Evaluation of the stability and pharmacokinetics of cabazitaxel‐loaded intravenous lipid microspheres: Beneficial effect of cholesterol

In this work, we describe the evaluation of the stability and pharmacokinetics of cabazitaxel‐loaded lipid microspheres (CTX‐LM) prepared by high‐pressure homogenization. Investigation of the physicochemical stability under different homogenization cycles and diverse sterilization times confirmed that 8 cycles at 800 bar and 121°C for 8 min were the optimal technological parameters. The beneficial effect of cholesterol on the physical stability of CTX‐LM was confirmed and its mechanism of action was identified. The stability of CTX‐LM using an aqueous isotonic glucose solution as a diluting agent was greater compared with using 0.9% NaCl solution as a result of an electric charge effect. CTX‐LM are stable under freeze‐thaw conditions and should not be exposed to high temperatures and protected from light during storage. Furthermore, all the changes in parameters were within an acceptable range at 4°C within 9 months, which supported the good long‐term stability of CTX‐LM. Finally, to compare the pharmacokinetics of CTX‐LM with cabazitaxel‐solution in vivo, a rapid, accurate UPLC‐MS/MS method was developed and used to determine cabazitaxel in rat plasma after a single intravenous administration of 4 mg/kg. An obviously larger area under the curve (AUC) of CTX‐LM was observed than that of CTX‐solution, which will improve the antitumor efficacy of cabazitaxel. Practical applications: As a novel semisynthetic taxane, cabazitaxel has shown antitumour activity in a broad range of cell‐lines and tumor models and has been approved in combination with prednisone for the treatment of patients with castration‐resistant metastatic prostate cancer. However, serious undesirable effects in humans, such as anaphylactoid hypersensitivity reactions and peripheral neuropathy were produced by the addition of polysorbate 80 to commercial products. In this paper, CTX‐LM was prepared by high‐pressure homogenization in order to overcome the above drawbacks. The good stability and markedly higher AUC of CTX‐LM may hasten their passage from a pre‐clinical phase to a clinical trial phase and allow their production on a large scale. In this paper, cabazitaxel lipid microspheres exhibited a great stability and had a higher AUC than cabazitaxel solution.