Development of Aqueous Based Formulation of Docetaxel: Safety and Pharmacokinetics in Patients with Advanced Solid Tumors

Abstract

A well characterized Nanosomal Docetaxel Lipid Suspension (NDLS) formulation was developed without using any detergent or toxic organic solvents to avoid hypersensitivity reactions caused by the marketed Taxotere ® product. The lyophilized NDLS formulation was easily resuspended in water and found to be physically and chemically stable for 48 hours. Physico-chemical characterization of NDLS confirmed a homogeneous formulation with an average particle size of less than 100 nm. Percent Docetaxel association with lipids in NDLS formulation was found to be greater than 95%. The in-vitro release assay showed a sustained release of 25% Docetaxel after 4 hours and 100% Docetaxel release after 42 hours of incubation. Sub-chronic toxicity in mice and rats showed comparable safety to Taxotere ®. However, a pharmacokinetics study in rats revealed greater systemic availability of Docetaxel after administration of NDLS compared to Taxotere ®. Further, a comparative safety and pharmacokinetic crossover study at 75 mg/m 2 of NDLS and Taxotere ® in patients with advanced solid tumor also showed higher exposure of Docetaxel with NDLS formulation than patients treated with Taxotere ® formulation.