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Pharmaceutical Research, Vol. 24, No. 12, December 2007 ( # 2007) DOI: 10.1007/s11095-007-9461-7
Research Paper Enhancement of the Solubility and Efcacy of Poorly Water-Soluble Drugs by Hydrophobically-Modied Polysaccharide Derivatives
Widad Henni-Silhadi,1 Michel Deyme,1 Marie-Martine Boissonnade,1 Martine Appel,2 Didier Le Cerf,3 Luc Picton,3 and Vronique Rosilio1,4
Received May 14, 2007; accepted September 17, 2007; published online October 3, 2007
Purpose. This work was intended to develop and evaluate a new polymeric system based on amphiphilic carboxymethylpullulans (CMP49C8 and CMP12C8) that can spontaneously self-assemble in aqueous solutions and efciently solubilize hydrophobic drugs.
Methods. The self-assembling properties of CMP49C8 and CMP12C8 were characterized by uorescence spectroscopy and surface tension measurements. The solubilization of benzophenone and docetaxel was assessed from surface tension measurements, UV spectrometry and HPLC assays. The in vitro cytoxicity of CMP49C8 solutions and the docetaxel commercial vehicle (Tween 80\/Ethanolwater) were evaluated in the absence and in the presence of docetaxel.
Results. Compared to CMP12C8, CMP49C8 in aqueous solutions appeared to self-organize into monomolecular aggregates containing hydrophobic nanodomains, and to signicantly increase the apparent solubility of benzophenone. Docetaxel solubility could also be improved in the presence of CMP49C8 but to a lower extent due to the surface properties of the drug. Nevertheless, in vitro, the cytotoxicity studies revealed that against cancer cells, the CMP49C8-docetaxel formulation was equipotent to the commercial docetaxel one. Furthermore, in the absence of the drug, CMP49C8
appeared less cytotoxic against macrophages than the Tween\ 80/Ethanolwater.
Conclusions. CMP49C8 is a good candidate for solubilizing hydrophobic drugs and could be applied to docetaxel formulations.
KEY WORDS: cytotoxicity studies; docetaxel; hydrophobically modied carboxymethylpullulan; solubilization; surface tension.
INTRODUCTION
In recent years, amphiphilic polymers have been the object of growing scientic attention because of their unique associative behaviour and their potential applications in pharmaceuticals. They are mainly constituted of hydrophilic and hydrophobic parts. In aqueous solutions, the hydrophilic segments are responsible for the polymer hydration, while the hydrophobic domains minimise their contact with water by self-assembling into aggregates (19). The rst studies describing an associative behaviour were published in 1951 with a poly(4-vinylpyridine) derivative bearing ethyl and dodecyl groups (10). From this date, the interest for these original
macromolecules increased as indicated by the numerous books and reviews on the subject (1118). The structure of such polymers...