For deworming of horses of drove breeding and wild animals in preserves of free feeding, we have developed an innovative drug based on ivermectin using the technology of mechanochemical modification of ivermectin substance with a mixture of polymers (polyvinylpyrrolidone /PVP/ and arabinogalactan /AG/ Siberian larch Larix sibirica). With this treatment, a solid dispersion of ivermectin (SDI) was obtained in the form of a beige powder, which is easily flowable. The pharmaceutical safety of SDI was studied, the parameters of general toxicity, acute cutaneous toxicity, irritant effects, and the effect of the drug on the eye mucosa were studied. Studies conducted on white mongrel rats. The LD50 of the study drug was found to exceed the test dose. According to GOST 12.1.007-76, the drug belongs to the 4th class of hazard (low hazardous substances). In the study of local irritation of the drug on the skin, it was noted that the integrity of healthy skin on the other hand, where the scratches were not injured, elasticity remained, there was no redness, after a month the sheared layer was healthy. Established the absence of irritating properties of SDI with a single application to the skin. As a result of studying the irritant effect of the drug on the mucous membrane of the eye, it was established that SDI has a moderate local irritant effect on the eyes of animals, estimated at 1 point.

Ivermectin-based preparations that have been intensively used in veterinary practice for more than 30 years have contributed to the development of resistance to drugs based on it, and this problem is very relevant in modern parasitology. One of the ways to solve this problem is the development of combined preparations based both on new ivermectin derivatives and the inclusion of preparations from other class-es of chemical compounds in their composition. We have proposed an alternative method, i.e. the mechanochemical modification of the substance ivermectin using water-soluble polymers. This paper presents the results of modifying the substance of ivermectin with arabinogalactan polysaccharide (AG), isolated from Siberian larch Larix sibirica by joint machining of components in a variable-voltage shred-der activator. During jointly machining ivermectin with samples of arabinogalactan from three alternative sources, compositions of "Ivermectin: AG" (1:10), which have increased solubility (more than 10 times as compared with the original substance of ivermectin), were obtained. The study of the parasiticidal efficacy of the obtained compositions of ivermectin in intestinal helminthiases was carried out on sheep. As a result of the experiments to evaluate the compositions of ivermectin with three samples of AG, it was found that their use of helminthic efficacy did not show the advantage of any of the batches of polysaccharide. To a greater extent, the effective-ness of the compositions of ivermectin was influenced by the dosage of the drug. Biological testing of the obtained compositions of ivermectin showed the possibility of reducing the dosage of ivermectin by 2 or more times while maintaining high ef-ficiency. The obtained data indicate the promising outlook for a mechanochemical approach for modifying the physicochemical and biological properties of prepara-tions based on ivermectin in solving problems of resistance.

A review of new directions in obtaining and manufacturing of innovative antiparasitic drugs is presented. The immobilization of antiparasitic drugs on or in nanoparticles to increase the efficacy and reduce side effects of drugs by improving the parameters of adsorption, bioavailability, slow release and intracellular permeability has been the most widespread direction in recent decades. Currently, such carriers as liposomes, polymer nanoparticles, solid lipid nanoparticles, nanosuspensions, nanocrystals, etc. are used as drug delivery systems for antiparasitic drugs. Studies conducted in our country have confirmed the efficacy of mechanochemical technology for producing solid dispersions of certain anthelmintic drugs (niclosamide, albendazole, fenbendazole, triclabendazole, praziquantel etc.) with excipients (arabinogalactan, polyvinylpyrrolidone, glycyrrhizic acid, etc.). On the example of solid lipid nanoparticles (SLN), the possibility and prospects of their further study and use as potential means of targeted delivery of antiparasitic drugs are shown, various manufacturing technologies are indicated, including homogenization methods, the use of supercritical fluids, the method of dry spray, evaporation, ultrasonic treatment, double emulsions, etc.

In order to increase the water solubility and biological activity of antihelminthics (medamin /BMC/, albendazole /ABZ/, fenbendazol /FBZ/) by the method of joint machining of their substances with polymers (PVP, arabinogalactan), solid dispersions (SD), which are easily flowing powders, were obtained. The analysis of solid dispersions of the “Drug: polymer” systems for solubility showed that this indicator depends on both the nature of the Drug and the Polymer. The possibility of increasing the water solubility of medamin by more than 50 times, albendazole by 27 times and fenbendazole by 24 times with varying times of their joint machining with polymers is shown. IR spectral studies and comparison with reference data suggest the formation of intermolecular complexes due to the formation of a hydrogen bond between the characteristic groups of antihelminthic substances and polymers. It was shown that solid dispersions of these substances with PVP can be obtained by an alternative method, i.e. by dissolving the components in ethanol and then removing the solvent. These SDs were mica-like solid films and had greater solubility than SDs produced in solid state. Comparison of the nematocidal activity of SD (ABZ with PVP and FBZ with PVP) obtained by alternative methods showed that they have the same activity at a dose of 2.0 mg/kg of active substances when tested on a laboratory model of trichinosis in white mice experimentally infused with T. spiralis. SD of ABZ with PVP and AG showed high efficacy in treatment of trichinosis and hymenolepiasis in white mice. These results were confirmed during treatment of nematodirosis and other gastrointestinal strongylatosis in sheep. SD of FBZ with arabinogalactane showed 100% efficacy in treatment of dictiocaulosis, strongyloidosis, and strongilatosis of the digestive tract and 98.3% activity in treatment of trichocephalosis in sheep. The obtained data indicate the promise of a mechanochemical approach for the development of innovative antihelminthics with increased solubility and high biological efficiency.

To study the possibility of increasing the solubility of the substance triclabendazole (TCB), we used the technology of mechanochemical modification of TCB using water-soluble polymers, polyvinylpyrrolidone (PVP) and arabinogalactan (AG) from Siberian larch Larix sibirica in particular. After joint machining of TCB with polymers (PVP, AG) in a LE-101 ball mill (made in Hungary), free flowing powder dispersions with an increased solubility (more than 50 times as compared to the original substance TCB) were obtained. This result was explained by the formation of intermolecular complexes of the type of hydrogen bond between the characteristic groups of TCB and polymers, which was confirmed by the data of IR-spectral studies. Tests of intermolecular complexes on spontaneously fasciola-infected sheep have shown high efficiency. As a result of the research, it was found that the complex of TCB: AG composition (1:9), which we named “triclafascid”, possesses a number of positive attributes in comparison with the substance of TCB and provides high fasciolocid and economic efficacy, and safety of use by reducing the therapeutic dose. Inclusion of arabinogalactan, which has hepatoprotective, antimutagenic, mitogenic, gastroprotective properties, in the preparation, made it possible to reduce the toxicity of the preparation proposed for practice. It was shown that residual amounts of TCB and its metabolites were not detected in tissues and organs on the 14th day of the experiment with triclafascid, which indicates the possibility of slaughtering an animal and using meat 14 days after using the drug. The drug has good solubility, bioavailability to helminthes, is non-toxic, and increases antihelminthic and economic efficiency. The obtained results confirmed the previously obtained data on the prospects of an innovative approach to improve the quality indicators of anthelmintic drugs and to obtain effective drugs for veterinary medicine.