Paclitaxel/β-cyclodextrin complexes for hyperthermic peritoneal perfusion : Formulation and stability

Bouquet, Wim; Ceelen, Wim; Fritzinger, Bernd; Pattyn, Piet; Peeters, Marc; Remon, Jean Paul; Vervaet, Chris

doi:10.1016/J.EJPB.2006.11.025

Title

Paclitaxel/β-cyclodextrin complexes for hyperthermic peritoneal perfusion : Formulation and stability

Author

Bouquet, Wim

Ceelen, Wim

Fritzinger, Bernd

Pattyn, Piet

Peeters, Marc

Remon, Jean Paul

Vervaet, Chris

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 β-cyclodextrins to form complexes with paclitaxel was investigated as a means to increase the aqueous solubility of paclitaxel. Methylated β-CDs (randomly methylated and 2,6-dimethylated) showed the best ability to solubilise paclitaxel compared to sulfobutyl-ether- and hydroxypropyl-β-CD. The minimal ratio of paclitaxel versus randomly methylated-β-cyclodextrin (RAME-β-CD) yielding 100% inclusion efficiency was 1/20 (mol/mol). Paclitaxel/RAME-β-CD inclusion complexes prepared via freeze drying were stable for at least 6 months when stored at 4 °C. A 5 mg/ml paclitaxel solution was formulated using paclitaxel/RAME-β-CD-complexes. Upon dilution of these solutions, no precipitation was seen. After 24 h storage at room temperature or 2 h at HIPEC conditions (41.5 °C) the 1/40 (mol/mol) ratio showed the highest stability at paclitaxel concentrations of 0.1 and 0.5 mg/ml. When hydroxypropyl methylcellulose (HPMC) was added to the reconstitution medium, the stability significantly increased, offering the opportunity to reduce the amount of RAME-β-CDs in the formulation.

Language

English

Source (journal)

European journal of pharmaceutics and biopharmaceutics. - Stuttgart

Publication

Stuttgart : 2007

ISSN

0939-6411

DOI

10.1016/J.EJPB.2006.11.025

Volume/pages

66 :3 (2007) , p. 391-397