Разработка и регистрация лекарственных средств (Nov 2022)

Application of Solid Dispersion Technology to Obtain a Model of Injectable Dosage Form of Indolocarbazole Derivative

  • A. P. Kolpaksidi,
  • M. V. Dmitrieva,
  • O. L. Orlova,
  • L. V. Ektova,
  • I. I. Krasniuk

DOI
https://doi.org/10.33380/2305-2066-2022-11-4-73-78
Journal volume & issue
Vol. 11, no. 4
pp. 73 – 78

Abstract

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Introduction. N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia synthesized an original derivative of indolocarbazole with the carbohydrate residue xylose, which has a pronounced cytotoxic and anti-angiogenic activity. The substance LCS-1269 is an amorphous powder that is almost insoluble in water, which causes difficulties in the development of an injectable dosage form (IDP). To solve this problem, a technological approach to obtain a solid dispersion (SD) of LCS-1269 has been proposed.Aim. To develop a model of IDP of the indolocarbazole derivative LCS-1269 based on SD.Materials and methods. We used a substance LCS-1269 synthesized in the Chemical Synthesis Laboratory of the N. N. Blokhin National Medical Research Center of Oncology. Emuxol 268, Kolliphor® P 188, Soluplus®, Lutrol® F68, Kollidon® 12 and Kollidon® 17, soybean phosphatidylcholine unsaturated S PC and saturated S PC-3 were investigated as carriers of the active substance. SD LCS-1269 was obtained by solvent removal: the active substance was dissolved in acetone, the carrier − in chloroform, the obtained solutions were mixed, transferred into a bottle and evaporated under vacuum (50 ± 5 mbar) in the desiccator at water bath temperature 65 ± 2 °С. To obtain aqueous solution of LCS-1269 dry mass was dissolved using different auxiliary substances or their mixtures: water for injection, ethanol 95 %, benzyl alcohol, Kollisolv® PEG 400, MONTANOX™ 80. To increase stability, the aqueous solution of LCS-1269 was lyophilized in an Edwards Minifast DO.2 freeze dryer.Results and discussion. Kollidon® 17 was chosen as the carrier material for the SD active substance. It was found that a clear solution of LCS-1269 with the concentration of the active substance 0.5 % was formed by dissolving the SD in ethanol 95 % and then gradually diluting the alcohol mixture with water for injection. In this case, the mass ratio of the components of the developed model IDF LCS : Kollidon® 17 : ethanol : water is 1 : 40 : 32 : 127. As a result of freeze-drying of the water-ethanol solution of LCS-1269 the IDF in the form of lyophilizate easily soluble in a 10 % solution of ethanol was obtained.Conclusion. An IDF model of the hydrophobic derivative of indolocarbazole LCS-1269 based on SD was developed and submitted for biological studies to evaluate its effectiveness.

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