Obtaining a Water-soluble Form of Hydrophobic Indolelocarbazole Derivative Using Solubilizer Complex

Abstract

Introduction. LHS-1269 is an indolocarbazole derivative with high antitumor activity. Due to the hydrophobic properties of the active substance, the use of organic co-solvents – dimethyl sulfoxide (DMSO) and ethanol – is required to obtain an injectable dosage form (DP). However, the inclusion of organic solvents in the composition of the DF carries a potential risk of side effects as a result of the use of the drug.Aim. Selection of auxiliary substances for obtaining an aqueous solution of hydrophobic indolecarbazole derivative, which allows minimizing the concentration of organic solvents in the composition of DF.Materials and methods. The object of the study is the active substance LHS-1269 series 010320, produced in the Chemical Synthesis Laboratory of the N. N. Blokhin National Medical Research Center of Oncology. The following auxiliary substances were used to obtain model compositions: Kollidon® 17 PF, Kollisolv® PEG-400, Kolliphor® P 188, Montanox™ 20, DMSO (p.a.), ethanol 95 % (standardized according to pharmacopoeia quality standard ФС.2.2.0019.18 of The State Pharmacopoeia of the Russian Federation). Analytical scales OHAUS Analytical Plus AP 100S and laboratory scales AND DL-120 were used for weighing LHS-1269 and auxiliary substances. The dissolution and mixing of the components was carried out on an IKA® C-MAG HS 4 magnetic stirrer.Results and discussion. In the course of the study, 2 groups of model compositions were obtained and estimated, comprising a complex of two or more auxiliary substances as a solubilizer. The first group of formulations contained DMSO at a concentration of 5 % and ethanol at concentrations from 0 to 15 %. The compositions of the second group included DMSO from 0 to 4 %. As a result, it was found that the addition of 5 % Kolliphor® P 188 to the composition of the solution reduces the content of ethanol to 5 %. In this case, with further decrease in ethanol, turbidity of the solution and precipitation are observed. Reducing the concentration of DMSO in the DF to 2 % was achieved by using a combination of 20 % ethanol and solubilizer complex – Kollidon® 17 (20 %), Kollisolv® PEG-400 (20 %) and Kolliphor® P 188 (5 %). In this case, the total dissolution of the active substance without DMSO was observed when compensating for the organic solvent by introducing additional auxiliary substances – Montanox™ 20 (5 %) and benzene (2 %).Conclusion. As a result of the research, the compositions of the auxiliary substances of solubilizers are selected, allowing to obtain an aqueous solution of the hydrophobic compound LHS-1269 with a minimum concentration of organic solvents.

Keywords

• hydrophobic derivative of indolocarbazole
• lhs-1269
• dosage form
• organic solvent
• solubilizers
• dmso
• ethanol