Today, the pharmaceutical industry is on the cusp of a “digital renaissance”, where artificial intelligence (AI) and science complement each other. The use of bioinformatics, machine learning, and AI unlocks new opportunities for optimising all stages of the medicinal product lifecycle and reducing the time and costs of drug development. Engaging in joint initiatives with academic institutions, which have consolidated the infrastructure for fundamental research, contributes significantly to the development of innovative medicinal products and shortens the research and development timelines. For drug developers selecting a direction for biological target identification, it is of importance to follow the vectors of national projects, which aim to foster technological sovereignty in the manufacturing of pharmaceuti­cals, advanced therapy medicinal products, and medical devices. This publication is a paired interview with Lyudmila I. Shcherbakova, President of Velpharm Group, and Pyotr P. Rodionov, General Director of GEROPHARM. In this interview, they analyse key technology trends shaping the landscape of the pharmaceutical industry and discuss current trends and prospects in drug development, such as the use of AI.

INTRODUCTION. Metal–organic frameworks (MOFs) as novel drug delivery systems are a promising area of research, primarily due to their potential for targeted drug delivery. Over the past few years, there have been numerous publications on the development of novel carriers for drug delivery, and intellectual property rights for these carriers have been secured through patents.

AIM. This study aimed to analyse the global practices in the use of MOFs as experimental drug delivery systems in order to assess the applicability of MOFs in the pharmaceutical industry and evaluate the readiness of existing technologies for practical application.

DISCUSSION. A comprehensive patent search was conducted to identify MOF-based drug delivery systems. As a result, the author formed a collection of 890 patents and used 442 patents that were active at the time of the study for further research. The author examined the geography of patenting and identified the most active patent holders of recent years. Furthermore, the research classified medicines loaded into MOFs, with an additional detailed analysis of MOF loading with antitumour agents as the most developed area. The analysis of antitumour agents considered examples of combination therapies using MOFs. In addition, this study characterised MOFs loaded with prodrugs and bioactive molecules.

CONCLUSIONS. The patent landscape, dominated by educational institutions, reflects a limited amount of preclinical data and a lack of significant commercial interest in MOF-based drug delivery systems. Key barriers to the development of MOF-based drug delivery systems are the toxicity of materials, the challenges associated with biocompatibility and loading efficiency, and the need for clinical trials to confirm the safety and effectiveness of MOFs as drug delivery systems.

INTRODUCTION. Phosphodiesterases (PDEs) are enzymes that regulate intracellular signalling by catalysing the hydrolysis of cyclic nucleotides. The commercial success of selective PDE5 inhibitors for erectile dysfunction and PDE4 inhibitors for respiratory and skin diseases has drawn the close attention of pharmaceutical companies to other PDEs as well. PDE10A, which is expressed in medium spiny neurons (MSNs) of the striatum, deserves special attention as a promising target in psychopharmacology.

AIM. This study aimed to analyse existing preclinical and clinical data on the use of PDE10A inhibitors and to assess possible barriers to the development of medicinal products of this class in neuropsychopharmacology.

DISCUSSION. Preclinical studies have shown that PDE10A inhibitors, which increase the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in MSNs, have antipsychotic and antiparkinsonian properties. Some researchers also believe that PDE10A inhibitors improve cognitive functions. Despite the promising results of preclinical studies, clinical trials of PDE10A inhibitors have not been successful. This review analyses the possible reasons for these failures, including a poor understanding of the function of striatal PDEs in both normal and pathological conditions, the possible development of tolerance to some effects of PDEs, the complex interactions of intracellular cAMP and cGMP signalling pathways, and the intricate workings of the cortico-striato-thalamo-cortical (CSTC) circuits.

CONCLUSIONS. Further research is needed to fully assess the therapeutic potential of PDE10A inhibitors, with a more detailed investigation of the mechanism of action of PDEs, the activity of MSNs, and the CSTC circuits. New data at these three levels of study (subcellular, cellular, and systemic) will create conditions for further development of PDE10A inhibitors.

INTRODUCTION. Quality by design (QbD) is a systematic approach to pharmaceu­tical development that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management. The QbD approach facilitates the production of medicinal products with target characteristics and quality profiles. There are currently no specific guidelines for the application of QbD principles to the development of individual dosage forms.

AIM. This study aimed to evaluate the possibility of and propose an algorithm for using QbD at the laboratory stage of pharmaceutical development for solid dosage forms, with tablets as a case study.

MATERIALS AND METHODS. This study analysed publicly available regulatory documents, scientific publications, and guidelines on pharmaceutical development using general scientific methods, including comparative and logical analysis. The regula­tory documents analysed included those issued by the International Council for Harmonisation (ICH), the Eurasian Economic Commission, and the State Pharmacopoeia of the Russian Federation. The sources searched included electronic databases, such as PubMed, Web of Science, eLIBRARY.RU, and Google Scholar.

RESULTS. Developing the quality target product profile (QTPP) and composition of tablets requires a comprehensive study of the active substance, as well as an assessment of its compatibility with the excipients. At the laboratory stage of pharmaceu­tical development, it is necessary to select and optimise the medicinal product composition while assessing potential risks. This approach provides for the preliminary identification of critical quality attributes, critical process parameters, and critical material parameters. This article presents an algorithm for applying QbD to tablet formulations at the laboratory stage of pharmaceutical development.

CONCLUSIONS. When implemented at the laboratory stage, the proposed algorithm with QbD elements will improve the overall efficiency of pharmaceutical development.

INRODUCTION. The traditional technology of layering components onto sugar gra­nules to produce medicinal products in the form of dragees has a number of disadvantages, including labour intensity, as well as the exposure of intermediates to liquids and high temperatures at certain production stages, which reduces the stability and effectiveness of the resulting medicinal products.

AIM. This study aimed to develop an alternative technology for producing coated spherical tablet cores, with a multivitamin product as a case study.

MATERIALS AND METHODS. The active ingredients used were retinol acetate, ascorbic acid, thiamine hydrochloride, and riboflavin. The excipients used included fillers (glucose, sorbitol, isomalt, and microcrystalline cellulose), glidants (talc and magnesium stearate), coating components (hydroxypropyl methylcellulose and titanium dioxide), etc. Tablet masses were produced by mixing accurately weighed amounts of active substances and excipients in a mixer for powdered materials. Individual tablet cores and tablets were weighed using a Shimadzu UW220H labo­ratory balance. They were tested for resistance to crushing using an Erweka TBH 125 tablet hardness tester. The content of water-soluble vitamins was determined by high-performance liquid chromatography (HPLC) in accordance with analytical procedures developed for Revit dragees by Uralbiofarm JSC. The labour intensity of multivitamin manufacturing technologies was estimated as the time required to produce a package of 100 dragees (by production process stage), and their efficiency was evaluated based on the process yield.

RESULTS. As an alternative to the traditional technology for producing dragees, the authors developed a new direct compression and coating technology involving the use of 7.0 mm concave punches with a 4 mm curvature radius to obtain spherical tablet cores for coating. Pilot-scale industrial tests confirmed smooth equipment operation and compliance of tablet cores/finished medicinal products with the applicable regulatory requirements. This study demonstrated the possibility of producing spherical tablet cores with a mass of 0.27±0.01 g, friability of 0.6±0.1%, disintegration time of 4.3±1.2 min, and resistance to crushing of 48.2±7.4 N. Subsequent coating of tablet cores resulted in finished medicinal products indistinguishable in appearance from traditional dragees. The yield of finished medicinal products was 87.14% for sugar-coated tablet cores and 91.07% for suspension-coated tablet cores. The study showed the traditional technology for producing dragees to be 1.8 times more labour intensive than direct compression and coating of tablet cores. Compared with vitamins formulated as traditional dragees, sugar-coated and suspension-coated tablet cores exhibited superior stability over 12 months.

CONCLUSIONS. The direct compression technology proposed for producing spherical tablet cores for subsequent coating instead of the traditional dragee technology will increase production efficiency, improve the stability of active components during storage, and reduce the duration and labour intensity of the production process. The proposed technology can be recommended to dragee manufacturers for implementation in industrial production.

INTRODUCTION. Syrups are an important dosage form used in medical practice, particularly in paediatrics. As of January 2024, there are 212 medicinal products formulated as syrups approved in the Russian Federation. The effi­cacy, safety, and quality of syrups are determined by their composition, including excipients.

AIM. This study aimed to analyse and systematise data on the role and safety of excipients in syrups included in the Russian State Register of Medicines.

DISCUSSION. This article reviews the major groups of excipients present in syrups, including sweeteners, preservatives, solvents, thickeners, pH modifiers, buffering agents, antioxidants, and colourants. The most prevalent group of excipients is sweeteners, including sucrose (66.51%), sorbitol (29.25%), and sodium saccharin (10.85%). Sucrose contributes to tooth decay and is contraindicated in patients with diabetes and obesity. Sorbitol may cause gastrointestinal disorders. Data on the long-term safety of artificial sweeteners are contradictory. Therefore, sweeteners should be selected rationally. The most widely used preservatives are parabens, including methylparaben (31.60%) and propylparaben (20.28%). Propyl­paraben exhibits potential oestrogenic activity, which makes methylparaben the para­ben of choice. Solvents and co-solvents include water, glycerol (25.94%), ethanol (24.53%), and propylene glycol (20.75%). Ethanol and propylene glycol can cause severe central nervous system disorders. The most commonly used thickener is hydroxyethyl cellulose (5.19%). Cellulose derivatives are considered safe but may have a laxative effect if consumed in excess. The most popular colourant is Sunset Yellow (7.54%). The lack of data on the safety of many colourants emphasises the need for their rational selection.

CONCLUSIONS. By analysing summaries of product characteristics and patient information leaflets for syrups available in the Russian State Register of Medicines, the authors have systematised data on the role, safety, and acceptable daily intake of excipients in used syrups, classified these excipients, and calculated the frequency of their use. The findings suggest that the current approaches to selecting excipients for syrups should be revised to minimise potential risks and to enhance the safety of medicinal products.

INTRODUCTION. Polymyxin B is a natural multicomponent antibiotic used in its sulfate form for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. Pharmacopoeial standards for polymyxin B medicinal products include limits for the sum of polymyxins B1, B2, B3, and B1-I and for individual polymyxins B3 and B1-I. Since polymyxins B1 and B2 differ in their nephrotoxicity, it is important to establish individual limits for their content in polymyxin B medicinal products. Establishing individual limits for polymyxins B1 and B2 requires determining the component composition of various polymyxin B samples. However, high-performance liquid chromatography (HPLC) may not always provide accurate results because of the lack of reference standards for individual polymyxin B components.

AIM. This study aimed to investigate the possibility of quantifying polymyxins B1, B2, B3, and B1-I in polymyxin B medicinal products by nuclear magnetic resonance (NMR) spectroscopy.

MATERIALS AND METHODS. The study focused on a reference standard for polymyxin B sulfate, as well as polymyxin B medicinal products from different manufacturers. NMR measurements were performed on an Agilent DD2 600 MHz NMR spectrometer. The study used high-performance liquid chromatography (HPLC) on an Agilent 1200 HPLC system as the reference method.

RESULTS. The 13C NMR spectrum contained signals characteristic of polymyxins B1, B2, B3, and B1-I. The authors determined the mole fractions of polymyxins B1, B2, B3, and B1-I by the internal normalisation method using the integrated intensities of the characteristic NMR signals. The results of NMR and HPLC quantification of the specified components in polymyxin B samples practically coincided (with due regard to the confidence intervals).

CONCLUSIONS. According to the results, the 13C NMR analytical procedure can identify and quantify the major active components in polymyxin B sulfate medicinal products without reference standards for individual polymyxins.

INTRODUCTION. The median lethal dose (LD₅₀) and the low lethal dose (LD₁₀) are critical parameters for the safety of medicinal products. Sometimes, the pharmacopoeial probit method (PM) fails to calculate the LD₁₀ value, and the calculation result is obviously lower than the true value. In such cases, the use of other computational techniques is warranted.

AIM. This study aimed to evaluate the potential of a script in the R environment as a tool for calculating the LD₅₀ and LD₁₀ of medicines.

MATERIALS AND METHODS. This study compared the results of determining LD₅₀ and LD₁₀ using the spreadsheet-based pharmacopoeial PM and a modified script in the R environment (MS). The lm() function (linear regression model) was used to establish the relationships between the LD50 and LD₁₀ values obtained using the PM and those calculated using the MS.

RESULTS. A script originally developed by S. Young for LD50 calculation was modified and supplemented to simplify its use. The modification reduced the amount of input data required for calculation, added the ability to calculate LD₁₀ values, and improved the visual clarity of the calculation results. Reducing the step size for the seq() function was shown to improve the output smoothness when the MS yielded a jagged mortality curve. The MS-derived LD₅₀ values were within the confidence limits for the values obtained using the PM (P=0.95). The regression analysis confirmed the accuracy of the MS-based LD₅₀ and LD₁₀ calculations, which was demonstrated by a statistically insignificant systematic error, a significant dose dependence at P=0.999, and a high coefficient of determination (R²). If the PM underestimates LD₁₀ values, the analyst should be guided by the LD₅₀ and LD₁₀ values calculated using the MS.

CONCLUSIONS. The experimental data demonstrate the applicability of the MS for testing medicines. In some cases presented in the article, the custom R script offers an advantage over the current pharmacopoeial method. A tentative direction for further work may be the automation of the MS-based LD₁₀ calculation.

INTRODUCTION. According to the literature, alcoholic extracts of Nonea rossica Steven have anticoagulant, antimicrobial, and antifungal properties, which may be due to the presence of caffeic acid and its derivatives in the plant. The standardisation of this herbal drug requires the development of an analytical procedure for the quantitative determination of caffeic acid, and the most promising method for this is high-performance liquid chromatography (HPLC).

AIM. This study aimed to develop and validate an analytical procedure for the quanti­tative determination of caffeic acid in Nonea rossica herb by HPLC.

MATERIALS AND METHODS. The study focused on the aerial parts of Nonea rossica plants collected in a steppificated meadow in the Novosibirsk Region during the flowering stage. The study used an Agilent 1100 Series HPLC system equipped with a Zorbax SB-C18 column (150 × 2.1 mm, 3.5 μm) and a detector operating at a wavelength of 330 nm.

RESULTS. The authors selected chromatographic conditions to obtain one peak per one molecular form of caffeic acid, an acceptable resolution of the extract components, and the maximum intensity of the analyte peak. The gradient elution conditions developed in this study were as follows: a two-component mobile phase, including a 0.01 M aqueous solution of KH2PO4 with a pH of 2.70 (Solvent A) and methanol (Solvent B), and a flow rate of 0.25 mL/min. Under these conditions, caffeic acid eluted at 13.5 minutes, and the total analysis time was 60 minutes. The analytical procedure was validated for its specificity, analytical range, detection limit, quantitation limit, accuracy, repeatability, and intralaboratory precision.

CONCLUSIONS. The developed and validated analytical procedure for the quantita­tive determination of caffeic acid in Nonea rossica herb by HPLC provides results with a relative standard deviation of ≤5.0%. The analytical procedure can be used to standardise the herbal drug Noneae rossicae herba for further use in medicinal practice.

INTRODUCTION. Chronic constipation is a widespread condition associated with substantial direct and indirect costs for diagnosis and treatment and a significant reduction in the quality of life of patients. There is a need for the development and clinical studies of novel medicinal products for chronic constipation due to the limited availability of effective treatment options and concerns regarding the long-term safety and tolerability of these options. Currently, the Russian Federation and other Member States of the Eurasian Economic Union (EAEU) lack guidelines governing the design and conduct of clinical trials of new medicinal products for chronic constipation.

AIM. This study aimed to analyse the relevant international approaches and methods as a potential basis for drafting a regional guideline for planning clinical trial programmes for novel medicinal products for chronic constipation.

DISCUSSION. This study analysed the main provisions of the European Medicines Agency (EMA) outlined in the Guideline on the evaluation of medicinal products for the treatment of chronic constipation (including opioid-induced constipation) and for bowel cleansing. The authors identified special considerations for conducting pharmacology studies and confirmatory clinical trials (selection of the clinical trial population, design, and duration; selection of primary and secondary efficacy endpoints; and safety assessment). Additionally, the authors highlighted special considerations for confirmatory clinical trials in paediatric and geriatric populations.

CONCLUSIONS. The EMA guideline covers all the requirements that are necessary for designing a clinical trial programme for a novel medicinal product for chronic constipation. Therefore, the EMA guideline can inform the ongoing development of the corresponding guideline for the Russian Federation and other EAEU Member States.