Inclusion complexation of amide-typed local anaesthetics with beta-cyclodextrin and its derivatives .2. Evaluation of affinity constants and in 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-hydroxypropyl-beta-cyclodextrin (HP beta CD) and heptakis (2,6-di-o methyl)-beta- cyclodextrin (DM beta CD), were studied in aqueous solution at 25 degrees C and 37 degrees C using the solubility method of Higuchi 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 improvement in LA biopharmaceutics provided more evidence about LA-CD complexation. 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 greatest 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-phase system, water with methylene chloride or n-octanol. The BVC-CDs complexation provided modifications in first-order transfer rate constants compared with BVC alone, showing a decrease in the transfer rate of BVC between the two phases.