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Vol 27, No 4 (2024)
Pharmaceutical chemistry
Development of nasal pharmaceutical products for systemic exposure: use of permeation enhancers to achieve target product profile
Abstract
In recent years, special attention has been paid to non-invasive parenteral routes of administration, which are an alternative to injectable drugs, as well as other dosage forms whose effectiveness and safety may be compromised by the administration route. At the same time, there is a paradigm shift in relation to nasal dosage forms: they are no longer considered as primarily drugs exhibiting local effects, and an increasing number of nasal medicinal products with systemic action are appearing on the market. There is a growing interest to the nasal delivery due to the possibility of maximizing the therapeutic potential of active substances that have proven themselves in clinical practice, for example, by quick targeted action to the site of the pathological process, increased bioavailability of the drug and reduced possible side effects. The nasal cavity as a site for systemic drug absorption has anatomical and physiological features that include a relatively large surface area, a porous endothelial basement membrane, a highly vascularized epithelial layer, high total blood flow, lack of first-pass metabolism, and easy access. Therefore, the development of a convenient (nasal) dosage form of the drug with a rapid onset of action is a promising approach. When developing a new pharmaceutical product, the factors that determine bioavailability should be taken into account and addressed by appropriate formulation and delivery techniques: the use of mucoadhesive components or substances that modulate mucociliary clearance, variation of the viscosity or osmolarity, or selection of an appropriate dosing device. Improving intranasal absorption is a promising direction for obtaining drugs with improved consumer properties. In addition to the functional properties of the formulations, safety aspects must also be taken into account. The article provides an analysis of the limiting factors for nasal preparations, strategies for increasing bioavailability, permeation enhancement mechanisms, and provides examples of the application of permeation enhancers used in developed and commercially available drugs. This review gives an idea on possible to use in nasal formulations permeation enhancers which have different mode of actions.
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Research of spain scorzonera (Scorzonera hispanica L.) for the development of functional nutritional foods based on i
Abstract
Introduction. The relevance of the study lies in the study of the chemical composition of the food culture of Scorzonera hispanica of the "Lechebnye" variety, identification of the most significant, from the point of view of therapeutic nutrition biologically active substances and prediction of further possible ways of using raw materials of this plant in the development of functional foods.
Purpose of the study. To study the qualitative and quantitative composition of substances determining the nutritional value of Scorzonera hispanic variety Lechebnye cultivated in the Krasnodar region, as well as a detailed study of the amino acid composition of the root and herb, and their water-extractable complexes for subsequent use in the development of food products of functional purpose.
Material and method. The object of the study was the roots and grass of the Scorzonera hispanica of the "Lechebnye" variety, harvested in 2021–2023 on the territory of the North Caucasus branch of FGBNU VILAR. Dry water-extractable complexes of Scorzonera herb and root were obtained according to a well-known technological scheme, including the stages of solid-phase extraction, concentration of the resulting extract, purification by filtration and drying of the extract. Physico-chemical indicators of the nutritional value of the root and herb of Scorzonera hispanica: qualitative and quantitative composition of nutrients (protein, fiber, fat, calcium and phosphorus), safety indicators (arsenic, cadmium, were determined using generally accepted methods for food raw materials. Capillary electrophoresis was used as an analytical method for studies of the composition and content of amino acids in the studied objects.
Results. It was found that the above-ground and underground organs of cultivated food plant Scorzonera hispanica cultivar Lechyorny in the Krasnodar Territory are characterized by a high content of physicochemical indicators of nutrients such as crude protein, fiber, fat. Thus, the mass fraction of crude protein in the root – 11.41%, in the grass – 10.43%, fiber in the root – 6.6% and 30.0% in the grass, crude fat in the root – 3.28%, in the grass –3.39%. The data of studies of amino acid composition of grass, roots of Scorzonera hispanica and their water-extractable complexes show that grass and root contain 12 amino acids, 7 of which are essential (threonine, valine, methionine, isoleucine, leucine, phenylalanine, lysine). The studied complexes revealed the presence of a number of substituted amino acids - tyrosine, cysteine, serine, proline, alanine, glycine and essential amino acids - phenylalanine, threonine, methionine, lysine, and valine, histidine and arginine, histidine and arginine (essential).
Conclusions. The research results obtained allow us to conclude that the herb and roots of Scorzonera hispanica of the "Lechebnye" variety are valuable as sources of essential nutrients, such as protein, fiber, fat, calcium, phosphorus and amino acids, which provides the opportunity to consider the creation of functional food products based on these plant materials.
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Discrete optimization of the implementation stages of pharmaceutical development for a spray treatment for oral diseases
Abstract
Introduction. All over the world more than 3.5 billion people suffer from oral diseases, which can lead to endogenous infectious diseases and create conditions for external infections. The growing antimicrobial resistance of bacterial strains is a global health threat. Oligoalkyleneguanidine polymers may be promising compounds to solve this problem. The spray form for the application of these substances is the most optimal.
The aim of the study is to apply discrete optimization to implement the stages of pharmaceutical development of a spray based on branched oligohexamethyleneguanidine for the treatment of oral diseases.
Material and methods. Experiments are carried out using various equipment and samples with different compositions have been developed. The implementation of the pharmaceutical development stages was carried out using a discrete optimization algorithm.
Results. When implementing discrete optimization in pharmaceutical development, it is necessary to prioritize criteria and limitations using the target quality profile of the drug being developed. As a result of the optimization cycles carried out, the optimal composition was selected, which corresponds to the target quality profile, including such parameters as pH, dynamic viscosity, sterilizing filtration, adhesion of the formulations to the oral mucosa and the spray torch. A discrete optimization was carried out, taking into account the wetting edge angle and particle size distribution. The optimal composition was sample No. 8, which has pseudoplastic properties, provides unhindered spraying and prevents the composition from draining from the mucous membrane of the oral cavity.
Conclusion. During the study, the optimal ratio of components was determined and the development of a spray based on oligohexamethyleneguanidine with the implementation of stages of pharmaceutical development for discrete optimization was proposed.
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New antimicrobial agents in the dihydroxanthone series: establishment of structure-activity relationships and standardization
Abstract
Introduction. Irrational use of antimicrobial drugs, chemical and biological agents leads to the emergence and spread of resistance in microorganisms. Therefore, there is an increasing need for the search and development of new antimicrobial compounds. Dihydroxanthone derivatives, which have a wide spectrum of action, are one of the promising groups of antimicrobial substances.
New derivatives of 4,4a-dihydroxanthone were obtained at the St. Petersburg State Chemical and Pharmaceutical University (SPCFU) at the Department of Organic Chemistry. Synthetic 4,4a-dihydroxanthones are structurally similar to antimicrobial xanthones of natural origin – fomalevones A and C. Therefore, 4,4a-dihydroxanthones are promising compounds for the creation of new antimicrobial substances.
Purpose of the study. To establish the relationship between the chemical structure of the synthesized dihydroxanthones and their antimicrobial activity and to standardize the active compound.
Materials and methods. 20 new derivatives of 4,4a-dihydroxanthone were synthesized. The structure and identity of the compounds was established using physical and chemical methods of analysis. The antimicrobial activity of these derivatives was studied by double serial dilution method. Quality standards for the most promising compound 5-bromo-7-chloro-4,4-dimethyl-9-oxo-4,4a-dihydroxanthone (a17) were developed.
Results. In preliminary studies, we found that 4,4a-dihydroxanthones synthesized in SPCFU have a pronounced effect against gram-positive bacteria. It was found, that the antibacterial activity of 4,4a-dihydroxanthone derivatives depended on their structure. The presence of substituents with acceptor properties led to an increase in activity, while donor substituents reduced the antimicrobial effect of the compounds. 5-Bromo-7-chloro-4,4-dimethyl-9-oxo-4,4a-dihydroxanthone (a17) turned out to be the most active compound, and we carried out its standardization for some indicators.
Conclusions. During the study of the antimicrobial activity of the synthesized dihydroxanthones, it was found that they are active against gram-positive bacteria. The antibacterial activity of 4,4a-dihydroxanthone derivatives depends on their structure. Among them, the most active compound was identified – leader a17, which has a pronounced antistaphylococcal effect. Its standardization has been carried out for some indicators.
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Complex research herb of the Fragrant violet growing in the North Caucasus and ways of its use
Abstract
Introduction. Fragrant violet (Viola odorata L., family Violaceae) is a perennial herbaceous plant, widespread in the North Caucasus and the European part of Russia. The aerial part of the plant contains various active biologically active substances, such as phenolic and triterpene glycosides, polysaccharides, phenolic compounds, coumarins and flavonoids, ascorbic acid, macro and microelements, which are responsible for its medicinal properties. In modern herbal medicine, fragrant violet is used as an anti-inflammatory, analgesic, antioxidant, diuretic, antihypertensive and antibacterial agent. However, further research is needed to confirm these medicinal properties.
Objectives. Preparation of a dry extract from the herb violet fragrant and evaluation of its antibacterial activity against the clinical strain of Staphylococcus aureus III.
Material and methods. The object of the study was a dry extract from the herb of fragrant violet, collected on the territory of three municipalities of the Stavropol Territory in the flowering phase of 2020-2022, obtained by exhaustive extraction with 70% ethyl alcohol. For microbiological studies, the serial dilution method was used. Meat-peptone broth (MPB) was used as a control, without adding a suspension of microorganisms to control the sterility of the environment and with the addition of microorganisms to control the growth of the microorganism, as well as a number of serial dilutions of the reference drug: “Ceftriaxone”. Results. It was established that the studied extract from fragrant violet has antibacterial properties, which is confirmed by the identified bacteriostatic effect (reduction in the number of colonies formed compared to the control) and a change in the cultural properties of the colonies relative to the control.
Conclusions. The obtained screening results actualize further study of the extract from the herb violet fragrant in relation to representatives of opportunistic flora and the prospects of its use as an antimicrobial and anti-inflammatory agent of plant origin.
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Medical chemistry
Succinate-receptor system of bone and cartilage tissue in patients with metabolic phenotype of osteoarthritis
Abstract
Introduction. Currently, osteoarthritis (OA) has been identified as a polyetiological disease, where several phenotypes have been identified based on the leading frequency. Obviously, each clinical phenotype corresponds only to its fundamental changes on the part of various organs and systems. Until recently, special attention was paid to the study of metabolic processes in osteoarthritis (OA) and was paid to the state of the cartilage, but more and more interest was focused on the biochemistry of the subchondral bone, its microarchitectonics and signal function.
Aid. To study the features of the manifestation of the succinate-receptor system of bone and cartilage tissue in patients with the metabolic phenotype of osteoarthritis.
Material and methods. 42 patients took part in the study and were divided into 2 groups: 1 group – patients without articular disease, normal body mass index; 2 group – patients with metabolic phenotype of OA. The subjects were collected complaints, anamnesis, as well as general clinical and orthopedic examination. The levels of succinate, succinate receptor (SUCNR1) and succinate dehydrogenase (SDH) are measured in bone and cartilage tissue homogenates.
Results. In the 2 group, an increase in SUCNR1 expression was detected in all studied areas of the joint in comparison with the 1 group. In the 2 group, the differences were tissue-specific in the distribution of SUCNR1 with a predominant increase in the amount of the receptor in the subchondral bone compared to the loaded (p=0.031) and non-loaded zone of cartilage (p=0.001). In the 1 group, the studied areas of cartilage and bone did not differ in the amount of SUCNR1 from each other. In the group of patients with the metabolic phenotype of OA, an increase in mitochondrial succinate was found both in the subchondral bone tissue and in different zones of cartilage compared to the 1 group. The final indicators of SDH activity in the mitochondria of the studied joint zones that we obtained turned out to be low in both groups, however, relatively high enzyme activity was observed in the subchondral zone of the bone of the group of metabolic phenotype of OA.
Conclusion. In patients with the metabolic phenotype of OA, high expression of SUCNR1 in joint tissues is observed, which is tissue-specific with a predominant increase in the amount of SUCNR1 in the subchondral bone. We found higher levels of succinate in the subchondral bone and cartilaginous areas of joints in patients with the metabolic phenotype of OA and suggest that the succinate-SUCNR1 interaction in affected joints in OA is adaptive in nature.
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Determination of the level of circulating endothelial cells and the expression of adhesive P-selectin as prognostic markers of the severity of psoriasis
Abstract
Introduction. Psoriasis is one of the most pressing problems of dermatologists, it accounts for up to 30% of all skin diseases. The study of the pathogenesis of psoriasis is currently due to an increase in the number of severe, disabling forms of the disease.
The purpose of the study. To evaluate the prognostic significance of markers of endothelial dysfunction and platelet functional activity in patients depending on the severity of psoriasis.
Materials and methods. The study included 80 patients with vulgar psoriasis (40 women and 40 men) with a course of moderate severity (n=33, PASI – 17±5, DLQI-7±2)), and severe (n=47, PASI -30±7, DLQI-16±3). The average age is 48±15 years. Circulating endothelial cells and P-selectin on platelets were determined on an FC500 flow cytometer (Beckman Coulter).
Results. In patients with moderate and severe psoriasis, a statistically significant increase in the level of circulating endothelial cells was found (10 [7.5-11.5]/3x105 WBC) and (14 [7.0-19.5]/3x105 WBC), respectively, compared with the control group (3.0 [1.0-5.0]/3x105 WBC), p<0.001. The number of platelets with P-selectin expression (1.9% [1.25-2.65]) in patients with moderate severity and (3.2% [1.5-5.4]) with severe course was significantly higher than in the control group (0,9% [0,7-1,7]). Correlation analysis showed that the level of P-selectin is directly correlated with the level of circulating endothelial cells. To increase the prognostic significance of these laboratory parameters and assess the severity of the condition, a ROC analysis was performed with the construction of ROC curves and the calculation of the area under the curve (AUC).
Conclusion. It was found that the level of P-selectin is a more sensitive prognostic marker of the severity of psoriasis, and the number of circulating endothelial cells is a specific prognostic marker for the development of possible cardiovascular outcomes.
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Study of HIF-1α-signaling pathway components in plasma of patients with COVID-19 infection of different degrees of severity
Abstract
Introduction. Recent work demonstrates that HIF-1α and NOS isoforms are detectable in plasma, representing their potential practical relevance as biomarkers. At the same time, data on the stability of these proteins in plasma are contradictory.
Aim of the study. To investigate the amount of HIF-1α and iNOS in plasma of patients with COVID-19 infection of different severity to assess the possibilities of adaptation to hypoxia.
Material and methods. The pilot study involved 50 patients divided into three groups: 1) 17 patients with moderate severity of the disease; 2) 17 patients in severe condition; 4) 16 patients with extremely severe course of the disease. The amounts of HIF-1α and iNOS were determined by competitive ELISA.
Results. Patients with extremely severe course of COVID-19 infection showed lower levels of HIF-1α and blood saturation compared to the moderate and severe course groups. The iNOS levels were significantly lower in the extremely severe course group compared to patients with moderate disease severity. When patients were evaluated according to the degree of lung damage based on CT scans, reduced HIF-1α levels were identified in the CT-3-4 group compared to the CT-0-1 (p = 0.0006) and CT-2 (p = 0.0031) groups.
Conclusions. Decreased levels of HIF-1α and iNOS in extremely critically ill patients may serve as an unfavorable prognostic marker.
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Problems of experimental biology and medicine
Immunomodulating activity of individual substanсes isolated from the aerial part of Rhaponticum uniflorum (L.) DC in experimental immunodeficiency
Abstract
Introduction. The development and introduction of new drugs with immunomodulatory effects is one of the priorities of modern medicine. Numerous studies have proven the immunotropic activity of individual substances isolated from medicinal plants (flavonoids, phenylpropanoids, polysaccharides, ecdysteroids, terpenoids, etc.). In this study, it is of interest to determine the immunomodulatory effect of individual substances isolated from Rhaponticum uniflorum (L.) DC.
The purpose of the study. Determine the immunomodulatory properties of 20-hydroxyecdysone, 5-О-caffeoylquinic acid and arabino-3,6-galactan, isolated from the aerial part of Rhaponticum uniflorum (L.) DC, in relation to the cellular and humoral components of the immune response during experimental immunosuppression caused by cyclophosphamide.
Material and methods. The experiments were performed on 100 male mice of the F1 line (CBAxC57Bl/6) weighing 18-20 g. Immunodeficiency was simulated by in traperitoneal administration of cyclophosphamide at a dose of 250 mg/kg once. The experimental group of animals received individual substances intragastricallyin the following doses: 5-О-caffeoylquinic acid - 10 mg/kg, arabino-3,6-galactan - 10 mg/kg, 20-hydroxyecdysone - 3 mg/kg, once a day for 14 days. The intact group of mice received purified water according to the analogous scheme. The state of humoral chain of the immune response was estimated according to the quantity of antibody-forming cells (AFC) determined with the use of Cunningham's plaque assay (1965). The state of the cellular chain of the immune response was estimated according to the delayed hypersensitivity reaction.
Study results. It has been established that 20-hydroxyecdysone, 5-О-caffeoylquinic acid and arabino-3,6-galactan, isolated from the aerial part of Rhaponticum uniflorum (L.) DC, have immunomodulatory effect on the cellular and humoral components of the immune response in immunosuppression caused by cyclophosphamide.
Conclusions. The obtained results argues the feasibility of further research of individual substances, isolated from the aerial part of Rhaponticum uniflorum (L.) DC, with a view to creating new effective immunomodulators of plant origin.
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