M. S. Khalikov’s research while affiliated with A. N. Nesmeyanov Institute of Organoelement Compounds and other places

The purpose of the research is modification of albendazole (ABZ) properties due to the formation amorphous mixtures with carboxylic acids and evaluation of their anthelmintic activity. Materials and methods. Amorphous mixtures of ABZ with carboxylic acids (citric, succinic, p-toluenesulfonic and oxalic) were obtained according to the method described by Shete A.S. et al. (2019) with minor modification and expansion of the spectrum of carboxylic acids. The obtained amorphous mixtures were characterized by water solubility and ABZ content by high-performance liquid chromatography. IR spectroscopy method was used to prove the formation of target products. The anthelmintic activity of ABZ amorphous mixtures with organic acids in 1 : 1 ratio was studied on 80 white mice experimentally infected with Trichinella spiralis . Various mixtures of anthelmintic were administered into the stomach of mice of experimental groups at a dose of 2 mg/kg of active substance (AS). ABZ substance was used as a basic drug at a dose of 2 mg/kg of AS. The animals of the control group did not receive the drugs. The animals were sacrificed by cervical dislocation on the fourth day after drugs administration. The anthelmintic activity of the drugs was assessed based on the results of the helminthological necropsy of the mice intestines, and the efficacy was calculated according to the “control test”. Results and discussion. An increase in the solubility of the obtained amorphous mixtures of ABZ with carboxylic acids was established, the highest indices were noted for mixtures of ABZ with citric and para-toluenesulfonic acids. IR analysis confirmed the formation of salt-like products. It was established that the efficacy of amorphous mixtures of ABZ is higher than the activity of the basic drug (31.22%) in experimental trichinellosis, in particular, salt forms of albendazole with p-toluenesulfonic acid obtained after joint grinding showed 69.25%; amorphous mixtures with citric acid obtained after boiling in isopropanol showed 68.24% activity. Thus, when ABZ is modified with organic acids, its physicochemical properties change and its biological activity changes towards an increase.

The purpose of the research is to study the anthelmintic efficacy of complex solid dispersion of fenbendazole and niclozamide against dictyocaulosis and trichuriosis of sheep. Materials and methods . The complex solid dispersion was obtained by mechanochemical processing of fenbendazole (FBZ), niclozamide (NZM) and polyvinylpyrrolidone (PVP) substances in the ratio of 2 : 20 : 78. The obtained samples of solid dispersion were studied for nematocidal activity on sheep naturally infected with Dictyocaulus filaria and Trichuris ovis. The solid dispersion was tested against dictyocaulosis of sheep at a dose of 2 mg/kg and against trichuriosis at doses of 2, 4 and 6 mg/kg according to FBZ. Results and discussion . The complex dispersion based on FBZ, NZM and PVP showed 98.9% efficacy against dictyocaulosis of sheep at a dose of 2 mg/kg according to FBZ. The basic preparation – a mechanical mixture of FBZ and NZM at the same dose revealed 25.8% effect. Against trichuriosis of sheep, 98.7; 93.5 and 78.8% efficacy of complex solid dispersion was obtained at doses of 6, 4 and 2 mg/kg according to the active substance, respectively. The mechanical mixture of FBZ and NZM showed a 24.6% effect at a dose of 6 mg/kg according to FBZ. The dose of the complex solid dispersion – 6 mg/kg according to FBZ is recommended as therapeutic against trichuriosis of sheep.

The purpose of the research is to study the anthelmintic efficacy of complex solid dispersion of fenbendazole (FBZ) and niclozamide (NZM) against monieziosis and gastro-intestinal nematode infection of sheep. Materials and methods . A complex solid dispersion was obtained by mechanochemical processing of FBZ, NZM and polyvinylpyrrolidone (PVP) substances in a ratio of 2 : 20 : 78 in LE-101 roller mill at an energy intensity level of 1 g for 4 hours at drum rotation speed of 60–70 rpm. The activity of the complex solid dispersion was studied on 119 sheep naturally infected with Moniezia expansa and gastro-intestinal strongyles. The sheep were divided into 3 groups for each disease. The complex solid dispersion was administered to the sheep of the first experimental groups once orally at a dose of 20 mg/kg of NZM against monieziosis and at a dose of 2 mg/kg of FBZ against gastro-intestinal nematode infection. The sheep of the second experimental groups received a mechanical mixture of FBZ, NZM and PVP in the same ratio in similar doses. The sheep of the 3 groups served as a control and did not receive any preparations. The efficacy of the drugs was calculated on the results of coproovoscopic studies using the flotation method before and 15 days after deworming according to the "control test". Results and discussion . The results of trials of complex solid dispersion against sheep helminthosis indicated 97.0% efficacy of the drug at a dose of 20 mg/kg of active substance (NZM) against monieziosis and 92.1% efficacy against gastrointestinal nematode infection at a dose of 2 mg/kg of FBZ. The basic drug – a mechanical mixture of FBZ and NZM in the same doses revealed 25.2–26.4 % efficacy.

Objective: This study aimed to examine the efficiency of newly formulated drugs based on mech¬anochemical modification of two widely used anthelmintic substances in suspension formulations against the main classes of helminths and parasitic arthropods. Materials and Methods: Solid-phase co-grinding of two substances, i.e., ivermectin (IM) and niclosamide (NS), with licorice extract and sodium succinate was performed in liquid-phase processing to obtain suspension formulations. Drug preparations were administered to the sheep of the experimental groups (5 experimental groups of 8 heads) with different concentrations of active substances, i.e., 3.0, 5.0, and 10.0 mg/kg of body weight (BW) NS and 0.2-mg/kg BW IM. Aqueous suspensions of the original substances in dosages of 0.2-mg/kg BW IM, 10.0-mg/kg NS, and placebo were included as controls. Efficacy of the formulations against gastrointestinal stron¬gyles, Trichuris spp., Moniezia spp., and nasal bot larvae (Oestrus ovis) was assessed in naturally infected sheep by the number of surviving adult parasites post-treatment in the gastrointestinal tract, nasal passages, and sinuses. Results: Formulated suspensions showed an increased solubility of 5.5–13.1 times compared to the original substances. Treatment of sheep with the SusIN-10 drug containing 0.2-mg/kg BW IM and 10.0-mg/kg NS showed 100% efficiency against gastrointestinal strongyles, Moniezia, and nasal bot larvae. Formulations containing 0.2-mg/kg BW IM and 3.0- and 0.5-mg/kg NS could eliminate all of the Trichuris worms. Administration of original substances of IM and NS with rec¬ommended dosages did not result in the adult parasites’ complete elimination. Conclusion: Modification of the anthelmintic substances through mechanochemical methods made it possible to create formulations with a targeted spectrum of action, significantly higher water solubility, and optimal parasiticidal activity.

The purpose of the research is to study the anthelmintic efficacy of suspensions based on a combined solid dispersion of Fenbendazole and Niclosamide. Materials and methods . Mechanochemistry methods were used to prepare suspensions of Fenbendazole (FBZ) and Niclosamide (NSM) substances, in particular, liquid phase grinding of substances with additives (licorice extract, polyvinylpyrrolidone (PVP)) in water or in aqueous sodium carboxymethylcellulose (NaCMC) solution. The grinding was conducted in LE-101 roller mill at energy intensity of 1 g for 1 hour at a roll rotation speed of 60–70 rpm. The resulting suspension samples of combined FBZ and NSM dispersions were studied for cestodocidal activity on a laboratory model of hymenolepiosis of white mice that were infected at a dose of 200 infective Hymenolepis nana eggs per animal. Results and discussion . The 100% efficacy of a combined NaCMC-based drug suspension containing FBZ 13 mg and NSM 130 mg in 1 g of suspension was achieved at a dose of 20 mg/kg of NSM and 2 mg/kg of FBZ. The suspension based on licorice extract, NaCMC, and dioctyl sulfosuccinate sodium salt containing FBZ 18.6 mg and NSM 186 mg in 1 g of suspension at the same dose, i.e. 20 mg/kg of NSM and 2 mg/kg of FBZ showed 71.43% efficacy against H. nana. The suspension based on licorice extract and NaCMC containing FBZ 24.6 mg and NSM 246 mg in 1 g of suspension at the same dose showed a 62.0% effect against H. nana. The activity of the basic drug, the FBZ and NSM suspension was 28.58% at this dose without using mechano-chemical treatment.

The research purpose was to study the dialysis of triclabendazole (TCB) and its solid dispersions (SDs) obtained by mechanochemical methods by modifying TCB with polyvinylpyrrolidone (PVP), arabinogalactan (AG) and succinic acid (SA). Solid dispersions of the following compositions were obtained: TCB:AG:PVP (1:4,5:4,5), TCB:SA:AG (1:1:8) and TCB:SA:PVP (1:1:8), which were characterized by their solubility in water. To study the TCB release from the obtained SDs (dialysis), we used a laboratory installation consisting of a thermostated glass with a buffered solution (sodium borate) with pH 9.18 (intestinal environment). The TCB substance concentration in the dialysate was determined by HPLC the data of which determined that the TCB release into the buffered solution at different rates depended on the SD composition. It was found that SA included in the SD composition significantly increased the TCB release rate, apparently due to the buildup of a salt form from TCB (weak base) and SA (weak acid). The following conclusions were drawn: the increase in the TCB solubility in the studied SDs, as well as the increase in the rate of the TCB release from the SDs with succinic acid was consistent with previously obtained data on high antiparasitic activity of these SDs in sheep fascioliasis.

The study purpose: systematization of research results on the production technology and properties of triclabendazole (TCB)-based solid dispersions and polymer substances. Research results: we performed the analysis of technology features for producing solid dispersions (SDs) of the TCB substance with various polymeric substances (polyvinylpyrrolidone, hydroxyethyl starch, pectins, arabinogalactan, etc.), physicochemical properties of the obtained SDs (solubility, TCB preservation and release in model systems), toxicity, and biological activity. HPLC and UV spectroscopy methods were used to study the TCB solubility, preservation, and release from SDs. The solubility rate was taken as an optimization parameter according to which Triclafascid was selected in the form of a SD in the formulation TCB:AG (1:9) for its further introduction into veterinary practice. We studied parameters of the toxicity and antifasciloid effect, process performance, and other parameters as required to introduce Triclafascid. To improve the solubility of Triclafascid, an alternative approach was used to obtain its salt forms by including succinic acid in its formulation. The resulting SDs had significantly higher solubility and efficacy parameters when the TCB dosage was reduced. A series of studies was conducted to develop laboratory regulations and pilot production regulations for introducing Triclafascid into veterinary practice. Conclusions: the systematization of the obtained data on formulation, and on studying physical, chemical, technological, and biological properties made it possible to determine measures to introduce Triclafascid into veterinary practice.

The importance of the role of a formulation in realizing the potential of a new substance and promoting the preparation (medicinal or pesticide) on the market is undeniable. When developing a pesticide formulation, it is necessary to address the following issues: a convenient application form, drug fixation on the plant surface, penetration of an active substance into the plant, and high efficiency against weeds, plant diseases and pests. The modern formulations of nanoscale pesticides facilitate better realization of the biological potential of an active substance. This article gives a brief overview of the literature on pesticide formulations and their varieties, the preparation methods and effectiveness published in the last 10 years, with a particular focus on the authors' own work.

The purpose of the research is to analyze the dynamics of fenbendazole (FBZ) and niclozamide (NZM) release from their solid dispersions (SD) of various compositions by dialysis through various semipermeable membranes in model systems that correspond to stomach and intestine environments. To evaluate the parasitocidal activity of experimental mixture compositions. Materials and methods. The study used substances of FBZ and NZM, and the polymer, polyvinylpyrrolidone (PVP). Mechanical processes were carried out in a LE-101 roller mill and an AGO-2 orbital centrifugal mill at different power density levels. The resulting SD of various compositions were studied for solubility. The dynamics of FBZ and NZM substance release from the SD were studied in a laboratory setup consisting of a temperature controlled glass with buffer solutions with pH = 9.18 (intestinal environment) and pH = 1.0 (stomach environment). The substance concentration in the dialysate was determined by HPLC and UV spectroscopy. The resulting complex SD of FBZ and NZM were studied for cestodocidal activity in a laboratory model of hymenolepiosis of white mice. Results and discussion. It was found that the substances release into a buffer solution with pH = 9.18 from the SD obtained in the roller mill is higher than that of the SD obtained in the AGO activator. The dialysis of the experimental compounds in a model system with a gastric juice medium observed only FBZ substance penetration through the membrane, which can be explained by protonation of the FBZ molecule which is a weak base. The NZM molecule, being a neutral molecule, does not penetrate through the semi-permeable partition into the hydrochloric acid environment; it remains entirely inside the dialysis bag. High anthelmintic efficacy rates (up to 100%) of SD complex FBZ : NZM : PVP obtained in the AGO activator and in the roller mill were recorded for the SD of composition 2 : 20 : 78 in the mice with hymenolepiosis. The activity of the base drug, the niclozamide substance, was 27.69%, which is 3 times lower than the activity of the resulting complex dispersions.

The substance fenbendazole is included in the composition of many anthelmintic drugs, in which the “chemical stability” parameter is one of the main characteristics when obtaining permission for the use of drugs in veterinary practice. Fenbendazole is characterized by low solubility in water and therefore the content of the substance is overestimated in its preparations, which increases the cost of the drug as well as the safety risks of pharmacotherapy. The possibilities of mechanochemical modification of fenbendazole were evaluated in order to improve the solubility index. During the mechanical processing treatment of the substance in the presence of polymeric substances, solid dispersions are formed, which have increased solubility and high anthelmintic activity. The inclusion in these dispersions of the third component, which is succinic acid, did not significantly change the solubility of fenbendazole. In all these dispersions, the substance remained unchanged both during the preparation of its solid dispersions and during their storage. When fenbendazole is modified in an organic solvent medium, the substance is partially converted into oxfendazole, which is one of its metabolites. The chemical stability of fenbendazole was confirmed via HPLC/MS and NMR spectroscopy. The anthelmintic activity of these compositions was evaluated and it was found that they have a high nematicidal activity.