Synthesis, characterization and in vitro evaluation of dimethyl-β-cyclodextrin-4-biphenylylacetic acid conjugate

• Published in: Journal of drug targeting 2003-05, Vol.11 (4), p.233-240
• Main Authors: VENTURA, C. A, PAOLINO, D, PEDOTTI, S, PISTARA, V, CORSARO, A, PUGLISI, G
• Format: Article
• Language: English
• Subjects: beta-Cyclodextrins; Biological and medical sciences; Caco-2 Cells; Cyclodextrins - chemical synthesis; Cyclodextrins - pharmacokinetics; Drug Evaluation, Preclinical - methods; General pharmacology; Humans; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phenylacetates - chemical synthesis; Phenylacetates - pharmacokinetics; Solubility
• ISSN: 1061-186X; 1029-2330
• DOI: 10.1080/10611860310001615965

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.