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).

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.

An assay method for the excipients (sucrose, phosphatidylcholine, and cholesterol) of liposomal medicinal formulations of the phthalocyanine photosensitizer lipophthalocyan by TLC with chromatodensitometry was validated. Coefficients of standard residual deviation for establishment of linearity were 3.48 for sucrose, 1.69 for phosphatidylcholine, and 1.36 for cholesterol. The coefficients of variation for determination of similarity and intermediate precision were less than 5%. The method was shown to be reliable over a wide range of conditions for the suitability of the system.

Introduction.Liposomal technologies are widely used in medicine and cosmetology as a delivery system for diagnostic and medicinal products and biologically active substances. The undoubted practical importance at the stage of development of a liposomal preparation is represented by the characteristic and assessment of the sustainability of the obtained product, and special attention is paid to the study of the latter. Essentially, the methods for their preparation affect the stability of liposomes; therefore, the study of the influence of technological factors on the properties of the product at various stages of the preparation of liposomes is very important. This article is devoted to the study of the dependence of the quality of liposomes loaded with a phthalocyanine photosensitizer – thiosens, on the conditions of their production.Aim.Detection of the influence of various technological factors on the stability indicators of the liposomal form of the thiosens photosensitizer.Materials and methods.For this purpose, an analysis of the average size, polydispersity and zeta (ζ) potential of the liposomes of thiosens obtained at the stage of hydration of the lipid film, filtration of the liposomal dispersion, its extrusion, homogenization, ultrasonic treatment, and lyophilization was carried out.Results and discussion.During the preparation of a liposomal preparation, various changes in conditions can be made within the framework of the technological process. At each stage of obtaining a liposomal form, there are many critical points and parameters that must be strictly monitored and controlled. In the course of the work, the influence of technological factors on the stability of liposomal intermediate and finished products was assessed. The conditions of the most effective hydration with the formation of a stable dispersion of multilayer liposomes of thiosens and the optimal method of their grinding have been determined. It was also shown that liposomes formed after rehydration of the lyophilisate are more uniform in size and have the highest ζ-potential value in comparison with non-lyophilized liposomal dispersion.Conclusion.Using the example of a thiosens phthalocyanine photosensitizer liposomes, the influence of various technological factors on the stability of this nanostructure is shown, therefore, the characteristic and assessment of the sustainability of the resulting product according to 3 main indicators – vesicle size, polydispersity index, and ζ-potential are of undoubted practical importance.

There are several methods for solving the problem of an adequate dosage form for the hydrophobic and poorly soluble pharmaceutical substances which comprise a structure modification, preparation of solid dispersion systems, a change in pH, the use of cosolvents and solubilizers introduction of substances in the formulation of lipid nature and complexation. In this review, special attention is paid to the preparation of nanostructured dosage form for these classes of drugs. Are examples of drugs used successfully in clinical practice the development of which applied these methods.

The work is dedicated to the development of technology for obtaining a freeze-dried dosage form LHS-1208 and the establishment of methods of quality control of the drug. The authors have shown spectrophotometric analysis techniques and flash chromatography.

Валидирована методика количественного определения вспомогательных компонентов (сахарозы, фосфатидилхолина и холестерина), входящих в состав липосомальной лекарственной формы фотосенсибилизатора из группы фталоцианинов — липофталоцина — методом ТСХ с хроматоденситометрией. Коэффициент стандартного остаточного отклонения при установлении линейности составил для сахарозы 3,48, фосфатидилхолина — 1,69, холестерина — 1,36. Коэффициент вариации при определении сходимости и промежуточной прецизионности составил меньше 5 %. Надежность метода установлена в широком диапазоне различных условий пригодности системы.

Despite the development of biotherapy, chemotherapy remains one of the main methods of treatment of cancer patients. Currently, there are more than 100 anticancer drug substances, however, every year new drugs enter clinical practice and various therapeutic regimens are tested, expanding the possibilities of therapy and improving the results of treatment. Therefore, the adequate use of modern chemotherapy requires constant updating of information about anticancer drugs and methods of their use. Oral administration of drugs is the most natural and convenient way to introduce drugs into the human body. There are about 75% of orally administered drugs that have the ability to be absorbed in the gastrointestinal tract within 1−3 hours after administration. Oral dosage forms (DF) are most common due to the relative simplicity of their production, convenience of use, accuracy of dosing and high stability. Therefore, pharmaceutical companies often reproduce generics in the form of tablets and capsules for oral administration. However, most active pharmaceutical ingredient (API) are destroyed by the action of the gastrointestinal tract environment, which makes it impossible to use the oral administration. This review of the literature describes the main groups of anticancer drugs that are effective when taken orally. The aim of the study is to compile the information on the main groups of anticancer drugs used internally. Materials and methods. The object of the study was well-known anticancer drugs approved for oral administration. The study was conducted using search information and library databases (eLibrary, PubMed, CyberLeninka, ResearchGate), as well as State Register of Medicinal Remedies. Results and discussion. Analyzing the arsenal of cytotoxic drugs, it should be noted that antitumor substances are characterized by high chemical lability they are photosensitive, heat-labile, hygroscopic and hydrolytically unstable. These properties complicate both obtaining reproducible therapeutic effect when taken orally and technological inprocesses. In addition, anticancer drugs have mutagenic, teratogenic, sensitizing and allergenic effects. Conclusion. Lack of sufficient selectivity of the antitumor effect of cytotoxic drugs and a small breadth of pharmacological action require the use of DF, ensuring control of drug delivery to the body, including dosage accuracy and standard bioavailability. DF plays a very important role in the delivery of drugs to the lesion site. Capsules and coated tablets are necessarily created to avoid high toxicity of anticancer drugs and local tissue reactions when taken orally.

Background. Over the last years the studies have increased interest in screening antitumor and anti-angiogenic substances that block several mechanisms of angiogenesis activation in tumors. A great attention is paid to development of effective and low toxic drugs as inhibitors of angiogenesis which are derived from herbal raw material. The article is devoted to the results of standardization of the dosage form of dimeric macrocyclic tannin (DMT) obtained from Chamerion angustifolium (L.) Holub in N.N. Blokhin National Medical Research Center of Oncology, which has a great potential as an antiangiogenic agent. Objective: to determine quality criteria for standardization of the drug “DMT, lyophilisate for preparation of solution for injections 100 mg”. Materials and methods. The study used “DMT, lyophilisate for preparation of solution for injections 100 mg” and DMT substance. Methods: spectrophotometry, infrared spectroscopy, high performance liquid chromatography, potentiometry, polarimetry. Results. Quality criteria for lyophilized DMT dosage form were determined with the account of Russian State Pharmacopoeia (XIII edn.) requirements to the drugs for injections and methods for their evaluation were defined. Conclusions. Laboratory studies demonstrated that the determined quality criteria and the defined methods for their evaluation are feasible for adequate quality control of dosage form “DMT, lyophilisate for preparation of solution for injections 100 mg”.

Lyophilization (freeze drying) is among the most effective methods used to stabilize drugs and increase their shelf life. It is influenced by many factors, the most important of which are the properties of the parent drug substance and the excipients and the freezing and drying conditions. This review considers in detail the excipients used in lyophilized dosage forms and gives examples of sublimation regimes used for the lyophilization of some antitumor drugs.

Background. Over the last years the studies have increased interest in screening antitumor and anti-angiogenic substances that block several mechanisms of angiogenesis activation in tumors. A great attention is paid to development of effective and low toxic drugs as inhibitors of angiogenesis which are derived from herbal raw material. The article is devoted to the results of standardization of the dosage form of dimeric macrocyclic tannin (DMT) obtained from Chamerion angustifolium (L.) Holub in N.N. Blokhin National Medical Research Center of Oncology, which has a great potential as an antiangiogenic agent. Objective: to determine quality criteria for standardization of the drug “DMT, lyophilisate for preparation of solution for injections 100 mg”. Materials and methods. The study used “DMT, lyophilisate for preparation of solution for injections 100 mg” and DMT substance. Methods: spectrophotometry, infrared spectroscopy, high performance liquid chromatography, potentiometry, polarimetry. Results. Quality criteria for lyophilized DMT dosage form were determined with the account of Russian State Pharmacopoeia (XIII edn.) requirements to the drugs for injections and methods for their evaluation were defined. Conclusions. Laboratory studies demonstrated that the determined quality criteria and the defined methods for their evaluation are feasible for adequate quality control of dosage form “DMT, lyophilisate for preparation of solution for injections 100 mg”.

Introduction. Governments around the world seek to reduce rapidly rising health care costs. Using the same high quality and often cheaper than the original brands, generics greatly reduces costs while providing an adequate quality of care. Therefore the development of generic medicines is an important task. The purpose of the study - the reproduction of the pharmaceutical dosage form for creation of national drug-generic epirubicin. Materials and methods. The study used a substance epirubicin (Ph. Eur current edition, Teva Pharmaceutical Industries Ltd., Israel); “Farmorubicin”, production “Pfizer Italia Srl” for “Pfizer Inc.”, Italy / US and excipients conforming to with relevant regulatory documents. Mice transplanted tumor: lymphocytic leukemia P388. Methods: technological, pharmaco-analytical, biological and pharmacological. Results. Pharmaceutical analysis of reproduced generic-drug “Epirubicin-RONC®” showed that itfully meets the requirements of manufacturer’s monograph. The results of “acute” toxicity study in rats and observations of the experimental animals within 30 days after a single administration suggest that both drugs have similar toxicological properties and are almost identical. Generic “Epirubicin RONC®” and “Farmorubicin” in lyophilized dosage form for injection 10.0 mg/vial, administered once, shows equal antitumor effect at two administration routes in mice with transplantable tumor: lymphocytic leukemia P-388. Conclusion. N.N. Blokhin Russian Cancer Research Center Ministry of Health of Russia has been reproduced generic - “Epirubi-cin-RONC®”, which is fully conform to the imported drug.

The improvement of the composition and technology for the preparation of the liposomal dosage form of ormustine is under consideration. Liposomes are prepared from egg lecithin, cholesterol, and PEG-2000-DSPE by the film hydration method, with 0.1% citric acid being added to the composition to stabilize the liposome dispersion. The efficiency of loading with ormustine is (60 ± 5)% and the average vesicle size is (190 ± 20) nm.

Background. In connection with the prospect of the use of an analog of the hypothalamic hormone somatostatin synthesized by the laboratory of chemical synthesis Institute of experimental diagnostics and chemotherapy of FSBI «N.N. Blokhin Russian Cancer Research Center» and showed a high anti-tumor activity as a drug arises a need to establish an optimal technology of its receipt. In preliminary studies in a modelformulation for an analog of the hypothalamic hormone somatostatin selected liposome technological process of which has a series of specific steps comprising. Objective. Development of technology for obtaining liposomal formulation hypothalamic hormone somatostatin analogue. Materials and methods. Liposomes analog of the hypothalamic hormone somatostatin obtained by method Bengema in modification for hydrophobic substances. To reduce the diameter of the liposome are used methods extrusion, homogenization and ultrasonic. Analysis of the size of the liposomes was performed by correlation spectroscopy light scattering using nanosizer. The pH of the liposomal dispersion was determined by potentiometry. The quantitative content of the drug substance was determined by spectrophotometry using a standard sample with X (282 ± 3) nm and an alcoholic solution of empty liposomes as a reference solution. Amount of incorporated drug was calculated as the ratio of the concentration of drug in the liposome dispersion after filtration to the concentration of drug in the dispersion after preparation. Results and Conclusion. The hydrophobic nature of the substance causes an analog of the hypothalamic hormone somatostatin technological features of obtaining liposomal formulation. Since the step of forming a film of the lipid substance is dissolved in an organic solvent together with lipids, film is hydrated by a solution of cryoprotectant. Grinding liposomes an analog of the hypothalamic hormone somatostatin appropriate to be carried out using homogenization or extrusion methods, due to the high efficiency of these methods, the preservation stability of the liposomes and a high percentage of inclusion an analog of the hypothalamic hormone somatostatin, included in the liposomal bilayer. At the stage of separating the non-inclusion of substance an analog of the hypothalamic hormone somatostatin due to the insolubility of the substance in the water, you can use the filtering method, without the need for complicated procedures gel filtration, dialysis, etc. Furthermore the process of separating a substance not included can be combined with the sterilization of the liposome dispersion by selecting a particular filter material.

At present, the hormone somatostatin analogues is increasing interest in connection with their activity against hormone-dependent tumors, which leads to the need to develop domestic drugs belonging to this group. In the laboratory of chemical synthesis Institute of experimental diagnostics and chemotherapy of FSBI «N.N. Blokhin RCRC» synthesized new domestic pentapeptide somatostatin analogue of hypothalamic hormone (AGGS). In preliminary studies of this substance demonstrated sufficiently high antitumor activity AGGS on transplanted solid tumors of mice. Due to the insolubility of the substance in the water as an alternative liposomal formulation proposed, allowing to increase the bioavailability of the drag due to the possibility of intravenous administration, increased therapeutic efficacy and reduce side effects, by improving the selectivity of action against tumor cells. During experiments on the development of the liposomal formulation AGGS pre-established model containing as essential components of the liposomal bilayer and egg lecithin PEG-2000-DSPE in a molar ratio 72/1 and as a ciyo- protectant - sucrose. In developing the technological parameters of the process of obtaining dosage form (LF) found that for an acceptable size derived phosphohpid vesicles needs about 7 cycles extrusion. The lack of stability of liposomal dispersion selected composition during storage has led to this problem by means of freeze-drying, which kept the physico-chemical parameters LF at the initial level. The efficacy of the model LF on transplantable tumors of mice - breast adenocarcinoma Ca-755, which was more than 60 % of ITG at a dose of 5 mg / kg and more than 80 % ITG with 20 mg / kg. The findings of biological experiments indicate the prospects for further research and improvement liposomal LF to produce high-performance domestic anticancer drag from the group of somatostatin analogues.

The laboratory for development of drug forms, N.N. Blokhin Russian Cancer Research Center developed a lyophilized liposomal dosage form (LLDF) of a new infrared photosensitizer phthalocyanine derivative - Thiosens. Previous studies determined optimal composition of the dosage form, technology of its production and methods of analysis; a number of biological experiments were performed. The next step of preclinical research is studying "acute" toxicity of LLDF, which is presented in this paper. The study of "acute" toxicity of LLDF Thiosens was carried out in the laboratory of Pharmacology and Toxicology. "Acute" toxicity of LLDF Thiosens was studied in the experiments on mice hybrids F1 (CBA » C57Bl / 6J) male and female and weinbrener outbred male rats. In the first series of experiments LLDF Thiosens was administered to male mice in the dose range of 5; 10; 20 and 30 mg/kg. In the second series of experiments, male and female mice were injected with LLDF Thiosens in the dosage range 6; 12 and 24 mg/kg. Male mice were treated by LLDF Thiosens intravenously; no symptoms of toxicity were registered at the doses of 5 and 10 mg/kg; death was observed in all experimental animals after administration at the doses of 20 and 30 mg/kg on the first day in the result of inactivity and piloerection. In the second series of experiments no sex differences were found in single intravenous injection of LLDF Thiosens. The results of the studies of "acute" toxicity in rats demon strated that when LLDF Thiosens was administered in doses 3, 6 and 9 mg/kg animal deaths were reported. A single intravenous LLDF Thiosens administration in rats in the excess of the expected dose for human in 1.5-4.5 times was well tolerated by the animals: animal mortality, clinical signs of toxicity and changes in behavioral responses were absent.

The research is devoted to development and study of photosensitizers on a base of injectable nanoparticular formulations of phthalocyanine derivatives absorbing at long wavelength (near-infrared) range of 710–740 nm: Thiosens [liposomal form of aluminum hydroxide 1,8,15,22-tetrakis(phenylsulfanyl)phthalocyanine] and Octasens [polymeric micellar form of zinc 1,4,8,11,15,18,22,25-octachloro-2,3,9,10,16,17,23,24-octakis-(decylsulfanyl)phthalocyanine based on domestic poloxamer Emuxol-268]. Experiments have shown that the photosensitizers under study show high selectivity of accumulation and prolonged retaining at high concentration in tumor, relatively fast clearance from normal tissue and high therapeutic efficiency of photodynamic treatment on model tumors.

The implementation of liposome delivery systems ensures the intravenous introduction of hydrophobic photosensitizers used in the treatment of tumors by the photodynamic therapy method with their preservation in a therapeutically effective nonaggregated form and high accumulation selectivity in the tumor. Phthalocyanines are one of the fastest growing classes of antineoplastic photosensitizers, most of which are hydrophobic compounds. In this study the authors have developed the unique composition and technology of preparing the lyophilized liposomal formulation of infrared photosensitizer: aluminum hydroxide tetra-3-phenylthiophtalocyanine (Thiosens). At the stage of biological experiments on model mouse tumors, the preservation of high accumulation selectivity in the tumor (selectivity index is higher than 4) and antineoplastic effectiveness (inhibition of tumor growth is from 70 to 94%) were found during the transition from the previously studied model dosage form to the created lyophilized liposomal one. To estimate chemical and pharmaceutical criteria and the photodynamic efficiency of the photosensitizer on a number of transplanted mice tumor models in vivo, we have conducted a preclinical study which has demonstrated the stability of antitumor activity and quality consistency of the developed dosage form for one and a half years.