Macozinone (MCZ) is the newest first-in-class clinical-stage benzothiazinone-based drug candidate for the treatment of tuberculosis. Yet, the extremely low oral bioavailability of MCZ, a major problem in clinical trials, needed to be addressed, and we are pleased to present our attempts to solve this issue.

Semaglutide is a representative of analogues of the incretin hormone human glucagon-like peptide-1 (GLP-1) and is currently used in Russia for the treatment of type 2 diabetes mellitus (T2DM; in monotherapy and in combination therapy), including patients with obesity and overweight.The aimof the work was to conduct a comparative assessment of the physicochemical properties, a biological activity, bioequivalence and safety, including tolerability and immunogenicity, of the drug Quincent® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) and the drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark) when administered to healthy volunteers.Materials and methods.To assess the degree of similarity of the study drug Quincenta®(semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) with a chemically synthesized active substance to the original (reference) drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark), a comparative study of physicochemical properties and a biological activity was carried out. To assess the bioequivalence of the study drug and the reference drug, an open randomized parallel comparative study with the participation of healthy volunteers (n=54), 54 participants of which had been included in the population, was conducted. The volunteers were randomized into 2 groups in a 1:1 ratio, and received a single dose subcutaneously either of the study drug (domestic semaglutide at a dose of 0.5 mg) or the reference drug (foreign semaglutide at a dose of 0.5 mg). The mode of administration was in the morning on an empty stomach. A semaglutide concentration was determined in serum samples using a previously validated enzyme-linked immunosorbent assay (ELISA) method. A quantitative determination of antibodies to semaglutide in the human serum by ELISA was carried out with a microplate photometer using ready-made kits pre-validated by the manufacturer. The conclusion about the bioequivalence of the compared drugs was made using an approach based on the assessment of 90% confidence intervals for the ratios of the geometric mean values of the parameters C_max, AUC_(0–t)of semaglutide in the measurement original units.Results.The results of the comparative analysis of the study drug and the reference drug demonstrate the comparability of their physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the test drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the C_maxvalue for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® it was 42.2556±7.84. Herewith, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the C_maxand AUC_0–tvalues of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. The tolerability of the drugs in the volunteers was notified as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of Results. The results of a comparative analysis of the study drug and the reference drug demonstrate the comparability of physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the study drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the C_maxvalue for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® this figure was 42.2556±7.84. At the same time, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the C_maxand AUC_0–tvalues of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. Tolerability of the drugs in volunteers was noted as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of the drug immunogenicity.Conclusion.In the course of the study, the comparability of the physicochemical properties and biological activity of the studied Russian drug with the chemically synthesized active substance Quincenta® to the reference drug Ozempic® was confirmed: the activity range of the studied drugs was within 80–120% in relation to the standard sample of semaglutide. The bioequivalence and a similar safety profile, including the immunogenicity and tolerability of the Russian drug Quincenta® (semaglutide 1.34 mg/ml, Promomed Rus LLC, Russia) were shown in comparison with the foreign drug Ozempic® (semaglutide 1.34 mg/ml, Novo Nordisk A/C, Denmark).

The article presents the results of an in vitro study of the synergetic effect evaluation of the combined preparation based on coordination complex ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate on energy metabolism and cell respiration.The aim of the study was to evaluate the mitochondria-directed action of the metabolic and antioxidant preparation based on succinic acid coordination complex with trimethylhydrazinium in relation to optimizing the energy metabolism in the cells under the oxidative stress conditions, as well as against the background of ischemic processes.Materials and methods. The study of the hydroxysuccinate complex effect of the drug Brainmax® components was carried out on isolated mouse liver mitochondria. In the course of the study, the potential of mitochondria, the generation rate of hydrogen peroxide during the respiration, the respiration rate were evaluated in the following positions: a) unstimulated by malate and pyruvate, b) stimulated by malate and pyruvate (complex I substrates), by succinate (complex II substrates), c) against the background of the initial section of the electron transport chain blockade by rotenone, d) in phosphorylation blockade by oligomycin, e) against the background of the FCCP-induced uncoupling, and f) in cyanide-blocked complex IV (cytochrome C oxidase).Results. It has been shown that the succinic acid coordination complex with trimethylhydrazinium, which is the active principle of the Brainmax® drug, significantly reduced the transmembrane potential of mitochondria (IC₅₀=197±5 µM), compared with the widely used preparations of ethylmethylhydroxypyridine succinate and trimethylhydrazinium propionate, which facilitates the transfer of the produced ATP into the cell and preserves a vital activity of mitochondria even under stress. In the study of the mitochondrial respiration stimulated by the substrates of complex I (NADP-coenzyme Q-oxidoreductase), pyruvate and malate, the studied drug led to a more pronounced increase in the oxygen consumption with IC₅₀=75±6 µМ. When evaluating the effect of the complex on the production of ATP by mitochondria, the most pronounced effect was observed with the addition of studied complex, which indicated to the uncoupling of respiration and oxidative phosphorylation at the given concentrations of the studied compounds. When assessing the effect of the complex on the production of hydrogen peroxide by isolated mitochondria, a significant decrease in the peroxide production was shown in the samples containing the complex of trimethylhydrazinium propionate and EMHPS.Conclusion. Based on totality of the results obtained, it can be assumed that a favorable conformation of the pharmacophore groups of ethylmethylhydroxypyridine succinate and trimethylhydrozinium propionate coordination complex included in the composition of Brainmax® leads to a synergetic interaction and more pronounced pharmacological effects on target cells. This complex provides stabilization of a mitochondrial function, intensification of the adenosine triphosphate energy production and the optimization of energy processes in the cell, reduces the severity of the oxidative stress and eliminates undesirable effects of an ischemic-hypoxic tissue damage.

Introduction.Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs. Aim.Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form a dispersible tablet for preparation of oral solution. Materials and methods.Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated. Results.The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) from 16.8 to 29 mg/l. It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.510-6cm/s in the forward direction from the apical to basolateral cell membrane, and 1.510-6cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented. Discussion.The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented. Conclusion.In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

Introduction. Due to increase in the frequency of detecting cases of tuberculosis caused by strains of mycobacteria with resistance not only to traditional, but also recently introduced into clinical circulation anti-tuberculosis drugs, it is urgent to search for and develop new drugs that can be effective against multidrug-resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains. One of the most promising classes of such compounds are fluorine derivatives of benzothiazinones, and particularly compound PBTZ169 (INN macozinone). This antibiotic has a high specificity against mycobacteria tuberculosis (M. tuberculosis), inhibiting one of the key enzymes of cell wall synthesis. However, macozinone as an active pharmaceutical ingredient has significant features of physical and chemical properties that hinder the development of oral dosage forms based on it. It is classified as class IV by BCS and is characterized by a very low solubility and lipophilicity, a pronounced dependence of dissolution rate on the pH of the medium, and very low bioavailability when taken orally.Aim. To substantiate the target profile, critical quality attributes and to develop a prototype of an oral dosage form with modified release of macozinone, allowing to maximize its pharmacological activity.Materials and methods. Using pharmaceutical substance macozinone hydrochloride and various excipients, experimental tablets with a dosage of 500 mg macozinone were developed. The influence of the composition of the media and the added excipients on the solubility of macozinone in various biorelevant media, the degree of swelling in the liquid and the degree of mucoadhesion of the experimental tablets to the mucus of the pig stomach were evaluated. The HPLC method was used to evaluate the kinetics of the release of the active substance.Results and discussion. In this work, the expediency of creating macozinone-containing gastro-retentive dosage forms with a slow release of the active substance, the delay mechanism of which is provided by swelling and increased adhesion to the gastric mucosa, has been substantiated. Various tablet samples were experimentally tested in which the modification of the release of the active substance and the degree of swelling and mucoadhesion were varied by introducing various excipients into the formulations, including known swelling and bioadhesive matrix agents.Conclusion. According to the results of the experiments, samples of high-dose (500 mg) swellable and mucoadhesive tablets created by the technology of two-stage granulation with the inclusion of macozinone - hydroxypropyl-beta-cyclodextrin mixtures in the primary granules and introduction of combinations of soluble and insoluble hydrophilic matrix agents into the intergranular space were recognized as the most promising for subsequent pharmacokinetic studies.

Today, there is an annualincrease in the prevalence of obesityandoverweightworldwide.Thisproblem is becomingparticularlyrelevant,sincetheseconditionsserve as keyriskfactors for the development of anumber of cardiovascularandmetabolicdisorders,including type 2diabetesmellitus(T2DM).On the territory of the Russian Federation, drugswerepresentedasagonists of glucagon-like peptide of the first type (GLP-1)receptors, the activesubstance of which was producedexclusively by biotechnologicalmeans. It is important to notethat solid-phasechemicalsynthesisisalsooneof the alternativemethods for obtainingGLP-1analogues. A significantadvantage of thismethodoverbiotechnologicalsynthesisis the exclusion of spontaneousamino acid substitutionsand the absence of impuritiescharacteristicofthismethod.The aim. Evaluation of the biological activity of the domestic medicinal product liraglutide (Enligria^®, solution for subcutaneous administration, 6 mg/ml, PROMOMED RUS LLC), obtained by chemical synthesis, and a foreign reference drug (Saxenda^®,solutionforsubcutaneousadministration,6 mg/ml,NovoNordiskA/C),obtainedbiotechnologically.Materials and methods. The effectiveness of liraglutide preparations was evaluated using a model of induced metabolic syndrome in CBA×C57BL/6 SPF mice (n=36,age6months)according to changes in body weight,feedintake,bloodglucoseandlipid levels, and adiposetissuemass.Results. According to the results of the study, it was shown that Enligria^® and Saxenda^® drugs have comparable efficacy parameters and statistically significantly (p < 0.05) reduce body weight (13.6±2.1% and 13.3±3.3%, respectively), glucose levels (18 ± 3% and 16 ± 9%), triglycerides (32 ± 12% and 40 ± 18 %) and cholesterol (16 ± 7% and 18 ± 9%) in the blood. Enligria^® reduced the mass of structural subcutaneous fat by 32 ± 3% (p < 0.0001), and visceral fat by 34 ± 4% (p < 0.0001). The studiedliraglutidepreparationsshowed a pronouncedhypoglycemiceffect,observedinalldoseranges. The observedhypoglycemiceffectwasdose-dependent.Conclusion. The results of the work indicate the high effectiveness of the synthetic drug Enligria^®, which is expressed in reducing body weight and improving metabolic parameters.