Solubilization of poorly water soluble drugs in micelles of hydrophobically modified hydroxypropylcellulose copolymers

• Published in: Journal of controlled release 2003-11, Vol.93 (1), p.59-68
• Main Authors: Francis, Mira F, Piredda, Mariella, Winnik, Françoise M
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Caco-2 Cells; Cellulose - analogs & derivatives; Cellulose - chemistry; Cellulose - pharmacokinetics; Cyclosporin A; Cytotoxicity; Dose-Response Relationship, Drug; General pharmacology; Humans; Hydrophobic and Hydrophilic Interactions; hydroxypropyl cellulose; Hydroxypropylcellulose (HPC); Immunomodulators; Medical sciences; Micelles; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polymeric micelles; Polymers - chemistry; Polymers - pharmacokinetics; Solubility - drug effects; Solubilization; Water - chemistry
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2003.08.001

The main objective of this study is to exploit the solubilizing potential of hydroxypropylcellulose- g-polyoxyethylene alkyl ether (HPC- g-(POE) y -C n ) polymeric micelles towards poorly water soluble drugs in order to improve their oral bioavailability. Hydrophobically modified HPC graft copolymers of various compositions were synthesized by attaching hexadecyl or octadecyl residues to the hydrophilic HPC backbone via short POE linkers of different lengths. The onset of micellization was estimated by fluorescence spectroscopy. The hydrodynamic diameter of different HPC- g-(POE) y -C n micelles was evaluated by dynamic light scattering (DLS). Cyclosporin A (CsA), a poorly water soluble immunosuppressant, was selected as model drug. CsA-loaded HPC- g-(POE) y -C n micelles were prepared by a dialysis procedure and the amount of CsA incorporated in the micelles was assayed by high-performance liquid chromatography. Following 24-h incubation with human colon adenocarcinoma, Caco-2 cells, the cytotoxicity of various HPC- g-(POE) y -C n copolymers was evaluated using the MTT colorimetric assay and compared to those of unmodified HPC and free (POE) y -C n . In aqueous solution, different HPC- g-(POE) y -C n copolymers formed polymeric micelles of low critical association concentrations (CAC) and micelle mean diameters ranging from 78 to 90 nm. CsA loading into HPC- g-(POE) y -C n polymeric micelles was significantly larger than in unmodified HPC. It increased with increasing number of (POE) y -C n units grafted per HPC chain. On the cellular level, unmodified HPC showed no cytotoxicity, while free (POE) y -C n molecules inhibited cell growth. Most importantly, the study revealed that HPC- g-(POE) y -C n exhibited no significant cytotoxic effect.