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Influence of Different Methods of Obtaining of Solid Dispersions and Crystals of Fenbendazole on Biological Activity
Abstract
Fenbendazole (FBZ) is one of the most widely used drugs in veterinary medicine. Modification of its physicochemical properties, in particular the parameter of solubility, contributes to a change of its biological activity, that is shown on the model of trichinellosis of white mice. The analysis of methods of obtaining new preparations of fenbendazole is presented: solid dispersions of fenbendazole with polymers, as well as the combinations with polymers and succinic acid (SA) and mixed crystals of FBZ with SA. The concentration of the active substance, stability and effect on biological activity were studied.
... Доказано, что янтарная кислота и сукцинаты являются активными адаптогенами, увеличивая сопротивляемость организма неблагоприятным воздействиям факторов внешней среды. С учетом этих уникальных свойств янтарной кислоты, нами были получены композиции [1] в виде твердых дисперсий путем совместной твердофазной механохимической обработки субстанции фенбендазола с поливинилпирролидоном и арабиногалактаном с добавлением янтарной кислоты при массовом соотношении компонентов 1:1:8. ...
The purpose of the research is to study the features of the mechanochemical modification of medicinal substances with low solubility in water. According to the Biopharmaceutics Classification System, about 6% of medicinal substances belong to the group of insoluble medicinal substances, and about 47%, to practically insoluble medicinal substances, i.e. more than a half substances have problems with solubility, and therefore bioavailability and pharmacological activity. To achieve the therapeutic effect of such substances, it is necessary to deliberately increase the dosage of the substance, which increases the cost of the drug, as well as safety risks of pharmacotherapy. The work evaluated possibilities of mechanochemical modification of a number of known anthelmintic substances with low solubility to increase this parameter. It was shown that during machining of such substances in the presence of polymeric substances, solid dispersions were formed that had increased solubility while maintaining high anthelmintic activity with decreased dosage of the active substance. Preparations in the form of solid dispersions can be used both orally and by a group method to 10-20 animals, mixed with compound feed. For low-melting substances, a liquid-phase machining method is proposed to obtain stable suspension concentrates that are convenient for oral administration. The prospects for obtaining mixed compositions based on two substances are shown, which makes it possible to obtain combined preparations with a wide spectrum of action with the minimized volume and frequency of their use.
Background: Parasitic infections are widespread in sheep farms of the Russian Federation, including Siberia. The infection of sheep with helminths and parasitic arthropods with a range of 70% to 100% in different regions, contributes to a decrease in the productivity and quality of products, and even death of animals. This study aimed to formulate drugs with pronounced parasiticidal effects based on ivermectin and albendazole, widely used to treat animal entomoses and helminth infections.
Methods: New formulations in the form of solid dispersed compositions were prepared by mechanochemical modification of ivermectin and albendazole using arabinogalactan polysaccharide. The efficacy of preparations on gastrointestinal strongylosis and monieziosis, and melophagosis of sheep was determined by parasitological examination and analysis of feces and urine.
Results: The new formulations demonstrated increased solubility and parasiticidal activity due to the formation of inclusion complexes when interact with water. The maximum efficacy values (> 95% efficiency) against intestinal Strongylida and Moniezia expansa, and ectoparasitic Melophagus ovinus were seen in doses lower than the recommended doses of the starting drugs.
Conclusion: The increased parasiticidal activity of innovative compositions can be explained by increased water solubility and bioavailability of the preparations, due to formation of inclusion complexes. The results of this study suggests the possibility of a significant reduction in the dosages of composed substances without losing their parasiticidal activity.
Solid dispersions of medamine and albendazole with water-soluble polymers (PVP, arabinogalactan) were obtained by mechanochemical technology to increase the aqueous solubility of poorly soluble anthelmintic drug substances. An analysis of solid dispersions of drug–polymer systems showed that their solubilities depended on the nature of both the drug and polymer. The aqueous solubilities of medamine and albendazole could be increased by greater than 50 and 27 times, respectively, by varying the joint processing time with the polymers. An analysis of IR spectra and a comparison of them with published data suggested that intermolecular complexes were formed in these systems. Innovative anthelmintic drugs with increased solubility for medicine and veterinary medicine could be created by using the proposed mechanochemical technology for obtaining solid dispersions. The resulting solid dispersions had several advantages over conventional dosage forms, in particular, they were obtained in one stage, their preparation did not require excipients (dispersants, surfactants, wetting agents, etc.), and they were more conveniently used and inexpensively priced.
ABSTRACT
Objective: Solubility and bioavailability are crucial for maximizing the activity of an antiparasitic
drug. This study aimed to develop a combined preparation for antiparasitic medicines using ivermectin
(Iver), fenbendazole (FBZ), and triclabendazole (TBZ), considering their solubility, bioavailability,
and activity.
Materials and Methods: Innovative preparations in solid dispersions (SD) were obtained using the
joint mechanical processing of drug substances with polyvinylpyrrolidone (PVP) in an LE-101 roller
mill. The preparations’ efficacy was studied in 140 sheep spontaneously infected with gastrointestinal
Strongylata, Dicrococelium dendriticum, Moniezia expansa, and Melophagus ovinus. The
preparations were given individually to the sheep in the form of an aqueous suspension orally.
Their effectiveness was evaluated using intravital and postmortem parasitological examinations.
Results: The results confirmed the increase in solubility of substances by 13–29 times. The experiments
have shown the high efficacy of SD composition of FBZ/Iver/PVP (1/1/9) containing FBZ
(at 3.0 mg/kg b/w) and Iver (at 0.2 mg/kg b/w) when used against gastrointestinal Strongylates
and M. expansa (95.8% and 100%, respectively), to a lesser extent against M. ovinus (38.5%). The
SD composition of TBZ/Iver/PVP (1/1/9) of TBZ (at 3.0 mg/kg b/w) and Iver (at 0.2 mg/kg b/w)
showed a high efficacy against gastrointestinal Strongylata and D. dendriticum (96.8% and 100%,
respectively) and less activity against M. ovinus (61.6%).
Conclusion: The high parasiticidal activity of SD based on FBZ, TBZ, and Iver in comparison with
initial substances is explained by the formation of inclusion complexes of these substances with
PVP when SD is dissolved in water and the synergistic effect of the active substances of the preparations.
The resulting complexes have increased solubility in water and bioavailability. The use of
such an SD suggests a significant reduction in the dosages of FBZ and TBZ without losing parasiticidal
activity.
The possibility of improving the solubility of drugs by obtaining solid dispersions (SDs) with polymers is demonstrated. The solubility of these SDs is dependent both on the nature of drug and polymer and on the conditions of their preparation. IR spectroscopy of the obtained SDs and the analysis of results found in literature indicate that inclusion complexes are formed within them.
Objective: The purpose of our research was to evaluate the effect of mechanochemical technology on the efficacy of supramolecular complex of fenbendazole (SMCF) with polyvinylpyrrolidone (PVP) polymer against some helminthosis of animals.
Materials and Methods: The SMCF samples with PVP were synthesized using a solid-state mechanochemical technology in activators of impact-abrading type and their physicochemical properties were analyzed. The efficacy of SMCF was studied on the laboratory model of Hymenolepis nana and Trichinella spiralis infection of mice and helminthosis of sheep.
Results: In the trials conducted on laboratory models, the supramolecular complex showed 93.94% and 98.56 % efficacy at the dose of 1 mg/kg of body weight (b/w), while the substance of fenbendazole showed 7.97% and 8.33% efficacy at the same dose. A high efficacy (>94%) of the SMCF was revealed at the dose of 2.0 mg/kg of b/w at oral administration against nematodes in naturally infected sheep by the results of the fecal examination, while the substance of fenbendazole was active at the dose of 5.0 mg/kg at single oral administration. Moreover, the SMCF demonstrated 97.37% efficacy at the dose of 2 mg/kg against Moniezia spp. infection of sheep. Physicochemical studies confirmed the increase in solubility of the complex, reducing of particle sizes, amorphization of fenbendazole substance, and incorporating it with micelles of PVP.
Conclusion: According to the results, supramolecular complex of fenbendazole with PVP was more active than the basic substance of fenbendazole and its anthelmintic properties were expanded. [J Adv Vet Anim Res 2019; 6(1.000): 133-141]
A facile and efficient visible-light-mediated method for directly converting sulfides into sulfoxides under clean conditions without using any photocatalysts is reported. This method exhibited favourable compatibility with functional groups and afforded a series of sulfoxides with high selectivity and yields. Moreover, in order to shed more light on such a transformation, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and eco-friendly nature of the developed method will endow it with attractive applications in chemical synthesis.
The aim of the study was to enhance the solubility and bioavailability of praziquantel (PZQ) through mechanochemical preparation of its solid compositions with the disodium salt of glycyrrhizic acid (Na2GA). The compositions were studied in the solid phase by means of scanning electron microscopy, powder X-ray diffraction and thermal analysis, and in solutions by means of HPLC, gel permeation chromatography, phase solubility assay and ¹H NMR spectroscopy. PZQ permeability was studied by means of parallel artificial membrane permeability assay and with a monolayer of Caco-2 cells. The pharmacokinetic characteristics and acute toxicity of PZQ and its compositions were studied on mice. Solubility of PZQ in the compositions increases up to 3.5 times. The micelles in Na2GA solutions possess a molecular mass of ∼60 kDa. An increase in PZQ solubility may be due to its inclusion into micelles of glycyrrhizic acid. The permeability of PZQ was found to be much higher from its composition with Na2GA in comparison with initial PZQ. An increase in PZQ bioavailability by a factor of 3 in laboratory mice and changes of pharmacokinetic curve shape were demonstrated for the oral administration of its composition with Na2GA. The solid compositions show high chemical stability under rapid storage test. The obtained PZQ compositions may be a promising basis for the development of anthelmintic preparations with increased efficiency.
Niclosamide is an anthelmintic that is widely used to treat cestode infection of animals. The efficacy of the supramolecular complexes of niclosamide obtained by mechanochemical technology and targeted delivery was studied in hymenolepiosis of mice and monieziosis of sheep. The efficacy of new substances of niclosamide with polyvinylpyrrolidone polymer in different ratios (1:10; 1:5; 1:2) was determined by the results of helminthological necropsy of the small intestine of sheep and mice. Pre-treatment eggs per gram (EPG) were not significantly different (P > 0.1) among groups. The controlled test was used to evaluate the efficacy. A high efficacy (>95% efficacy) of the supramolecular complexes of niclosamide with PVP (SCoNwPVP) was shown in different ratios (1:10; 1:5 and 1:2) at a dose of 20 mg/kg of body weight at oral administration against Hymenolepis nana in mice and Moniezia expansa in sheep. Whereas the basic drug − substance of niclosamide was effective at a dose of 100 mg/kg of b/w. No adverse effects of the drugs on animal health were detected during the study.
Inclusion complexes of albendazole (ABZ) with the polysaccharide arabinogalactan from larch wood Larix sibirica and Larix gmelinii were synthesized using a solid-state mechanochemical technology. We investigated physicochemical properties of the synthesized complexes in the solid state and in aqueous solutions as well as their anthelmintic activity against Trichinella spiralis, Hymenolepis nаna, Fasciola hepatica, Opisthorchis felineus, and mixed nematodoses of sheep. Formation of the complexes was demonstrated by means of intrinsic solubility and the NMR relaxation method. The mechanochemically synthesized complexes were more stable in comparison with the complex produced by mixing solutions of the components. The complexes of ABZ showed anthelmintic activity at 10-fold lower doses than did free ABZ. The complexes also showed lower acute toxicity and hepatotoxicity. These results suggest that it is possible to design new drugs on the basis of the ABZ:arabinogalactan complex that are safer and more effective than albendazole.
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- В А Марченко
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Создание антигельминтных препаратов повышенной эффективности на основе межмолекулярных комплексов действующих веществ с водорастворимыми полимерами, в том числе с полисахаридами // Химия в интересах устойчивого развития
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