The dissertation is devoted to the theoretical and experimental substantiation of the rational composition, the development of optimal technology and quality control methods of new drug with probiotic activity in the form of pessaries for the treatment and prevention of dysbiotic conditions of the female urogenital tract.
The first chapter of the dissertation is regarded to the literature review about the prevalence of bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) as the most common pathologies of the female urogenital tract, which are accompanied by dysbiotic processes in vagina with significant decrease or absence of Lactobacillus spp. bacteria and the presence and increase of pathogens and opportunistic strains. The basic therapy of these pathologies includes the use of antibacterial drugs, which often do not cause the expected clinical effect and lead to a large number of reccurences. From the position of evidence-based medicine the use of probiotic preparations (especially containing lactobacilli) is effective in the treatment and prevention of dysbiotic processes of the vagina. This strain is used to obtain lyophilized biomass as an active pharmaceutical ingredient (API) for the preparation of drugs with immunomodulatory and interferonogenic properties.
The research of optimal surface-active substance and its concentration choice in the composition of pessaries samples on different bases was conducted. It was determined that the optimal surfactant is polysorbate-80, which should be used in the concentration of 5 % for samples on a hydrophobic basis, 2,5-3 % - on hydrophilic and diphilic bases. The optimal composition of the new LBP in the form of pessaries was developed and substantiated: Lactobacillus casei IMB B-7280 substance, diphyllic base: hard fat, PEG-400, PEG-1500, PEG-4000, polysorbate-80, purified water due to the complex results of the conducted researches. The rational technology for the production of pessaries with the conditional name «Lactovagin» has been developed, the main critical technological parameters of production have been established: preparation of the hydrophilic phase: temperature - (40±2) oC, duration of mixing - 45 minutes, speed of mixing - 50 revolutions/minute; preparation of suppository mass: temperature (40±2) oС, duration of mixing - 30 minutes, speed of mixing - 75 revolutions/minute; dosing of the suppository mass – (40±2) oС; cooling of pessaries: temperature – (10-12)oC, duration – 22-25 minutes. The technological flowchart for the production of drug for vadinal use in the form of pessaries with the conventional name «Lactovagin» has been developed and proposed.
The fourth chapter of the dissertation is devoted to the theoretical assessment of the quality risks of drugs for vaginal use at the stage of pharmaceutical development according to the «Quality by Design» concept. The Ishikawa diagram of quality indicators of developed pessaries was constructed. The quality control methods project on a pessary with the conventional name «Lactovagin» has been developed. The specification includes the following chapters: description, homogeneity, identification, average weight, pH, disintegration, quantitative determination, microbiological purity. A method for determining the microbiological purity of pessaries with Lactobacillus casei IMB B-7280 has been developed. The developed drug meets acceptance criteria: aerobic microbial contamination count (AMCC), yeasts and moulds contamination count (YMCC) and the absence of Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans for LBP for vaginal use. The study of the stability of the developed pessaries at two temperature regimes was conducted according to all quality control indicators. The shelf life of the developed drug was experimentally established - 12 months at a temperature of 2-8oC, with possible storage for 6 months at room temperature. Their results testify about the high ability to produce lactic acid and reduce the pH value in the vagina, the high adhesiveness of this strain, which ensure a high degree of adhesion during intravaginal
administration of drug in the form of pessaries, moderate antagonistic activity against pathogenic and opportunistic strains of microorganisms, which meet the LBP characteristics, the possibility of use in the combined treatment of vaginal dysbiotic disorders with antibiotics and antimycotics, which is effective in better therapeutic effect and preventing reccurences. According to the results of the study of the acute toxicity of pessaries with
the conventional name «Lactovagin», it was determined developed drug is relatively safe and harmless.
The patent of Ukraine for the utility model No. 141286 «Suppositories with probiotic activity for vaginal use» dated March 25, 2020 was obtained according to the research results.
