INCLUSION COMPLEXATION OF AMIDE-TYPED LOCAL-ANESTHETICS WITH BETA-CYCLODEXTRIN AND ITS DERIVATIVES .2. EVALUATION OF AFFINITY CONSTANTS ANDIN-VITRO TRANSFER RATE CONSTANTS

The inclusion complex-forming abilities of five local anaesthetics of the amide-type (LAs), bupivacaine (BVC), etidocaine (EDC), lidocaine ( LDC), mepivacaine (MVC) and prilocaine (PLC), with three cyclodextrins (CDs), beta-cyclodextrin (beta CD) and its alkylated derivatives 2-hy droxypropyl-beta-cyclodextrin (HP beta CD) and heptakis (2,6-di-o meth yl)-beta- cyclodextrin (DM beta CD), were studied in aqueous solution at 25 degrees C and 37 degrees C using the solubility method of Higuch i and Conners (1965) (Adv. Anal. Chem. Instr., 4 (1965) 117-212) based on changes in the solubility of substrates (LAs) upon the addition of ligands (CDs. The interaction was quantified for each LA-CD system by determination of the stability constant, from the slope of the phase- solubility diagram. This second part of a study dealing with improveme nt in LA biopharmaceutics provided more evidence about LA-CD complexat ion. The solubility increase of the LAs in the presence of CDs was in the rank order DM beta CD, HP beta CD >> beta CD; BVC showed the great est stability constant values of all LAs tested, for all CDs and there was an influence of the temperature upon the complexation, only with beta CD. Then, the effect of DM beta CD and HP beta CD on transfer of BVC from an aqueous to an organic phase was investigated with a two-ph ase system, water with methylene chloride or n-octanol. The BVC-CDs co mplexation provided modifications in first-order transfer rate constan ts compared with BVC alone, showing a decrease in the transfer rate of BVC between the two phases.