Synthesis, characterization and in vitro evaluation of dimethyl-beta-cyclodextrin-4-biphenylylacetic acid conjugate.
Biphenylylacetic acid (BPAA) was linked to the free hydroxyl group of 2,6-di-O-methyl-beta-Cyclodextrin (DM-beta-CyD) through an ester linkage to obtain the site specific release of the drug to the colon. The conjugate at 1:1 mole ratio was separated from the reaction mixture by semipreparative reverse-phase HPLC and characterized by 1H-NMR, 13C-NMR, IR spectroscopy, mass spectrometry and elemental analysis. Chemico-physical characteristics, such as water solubility and dissolution rate, were evaluated comparatively to the BPAA-DM-beta-CyD inclusion complex. Hydrolysis rates were investigated in media simulating gastro-intestinal fluids and at pH 7.4 in the presence of porcine liver esterase. A rapid release of the drug was observed at acid pH value. In all cases a first order kinetic was observed, characterized by t1/2 value of 1.19, 19 and 4 h for chemical hydrolysis at pH 1.1, at pH 7.4 and enzymatic hydrolysis, respectively. In vitro permeation studies through caco-2 cells confirmed the ability of DM-beta-CyD to increase the absorption of included BPAA. A slow permeation was observed for the drug conjugate to DM-beta-CyD due to the slow release of BPAA.
Dipartimento Farmaco-Chimico, Università di Messina, Italy.
C A
CA
Ventura
D
D
Paolino
S
S
Pedotti
V
V
Pistarà
A
A
Corsaro
G
G
Puglisi
D018938:Caco-2 Cells; D003505:Cyclodextrins / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D012995:Solubility; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D010648:Phenylacetates; D047392:beta-Cyclodextrins; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; C012776:biphenylylacetic acid