The development of a rational dosage form for an API is one of the main links in the chain of comprehensive research to create a drug. The purpose of this study was to use physicochemical and technological methods to create various parenteral forms based on the practically water-insoluble API LCS-1269 and to conduct a comparative study of the developed dosage forms according to the main quality indicators characteristic of injectable dosage forms. Compositions and technologies for producing three model dosage forms based on LCS-1269 were evaluated during the work. Their main advantages and disadvantages were shown.

Background. Test Dissolution, which confirms the release of the active substance, is one of the most important criteria for the quality of tablets. This test significance is determined by potential correlation between the drug absorption in vivo and its release from the dosage form. It is especially difficult to develop the test Dissolution for substances that are poorly soluble in water. Aim. To develop a test Dissolution method for cyphetrylin tablets, 60 mg and to study the release of active substance. Materials and methods. In the work we used an original analogue of somatostatin – cyphetrylin, synthesized in the laboratory of chemical synthesis of N.N. Blokhin National Medical Research Center for Oncology of the Russian Ministry of Health. The test was developed for cyphetrylin tablets, 60 mg. The study was carried out on a dissolution tester Erweka series 700 (type II – Paddle (Erweka, Germany), using hydrochloric acid and isopropyl alcohol and their mixture as a dissolution medium. Quantitative determination of released cyphetrylin was carried out on a Agilent Cary® 100 recording spectrophotometer (Agilent Technologies, USA). Results. Optimal conditions were selected to determine the release of cyphetrylin from tablets, 60 mg. Since cyphetrylin is insoluble in water, it is proposed to use a mixture of hydrochloric acid and isopropyl alcohol in a ratio 3:2 as a dissolution medium. It was shown that a paddle rotation speed of 100 rpm provides the release of cyphetrylin normalized quantity into the dissolution medium in 45 min. A method for cyphetrylin assay in a medium by direct spectrophotometry has been developed. Evaluation of the cyphetrylin release profile showed its gradual release from the tablets, which can be described by a linear relationship in accordance with the Higuchi equation. Conclusion. As a result of the research, a test Dissolution procedure has been developed and the release profile of cyphetrylin from tablets, 60 mg, was assessed. Experimental data showed that in the selected conditions cyphetrylin release from the tablets is more than 80 % and meets the requirements of the Russian State Pharmacopoeia XV ed.

The indolocarbazole derivative LCS-1269 has a multitarget mechanism of action on tumors and blocks vasculogenic mimicry. The hydrophobic character of LCS-1269 hampers the development of an injectable dosage form (IDF), the need for which was determined in series of in vitro and in vivo biological experiments. The purpose of this study was to select an excipient composition for creating a model IDF of LCS-1269 with high antitumor activity and low toxicity and to develop the technology for LCS-1269 IDF production. Acomposition of a model IDF of LCS-1269 including EtOH (95%), Kollidon 17 PF, and polysorbate 80 and the technology for obtaining a true solution were developed during preliminary experimental studies. The selected model was lyophilized to exclude EtOH from the composition and to increase the shelf life of the compound.

Производное индолокарбазола ЛХС-1269 обладает мультитаргетным механизмом воздействия на опухоль и блокирует васкулогенную мимикрию. По своим свойствам ЛХС-1269 относится к гидрофобным соединениям, что затрудняет получение инъекционной лекарственной формы (ИЛФ), необходимость создания которой определена в ходе ряда биологических опытов in vitro и in vivo. Цель настоящего исследования: выбор композиции вспомогательных компонентов для создания модели ИЛФ ЛХС-1269 с высокой противоопухолевой активностью и низкой токсичностью и разработка технологии ее получения. В ходе предварительных экспериментальных исследований разработаны состав модели ИЛФ ЛХС-1269, включающий спирт 95 %, Kollidon 17PF и полисорбат 80, и технология, позволяющая получить истинный раствор ЛХС-1269. Для исключения спирта из состава и для увеличения срока годности проведена лиофилизация выбранной модели.

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.

Лапатиниб одобрен Министерством здравоохранения РФ в качестве препарата 1 линии терапии наиболее агрессивной формы рака молочной железы (РМЖ), связанного с гиперэкспрессией рецептора эпидермального фактора роста 2-го типа (Human epidermal growth factor receptor 2; ErbB2 (HER2/neu)). Режим дозирования препарата предполагает прием от 4 до 6 таблеток лапатиниба в сутки в течение как минимум 14 дней. В условиях нарушения цепочек поставок препаратов на территорию РФ на первый план выходит создание эффективного и безопасного воспроизведенного препарата (дженерика) для беспрерывного обеспечения им пациентов. Целью данной работы являлось проведение комплексного исследования по изучению возможности использования прямого прессования для получения воспроизведенного лекарственного препарата Лапатиниб (таблетки, покрытые пленочной оболочкой 250 мг). В состав таблетки оригинального препарата входит около 42 % микрокристаллической целлюлозы, которая используется как наполнитель и связующее вещество для улучшения текучести смеси для таблетирования и повышения прочности таблетки. Это указывает на возможность применения прямого прессования, как наиболее простого и доступного метода. В ходе исследования показано, что смесь для таблетирования, воспроизведенная по прописи оригинального препарата, вне зависимости от способа смешения ингредиентов не обладает необходимыми технологическими характеристиками для получения таблеток методом прямого прессования, несмотря на хорошую прессуемость смеси и прочность полученных таблеток (прочность на раздавливание 80 H). Работа по воспроизведению таблеток лапатиниба будет продолжена с использованием метода влажного гранулирования. Lapatinib is approved by the Ministry of Health of the Russian Federation as a first-line drug for the most aggressive form of breast cancer (BC) associated with overexpression of the Human epidermal growth factor receptor 2 (ErbB2 (HER2/neu)). Patients need to take 4 to 6 lapatinib tablets per day for at least 14 days. In the context of a disruption in the supply chains of drugs to the territory of the Russian Federation, it is necessary to create an effective and safe generic drug for the continuous provision of patients with it. The purpose of this work was to conduct a comprehensive study to discover the possibility of using direct compression to obtain a generic drug Lapatinib, film-coated tablets 250 mg. The tablet of the original drug contains about 42% microcrystalline cellulose, which is used as a filler and binder to improve the fluidity of the tablet mass and increase the strength of the tablet. This indicates the possibility of using direct pressing as the simplest and most accessible method. The study showed that the mixture for tableting, reproduced according to the prescription of the original drug, regardless of the method of mixing the ingredients, does not have the necessary technological characteristics for obtaining tablets by direct compression, despite the good compressibility of the mixture and the strength of the obtained tablets (diametrical crushing strength of 80 H). Work on reproducing lapatinib tablets will continue using the wet granulation method.

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.

Personalized neoantigen vaccines are a group of individually designed cancer vaccines that enhance patients’ own antigen-specific immune responses. These include vaccines based on dendritic cells, DNA, mRNA and synthetic peptides. An analysis of 98 clinical trials of neoantigenic vaccines from the ClinicalTrials.gov database found that peptide vaccines are one of the most popular cancer vaccines, accounting for about 50 % of clinical trials. They usually consist of a mixture of long or short peptides, dissolved depending on their properties in an appropriate solvent, and an adjuvant that stabilizes and increases their effectiveness. The most used immunoadjuvants in the formulation of neopeptide vaccines are Toll-like receptor agonists (poly-ICLC) and granulocyte-macrophage colony-stimulating factor. The development of neoantigenic vaccines presents a number of distinctive challenges compared to other types of vaccines. The process should cover and validate the various steps in the development, production and administration processes in order to maximize the efficacy and safety of vaccines. In the technology for the production of peptide vaccines, 3 main stages can be distinguished: 1) screening and identification of neoepitopes using the approaches of computer prediction, co-immunoprecipitation, mass spectrometry and cytotoxic experiments; 2) synthesis of peptides by methods of standard solid-phase synthetic peptide chemistry; 3) actually obtaining a vaccine preparation suitable for storage, transportation and administration to the patient. Taking into account the specificity of the drug, the manufacturing process must be carried out strictly according to the Good Manufacturing Practice standard with mandatory quality control of intermediate and finished products

Introduction. Due to the discovery of antibodies (Ab) targeting molecule with high specificity to the ligand, the "magic bullet" concept has been successfully implemented with various immunoconjugated drugs. Since 1980, Ab conjugates with liposomes, i.e., immunoliposomes (ILs), have been widely investigated to improve the specificity and efficacy of drug therapy. This review is devoted to the characteristic of the basic structural units of ILs on the basis of data analysis of original and review articles on the topic from PubMed, ResearchGate and CyberLeninck databases.Text. ILs are liposomes to which Ab, their fragments or other ligands are usually attached by a special linker. ILs are used to deliver antitumor, cardiovascular, antiviral, antiprotozoal drugs, genetic material, imaging molecules, etc. ILs can be derived from various phospholipids of both natural and synthetic origin, charged or neutral. The most widely used phospholipids in immunoliposomal construction are phosphatidylcholines. To increase the mechanical stability of the bilayer, sterols are introduced into the lipid composition. For selective liposome delivery, targeting ligands must be attached to the nanocarrier via the spacer arm of the PEG. Several types of end-group functionalized lipopolymers are used for this purpose, usually of the general formula X-PEG-LI, where X represents a fragment containing a reactive functional group − maleimide, biotin, cyanur, amine, etc. These lipid PEG-conjugates exhibit excellent amphiphilic properties and offer excellent advantages for the modification, formulation, and delivery of various drugs. The Ab used should enhance the accumulation of the liposomal drug in the target areas with minimal cross-reactivity with healthy tissues. Ready-made drugs based on monoclonal Ab, such as trastuzumab, cetuximab, panitumumumab, bevacizumab; commercial Ab intended for research purposes, and laboratory synthesized Ab and their fragments are used in the preparation of ILs. Ab can be attached to liposomes by two main methods: direct covalent conjugation and postinsertion.Conclusion. The results of this study allowed us to summarize the variety of literature data on the composition of ILs and the possibility of using auxiliary components to achieve the goal in the development of the drug.

Introduction. The Laboratory for the development of dosage forms of the N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation has developed a composition of an injectable liposomal dosage form based on soybean phosphatidylcholine, a hydrophobic analog of the hypothalamic hormone somatostatin − cyphetrylin, intended for the treatment of neuroendocrine tumors.Aim. Determination of optimal technological conditions for the process of obtaining a liposomal dosage form of cyphetrylin.Materials and methods. The study used the substance cyphetrylin synthesized in the of Chemical Synthesis Laboratory of the N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation; soybean phosphatidylcholine S PC and polyethylene glycol-2000-distearoylphosphatidylethanolamine, produced by Lipoid GmbH (Germany); cholesterol ≥99 % (Sigma-Aldrich, Japan). For the preparation of phospholipid vesicles loaded with cyphetrylin and "empty", the methods of lipid film hydration with subsequent extrusion or homogenization of the dispersion of multi-layer liposomes were used. The obtained liposomal samples were evaluated by quality indicators − the effectiveness of the inclusion of cyphetrylin in vesicles, their average size and surface charge (zeta potential), the viscosity of the dispersion. To evaluate these characteristics, the methods of spectrophotometry, laser scattering spectroscopy, determination of the electrophoretic mobility of particles and viscometry were used.Results and discussion. It was found that the most suitable organic solvent for obtaining a solution of cyphetrylin and lipid components of the dosage form is chloroform. The duration of the drying period of the lipid film under vacuum to remove the residual solvent is determined by the ratio of the volume of the distillation flask used and the mass of its loading its loading. At the same time, hydration off the lipid film with water for injection should be carried out under conditions of low-pressure and room temperature. To obtain a dispersion of single-layer cyphetrylin liposomes of the required size, an extrusion method using nylon and polycarbonate membranes with a filter pore diameter of 0.22 and 0.2 um, respectively, was chosen.Conclusion. The optimal technological conditions for the process of obtaining a liposomal dosage form in the form of a dispersion of a hydrophobic analog of the hypothalamic hormone somatostatin − cyphetrylin are determined.

Abstract Objective Study of embryotoxicity, teratogenicity and reproductive toxicity of the new drug Lipophtalocyan in rats. Material and Methods Studies were conducted on 210 non-inbred female rats and 105 non-inbred male rats. The drug was administered daily via i. v. injection for 48 days (males) and for 15 days (females) in 2 total doses corresponding to the therapeutic dose (TD) for mice when converted to rats and 10 TD. Results and Conclusion When mating with intact female rats, no changes in sexual behavior were observed, but the index of the ability to fertilize and conceive decreased when compared to the values of the control group by 35–40% (TD index=60%) and by 75–80% (10 TD index=20%). The index of the ability to fertilize and conceive differed from the values of the control group by 90% (TD index=5%) and by 15% (10 TD index=80%). There were no differences in the indicator of embryotoxicity and teratogenicity in intact and drug-treated female rats, compared with the control group. Lipophtalocyan has a negative effect on the male and female reproductive function in rats and has an embryotoxic effect according to the index of the ability to fertilize and conceive, as well as the indices of preimplantation and post-implantation fetal death. The drug does not have a teratogenic effect, neither it affects the physical development of offspring or the rate of maturation of sensory-motor reflexes during feeding.

Objective The current scientific research direction is development of drugs with a targeted effect on malignant tumors. One of the promising groups is indolocarbazoles and their derivatives, which can initiate various tumor cell death pathways. Russian scientists from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation has developed a new experimental drug form of the original compound LCS 1269 with cytotoxic and antiangiogenic properties, blocking vasculogenic mimicry in tumor. The study aim is the experimental drug form LCS 1269 antitumor activity on models of transplantable mouse tumors B-16 melanoma and Lewis epidermoid lung carcinoma (LLC) with different routes and modes of administration. Material and methods Female F1 hybrid mice (C 57 Bl/ 6 x DBA/2) and male and female linear mice C 57 BL/ 6 were used for management of tumor strains. Mice were obtained from N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russian Federation vivarium. The antitumor effect was assessed by tumor growth inhibition (TGI) and increase of treated animal’s life span (ILS) compared to the control. Results The experimental drug form showed high antitumor activity when administered intravenously once at doses of 100 and 120 mg/kg (TGI = 98–82% and TGI = 95–77%, respectively, ILS = 24%, p < 0.05) on melanoma B-16 mice. On LLC mice, the experimental drug form showed that the intravenous administration route was effective in the range of doses from 60 to 80 mg/kg with a 5 day administration regimen with an interval of 24 h. A dose of 70 mg/kg had maximum effect at the level of TGI = 96–77% ( p < 0.05) with its retention for 20 days after the end of treatment. Conclusion The studies have shown that the new compound LCS 1269 in the original drug form, has a pronounced antitumor activity and significantly reduces the volume of tumor mass both on melanoma B-16 and on LLC. It allows us to recommend continue the search for sensitivity of animal transplantable tumors to LCS 1269.

Introduction. One of the key tasks in freeze‑drying of drug is to choose the optimal cryoprotector that provides a high‑quality lyophilized product.The aim of research. Selection of cryoprotectant and its concentration for the preparation of lyophilizate of the liposomal dosage form of the indolocarbazole derivative LHS‑1269.Materials and methods. Substance LHS‑1269 ≥99 % (N. N. Blokhin National Medical Research Center of Onco logy), egg phosphatidylcholine Е РС S (Lipoid, Germany), cholesterol ≥99 % (Sigma‑Aldrich, Japan), polyethylene glycol‑2000‑distearoyl phosphatidylethanolamine (Lipoid, Germany), mannose‑d (+) 99 % (Kaden, Germany), sucrose (Himmed, Russia), trehalose dihydrate (Himmed, Russia). To obtain LHS‑1269 liposomes, the Bangham method was used in modification for hydrophobic substances with subsequent extrusion of the dispersion of multilayer phos‑ pholipid vesicles. The prepared liposomal dispersion was dosed into vials of 6 ml and lyophilized in the freeze‑dryng chamber using the «step‑by‑step» freezing mode. LHS‑1269 liposomes were analyzed before and after freeze‑drying using laser scattering spectroscopy and determination of the electrophoretic mobility of particles.Results. To prevent the destruction of LHS‑1269 liposomes during lyophilization, substances from the carbohy‑ drates class – mannose, sucrose and trehalose – were studied in two concentrations. In the course of compara‑ tive evaluation of the obtained lyophilizates in terms of quality, appearance, rehydration, size and zeta potential of liposomes before and after sublimation, it was found that sucrose introduced into the liposomal dosage form LHS‑1269 in the molar ratio sucrose / egg phosphatidylcholine 5:1 has optimal cryoprotective properties.Conclusion. As a result of the study, the optimal cryoprotector and its concentration were selected, which ensure the production of high‑quality lyophilizate of the liposomal composition of the indolocarbazole derivative LHS‑1269.

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.

Objective: Development of a lyophilized injectable dosage form LCS-1208, an original antitumor drug based on an indolocarbazole derivative. Methods: The prepared solution of the injectable dosage form LCS-1208 is transferred to sterilizing filtration, which is carried out under vacuum on a «Stericup» filter unit with a filter pore size of 0.22 μm. The sterile solution of the injectable dosage form LCS-1208 is poured into sterile vials using a dispenser and lyophilized in a freeze-drying chamber. At the end of drying, the preparation is corked in the chamber of a sublimation unit using a hydraulic device and transferred to crimping with aluminum caps using a seaming machine. Quantitative determination of the drug content was determined by spectrophotometry using a standard sample at λ = 320±2 nm. The pH was determined by potentiometry. Results: A freeze-drying regimen for the injectable dosage form LCS-1208 has been developed. The required solution freezing temperature was established taking into account the presence of 2 eutectic zones: a solution of LCS-1208 in DMSO (-35 ÷-32) °С, an aqueous solution of Kollidon 17PF (-10 ÷-8) °С. As a result of a series of experiments, the optimal lyophilization regime was chosen that does not require preliminary freezing in a low-temperature chamber, with freezing on the shelves of freeze-drying at a temperature of-47 °C without their preliminary cooling. The most acceptable vial filling volume was determined, amounting to 3 ml, and the rate of temperature rise during secondary drying of the preparation was justified. When using the developed regime of lyophilization of the LCS-1208 solution, it was shown that it can be sublimated while preserving the initial qualitative and quantitative characteristics. Conclusion: In this article, using the example of creating a lyophilized injectable dosage form LCS-1208 (the original antitumor drug from the indolocarbazole group), the main problems that arose during the lyophilization of the selected composition of the model solution, as well as ways to improve the process.

We studied specific antitumor activity of a liposomal drug based on tetra-3-phenylthiophthalocyanine aluminum hydroxide (lipophthalocyan) intended for photodynamic therapy. The optimal dose and protocol for photodynamic therapy with lipophthalocyan were chosen in experiments on mice: single intravenous dose of 6 mg/kg with a 5-h interval between administration and laser exposure and irradiation energy density of 400 J/cm2. A wide spectrum antitumor activity of lipophthalocyan was demonstrated in vivo for various transplantable mouse tumors (Lewis lung epidermoid carcinoma, S37 sarcoma, and colon adenocarcinoma AKATOL). The results show the possibility of using lipophthalocyan for photodynamic therapy of tumors of surface localization (skin and mucosa tumors).

В процессе создания противоопухолевого препарата важное место занимает обоснование оптимальной лекарственной формы (ЛФ), отобранной в экспериментальных исследованиях активной фармацевтической субстанции (АФС). На примере лекарственных препаратов, разработанных в НИИ ЭДиТО ФГБУ «НМИЦ онкологии им. Н. Н. Блохина» Минздрава России, показано влияние фармацевтических факторов на получение рациональной ЛФ, позволяющей реализовать возможности противоопухолевой субстанции. В процессе фармацевтической разработки определен рациональный путь введения АФС, выбрана оптимальная композиция ЛФ, изучено взаимодействие инъекционной ЛФ с кровью и тканями в месте введения препарата, выявлена эффективность моделей ЛФ и зависимость противоопухолевого эффекта от состава вспомогательных веществ, введенных в ЛФ. Изучена устойчивость полученных композиций ЛФ во время производства и в последующем хранении. Разработана рациональная технология получения качественных инъекционных ЛФ противоопухолевых АФС сублимационным высушиванием.

Aim. The aim of this work was to create a lyophilized liposomal dosage form of native hydrophobic antitumor compound from the group of indolocarbazole derivatives — LHS-1208. Materials and methods. Quantitative determination of the drug content was carried out on a Cary 100 spectrophotometer using a standard sample at λ = 320 ± 2 nm. The analysis of the average diameter of liposomes was carried out by the method of correlation spectroscopy of light scattering using devices Nicomp-380 nanosizer and Zetasizer Nano ZS zetasizer, using the latter, the zeta potential of the liposomal dispersion was also measured. To measure the pH of the solution, a HANNA pH 211 pH meter was used. The dynamic viscosity was measured on a Vibro Viscometer SV-10 viscometer. Lyophilization was carried out in an Edwards Minifast DO.2 freeze-drying chamber. Results. Experimental models of compositions of lyophilized liposomal dosage form LHS-1208 with various molar ratios of components were obtained and analyzed. TLC analysis using several solvent systems can be used to detect and identify LHS-1208 in a liposomal dosage form. According to the results of the study, a spectrophotometric method was developed for the quantitative determination of the LHS-1208 content in the composition of a liposomal dosage form. Based on the studies carried out, quality indicators were selected for standardization of lyophilized liposomal dosage form LHS-1208 and subsequent development of the draft regulatory documentation. Conclusion. As a result of the complex pharmaceutical research, the optimum composition of the components was determined, and the technology for production of liposomal dosage form LHS-1208 was developed.

Objective: Was to create the composition of the liposomal pharmaceutical form for injections of somatostatin analogue cyphetrylin using soybean phosphatidylcholine (SPC). Methods: The cyphetrylin, active pharmaceutical ingredient (API), developed in the Chemical Synthesis Laboratory, the N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation; SPC and polyethylene glycol-2000-distearoylphosphatidylethanolamine (PEG-DSPE, Lipoid, Germany); cholesterol ≥99% (Sigma-Aldrich, Japan). The lipid film hydration method with subsequent liposomal dispersion filtration/extrusion through nylon membrane filters was used for the phospholipid vesicle production. Based on API and lipid components in different molar ratios, we studied over 15 model liposomal compositions and assessed each lipid's impact in use on quality attributes of resulting dispersions. Derived model samples of liposomal dispersion were estimated in terms of quality and efficiency of cyphetrylin encapsulation into vesicles, their average size and the surface charge (zeta potential), polydispersity index (PDI) and dispersion viscosity. We used spectral photometry, dispersion laser spectroscopy, electrophoretic particle mobility assay, and viscometry to assess these features. Results: Pharmaceutical form components' desirable molar ratios determined: cyphetrylin/SPC at 1:60.0 and SPC/cholesterol/PEG-DSPE at 1:0.2:0.004, were determined. This composition allows cyphetrylin liposomal dispersion production with relatively stable vesicles of uniform size, 176 nm in diameter, and a 100% maximum rate of API encapsulation into the bilayer. Conclusion: Technological and chemical/pharmaceutical studies resulted in selecting a preferable composition of an injectable liposomal pharmaceutical form model of somatostatin analog-based on the SPC.