Improvement of the pharmacokinetic/pharmacodynamic relationship in the treatment of invasive aspergillosis with voriconazole. Reduced drug toxicity through novel rapid release formulations

[Display omitted] •Micellar systems diminished crystallinity of voriconazole and increased its dissolution rate.•Minimum inhibitory concentration was lower since micelles facilitated penetration.•Area under the curve of voriconazole raised in the new formulation.•A higher pharmacokinetic/pharmacodynamic ratio indicates a more effective treatment.•Smaller amount of drug was accumulated in the liver, reducing hepatotoxicity. Voriconazole (VCZ) is currently the first-line treatment for invasive aspergillosis, although the doses are limited by its poor solubility and high hepatic toxicity. The aim of this study was to develop a solid self-dispersing micellar system of VCZ to improve the pharmacokinetic/pharmacodynamic (PK/PD) relationship and reduce hepatotoxicity. In this work, solid micellar systems of VCZ are formulated with different polysorbate 80 ratios using mannitol as a hydrophilic carrier. The novel micellar systems were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and dissolution studies. Self-dispersing micellar systems reduced VCZ crystallinity, leading to an improvement in its dissolution rate. The in vitro susceptibility test also revealed that the most common microorganisms in invasive aspergillosis exhibited low minimum inhibitory concentration (MIC) values for micellar systems. Pharmacokinetic studies indicated an improvement in bioavailability for MS-1:3:0.05, and changes in its biodistribution to different organs. MS-1:3:0.05 showed an increased concentration in lungs and a significant decrease in VCZ accumulated in the liver.