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Authors
Advisor(s)
Abstract(s)
O tratamento específico de patologias do cólon pode ser conseguido pelo desenvolvimento de
profármacos resultantes da conjugação de um fármaco com ciclodextrinas (CDs). A formação
destes conjugados permite que os fármacos atinjam o cólon de forma intacta, local no qual
sofrem degradação enzimática por acção da vasta microflora existente no cólon,
nomeadamente Bacteróides. Estas bactérias quebram as ligações glicosídicas das CDs
originando pequenos sacáridos, permitindo a sua absorção bem como a do fármaco.
A entrega direccionada de fármacos ao cólon permite o tratamento da doença no alvo
terapêutico, e consequentemente, permite reduzir a dosagem administrada e os efeitos
adversos associados.
Entre os vários tipos de anti-inflamatórios não esteróides (AINEs), o diclofenac de sódio é um
potencial candidato na terapêutica para libertação específica no cólon devido às suas
propriedades anti-inflamatorias e quimiopreventivas do cancro do cólon. A conjugação do
diclofenac com ciclodextrinas é um processo pouco explorado, tornando-se inovador com
recurso ao microondas. Neste trabalho experimental, procedeu-se à variação da temperatura
utilizada no microondas, entre os 100 e 200ºC, variando-se também os solventes utilizados,
PEG-200 e DMF, mantendo uma potência de 75W e um tempo de reacção de 40 minutos. O
principal objectivo do trabalho foi optimizar a síntese do conjugado βCD-Diclofenac. Os
melhores resultados foram obtidos para as temperaturas de 140ºC e 160ºC no solvente DMF.
Para as mesmas temperaturas em PEG-200, os rendimentos obtidos foram significativamente
inferiores. Estes resultados sugerem a necessidade de continuar a explorar as melhores
condições de reacção de síntese do conjugado βCD-Diclofenac de forma a obter maior
rendimento, recorrendo a solventes polares apróticos (que favorecem reacções SN2), bem
aquecidos pelo microondas e que apresentem baixa toxicidade.
The specific treatment of colon pathologies can be achieved by designing prodrugs in which a drug is covalently bound to cyclodextrins (CDs). The formation of these conjugates enables the drugs to reach the colon unmodified, where they undergo enzymatic degradation by the vast microflora present in the colon, mainly Bacteroides. These bacteria break the linkage between glucose units of the CDs forming small saccharides, allowing its absorption as well as the drugs’. Targeted drug delivery to the colon ensures the direct treatment at the disease site and consequently lowers the dosage and reduces the adverse side effects. Among the diverse nonsteroidal anti-inflammatory drugs (NSAIDs), sodium diclofenac is a potential candidate for specific drug delivery to the colon due to its anti-inflammatory and quimiopreventive properties of colon cancer. The conjugation of diclofenac with CDs is a process which has been poorly explored, and is considered novel using microwave heating. In this experiment, the temperature of the microwave varied between 100 and 200ºC, and the solvents used in the reaction also varied between PEG-200 and DMF. The microwave´s power and time reaction were maintained at 75W and 40 minutes, respectively. The aim of this experiment was to optimize the synthesis of the βCD-Diclofenac conjugate. The best results were achieved at temperatures of 140ºC and 160ºC in the solvent DMF. For the same temperatures in PEG-200, the yield was significantly lower. These results suggest the need to continue exploring the best reaction conditions for the synthesis of the βCD-Diclofenac conjugate in order to increase the yield, using polar aprotic solvents (that favor SN2 reactions) with well heated properties by microwave, and that present low toxicity.
The specific treatment of colon pathologies can be achieved by designing prodrugs in which a drug is covalently bound to cyclodextrins (CDs). The formation of these conjugates enables the drugs to reach the colon unmodified, where they undergo enzymatic degradation by the vast microflora present in the colon, mainly Bacteroides. These bacteria break the linkage between glucose units of the CDs forming small saccharides, allowing its absorption as well as the drugs’. Targeted drug delivery to the colon ensures the direct treatment at the disease site and consequently lowers the dosage and reduces the adverse side effects. Among the diverse nonsteroidal anti-inflammatory drugs (NSAIDs), sodium diclofenac is a potential candidate for specific drug delivery to the colon due to its anti-inflammatory and quimiopreventive properties of colon cancer. The conjugation of diclofenac with CDs is a process which has been poorly explored, and is considered novel using microwave heating. In this experiment, the temperature of the microwave varied between 100 and 200ºC, and the solvents used in the reaction also varied between PEG-200 and DMF. The microwave´s power and time reaction were maintained at 75W and 40 minutes, respectively. The aim of this experiment was to optimize the synthesis of the βCD-Diclofenac conjugate. The best results were achieved at temperatures of 140ºC and 160ºC in the solvent DMF. For the same temperatures in PEG-200, the yield was significantly lower. These results suggest the need to continue exploring the best reaction conditions for the synthesis of the βCD-Diclofenac conjugate in order to increase the yield, using polar aprotic solvents (that favor SN2 reactions) with well heated properties by microwave, and that present low toxicity.
Description
Keywords
Ciclodextrinas - Cancro do cólon Diclofenac de sódio - Cancro do cólon Diclofenac - Ciclodextrinas
Citation
Publisher
Universidade da Beira Interior