title: Paclitaxel/beta-cyclodextrin complexes for hyperthermic peritoneal perfusion - formulation and stability.
abstract: Due to its low aqueous solubility paclitaxel is currently formulated in a Cremophor EL/ethanol mixture. However, the vehicle of this formulation causes several side-effects. Our objective was to formulate a tensioactive-free and solvent-free paclitaxel solution, which can be used for a hyperthermic intraperitoneal chemoperfusion procedure (HIPEC). The potential of chemically modified beta-cyclodextrins to form complexes with paclitaxel was investigated as a means to increase the aqueous solubility of paclitaxel. Methylated beta-CDs (randomly methylated and 2,6-dimethylated) showed the best ability to solubilise paclitaxel compared to sulfobutyl-ether- and hydroxypropyl-beta-CD. The minimal ratio of paclitaxel versus randomly methylated-beta-cyclodextrin (RAME-beta-CD) yielding 100% inclusion efficiency was 1/20 (mol/mol). Paclitaxel/RAME-beta-CD inclusion complexes prepared via freeze drying were stable for at least 6 months when stored at 4 degrees C. A 5mg/ml paclitaxel solution was formulated using paclitaxel/RAME-beta-CD-complexes. Upon dilution of these solutions, no precipitation was seen. After 24h storage at room temperature or 2h at HIPEC conditions (41.5 degrees C) the 1/40 (mol/mol) ratio showed the highest stability at paclitaxel concentrations of 0.1 and 0.5mg/ml. When hydroxypropyl methylcellulose (HPMC) was added to the reconstitution medium, the stability significantly increased, offering the opportunity to reduce the amount of RAME-beta-CDs in the formulation.
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Bouquet
authors.forename: Wim
authors.initials: W
authors.lastname: Ceelen
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzinger
authors.forename: Piet
authors.initials: P
authors.lastname: Pattyn
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Remon
authors.forename: Chris
authors.initials: C
authors.lastname: Vervaet
mesh_terms: D002626:Chemistry, Pharmaceutical; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D004355:Drug Stability; D006979:Hyperthermia, Induced; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D010537:Peritoneum; D012995:Solubility; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D047392:beta-Cyclodextrins; C031215:betadex; D017239:Paclitaxel