Abstract
Objective: Development of a technology for the production of a stable injectable dosage form (IDF) of indolocarbazole derivative LHS-1269. Methods: LHS-1269 is an active pharmaceutical ingredient that was synthesized in the N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation. The IDF includes dimethyl sulfoxide (DMSO), 95% ethanol, Kollidon® 17PF and water for injection. Magnetic stirrer and overhead stirrer with a propeller stirring element were used to prepare the model solution of the IDF of LHS-1269. Sterilizing filtration of the solution was performed with 0.2−0.22 um polycarbonate, cellulose, polyvinylidene fluoride, polyethersulfone and nylon membrane filters. The aqueous solution of LHS-1269 was lyophilized in Edwards Minifast DO.2 freeze dryer. Assay of LHS-1269 was performed by spectrophotometry at 320±3 nm. Potentiometry was used to measure pH, a viscosimetry method was used to measure the viscosity of the solutions. The average weight was estimated by weighing a sample of 10 vials with the concentrate. Results: 0.5% aqueous solution of LHS-1269 was produced by mixing the solution of the active substance in DMSO and ethanol with an aqueous solution of polyvinylpyrrolidone gradually at the ratio of LHS-1269/DMSO/ethanol/Kollidon® of 1/11/32/40 by weight. The aqueous solution of the study substance cannot be lyophilized, so a sequence of technological operations was presented to produce an anhydrous concentrate “LHS-1269, concentrate for solution for injection and infusion 25 mg”. Conclusion: A technology was developed to produce a stable IDF of a hydrophobic indolocarbazole derivative LHS-1269, a high-potential antitumor drug.
Highlights
Indolocarbazoles are natural and synthetic compounds that have attracted considerable attention due to their distinctive structural features and therapeutic potential
While developing a water-soluble LHS-1269 dosage form, we considered a few pharmaceutical technological approaches that comply with the physical and chemical properties of the active substance
Freeze drying of the aqueous solution of LHS-1269 is not possible, so we propose producing a stable injectable dosage form of LHS-1269 as a concentrated mixture of drug substance, dimethyl sulfoxide (DMSO), 95% ethanol, and Kollidon® 17PF
Summary
Indolocarbazoles are natural and synthetic compounds that have attracted considerable attention due to their distinctive structural features and therapeutic potential. The class of indolocarbazoles includes 5 subclasses with different structures of the planar aromatic ring. The widest, most biologically significant, and wellknown is the indolo[2,3-а]carbazole subclass that includes mostly substances with a structural basis of indolo[2,3-a]pyrrolo[3,4c]carbazole ring, where 2 indole fragments are connected to amide or imide group via benzene ring. The indole fragments are connected to the carbohydrate fragment via 1 link (rebeccamycin group) or 2 links (staurosporine and its derivatives) [1]. Clinical studies of various indolocarbazole derivatives demonstrated a wide range of potential therapeutic indications and good compatibility with the known drugs. The antitumor effect is based on various mechanisms of action, including intercalation in DNA, inhibition of topoisomerases I and II, protein kinases C and A, cyclin-dependent kinases [2, 3]
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