Factors affecting shear thickening behavior of a concentrated injectable suspension of levodopa.

摘要

Previous clinical studies on a subcutaneous injectable suspension of levodopa showed poor injectability into human tissue. When this formulation was rheologically characterised, a clinical shear thickening interval was observed at increased shear rates. The formulation parameters that contributed to this rheological behavior were systematically evaluated with the aim of removing this flow limitation while maintaining the concentration of 60% levodopa to retain the clinical applicability. The three suspension parameters examined were: levodopa volume fraction, concentration of the HPMC suspending vehicle, and particle size distribution. Shear thickening increased with the drug concentration and the critical shear rate was inversely dependent on the drug concentration. Increasing the vehicle concentration retarded the shear thickening but increased the overall suspension viscosity. There was an increase in shear thickening with increased average particle diameter. Combinations of micronized and non-micronized particles were used to prepare bimodal particle size distributions. The rheology of these bimodal distributions resulted in removal of shear thickening. This allowed the preparation of 60% levodopa formulations that showed a range of flow characteristics spanning near Newtonian flow or shear thinning at initial injectable viscosities of about 0.6 Pa.s and final viscosities in the range of 0.1 Pa.s, alleviating the shear thickening limitation of these levodopa formulations.