Розробка складу та технології таблеток з екстрактом листя чорниці звичайної для лікування цукрового діабету

Abstract

Робота присвячена розробці нового вітчизняного препарату із сухим екстрактом листя чорниці у формі пролонгованих таблеток матричного типу для лікування цукрового діабету 2 типу та метаболічного синдрому зі стійкою інсулінорезистентністю. На підставі результатів органолептичних, фізико-хімічних, фармако-технологічних, біофармацевтичних та фармакологічних досліджень обґрунтовано склад допоміжних речовин таблеток, а саме (мг/таб.): метакрилового полімеру марки Eudragit L100 – 162,5, ГПМЦ марки Methocel K4M – 26,0, ГПМЦ марки Methocel K100LV – 26,0, целюлози мікрокристалічної марки Avicel PH-101 – 128,0, магнію стеарату – 6,5. Розроблено раціональну технологію пролонгованих таблеток матричного типу для лікування ЦД 2 типу та досліджено основні показники їх якості. Розроблено ТР і проект МКЯ на препарат «Міртаргін ретард».

Работа посвящена разработке нового отечественного препарата с сухим экстрактом листьев черники «Миртаргин» в форме пролонгированных таблеток матричного типа для лечения сахарного диабета 2 типа и метаболического синдрома с устойчивой инсулинорезистентностью. На основании результатов органолептических, физико-химических, фармако-технологических, биофармацевтических и фармакологических исследований обоснован состав вспомогательных веществ таблеток, а именно (мг/таб.): метакрилового полимера марки Eudragit L100 – 162,5, ГПМЦ марки Methocel K4M – 26,0, ГПМЦ марки Methocel K100LV – 26,0, целлюлозы микрокристаллической марки Avicel PH-101 – 128,0, магния стеарата – 6,5. Разработана рациональная технология пролонгированных таблеток матричного типа для лечения СД 2 типа и исследованы основные показатели их качества. Разработаны ТР и проект МКК на препарат «Миртаргин ретард».

The thesis is devoted to the development of composition and technology of the new domestic preparation with Vaccinium myrtillus leaf dry extract «Myrtargin» in the form of prolonged matrix-type tablets for the treatment of type 2 diabetes mellitus (T2DM) and metabolic syndrome with persistent insulin resistance. The prospects of the use Vaccinium myrtillus leaf extracts in the treatment of T2DM are discussed. Based on the available in scientific literature pharmacokinetic and pharmacodynamic properties of biologically active substances (BAS) of bilberry leaf extract, the dosage form – prolonged matrix-type tablets – was selected, that would allow releasing most of the extract dose in the small intestine and, in addition, contributing to avoiding significant fluctuations in plasma blood concentrations of BAS, reducing the multiplicity of drug administration and, accordingly, increasing the patients’ compliance. The results of theoretical and experimental studies on the selection of excipients composition of the tablets are presented. Taking into account the physicochemical and pharmaco-technological characteristics of the active pharmaceutical ingredient – bilberry leaf dry extract «Myrtargin», the chosen release modifiers, as well as their binary mixtures (1:1) the wet granulation was substantiated as a method for obtaining prolonged matrix-type tablets. The selection of the ratio of release modifiers in tablets was accomplished by constructing an artificial neural network using a set of experimental data on the release of extract BAS at time points of 2, 8 and 16 hours of the «Dissolution» test. To predict the release of matrix tablets with hypothetical ratios of prolonging agents, the artificial neural network simulation function was used, based on which the following ratios of prolonging agents was selected (mg per tablet): Methocel K4M – 26.0; Methocel K100LV – 26.0; Eudragit L100 – 162.5. The in vitro release profile for the tablets with the selected ratios of prolonging agents has been experimentally investigated. With the use of zero-order kinetics, first-order kinetics, Higuchi, Hixson-Crowell and Korsmeyer-Peppas mathematical models the kinetics and release mechanism of BAS from the tablets was established. By the method of the design of experiment using three-factor dispersion analysis, the optimal parameters for the manufacture of the tablets through wet granulation, such as type of binder agent in the granulating liquid, residual moisture content of tableting mass and the fractional composition of the tableting mass were substantiated. The choice of primary package – a strip pack made from combined material on the basis of paper, aluminum foil and polyethylene, which provides reliable protection of the tablets from the environmental humidity, was experimentally substantiated. The rational industrial technology for the manufacture of prolonged matrix-type tablets under the conventional name «Myrtargin retard» was developed, according to which the technological scheme of their production was constructed. The method for the assessment of the risks associated with excipients has been developed and applied for the excipients of «Myrtargin retard» tablets. The methods for quality control of the tablets with prolonged action «Myrtargin retard» have been developed: identification – by thin layer chromatography method; determination of the quantitative content of the main groups of BAS – flavonoids and polyphenols – by spectrophotometry method in the visible region; quantitative determination of BAS released in «Dissolution» test – based on the spectrophotometric method for the determination of polyphenols. The quality attributes for the developed tablets are determined according to the requirements of the SPhU: characters, identification, average mass and uniformity of mass, friability, resistance to crushing, dissolution, microbiological purity and quantitative content. The compatibility of bilberry leaf dry extract «Myrtargin» with selected excipient was investigated by the method of thermogravimetric analysis and IR spectroscopy using Pearson correlation analysis. The stability of the developed tablets has been proved and their shelf life is set to 2 years at a temperature not exceeding 25°С, when stored in the primary packaging. In the study on the model of experimental alimentary obesity in Syrian hamsters it was found that bilberry leaf dry extract «Myrtargin» in the doses of 25 and 35 mg/kg has a moderate effect against weight gain and visceral fat tissue increase, and also has a significant positive effect on the normalization of lipid metabolism disorders. On the model of the experimental metabolic syndrome with persistent insulin resistance in Syrian hamsters a pharmacological evaluation of the «Myrtargin retard» tablets as an antidiabetic agent in comparison with API and the reference drug of synthetic origin – voglibose tablets («Voksid» 0.2 mg, manufactured by Kusum Pharm LLC) was performed. It is determined that the developed tablets are more effective than API and are practically do not inferior to the reference drug. The obtained results prove that the developed dosage form – prolonged-release matrix tablets – improves the bioavailability and therapeutic efficiency of bilberry leaf dry extract BAS.