Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-ß-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant.

Vestipitant is a potent and selective neurokinin 1 (NK-1) receptor antagonist that was investigated as a potential treatment for post-operative nausea and vomiting (PONV). A previous mannitol-based formulation of vestipitant was associated with hemolytic activity in preclinical studies. In an effort to reduce the hemolytic potential and develop an IV formulation of vestipitant that could be administered more rapidly, an IV formulation containing sulfobutylether-7-beta-cyclodextrin (SBE7-ß-CD, Captisol™) was developed and tested in a phase 1 clinical study. This was a randomized, single-blind (subjects and investigator-blinded, sponsor-unblinded), placebo controlled, dose escalation study in healthy subjects in which 7 cohorts of 8 subjects per cohort received SBE7-ß-CD -based vestipitant (2 mg/mL) or placebo (saline) in a 3:1 ratio (active:placebo) at different doses and infusion rates. The results demonstrated the ability to infuse up to 48 mg vestipitant in a 2 mg/mL formulation over 30 seconds with no evidence of hemolytic effects. Cohorts of subjects at lower doses and longer infusion duration (>1 minute) reported more AEs related to the infusion site than those at the higher doses and faster infusion rates.

Polysorbate 80 and Cremophor EL micelles deaggregate and solubilize nystatin at the core-corona interface.

The extent and the location of nystatin solubilization by nonionic surfactant micelles were determined. The critical aggregation concentrations (CAC) of nystatin in 4 x 10(-3) M surfactant were determined by dynamic light scattering. The resulting CAC values for nystatin in Cremophor EL (CrEL), Tween 80 (T80), and Nofable ESO-9920 (NOF) were 150, 150, and 300 microM compared to 10 microM for the phosphate-buffered saline (PBS) control. The surfactants were able to solubilize and deaggregate nystatin from 50 to 75 times more than the PBS control. The core polarity of CrEL micelles, determined by pyrene fluorescence, was significantly lower than T80 and NOF micelles. The micelle-water partition coefficients (P) of nystatin and pyrene were determined by fluorescence spectroscopy. The partition coefficient values of 7.5 microM nystatin in CrEL and NOF micelles were 1100 +/- 60 and 1000 +/- 110, an insignificant difference (p > 0.1). However, there was a significant increase in pyrene partitioning in micelles with lower core polarity. Additionally, the P of nystatin decreased when the nystatin concentration was increased, whereas the pyrene P did not. The unusual partitioning behavior of nystatin revealed a good fit with the Langmuir adsorption isotherm, indicating solubilization at the micellar core-corona interface.

The effects of Pluronic block copolymers on the aggregation state of nystatin.

The purpose of this work was to characterize the effect of block copolymer composition on the aggregation state of nystatin in the presence of Pluronic micelles. The critical aggregation concentrations (CACs) of nystatin were determined by dynamic light scattering (DLS). The CAC of nystatin in phosphate-buffered saline was 20 microM at 37 degrees C. Addition of Pluronics significantly increased the CAC of nystatin up to >350 microM at 37 degrees C at the concentrations studied. The CAC values corresponded directly to the size of the Pluronic hydrophobic blocks, and inversely with Pluronic critical micellization concentration (CMC). Predictably, increasing Pluronic concentration and temperature revealed increases in CACs. The micelle-water partition coefficient (P) of nystatin was determined by nystatin fluorescence. The P for nystatin at 37 degrees C was calculated in F68, F98, P105, and F127 to be 15, 21, 73, and 79, respectively. Pluronic micelle core polarity experiments, determined by pyrene fluorescence, revealed decreased polarity with increasing hydrophobic block length and temperature. Thus, nystatin CACs in the presence of Pluronics correlated directly with the partition coefficients, and inversely with core polarity. These results point to the number of micelles in solution as the primary factor responsible for nystatin solubilization by Pluronics.