A. N. Vorobiev

Cocktail" test systems are used for phenotyping the metabolic activity of human cytochrome P450 isoenzymes. The vast majority of "cocktails" for phenotyping include caffeine, based on data on the metabolism of which the activity of the CYP1A2 isoenzyme is determined. The use of pellets as a dosage form consisting of many particles for "cocktail" test systems makes it easy to change the composition and dosage of the test system depending on the needs of CYP research, and also provides easier acceptance of the test system by the patient in geriatric studies. Aim. Development of pellets containing caffeine for a "cocktail" test system using the methodology of a complete factor experiment. Materials and methods. Pellets containing caffeine (Shandong Xinhua Pharmaceutical Co., Ltd., China) were manufactured by extrusion-spheronization in the ESI 25 apparatus (Tofflon, China). The obtained pellets were subjected to technological tests in accordance with the GF of the Russian Federation XV. The quality of the pellets obtained and their dissolution profile were evaluated. Results and discussion. With the help of a complete factorial experiment, the optimal composition of pellets was selected, the optimal amount of granulating liquid was selected, and the parameters of the extrusion-spheronization process were worked out. Conclusion. As a result of the conducted research, the composition and technology of production of caffeine pellets for the cocktail test system were developed using a complete factorial experiment. A technological scheme for the production of pellets has been developed. Optimal conditions for humidification of the pellet mass were selected for the extrusion-spheronization technology.

Разработка таблеток для приема внутрь на основе дигидрокверцетина и оценка их общетоксического действия

The possibility of using arabinogalactan in the preparation of oral tablets based on the natural bioflavonoid dihydroquercetin has been shown. The composition and technology of tablets using the wet granulation method has been developed. The quantitative content of dihydroquercetin in tablets was determined by HPLC. Aim. Development the composition and technology of dihydroquercetin tablets for oral administration using arabinogalactan.

Dihydroquercetin (DHQ) is a bioflavonoid from the flavonol group with a wide spectrum of pharmacological activity. Antioxidant, strengthens the walls of blood vessels. Medicinal product based on dihydroquercetin for topical use. Aim. Development of a dosage form of dihydroquercetin in the form of a gel for topical use and evaluation of its physicochemical properties, general toxic effects and safety. Materials and methods. The gel was obtained on an EKROS PE-8100 laboratory overhead stirrer (EKROS, Russia). The substance of dihydroquercetin of the LLC "Chemistry of Woods" company was used. Dimethyl sulfoxide, glycerin, and polyethylene glycol 400 were used as solvents for the active substance. Gelling agents were used, such as: hydroxyethyl cellulose, carbomer brand Carbopol Ultrez 10, poloxamer 407, polymer compositions of the French company Seppic Sepineo p600 and Sepineo Derm. Benzyl alcohol and sodium benzoate are used as antimicrobial preservatives. Trilon B was used as a stabilizer. Purified water served as a dispersion medium. Aggregate stability of the gels was evaluated according to GOST 29188.3-91 COSMETIC PRODUCTS [1]. Colloidal stability - on the centrifuge of the laboratory brand PE-6906. Thermal stability was determined by thermostating the gel samples in an electric dry-air thermostat of the TS-1/20 SPU brand. Dynamic viscosity was determined on a Brookfield DV3T rotational viscometer [2]. The release of DHQ from the model gel compositions was determined by L. The content of DHQ in the dialysate was determined by HPLC (n=5) [3]. Results and discussion. The solubility of the substance of dihydroquercetin was determined for the implementation of the technological process for the manufacture of a gel based on it with increased bioavailability. Chromatography conditions were selected for the determination of dihydroquercetin in the gel by HPLC-UV. The safety and absence of a local irritant effect were established with the use of 2% dihydroquercetin gel. Conclusion. As a result of the research, the composition and technology of a 2% dihydroquercetin gel for topical use have been developed. A technological scheme for obtaining the gel has been developed. The results of the toxicity study of 2% dihydroquercetin gel showed that the gel is non-toxic and safe drug.

Introduction. Treatment of infectious and inflammatory diseases demands active substances (AS), characterized by low resistance of microorganisms, high specificity of the mechanism of action and a wide range of antimicrobial activity. Though furazolidone (FZ) – AS meets these criteria, however, practically insolubility in water significantly limits its use. Use of the solid dispersion method (SD) could increase the solubility and dissolution rate of AS with low water solubility. revious studies indicate an increase in the solubility and dissolution rate of FZ in water from SD with polyvinylpyrrolidone-24 000 (PVP-24 000) in a ratio with AS > 6 : 1 by weight. As a result, it becomes possible to introduce SD FZ into the composition of rapidly dissolving effervescent dosage forms, for example, granules for obtaining solutions for external use for the treatment of infectious and inflammatory diseases.Aim. Development of the composition and technology for producing effervescent granules based on solid dispersions of FZ for obtaining a solution for external use.Materials and methods. FZ substance, polyvinylpyrrolidone-24 000 ± 2000 (PVP-24 000 ± 2000), tartaric acid, malic acid, sodium carbonate anhydrous, ethyl alcohol 96 %, purified water. We provided the granules through fluidized bed granulation. The analysis of the obtained granules included the following parameters: description, granule size, loss in mass on drying, disintegration, uniformity of dosage according to GPМ 1.4.1.0004.15 "Granules". Then followed a qualitative and quantitative determination of AS and analysis of the pH of the aqueous solution of the granules. To study the stability and shelf life of the samples of granules, we laid them to the storage in accordance with GPМ 1.10009.15 "Stability and shelf life of drugs".Results and discussion. We developed he composition and technology of FZ effervescent granules for obtaining a solution for external use. Granules are obtained by separate granulation of the main (containing a SD AS) and acid components, followed by mixing in ratios that provide a solution of FZ with a concentration of 0.004 % in water at room temperature. Later we assessed the quality of the obtained compositions and determined, the shelf life (2 years) and storage conditions (in a dry, dark place at a temperature of 25 °C) of the developed compositions of granules.Conclusion. As a result of technological and chemical-pharmaceutical research using the SD method, we developed a new FZ dosage form – effervescent granules, which makes it possible to obtain an aqueous solution with a concentration of FZ 0.004 % in less than 5 minutes without heating. Based on the results of the work, an application was filed with Rospatent No. 2021105988 dated 10.03.2021, "Fast-dissolving dosage form of furazolidone and a method for its production".

The aim of the work is to study the effect of solid dispersions using polyethylene glycols of various molecular weights on the solubility of metronidazole in water. Metronidazole is an antimicrobial and antiprotozoal drug. Its low solubility in water limits the use of metronidazole, causing technological difficulties and reducing its bioavailability. The solubility and release of the active substance from dosage forms can be increased using the solid dispersion methods. Solid dispersions are bi- or multicomponent systems consisting of an active substance and a carrier (a highly dispersed solid phase of the active substance or molecular-dispersed solid solutions) with a partial formation of complexes of variable compositions with the carrier material.Materials and methods. The substance of metronidazole used in the experiment, was manufactured by Hubei Hongyuan Pharmaceutical Technology Co., Ltd. (China). To obtain solid dispersions, polyethylene glycols of various molar masses – 1500, 2000 and 3000 g/mol – were used. The solid dispersions were prepared by “the solvent removal method”: metronidazole and the polymer were dissolved in a minimum volume of 96% ethyl alcohol (puriss. p.a./analytical grade) at 65±2°C, and then the solvent was evaporated under vacuum to the constant weight. A vacuum pump and a water bath were used at the temperature of 40±2°C. The dissolution of the samples was studied using a magnetic stirrer with heating, and a thermostatting device. The concentration of metronidazole was determined on a spectrophotometer using quartz cuvettes at the wavelength of 318±2 nm. To filter the solutions, syringe nozzles were used, the pores were 0.45 μm, the filter was nylon. Microcrystalloscopy was performed using a microscope with a digital camera. The optical properties of the solutions were investigated using a quartz cuvette and a mirror camera (the image exposure – 20 sec).Results. Obtaining solid dispersions increases the completeness and rate of the metronidazole dissolution. The solubility of metronidazole from solid dispersions increases by 14–17% in comparison with the original substance. The complex of physical-chemical methods of the analysis, including UV spectrophotometry, microcrystalloscopy and the study of the optical properties of the obtained solutions, makes it possible to suggest the following. The increase in the solubility of metronidazole from solid dispersions is explained by the loss of crystallinity and the formation of a solid solution of the active substance and the solubilizing effect of the polymer with the formation of colloidal solutions of metronidazole at subsequent dissolution of the solid dispersion in water.Conclusion. The preparation of solid dispersions with polyethylene glycols improves the dissolution of metronidazole in water. The results obtained are planned to be used in the development of rapidly dissolving solid dosage forms of metronidazole with an accelerated release and an increased bioavailability.

Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof (AUC_0–t, C_max, t_max, and k_a). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar AUC_0–t and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models.

Indomethacin, a non-steroid anti-inflammatory drug (NSAID), has been used in different spheres of medicine since the 1960s. It is successfully administered as an anti-inflammatory and pain-relieving medication in rheumatoid and other diseases. According to recent research, indomethacin may become a promising drug enhancing endogenous remyelination in patients with multiple sclerosis. Also, indomethacin affects cell proliferation and invasion, thus it is used to manage pancreatic cancer in patients with hyperglycemia. In addition, indomethacin can inhibit protein synthesis in colorectal carcinoma and other types of cancer cells. The article reviews modern indomethacin medications and the different dosage forms on the Russian pharmaceutical market. Indomethacin poor water solubility is one of the reasons for decreasing its biopharmaceutical characteristics. According to the conducted research, a prospective way to improve indomethacin solubility and bioavailability is the Solid Dispersion (SD) method. SDs are bi- or multicomponent systems consisting of the drug and the carrier. They are a highly dispersed solid phase of the drug or molecular-dispersed solid solutions with a partial formation of a variable composition complex and a carrier. The article provides a brief overview on different aspects of obtaining, investigating, and applying indomethacin SDs with various polymers.