Development of Paclitaxel Injection Concentrate for Nanodispersion.

This work provides details of development of paclitaxel injection concentrate for nanodispersion (PICN) which includes excipient screening, optimization process, and stability studies of the PICN formulation. A systematic evaluation of various fatty acids, sterol analogues, polymers, and solvents led to the selection of a synergistic excipient system for PICN consisting of sodium cholesterol sulphate, caprylic acid and povidone K12 dissolved in polyethylene glycol 400 and ethanol. PICN reliably forms nanodispersion with particle sizes in the 50-150 nm range upon reconstitution in 5% dextrose solution (D5W). Transmission electron microscopy of nanodispersion demonstrated that the nanoparticles are amorphous and non-crystalline which was confirmed by differential scanning calorimetry and X-ray diffraction studies showing a complete loss of paclitaxel crystallinity. Small angle X-ray scattering data showed that the nanoparticles exist in sponge-like coacervate phase. Reconstitution studies in D5W infusion bag, mimicking injection time and shaking speed of the diluent bag, showed minimal impact on particle size of the nanodispersion. The in-vitro release profile was consistent from the range of particle sizes produced. Stability data of PICN under ICH conditions confirmed assay values of 97-101% with low total impurities (< 0.65%) over 24 months. The stability of the reconstituted nanodispersion did not show any change in physicochemical quality attributes over 24 h. These results not only validate our hypothesis of paclitaxel self-assembly driven in the presence of selected lipid and polymers reported in previous paper but also demonstrates that a convenient, scalable and stable protein-free alternative to existing paclitaxel formulations is offered for clinical use.