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

J Drug Target. 2003 May;11(4):233-40. doi: 10.1080/10611860310001615965.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Cyclodextrins / chemical synthesis*
  • Cyclodextrins / pharmacokinetics*
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Phenylacetates / chemical synthesis*
  • Phenylacetates / pharmacokinetics*
  • Solubility
  • beta-Cyclodextrins*

Substances

  • Cyclodextrins
  • Phenylacetates
  • beta-Cyclodextrins
  • heptakis(2,6-O-dimethyl)beta-cyclodextrin
  • biphenylylacetic acid