Micronization of the pharmaceutical substance levofloxacin hemihydrate (LFC) was studied by the RESS method with trifluoromethane (CHF3) as a polar supercritical solvent. Scanning electron microscopy showed that, at a CHF3 temperature of 50°C, particles of micronized LFC have the shape of microgranules of submicron size. At a temperature of 100°C, the particles take the shape of thin (less than 0.1-μm-thick) elongated plates with rounded edges. At this temperature, an increase in the CHF3 pressure from 20 to 35 MPa leads to an increase in the average particle size from 1 to 2 μm, respectively. X-ray powder diffraction analysis of samples obtained at a temperature of 50°C determined the identity of the original and micronized LFC substances, which correspond to the structure of levofloxacin hemihydrate C36H40F2N6O8⋅H2O. An increase in the process temperature to 100°C leads to the formation of one of pseudopolymorphs of levofloxacin—levofloxacin monohydrate C18H20F2N3O4⋅H2O—in the micronized LFC.

Supercritical fluid encapsulation of gentamicin, levofloxacin and tetracycline into bioresorbable poly(lactic-co-glycolic)acid (PLGA) scaffolds at 20 wt % was performed by PLGA plasticization in supercritical carbon dioxide with its subsequent foaming. The effect of incorporated antibiotics on the rate of PLGA hydrolytic degradation, determined by weekly measurements of the polymer molecular weight and decrease in gravitational masses during 6 weeks of incubation of scaffolds in a phosphate-buffered saline (PBS) solution, was studied. Measurements of pH of PBS containing scaffolds were carried out in the same way. The rate constants of PLGA hydrolysis for different scaffolds comprising various drugs were determined. It was shown that tetracycline significantly reduced the rate of PLGA degradation compared to the rate of degradation of control (pure polymer) scaffolds. At the same time, the presence of gentamicin and levofloxacin in the scaffolds had no visible effect on their degradation. These results enhance the predicting potential for the kinetics of release of the considered antibiotics from bioresorbable polymer carriers into bioactive media, which is necessary for the development of highly efficient sustained-release dosage forms.

The solubility of levofloxacin (LFC) in supercritical carbon dioxide and trifluoromethane has been measured within the pressure range of 10–30 MPa at temperatures of 323 and 373 K. The solubility was determined by changes in the mass of the LFC sample kept in an SC fluid at the given temperature and pressure. The obtained value of LFC solubility in supercritical trifluoromethane at a pressure of 30 MPa and temperature of 323 K is almost an order of magnitude higher than its solubility in supercritical carbon dioxide under the same conditions: (5.6 ± 0.3) × 10–5 mole fractions compared to (5.9 ± 0.3) × 10–6 mol fractions. At the pressure of 30 MPa and temperature of 373 K, the LFC solubility in supercritical trifluoromethane reaches a value of (8.3 ± 0.3) × 10–5 mol fractions. The obtained results are the basis for further development and optimization of SCF-micronization processes of various antibiotics of the fluoroquinolone group without a liquid cosolvent.

This paper investigates changes in the surface morphology, internal structure, and the molecular mass distribution of amorphous poly-DL-lactides during their hydrolytic degradation in the presence of extra-germinal mesenchymal stem cells (MSCs) (Wharton’s jelly of umbilical cord) of the rat and their metabolic products. It is shown that the degradation of initially monolithic polymer samples in culture and conditioned media is almost identical. However, in a culture medium containing MSCs, this process is much more intense. This effect can be interpreted in terms of the influence of enzymes secreted by living cells, which diffuse from the surface deep into the polymer sample and accelerate its hydrolysis, participating in a catalytic reaction with the ester bonds of polylactide molecules. We developed and verified a mathematical model that takes into account both noncatalytic and catalytic channels of hydrolysis, changes in the porosity of the polymer sample, and diffusion of short-length oligomers; this model is used to adequately interpret the experimental results.

Gentamicin and levofloxacin are encapsulated into bioresorbable polymer scaffolds and microparticles by the SCF methods: particles from gas saturated solutions (PGSS) and plasticization, with the subsequent foaming of amorphous polymers using supercritical carbon dioxide. The kinetics of the release of the incorporated drug substances into model physiological media are studied. It is shown that the use of the developed methods of SCF-encapsulation of drugs in bioresorbable carriers allows varying the size, shape, and morphology of the formed structures and, accordingly, the rate of release of the drugs into the physiological environments. In our opinion, this approach can be very promising for the development of components of new highly effective antibacterial prolonged action dosage forms.

The antibacterial drug levofloxacin (LF) is micronized by the Rapid Expansion of the Supercritical Solution (RESS) method to obtain microparticles with a high level of bioavailability. Ethanol is used as a cosolvent to increase the solubility of LF in supercritical carbon dioxide. Spherical LF microparticles with the characteristic size of <10 microns are obtained.

In this study, the nanoscale transformation of the polylactic-co-glycolic acid (PLGA) internal structure, before and after its supercritical carbon dioxide (sc-CO2) swelling and plasticization, followed by foaming after a CO2 pressure drop, was studied by small-angle X-ray scattering (SAXS) for the first time. A comparative analysis of the internal structure data and porosity measurements for PLGA scaffolds, produced by sc-CO2 processing, on a scale ranging from 0.02 to 1000 μm, was performed by SAXS, helium pycnometry (HP), mercury intrusion porosimetry (MIP) and both “lab-source” and synchrotron X-ray microtomography (micro-CT). This approach opens up possibilities for the wide-scale evaluation, computer modeling, and prediction of the physical and mechanical properties of PLGA scaffolds, as well as their biodegradation behavior in the body. Hence, this study targets optimizing the process parameters of PLGA scaffold fabrication for specific biomedical applications.

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.

Supercritical fluid encapsulation of doxycycline into aliphatic polyesters was used to fabricate bioresorbable antibacterial polylactoglycolide scaffolds. The distributions of doxycycline concentration on the surface and in the bulk of polymer structures were analyzed using high (≈1 μm) spatial resolution Raman spectroscopy. The release kinetics of doxycycline from these scaffolds into saline solution was studied. It is shown that, with the exception of the first 3 h, when about 15% of its total amount goes into the solution, the release of doxycycline occurs almost linearly. During the first day, the total yield of the antibiotic was about 22%. In 15 days (maximum observation time), the total amount of doxycycline released from polylactoglycolide scaffolds was about 70%. Thus, bioresorbable polymer scaffolds fabricated with supercritical carbon dioxide can be used for local sustained release of antibiotics, as well as for biologically active scaffolds for tissue engineering.

The processes of changes in the surface morphology and internal structure, as well as the molecular mass distribution of amorphous D, L polylactides during their hydrolytic degradation in the presence of extra-germinal mesenchymal stem cells (MSCs) (ratschwart jelly umbilical cord) of the rat and their metabolic products have been studied. It was shown that the degradation of initially monolithic polymer samples in culture and conditioned media occurs almost identically. However, in a culture medium containing MSCs, this process is much more intense. This effect can be interpreted in terms of the influence of enzymes secreted by living cells, which diffuse from the surface into the polymer sample and accelerate its hydrolysis, entering into a catalytic reaction with the ether bonds of polylactide molecules. A mathematical model has been developed and verified that takes into account both non-catalytic and catalytic channels of hydrolysis, changes in the porosity of the polymer sample, diffusion of short-length oligomers, and adequately interprets the experimental results.

Исследована микронизация антибактериального препарата левофлоксацина методом RESS с целью получения микрочастиц, обладающих высокой биологической доступностью. Для увеличения растворимости левофлоксацина в сверхкритическом диоксиде углерода быш использован этанол в качестве сорастворителя. Получены микрочастицы левофлоксацина сферической формы с характерными размерами менее 10 мкм. Micronization of anti-bacterial drug levofloxacin (LF) by the RESS method for obtaining microparticles with high bioavailability was performed. Ethanol was used as a cosolvent to increase the solubility of LF in supercritical carbon dioxide. Spherical LF microparticles with characteristic sizes < 10 microns were obtained.

Poly(D,L-lactide) microparticles impregnated with a number of bioactive paramagnetic compounds have been fabricated using two SCF techniques: 1). PGSS (Particles from Gas Saturated Solution) and 2). polymer plasticization and swelling by supercritical carbon dioxide followed by its cryomilling. Electron paramagnetic resonance (EPR) spectroscopy manifested homogeneous spatial distribution for the most of these substances encapsulated into the polymer. Irreversible relaxation processes in the prepared polymer structures and formulations were not observed. The qualitative difference in the release kinetics of paramagnetic molecules of different structure from the polymer microparticles into the phosphate-buffered saline (PBS, pH = 7.4) was demonstrated, pH-sensitive ATI spin probe proved the decrease (up to <= 4.5) of local pH inside the microparticles during the first 9 days after its immersion in PBS.. ID (C) 2019 Elsevier B.V. All rights reserved.

Supercritical fluid micronization by rapid expansion of supercritical solutions setup using supercritical carbon dioxide as a fluid and the dinuclear complex (Hpiv)(6)Tb-2(piv)(6) (1) as the starting compound allows the preparation of either the single-phase dinuclear complex (Hpiv)(6)Tb-2(piv)(6) (1a) or the coordination polymer {Tb(piv)(3)}(n) (2a, 2b, 2c) as (sub)microcrystals with a controlled size depending on the processing parameters. It was shown that {Tb(piv)(3)}(n) (2) can in principle be synthesized by supercritical carbon dioxide processing as polycrystalline particles with different morphologies. A decrease in the size of polycrystalline particles (aggregates) of 1 and 2 and an increase in the fraction of defects in the crystal structure, respectively, lead to an increase in the degree of photoluminescence quenching at these defects and a change in magnetic properties of 1. (C) 2019 Elsevier B.V. All rights reserved.

The results of laser-induced formation of luminescent structures on the surface of poly-2.2’- n -oxydiphenylene-5.5’-bis-benzimidazole films, obtained by the coating method from a formic acid solution, are presented. The structures are formed using cw 405-nm laser radiation with intensities of 10 2 – 10 4 W cm –2 . It is shown (using methods of optical, atomic-force, and electron microscopy) that the structures formed on the surface are microbubble foam-like aggregations. Their formation is modelled as a sequence of the following processes: release of formic acid molecules, their condensation on matrix defects in the surface layer, and explosive boiling as a result of heating this layer of polymer film by the laser beam. The luminescence of these structures is due to the weakening of the concentration quenching from closely spaced luminescence centres in benzimidazole cycles during their emergence to the surface and the increase in the distance between them due to the extension on bubble aggregates on the surface.

The work is dedicated to the development of mathematical models of hydrolysis of aliphatic polyesters in aqueous media under conditions of water and oligomers diffusion. Water molecule is considered as a reagent in hydrolysis reactions, oxidation reactions and influence of the autocatalytic channel are taken into account. The analysis of the spatiotemporal distribution of molecular weight of the polymer depending on the hydrolysis reaction rate constants, the diffusion coefficients of water and short oligomers has been carried out. In case of large water diffusion coefficients, the heterogeneous channel of polymer hydrolysis is actually described by the equation of pseudo-first order, as in most modern models, and occurs predominantly in the volume (V-type). With the decreasing water diffusion coefficient, the participation of water as a reagent becomes very important. The resorption of the polymer occurs mainly near the surface (S-type). The comparison/verification of the developed computer model has been carried out basing on experimental data for molecular weight dynamic of monolithic polylactoglycolide samples (75:25) of different thicknesses in phosphate-buffer saline. The choice of kinetics parameters of hydrolysis reactions and diffusion coefficients of water and oligomers has been justified by fitting of experimental and model data.

The destruction of porous matrix polylactoglycolide (PLG) structures with different ratios of lactic and glycolic acids is experimentally studied in phosphate buffer saline. A mathematical model of this destruction that takes into account both the heterogeneous and autocatalytic hydrolysis of PLG as well as diffusion of their oligomers in the buffer solution and polymer free volume is developed. Gel-penetrating chromatography is used to analyze changes in the weight-average molecular weight of specimens studied and to determine the kinetic parameters of this process.

The effects of acetylsalicylic acid, ibuprofen, 6-methyluracil, and chondroitin sulfate impregnated in poly-(lactide-co-glycolide) scaffolds of different chemical compositions and molecular weights using supercritical carbon dioxide on the processes of scaffold degradation in phosphate-buffered saline pH 7.4 were studied and the rate constants of these processes were determined. Incorporation of acetylsalicylic acid and ibuprofen into poly(lactide-co-glycolide) scaffolds was found to produce significant increases in the rate of hydrolysis of the polymer base, while the presence of methyluracil and chondroitin sulfate had virtually no effect.

Исследовано влияние ацетилсалициловой кислоты, ибупрофена, 6-метилурацила и хондроитин сульфата, импрегнированных в полилактогликолидные матриксы различного химического состава и молекулярной массы c помощью сверхкритического диоксида углерода, на процессы деградации матриксов в растворе фосфатно-соленого буфера pH 7,4 и определены константы скоростей этих процессов. Показано, что включение в полилактогликолидный матрикс ацетилсалициловой кислоты и ибупрофена значительно увеличивает скорость гидролиза полимерной основы, в то время как присутствие метилурацила и хондроитин сульфата их практически не меняют.

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.

Rigid-chain heat resistant polymers (with poly-2,2'-p-oxydiphenylene-5,5′-bisbenzimidazole as example) were impregnated for the first time with a silver-containing precursor in formic acid and in supercritical carbon dioxide. A procedure allowing the precursor reduction to silver nanoparticles both throughout the volume by thermal annealing of the films in the temperature interval 100–150°С and in the targeted mode using lasers operating at 405 and 532 nm was developed. It opens prospects for developing a process for production of heatresistant optical gratings and light guides. The reduces nanoparticles and their agglomerates have the size in the interval 50–200 nm and give a plasmon band in the range 450–460 nm.