Primary Studies On The Docetaxel Nanosuspensions

Docetaxel(DCT), an anticancer drug, has extraordinary therapeutic effect on refractoriness breast cancer, small cell lung cancer and so on. Due to poor water solubility of DCT, it must be administrated with ethanol and Tween 80, which lead to seriously allergic response and poor compliance. Nanosuspension, a novel drug delivery system, could improve the drug loading capacity and avoid the application of organic solvent for the undissolved drugs. The objective of this paper was to develop a good and stable nanosuspension of DCT for intravenous administration.Precipitating-homogenization method was adopted to prepare DCT nanosuspension. The effect of operate temperature, stir speed, intermix rate, kind of organic solvent, type, amount and add method of surfactants, pH and buffer salt of the aqueous phase, homogenization pressure and cycle times on the particle distribution of nanosuspension were studied in the single factor test. Then orthogonal design was conducted to obtain the optimized formulation and process parameters. The optimized preparation was obtained under 600bar,20cycles while the drug load capacity was 5mg/ml, the mass ratio of lecithin and DCT was 1:2, stirring speed was 400rpm, pH of aqueous phase was 6.5.The pharmaceutical properties of DCT nanosuspension were studied. The mean particle size of the nanosuspension was 200nm. The results of DSC showed that the DCT still existed in the crystal state after precipitate and homogenization process. In the dissolution test, the accumulated release rate of DCT suspension obtained by precipitate without homogenization in 30min was 96% while that of the DCT coarse grain was only 54%. The apparent solubility of DCT nanosuspension was 20.4mg/ml, which was 3.15 times of the DCT coarse grain. Thus it can be predicted that the dissolution rate of nanosuspension will be remarkably improved.Freeze-drying (lyophilization) technique was utilized to prepare freeze-dried DCT nanosuspension for better stability. The freeze-dried product has a smooth appearance and the paricle size of the rehydrated product was slightly increased but still qualified for intravenous administration.The DCT nanosuspension didn’t cause hemolysis in vitro. HPLC method was developed to determine the DCT concentration in plasma. Pharmacokinetic study of DCT commercial injection and DCT nanosuspension were conduct in male rats. DASS program was used to calculate the pharmacokinetic parameters.Both of them fit to the three compartment-model DCT nanosuspension and had same elimination rate. But the MRT and AUC of nanosuspension has remarkably increased while the maximum concentrate was little decreased. The DCT nanosuspension exhibited sustained release profile in vivo.