title: Microwave synthesis and in vitro stability of diclofenac-β-cyclodextrin conjugate for colon delivery.
abstract: The aim of this work was to synthesize an ester prodrug of diclofenac and β-cyclodextrin suitable for colonic delivery. The synthesis of an ester linkage between diclofenac and β-cyclodextrin was conducted by the nucleophilic substitution of mono-6-tosyl-β-cyclodextrin under microwaves irradiation. After purification, the conjugate was characterized by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry; infrared (IR) spectroscopy; proton nuclear magnetic resonance ((1)H NMR) spectroscopy; and two-dimensional rotating frame nuclear overhauser effect (ROESY) spectroscopy. The purity was qualified by high pressure liquid chromatography (HPLC). To assess its potential for colonic delivery, the conjugate was evaluated for stability in simulated gastric and small intestinal fluids, and in fecal material from humans processed within a slurry under anaerobic conditions. The conjugate was successfully synthesized with a yield of 20% following purification. The mass spectra showed the parent peak m/z 1434 corresponding to [conjugate+Na] adduct. IR and NMR results confirmed that the carboxyl group of diclofenac is covalently bound to one of the hydroxyl groups of cyclodextrin by an ester linkage. Moreover, ROESY data indicated that the formation of the conjugate is not accompanied by the inclusion of diclofenac within the cyclodextrin. The conjugate was otherwise stable in simulated gastric and small intestinal conditions, but was also readily hydrolyzed liberating diclofenac in less than 2h within the human fecal slurry. This confirmed the potential for this new prodrug as a carrier for colonic delivery.
authors.affiliation: Centre for Pharmaceutical Studies, Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Portugal.
authors.forename: Amélia C F
authors.initials: AC
authors.lastname: Vieira
authors.forename: Arménio C
authors.initials: AC
authors.lastname: Serra
authors.forename: Rui A
authors.initials: RA
authors.lastname: Carvalho
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gonsalves
authors.forename: Ana
authors.initials: A
authors.lastname: Figueiras
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Veiga
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Basit
authors.forename: António M d'A
authors.initials: AM
authors.lastname: Rocha Gonsalves
mesh_terms: D000693:Anaerobiosis; D001826:Body Fluids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000737:chemistry*; D004008:Diclofenac / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D005243:Feces; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008872:Microwaves; D011355:Prodrugs / Q000008:administration & dosage; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013997:Time Factors; D047392:beta-Cyclodextrins / Q000008:administration & dosage*
chemical_list: D004337:Drug Carriers; D011355:Prodrugs; D047392:beta-Cyclodextrins; D004008:Diclofenac