Retinoids are a class of structural analogs of Vitamin A which influence cellular proliferation and differentiation, and exhibit broad chemopreventive activity in carcinogenesis models. Some synthetic analogs that are active as chemopreventive agents also induce apoptosis in malignant cell lines without acting through classical intracellular retinoid receptors. With the exception of retinoic acid isomers and derivatives that can be administered intravenously, most synthetic retinoids have neutral charge and are poorly soluble, and current oral dosage forms are unable to achieve pharmacologically active blood levels. A recent Phase I clinical trial of fenretinide (4HPR) found a ceiling on achievable plasma levels of drug with an oral dosage form that were well below levels required to induce tumor cell apoptosis in preclinical models. The limited options for administration of retinoids are a major impediment to realizing their therapeutic potential. SciTech has undertaken a research program to develop formulations for the intravenous administration of poorly soluble synthetic retinoids. The long-term goals of this SBIR project are to develop formulations that are well tolerated (e.g., without cremophor, tween, and other polyoxy surfactants) and pharmacologically active, and possess favorable pharmaceutical characteristics required for multi-day infusion in patients with solid tumors. During the SBIR Phase 1 period, five formulation strategies were evaluated and the feasibility of reaching stable and high drug concentrations was proven for three of them. One was selected as the lead product and was proven to possess pharmacological activity in animal models despite substantial changes in the physical form of drug presented in vivo. The goals of this SBIR Phase 2 application are to optimize the lead product, develop a documented manufacturing process that could be implemented in a sterile product facility in Phase 3, and understand the physiological and pharmacological principles that govern tissue distribution of HPR.
