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Most drug substances are poorly soluble in water so that their efficacies must be improved by increasing the dosage, which not only creates economic problems but also increases the toxicity of the future medicine. These problems can be solved by developing various dosage forms, which involves additional financial costs, complicates the technology, increases development times to introduce the future medicine, etc. Another approach to improving the solubility of such drug substances is the development of methods and technologies for producing solid dispersions of these drug substances with excipients (polymers, dispersants, surfactants, etc.). The present review covers the development and application of mechanochemical technology to modify sparingly soluble anthelmintic drugs. The technology consists essentially of joint mechanical treatment of a drug substance and polymer in grinder-activators of controlled energy. This technology uses one stage and avoids the use of solvents, heating, evaporation, etc. The resulting solid dispersions include supramolecular systems with increased solubility and better bioavailability and are also highly active with reduced consumption of the active ingredients.

Changes in the molecular weight characteristics of polysaccharide macromolecules - arabinogalactan, hydroxyethyl starch 200/0.5, Fibregum, and dextrans 10, 40, and 70 - were studied during mechanochemical processing. A preference for “gentle” conditions for mechanical processing (~1 g) were established, as these conditions do not lead to destruction of polysaccharide macromolecules. An additional advantage of these mechanical processing regimes is that they can be scaled up to industrial flow mills. Mechanochemical processing had no adverse effect on the toxicity measures of the polysaccharides studied. Toxicological studies of mechanically processed arabinogalactan, hydroxyethyl starch 200/0.5, Fibregum, and dextrans 10, 40, and 70 showed that these polysaccharides and the products of their mechanochemical processing can be classified as class 4 (low-toxicity) substances.

The synthesis of a water-soluble compound belonging to the group of terpenoids-disodium salt of a resorcinol derivative of caryophyllene-is described. The biological properties of the new compound have been studied in mice in comparison to some native terpenoids and atorvastatin. The synthesized terpenoid (5 mg/mouse) decreases the rate of cholesterol biosynthesis in murine liver. Similar effects were observed for atorvastatin (0.2 mg/mouse) and the native terpenoids (8.5 mg/mouse), except for perillic alcohol (which produced a stimulating action). In addition, the obtained resorcinol derivative of caryophyllene inhibits mitogen-stimulated murine splenic cell proliferation in vitro in a dose-dependent manner. The drug efficacy in this reaction is comparable with that of perillic alcohol and α-terpineol, while being less pronounced than the effect of dipentene and atorvastatin.

A series of 2(4)-hydroxybenzyl-and 3-(4-hydroxyaryl)propylamines and their hydrochlorides were synthesized based on 2,4-and 2,6-alkylsubstituted phenols. The synthesized hydrophilic derivatives are characterized by average half-lethal doses (LD50), which fall within 50–170 mg/kg for intraperitoneal administration in mice. Some of the synthesized compounds in a dose of 0.1LD50 show pronounced hepatoprotector activity with respect to tetrachloromethane-induced model toxic hepatitis in mice.

One of the main mechanisms in the pathogenesis of toxic liver damage is destabilization of the membranes of hepatocytes as a result of lipid peroxidation (LPO). In the case of such liver disorders, a pronounced protective action is offered by phenolic antioxidants such as -tocopherol [1], potassium phenosane, synthetic derivatives of hydroxycynnamic acids, ionol, ubiquinone, and some other natural compounds [2]. According to [3], some derivatives of hydroxycynnamic acids are superior to -tocopherol with respect to hepatoprotector action. The high hepatoprotector activity of hydroxycynnamic acid derivatives can be due to their hydrophilicity, which accounts for the high rate of transport and biological accessibility of these molecules. Below we report on a comparative study of the antioxidant activity and hepatoprotector properties of a series of water-soluble 2,6-di-tert-butyl-4-propylphenol derivatives (I – IV) and some analogous compounds (V – VIII) not containing tert-butyl groups.

The use of solid-state technologies in the pharmaceutical industry significantly increases the possibilities of creating both original drugs and new forms of the preparations. At the Institute of Solid State Chemistry and Mechanochemistry, a new technology for obtaining dispersed solid systems of pharmacologically active compounds based on impact-wear processing of a powder mixture of the initial substances in special mills [1] was developed. Recently, this technology was used to develop a new rapidly soluble form of aspirin [2]. We have studied the possibility of using the new method for obtaining dispersed solid preparations of nonsteroidal antiinflammatory drugs (NSAIDs) with -glycyrrhizic acid (GA). GA is a biologically active triterpene glycoside extracted from roots of licorice (Glycyrrhiza sp.), known to exhibit high antiinflammatory activity without the complications typical of NSAIDs [3 – 5]. Previously, it was established that molecular complexes of GA with acetylsalicylic acid (ASA), orthophen (ORT), and butadione exhibit a lower toxicity and a less pronounced ulcerogenic effect than the same drugs without GA [6, 7]. The purpose of this study was to determine the average lethal doses (LD50), evaluate the ulcerogenic action, and assess the antiinflammatory effect of GA – ASA and GA – ORT complexes obtained by solid-state synthesis and compare these properties to those of the analogous compounds synthesized by conventional chemical synthesis in solution. EXPERIMENTAL CHEMICAL PART