We present a new interview from the «Leadership Opinion» series. This time we spoke with Vladislav N. Shestakov, Director of FSI «State Institute of Drugs and Good Practices» (FSI «SID & GP»). The interview was conducted by Natalia V. Kuldjanova, Director of the scientific and production journal «Drug Development & Registration».

The fifth part of the article provides information about the function of the Apothecary prikaz to supply the Russian state with medicinal plant raw materials. Medicinal plants were purchased abroad, in Moscow merchant’s rows, and were also cultivated and introduced in apothecary gardens. Over time, more and more attention was paid to this work of the Apothecary prikaz, and this function gradually became a duty.

Skorohod HPLC series is manufactured by family enterprise Sevko & Co on its own production facilities in Pushkinsky district of Moscow region. This series occupies the unique position on Russian market of analytical equipment not only because of the maximum localization of all the components in one production enterprise and independence of the whole tool on the scarce Western analogue details. Technical solutions, implemented in Skorohod, let it possible to put this HPLC on the same level with high-end Western HPLC manufacturers, which left Russian market. Some of technical solutions are exclusive by world standards as well. In this article we will discuss the autosampler from Skorohod series that utilizes direct injection (split-loop), commonly used between the largest producers of HPLC, but so far not available for Russian users.

Introduction. Osteoarthritis is one of the most common joint diseases. The number of patients is growing rapidly and by 2050, the number of people in the world suffering from osteoarthritis is expected to exceed 1 billion. In a number of European countries, radiosynoviorthesis is used as a treatment. It is based on irradiation of the joint synovium with intra-articular administration of various radiopharmaceuticals containing β-emitting radionuclides.

Aim. Development of a radiopharmaceutical composition for radiosynoviorthesis based on rhenium-188 and hyaluronic acid as a particle stabilizer.

Materials and methods. Sodium perrhenate solution, ¹⁸⁸Re was obtained from a ¹⁸⁸W/¹⁸⁸Re generator "GREN-1" (JSC "SSC RF – IPPE", Russia). Eluate activity was measured on an ISOMED 2010 (PTW-Freiburg, Germany). Radiochemical purity was determined by thin-layer chromatography on thin-layer silica gel plates on aluminum substrate in acetone. The activity of chromatogram was measured on a Scan-RAM chromatogram scanner (LabLogic Systems Ltd., United Kingdom). pH was measured on S20 Seven Easy pH meter (METTLER TOLEDO, Switzerland). Particle size was determined by laser diffraction on an LA-350 device with a detection range of 0.1–1000 μm (HORIBA, Japan). Accumulation in the joint was determined on a Wizard 2480 gamma counter (PerkinElmer, USA) after intra-articular administration of the composition to mature conventional albino rats (females).

Results and discussion. The study included a comparison of the physic-chemical properties of the synthesized compositions with different volume activities, the optimal concentration of hyaluronic acid, and the methods for obtaining the radiopharmaceutical composition both from the liquid and freeze-dried reagents. The biological behavior of the radiopharmaceutical composition after intra-articular administration to mature conventional albino rats (females) were studied.

Conclusion. Radiopharmaceutical composition containing rhenium-188, tin dichloride and hyaluronic acid with a radiochemical purity of more than 95 % has been developed. The accumulation of the composition in the knee joint was more than 96 % 3 hours after intra-articular administration. This composition is of interest for further study as a radiopharmaceutical for radiosynoviorthesis.

Introduction. The use of synthetic drugs is associated with a number of side effects. When choosing a therapy to correct symptoms and treat dental diseases such as stomatitis, periodontitis, gingivitis, cheilitis, it is preferable to use herbal medicines in combination with traditional therapy, which would improve the resistance of periodontal tissues to pathogenic microorganisms. Herbal preparations are highly effective and well tolerated, which allows them to be used in modern medicine.

Aim. To develop a medicinal collection with antimicrobial, anti-inflammatory, and wound-healing effects.

Materials and methods. The following substances and reagents were used as research materials: Achilleae millefolii herba, Bidentis tripartitaе herba, Alni fructus, Anisi vulgaris fructus in a ratio of 1 : 1 : 1 : 1, diclofenac sodium, ascorbic acid, phosphate buffer, sodium citrate, luminol, iron (II) sulfate, heparinized blood, zymosan, saline solution, 2 % formalin solution, 10 % neutral formalin solution, hematoxylin, eosin. Antimicrobial activity was studied by comparing growth retardation of pathogenic microorganisms, antioxidant activity was studied on a chemoluminometer HLM-003 (Russia), hematological tests on mice were carried out using the ImageJ software package, Sysmex KX-21N (Sysmex, Japan), Leica RM 2145 microscope (Leica Biosystems Nussloch GmbH, Germany), binocular microscope Leica CME (Leica Biosystems Nussloch GmbH, Germany).

Results and discussion. The evaluation of the anti-inflammatory, antioxidant, wound healing and antimicrobial activities of the plant herbal mixture was carried out. According to the results of the experiment, it was found that the herbal mixture has moderate antioxidant, wound healing and pronounced anti-inflammatory activity comparable to the comparison drug.

Conclusion. A herbal mixture has been developed that has anti-inflammatory, antimicrobial and regenerating effects.

Introduction. Diarylquinolines are considered a group of optimal candidates for anti-tuberculosis drugs (ATDs) in the treatment of tuberculosis caused by Mycobacterium tuberculosis exhibiting multidrug resistance.

Aim. To perform a computer-aided analysis and evaluation of the potential molecular targets of the domestic anti-tuberculosis drug thiozonide using modern bioinformatics approaches.

Material and methods. The SEA Search Service was employed to predict the drug targets. Based on the degree of chemical similarity calculated by the Tanimoto coefficient, this service predicts the effect of the investigated ligand on known targets. Compounds from the ChEMBL database were selected for the analysis, and structurally similar molecules were identified using the Tanimoto similarity measure. Possible targets of thiozonide were predicted using the PPB (Polypharmacology Browser for Target Prediction) service, which utilized six different fingerprints and four of their combinations. A significant potential of thiozonide to bind mycobacterial proteins, including those of M. tuberculosis, was revealed. Additionally, computer-based prediction of potential biological targets for thiozonide was carried out using the PPB (Polypharmacology Browser for Target Prediction in ChEMBL) service to analyze its polypharmacology. A search query initiated based on the chemical structure of thiozonide in SMILES format enabled the identification, among various targets listed in the ChEMBL database, of those most likely to interact with the studied compound.

Results and discussion. According to the computer screening results, thiozonide demonstrated the most pronounced predicted activity against various representatives of the genus Mycobacterium, including M. tuberculosis. Based on the study findings, the most likely binding targets were the subunits of bacterial ATP synthase. This enzyme plays a central role in cellular energy metabolism by linking ATP synthesis and hydrolysis with proton translocation across the membrane. Although some human proteins were also identified as potential targets for thiozonide, the affinity of thiozonide to these human targets is considered rather low.

Conclusion. The study results demonstrate the selective activity of thiozonide against mycobacteria, particularly M. tuberculosis strains. Thiozonide selectively interacts with the key subunits of the bacterial ATP synthase complex, thereby disrupting its catalytic function. Moreover, thiozonide exhibits low affinity towards human targets (affinity not exceeding 0.1).

Introduction. Metabolic syndrome is a multifactorial complex of metabolic disorders accompanied by type 2 diabetes mellitus and abdominal obesity. In the pharmacological correction of obesity and type 2 diabetes mellitus, the greatest effect is demonstrated by dual agonists of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in particular tirzepatide. The original drug (Mundjaro, pln: tirzepatide) is not registered in the Eurasian Economic Union (EAEU), which limits its availability to patients and leads to the need to develop a domestic generic.

Aim. Conducting a physicochemical and biological characterization of the drug Sejaro® (GP30931) in comparison with the original drug Mundjaro® to establish their comparability.

Materials and methods. Three batches of each drug (solution for subcutaneous administration, 25 mg/ml) were studied. The primary structure was verified using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS), peptide mapping and NMR (2D-NMR-¹H-¹H TOCSY). Secondary structure, higher order structures and aggregation were assessed by circular dichroism (CD), high-resolution nuclear magnetic resonance (NMR), fluorescence quantum yield (FQY) and dynamic light scattering (DLS). Impurity profiles were analyzed using size-exclusion and reversed-phase HPLC. Functional activity was determined in cellular tests for activation of calcium currents through GLP-1 and GIP receptors with an assessment of the half-maximal effective concentration (EC₅₀); equivalence was confirmed by the two-sided test (TOST, 90 % confidence interval).

Results and discussion. HPLC-MS and mapping confirmed identical mass (4,810.52 Da) and amino acid sequence. NMR spectra, CD and CF profiles, and DLS were completely consistent, which allows us to conclude that the secondary and tertiary structures of the preparations are structurally identical. The content of all types of impurities in GP30931 did not exceed the Munjaro values. The difference in EC₅₀ values for activation of GLP-1 and GIP receptors was ≤5 %, the comparative biological activity was within 0.80–1.25.

Conclusion. The complex of studies conducted using orthogonal methods showed that "Sejaro" (GP30931) and "Mundjaro" are structurally identical, comparable in impurity profile and biologically equivalent. The obtained data make a significant contribution to the scientific substantiation of the equivalence of the reproduced drug tirzepatide and the reference original drug, thereby providing a reliable basis for further registration and clinical use of Sejaro® without conducting additional clinical studies.

Introduction. Direct compression is one of the most preferred methods for the production of tablet dosage forms in terms of efficiency, since it allows you to minimize the technological process down to the level of "mixing-tableting-filling and packaging". However, this method requires excipients that have appropriate flowability and compressibility. One of the widely used examples of such excipients is granulated lactose. In this work, samples of pure granulated lactose were produced by fluid bed granulation and high shear granulation in order to compare the technological properties of the product obtained using different technologies.

Aim. Selecting the preferred method for producing granulated lactose using the wet granulation method without the use of binders.

Materials and methods. Lactose 80 mesh (Ningbo Samreal Chemical Co., Ltd., China and Aurora Industry Co. Ltd., China), lactose 200 mesh (DMV-Fonterra Excipients GmbH & Co KG, Germany) were used as raw materials. A Hüttlin fluid bed was used for granulation and for drying. High-shear granulation was performed in high-shear mixer-granulator Evio G10H (LLC "PharmTechnologies", Russia). Tableting was carried out on a rotary tablet press. Vibrating sieves, bulk density tester and flowability tester were used for the analysis of powders, and strength and disintegration testers were used for the analysis of tablets.

Results and discussion. Three approaches to obtain lactose for direct compression were tested: 1) lactose granulation in a fluidized bed; 2) modifying the surface of lactose 80 mesh particles by spraying lactose solution in a fluidized bed; 3) lactose high-shear granulation. Flowability was chosen as the first acceptance criterion for evaluating the obtained samples. When the required flowability was achieved, we proceeded to tableting the model mixture. The results obtained demonstrate that the best product is obtained by high-shear granulation.

Conclusion. A comparison was made of different methods for producing granulated lactose. Based on the comparison results, shear granulation technology was selected. The properties of the resulting granulate and model tablets meet the established acceptance criteria.

Introduction. The actual trend of modern drug development is the creation of stimuli-sensitive systems capable of solution-gel phase transition in the human body under the influence of various physiological factors (ionic composition of the medium, temperature, pH, etc.). One of the most promising stimuli-responsive natural polymers is a deacetylated derivative of the main structural component of crustacean shells, chitin – chitosan. This polymer has proven high compatibility with animal tissues, biodegradability and its own antimicrobial action, which allows its non-limited use in pharmaceutical compositions. It is also worth noting the high prevalence of chitosan in nature, which makes it an easily obtainable raw material for the creation of new dosage forms and, in particular, for import substitution of foreign polymers in Russian pharmaceutical technology.

Text. The aim of the survey presented here is to systematise information and studies on chitosan, its production, physical and chemical properties and factors on which the above depend, and, most importantly, pharmaceutical compositions based on the studied polymer and its modifications and stimuli, due to which the phase transition occurs in delivery systems involving this deacetylated natural polysaccharide. Chitosan, an amino polysaccharide composed of β-(1 → 4)-linked D-glucosamine and N-acetyl-D-glucosamine residues, has been known in the pharmaceutical industry since the middle of the XX century. Over the years of research, its biocompatibility, mucoadhesiveness and gel-forming abilities in aqueous solutions at pH in the range up to 6–7 have been proven. The most investigated chitosan-based compositions included various low molecular weight auxiliary components to achieve in situ transition of its aqueous solutions under physiological conditions, but many crosslinking components resulted either in the formation of stationary hydrogels or possessed toxic properties. One of the most promising and investigated combinations to the present day appears to be the combination of chitosan with beta-glycerophosphate.

Another interesting strategy for providing chitosan with stimulus-sensitive properties is to modify the free amino groups of the polymer chain with other high molecular weight compounds by crosslinking them through imine or amide bonds (as in methoxypolyethylene glycol-chitosan, for example), which are able to hydrolyse in the body's environment. In such way, it is possible to increase the solubility of chitosan and to achieve pH- and/or thermosensitivity in the polymers studied.

Conclusion. In the write-up of this review, the most important aspects of chitosan production and modification have been highlighted, and ways to impart pH- or thermosensitive properties to chitosan through different strategies have been demonstrated and their advantages and disadvantages have been shown. Significantly, no work was found to prove the presence of stimulus-sensitive properties in individual chitosan solutions.

Introduction. A professional approach to the development of a medicine and in particular the dosage form (DF) includes a comprehensive analysis of the active pharmaceutical ingredient (API) and excipients. Therefore, a detailed study of the technological and physico-chemical properties of a pharmaceutical substance is a fundamental step in the development of a drug, due to which it is possible to choose a suitable drug and predict the technological process based on the characteristics of the medicinal substance.

Aim. The aim of this work is to study the technological and physico-chemical characteristics of doxepin hydrochloride.

Materials and methods. Doxepin hydrochloride ((E)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine hydrochloride) (experimental sample), scanning electron microscope JSM-6510LV (JEOL, Japan), vibrating sieve CISA RP 200N (CISA Cedaceria Industrial S.L., Spain), bulk density tester ERWEKA SVM 102 (ERWEKA GmbH, Germany), flowability tester ERWEKA GTL (ERWEKA GmbH, Germany), drying oven BINDER FD 115 (BINDER GmbH, Germany) were used as the material.

Results and discussion. In the course of a number of experiments, data were obtained on the nature of crystals, solubility, particle size distribution, flowability and bulk tapped density of the studied powder. As a result of the study of API, it was revealed that the substance has an average degree of compressibility, the powder does not have a flowability property due to high statics, which is typical for the confirmed crystal shape of the powder under study. The above technological characteristics of the API should be taken into account when choosing the optimal DF.

Conclusion. As a result of the experiments conducted in this article, it was found that API of doxepin hydrochloride is a white crystalline non-loose powder with an average bulk density and degree of compressibility. The strong static of the powder is explained by the shape of its crystals in the form of plates with a large area of contact with each other. The substance is freely soluble in water, alcohol and a solution of PEG-400 : water (1 : 2). The technological properties described above will not allow the development of a solid dosage form by direct pressing without the use of excipients that improve the initial technological characteristics of the medicinal substance. An alternative method of manufacturing technology may be the use of granulation, or the choice of a different DF (for example, a liquid dosage form).

Introduction. A promising source for isolating fucoidan is Fucus vesiculosus L., a widespread species of brown algae. In recent years, the possibility of using fucoidan in medicine and pharmacy has been widely studied. The method of extracting polysaccharides significantly affects their characteristics and properties. To improve extraction efficiency, the possibility of using ultrasonic-assisted extraction (UAE) has recently been widely explored.

Aim. Study of the influence of the time of low-frequency UAE of brown algae F. vesiculosus on the kinetics of fucoidan degradation and its properties.

Materials and methods. Fresh frozen brown algae F. vesiculosus L. were used as raw material. UAE was carried out at an oscillation frequency of 22 kHz and a temperature of 25 °C. The extract was obtained at a temperature of 60 °C using the dynamic maceration method. The homogeneity and molecular weight of fucoidan were analyzed by high-performance size exclusion chromatography (HPSEC). FT-IR spectra of fucoidan were obtained on a VERTEX 70 spectrometer. Quantitative determination of fucose and sulfates was performed using a spectrophotometric method. The antioxidant activity (AOA) of fucoidan was assessed using FRAP test. Mathematical and statistical processing of the results was carried out in accordance with Russian Federation Pharmacopeia XV edition using MO Excel 2007 software.

Results and discussion. The calculated rate of fucoidan degradation was 19.5 %/h. The reaction rate constant and half-life calculated using the second-order model (R² > 0.97) were 5.8 · 10^–6 mol/(g · min) and 110 min. Ultrasonic degradation of fucoidan occurred predominantly due to random scission model (R² > 0,98). Using FTIR spectrometry, it was found that the preliminary structures of fucoidan without ultrasound and after ultrasound extraction were not changed. Analysis of antioxidant activity showed that fucoidan after ultrasonic extraction, despite a decrease in molecular weight, demonstrated significant antioxidant activity in vitro.

Conclusion. For the first time, a change in the conformational and antioxidant properties of fucoidan caused by low-frequency UAE was shown. UAE of fucoidan leads to a decrease in average molecular weight and degradation of fucoidan without significant destruction of sulfate groups. Overall, this study shows that the low frequency ultrasonic extraction, which is a gentle, environmentally friendly method that can be completed in a short period, can be effectively used to extract fucoidan without critically changing the molecular weight and antioxidant activity.

Introduction. 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine is a promising substance-inducer of the monooxygenase system of hepatocytes, according to preclinical studies, increasing the detoxifying function of hepatocytes in models of acute hypobaric hypoxia, liver ischemia, unconjugated hyperbilirubinemia, toxic hepatitis. Previously, the possibility of tablets based on 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine by direct pressing was shown. However, during the development process, with an increase in batch volumes of tablet masses, insufficient completeness of loading of the tablet press matrix was revealed. This is due to the low flowability of the tablet mass. This led to a deterioration in the uniformity of dosage and the appearance of defects in the average weight. During pharmaceutical development was made to use the wet granulation method to obtain 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine tablets to improve the technological properties of the tablet mass. The composition of filler excipients (lactose monohydrate and microcrystalline cellulose), tablet form, and parameters of quality preserved. For this aim the influence of binders, antifriction agents and granule size on the technological properties of the tablet mass was studied. The crushing strength and disintegration of the tablets analyzed.

Aim. Development of a composition for wet granulation of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine to obtain granules with optimal technological parameters to obtain high-quality tablets that pass tests according to the State Pharmacopoeia of the Russian Federation.

Materials and methods. To obtain granules, 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine of the DPDTX280424001 series was used as a starting material. Lactose monohydrate (200-559-2, LLC "Neftegazkhimkomplekt", Russia), microcrystalline cellulose (100-32-2, Silverline chemicals Ltd., India), potato starch and hydroxypropylcellulose (ZW180113, Fengchen Group Co., Ltd., China) were used as filler excipients. 5 % polyvinylpyrrolidone gel, 5 % starch mucus and 5 % hydroxypropyl methylcellulose gel were considered as binder excipients. Magnesium stearate (209-150-3, Ataman Chemicals, Türkiye), calcium stearate and talc (LLC "Agat-Med", Russia) were used as antifriction agents. Tablet masses assessed in terms of the force of ejection of the tablet from the matrix, flowability, bulk density, and compressibility. An EP-1 tablet press (ERWEKA GmbH, Germany) used as a press machine. The crushing strength, disintegration, and average weight of the resulting tablets assessed. Tests carried out in accordance with the State Pharmacopoeia of the Russian Federation.

Results and discussion. Based on the Latin square using the Harrington desirability function with analysis of variance of experimental data, it was found the greatest effect on the flowability of granules is on the granule size (influence to 77.68 %, granule size 0.5–1 mm). Influence of binder excipients to disintegration and crushing strength reached to 99.38 and 95.35 %. 5 % starch mucus as a binder excipient for obtain to granules possible to improve the flowability of the tablet mass from 3.5–4.0 to 12.5–12.9 g/s in comparison with the direct pressing method. The crushing strength and disintegration tests were successfully completed.

Conclusion. As a result of the experiments, the effect of wet granulation on the technological properties of the tablet mass of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazole[2,3]-F-xanthine was studied. The obtained granules had improved flowability compared to the initial tablet mass. This made it possible to ensure a more complete filling of the tablet press matrix, better uniformity of dosage, eliminate tablet defects and maintain strength and disintegration compared to direct pressing. The improvement of flowability due to granulation also makes it possible to consider capsules and sachets as alternative dosage forms for 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine.

Introduction. The influence of the dosage form on the pharmacological effect has been known since ancient times. The strategy for the preparation of micellar dosage forms for active antitumour substances was formulated in the last century. However, it has become widespread in practice in recent decades. This is largely due to advances in the synthesis of new structural components for the formation of micellar carrier, as well as to the acquisition of better knowledge of biochemical processes occurring in the tumour cell.

Text. This review is devoted to the achievements in the field of application of nanomicellar forms of antitumor drugs to improve the effectiveness of cancer therapy, which cover the period from 2019 to 2024. For this purpose, excipients used to obtain nanomicellar forms of antitumor substances are considered and analyzed, using docetaxel, paclitaxel, doxorubicin, and photosensitizers as examples. The creation of micellar forms allowed us to take a new look at these substances known in oncological practice.

Conclusion. Available achievements in the field of nanomicelles application for increasing the effectiveness of antitumour substances undoubtedly show the promising development of this technological direction. However, there are still many unresolved issues related to the stability of nanomicelles when administered into the body, as well as legal regulation in the field of creation and introduction of this new pharmaceutical form. These questions still need to be resolved by pharmaceutical science.

Introduction. The use of the solid disperse systems method to increase the solubility of lipophilic active pharmaceutical ingredients is industrially applicable using different technologies, but the influence of particle size on the dissolution of these systems, depending on the method, is not sufficiently reflected in the literature.

Aim. To study the influence of the particle size of amorphous solid disperse systems "darunavir-water-soluble polymer" obtained by solvent removal and hot melt extrusion on the dissolution of Darunavir in the biological pH range of 1.2; 4.5 and 6.8.

Materials and methods. Amorphous solid disperse systems were obtained in two ways: solvent removal and hot melt extrusion. Amorphism was determined by X-ray powder diffraction and electron microscopy. The efficiency of disperse systems was compared based on the results of the "Dissolution" test of powders mechanically ground to the same particle size in the biological pH range. The concentration of Darunavir in solution was determined using high-performance liquid chromatography with diode array detection.

Results and discussion. The best result was shown by a solid dispersion system based on the Eudragit® E PO polymer with a particle size D₉₀ of less than 10 μm. The increase in the concentration of Darunavir relative to the crystalline form corresponding to Darunavir ethanolate was 324, 2485, and 740%, respectively, in dissolution media with pH 1.2; 4.5, and 6.8.

Conclusions. Methods for obtaining solid dispersion systems, such as solvent removal and hot melt extrusion with the same particle size, do not affect the concentration of the Darunavir API in solution in the biological pH range during the Dissolution test.

Introduction. Adhesive baseplates, designed to fix ostomy bags and protect the skin of the peristomal area of ostomy patients, are a key element of an ostomy bag or urine bag. The functionality of adhesive baseplates is ensured by a set of their technical characteristics and design features, which makes the choice of appropriate baseplate testing methods an important aspect in the development, production and quality control of these medical devices.

Text. For testing adhesive baseplates, methods provided by Russian and international standards, as well as those not included in them, can be used. The methods provided by the standards include description of appearance (size), testing of adhesive strength, study of surface pH, as well as tests for wet integrity and water absorbancy. Methods not included in the standards for adhesive plates, but widely described in the scientific literature and used by researchers in practice include testing of some adhesive and mechanical properties, such as tack, shear strength, as well as tensile or bending tests to characterize the strength and deformation properties of the baseplate material. In addition, for adhesive baseplates, methods for testing medical properties common to all medical devices that are exposed to skin can be used. Besides this, it is shown how the adhesive properties of baseplates can be predicted based on the rheological properties of the adhesive layer, and factors important in the selection of materials modeling skin for in vitro tests are described.

Conclusion. The review presents a detailed description of methods of interest for testing adhesive baseplates, in particular their general principles and conditions of implementation, as well as methods that allow predicting the adhesive properties of plates and determining the relationship between adhesion tests in vivo and in vitro. A number of the described methods are of interest to include in normative documentation for adhesive baseplates tests, subject to their unification and modification taking into account the characteristics of this medical device.

Introduction. Polymer compositions, which are the basis of most dosage forms intended for application to the skin, including transdermal patches, determine both the biopharmaceutical properties of the drug and the consumer properties of the dosage form. Consumer properties are important for the patient. They determine the patient's commitment not only to therapy, but also to a specific manufacturer. Adhesive plates of colostomy bags are used for fixing ostomy bags and protecting the skin of the peristomal area. They are characterized by a set of consumer properties that determine their quality and may be a good model for studying the influence of consumer properties on patient preferences.

Aim. Development of comparative analysis method of adhesive plates polymer compositions based on consumer properties.

Materials and methods. To achieve the research goal, a set of methods was used, including bibliographic, analytical, comparative, survey and structural-functional analysis. To determine the weighting coefficients of various consumer characteristics of adhesive plates, a survey of experts was conducted.

Results and discussion. The main consumer properties of adhesive plates of ostomy pouches have been determined, which include: no adhesive residue on the skin after removal, ease of removal, wearing time, flexibility, ease of use, resistance to moisture and secretions, comfort of use, adhesion, strength of adhesion to the skin, prevention of leakage and no peristomal complications. Based on expert evaluation, weighting coefficients for each consumer property were determined, and a methodology for comparative evaluation of adhesive plates of ostomy pouches was proposed. The methodology can be used for comparative analysis of adhesive plates from different manufacturers.

Conclusion. A methodology for the comparative evaluation of ostomy pouches was successfully developed. It can be used as a basis for developing a similar methodology for evaluating skin-applied dosage forms based on their consumer properties.

Introduction. Cynara scolymus shows potential benefits in various fields. Its nutritional value and health benefits make it a promising candidate for improving general well-being. C. scolymus exhibits anti-inflammatory, antioxidant, hepatoprotective, choleretic, antimicrobial and lipid-lowering neuroprotective properties. The large amount of polyphenol found in C. scolymus has antioxidant activity, which allows it to neutralize free radicals, preventing cell damage. This reduces the subsequent risk of developing conditions such as cancer, diabetes and cardiovascular disease. Therefore, this plant could potentially be developed as a candidate for new domestic pharmaceuticals. Plant characteristics including microscopic, physicochemical properties and phytochemical profiles are essential information to ensure the quality of raw materials in drug development.

Alm. To study the macro and micromorphological characters of C. scolymus leaves for introduction into medical practice.

Materials and methods. Dried leaves of artichoke (Cynara scolymus L.), collected in the flowering phase (June) of 2023, in the Osh region of the Kyrgyz Republic, were used as the object of the study. To detect characteristic external features of artichoke prickly leaves, an external examination of the analytical sample was carried out visually (10 × ). Microscopic and histochemical examination was carried out in accordance with GF RF XV ed. OFS 1.5.3.0003 "Microscopic and microchemical analysis of medicinal plant raw materials and drugs of plant origin" on a microscope Leica DM1000 (Leica Microsystems CMS GmbH, Germany) with an eyepiece 10×/20 and lenses 10×/0.25, 40×/0.65, 100×/1.25. The images were displayed through the program "Leica LAS v4.13 Software".

Results and discussion. As a result of the research, characteristic morphological and anatomical features of artichoke leaves were established. Macroscopic features: leaves of oblong, broadly lanceolate shape, 50–70 cm long and 20–40 cm wide, unpaired, pinnately pinnately dissected, leaf margin coarsely ridged; petiole is fleshy, weakly expressed, ribbed; veining is pinnate. At the ends of leaf plates there are thin spike-like outgrowths. The color of the upper surface is grayish-green, the lower surface is silvery-gray or white-white. The odor when rubbed is weak, the taste of aqueous extract is sharply bitter. Microscopic features: upper epidermis consists of isodiametric and polygonal polygonal cells with straight walls, above veins epidermal cells are elongated. Stomata of the upper epidermis are oval, those of the lower epidermis are more rounded. Stomata are surrounded by 4–5 epidermal cells. Artichoke leaf trichomes are represented by simple and cephalic hairs. Simple hairs are multicellular, have a single row base consisting of 2–8 short, sometimes expanded cells. Simple setae end in a long, slender, sinuous thin-walled cell. Cephalic setae have a short multicellular bilobed pedicel and a rounded unicellular head, sometimes with a conspicuous yellowish oily content. The transverse section of the main vein (without leaf lamina) is semi-rounded with a slightly concave adaxial and convexly ribbed abaxial surface. Conductive bundles are collateral, large ones open and small ones closed. Simple and cephalic hairs can be observed on the epidermis of the vein.

Conclusion. For the first time studies on macro- and microscopic features of leaves of prickly artichoke, grown in the conditions of the Kyrgyz Republic, necessary to establish the authenticity and quality assessment of raw materials have been carried out.

Introduction. The new selective inhibitor of PAR-2 receptors, 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxamide (R004), is at the stage of preclinical trail. The excretion of R004 and its metabolites has not been studied before.

Aim. Investigation of excretion of R004 and its metabolites in urine and feces after a single oral and intraperitoneal administration of substance.

Materials and methods. The study was carried out on 2 groups of 6 Wistar rats. The R004 substance was administered orally to the first group at a dosage of 10 mg/kg, to the second group intraperitoneally at a dosage of 10 mg/kg. Biomaterial sampling was carried out with using metabolic cages. Urine was collected before administration of the drug and in the intervals of 0–4, 4–8, 8–12, 12–24, 24–48, 48–72, 72–96, 96–120 h after administration. Feces were collected before administration of the drug and in the intervals of 0–12, 12–24, 24–48, 48–72, 72–96, 96–120 h. The samples were analyzed using HPLC-MS/MS.

Results and discussion. The analytical range of the urine quantification method for R004 and 4-methoxy-3-(trifluoromethyl) aniline (М2) was 5–2000 ng/ml, and 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (M1) – 100–40 000 ng/ml. In feces concentrations of R004 were measured in the range of 0.5–500.0 µg/g, M1 – 4–4000 ng/g, M2 – 40–40 000 ng/g. The main part of the drug and metabolites was excreted within 48 h after administration. Complete elimination was achieved after 96 h. R004 is excreted unchanged only with feces: 94.83 ± 0.78 % after oral administration and 67.04 ± 0.59 % after intraperitoneal administration (M + m). The metabolite M1 is mainly excreted by renal route, the metabolite M2 is mainly excreted through intestine.

Conclusion. Bioanalytical methods for determination of R004, M1 and M2 in urine and feces have been successfully validated. Most part of the R004 is eliminated unchanged by enteric route. M1 is excreted mainly in urine, M2 – mainly in feces.

Introduction. Adaptive design in clinical bioequivalence studies offers a more flexible approach, allowing for modifications to protocols during the trial based on accumulated data. This is particularly relevant for drugs that are analogs of endogenous compounds, such as ademetionine, due to the presence of endogenous concentrations, potential physiological fluctuations, and homeostatic mechanisms. Given that ademetionine is included in the clinical guidelines by the Ministry of Health of the Russian Federation for treating various liver diseases, there is significant interest in developing generic formulations, which necessitates careful planning of clinical studies.

Aim. The aim of this work is to analyze approved protocols for bioequivalence studies with adaptive designs for a drug product that is an analog of the endogenous compound ademetionine, specifically enteric-coated tablets.

Materials and methods. A search was conducted in the database of approved clinical trials by the State Register of Medicines of the Ministry of Health of the Russian Federation using keywords "adaptive design" and "bioequivalence" for the period from 2023 to 2024.

Results and discussion. The article analyzes nine bioequivalence protocols with adaptive designs related to Potvin C's methodology for drugs analogous to the endogenous compound ademetionine in enteric-coated tablet form. The primary endpoints were pharmacokinetic parameters C_max and AUC_0–t. Ademetionine was studied as the evaluated analyte. In 77.8 % of the protocols, there was a planned assessment of the endogenous background of ademetionine followed by adjustments to pharmacokinetic parameters. Sample size calculations were not performed in these protocols due to the lack of reported values for the coefficient of intra-individual variation (CV_intra) for C_max and AUC_0–t of ademetionine in literature.

Conclusion. The analysis results indicate that a well-planned bioequivalence study with an adaptive design (until CV_intra values for ademetionine are published in specialized literature) is rational for developing generic formulations of ademetionine, with an assessment of the endogenous background. Considering the modified dosage form, it is necessary to conduct bioequivalence studies with administration both fasting and after meals.

Introduction. The search for effective approaches to the treatment of anxiety disorders, in particular, the development and study of drugs with anxiolytic action, is currently one of the most urgent tasks of neurobiological research. The study of behavioral changes in Danio rerio after exposure to a new group of substances – chromone-containing allylmorpholines – revealed their ability to exert dose-dependent sedation, and one of the compounds of the series – (E)-4-[3-(6-chloro-4-oxo-4H-chromene-3-yl)-4-cyclohexylallyl]morpholin-4-ium chloride (33a), in addition to sedative, also exerted anxiolytic action at low concentrations. Danio rerio is an evolutionary species much older than humans, and therefore the structural and functional differences between the receptors may be quite significant, making it necessary to evaluate the pharmacological profile of the new compounds in a translational model with more genetic similarities to humans, for example, in rodents.

Aim. The present study investigated the effects of 33a on anxiety behavior, cognitive functions, and grip strength of BALB/c mice after acute and chronic administration.

Materials and methods. Pharmacological activity was assessed using Open Field, Elevated Plus Maze, Light/Dark Box, T-maze, Marble burying, Tail suspension and Grip strength tests in BALB/c mice after acute administration of 33a at doses 1, 10 and 50 mg/kg, and two-week administration at doses 1 and 10 mg/kg.

Results and discussion. With acute administration, 33a at a dose of 50 mg/kg reduced the number of buried marbles, and at a dose of 10 mg/kg with chronic administration, it reduced the latency time of the first transition from a dark chamber to a white one in the Light/Dark Box test, which can be considered as manifestations of anxiolytic action. However, in the classical Elevated Plus Maze test, there were no statistically significant effects indicating the anxiolytic effect of 33a. The study did not reveal any negative effect of the studied substance on spatial memory and grip strength of mice, which may indicate the absence of its neurotoxic effect.

Conclusion. The results obtained confirmed the ability of compound 33a to exert dose-dependent inhibition of locomotor activity, however, this effect was not demonstrated in all tests. Further expansion of the range of used behavioral tests, as well as the use of experimental models may allow to reveal the specific activity of compound 33a, as well as other chromone-containing derivatives of allylmorpholine.

Introduction. Aronia × mitschurinii A. K. Skvortsov & Maitul. is a cultigenic species bred in the late 19th century as a result of breeding work by I. V. Michurin by crossing Aronia melanocarpa (Michx.) Elliott with distantly related species of the rowan genus (Sorbus). The fruits of this plant have long been used in folk and traditional medicine, being, first of all, a source of anthocyanin compounds. The leaves are currently only a by-product in the preparation of fruits, however, they can be used as a promising source of such groups of biologically active substances as flavonoids, tannins, leucoanthocyanins, which makes it possible to use this raw material to obtain herbal medicinal products (HMP). Therefore, primary in vitro screening studies to assess the toxicity and biostimulating effect of extracts from the leaves of Aronia michurini should be considered relevant to assess the prospects and determine the directions of subsequent preclinical trials. The aim of the study was to investigate the biostimulating and membrane-protective effect of Michurin's chokeberry leaf extracts (using a decoction as an example) in vitro using the Parameсium caudatum ciliate test system in the «functional load» test.

Materials and methods. Michurin's chokeberry leaves were harvested for the study at different periods of leaf blade development (May, June, August and September 2023) from plants cultivated on the territory of the I. V. Michurin Federal Scientific Center (Michurinsk, Tambov Region). For the study, aqueous extracts were prepared from the studied raw materials as a decoction in accordance with general pharmacopoeial monograph.1.4.1.0018.15 «Infusions and decoctions» for raw materials containing tannins. To study the biostimulating effect of the decoction of Michurin's chokeberry leaves, an in vitro test system of Parameсium caudatum ciliates in the stationary growth phase was used. The biostimulating and membrane-protective effect of the studied decoction was assessed in the «functional load» test under the damaging effect of a hypertonic sodium chloride solution.

Results and discussion. Using the test system of the Parameсium caudatum ciliates in the «functional load» test, it was established that a decoction of Michurin’s chokeberry leaves in vitro in a 1 : 10 dilution at all times of the medicinal plant raw material preparation reduces the survival time of ciliates under the damaging effects of a hypertonic sodium chloride solution during an incubation of 24 hours by no less than 43.5 % compared to the control sample, which probably indicates an increase in the permeability of biological membranes under the influence of tannins and sterols of the leaves and is consistent with their known astringent and antibacterial action. A decoction of Michurin's aronia leaves (when harvesting medicinal plant raw materials in June) in vitro in dilutions of 1 : 1000 and 1 : 10 000 close to the ranges of therapeutic doses, exhibits the greatest biostimulating and membrane-protective effect, which is confirmed by a significant reliable increase in the survival time of ciliates under the damaging effects of hypertonic sodium chloride solution, by a maximum of 39.3 % compared to the control sample during 24 h incubation, which is probably associated with the content of flavonoids and leucoanthocyanins and is consistent with their known capillary-protective and antioxidant effects.

Conclusion. A decoction of Michurin's chokeberry leaves (diluted 1 : 1000 when harvesting medicinal plant raw materials in June) significantly and reliably increases the survival time of the Parametium caudatum ciliate test system under the damaging effects of sodium chloride solution in the «functional load» test, by a maximum of 39.3 % compared to the control sample during 24-hour incubation, which indicates the presence of a biostimulating and membrane-protective effect.