An Erratum to this paper has been published: https://doi.org/10.1134/S1990793125350015

Переработку гидролизного лигнина в среде сверхкритического н-гексана осуществляли в две стадии: 1) термическая обработка лигнина в автоклаве при 250°С и 15 MПa в среде аргона; 2) гидрирование раствора полученных на первой стадии продуктов при 250°С и 9,0 MПa в присутствии катализатора Ru/C. Полученные на первой и второй стадиях продукты анализировали методами высокоэффективной жидкостной хроматографии, гель-проникающей хроматографии и газовой хроматографии, хромато-масс-спектрометрии и элементного анализа. На первой стадии степень деполимеризации составила 17 %; перешедшие в раствор в результате деполимеризации моно- и олигомерные фрагменты лигнина имеют молекулярномассовое распределение (ММР) в пределах от 65 Да до 270 кДа. Определен состав мономеров в продуктах деполимеризации первой стадии: моно-, ди, три- и тетраалкилпроизводные бензола (2,8 мас. %), гваякол и его 4-алкилпроизводные (0,6 мас. %), в том числе конифериловый спирт (0,06 мас. %). На второй стадии происходят следующие процессы: 1) деполимеризация олигомеров до мономеров; 2) гидрирование мономерных фенолов в оксо- и алкилпроизводные циклогексана; 3) образование газовых продуктов (преимущественно метана, 95 об. %) вследствие каталитического гидрокрекинга растворителя. Depolymerization of hydrolysis lignin in supercritical n-hexane medium was carried out in two stages: 1) lignin treatment in an autoclave at 250°C and 15 MPa; 2) hydrogenation of the solution obtained in the first stage at 250°C and 9 MPa on a Ru/C catalyst. The products of the first and second stages were analyzed by HPLC, GPC, gas chromatography, chromatography-mass spectrometry, and elemental analysis. At the first stage, the degree of depolymerization was 17 %, the mono- and oligomeric fragments of lignin that passed into solution as a result of depolymerization have an MMD from 65 Da to 270 kDa. Monomer composition of the solution: mono-, di-, tri- and tetraalkyl derivatives of benzene (2.8 wt. %), guaiacol and its alkyl derivatives (0.6 wt. %), including coniferyl alcohol (0.06 wt. %). At the second stage of transformation the following processes occur: 1) depolymerization of oligomers to monomers; 2) hydrogenation of monomeric phenols to derivatives of cyclohexane and its oxo derivatives; 3) formation of gas products, mainly methane (95 vol. %), as a result of hydrocracking of the solvent.

С помощью СКФ-методов формирования частиц из газонасыщенных растворов (PGSS) и пластификации с последующим вспениванием аморфных полимеров при использовании сверхкритического диоксида углерода (СК-С0) осуществлена инкапсуляция гентамицина и левофлоксацина в биорезорбируемые полимерные матриксы и микрочастицы. Исследована кинетика высвобождения включенных лекарственных субстанций в модельные физиологические среды. Показано, что разработанные методы СКФ-инкапсулирования лекарственных субстанций в биорезорбируемые носители позволяют варьировать размеры, форму и морфологию формируемых структур и, соответственно, скорость их деградации и высвобождение из них лекарственных субстанций в физиологические среды. Применение СКФ-технологий для формирования биорезорбируемых полимерных структур, инкапсулированных лекарственными субстанциями без использования органических растворителей, может быть весьма перспективным для разработки компонентов новых высокоэффективных антибактериальных лекарственных форм адресного и пролонгированного действия. Gentamicin and levofloxacin were encapsulated into bioresorbable polymer scaffolds and microparticles by SCF methods - PGSS and plasticization and subsequent foaming of amorphous polymers using supercritical carbon dioxide. Release kinetics of incorporated drug substances into model physiological media was studied. It was shown that the use of the developed methods of SCF-encapsulation of drugs in bioresorbable carriers allows varying the size, shape and morphology of formed structures and accordingly the rate of release of drugs into physiological environments. In our opinion, this approach can be very promising for the development of components of new highly effective antibacterial prolonged dosage forms.

Sozdaniye protivotuberkuleznykh preparatov prolongirovannogo deystviya krayne perspektivno, tak kak pozvolyayet sokhranit' priverzhennost' bol'nykh k lecheniyu pri dlitel'nykh kursakh terapii, osobenno pri khimioterapii tuberkuleza s mnozhestvennoy lekarstvennoy ustoychivost'yu. Traditsionno ispol'zuyemyy dlya otsenki kinetiki vykhoda preparatov iz polimernykh nositeley metod UF-spektrofotometrii ne podkhodit dlya primeneniya v mnogokomponentnykh pitatel'nykh sredakh dlya kul'tivirovaniya mikobakteriy tuberkuleza. Tsel'yu issledovaniya bylo razrabotat' metod otsenki vysvobozhdeniya protivotuberkuleznykh preparatov iz biorezorbiruyemykh polimernykh nositeley, pozvolyayushchiy provodit' skrining bol'shogo chisla inkapsulirovannykh prolongirovannykh form protivotuberkuleznykh preparatov i otbirat' naiboleye perspektivnyye kompozitsii. Pri izuchenii dinamiki rosta laboratornogo chuvstvitel'nogo shtamma M. tuberculosis H37Rv v prisutstvii serii kontsentratsiy levofloksatsina (ot 0,03 do 0,4 mkg/ml) byla razrabotana model', predstavlyayushchaya soboy dva parallel'no provodimykh opyta, pozvolyayushchikh otsenit' kinetiku vysvobozhdeniya preparata v kul'tural'nuyu sredu. Vse eksperimenty provodili trekhkratno, pri otsenke ispol'zovali metody opisatel'noy statistiki. Rezul'taty, poluchennyye v etoy modeli dlya trekh inkapsulirovannykh form levofloksatsina v biorezorbiruyemykh polimernykh nositelyakh iz polilaktoglikolida (chastitsy 50 i 100 mkm i matriks), pokazali, chto kinetika nakopleniya preparata v srede sushchestvenno zavisit ot vida polimernogo nositelya. Naiboleye perspektiven iz nikh matriks, kotoryy khorosho vklyuchayet v sebya levofloksatsin i dostatochno ravnomerno vysvobozhdayet yego pri inkubatsii v pitatel'noy srede.

An HPLC-UV method for determination of acetylsalicylic acid and its main metabolite, salicylic acid, in a model solution and in rabbit blood plasma was developed. Plasma samples were prepared by salting out. Chromatographic analysis was performed in isocratic mode over a Hypersil BDS C18 column using mobile phase MeCN—H2O (pH 2.5, 30:70) with detection at 230 nm. The limit of quantitation for acetylsalicylic and salicylic acids in the model solution was 0.05 μg/mL; in blood plasma, 0.2 μg/mL. The developed method was applied to the development of new acetylsalicylic-acid dosage forms based on biocompatible polymer carriers, including pharmacokinetic studies after i.m. implantation.

Fabrication of fine-grained (10–100 μm) bioresorbable powders of aliphatic polyesters containing therapeutically significant (up to 10 wt %) concentrations of acetylsalicylic acid using supercritical CO2 is studied. The process for fabricating the components of sustained-release injectable dosage forms of acetylsalicylic acid is elaborated. The kinetics of release of acetylsalicylic acid from polylactide microparticles into the normal saline solution in vitro is studied by high-performance liquid chromatography.

Comparative studies on the temperature dependence of the dehydrogenation of cis- and trans-isomers of perhydro-m-terphenyl are performed in a flow catalytic reactor. Rate constants and equilibrium constants of all elementary acts of this reaction are calculated on basis of experimental data using the KINET 0.8 program for the mathematical modeling of the kinetics of complex reactions. The resulting data indicate that perhydro-m-terphenyl cis- and trans-isomers structural differences have no appreciable effect on dehydrogenation.

The process of supercritical fluid encapsulation of pharmaceutical grade risperidone into bioresorbable D,L-polylactide microparticles via the PGSS (Particles from Gas-Saturated Solutions) method was examined. Micronization and changes in the morphology of risperidone crystals during its encapsulation into a polymer plasticized with supercritical carbon dioxide were experimentally observed. This result made it possible to prepare the polymer structures of various dispersities (from 10 to 100 μm) and morphologies containing up to 40 wt % of risperidone without the use of organic solvents. The kinetics of release of risperidone from polymer microparticles in saline solution was studied by UV spectrophotometry. It was shown that the use of D,L-polylactides of various molecular weights makes it possible to achieve a controlled increase in the time of release of risperidone from bioresorbable polymer particles prepared via the PGSS technique up to ten days.

The kinetics of the dehydrogenation of the individual ortho, meta, and para isomers of perhydroterphenyl and their mixtures over a (3 wt % Pt)/C catalyst has been investigated in a flow reactor at 280–340°C. The rate of the isomerization of the stereoisomers of the initial substrate (perhydroterphenyl) and terphenyl dehydrogenation products has an effect on the hydrogen release kinetics. The highest reactivity in isomerization is shown by the ortho isomer. The largest amount of hydrogen (7.0 wt %) is released in the dehy-drogenation of perhydro-meta-terphenyl and perhydro-para-terphenyl, whose conversion at 320°C is 96%.

The microstructure and properties of amorphous D,L-polylactide subjected to different treatments in supercritical carbon dioxide (SC-CO 2 ) were investigated. Atomic force microscopy analysis demonstrated that plasticization and subsequent foaming of the polymer in SC-CO 2 leads to significant changes in its internal structure, which are caused by the rearrangement of the supramolecular structure of polylactic acid. The formation of micro and meso pores and an accompanying increase of polylactide void volume are directly related to the destruction of polymer initial intermolecular bonds during the release of SC-CO 2 . These changes facilitate the formation of thermodynamically more stable conformations, which is manifested in a significant (1.7–5.0-fold) increase of the values of exothermic effects registered by differential scanning calorimetry in the temperature range from −30 to −10°C and near 30–40°C.

A new method for fabrication of highly porous bioresorbable polymer structures on the basis of various aliphatic polyesters for tissue engineering has been successfully designed and worked out. It has been shown that injection of polymer compositions plasticized in sub- or supercritical carbon dioxide into press forms at temperatures from 20 to 40°C through a nozzle of a certain diameter under atmospheric or elevated (up to 6 MPa) CO2 pressure allows obtaining polymer matrices with a desired structure and morphology and mean porosity of up to 96 vol % with high reproducibility and avoiding the use of toxic organic solvents. The effect of chemical composition and molecular mass of starting polymers, as well as temperature and CO2 pressure in the reaction cell and the receiver, on the morphology and internal structure of fabricated samples was studied using the method of scanning-electron microscopy.

The processes of fabrication of highly porous (60–90 vol %) bioactive heparin-containing polylactic scaffolds in supercritical carbon dioxide followed by their hydrophilization by dielectric barrier discharge plasma treatment in the atmosphere were studied. A homogeneous distribution of heparin (HP) over the polymer volume was demonstrated by spatially resolved Raman scattering (RS) spectroscopy. The kinetics of heparin release from the scaffolds in distilled water was studied by spectrophotometry. A virtually linear increase in heparin concentration in a solution was shown from the second until the 15th day of experiments. Comparative in vitro study of cytotoxicity and matrix properties of pure polymer and heparin-containing scaffolds using NIH 3T3 mice fibroblast cultures demonstrated a positive effect of heparin distribution over the polylactic scaffolds on both cell adhesion and proliferation.

Biodegradable microparticles based on poly-D,L-lactide with entrapped mixture of herbal water-soluble extracts of Plantago major and Calendula officinalis were prepared. For preparation of these microparticles the previously developed method based on the usage of supercritical carbon dioxide (SC-CO2) was proposed. Microparticles were obtained by two techniques: 1) by preparing porous polymer monolith containing entrapped mixture of herbal extracts, which was then reduced to fine microparticles (ca. 0.1 mm) by dry ice grinding (called here as "monolithisation technique") and 2) by spraying of this polymer/extracts mixture through a jet (spray technique). In vitro release kinetic profile of herbal extract mixture was found to depend on the microparticle preparation technique, on the microparticle structure as well as on the initial ratio polymer/extracts (w/w). The microparticles were used for gastric ulcer treatment in a rat model. The extracts released from microparticles were found to accelerate tissue repair.