Introduction. Sponges are the most widely used form of topical hemostatic agents. Regulatory requirements for sponges are often incomplete and do not cover some properties, especially at the pharmaceutical development stage. Aim. To evaluate the effect of polymers on the properties of hemostatic sponges. Materials and methods. The study used sodium carboxymethylcellulose (Na-CMC), sodium alginate, polyethylene glycol (PEG-6000), and a copolymer of methacrylic acid and ethyl acrylate (CMAEA). Samples were prepared by freeze-drying and evaluated for appearance, density, porosity, absorption capacity, swelling ratio, and swelling kinetics. Data normalization was performed to compare the results. Results and discussion. The appearance of the samples depended on the starting component. An increase in component concentration led to higher sponge density. Maximum porosity was observed in compositions containing 3 % PEG-6000 or CMAEA. The matrix-forming components showed similar absorption capacity, while the addition of synthetic polymers reduced this parameter. The swelling ratio decreased in the order Na-CMC > sodium alginate > PEG-6000/CMAEA, and the composition with 1 % Na-CMC showed the maximum swelling ratio. Conclusion. The effect of sponge components on appearance, density, porosity, absorption capacity, swelling ratio, and swelling kinetics was considered. The nature of the effect of individual components on specific physicochemical and mechanical properties of the sponges was determined. The results can be used to justify the choice of excipients in the development of hemostatic sponges.
Introduction. During the early stages of pharmaceutical development, selecting the optimal polymer carrier for a particular active pharmaceutical ingredient (API) is a crucial step in designing the composition of solid dispersions prepared by hot melt extrusion. Currently, there is no general approach for assessing the compatibility of components that combines an analysis of thermal characteristics with the mutual solubility of the API and the carrier. Existing predictive methods are not fully effective in achieving the desired results, which complicates product development and may lead to losses in the quality of solid dispersions. Aim. To develop an approach for assessing the effect of polymer carriers on quercetin solubility properties in order to select the composition of solid dispersions. Materials and methods. Objects: quercetin (Molekula Limited, UK), VIVAPHARM® PVP/VA 64 (PVPVA 64, JRS Pharma GmbH & Co. KG, Germany), Soluplus® (BASF, Germany), Kollidon® 17 PF (PVP K17, BASF, Germany), Kollidon® 25 (PVP K25, BASF, Germany), Kollidon® 90 (PVP K90, BASF, Germany), Kolliphor® P188 (poloxamer, BASF, Germany), and polyvinyl alcohol (PVA, VIVAPHARM® PVA 05 fine, JRS Pharma GmbH & Co. KG, Germany). Phase solubility of quercetin in aqueous solutions of polymer carriers was assessed using a modified Higuchi and Connors method. The quantitative content of quercetin was determined by UV spectrophotometry. The influence of variable factors was evaluated by multivariate analysis of variance (ANOVA); statistical analysis was performed in RStudio. Results and discussion. Using quercetin as the model API, an approach for selecting the optimal polymer carrier was proposed. It combines an analysis of thermal properties with an evaluation of mutual (phase) solubility. Two promising carrier candidates were identified: PVPVA 64 and Soluplus®. The highest phase association constant ( K s ) was observed for the quercetin — PVPVA system ( K s = 7400.27, R 2 = 0.9993), corresponding to a 243-fold increase in solubility compared with the initial value. In the Soluplus® system, the increase was 223-fold, with an association constant of 6673.30 ( R 2 = 0.9963). These results were supported by strong positive correlations between the effects of the carriers on quercetin solubility ( p -value < 0.001). Conclusion. When assessing the phase solubility of quercetin in PVPVA 64 solutions, the highest association constant values were obtained, indicating a strong tendency toward complex formation between the ligand and the polymer. The use of Soluplus®, which has limitations such as slow dissolution in warm water and high melt viscosity, complicates the extrusion process and is therefore not a priority. Based on the evaluation of the key characteristics of the polymer carriers that may affect the stability and solubility of the API, PVPVA 64 was identified as an effective carrier.
Introduction. The similarity factor f 2 (Moore & Flanner, 1996) remains the gold standard for assessing dissolution profile equivalence in pharmaceutical development, biowaiver procedures, and the justification of post-approval changes. However, the mathematical framework of this metric was conceived in the late 1990s strictly for routine quality control under complete dissolution conditions ( Q > 85 %). The international guideline ICH M13B establishes a threshold rule: dissolution profiles with less than 10 % release are deemed comparable without mathematical evaluation, whereas profiles exceeding 10 % release require calculation of f 2 (or Bootstrap f 2 ). Under non-sink conditions, typical for Biopharmaceutics Classification System (BCS) Class II and IV active substances in physiological media lacking surfactants, the f 2 metric loses sensitivity to relative kinetic discrepancies. Aim. To analyze the mathematical limitations of the similarity factor f 2 under incomplete dissolution, to perform a comparative evaluation of f 2 , the difference factor f 1 , and the Two One-Sided Tests (TOST) procedure, and to provide recommendations for statistical evaluation of comparative in vitro dissolution test (CIDT) data within the framework of EAEU regulations and the ICH M13B guideline. Materials and methods. Using a critical model CIDT scenario for a poorly soluble compound with mean dissolution profiles of the test product T = (6,0 %; 10,0 %; 13,0 %; 18,0 %); and the reference product R = (11.0 %;18.0 %; 22.0 %; 30.0 %); parallel calculations of f 2 and f 1 were performed in accordance with Annex 5 to the EEC Council Decision No. 85 dated November 3, 2016, along with an equivalence assessment on a relative logarithmic scale (TOST approach). Results and discussion. For the analyzed dataset, the f 2 metric was 52.49, formally satisfying the similarity criterion (f 2 ≥ 50), despite the reference product releasing 1.7—1.9 times faster and more completely than the test product. Conversely, calculation of the difference factor f 1 yielded 41.98 %, which is nearly three times higher than the regulatory threshold for acceptable difference (f 1 ≤ 15 %). The mean dissolution ratio T / R ranged between 54.55 % and 60.00 %, falling well outside the bioequivalence acceptance interval (80.00—125.00 %). This paradox arises from the absolute dimensionality of the Moore and Flanner metric, which is anchored to a 0—100 % scale and remains indifferent to substantial relative discrepancies at low analyte concentrations. Conclusion. Relying on f 2 within the range of incomplete dissolution (from 10 % to 30—40 %) introduces substantial regulatory and technical risks of concluding pseudo-equivalence between batches. When conducting CIDT for poorly soluble BCS Class II and IV compounds in physiological media without surfactants, a comprehensive statistical evaluation is required, including mandatory calculation of f 1 , application of TOST on a relative scale, and physiologically based pharmacokinetic (PBPK) modeling.
Introduction. Phytomedicines (PM) are medicinal products that contain at least one plant-based component with established pharmacological activity. The global PM market has demonstrated steady growth for many years. Despite growing demand, the Russian PM market remains understudied. Aim. To assess the current state and structure of the Russian PM market over the period 2020–2025. Materials and methods. The data from the analytical agency DSM Group (2020–2025) were used for the market assessment. PM containing at least one herbal-based component were included in our analysis. A modified Boston Consulting Group (BCG) matrix was used for the strategic assessment of the PM market segments. Results and discussion. In 2025, the total Russian PM reached 152.6 bln rubles ($1.9 bln) and 393.4 mln packs. PM account for 6.2 % of the total pharmaceutical market in value and 8.6 % in volume terms, respectively. Domestic manufacturers lead the sales structure in volume (up to 80 %), while imported PM dominate in value (up to 57 %). The top 3 medicinal plants most frequently included in PM (in 2025) are Valeriana officinalis L., Mentha piperita L., and Glycyrrhiza spp. The herbal medicinal products (HMP) with individual compounds (IC) isolated from plant materials are widely presented on the market. Of these, more than 14 % are PM with alkaloids (morphine from Papaver somniferum L., pilocarpine from Pilocarpus pennatifolius Lem., atropine from Atropa belladonna L., platyphylline from Porella biedermannii Frank Müll., vinpocetine from Vinca minor L., and paclitaxel from Taxus spp.). By 2025, the average annual growth rate exceeded 8 % in monetary terms and 2 % in packages for alkaloid-based drugs. Considering classification by pharmacotherapeutic groups, bioflavonoids (HMP) based on diosmin, hesperidin, rutin, and their combinations) lead the market in monetary terms for 2025. Sleeping and sedatives PM are leaders in unit sales. Expectorants and respiratory medications hold second place in both monetary and packages terms. The promising niche of brown algae-based medicines (kelp) is also showing dynamic growth, with sales reaching 8.9 bln rubles. Among tonic PM, phytoadaptogens hold a significant position, with sales totaling 3.4 bln rubles in value and 38.7 mln packs in volume for the 2020–2025 period. The Compound Annual Growth Rate (CAGR) for the PM market is +6 %. The category of homeopathic medicines, despite its minimal market share (1.6 %), is the most dynamic (CAGR +9 %). The category of combination drugs with PM ranks second in terms of sales (24.8 %) and 32.6 % of packages). The CAGR for this category is +3 % and the drivers with a CAGR of +12 % are PM with medicinal plant materials (MPM). The category of herbal medicines is growing by 8 % and is the clear leader in terms of packages sales (35.3 %). The herbal medicines category, while leading in terms of sales value (54.3 %), is showing moderate growth (CAGR +5 %). According to the BCG matrix estimate for 2020–2025, the only segment that occupies the "Star" position in the PM market structure is the HMP with IC (the segment accumulates 31.0 % of the total sales volume (RUB 249.2 bln) with a CAGR of 6 %). The "Cash Cows" category encompasses the largest number of segments, but the dominant positions are held by galenic HMP (tinctures, extracts, elixirs, juices, and syrups) with a CAGR of 5 % and HMP (CAGR of 8 %). Solid dosage forms predominate in the PM market, accounting for approximately 63 % by value and 44.1 % by packages. The share of tinctures and drops accounts for 13.1 % and 12.2 % in monetary terms and in packages, respectively. Conclusion. A key direction for PM Industry development is to increase the share of locally produced drugs with high added value. The strategic priority for the development of the PMs market is to support the segments of HMPs with IC, galenic HMPs and plant-based medicines (PbM), as well as scaling the segments of combinations of combined medicine (CM) with MPM as the fastest growing.
Introduction. Overexpression of human epidermal growth factor receptor 2 (HER2) is a critical driver of malignancy in multiple solid tumors, underscoring the demand for innovative targeted therapeutics. Protein–drug conjugates offer selective delivery of highly potent cytotoxic payloads directly to tumor cells. Designed ankyrin repeat proteins (DARPins) represent a viable alternative to full-length monoclonal antibodies owing to their high binding affinity, thermal stability, and efficient production in prokaryotic expression systems. However, analytical characterization and standardization of DARPin-based conjugates necessitate dedicated, validated methodology. Aim. To develop a targeted therapeutic conjugate comprising DARPin G3 and the cytotoxic agent emtansine, and to establish standardized analytical methods tailored for its quality control as an active pharmaceutical ingredient. Materials and methods. The study evaluated the HER2-specific therapeutic conjugate DARPin G3-ABD covalently linked to emtansine (DM1) via a non-cleavable maleimide linker. Manufacturing involved site-specific protein reduction, chemical conjugation, and size-exclusion chromatographic purification. Physicochemical characterization was performed using UV spectrophotometry, the bicinchoninic acid (BCA) colorimetric assay, nano-HPLC-MS/MS, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Biological activity was assessed in HER2-overexpressing human breast adenocarcinoma SKBR3 cells using the MTT cell viability assay. Method validation was conducted in accordance with pharmacopoeial guidelines. Results and discussion. Comprehensive analytical profiling of the conjugate encompassed identity, related impurities, quantitative assay, and in vitro potency. Identity was verified by nano-HPLC-MS/MS, demonstrating 100 % amino acid sequence coverage. SDS-PAGE revealed a single major monomeric band with high electrophoretic purity and homodimeric impurities below 6 %. Quantitative determination was evaluated by direct UV spectrophotometry at 252 nm and the BCA assay. Validation demonstrated that the UV spectrophotometric assay is specific, linear ( R = 0.999), free from systematic error, and highly precise (RSD ≤ 2.06 %). Conversely, the BCA assay exhibited a statistically significant systematic bias (δ = 2.76 %), confirming the superiority of direct UV spectrophotometry for active ingredient assay. The conjugate demonstrated dose-dependent cytotoxicity against HER2-positive cells with an IC 50 = 40 ± 10 нМ, whereas the payload-free protein control showed no antiproliferative effect. Conclusion. A targeted conjugate based on DARPin G3-ABD and emtansine was successfully engineered and characterized, displaying high purity, confirmed primary sequence identity, and potent HER2-dependent cytotoxic activity. The established analytical panel provides a reliable basis for quality control of the conjugate as an active pharmaceutical ingredient in preclinical development.
