АСПЕКТЫ ПРИМЕНЕНИЯ ИНДОМЕТАЦИНА В МЕДИЦИНЕ И ФАРМАЦИИ

Indomethacin, a non-steroid anti-inflammatory drug (NSAID), has been used in different spheres of medicine since the 1960s. It is successfully administered as an anti-inflammatory and pain-relieving medication in rheumatoid and other diseases. According to recent research, indomethacin may become a promising drug enhancing endogenous remyelination in patients with multiple sclerosis. Also, indomethacin affects cell proliferation and invasion, thus it is used to manage pancreatic cancer in patients with hyperglycemia. In addition, indomethacin can inhibit protein synthesis in colorectal carcinoma and other types of cancer cells. The article reviews modern indomethacin medications and the different dosage forms on the Russian pharmaceutical market. Indomethacin poor water solubility is one of the reasons for decreasing its biopharmaceutical characteristics. According to the conducted research, a prospective way to improve indomethacin solubility and bioavailability is the Solid Dispersion (SD) method. SDs are bi- or multicomponent systems consisting of the drug and the carrier. They are a highly dispersed solid phase of the drug or molecular-dispersed solid solutions with a partial formation of a variable composition complex and a carrier. The article provides a brief overview on different aspects of obtaining, investigating, and applying indomethacin SDs with various polymers.Синтезированный в шестидесятых годах прошлого столетия типичный представитель класса нестероидных противовоспалительных средств индометацин нашел широкое применение в различных областях медицины. Сочетание противовоспалительного и обезболивающего действия обусловило успешное применение индометацина при ревматических заболеваниях. Новейшие исследования выявили, что препарат может стать перспективным средством и в терапии ряда иных патологий. В статье приведен краткий обзор ассортимента современных препаратов и различных лекарственных форм индометацина на отечественном фармацевтическом рынке. Одним из факторов, снижающих биофармацевтические характеристики препаратов индометацина, является его малая растворимость в воде. Согласно результатам анализа литературных данных, одной из перспективных технологий, способных успешно увеличить растворимость и биодоступность индометацина, является метод получения его твердых дисперсий. Твердые дисперсии ― это би- или многокомпонентные системы из лекарственного вещества и носителя, представляющие собой высокодиспергированную твердую фазу лекарственного вещества или молекулярно-дисперсные твердые или жидкие растворы с частичным образованием комплексов переменного состава с материалом носителя. Представлен краткий обзор работ, посвященных различным аспектам получения, исследования и применения твердых дисперсий индометацина с разными полимерами-носителями

ДИНАМИКА ИНСУЛИНОПОДОБНОГО ФАКТОРА РОСТА 1 (ИФР-1) ПРИ ТРАНСПЛАНТАЦИИ ПЕЧЕНИ ДЕТЯМ ОТ ДОНОРА, НЕ СОВМЕСТИМОГО ПО ГРУППЕ КРОВИ

It is shown that liver transplantation (LT) from donor with incompatible blood type (AB0i) may be effective and safe, but the impact of such operation upon the various systems of the body has not been investigated yet. Insulinlike growth factor-1 (IGF-1) is synthesized in the liver and mediates the action of growth hormone. The level of IGF-1 is a marker of the processes of cell proliferation and tissue regeneration. Aim. To evaluate levels of IGF-1 in children-recipients with liver transplant from AB0i (incompatible) and AB0c (compatible) donors.Materials and methods. 140 children aged 3 to 36 (19,5 ± 16,5 months) with congenital diseases of the hepatobiliar system, 58 of them boys, were surveyed. All patients underwent transplantation of left lateral liver sector from living related donors: 111 children were transplanted with fragment of the liver from AB0c donors, 29 – from AB0i donors; in 10 children with AB0i liver before and/or after LT operation anti-group antibodies (anti-A/B) were revealed. The concentration of IGF-1 was determined by ELISA using specifi c kits (Immunodiagnostic System, USA) in samples of blood plasma, which were received up to a month and a year after a liver transplant.Results. Average level of IGF-1 21,0 ± 29,5 μg/l in patients before LT was signifi cantly lower than in healthy children (52,2 ± 26,3 μg/l, p < 0,001) and did not vary in children, having received later a piece of liver from a compatible (AB0c) donor and from donor AB0i (23,5 ± 30,9 and 21,2 ± 23,2 μg/l respectively, p = 0,70). In patients with anti-A/B prior to surgery average level of IGF-1 was not different from that of the patients without antibodies (32,6 ± 27,6 and 22,3 ± 29,6 μg/l respectively, p = 0,4). One month after LT level of IGF-1 has increased both in the general group, and in patients with AB0c and AV0i liver (92,1 ± 77,8 and 131,2 ± 106,7 μg/l respectively, p = 0,09). The level of IGF-1 was not varied in the group with antibodies (152,5 + 150,4 μg/l) and without them (95,9 ± 77,0 μg/l). A year after LT the average level of IGF-1 in recipients of AV0c and AV0i liver was not varied and was signifi cantly higher than before LT (82,0 + 60,7 and 91,2 ± 77,8 μg/l, p < 0,005 and p = 0,03 respectively). The content of IGF-1 in patients with anti-A/B and without them (104,7 ± 67,5 and 84,7 ± 63,7 μg/l respectively) also did not differ.Conclusion: the results of our studies have shown that restoration of the level of IGF-1 is not dependent on transplantation of compatible or incompatible blood type liver, as well as on the availability of anti-group antibodies.Показано, что трансплантация печени (ТП) от не совместимого по группе крови (АВ0н) донора может быть эффективной и безопасной, однако вопросы, связанные с эффектом такой операции на различные системы организма, не исследованы. Инсулиноподобный фактор роста 1 (ИФР-1) синтезируется в печени и опосредует действие гормона роста, его уровень является маркером процессов пролиферации и регенерации тканей.Цель: исследовать динамику уровня ИФР-1 у детей – реципиентов печени при трансплантации от родственного совместимого и не совместимого по группе крови донора.Материалы и методы. Обследовано 140 детей с врожденными заболеваниями гепатобилиарной системы в возрасте от 3 до 36 (19,5 ± 16,5) месяцев, из них 58 мальчиков. Всем пациентам была проведена трансплантация левого латерального сектора печени от живого родственного донора: 111 детям был пересажен фрагмент печени от АВ0с донора, 29 – от АВ0н донора; у 10 детей с АВ0н ТП до и/или после операции обнаруживались антигрупповые антитела (анти-А/В). Концентрацию ИФР-1 определяли методом ИФА в образцах плазмы крови.Результаты. Средний уровень ИФР-1 21,0 ± 29,5 мкг/л у пациентов до ТП был достоверно ниже, чем у здоровых детей (52,2 ± 26,3 мкг/л, p < 0,001), и не различался у детей, позднее получивших фрагмент печени от совместимого (АВ0с) и от АВ0н донора (23,5 ± 30,9 и 21,2 ± 23,2 мкг/л соответственно, p = 0,70). У пациентов с анти-А/В до операции средний уровень ИФР-1 не отличался от такового у пациентов без антител (32,6 ± 27,6 и 22,3 ± 29,6 мкг/л соответственно, р = 0,4). Через месяц после ТП уровень ИФР-1 повысился как в общей группе, так и у пациентов с АВ0с и АВ0н ТП (92,1 ± 77,8 мкг/л и 131,2 ± 106,7 мкг/л соответственно, р = 0,09). Уровень ИФР-1 не различался в группе с антителами (152,5 ± 150,4 мкг/л) и без них (95,9 ± 77,0 мкг/л). Через год после ТП средний уровень ИФР-1 у реципиентов АВ0с и АВ0н печени не различался и был достоверно выше, чем до ТП (82,0 ± 60,7 и 91,2 ± 77,8 мкг/л, р < 0,005 и р = 0,03 соответственно). Содержание ИФР-1 у пациентов с анти-А/В и без них (104,7 ± 67,5 мкг/л и 84,7 ± 63,7 мкг/л соответственно) также не отличалось.Заключение. Результаты исследования показали, что восстановление уровня ИФР-1 не зависит от того, был ли донор фрагмента печени совместимым по системе АВ0 или нет и содержались ли у реципиента в крови антигрупповые антитела до трансплантации

Development of Compositions and Production Technology for Gels with a Solid Dispersal of Nitrofural

Compositions of gels with solid dispersions of nitrofural at a concentration of 0.04% were screened. Studies of the organoleptic properties, identity, assay of active ingredient, pH, and release led to selection of four compositions. The shelf life was determined (two years) and the storage conditions for the gel compositions developed here were identified. The proposed production technology for gels with solid dispersals of nitrofural yielded stable compositions with an active ingredient concentration of 0.04%, providing higher levels of nitrofural release than the currently available 0.2% furacillin ointment due to greater solubility and a greater rate of dissolution of active ingredient. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

Pharmacokinetics, safety, and tolerance of anagrelide, the first domestic generic, compared with reference drug [Фармакокинетика, безопасность и переносимость первого отечественного дженерика анагрелида в сравнении с референтным препаратом]

Background. Anagrelide is used for the treatment of essential thrombocythemia. This drug selectively affects thrombocytes without inducing pronounced myelosuppression, which provides a satisfactory safety profile. Aim. To compare pharmacokinetics and to assess bioequivalence of two anagrelide drugs for oral administration in healthy volunteers. Materials & Methods. Open, randomized, two-period, two-sequence, crossover study comparing pharmacokinetics and bioequivalence of anagrelide included 30 volunteers. The participants received a single dose of either test or reference drug, depending on the study period. Serial blood samples for pharmacokinetic analysis were collected within 12 hours after drug administration. Plasma anagrelide concentration was measured by high-performance liquid chromatography/mass spectrometry. Pharmacokinetic parameters were analyzed by non-compartmental method. ANOVA analysis of variance was used for assessing the difference between the mean values of the AUC0-t, AUC0-∞ and Cmax pharmacokinetic parameters at 5 % significance level. Results. The mean values of maximum concentration (Сmax) after a single dose of anagrelide were 12.68 ± 2.99 ng/mL and 12.46 ± 3.15 ng/mL for test and reference drugs, respectively. Relative bioavailability was 1.16 ± 0.18. The AUC0-12 mean values calculated by anagrelide concentrations after a single dose of test and reference drugs were 30.38 ± 7.0 ng • h/mL and 28.78 ± 7.50 ng • h/mL, respectively, and the AUC0-∞ mean values were 31.13 ± 7.15 ng • h/mL and 29.55 ± 7.61 ng • h/mL, respectively. The assessment of main vital functions and laboratory parameters did not reveal any effect of the drugs on the health status of trial participants. Conclusion. Pharmacokinetic profile of the test drug (generic anagrelide) did not considerably differ from that of reference drug, which indicates in vivo bioequivalence of it. The assessment of drug safety yielded satisfactory tolerance; no serious adverse events have been reported. © 2020 Practical Medicine Publishing House. All rights reserved

DYNAMICS OF INSULIN-LIKE GROWTH FACTOR-1 (IGF-1) IN CHILDREN AFTER AB0-INCOMPATIBLE LIVER TRANSPLANTATION

It is shown that liver transplantation (LT) from donor with incompatible blood type (AB0i) may be effective and safe, but the impact of such operation upon the various systems of the body has not been investigated yet. Insulinlike growth factor-1 (IGF-1) is synthesized in the liver and mediates the action of growth hormone. The level of IGF-1 is a marker of the processes of cell proliferation and tissue regeneration. Aim. To evaluate levels of IGF-1 in children-recipients with liver transplant from AB0i (incompatible) and AB0c (compatible) donors.Materials and methods. 140 children aged 3 to 36 (19,5 ± 16,5 months) with congenital diseases of the hepatobiliar system, 58 of them boys, were surveyed. All patients underwent transplantation of left lateral liver sector from living related donors: 111 children were transplanted with fragment of the liver from AB0c donors, 29 – from AB0i donors; in 10 children with AB0i liver before and/or after LT operation anti-group antibodies (anti-A/B) were revealed. The concentration of IGF-1 was determined by ELISA using specifi c kits (Immunodiagnostic System, USA) in samples of blood plasma, which were received up to a month and a year after a liver transplant.Results. Average level of IGF-1 21,0 ± 29,5 μg/l in patients before LT was signifi cantly lower than in healthy children (52,2 ± 26,3 μg/l, p < 0,001) and did not vary in children, having received later a piece of liver from a compatible (AB0c) donor and from donor AB0i (23,5 ± 30,9 and 21,2 ± 23,2 μg/l respectively, p = 0,70). In patients with anti-A/B prior to surgery average level of IGF-1 was not different from that of the patients without antibodies (32,6 ± 27,6 and 22,3 ± 29,6 μg/l respectively, p = 0,4). One month after LT level of IGF-1 has increased both in the general group, and in patients with AB0c and AV0i liver (92,1 ± 77,8 and 131,2 ± 106,7 μg/l respectively, p = 0,09). The level of IGF-1 was not varied in the group with antibodies (152,5 + 150,4 μg/l) and without them (95,9 ± 77,0 μg/l). A year after LT the average level of IGF-1 in recipients of AV0c and AV0i liver was not varied and was signifi cantly higher than before LT (82,0 + 60,7 and 91,2 ± 77,8 μg/l, p < 0,005 and p = 0,03 respectively). The content of IGF-1 in patients with anti-A/B and without them (104,7 ± 67,5 and 84,7 ± 63,7 μg/l respectively) also did not differ.Conclusion: the results of our studies have shown that restoration of the level of IGF-1 is not dependent on transplantation of compatible or incompatible blood type liver, as well as on the availability of anti-group antibodies

Разработка состава и технологии геля с твердой дисперсией нитрофурала

The screening of gel compositions containing a solid dispersion of nitrofural with a concentration of 0,04% was carried out. Based on the study of organoleptic properties, authenticity, quantitative determination of the active substance, pH, drug release four compositions were selected. The shelf life (2 years) and storage conditions of the selected gel formulations were determined. The proposed technology for the production of gels with solid nitrofural dispersion ensures obtaining stable compositions with active substance concentration of 0.04% and provides a higher release of nitrofural as compared to the commercially available ointment with a concentration of 0.2%, by increasing the solubility and dissolution rate of the active substance.Проведен скрининг составов гелей с твердой дисперсией нитрофурала с концентрацией 0,04 %. На основании изучения органолептических свойств, подлинности, количественного определения действующего вещества, рН, высвобождения выбраны 4 состава. Определен срок годности (2 года) и условия хранения разработанных составов гелей. Предложенная технология получения гелей с твердой дисперсией нитрофурала позволяет получить стабильные составы с концентрацией действующего вещества 0,04 %, обеспечивающие более высокое высвобождение нитрофурала по сравнению с имеющейся на рынке фурацилиновой мазью с концентрацией 0,2 %, за счет повышения растворимости и скорости растворения действующего вещества

Development of Effervescent Granules with Solid Dispersion of Furazolidone

Introduction.In the treatment of infectious and inflammatory diseases, active substances (AI) are in demand, characterized by low resistance of microorganisms, high specificity of the mechanism of action and a wide spectrum of antimicrobial activity. Furazolidone (FZ) is an active substance that meets these criteria, but the fact that it is practically insoluble in water significantly limits its use. To increase the solubility and dissolution rate of active substances with low solubility in water, the method of solid dispersions (SD) allows. Previous studies indicate an increase in the solubility and dissolution rate of FZ in water from TD with polyvinylpyrrolidone-24000 (PVP-24000) in a ratio with AI > 6: 1 by weight. As a result, it becomes possible to introduce TD FZ into the composition of instant effervescent dosage forms, for example, Target. Development of the composition and technology for obtaining effervescent granules based on solid dispersions of FZ for obtaining a solution for external use. Materials and methods. FZ substance, polyvinylpyrrolidone-24000 ± 2000 (PVP-24000 ± 2000), tartaric acid, malic acid, anhydrous sodium carbonate, ethyl alcohol 96%, purified water. The granulates were obtained by fluidized bed granulation. The analysis of the obtained granules was carried out according to the following indicators: Description, granule size, weight loss upon drying, disintegration, dosing uniformity according to GPM.1.4.1.0004.15 "Granules". Also carried out a qualitative and quantitative determination of DI, analyzed the pH of an aqueous solution of granules. In order to study the stability and shelf life, the samples of granules were stored in accordance with OFS.1.10009.15 "Stability and shelf life of medicines".Results and discussion. The composition and technology of FZ effervescent granules for obtaining a solution for external use have been developed. The granules were obtained by separate granulation of the main (containing TD DV) and acidic components, followed by mixing in proportions that provide a solution of FZ with a concentration of 0.004% in water at room temperature. The quality of the resulting compositions was assessed, the shelf life (2 years) and storage conditions (in a dry place protected from light at a temperature of 25 °C) of the developed granule compositions were determined. Conclusion. As a result of technological and chemical-pharmaceutical studies using the TD method, a new dosage form of FZ has been developed - effervescent granules, which makes it possible to obtain an aqueous solution with an AI concentration of 0.004% in less than 5 minutes without heating. Based on the results of the work, an application was filed with Rospatent No. 2021105988 dated March 10, 2021 "Instantly soluble dosage form of furazolidone and a method for its preparation.". © Elagina A. O., Beliatskaya A. V., Krasnyuk (Jr.) I. I., Krasnyuk I. I., Stepanova O. I., Vorob'yov A. N., Fateeva T. V., 2022

Dissolution of Ketoprofen from Poly(Ethylene Glycol) Solid Dispersions

The effect of solid dispersions (SDs) on the solubility of the nonsteroidal anti-inflammatory drug ketoprofen was determined. Ketoprofen and its SDs with poly(ethylene glycol) PEG-400, -1000, -1500, -2000, and -3000 were studied. Dissolution of ketoprofen from the SDs increased by 1.2 – 1.8 times; the dissolution rate, by 1.7 – 2.4 times. The improved release of ketoprofen from the SDs was proposed to be due to several factors such as solubilization and amorphization of the compound and formation of intermolecular H-bonds. The results could be used to develop rapidly dissolving ketoprofen solid dosage forms. © 2019, Springer Science+Business Media, LLC, part of Springer Nature