Solubilization of 3-hydroxyquinazoline derivative with antitumor activity

Abstract

Background. Increasing the solubility of new pharmacologically active substances is one of the main tasks of pharmacy. It becomes even more relevant in the field of creating dosage forms for difficult-to-solubilise substances with a new mechanism of action, as in the case of 3-hydroxyquinazoline derivatives, which have shown in vivo experiments the ability to activate tumour cell death by ferroptosis. This includes OVF-009 – an original domestic substance. Due to the solubility of this compound in oils, the technology of its solubilisation using modified castor oil (Kolliphor® ELP, BASF, Germany), approved for parenteral use, was proposed.Aim. To create a model dosage form for a new hydrophobic quinazoline derivative in order to further evaluate the spectrum of its antitumour activity in in vivo experiments.Materials and methods. OVF-009, Kolliphor® ELP, 95 % ethanol, Kollidon 17 PF (BASF, Germany), sodium hydroxide, phosphate buffer, water for injection; spontaneous micelle formation, ultrasound, potentiometry, dynamic light scattering, electrophoretic method, viscometry method, etc.Results. The main properties of micelle-forming solubiliser Kolliphor® ELP and its aqueous solutions were considered; 10 model solutions OVF-009 based only on Kolliphor® ELP and with addition of ethanol and Kollidon 17PF in different concentrations were obtained; the quality of the obtained compositions was evaluated by parameters – appearance, solution transparency, pH, stability over time and tolerability by laboratory animals. As a result, two formulations prepared on phosphate buffer were chosen: formulation No 5, which contains 10 % Kolliphor® ELP and additionally 10 % polyvinylpyrrolidone, and formulation No 8, in which in addition to the main solubiliser 10 % ethanol and 16 % polyvinylpyrrolidone were added. Both formulations have neutral pH, can be stored for 24 h and are tolerated by laboratory animals.Conclusion. The selected model compositions for solubilisation of the substance OVF-009 on the basis of Kolliphor® ELP allowed to provide the concentration of the active substance in the solution suitable for further biological experiments on animals.