MECHANOCHEMICAL ACTIVATION OF PHARMACEUTICAL SUBSTANCES AS A FACTOR FOR MODIFICATION OF THEIR PHYSICAL, CHEMICAL AND BIOLOGICAL PROPERTIES

Objective: Study the influence of the mechanical preparation methods (grinding, fluidization) of solid pharmaceutical substances (PS) and herbal raw material on their physicochemical properties and biological activities. Methods: Test substances and solvents-Lactose monohydrate (DFE Pharma, Germany). Sodium chloride, bendazol hydrochloride (all Sigma-Aldrich, USA) and herbal raw material (Callisia fragrans). The dispersity and native structure of pharmaceutical substances were analyzed by several methods: optical microscopy–Altami BIO 2 microscope (Russia); low angle laser light scattering (LALLS) method (Malvern Instruments, UK); Spirotox method–Quasichemical kinetic of cell transition of cellular biosensor Spirostomum ambiguum; Fourier-transform infrared spectroscopy–the analysis in the middle IR region was carried out using an IR Cary 630 Fourier spectrometer (Agilent Technologies, USA). The analysis of dried leaves of C. fragrans before and after mechanical activation was performed using Shimadzu EDX-7000 X-ray fluorescence spectrophotometer without mineralization (Shimadzu, Japan). Results: It was established that the mechanical change, such as dispersion and drying, alters the biological activity of PS and herbal raw materials. The observed increase in the influence of the dispersed substance on the biosensor S. ambiguum is quantitatively estimated from the values of the activation energy (obsEa), which turns to be valued 1,5 (P≤0,05) times more than for the native form substance. In the study of the dependence of the availability of chemical elements K, Ca, Zn on the degree of dispersion of herbal raw materials was established a quantitative 4-fold (P≤0,05) increase in the concentration of elements in mechano-activated raw materials. Conclusion: By the example of the biological model of Spirotox (single-celled biosensor S. ambiguum) and herbal raw materials obtained from C. fragrans, the increase of biological activity of PS at the dispersion of initial preparations was proved

Лекарственные препараты на основе релиз-активных антител

A number of the released-active drugs with proved safety and efficacy against viral infections, cough, stress and anxiety, brain circulation impairments, metabolic disorders, etc., exist in the pharmaceutical market for more than 15 years. Results of the preclinical studies have revealed some of the aspects of the released-active antibodies action. Nevertheless, the exact mechanism of each drug's action is still a subject of research. The aim of the present review is to investigate the physical-chemical principles of mechanism of action of the released-active drugs.Более 15 лет на фармацевтическом рынке представлена группа релиз-активных препаратов с доказанной эффективностью и безопасностью в лечении вирусных инфекций, кашля, стресса и тревоги, нарушений мозгового кровообращения, расстройств метаболизма и др. Результаты доклинических исследований позволили получить представление о некоторых аспектах действия антител в релиз-активной форме. Тем не менее точный механизм развития эффектов каждого препарата остается предметом изучения. Цель настоящего обзора - рассмотреть физико-химические основы механизма действия релиз-активных препаратов

Slow quasikinetic changes in water-lactose complexes during storage

Objective: To investigate kinetic changes in the spectral characteristics by Fourier Transform Infrared spectroscopy (FTIR) of water-lactose complexes (SMC), derived during the manufacturing process of the drug, containing release-active forms of antibodies. Methods: lactose monohydrate substance, saturated with release-active forms of affinity-purified polyclonal rabbit antibodies to recombinant human interferon-gamma (RA forms of Abs); tablets produced from this substance by direct compression after the addition of excipients (microcrystalline cellulose, magnesium stearate). Powdered and tableted placebo samples saturated with technologically processed water or phosphate-buffered saline, as well as with intact ethanol were used as control. Kinetic changes in SMC were studied using an Agilent Cary 630 FTIR spectrophotometer with a diamond ATR accessory (Agilent Technologies, USA). We used the method of X-ray fluorescence spectroscopy (EDX-7000 Shimadzu energy dispersive X-ray fluorescence spectrometer) to track changes in the fluorescence signal at certain wavelengths. The range of measured elements-11Na-92U. Results: Control of some technological characteristics of the obtained active substance (moisture, flowability) and dosage form (mean mass, disintegration rate) was used as indirect indicators of quality, but they did not allow reliably distinguishing intact lactose from the saturated one. Long-period oscillations on FTIR spectra were characteristic for all types of samples; oscillations occur at approximately two-week intervals; S/N indices were more stable for samples of RA forms of Abs than for placebo samples. On some days, the substance saturated with RA forms of Abs significantly differed from the intact lactose powder. The kinetics of the X-ray fluorescence intensity at certain wavelengths indicates the possibility of a periodic cooperative trigger transition of the system. Reversible conformational transitions are observed for powders on the 30th and 130th days (Ka 3.313 keV). For tablets at Ka 3.313 keV and Ka 1.740 keV small changes were visualized on those days (100-110th day) when hysteresis phenomena were recorded in the IR spectra of these samples. Conclusion: As a result, the evidence for a long-period dramatic conformational mobility of the water-lactose complex was obtained. Based on the data on the semiannual kinetics of IR spectra, a universal criterion for the identity of lactose powder saturated with RA forms of Abs was obtained. Also, it was confirmed that the lactose conformation state was changed by saturation with RA forms of Abs. © 2021 The Authors

АКТИВАЦИЯ ИЗМЕЛЬЧЕНИЕМ КАК СПОСОБ ИЗМЕНЕНИЯ БИОЛОГИЧЕСКОЙ АКТИВНОСТИ И ФИЗИКО-ХИМИЧЕСКИХ СВОЙСТВ ЛЕКАРСТВЕННЫХ СУБСТАНЦИЙ НА ПРИМЕРЕ НИКОТИНАМИДА

It is known that substances change their composition and properties under the influence of mechanical forces. In a highly dispersed state, compounds become more chemically active, which can be used to accelerate chemical reactions, produce new materials and increase the efficiency of pharmacotherapy [1]. Studies conducted by the authors [2] have shown a significant role in the chemoprophylaxis of skin cancer amide form of vitamin B3 - nicotinamide/Nicotinamide (NAM). The therapeutic niacinamide index is wide, but at very high doses in animals and humans, reversible hepatotoxicity was observed. Consequently, high doses of niacinamide (obsЕа,(kJ/mol) of cell biosensor transition to the "dead cell" state. Mechanical activation at a high rate of deformation of the NAM substance powder has led to changes in physical, chemical and biological properties of the drug, which can be used in medicine to increase efficiency and reduce doses of pharmacotherapy.Известно, что вещества изменяют свой состав и свойства под действием механических сил, что можно использовать для ускорения химических реакций, получения новых материалов и увеличения эффективности фармакотерапии [1]. В последние десятилетия во всем мире отмечается рост заболеваемости раком кожи. Исследования, проведенные авторами [2], показали значимую роль в химиопрофилактике рака кожи никотинамида (NAM). Терапевтический индекс никотинамида широк, но при очень высоких дозах у животных и человека отмечалась обратимая гепатотоксичность. Следовательно, высокие дозы никотинамида (<3г) следует рассматривать как терапию, обладающую токсическим потенциалом. С этой целью нами проведены физико-химические и биологические исследования активированной тонким помолом активной фармацевтической субстанции (АФС), доказывающие изменение свойств и увеличение активности никотинамида (NAM). Материалы и методы: для оценки физико-химических и биологических свойств АФС никотинамида были применены прямые и косвенные оптические методы анализа (микроскопия, лазерная дифракция), ИК-спектроскопия, биотестирование с применением метода Spirotox, рН-метрия. Результаты: Результаты проведенного исследования показали увеличение скорости химического процесса растворения механоактивированного NAM, а также увеличение биологической активности на примере клеточной культуры Spi-rostomum ambiguum. Заключение. Механическая активация при большой скорости деформации порошка субстанции NAM привела к изменению физико-химических и биологических свойств лекарственного вещества, что может быть использовано в медицине для увеличения эффективности и снижении доз фармакотерапии

Mechanical Transformation of Compounds Leading to Physical, Chemical, and Biological Changes in Pharmaceutical Substances

This study demonstrates the link between the modification of the solid-phase pharmaceutical substances mechanical structure and their activity in waters with different molar ratio «deuterium-protium». Mechanochemical transformation of the powders of lactose monohydrate and sodium chloride as models of nutrients and components of dosage forms was investigated by the complex of physicochemical and biological methods. The solubility and kinetic activity of substances dispersed in various ways showed a positive correlation with the solvent isotope profile. Substances dissolved in heavy water were more active than solutes in natural water. Differential IR spectroscopy confirmed the modification of substituents in the sample of lactose monohydrate, demonstrating physicochemical changes during mechanical intervention. The biological activity of the compounds was determined by the method of Spirotox. The activation energy was determined by Arrhenius. Compared with the native compound, dispersed lactose monohydrate showed lower activation energy and, therefore, greater efficiency. In conclusion, proposed data confirm the statement that mechanical changes in compounds can lead to physicochemical changes that affect chemical and biological profiles. © 2018 A. V. Syroeshkin et al

МЕТОД ДВУМЕРНОГО ДИНАМИЧЕСКОГО СВЕТОРАССЕЯНИЯ ДЛЯ ОПРЕДЕЛЕНИЯ ПОДЛИННОСТИ МАТЕРИАЛОВ И ЛЕКАРСТВЕННЫХ СРЕДСТВ

A method of two-dimensional dynamic backscattering (2D-DLS) with data processing according to a mathematical model of topological descriptors is proposed. The set of topological descriptors makes it possible to fingerprint of the surface, which is in one-to-one correspondence with the chemical composition and the method of its preparation. The 2D-DLS method was introduced at a pharmaceutical enterprise to control powdered medicinal substances obtained in fluidized bed chambers, as well as at two plants for the production of water with a modified isotopic composition for operational control of drugs in terms of the performance of distillation columns in terms of "authenticity".Предложен метод двумерного динамического обратного светорассеяния (2D-DLS) с обработкой данных по математической модели топологических дескрипторов. Метод основан на изменении топологии светорассеяния от поверхности при низкочастотном колебаниях супрамолекулярных комплексов. Набор дескрипторов позволяет формировать фингерпринт поверхности, находящийся во взаимно-однозначном соответствии с химическим составом и способом его приготовления. Метод 2D-DLS внедрен на фармацевтическом предприятии для контроля порошкообразных лекарственных веществ, получаемых в камерах псевдоожиженного слоя, а также на двух заводах по производству воды с измененным изотопным составом для оперативного контроля препаратов