SCIENCE-BASED APPROACH TO THE EXPERIMENTAL DEVELOPMENT OF A BIODEGRADABLE CHITOSAN BASED CARRIER.

The aim of the study was to develop a science-based approach to the development of a carrier of a pharmaceutical substance using the modification of chitosan. Studies were carried out to determine the upper limit of acidity - ascorbic and acetic to obtain salt forms of chitosan, the choice of modification of chitosan and the experimental development of a method for obtaining its solid salt form. A scientifically based approach to research has made it possible to develop a technology for obtaining a water-soluble biodegradable carrier based on salt forms of chitosan. The experimental approach to research made it possible to establish the upper limit of the acidity of the medium, at which transparent solutions of chitosan were obtained, for acetic and ascorbic acids, which are necessary for modifying the native form of chitosan and obtaining its salt forms. Taking into account the better organoleptic properties compared to chitosan acetate, as well as higher pH values, which are close to the pH of wound exudate, and higher viscosities of the obtained solutions of salt forms of chitosan, it was possible to select a water-soluble form - chitosan ascorbate for further development of the composition of the dosage form. The optimal mode of freeze-drying in laboratory conditions was established to obtain a solid form of chitosan ascorbate with the following parameters: freezing for 2-3 hours at a temperature of minus 80 °C; drying mode for 40 hours, pressure - 0.34 mbar; post-drying mode for 8 hours, pressure - 0.12 mbar; condenser temperature minus 80°C.

IN SILICO PROFILING OF THE NEW ALLOSTERIC MODULATOR OF AMPA RECEPTORS.

The aim of this study is to investigate the computer-aided prediction of pharmacological activity and mechanisms of action of 6-[4-methoxy-3-(1H-pyrazol-1-ylmethyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trione (TCT-9). The compound was designed for modulation of ionotropic glutamate AMPA receptors, and its affinity for the receptor has been earlier proven experimentally. A cognitive stimulating effect of TCT-9 has been shown using a model of freezing behavior in mice. The drug candidate TCT-9 is now under the development process: it is intended for the treatment of cognitive impairments in case of brain injury. Following the existing requirements, the present study was carried out in the framework of secondary pharmacodynamic studies to determine possible off-target effects and interaction of the compound with regulatory signaling and metabolic networks/pathways. In silico study of the TCT-9 binding to pharmacologically significant targets and the new AMPA receptor modulator's effects on signaling pathways was carried out by the analysis of structure-activity relationships. Prediction of biological activity spectra was performed using PASS (Prediction of Activity Spectra for Substances), which estimates the probabilities for more than five thousand biological activities. The PharmaExpert program assessed information on the belonging of the targets predicted by the PASS program to the signaling and metabolic pathways. The prediction results are the basis for the experimental verification of the binding of the TCT-9 to the steroid hormone receptor ERR1 and further studies of the drug activity in animal models of diseases.

[The development of the physicochemical characteristics of the new original nootropic substance TST-9]. / Izuchenie fiziko-khimicheskikh svoistv novogo original'nogo nootropnogo sredstva TST-9.

Physicochemical properties of the original pharmaceutical substance TST-9 based on the 3,7-diazabicyclo[3.3.1]nonane derivative with the chemical name IUPAC 6-[4methoxy-3-(1H-pyrazol-1-ylmethyl) benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trion, were studied. TST-9 is used as an active substance for the development of the composition and technology for the preparation of an innovative oral drug. The pharmaceutical substance TST-9 is an amorphous white powder, odorless, soluble in chloroform, acetonitrile, methylene chloride, acetone, dimethyl sulfoxide, dimethylformamide and alcohol, sparingly soluble in diethyl ether, dioxane and is very slightly soluble in water, hexane, and heptane. The melting point ranged from 94°C to 96°C without visible decomposition of the substance. The microbiological purity corresponds to category 2.2. Residual organic solvents in the form of chloroform did not exceed 0.006%. The amount of impurities was not more than 0.15%. The loss in mass upon drying was not more than 0.5%. The "identity" was confirmed using nuclear magnetic resonance spectroscopy and HPLC with UV detection. The data obtained in the study will contribute to the further development of the dosage form, the choice of the route of administration and the dosage regimen, as well as the selection of analytical methods for analyzing the quality of the finished dosage form and the effective, high-precision determination of the content of the active substance and its likely decay products.

[Pharmacokinetic properties of an innovative nootropic agent based on a derivative of 3,7-diazabicyclo[3.3.1]nonane]. / Farmakokineticheskie svoistva veshchestva na osnove proizvodnogo 3,7-diazabitsiklo[3.3.1]nonana.

The pharmacokinetics and bioavailability of a derivative of 3,7-diazabicyclo[3.3.1]nonane exhibiting a nootropic effect, were studied after a single dose to rats. The pharmacokinetics of the compound was studied after oral and intravenous administration to 270 male rats Sprague Dawley at doses of 2.5 mg/kg, 13 mg/kg and 25 mg/kg. Its distribution in organs and tissues (brain, thymus, heart, lungs, liver, kidneys, and spleen) was also investigated. It was found that after a single intravenous administration, the investigated substance was determined in the blood of animals for 24 h; the half-life was 4.69 h. The relative bioavailability of the 3,7-diazabicyclo[3.3.1]nonane derivative after oral administration was 42.3%, thus suggesting the prospect of creating dosage forms for oral administration. After a single oral administration, the dose dependence of AUC0-t was exponential. The substance is characterized by heterogeneous distribution in the body with preferential accumulation mainly in well-vascularized tissues.