The dissertation is devoted to the development of the scientific foundations of the technology for creating polymer matrix compositions for the production of drugs with a predictable release profile based on experimental data and mathematical modeling of release and dissolution.
The study of the release from polymer matrix composite tablets of drugs containing isosorbide dinitrate, 2-(2-carboxylatoethyl)-1,1,1-trimethylhydrazinium and 2-ethyl-6-methyl-3-hydroxypyridine succinate. For isosorbide dinitrate, a composition is proposed that contains granules of a substance coated with a polymer. An experimental and statistical study of the kinetics of the release of isosorbide dinitrate from polymer matrix granules of different sizes at different pH values of the release medium was carried out. It was found that the release of isosorbide dinitrate does not depend on the acidity of the medium and does not depend on the size of the granules. For the first time, a mathematical model of the release was developed depending on the composition of the preparation granules, which makes it possible to determine the required amounts of matrix granules to achieve the required release kinetics. The high accuracy of modeling has been experimentally confirmed. As a result of research and modeling, a drug with a given release profile was obtained. For 2-(2-carboxylatoethyl)-1,1,1-trimethylhydrazinium by obtaining experimental data and statistical analysis, the kinetics of drug release from polymer composite tablets with prolonged action was investigated. The dependence of the kinetics of the release of 2-(2-carboxylatoethyl)-1,1,1-trimethylhydrazinium on pH has been established. A statistical computer model of the release of a drug substance in the gastrointestinal tract has been created based on in vitro parameters, taking into account pH changes in the gastrointestinal tract zones. A computer model of the release of the substance from tablets based on the bootstrap method in combination with spline data interpolation is proposed. Experimental and statistical studies of the release of 2-ethyl-6-methyl-3-hydroxypyridine succinate from polymer composite tablets with prolonged action have established a weak dependence of the release rate on the viscosity of hydroxypropyl methylcellulose in the range from 6 to 200 Pa·s. Based on the research, a polymer matrix was selected for economic reasons. The dependence of the kinetics of the release of 2-ethyl-6-methyl-3-hydroxypyridine succinate on pH has been established. It was found that the data on the kinetics of the release of 2-ethyl-6-methyl-3-hydroxypyridine succinate have a normal distribution. A computer model has been created for the release of an active pharmaceutical ingredient in the gastrointestinal tract based on the indicators of the normal distribution of laboratory data and taking into account the change in pH in the zones of the gastrointestinal tract. On the basis of the model, a procedure for predicting the corridor of the boundaries of the release of a substance in the gastrointestinal tract was developed. For sildenifil citrate, the regularities of solubility in polymer systems containing polyethylene glycols and in polyethylene glycol - propylene glycol - hydrochloric acid systems were experimentally revealed. The synergism of the action of PEG and hydrochloric acid was revealed, the conditions for optimal solubility were selected, and a mathematical model of dissolution was created as a modified model of Jouyban-Acree. A liquid form of a composite polymer-containing drug of instant release in the form of an oral spray of sildenafil citrate has been created. A technological process for the production of a polymer composite preparation 2-ethyl-6-methyl-3-hydroxypyridine succinate with prolonged action has been developed. The polymer composition in the form of film-coated matrix tablets consists of compressed matrix granules. Matrix granules contain an active substance in a polymer matrix and neutral auxiliary components. The technological process consists of the following main stages: mixing, granulation, drying, pressing, film coating. A scheme for obtaining the drug was drawn up, the material balance was calculated by stages. The introduction of technologies into production was carried out.
