Abstract 3718: An injectable nanoparticle formulation of valrubicin

Introduction: Valrubicin [AD-32 (N-trifluoroacetyladriamycin-14-valerate)], a cancer therapeutic agent, is used for treating bacillus Calmette Guerin (BCG)-resistant bladder cancer. Although valrubicin has been found to be less toxic to normal tissues than doxorubicin during preclinical studies, its therapeutic applications have been restricted to nonsystemic administration due to its poor aqueous solubility. Its proven antineoplastic properties make it a promising candidate to serve as an effective chemotherapeutic agent for systemic use as a soluble nanoparticle formulation with injectable excipients. The current study was undertaken to formulate valrubicin as nanoparticle formulation using our proprietary Quanticle™ Technology. Here we report the use of biocompatible and injectable phospholipid and protein to produce a stable nanoparticle formulation of valrubicin for systemic use. Methods: We developed Quanticle manufacturing process, which subjected the nanoparticle to a minimum number of fixed passes to avoid the deterioration of excipients by microfluidization process. This was possible through judicious combination of proprietary ternary solvent mixture and excipients. A Quality by Design (QbD) approach was utilized to design the experimental study and understand the effect of process variables on critical quality attributes (CQAs) during our proprietary medicinization of valrubicin. Drug loading, nanoparticle size (before and after filtration), particle size distribution, ease of filtration, and physical stability of particle during storage at room temperature were evaluated as CQA. The process variables being evaluated were aqueous to organic phase ratio, ratios of solvents constituting the total organic phase, amount of drug, microfluidizer pressure, number of passes, and evaporation temperature. Valrubicin was also examined for its incorporation into whole human plasma or human plasma components (HDL, LDL and serum albumin (HSA). Results: Quanticle formulation with human serum albumin as excipients produced nanoparticle formulation of very small size of ~100 nm. The formulation was stable for 24 h at RT. This formulation was also lyophilizable and reconstitutionable to its original size and the reconstituted formulation is stable for more than 24 at RT. The formulation was reconstitutionable in less than 3 minutes with 0.9% (w/v) saline; the final conc. of the formulation was ~2 mg/mL and the drug recovery was very high. Valrubicin distributes