Study on Formulation, in vivo Exposure, and Passive Targeting of Intravenous Itraconazole Nanosuspensions

Organic itraconazole (ITZ) solutions were mixed with aqueous solutions to precipitate sub-300 nm particles over a wide range of energy dissipation rates, even for drug loadings as high as 86% (ITZ weight/total weight). The small particle sizes were produced with the stabilizer poloxamer 407, which lowered the interfacial tension, increasing the nucleation rate while inhibiting growth by coagulation and condensation. The highest nucleation rates and slowest growth rates were found at temperatures below 20 degrees C and increased with surfactant concentration and Reynolds number (Re). This increase in the time scale for growth reduced the Damkohler number (Da) (mixing time/precipitation time) to low values even for modest mixing energies. As the stabilizer concentration increased, the average particle size decreased and reached a threshold where Da may be considered to be unity. Da was maintained at a low value by compensating for a change in one variable away from optimum conditions (for small particles) by manipulating another variable. This tradeoff in compensation variables was demonstrated for organic flow rate vs Re, Re vs stabilizer concentration, stabilizer feed location (organic phase vs aqueous phase) vs stabilizer concentration, and stabilizer feed location vs Re. A decrease in the nucleation rate with particle density in the aqueous suspension indicated that secondary nucleation was minimal. A fundamental understanding of particle size control in antisolvent precipitation is beneficial for designing mixing systems and surfactant stabilizers for forming nanoparticles of poorly water soluble drugs with the potential for high dissolution rates.

The effect of stabilizer type (small molecule vs. polymeric) and the amount of micellar solubilized drug on Ostwald ripening of nanosuspensions was investigated. Indomethacin nanosuspensions were prepared with small molecule stabilizers (sodium lauryl sulfate (SLS) and Dowfax 2A1 (DF)) and a polymeric stabilizer (hydroxypropyl methyl cellulose (HPMC)). Two different drug:stabilizer ratios were used to evaluate the effect of micellar solubilized drug. The Ostwald ripening potential of nanosuspensions was evaluated by subjecting them to various stress conditions (temperature (15, 25, 35 and 45°C), thermal cycling, and mechanical shaking) for three months. The mean particle size increased in all SLS and DF formulations stored under different stress conditions. No effect of micellar solubilized drug on the Ostwald ripening rate was observed. In the case of HPMC formulations only those stored at higher temperatures (35 or 45°C) exhibited an increase in mean particle size. The increase in size in the HPMC formulation stored at 45°C was attributed to dehydration of the HPMC chains and subsequent loss of protection of the nanoparticles. The cube of the mean particle diameter versus time plot was determined to be non-linear for all formulations exhibiting Ostwald ripening. Therefore, according to the Lifshitz, Slyozov and Wagner theory the process was not diffusion controlled. The most probable mechanism for Ostwald ripening was surface nucleation controlled.

The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50% wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive "T11" mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials.