The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products / Ведомости Научного центра экспертизы средств медицинского применения
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Совершенствование нормативной базы по проведению доклинических исследований контрастно-диагностических препаратов
No full textThis paper analyses modern hi-tech methods of diagnosing health problems with the help of X-ray contrast agents used in combination with such technologies as magnetic resonance imaging, single-photon emission computer tomography, etc. The lack of Russian diagnostic drugs is the main hindrance to a wide clinical use of advanced medical diagnostic technologies. The article demonstrates the necessity of developing guidelines which would standardize the scope and nature of preclinical studies for all classes of X-ray contrast agents. The article suggests the main concepts that the guidelines should contain: the definition of the term «diagnostic drug»; the classification of diagnostic drugs by their chemical structure and/or pharmacological action; the required scope of obligatory and additional studies for new drugs and for new indications for already approved drugs; the objectives of experimental pharmacokinetic studies and acceptable methods of obtaining primary data; the list of methods to be used for electronic processing of primary data; evaluation of X-ray contrast agents safety (especially radiopharmaceuticals and PET radiopharmaceuticals), and the standard protocol of test results
О необходимости совершенствования законодательства в сфере использования лабораторных животных
No full textThe authors have analyzed international experience in creating legal documents regulating the use of animals for scientific purposes. Topical issues related to the use of laboratory animals for scientific purposes in the Russian Federation, including for the purpose of preclinical studies on the efficacy and safety of new medicines, are discussed. The negative effects of the lack a clear and consistent legal framework for the organization and limits of the use of laboratory animals for research purposes in the Russian Federation are identified. Particular attention is paid to the issue of bioethics, the principles of ethical expertise of research activities involving laboratory animals and the issues of bioethical committees activities. The basic directions of perfection of normative-legal acts and methodological documents in the field of organization and limits of the use of laboratory animals for research purposes are proposed.Проведен анализ международного опыта создания нормативно-правовых документов, регламентирующих использование животных в научных целях. Рассмотрены актуальные вопросы, связанные с использованием лабораторных животных в научных целях в Российской Федерации, в том числе для целей проведения доклинических исследований эффективности и безопасности новых лекарственных средств. Выявлены негативные последствия отсутствия в Российской Федерации четкой и непротиворечивой законодательной базы в области организации и ограничений использования лабораторных животных в научных целях. Особое внимание уделено проблеме биоэтики, принципам проведения этической экспертизы научной деятельности с использованием лабораторных животных и вопросам организации деятельности биоэтических комиссий. Предложены основные направления совершенствования нормативно-правовых актов и методической документации в области организации и ограничений использования лабораторных животных в научных целях
АПРОБАЦИЯ МОДИФИЦИРОВАННОЙ ТЕХНИКИ ВЫПОЛНЕНИЯ ИНТРАВИТРЕАЛЬНОГО ВВЕДЕНИЯ ЛЕКАРСТВЕННЫХ СРЕДСТВ В ГЛАЗ КРОЛИКА
Get PDFThe article describes theoretical foundations and successful experimental testing of a modified method of intravitreal injection (IVI) in the rabbit eye performed in the laboratory. The method needed modification because preoperative preparation described in available guidelines on IVI requires the use of medicines that are not suitable for use in vivariums in the Russian Federation. The IVI procedure for rabbits was modified by using an anesthetic regime reproducible in Russia and available eye preparations. The anesthetics used were Zoletil 50® («Virbac», France) At a dose of 1.1 mg/kg and Rometar («Bioveta, a.s.», Czech Republic) At a single intravenous dose of 5.6 mg/kg. additional analgesia was achieved by a single intramuscular injection of Ketonal® («Lek d.d.», Slovenia) At a dose of 5 mg/kg. The local anesthetic used was Inokain® eye drops («Promed Exports Pvt. Ltd.», India), the antiseptic used was Betadine® (JSC «EGIS Pharmaceutical plant», Hungary) diluted with water in the proportion of 1:10. The results of clinical examination of animals following IVI performed by lab researchers during unassisted skill training were analysed, and the results of assessment of adverse reactions associated with IVI were expressed as scores and reflected in primary records. The suggested method demonstrated good reproducibility and, therefore, may be recommended for use in preclinical studies of ophthalmic drug products in Russia
Подходы к определению высокомолекулярных агрегатов в глатирамоидах
Get PDFThe approaches to the selection of the optimal chromatographic conditions to assess the content of high molecular weight aggregates in glatiramer acetate - compounds belonging to nonbiological medicines of complex chemical structure - are described. It is found that accelerated aggregate formation occurs under stringent conditions, and in this case it is accompanied by a change in the molecular weight distribution of a basic compound. The number of aggregates formed relatively small. Samples not subjected to accelerated aging are substantially free of aggregates. Clarification of the composition and the molecular weight of the resulting units, as well as an assessment of their stability, is the subject of further research, which will recommend approaches to standardization of pharmaceutical preparations containing glatiramer acetate.Описаны подходы к выбору оптимальных хроматографических условий, позволяющих оценить содержание высокомолекулярных агрегатов в глатирамоидах - соединениях, относящихся к небиологическим лекарственным средствам сложного химического строения. Установлено, что ускоренное образование агрегатов протекает в жестких условиях и в этом случае сопровождается изменением молекулярно-массового распределения основного соединения. При этом количество образовавшихся агрегатов относительно невелико. Образцы, не подвергавшиеся ускоренному старению, практически не содержат агрегатов. Уточнение состава и молекулярной массы образовавшихся агрегатов, а также и оценка их стабильности, являются предметом дальнейших исследований, что позволит рекомендовать подходы к стандартизации лекарственных препаратов, содержащих глатирамера ацетат
Фармакологическая регуляция активности изоферментов цитохромов P450 3A4 и P450 2C9 витаминами и природными соединениями
No full textThe influence of vitamins with antioxidant properties (vitamins A, E, C), B vitamins (B1, B2, B6) and vitamin-like substances (coenzyme Q10, taurine and L-carnitine) on the enzymes of the first phase of xenobiotic metabolism - cytochromes P450 3A4 and P450 2C9 has been studied. The experiments with informed volunteers have shown that B vitamins can shorten the duration of nonsteroidal anti-inflammatory drug diclofenac therapy and reduce the daily need for it. The positive effect of B vitamins in reducing the pain syndrome, shortening the duration of therapy and reducing the need for daily intake of diclofenac. Pharmacodynamic and pharmacokinetic data have been confirmed by electrochemical tests of electrocatalytic activity of cytochrome P450 3A4 (CYP3A4). Electrochemical approach to the study of catalytic activity of cytochrome P450 and the impact of vitamins and natural compounds on electrocatalysis is an accurate and effective touch-sensitive method allowing to use low concentrations of protein at an electrode (10-15 mol/electrode), to conduct the analysis without using protein pairs (cytochrome B5, NADPH-dependent reductase) and to identify the interaction of drugs in preclinical studies. When comparing the influence of B vitamins (B1, B2, B6) in the same concentration (300 μM) according to the electrochemical analysis, riboflavin (vitamin B2) is most effectively inhibits the interaction of diclofenac with cytochrome P450 3A4. Vitamin-like substance taurine with antioxidant properties and antioxidant vitamins stimulated electrochemical reduction of cytochromes P450 3A4 and P450 2C9. The obtained data confirm that it is possible that the influence of vitamins on cytochromes P450 3A4 (CYP3A4) и P450 2C9 (CYP2C9) allows to regulate pharmacokinetic parameters and the pharmacodynamic effect intensity
Методические особенности определения молекулярно-массового распределения декстранов методом гель-проникающей (эксклюзионной) хроматографии в нормативной документации на лекарственные средства различных групп
No full textThe article analyses the results of quality evaluation of dextran substances and medicines produced thereof which was carried out by the Institution as part of pre-authorisation testing and involved the analysis of the «molecular mass distribution» parameter. The article gives recommendations on how to present data on determination of dextran molecular mass distribution by size-exclusion chromatography in corresponding sections of product specifications with due consideration for specificity of the tested products and methods of their analysis, as well as on how to interpret the obtained results. It is suggested that particular attention should be paid to the creation of a calibration curve (choice of reference standards, type of experimental curve approximation) and testing of its suitability. The validation/verification (practical testing) of procedures used for determination of dextran molecular mass distribution which was carried out as part of pre-authorisation testing, made it possible to compile a list of documents that have to be submitted to the Institution for evaluation
ОСОБЕННОСТИ АНАЛИЗА ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ ДЛЯ ПАРЕНТЕРАЛЬНОГО ПРИМЕНЕНИЯ МЕТОДОМ ЭЛЕКТРОЧУВСТВИТЕЛЬНЫХ ЗОН
Get PDFThe article describes standard methodological approaches to the determination of subvisible particles by electrical sensing zone method (the Coulter principle). The standard procedure of lyophilisate and powder preparation includes their dilution with Isoton® II Diluent (Beckman Coulter, USA) — 0.9 % sodium chloride solution containing a preservative agent (hereinafter — Isoton) under conditions free from particulate matter. The article provides a brief description of the Coulter principle which was included into the General monograph «Subvisible particulate matter in parenteral preparations» of the State Pharmacopoeia of the Russian Federation, 13th edition. It was demonstrated that most solutions for injection and infusion do not need special preparation before testing, whereas 13 % of such preparations need the addition of the diluent Isoton to increase their electrical conductivity for determination of subvisible particulate matter. The article presents the results of experimental studies that were aimed at modification of the standard sample preparation procedure for different medicinal products for the purpose of their evaluation in terms of subvisible particulate matter. A number of lyophilisates, powders, suspensions, and oily solutions can not be diluted with Isoton because of precipitate formation, so recommendations are offered for these types of products regarding the choice of alternative diluents (water, 4 % sodium chloride solution, ammonium thiocyanate solution in isopropanol, acetone, etc.) for obtaining electrically conductive solutions. Alternatively, it may be recommended to change the dilution mode (increase the time of dilution and/or diluent volume). Thus, the article provides rationale for using the Coulter principle for determination of subvisible particulate matter in various pharmaceutical forms
СРАВНИТЕЛЬНЫЙ АНАЛИЗ ТРЕБОВАНИЙ К ОЦЕНКЕ КАЧЕСТВА ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ, СОДЕРЖАЩИХ ЭТИНИЛЭСТРАДИОЛ И ЛЕВОНОРГЕСТРЕЛ
Get PDFThe article compares test methods and levels of requirements laid out in the world’s leading pharmacopoeias and in manufacturers’ specifications with regard to the quality of levonorgestrel and ethinyl estradiol containing medicinal products used as oral contraceptives. The study analysed medicines containing a combination of levonorgestrel and ethinyl estradiol (Vezantra, Melleva, Microgynon, Minisiston, Modelle Libera etc.) that were tested at the FSBI «SCEEMP» of the Ministry of Health of the Russian Federation as part of premarketing evaluation. The comparison of the obtained data revealed that the test methods recommended by foreign pharmacopoeias and manufacturers’ specifications for quality control of medicines containing levonorgestrel and ethinyl estradiol are in line with the current trends in the pharmaceutical analysis and make it possible to adequately assess the quality of this group of medicines that are authorised in the Russian Federation. Manufacturers’ specifications include additional parameters, such as «Related impurities», «Microbiological purity», and, in some cases, «Identification of colouring agents» (titanium dioxide, iron oxide), «Average weight», «Disintegration», «Water», and «Residual organic solvents». The study showed that the requirements included into manufacturers’ specifications meet the requirements of the world’s leading pharmacopoeias or even exceed them, as in the case of the «Assay» parameter
Определение содержания алюминия в цветках ромашки аптечной методом атомно-эмиссионной спектрометрии с индуктивно связанной плазмой
No full textThe article presents the results of determining aluminum in Chamomile flowers by domestic manufacturers. A comparative analysis of the ability to accumulate aluminum for various medicinal plants has been performed. It has been shown that chamomile is defined by increased resistance to excessive concentrations of aluminum in comparison to other herbal substances.В статье представлены результаты измерения содержания алюминия в цветках ромашки аптечной отечественных фирм-производителей. Проведен сравнительный анализ кумулятивной способности к алюминию различных лекарственных растений. Показано, что ромашка аптечная характеризуется повышенной устойчивостью к избыточным концентрациям алюминия по сравнению с другими видами лекарственного растительного сырья
Сравнительная оценка методов количественного определения антраценпроизводных в лекарственном растительном сырье и лекарственных растительных препаратах
Get PDF The use of assay methods with different test conditions for determination of anthracene derivatives in herbal substances and herbal medicinal products requires adjustment of the established limits for total anthracene derivatives content based on the test method used.The aim of the study was to compare different pharmacopoeial methods of quantitative determination of anthracene derivatives, and established limits for the active substance content, and to analyse the possibility of adjusting the limits based on the test method used.Materials and methods: the total content of anthracene derivatives was measured in the samples of frangula bark (fragmented bark and powder) and senna leaves (fragmented leaves and powder) using the test methods described in the State Pharmacopoeia of the Russian Federation (XI and XIII editions), and the European Pharmacopoeia.Results: the analysis of Russian and foreign pharmacopoeial requirements for determination of anthracene derivatives in laxative herbal medicinal products demonstrated differences in extraction solvents, extraction conditions, and calculation methods used. The experiments showed that the optimal extraction solvent was 70 % alcohol solutions, and that an indirect cobaltic chloride reference standard should be replaced by specific absorbance of glucofrangulin A and sennoside B. It was shown that the limits for total anthracene derivatives content should be chosen based on the extraction conditions used.Conclusions: comparative theoretical research and experimental studies helped to determine optimal assay conditions and respective limits for total anthracene derivatives content to be used in quality control of herbal substances and herbal medicinal products.