Study of wound-healing activity of sodium 2-(adamantane-1-yl)-2-hydrazino-5-phenyl-4-oxobutanoate

Objective. To study a wound-healing activity of the earlier synthesized compound-leader sodium 2- (adamantan-1-yl)-2-hydrazino-5-phenyl-4-oxobutenoate (1), as well as to establish the possibility of its practical application in the ointment dosage form. Materials and methods. The substance-leader 1 was synthesized by the chemical methods described earlier. The experimental 5 % ointment composition based on an aqueous solution of sodium alginate was developed in compliance with the rules for preparing homogeneous ointments. Its effect on the healing of linear aseptic skin wounds in white rats was studied by the method of wound-tensiometry. Results. The experimental 5 % ointment composition with compound 1 was found to significantly increase the scar tensile strength compared to control without treatment. The developed model ointment showed wound-healing activity comparable to that of the reference drug (Levomekol ointment). Conclusions. The selected substance-leader 1 in the composition of a model 5 % hydrophilic ointment based on sodium alginate exhibits pronounced biological activity and is a candidate for further research as a potential pharmaceutical substance with complex wound-healing and anti-inflammatory property.

Standardization of the Pharmaceutical Substance of the Drug LCS-1208

Introduction. Indolocarbazole derivatives are of increasing scientific interest for practical oncology. A number of N-glycosides, indolo[2,3-a] carbazole under the laboratory code LCS, were synthesized in the laboratory of chemical synthesis of the National Medical Center of Oncology named after N.N. Blokhin. Currently, one of the most promising compounds in this class is LCS-1208, a representative of the arabinoside class of indolo [2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione. According to the mechanism of biological action, LCS-1208 is a protein kinase C inhibitor and is of great interest for the treatment of malignant neoplasms.Aim. chemical and pharmaceutical standardization of the pharmaceutical substance LCS-1208.Materials and methods. Laboratory samples of pharmaceutical substance LCS-1208. Methods of investigation: gravimetry, spectrophotometry, polarimetry, high-performance liquid chromatography (HPLC), high-resolution nuclear magnetic resonance (NMR) spectroscopy and infrared (IR) spectroscopy.Results and discussion. The quality assessment of LCS-1208 was carried out according to the indicators adopted in the XIV edition of the State Pharmacopoeia of the Russian Federation for quality control of pharmaceutical substances. LCS-1208 - orange amorphous powder, odorless; soluble in dimethylsulfoxide (DMSO) and dimethylformamide (DMF); very slightly soluble in 95 % ethyl alcohol and practically insoluble in water. The authenticity of the substance is confirmed by NMR and IR spectra, as well as electronic absorption spectra. The values of the specific optical rotation of LCS-1208 (1 % solution in DMF) are placed in the range from +58° to +61°. All the studied samples of the substance were free of inorganic impurities, sulphate ash, heavy metals and contained no more than 1.0 % water, determined by the K. Fischer titration method. The content of possible related impurities in the substance LCS-1208 and the content of the main active substance were determined by HPLC. The studied laboratory series of the pharmaceutical substance LCS-1208 contained no more than 1.0 % of any single and no more than 3 % of the total unidentified impurities. The content of the main active substance was more than 97 %.Conclusion. As a result of the work carried out, quality criteria and parameters were selected and methods for their determination were developed, which allow to adequately assess the quality and standardness of the pharmaceutical substance LCS-1208.

Modern Approaches to the Technology of Tablet Dosage Forms of Thioctic Acid (Review)

Introduction. Thioctic (α-lipoic) acid is an endogenous antioxidant and is used for liver diseases, poisoning with salts of heavy metals, hyperlipidemia, atherosclerotic heart disease, neuropathy, insulin-resistant forms of diabetes mellitus, etc. technologies for producing tableted medicinal preparations of thioctic acid, necessary for the pharmaceutical development of thioctic acid tablets at pharmaceutical industry enterprises.Text. The review considers the physicochemical properties of the pharmaceutical substance thioctic acid, the features of its pharmaceutical and technological properties, and compatibility with excipients. In the technology of thioctic acid tablets, methods of direct compression and compression with preliminary wet granulation, including those using organic solvents, are used. To increase photostability, thioctic acid tablets are coated. Information on excipients in the composition of core tablets and film coat of thioctic acid tablets registered in Russia is presented. The problems of tabletting thioctic acid are described: sintering of the granulate during the drying process, adhesion of the tabletting mass to the pressing tool and the resulting unevenness of the tablet surface. The ways of optimizing the tabletting process of thioctic acid using various compositions of excipients, improving the flowability of a pharmaceutical substance both during its synthesis and as a result of technological processing, choosing the optimal modes of granulation, drying, pressing are considered.Conclusion. As a result of the analysis of the literature data, the features of the technology for producing thioctic acid tablets were revealed, which are due to the high content of the pharmaceutical substance in tablets (up to 600 mg), the need to use a minimum amount of excipients (from 27 to 51 %), poor flowability, and low melting point of the pharmaceutical substance. Improvement of compressibility and prevention of adhesion can be achieved by using the pharmaceutical substance thioctic acid of a certain granulometric composition, auxiliary substances of the basic nature and a high content of glidants (up to 6 %). The identified manufacturing features should be taken into account in the pharmaceutical development of thioctic acid tablets.

THE DEVELOPMENT OF BISCHOFITE ANTI-SCAR GEL COMPOSITION

The development of an external gel containing purified bischofite will allow the scars treatment in the stage of prevention and formation due to the effect on various links of pathological wound healing. This study’s aim was the development of a gel with bischofite for the scars prevention and treatment. Bischofite brine from the purified Volgograd deposit was selected as the active pharmaceutical substance. Polymer gelling agents: methylcellulose-100, sodium carboxymethyl cellulose, hydroxymethyl cellulose, aerosil, Tizol®. The QTPP requirements for developed bischofite gel are aimed at effective wound healing and prevention of pathological scarring, which corresponds to the ointments used at the III stage of the wound process. Comprehensive technological studies of model samples of gels with bischofite were carried out: determination of external signs and the application to the skin, smearing, thermal stability and pH, study of osmotic activity and release of bischofite (in terms of magnesium ions). The maximum amount (8 points) was observed in the composition using the Tizol® gel-forming agent, the model sample based on it provided the maximum degree of release, minimal osmotic activity, and good smearing. In addition, Tizol® possesses anti-inflammatory activity. The optimal concentration of the aqueous phase is justified by the assessment of the consistency properties, the spreadability and rheological properties. Thus, as a result the composition of the bischofite gel was developed using Tizol® as a base, containing glycerin as a plasticizer and a moisture agent, the preservative sodium benzoate and purified water.

ACUTE TOXICITY OF A NEW BENZIMIDAZOLE DERIVATIVE WITH ANTITHROMBOGENIC PROPERTIES

The paper presents the results of studying the toxicological profile of a new pharmaceutical substance RU891 with antithrombogenic properties. The minimum toxic dose (TDmin) for RU-891 by peroral administration is 230 mg/kg < TDmin ≤ 460 mg/kg. In experiments on the acute toxicity of the compound RU-891, the nature and severity of its damaging effect on the body of experimental animals were established and the safety of its action was evaluated. When studying the toxic effect of the test sample, the tolerated and toxic doses of RU-891 were determined, and the most sensitive organs and systems of the body were identified.

STUDY OF THE STABILITY OF THE SUBSTANCE 3-[2-(4-PHENYL-1-PIPERAZINO)-2-OXOETHYL]QUINAZOLINE-4(3Н)-ONE UNDER STRESSFUL CONDITIONS

The aim of the research was to study the stability of a new pharmaceutical substance 3-[2-(4-phenyl-1-piperazino)-2-oxoethyl]quinazoline-4(3Н)-one under stress conditions.Materials and methods. The study was conducted in accordance with the recommendations of the ICH guidelines. The object of the study was a previously unknown derivative of quinazoline-4(3H)-one: 3-[2-(4-phenyl-1-piperazino)-2-oxoethyl] quinazoline-4(3Н)-one synthesized in Volgograd state medical university. The following laboratory equipment was used: HPLC chromatograph, HPLC-MS, centrifuge, electronic scales, pH meter, thermostat, laboratory filters. The computational experiment was conducted on a computer with an Intel Xeon E3-1230 processor using the programs ORCA 4.1. and GROMACS 2019.Results. The influence of the most unfavorable environmental factors, such as high temperature, light, oxidants, hydrolysis in acidic and alkaline environments, affect the stability of the test substance. The results of the computer-based stability prediction were confirmed by HPLC and HPLC-MS, and the degradation products of the substance under stressful conditions were determined. The conducted studies showed that the test substance is stable to UV radiation at the wavelength of 365 nm, at the elevated temperature (80°C), to the action of oxidants. But it is unstable to hydrolysis: in an alkaline medium of sodium hydroxide 1M, a break in the amide group occurs with the formation of 2-(4-oxoquinazoline-3-yl)acetic acid and 1-phenylpiperazine. And in an acidic environment, hydrochloric acid 1M is also destroyed, but it is significantly reduced, presumably due to the protonation and stabilization of tertiary nitrogen atoms in the molecule.Conclusion. The conducted research makes it possible to conclude that the test substance 3-[2-(4-phenyl-1-of piperazino)-2-oxoethyl]quinazoline-4(3Н)-one is stable to aggressive environmental factors, with the exception of hydrolysis in an alkaline environment that will be further considered in the preparation of regulatory documents for this pharmaceutical substance.

The comparison of methods for the quantification of the pharmaceutical substance bismuth subsalicylate by UV-spectrophotometry and stripping voltammetry

The results of a comparative study of methods for the quantitative determination of the active pharmaceutical substance (APS) bismuth subsalicylate by UV-spectrophotometry and stripping voltammetry (SV) are presented. Partial validation of the compared methods was carried out according to the following characteristics: linearity, detection limit, limit of quantification, accuracy. In the course of linearity assessment, the values of the correlation coefficient of the methods were established — 0.9987 for UV-spectrophotometry and 0.9982 for SV. The detection limit and the limit of quantification for UV-spectrophotometry were 2.35 and 7.12 μg/ml respectively, for SV — 1.16 and 3.52 μg respectively. The accuracy was determined by the constant term of the linearity equation, which was 3.34% of the interval’s middle value when analyzed by UV-spectrophotometry and 1.93% by SV. Thus, both methods can be used for the quantitative determination of the APS of bismuth subsalicylate; however, due to the fact that the content of bismuth is mainly determined in this case, the SV method is more preferable since it allows analyzing this particular part of the molecule.

Development of soft dosage forms of pyrimidine derivatives based on carbopols

In the process of improving the technology for obtaining and expanding the range of dosage forms of known pharmaceutical substances, an important aspect is to reduce side effects and ensure ease of use. At the same time, medicines should provide the most important properties of pharmaceutical substances, namely, their most rapid and complete release from the base of the dosage form and penetration into the target organ, which should serve as factors in justifying formulations and technologies of effective and safe medicines [3, 4]. Due to the lesser manifestation of side effects and ease of use, soft dosage forms (gels, ointments) are among the most demanded dosage forms on the modern pharmaceutical market. The trend towards replacing hydrophobic bases in soft dosage forms with hydrophilic ones has been traced in pharmacy for quite a long time, since gels provide higher efficiency in application due to better penetration of pharmaceutical substances through the skin barrier relative to hydrophobic ointments. The presence of a polymer-gelling agent in gels determines not only the rheological properties of medicines, but also allows a highly dispersed solid phase of a pharmaceutical substance to be included in the network structure of a polymer and to maintain the dispersion of a pharmaceutical substance poorly soluble in water during storage. Methyluracil, also known as dioxomethyltetrahydropyrimidine, is a derivative of pyrimidine, a structural element of nucleic acids and is used in the treatment of diseases of various etiologies, mainly to improve the course of regeneration in damaged tissues. A significant disadvantage of methyluracil is its low solubility in water, which significantly affects the degree of release of the pharmaceutical substance from the base of the drug [1]. Due to the lack of methyluracil gels on the pharmaceutical market, their development using acrylic acid derivatives in order to improve the biopharmaceutical properties of a pharmaceutical substance is an important problem in pharmacy.