RESUMO
Recently non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed to prevent or to cure Alzheimer's disease. In this respect, we synthesized new potential prodrugs of several NSAIDs in order to increase their access to the brain. The carboxylic group of NSAIDs was attached to the 1,4-dihydro-1-methylpyridine-3-carboxylate moiety, which acts as a carrier, via an amino alcohol bridge, according to the chemical delivery approach developed by Bodor. The lipophilicity of potential prodrugs was evaluated both via traditional experimental parameters, such as partition coefficient and chromatographic R(m) value, and by predictive computational methods. From experimental parameters, all prodrugs were more lipophilic when compared to their corresponding parent compounds and consequently a better blood brain barrier (BBB) penetration is hypothesised. Prodrug lipophilicity was correlated with a calculated log P value according to Kowwin's method. The correlation between experimental Rm0 and calculated log P, determined by PLS analysis, was good for all compounds with the exception of compound 7i. In addition the BBB permeation profile of our synthesized compounds was predicted using the BBB VolSurf model and seven of the synthesized prodrugs resulted in good candidates for BBB penetration.
Assuntos
Anti-Inflamatórios não Esteroides/química , Sistema Nervoso Central/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Pró-Fármacos/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Biologia Computacional/métodos , Simulação por Computador , Permeabilidade/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinéticaRESUMO
A new approach of improving drug dissolution properties is described. This method exploits the property of a carrier owing to the hydrotalcite-type anionic clays (HTlc). HTlc is an inorganic layered solid that lodges anionic compounds among its layers. As HTlc dissolves at acidic pH values (pH < 4), the anions intercalated among the layers are promptly released in the medium. In this article some nonsteroidal antiinflammatory drugs were chosen as models of poorly water-soluble drugs. They were intercalated in HTlc and solubility measurements in acidic medium were performed. A remarkable improvement of drug solubility was observed especially in the case of indomethacin.
Assuntos
Hidróxido de Alumínio/análise , Hidróxido de Magnésio/análise , Preparações Farmacêuticas/análise , Água/análise , Hidróxido de Alumínio/química , Hidróxido de Magnésio/química , Preparações Farmacêuticas/química , Solubilidade/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Termogravimetria/métodos , Água/químicaRESUMO
The purpose of this study was to investigate whether hydrotalcite is able to intercalate diclofenac, a nonsteroidal anti-inflammatory drug, and release it in a controlled manner. Layered Mg-Al hydrotalcite in the chloride form was used as a host, and the intercalation compound was prepared by Cl-/diclofenac anionic exchange. Drug release from the intercalation compound was performed in vitro in simulated intestinal fluid at pH 7.5 according to USP 24 and in a pH 7.0 solution designed to mimic the ionic conditions of the small intestine. Results from the intercalation process show that hydrotalcite is able to intercalate diclofenac with a simple procedure and with a good drug loading (55% wt/wt). The in vitro drug release was remarkably lower than that from the corresponding physical mixture at both pH 7.5 and pH 7.0. In the latter case, the release was not complete at 24 hours. The kinetic analysis shows the importance of the diffusion through the particle in controlling the drug release rate. The obtained results show that hydrotalcite may be used to prepare modified release formulations.