Розробка складу та технології твердих лікарських форм у вигляді таблеток з важкорозчинних субстанцій рилузол та німодипін

Abstract

Дисертація присвячена теоретичному й експериментальному обґрунтуванню складу та розробці технології генеричних лікарських засобів у вигляді таблеток Боризол та Німодипін із важкорозчинними субстанціями. Теоретично обґрунтовано і комплексними фізико-хімічними, фармако-технологічними, біофармацевтичними та клінічними дослідженнями підтверджено склад і технологію розроблених препаратів. Розроблено проєкти технологічних регламентів на виробництво таблеток Боризол та Німодипін і методи контролю їх якості.

Диссертация посвящена теоретическому и экспериментальному обоснованию состава и разработке технологии генерических лекарственных средств в виде таблеток Боризол и Нимодипин с трудно растворимыми субстанциями. Теоретически обоснованы и комплексными физико-химическими, фармако-технологическими, биофармацевтическими и клиническими исследованиями подтверждены состав и технология разработанных препаратов. Разработаны проекты технологических регламентов на производство Боризола и Нимодипина и методов контроля их качества.

The dissertation is devoted to complex researches (physical, physicochemical, phar-macotechnological, biopharmaceutical, microbiological and clinical) on the development of generic drugs in the form of tablets with insoluble substances, and dependence of in vitro dissolution kinetics of release API from solid dosage forms on the properties of API, excipients and technological methods of production. A chemical structure of substances riluzole and nimodipine was evaluated by com-plex physical and chemical studies, which made it possible to establish the pronounced reaction centers of molecules and predict the compatibility of substances with excipients. The study of morphological and pharmacotechnological indicators of substances riluzole and nimodipine was determined a need to use in generic drugs excipients that can improve the pharmacotechnological properties of medicinal substances (fluidity, bulk density, etc.) or technology of production. The biopharmaceutical studies of substances were performed to determine the characteristic of in vitro release kinetics of riluzole and nimodipine from original drugs "Rilutek" and "Nimotop". Based on the obtained results were established that the improvement of the release of the substance riluzole from tablets should be carried out at the expense of excipients, and the improvement of the release of the substance nimodipine - by using technological methods of physical modification of the substance. According to the results of research on the development of tablets based on the substance riluzole were established that the technological process is most appropriate using di-rect compression technology, while the amount of fillers a calcium hydrogen phosphate an-hydrous and a microcrystalline cellulose should be 40,5 and 30,0% respectively; disinte-grant – a croscarmellose sodium - 4%; glidant – a colloidal silicon dioxide - 2.0%, lubricant – a magnesium stearate - 1% per tablet. According to results of research on pharmaceutical development of tablets based on the substance nimodipine were established that among such methods of physical modifica-tion of the substance, which allow without changing a chemical structure of the active substance to achieve significant improvement of its solubility in aqueous medium, such as micronization, ultrasonic despergation, formation of solid dispersion by melting method, formation of solid dispersion by using an organic solvent, complexation with β-cyclodextrin molecules, the greatest similarity with the original drug «Nimotop» is achieved for laborato-ry batches of tablets (similarity f2 is 72.4%), which was obtained by the method forming a solid dispersion with the organic solvent (95% ethyl alcohol). The composition and technology of the generic drug tablet "Borizol" was developed for the first time in Ukraine, which is protected by the patent of Ukraine «Method of manu-facturing a tablet form of the drug based on riluzole»; appropriate registration documenta-tion has been developed for the drug; identified critical quality attribute for manufacture. The drug was registered by the Ministry of Health of Ukraine, approved for medical use and introduced into serial manufacture at PJSC SIC "Borshchahivskiy СPP". The composition and technology of the generic drug Nimodipin tablets was developed for the first time in Ukraine, appropriate registration documentation has been developed for the drug; identified critical quality attribute for manufacture. The drug was registered by the Ministry of Health of Ukraine, approved for medical use and introduced into serial manufacture at PJSC SIC «Borshchahivskiy СPP». For drugs «Borizol» and «Nimodipine» were developed methods for quality control of tablets on the following test parameters: «Description», «Identification», «Average weight», «Uniformity of dosage units», «Related substances», «Dissolution», «Assay» and «Microbial limits». The method for monitoring a test parameter «Ethanol content» was also developed for Nimodipine. For identification and assay of riluzole in tablets were used two methods: spectropho-tometric method and liquid chromatography method. Assay of active substance riluzole should be in the range from 47,5 mg to 52,5 mg in one tablet. For identification of nimodi-pine in tablets was used a liquid chromatography method. Determination of assay a sub-stance nimodipine in the composition of tablets was performed by adsorption spectropho-tometry in the UV region. Assay of active substance nimodipine should be in the range from 27,75 mg to 32,25 mg in one tablet. The developed methods of assay determination of active substance in tablets «Bori-zol» and «Nimodipine» were validated and tested for such characteristics as specificity, lin-earity, range of application, limit of detection, accuracy, robustness and precision. Shelf life and conditions of storage for tablets with substances riluzole and nimodi-pine were established by results of research accelerated and long-term tests stability. Shelf life for tablets «Borizol» is 3 years, for tablets «Nimodipine» is 5 years under storage conditions in an original packaging at a temperature not exceeding 25 ° C. For developed drugs «Borizol» and «Nimodipine» a similarity of dissolution kinetics «in vitro» to the original drugs «Rilutek» and «Nimotop» were established in environments close to biological: acetate buffer solution (pH 4.5), phosphate buffer solution (pH) 6,8), 0,1 M hydrochloric acid solution (pH 1,2). For drug «Borizol» a research of its bioequivalence was performed. Results of research conforming the criterion of bioequivalence - 80-125% were obtained for drug «Borizol». Therefore, clinical research has showed that the drug «Borizol» produced by PJSC SIC «Borshchahivskiy СPP» is a bioequivalent to the original drug «Rilutek» produced by «Aventis».