title: 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-beta-cyclodextrin (HP-beta-CD), sulfobutylether-beta-cyclodextrin (SBE-7-beta-CD), and maltosyl-beta-cyclodextrin (malt-beta-CD). Analysis of fentanyl was done with HPLC-UV. The inclusion capacity of HP-beta-CD was determined from phase-solubility diagrams at pH 6.5, 7.2 and 8.0, and those of SBE-7-beta-CD and of malt-beta-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-beta-CD and malt-beta-CD, much higher than with SBE-7-beta-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.
authors.affiliation: Department of Pharmaceutical Technology and Physical Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Holvoet
authors.forename: J
authors.initials: J
authors.lastname: Plaizier-Vercammen
authors.forename: Y
authors.initials: Y
authors.lastname: Vander Heyden
authors.forename: M
authors.initials: M
authors.lastname: Gabriëls
authors.forename: F
authors.initials: F
authors.lastname: Camu
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D015360:Analgesia, Epidural / Q000379:methods*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004355:Drug Stability; D004987:Ethers / Q000008:administration & dosage / Q000737:chemistry; D005283:Fentanyl / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008320:Maltose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D008567:Membranes, Artificial; D012995:Solubility; D047392:beta-Cyclodextrins
chemical_list: D000701:Analgesics, Opioid; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D004987:Ethers; D008567:Membranes, Artificial; D047392:beta-Cyclodextrins; C433303:maltosyl-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C093196:SBE4-beta-cyclodextrin; D008320:Maltose; D005283:Fentanyl