Preparation and in-vitro release rate of fentanyl–cyclodextrin complexes for prolonged action in epidural analgesia

Abstract

Fentanyl was complexed with cyclodextrin derivatives with the intention to obtain parenteral solutions able to provide prolonged analgesia following epidural administration. Three cylodextrins (CDs) suitable for parenteral use were used: hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin (SBE-7-β-CD), and maltosyl-β-cyclodextrin (malt-β-CD). Analysis of fentanyl was done with HPLC-UV. The inclusion capacity of HP-β-CD was determined from phase-solubility diagrams at pH 6.5, 7.2 and 8.0, and those of SBE-7-β-CD and of malt-β-CD at pH 8.0. Solubility of fentanyl increased linearly (i) as a function of the CD concentration, and (ii) with decreasing pH. Complexation was highest with HP-β-CD and malt-β-CD, much higher than with SBE-7-β-CD, with stability constants at pH 8.0 of 801, 729 and 1309 M −1, respectively. The CD concentration was calculated to obtain a fentanyl–CD formulation, with the desired amount free fentanyl as loading dose in solution and the rest complexed with CD, as reservoir for prolonged action. A suitable membrane and a release-rate apparatus were selected for in-vitro release-rate studies. Best results were obtained with Spectrapor membranes and a home-made release-rate apparatus. Release rate was evaluated in static and dynamic conditions. For both modes, the release rate of fentanyl decreased as a function of CD concentration, due to complex formation of fentanyl, which suggests the possibility to provide prolonged pharmacodynamic effects in vivo.