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Introduction. Tranexamic acid is one of the most common drugs used to stop bleeding after trauma, in surgery and gynecology. The most common analytical method for the determination of this compound is reversed-phase high-performance liquid chromatography (HPLC). However, this compound belongs to the group of so-called poorly retained compounds due to its chemical structure. It is necessary to develop an analytical method that will allow the determination of tranexamic acid in human blood plasma with the least time, resource costs and without the use of specialized columns.Aim. The aim of this study is to develop a method for tranexamic acid in human plasma by high performance liquid chromatography with tandem mass-spectrometry (HPLC-MS/MS) for pharmacokinetic studies.Materials and methods. Determination of tranexamic acid in plasma by HPLC-MS/MS. The samples were processed by acetonitrile protein precipitation.Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification, carry-over effect and stability.Conclusion. The method of the determination of tranexamic acid in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 100.00–15000.00 ng/ml. Method could be applied to tranexamic acid determination in plasma for pharmacokinetics and bioequivalence studies.

Introduction. B-cell malignancies of the plasma cell leads to the second most spread hematological malignancy disease, called multiple myeloma. Pomalidomide is used in case of previous multiple myeloma ineffective treatment. Pomalidomide is a thalidomide synthetic derived, approved as immunomodulatory drug by the Food and Drug Administration (FDA). Nowadays, detection of pomalidomide in blood plasma by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) is not spread. Moreover, the detection and the experimental setting accumulated data are varying greatly. This investigation provides development and validation of pomalidomide aiming to determine human blood plasma by HPLC-MS/MS method. The samples were processed by methanol protein precipitation.Aim. The aim of this study is to develop a method for the pomalidomide in human plasma by HPLC-MS/MS for pharmacokinetic studies.Materials and methods. Determination of pomalidomide in plasma by HPLC-MS/MS. The samples were processed by methanol protein precipitation.Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, spike recovery, lower limit of quantification, detection limit, carry-over and stability. Conclusion. The method of the determination of pomalidomide in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 1,00 – 500,00 ng/ml. Method could be applied to pomalidomide determination in plasma for PK and BE studies.

The oncolytic potential of the attenuated mumps virus (MV) vaccine strain Leningrad-3 (L-3) was evaluated in a panel of four human metastatic melanoma cell lines. The lines were shown to be susceptible and permissive to MV infection. Efficient MV replication led to death of melanoma cells, but the effect differed among the cell lines. Possible mechanisms mediating the selectivity of MV L-3 towards the cell lines were explored. Replicative and oncolytic activity of MV was found to depend on the expression pattern of type I interferon genes. None of the melanoma cell lines showed induction of expression of the total spectrum of genes required to inhibit virus replication. Based on the results, MV L-3 was assumed to be a promising oncolytic agent for human melanoma cells.

To compare release parameters of various betahistine drugs in vitro using a comparative dissolution kinetics test.Objects of research are solid dosage forms (tablets) containing betahistine in a dose of 24 mg permitted for medical use in the Russian Federation. A method of comparative dissolution kinetics test was carried out as follows. The study was performed on a paddle stirrer at a speed of 50 rpm in three different pH dissolution media (pH 1.2, 4.5, 6.8), simulating the main sections of the digestive tract in which the active ingredient was decomposed, released and absorbed. This was performed in a quality controlled environment using a citrate buffer solution with pH 6.8. The time points for sampling the medium were 10 min, 15 min, 20 min and 30 min.The results of betahistine release were significant (RSD10%) for all time points, except the first time point (RSD20%). Regardless of pH, there was a complete release (≥85% over 15 minutes,10%) of betahistine from betaserc, 24 mg, tablets (manufactured by Mylan Laboratories SAS). The dissolution profiles of betahistine in other investigational drugs did not show complete drug release (parameter85% in 15 minutes,10%) in different pH media. Therefore, dissolution profiles of the studied drugs were not comparable to the reference profile.Starting from 10 minutes, the reference drug of betahistine (betaserc, 24 mg) has a consistently higher release at different pH levels (representing the various stages of gastric digestion), vs. other studied generic analogues showing significantly lower levels of betahistine release. None of the studied drugs were found to be equivalent in vitro.Цель исследования. Провести сравнительный анализ параметров высвобождения различных препаратов бетагистина в условиях in vitro с использованием сравнительного теста кинетики растворения. Материал и методы. Объекты исследования - лекарственные средства в твердой дозированной лекарственной форме (таблетки), содержащие бетагистин в дозе 24 мг, разрешенные к медицинскому применению в Российской Федерации. Методика проведения сравнительного теста кинетикb растворения: исследование проводили на аппарате 'лопастная мешалка' при скорости 50 об/мин в трех средах растворения с различным значением pH (рН 1,2; 4,5; 6,8), моделирующих основные разделы ЖКТ, в которых происходит распадение таблетки, высвобождение и абсорбция активного ингредиента. Также исследование было проведено в среде контроля качества с использованием цитратного буферного раствора с рН 6,8. Временными точками отбора проб среды были 10, 15, 20 и 30 мин. Результаты. Полученные результаты высвобождения бетагистина из всех исследуемых препаратов были признаны достоверными (RSD10%) для всех временных точек, за исключением первой временной точки (RSD20%). Вне зависимости от величины рН наблюдалось полное высвобождение (≥85% за 15 мин, RSD10%) бетагистина из препарата Бетасерк, 24 мг, таблетки (производства 'Майлан Лэбораториз САС'). Профили растворения бетагистина других исследуемых препаратов не обнаружили полного высвобождения лекарственного вещества (85% за 15 мин, RSD10%) в средах с различным рН. Таким образом, профили растворения воспроизведенных препаратов были признаны несопоставимыми референтному. Заключение. Начиная с 10-й минуты, референтный препарат бетагистина (Бетасерк, 24 мг) обладает стабильно высоким высвобождением in vitro при различных параметрах рН (моделирующих различные стадии пищеварения) по сравнению с другими исследуемыми воспроизведенными аналогами, показавшими значительно более низкие уровни высвобождения бетагистина. Ни один из исследуемых препаратов не был признан эквивалентным in vitro препарату Бетасерк, 24 мг, таблетки, согласно тесту кинетики растворения.

The oncolytic potential of the attenuated mumps virus (MV) vaccine strain Leningrad-3 (L-3) was evaluated in a panel of four human metastatic melanoma cell lines. The lines were shown to be susceptible and permissive to MV infection. Efficient MV replication led to death of melanoma cells, but the effect differed among the cell lines. Possible mechanisms mediating the selectivity of MV L-3 towards the cell lines were explored. Replicative and oncolytic activity of MV was found to depend on the expression pattern of type I interferon genes. None of the melanoma cell lines showed induction of expression of the total spectrum of genes required to inhibit virus replication. Based on the results, MV L-3 was assumed to be a promising oncolytic agent for human melanoma cells.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bio in equivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of C max ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of C max for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo .

The Customs Union of Belarus, Kazakhstan and Russia is a form of trade and economic integration of Belarus, Kazakhstan and Russia which provides a unified customs territory within the mutual trade in goods and does not apply customs duties and economic restrictions, except for special protective, antidumping and countervailing measures. The Republics of Belarus and Kazakhstan and the Russian Federation, in accordance with the Agreement of October 6, 2007, established the Commission of the Customs Union, a single permanent regulatory agency of the Customs Union. At present the Commission of the Customs Union is expected to sign the Agreement on common principles of the circulation of goods and services (which includes drug products). In connection with this Agreement which contains an approach to prepare a unified guidance for BE studies, a plan for document preparation has been approved (a Custom Union BE guidance was approved in May 2017).

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing ketoprofen are reviewed. Ketoprofen's solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA)/dissolution data were taken into consideration. The available data suggest that according to the current Biopharmaceutics Classification System (BCS) and all current guidances, ketoprofen is a weak acid that would be assigned to BCS Class II. The extent of ketoprofen absorption seems not to depend on formulation or excipients, so the risk of bioinequivalence in terms of area under the curve is very low, but the rate of absorption (i.e., BE in terms of peak plasma concentration, C(max) ) can be altered by formulation. Current in vitro dissolution methods may not always reflect differences in terms of C(max) for BCS Class II weak acids; however, such differences in absorption rate are acceptable for ketoprofen with respect to patient risks. As ketoprofen products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR ketoprofen solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients present also in IR solid oral drug products containing ketoprofen, which are approved in International Conference on Harmonisation or associated countries, for instance, as presented in this paper; (b) both the test drug product and the comparator dissolve 85% in 30 min or less in pH 6.8 buffer; and (c) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When one or more of these conditions are not fulfilled, BE should be established in vivo.

This paper describes the evaluation of the in vitro equivalence of capsules containing a BCS Class II compound, k etoprofen, marketed in Russia under biowaiver conditions and the innovator product. The in vitro equivalence test was carried out according to WHO Technical Report Series, No. 937, Annex 8. Dissolution profiles of test and reference (innovator) ketoprofen capsules are considered equivalent at pH 6.8 without statistical treatment, equivalent at pH 4.5 (f1 = 3 and f2 = 80), and not equivalent at pH 1.2 (f1 = 22 and f2 = 41). Generally, the evaluated capsules did not meet biowaiver criteria for drugs containing BCS Class II API, possibly due to the effect of surfactant (sodium lauryl sulfate) contained in the test preparation on the solubility.

The current paper is devoted to in vitro dissolution kinetics studies of amlodipine tablets marketed in Russia under biowaiver conditions. Dissolution kinetics studies were carried out according to WHO Guidance. Dissolution profiles of test and reference (innovator) amlodipine tablets were considered equivalent. INTRODUCTION Over the past three decades, dissolution testing has evolved into a powerful tool for characterizing the quality of oral pharmaceutical products. For some solid dosage forms containing active pharmaceutical ingredients with special properties, a comparative in vitro dissolution profile similarity can be used to establish equivalence of test with reference product. Such studies, used to approve equivalence other than through in vivo equivalence testing, are called “biowaiver” (1). Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. It is indicated for the treatment of hypertension, chronic stable angina, and confirmed or suspected vasospastic angina (2). The chemical name of amlodipine is 3-ethyl 5-methyl 2-[(2aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate. Its structure is shown in Figure 1. Solubility Amlodipine is described as slightly soluble in water in different Pharmacopoeias (3, 4). The experimental water solubility for amlodipine is 75.3 mg/L (5). The lowest solubility in the pH range from 1 to 6.8 at 37 °C is 1 mg/mL (1). Within the gastrointestinal pH range, amlodipine is an ionized compound (weak base) (5). The pKa of amlodipine is about 8.6 at 25 °C (5). Dosage form strength is expressed in mg of salt and is not equivalent to the free base. Amlodipine is listed in the WHO Model list of medicines as an antihypertensive medicine in a 5-mg tablet strength (6). Russia has Marketing Authorizations for amlodipine as an immediate-release dosage form in strengths of 2.5; 5, and 10 mg (7). Thus the D/S ratio for the amlodipine WHO Model List of Essential Medicines dose (5 mg) at a pH range of 1.2–6.8 is 5 mL and 10 mL for the highest dose marketed in Russia. Therefore, amlodipine is a “highly soluble” drug according to WHO Guidance (D/S ratio ≤ 250 mL). Permeability When an active pharmaceutical ingredient is absorbed to an extent of 85% or more, it is considered “highly permeable.” Amlodipine’s absolute bioavailability is 60–65%, but its permeability is classified as “high” due to metabolite excretion in urine (90–95%). Taking amlodipine solubility and permeability into account, according to WHO Guidances, amlodipine is assigned to BCS Class I (1). Thus, amlodipine in vitro equivalence may be evaluated under biowaiver conditions for BCS Class I (1). MATERIALS AND METHODS Chemicals Analytical grade concentrated hydrochloric acid, glacial acetic acid, potassium dihydrophosphate, disodium hydrophosphate dodecahydrate, and potassium chloride were used. e-mail: ramenskaia@mail.ru *Corresponding author. Figure 1. Structure of amlodipine. diss-17-03-04.indd 20 8/18/2010 1:42:43 PM dx.doi.org/10.14227/DT170310P20