A novel conjugated system for colon specific drug delivery
Francisco Veiga
Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra; Rua do Norte, 3000 Coimbra,Portugal
Abstract:
Purpose: The aim of this work is to prepare prodrugs containing ß- and ?- cyclodextrin conjugated with diclofenac and to investigate the pharmaceutical approach of this system for colon specific release of the model drug. For this purpose, the carboxylic group of the drug is covalently conjugated with one of the hydroxyl groups of ß- or ?- cyclodextrin through an ester linkage.
Methods: The conjugate formed between ß- or ?-cyclodextrin and diclofenac are prepared in two steps. In the first step, one of the hydroxyl groups of cyclodextrin is tosylated using p-toluenesulfonyl chloride. The tosylation of ß-cyclodextrin is carried out in water and with ?-cyclodextrin in pyridine. In the second step, sodium salt of diclofenac is added to the tosylated-cyclodextrins in dimethylformamide (DMF). This reaction is carried out under microwaves irradiation. The conjugates are purified by ion exchange chromatography and then lyophilized. The chemical structures of the monoester conjugates were identified by proton nuclear magnetic resonance (1H NMR) spectroscopy and matrix-assisted laser desorption/ionization (MALDI) spectra. 1H NMR spectra were recorded on a Varian Unity-500MHz spectrometer, using dimethyl sulfoxide (DMSO) as solvent. Mass spectra were performed on a Autoflex III , Bruker using methanol and water as solvents and a-cyano-4-hydroxy-cinnamic acid (HCCA) as matrix.
Results: The obtained results indicate that the carboxyl group of diclofenac is covalently bound to one of the hydroxyl groups of both cyclodextrins. The mass spectra show the parent peaks corresponding to molecular weights of the conjugates and the RMN results confirmed the presence of a covalently bound diclofenac.
Conclusions: Strong evidence support that the nucleophylic substitution approach using the p-toluenesulphonyl derivative of cyclodextrin allows the synthesis of the conjugate with diclofenac. However, the success of the reaction depends on the use of microwave activation. In future studies we pretend to evaluate the hydrolysis of the formed conjugates in different physiological conditions.
Keywords: cyclodextrins, conjugated, colon drug delivery
