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2Вестник Томского государственного университета. Химия. 2024. № 33. С. 33-44
Tomsk State University Journal of Chemistry, 2024, 33, 33-44
Original article
UDK 542.9
doi: 10.17223/24135542/33/3
Investigation of Some Properties of a Composite Biomaterial Based on Betulin Treat Infected Wounds and Burns
Dmitriy A. Fedorishin1, Abdigali A. Bakibaev2, Maria V. Lyapunova3, Altynaray T. Takibayeva4, Olga V. Demets5, Irina A. Kurzina6, Elena A. Mamaeva7, Madina R. Aliyeva8
i,2, 3, 6 jomsk State University, Tomsk, Russia 4 5 Karaganda Technical University named after Abylkas Saginov, Karaganda, Kazakhstan 7 Tomsk Polytechnic University, Tomsk, Russia 8 Karaganda University named after Y.A. Buketov, Karaganda, Kazakhstan
1 strixi87@yandex. ru
3 [email protected] 4 althynarai81@mail. ru 5 [email protected] 6 kurzina99@mail. ru 7 mamaeva. elena@mail. ru 8 madiko8707@mail. ru
Abstract. An urgent problem of modern medicine is the problem of treatment of infected wounds, which is associated with the prevalence of wounds of various etiologies, purulent complications, high mortality, and high material costs of treatment. For the treatment of wounds most often used local effects of drugs, in particular, use a variety of coatings and dressings. Types of these dressings are quite diverse. They can be created on the basis of bioresorbable materials, contain other therapeutic substances such as enzymes, anesthetics, antibiotics in order to have a complex effect on the wound healing process. The choice of optimal local wound coatings or their effective combinations with physiotherapeutic methods of treatment of local superficial and deep wounds and prevention of wound infection remains an unsolved problem. In this regard, the creation of new wound healing preparations and wound coatings based on them seems to be very relevant.
At the moment, there are many biologically active substances suitable for the therapy of wounds and burns. These substances can have a variety of origins - both synthetic and natural. Recently, the attention of specialists to drugs of natural origin is constantly growing. Interest in the use of such drugs is justified by their high efficiency, the lack of the need for complex synthesis, a wide range of pharmacological activity, as well as the possibility of using them for a long time without complications and side effects. The specific weight and volume of production of medicines obtained by synthetic transformations of substances extracted from wild and cultivated plants is increasing worldwide. Substances of plant origin are now increasingly being used in medical products for a wide range of purposes.
One of such substances are derivatives of natural pentacyclic triterpenoid betulin extracted from birch bark. Betulin and its derivatives have high biological activity. This substance and its derivatives exhibit a complex of biologically active properties such as
© D.A. Fedorishin, A.A. Bakibaev, M. V. Lyapunova et al., 2024
wound healing, antibacterial, antitumor, hypolipidemic, hepatoprotective, antiviral and others. Betulin, overcoming resistance, induces apoptosis of malignized cells in various human cancers. It should also be noted that sufficient raw material base and biological activity of betulin put it in a number of valuable natural sources for use both in the native state and in the form of various transformation products, which makes it relevant to develop drugs based on it.
Keywords: botulin, glycoluryl, carbomethoxycellulose, biomaterial, physico-me-chanical properties, films, cytotoxicity, antibacterial activity
Acknowledgments: This research was funded by the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan (grant No. АР AP08856688-OT-22 "Development of methods for the extraction of natural triterpenoids from plants and their chemical transformation in order to investigate for new biologically active substances"). This study was supported by the Tomsk State University Development Programme (Priority-2030).
For citation: Fedorishin, D.A., Bakibaev, A.A., Lyapunova, M.V., Takibayeva, A.T., Demets, O.V., Kurzina, I.A., Mamaeva, E.A., Aliyeva, M.R. Investigation of Some Properties of a Composite Biomaterial Based on Betulin Treat Infected Wounds and Burns. Vestnik Tomskogo gosudarstvennogo universiteta. Chimia - Tomsk State University Journal of Chemistry, 2024, 33, 33-44. doi: 10.17223/24135542/33/3
Научная статья
doi: 10.17223/24135542/33/3
Исследование некоторых свойств композиционного биоматериала на основе бетулина для лечения инфицированных ран и ожогов
Дмитрий Александрович Федоришин1, Абдигали Абдиманапович Бакибаев2,
Мария Вячеславовна Ляпунова3, Алтынарай Темирбековна Такибаева4, Ольга Владимировна Демец5, Ирина Александровна Курзина6, Елена Андреевна Мамаева7, Мадина Раманкуловна Алиева8
1,2, з, б томский государственный университет, Томск, Россия 45 Карагандинский технический университет им. Абылкаса Сагинова, Караганда, Казахстан 7 Томский политехнический университет, Томск, Россия 8 Карагандинский университет им. академика Е.А. Букетова, Караганда, Казахстан
1 strix187@yandex. ru
2 bakibaev@mail. ru
3 [email protected] 4 althynarai81@mail. ru 5 [email protected] 6 kurzina99@mail. ru 7 mamaeva. elena@mail. ru 8 madiko8707@mail. ru
Аннотация. Актуальной проблемой современной медицины является проблема лечения инфицированных ран, что связано с распространенностью ран различной этиологии, гнойными осложнениями, высокой летальностью и большими материальными затратами на лечение. Для лечения ран чаще всего применяют местное воздействие лекарственных препаратов, в частности используют различные покрытия и повязки. Виды таких повязок весьма разнообразны. Они могут создаваться на основе биорезорбируемых материалов, содержать другие лечебные вещества, такие как ферменты, анестетики, антибиотики, чтобы оказывать комплексное воздействие на процесс заживления ран. Выбор оптимальных местных раневых покрытий или их эффективных сочетаний с физиотерапевтическими методами лечения местных поверхностных и глубоких ран и профилактики раневой инфекции остается нерешенной проблемой. В связи с этим создание новых ранозаживляющих препаратов и раневых покрытий на их основе представляется весьма актуальным.
В настоящее время существует множество биологически активных веществ, пригодных для терапии ран и ожогов. Эти вещества могут иметь самое разное происхождение - как синтетическое, так и природное. В последнее время внимание специалистов к препаратам природного происхождения постоянно растет. Интерес к использованию таких препаратов обоснован их высокой эффективностью, отсутствием необходимости сложного синтеза, широким спектром фармакологической активности, а также возможностью их длительного применения без осложнений и побочных эффектов. Удельный вес и объем производства лекарственных средств, полученных путем синтетических превращений веществ, выделенных из дикорастущих и культурных растений, растут во всем мире. Вещества растительного происхождения в настоящее время все чаще используются в медицинских препаратах самого разного назначения.
Одним из таких веществ являются производные природного пентацикличе-ского тритерпеноида бетулина, добываемого из коры березы. Бетулин и его производные обладают высокой биологической активностью, проявляют комплекс биологически активных свойств, таких как ранозаживляющее, антибактериальное, противоопухолевое, гиполипидемическое, гепатопротекторное, противовирусное и др. Бетулин, преодолевая резистентность, индуцирует апоптоз малигни-зированных клеток при различных видах рака человека. Следует также отметить, что достаточная сырьевая база и биологическая активность бетулина ставят его в ряд ценных природных источников для использования как в нативном состоянии, так и в виде различных продуктов трансформации, что делает актуальной разработку лекарственных препаратов на его основе.
Ключевые слова: бетулин, гликолурил, карбометоксицеллюлоза, биоматериал, физико-механические свойства, пленочные материалы, цитотоксичность, антибактериальная активность
Благодарности: Исследование выполнено при финансовой поддержке Комитета по науке Министерства науки и высшего образования Республики Казахстан (грант № АР АП08856688-ОТ-22 «Разработка методов выделения природных тритерпеноидов из растений и их химической трансформации с целью поиска новых биологически активных веществ») и Программы развития Томского государственного университета (Приоритет 2030).
Для цитирования: Федоришин Д.А., Бакибаев А.А., Ляпунова М.В., Такиба-ева А.Т., Демец О.В., Курзина И.А., Мамаева Е.А., Алиева М.Р. Исследование некоторых свойств композиционного биоматериала на основе бетулина для лечения инфицированных ран и ожогов // Вестник Томского государственного университета. Химия. 2024. № 33. С. 33-44. doi: 10.17223/24135542/33/3
Introduction
The World Health Organization affirms that burns and injuries are a global public health problem. An estimated 180000 deaths annually are caused by this type of injury all over the world. Currently, many biologically active substances, including the popular natural ones to treat wounds and burns have been developed [1, 2].
One of the promising natural substances is betulin isolated from birch bark [3]. Betulin is a natural pentacyclic lupane-type triterpenoid with the proven antimicrobial and antiviral properties. Betulin has no the toxic effect.
Betulin has the sufficient raw material base and a broad spectrum biological activity. Consequently, it is the valuable natural source, and it may be used in its native state and in form of the various transformation products or as part of composition [4, 5].
Results and discussion Results on the mechanical tests of composite biomaterial samples
One of the research objectives was to select some adjuvants for the composite biomaterial. CMC-Na is commercially available in various degrees of substitution. The aim of the physical-mechanical tests of the composite biomaterial samples was to study the effect of the degree of substitution and the CMC-Na molecular weight on the mechanical film strength [6, 7]. These films have been formed after the drying of composite biomaterial.
As a result, 5 samples with CMC-Na included in their composition with different molecular weights and degrees of substitution have been developed [8]. Each sample has been carefully placed on the Petri dish. After the drying of each sample, a polymer film has been carefully peeled out the Petri dish bottom and cut into the equal rectangular strips. Then the obtained strips have been tested on a tensile testing machine [9, 10].
These tests have determined differences in the mechanical properties of the obtained samples of No. 1-5. The measurement has demonstrated that sample No. 5 had the worst strength and the elastic characteristics. In contrast, samples of No. 1 and 2 had the best strength and elastic characteristics of all the samples (Table).
Thus, it could be concluded that samples of No. 3 and No. 4 had less strain capacity than samples of No. 1 and No. 2 had. The total tensile strain before rupture of samples of No. 1 and No. 2 was 0.87 and 0.92 mm, respectively, while sample No. 5 was 0.18 mm (p < 0.05).
It might be stated that the elongation values before rupture in samples of No.1 and No. 2 did not statistically differ from each other (p > 0.05), but sample No. 1 exceeded sample No 2 in the tensile strength value (p < 0.05). The strength to break sample No. 3 was higher (p < 0.05) than for other samples. However, the strength to break sample No. 5 was less than for the others (p < 0.001).
The composite films based on betulin depending on degree of substitution and molecular weight of CMC-Na
No. Molecular Weight Degree of Substitution Drying Conditions
1 90,000 0.7 Air
2 90,000 0.7 Vacuum
3 250,000 0.7 Air
4 250,000 0.9 Air
5 250,000 1.2 Air
160 140
« "0
rf 100
tf> V
G
60
H
40
20 0
Elongation at tension, mm
Fig. 1. Mechanical properties of samples. The highest tensile stress to rupture is seen
in Sample No. 3 (p < 0.05). The values of elongation to rupture in samples No. 1 and 2 do not statistically differ from each other (p > 0.05), however, sample No. 1 slightly exceeds sample No. 2 in terms of tensile resistance (p < 0.05). The sample numbers correspond to the sample numbers in Table
The Figure 1 have illustrated that the mechanical tests determined a correlation between the degree of CMC-Na substitution and the strength sample characteristics [11].
The film samples containing CMC-Na with a degree of substitution of 0.7 had the highest strength characteristics. These samples were characterized by the highest elongation and averaged elastic modulus. It has been found that the low degree of CMC-Na substitution led to the higher film tensile strength [12].
The physical and mechanical properties of the solid dosage forms to treat the infected wounds are a significant characteristic of their technical and medical value. Hence, in order to determine these properties is the most important test. Thus, each solid dosage form should be tested. The usability of the obtained films for the wound therapy has directly depended on their mechanical properties: load,
duration of their action, the environmental humidity and other factors [13]. The effect of these parameters on usability of the wound dressings should be included to select the adjuvant structural substances for their manufacture.
The physical and mechanical tests have determined the tensile strength and strain. The studied samples were films consisting of the biologically active organic substances. In order to prepare samples, the component solution of sample No. 2 has been under the vacuum degassing. Thus, a value of the total strain before rupture has been slight increased. However, the statistically significant differences have not been found between sample No. 2 and No. 1. The vacuum degassing has not used for these samples [14].
In this regard, we considered the use of vacuum to be inexpedient and economically unprofitable.
Investigation of antibacterial activity
The antibacterial activity of films obtained by drying of the composite biomaterial samples has been examined with using a modified well-diffusion method.
The studied ABD sample (composite material sample without miramistin) (Figure 2) has demonstrated the antibacterial activity against gram-negative microflora (Escherichia coli). In addition, the activity sample level against gramnegative microflora has not differed from the control (p > 0.05).
The activity has not been found against gram-positive microflora (Staphylococcus aureus). The inhibition zones have not been observed.
C _£
k v.
w
5.
ao
b V v
o S
5
The control ABD
Fig. 2. The antibacterial activity level of samples against gram-negative microflora
The figure has illustrated that the antibacterial activity of the ABD sample has not differed from the control (p > 0.05).
The inhibition zones of Escherichia coli growth have averaged 14.3 mm for the sample dosage form (ABD), and 14.1 mm for the 10 mg/ml aqueous solution of the miramistin substance. The value for the ABD sample is higher than for the control sample.
14.5 14.3
It could be stated that very urgent problem is to constantly introduce the new antibacterial drugs into the clinical practice, and also lack of literature data on effectiveness of the full range of the modern antibiotics used in medicine [15].
The microbial resistance to antibiotics has been constantly increasing and varying from year to year. As a result, it might be hypothesized that a studied strain of Staphylococcus aureus has developed resistance to miramistin.
The extraneous microflora has not been defined on the nutrient medium. The entire lawn and colonies have been attributed to the test objects by the morphological features.
Investigation on cytotoxicity of the composite biomaterial
This investigation has examined the cytotoxicity of some composite sample biomaterials by the MTT test. A sample of the composite biomaterial has been used as a positive control without the ABD miramistin. The standard complete nutrient medium for this cell line has been applied as a negative control (CM). And a sample with ABD + MRM miramistin in its composition has been also utilized.
The experiment has included the sample solutions in the complete nutrient medium with concentrations of 7 mg/mL; 0.7 mg/ml; 0.07 mg/mL; 0.007 mg/mL; 0.0007 mg/mL; 0.00007 mg/mL and 0.000007 mg/mL. The incubation duration of the fibroblast culture with the sample was 48 h, 72 h and 120 h.
As a result, this experiment has found that the studied sample of ABD+MRM composite biomaterial had cytotoxicity (Figure 3). Its cytotoxicity has been defined to be higher than complete nutrient media (p < 0.05).
The effect has been observed at a sample concentration of 7 mg/mL. If the number of live cells in the negative control sample was taken as 100%, the sample should reduce their number by 50%.
In contrast, the ABD positive control sample in the working concentration has showed the absence of any cytotoxicity and a significant increase in the fibroblast proliferation. Thus, it could be determined by an increase in the optical density by 90% (Figure 3). It has been confirmed statistically (p < 0.05). It should be pointed out that effect was observed in a sample concentration of 7 mg/mL. The increase of proliferation in other concentrations has not differed from the control.
It has been determined that the greatest effects of both samples have been recorded at incubation for 48 h. Many dead cells have been found in all cultures at incubation for 72 h. All results have not differed from the negative control (p > 0.05) at incubation for 120 h.
The higher effects of both samples of (СМ at 7 mg/mL) and the positive control sample (ABD) have been determined at incubation for 48 h.
A complete medium has been used as a negative control. A sample of the same composition without miramistin has been applied as a positive control.
The sample (ABD+MRM) has been shown to be cytotoxic (p < 0.05). In contrast, the positive control sample (ABD) had no cytotoxicity and increased the fibroblast proliferation (p < 0.05).
200№ ibok
160K 140% "% 12056 •g 100K
"3 80%
20% 0%
Complete medium ARD7mg/m.L AB-D + MRM 7m^/mL
Fig. 3. Cytotoxicity level of the prototype solid dosage form
Thus, the experiment has determined that the sample dosage form (ABD + MRM) with miramistin had cytotoxicity against fibroblasts. However, a sample (ABD) of a similar composition without miramistin has accelerated the fibroblast proliferation.
The literature data have described that betulin in a dosage form had the regenerative properties, directly affecting on the fibroblast proliferation and indirectly on collagen synthesis [16-18]. It might be stated that miramistin had a toxic effect on fibroblasts. Thus, the use of miramistin causes the slower reparation processes for the damaged tissues.
Thus, the research results have demonstrated that inclusion of miramistin in the sample dosage form led to an increase in its toxicity.
Experimental part Extraction of betulin from birch bark
The microwave activation method has been used to isolate betulin from birch bark [19, 20]. Extraction has been performed in a microwave oven. The birch bark has been extracted by 20% sodium hydroxide solution with butanol.
The reaction mixture has been placed in a microwave reactor for 9 min. Then a reaction mixture has been filtered from the non-hydrolyzed birch bark residue on the Büchner funnel. The raw betulin has been precipitated with an aqueous-alcoholic mixture, separated by filtration and dried to a constant weight in a drying chamber at 60°C.
The product has been recrystallized in isopropanol (m.p. of 243°C). The yield of betulin was 18%.
Synthesis of glycoluril
This investigation has showed that the synthesis of glycoluril has been performed by reaction of glyoxal and urea with using the sulfuric acid as a catalyst.
The application of this method has provided conditions where the urea did not decompose [21].
In order to obtain glycoluril, 300 g (5 mol) of urea and 300 g of water have been loaded into a 1 L three-neck flask equipped with a stirrer, a dropping funnel and a reflux condenser. After dissolution of urea with the constant stirring, 27 ml (0.5 mol) of the concentrated sulfuric acid (d = 1.84; C = 98%) and 290 g (2 mol) of 40% aqueous glyoxal solution have been added. Then the reaction mixture has been heated to boiling, and boiled for 20 min. Thereafter the reaction mixture has been cooled to a room temperature. The residue has been filtered by the vacuum filtration, washed with 300 mL water and dried at a room temperature. The result was 242 g of the white crystalline powder. The product yield was 85%.
The obtaining of film materials
The composite film materials have been prepared from aqueous solutions of glycoluril. Their purity was less 99.0%. The percent concentrations were 0.01 and 0.05 with using the following technology. At the first stage, 500 g of a 0.5% solution have been prepared by adding a sample (2.5 g) weighed on an A&D HR-250AZG analytical balance (A&D SCALES Co., LTD, Tokyo, Japan) to 500 ml volumetric flask and brought to the mark with distilled water.
The 0.5% aqueous solution has been further diluted to concentrations of 0.01 and 0.05 wt % in 45 ml glass weighing bottle (KSH 34/12) to obtain a total mass of each solution of 40 g.
At the second stage, to 0.2 g of a film-forming compound Na-CMC with the appropriate molecular weight and degree of substitution (Acros Organics BVBA, Belgium), the 1 ml of miramistin at a concentration of 10 mg/ml, an aqueous solution of glycoluril at a concentration of 0.01 wt. % and 0.5% water-alcohol solution of betulin up to a total solution weight of 10 g have been added, and then solutions have been homogenized at room temperature for 30 min with using an IKA RCT basic magnetic stirrer (IKA-Werke GmbH & Co. KG, Staufen, Germany) equipped with a built-in temperature controller at 25°C. The solutions have been placed into Petri dishes CHBN-2 (100x20 mm by GOST 23932-90) and dried in a vacuum drying chamber LT-V0/50 (Labtech LLC, Moscow, Russia) for 8 h at 25°C and a residual pressure no more 50 mbar with using a Buchi V-710 vacuum pump equipped with a vacuum controller (BUCHI Labortechnik AG, Flawil, Switzerland).
Investigation on the physical and mechanical properties of film materials
In order to study the physical and mechanical properties of the composite biomaterial samples, an Instron 3347 tensile machine has been used.
Five samples have been tested with CMC-Na of different molecular weight and degree of substitution. After drying of the composition, the obtained polymer film has been carefully separated from the Petri dish bottom and cut into rectangles of 50 mm long and 30 mm wide. The geometric dimensions of the samples have
been measured to an accuracy of 0.1 mm. Thickness of each sample has been measured on three points with using a digital micrometer, and its accuracy was
0.01.mm.
Conclusions
1. A composition of the biomaterial based on betulin as a solid dosage form to treat the infected wounds and burns has been developed.
2. As a result, the physical and mechanical tests for films with CMC-Na having the different molecular weight and degree of substitution have found that the sample containing CMC-Na with degree of substitution (0.9) and molecular weight (250000 g/mol.) had the highest strength.
3. The investigation on the antibacterial activity of the composite biomaterial has showed that it had the antibacterial activity against Escherichia coli.
4. The studied sample of composite biomaterial containing miramistin had the cytotoxicity.
5. However, a similar sample of the composite biomaterial without miramistin had no cytotoxicity and has accelerated the fibroblast proliferation increasing their number in culture by 90% compared to the negative control.
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Information about the authors:
Fedorishin Dmitriy A. - Junior Researcher at the Center for Research in Materials and Technology, Assistant at the Department of Natural Compounds, Pharmaceutical and Medicinal Chemistry, Tomsk State University (Tomsk, Russian Federation). E-mail: [email protected] Bakibaev Abdigali A. - Doctor of Chemical Sciences, Leading Researcher at the Laboratory of Organic Synthesis, Tomsk State University (Tomsk, Russian Federation). E-mail: [email protected]
Lyapunova Maria V. - Junior Researcher at the Laboratory of Organic Synthesis, Tomsk State University (Tomsk, Russian Federation). E-mail: [email protected] Takibayeva Altynaray T. - Candidate of Chemical sciences, Head of the Department of Chemistry and Chemical Technology, Karaganda Technical University named after Abylkas Saginov (Karaganda, Kazakhstan). E-mail: [email protected]
Demets Olga V. - Master of Chemistry, Senior Teacher, Karaganda Technical University named after Abylkas Saginov (Karaganda, Kazakhstan). E-mail: [email protected] Kurzina Irina A. - Doctor of Physical and Mathematical Sciences, Associate Professor, Head of the Department of Natural Compounds, Pharmaceutical and Medicinal Chemistry, Tomsk State University (Tomsk, Russia). E-mail: [email protected]
Mamaeva Elena A. - Candidate of Chemical sciences, Tomsk Polytechnic University (Tomsk, Russian Federation). E-mail: [email protected]
Aliyeva Madina R. - Doctoral student at the Department of Inorganic and Technical Chemistry, Karaganda University named after Y.A. Buketov (Karaganda, Kazakhstan). E-mail: [email protected]
Contribution of the authors: the authors contributed equally to this article. The authors declare no conflicts of interests.
Сведения об авторах:
Федоришин Дмитрий Александрович - младший научный сотрудник центра исследований в области материалов и технологий, ассистент кафедры природных соединений, фармацевтической и медицинской химии Томского государственного университета (Томск, Россия). E-mail: [email protected]
Бакибаев Абдигали Абдиманапович - доктор химических наук, ведущий научный сотрудник лаборатории органического синтеза Томского государственного университета (Томск, Россия). E-mail: [email protected]
Ляпунова Мария Вячеславовна - младший научный сотрудник лаборатории органического синтеза Томского государственного университета (Томск, Россия). E-mail: [email protected]
Такибаева Алтынарай Темирбековна - кандидат химических наук, заведующая кафедрой химии и химической технологии Карагандинского технического университета им. Абылкаса Сагинова (Караганда, Казахстан). E-mail: [email protected] Демец Ольга Владимировна - магистр химии, преподаватель химии Карагандинского технического университета им. Абылкаса Сагинова (Караганда, Казахстан). E-mail: [email protected]
Курзина Ирина Александровна - доктор физико-математических наук, доцент, заведующая кафедрой природных соединений, фармацевтической и медицинской химии Томского государственного университета (Томск, Россия). E-mail: [email protected] Мамаева Елена Андреевна - кандидат химических наук, Томский политехнический университет (Томск, Россия). E-mail: [email protected]
Алиева Мадина Раманкуловна - докторант кафедры неорганической и технической химии Карагандинского университета им. Е.А. Букетова (Караганда, Казахстан). E-mail: [email protected]
Вклад авторов: все авторы сделали эквивалентный вклад в подготовку публикации. Авторы заявляют об отсутствии конфликта интересов.
The article was submitted 23.07.2023; accepted for publication 16.04.2024 Статья поступила в редакцию 23.07.2023; принята к публикации 16.04.2024
