Development of a model of a dosage form for a new domestic compound (pyrrolo[3,2-l]acridinone derivative) and studying its cytotoxic activity

Background. Expanding the list of safe and effective medicines are the main directions of development of modern medicine and pharmacy. Acridine derivatives are an interesting object of study due to their proven antitumor effect on leukemia and lymphoma. The mechanism of their antitumor effect is the ability to intercalate DNA, as well as to inhibit topoisomerases and telomerase, initiate ROS-mediated oxidative stress, arrest the cell cycle, and interact with glycoprotein-P.

Aim. To develop the composition and technology for obtaining a model pharmaceutical form (PF) for parenteral use of a new compound a pyrrolo [3,2-l] acridinone derivative with antitumor activity.

Materials and methods. Substance MOB 265 S (Institute of Technical Chemistry of Ural Branch of Russian Academy of Sciences – Perm Federal Research Center, Ural Branch of Russian Academy of Sciences, Russia), polyvinylpyrrolidone (PVP, Kollidon® 17PF, BASF, Germany), polyoxyl-35-castor oil (Cremophor® ELP, BASF, Germany), macrogol (15) – hydroxystearate (Cremophor® ELP, BASF, Germany), water for injection. Technological (solubilization, dissolution, filtration, lyophilization), analytical (spectrophotometry, potentiometry) and biological (in vitro) methods were used in the experimental work. Cytotoxic activity was determined on cell lines of T-cell lymphoblastic leukemia Jurkat, PC-3 prostate carcinoma, A549 lung carcinoma, colon carcinoma HCT-116, breast adenocarcinoma MCF-7.

Results. In the course of experimental studies using various solubilizers, model compositions of a PF based on MOB 265 S were obtained, in which water for injection was used as a solvent. The formation of a clear solution was observed only in the model with PVP, which was characterized by basic pharmaceutical parameters and studied in vitro. The inhibitory concentration causing 50 % cell death on various cell lines was 29.6–65.5 μM.

Conclusion. Model of the PF a new domestic compound (pyrrolo [3,2-l] acridinone derivative) in the form of a lyophilisate with a mass ratio of MOB 265 S: PVP – 1:5, as well as a technology for its production in 5 stages. The main quality indicators of the resulting model were selected. The results of cytotoxic activity showed that the composition is effective in all used cell cultures, with maximum cytotoxicity observed in the Jurkat leukemia cell line, which coincides with literature data on the cytotoxic activity of acridine derivatives on leukemia and malignant lymphomas. The new PF is promising for further research as an import substitution, due to the lack of acridinone derivative drugs in Russia.