requires the drug remains in contact with the stomach mucosa, but the permanence time of pharmaceutical forms is impaired by the time of gastric emptying, which is about 2 h. One strategy that can be used to circumvent these limitations is the use of a gastroretentive and controlled-release systems with targeting to the stomach. In this regard, the development of polymeric microparticles using mucoadhesive polymers such as hydroxypropylmethylcellulose (HPMC) and chitosan (CS), capable of controlling the release of drugs and triggering the release only in acidic media can be extremely advantageous. Thus, the aim of this study was to develop and characterize polymeric microparticles prepared by ionotropic gelation from CS/HPMC and sodium tripolyphosphate (TPP) for gastroretentive delivery of curcumin and to evaluate its in vivo antiulcer potential. The microparticles formulation could be selected using a quality by design methodology through inotropic gelation and lyophilization processes. Microparticles were spherical in shape and show diameter between 620 and 820 µm. Scanning electron microscopy shows that particles containing curcumin have large pores in their interior, while those without curcumin present uniformity throughout their matrix. Fourier Transform Infrared Spectroscopy (FTIR) indicated as the main polymeric interaction regions; X-Rays Diffraction (XRD) was able to show that the microencapsulation process led to amorphization of curcumin. The encapsulation efficiency was greater than 50% and microparticles completely released curcumin after 24h, while the lyophilized ones had higher release rates than non-lyophilized ones, which showed the impact of the drying process. The same behavior was observed in liquid absorption tests. Thermal and gravimetric analyzes showed changes in the structure of polymers and curcumin and confirmed a polymeric interaction, mainly through hydrogen bonds and van der Waals forces. Mucoadhesion analysis showed that all microparticles obtained presented adhesion in the mucin disc. Results of the invivo study point in the direction that these systems are promising tools in the prevention of gastric lesions associated with NSAID use, presenting index of gastroprotection almost same omeprazole. From these results, developed MPs can be explored as a controlled release system of drugs with triggering mechanisms to acidic environments, with potential for application in gastroprotection, especially in patients that use NSAID chronically.
Gastric ulcers are pathologies caused by bacteria or use of medication, especially non steroidal anti inflammatory drugs (NSAIDs).The lack of treatment for this condition can lead to aggravation of the lesion and cause gastric cancer. Curcumin is a natural compound extracted from the rhizomes of the long turmeric plant and has been used in traditional Indian medicine for many centuries. However, due to its low solubility in aqueous media, its use is limited. The treatment of gastric diseases requires the drug remains in contact with the stomach mucosa, but the permanence time of pharmaceutical forms is impaired by the time of gastric emptying, which is about 2 h. One strategy that can be used to circumvent these limitations is the use of a gastroretentive and controlled-release systems with targeting to the stomach. In this regard, the development of polymeric microparticles using mucoadhesive polymers such as hydroxypropylmethylcellulose (HPMC) and chitosan (CS), capable of controlling the release of drugs and triggering the release only in acidic media can be extremely advantageous. Thus, the aim of this study was to develop and characterize polymeric microparticles prepared by ionotropic gelation from CS/HPMC and sodium tripolyphosphate (TPP) for gastroretentive delivery of curcumin and to evaluate its in vivo antiulcer potential. The microparticles formulation could be selected using a quality by design methodology through inotropic gelation and lyophilization processes. Microparticles were spherical in shape and show diameter between 620 and 820 µm. Scanning electron microscopy shows that particles containing curcumin have large pores in their interior, while those without curcumin present uniformity throughout their matrix. Fourier Transform Infrared Spectroscopy (FTIR) indicated as the main polymeric interaction regions; X-Rays Diffraction (XRD) was able to show that the microencapsulation process led to amorphization of curcumin. The encapsulation efficiency was greater than 50% and microparticles completely released curcumin after 24h, while the lyophilized ones had higher release rates than non-lyophilized ones, which showed the impact of the drying process. The same behavior was observed in liquid absorption tests. Thermal and gravimetric analyzes showed changes in the structure of polymers and curcumin and confirmed a polymeric interaction, mainly through hydrogen bonds and van der Waals forces. Mucoadhesion analysis showed that all microparticles obtained presented adhesion in the mucin disc. Results of the invivo study point in the direction that these systems are promising tools in the prevention of gastric lesions associated with NSAID use, presenting index of gastroprotection almost same omeprazole. From these results, developed MPs can be explored as a controlled release system of drugs with triggering mechanisms to acidic environments, with potential for application in gastroprotection, especially in patients that use NSAID chronically.
Descrição
Palavras-chave
Micropartículas, Curcumina, Liberação controlada, Geleificação Ionotrópica, Liofilização, Liberação gastroretentiva, Curcumin, gastroretentive drug release, Ionotropic Gelation, Lyophilization