Parenteral formulation of larotaxel lipid microsphere tackling poor solubility and chemical instability

The purpose of this study was to develop a parenteral larotaxel lipid microsphere (LTX-LM) and evaluate its stability. The preformulation study showed that LTX possessed poor solubility (0.057 μg/mL in aqueous phase) and chemical instability. LM was selected as the drug carrier due to its higher drug-loading capacities, higher physicochemical stability and reduced irritation and toxicity. High speed shear mixing and high-pressure homogenization were employed to prepare the LTX-LM. Particle size distribution (PSD), zeta-potential, drug content and entrapment efficiency (EE) were taken as indexes to optimize formulations. The dissolution studies were performed using a ZRS-8G dissolution apparatus according to the paddle method. Degradation kinetics test, freezing and thawing test and long term stability test were combined to evaluate the physicochemical stability of LTX-LM. From the degradation kinetics results, the shelf lives (T90%) of LTX in LM at 25 and 4 °C (165, 555 days) were about 20 times as long as those in aqueous phase (200, 676 h), which were dramatically prolonged. The activation energies in aqueous solution and in LM calculated from the slopes were 41.93 and 42.25 kJ/mol. And its frequency factors (A) were 4.9 × 103/s and 2.3 × 102/s, respectively. Freezing and thawing test showed the PSD of LTX-LM became larger and wider increasing from 166.9 ± 53.2 nm to 257.4 ± 85.5 nm with more freeze–thaw cycles. From the long term stability test results, all the parameters changes were in qualified range.

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